Becky McCall

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

A version of this article first appeared on Medscape.com.

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

A version of this article first appeared on Medscape.com.

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

A version of this article first appeared on Medscape.com.

Signs of cardiometabolic damage in children who are overweight appear as early as 6-8 years of age, but were not evident in preschoolers, providing a window of opportunity for intervention, show the latest results from a long-running Danish study of childhood weight.

The proportion of children who were overweight (nearly 14% in 2015) was similar between the two groups – those of preschool age (2-5 years) and school age (6-8 years) – but only the latter showed significant signs of cardiometabolic abnormalities.

The results, published in Obesity Research & Clinical Practice, are the latest in a series of many findings from the HOLBAEK study (formerly known as The Danish Childhood Obesity Biobank) that have emerged since it began in 2007. They were presented, along with a meta-analysis of much of their work, at the European Congress on Obesity (ECO) 2022.

“When comparing children with and without overweight, there were only barely significant differences among the preschool children,” said investigator Christine Frithioff-Bøjsøe, MD, but in contrast, “the school children with overweight exhibited significantly higher systolic blood pressure, glucose, insulin, and higher HDL cholesterol,” among other markers, she noted.

“Detection needs to start as early as age 2-5 years because if you wait just a few years longer these children will show early signs of disease starting to take hold. This could provide a critical window to detect and manage overweight,” said Frithioff-Bøjsøe, PhD, of the Children’s Obesity Clinic, Copenhagen University, Hospital Holbaek, Denmark.

Asked to comment, Aaron S. Kelly, PhD, professor of pediatrics, codirector, University of Minnesota Center for Pediatric Obesity Medicine in Minneapolis, said: “Recent results from HOLBAEK highlight the critical importance of identifying obesity early in life, before its complications spring up.

“Ideally, we should be in the business of managing and reducing excess adiposity as soon as it surfaces with the goal of preventing the onset of cardiometabolic risk factors, not watchful waiting and hoping for the best.”
 

Routine dental visits checked overweight

In the newest study, the researchers trained dental assistants to measure weight and height and carried out body mass index assessments during routine appointments.

A total of 335 preschool and 657 school-age children were recruited for the study. Of these, 40% attended additional hospital-based examinations including blood pressure measurement and a blood sample. Children were reexamined approximately 1 year later.

Systolic blood pressure, for example, was significantly higher in 6- to 8-year-olds with overweight compared to those of normal weight (P = .001). There was no significant difference between systolic blood pressure of 2.5- to 5-year-olds without and with overweight.

Likewise, with insulin resistance, there was no significant difference between preschoolers with and without overweight. However, in schoolchildren, homoeostasis model of assessment–insulin resistance (HOMA-IR) was significantly higher in those with overweight, at 2.2, compared to those without, at 0.9 (P < .001).

Also, during follow-up (around a year later), the prevalence of overweight did not change in preschool children but increased from 13.7% to 17.0% in schoolchildren.

The researchers noted that, in Europe, it is the primary health care sector that has continuous contact with the pediatric population, with the potential for early evaluation of children at risk. Their decision to use dental health care assistants to assess weight in this particular study is novel, but feasible, they observed.
 

Danish model for treating overweight and obesity is ‘game-changing’

As part of the HOLBAEK initiative, clinical data and biological samples have been collected from children and adolescents receiving treatment at The Children’s Obesity Clinic, Holbaek Hospital, using a population-based cohort as a reference group. Data have been collected on about 8,000 children and adolescents so far.

Jens-Christian Holm, PhD, along with colleague and research assistant Maria Frauland, both from Copenhagen University, Hospital Holbaek, presented a review of the HOLBAEK studies (2007-2021) at ECO 2022. They said the results highlight the importance of taking an integrated approach to managing children and adolescents with obesity.

The review, which included 82 papers, found a wide variety of obesity-related complications already present at a young age in some of the cross-sectional studies, including dyslipidemia in 28% of children with obesity, hepatic steatosis in 31%, obstructive sleep apnea in 45%, and prehypertension or hypertension in 52%.

The family-based interventional weight management programs adopted by HOLBAEK showed a 75% reduction in the “degree of obesity,” which comprised a measure of dyslipidemia, hypertension, hepatic steatosis, sleep apnea, and parental obesity.

“The HOLBAEK method is a holistic approach where we integrate everything,” Dr. Holm told this news organization.

Ms. Frauland said: “The HOLBAEK study has provided important insights into childhood overweight. It has highlighted that obesity is a serious multisystem disease that can be managed and treated effectively, reducing the degree of overweight and improving overweight-related complications.”

Dr. Kelly, the U.S. pediatrician, applauded the HOLBAEK philosophy, which emphasizes that obesity is not the fault of the child or parent, but rather the manifestation of dysregulated energy metabolism. “The recognition that obesity is a biologically driven, chronic, refractory, and relapsing disease is interwoven into the approach, which shifts the responsibility to the care provider for ensuring positive outcomes of treatment.

“Highlighting this fact to the parents and child can be game-changing since it removes the blame and shame associated with obesity and unburdens the family by framing the problem in a different light,” Dr. Kelly stressed.

Dr. Frithioff-Bøjsøe has reported no relevant financial relationships. Dr. Holm has an obesity management company called Holm. Dr. Kelly serves as an unpaid consultant for Novo Nordisk, Vivus, Eli Lilly, and Boehringer Ingelheim and receives donated drug/placebo from Vivus for a clinical trial funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Signs of cardiometabolic damage in children who are overweight appear as early as 6-8 years of age, but were not evident in preschoolers, providing a window of opportunity for intervention, show the latest results from a long-running Danish study of childhood weight.

The proportion of children who were overweight (nearly 14% in 2015) was similar between the two groups – those of preschool age (2-5 years) and school age (6-8 years) – but only the latter showed significant signs of cardiometabolic abnormalities.

The results, published in Obesity Research & Clinical Practice, are the latest in a series of many findings from the HOLBAEK study (formerly known as The Danish Childhood Obesity Biobank) that have emerged since it began in 2007. They were presented, along with a meta-analysis of much of their work, at the European Congress on Obesity (ECO) 2022.

“When comparing children with and without overweight, there were only barely significant differences among the preschool children,” said investigator Christine Frithioff-Bøjsøe, MD, but in contrast, “the school children with overweight exhibited significantly higher systolic blood pressure, glucose, insulin, and higher HDL cholesterol,” among other markers, she noted.

“Detection needs to start as early as age 2-5 years because if you wait just a few years longer these children will show early signs of disease starting to take hold. This could provide a critical window to detect and manage overweight,” said Frithioff-Bøjsøe, PhD, of the Children’s Obesity Clinic, Copenhagen University, Hospital Holbaek, Denmark.

Asked to comment, Aaron S. Kelly, PhD, professor of pediatrics, codirector, University of Minnesota Center for Pediatric Obesity Medicine in Minneapolis, said: “Recent results from HOLBAEK highlight the critical importance of identifying obesity early in life, before its complications spring up.

“Ideally, we should be in the business of managing and reducing excess adiposity as soon as it surfaces with the goal of preventing the onset of cardiometabolic risk factors, not watchful waiting and hoping for the best.”
 

Routine dental visits checked overweight

In the newest study, the researchers trained dental assistants to measure weight and height and carried out body mass index assessments during routine appointments.

A total of 335 preschool and 657 school-age children were recruited for the study. Of these, 40% attended additional hospital-based examinations including blood pressure measurement and a blood sample. Children were reexamined approximately 1 year later.

Systolic blood pressure, for example, was significantly higher in 6- to 8-year-olds with overweight compared to those of normal weight (P = .001). There was no significant difference between systolic blood pressure of 2.5- to 5-year-olds without and with overweight.

Likewise, with insulin resistance, there was no significant difference between preschoolers with and without overweight. However, in schoolchildren, homoeostasis model of assessment–insulin resistance (HOMA-IR) was significantly higher in those with overweight, at 2.2, compared to those without, at 0.9 (P < .001).

Also, during follow-up (around a year later), the prevalence of overweight did not change in preschool children but increased from 13.7% to 17.0% in schoolchildren.

The researchers noted that, in Europe, it is the primary health care sector that has continuous contact with the pediatric population, with the potential for early evaluation of children at risk. Their decision to use dental health care assistants to assess weight in this particular study is novel, but feasible, they observed.
 

Danish model for treating overweight and obesity is ‘game-changing’

As part of the HOLBAEK initiative, clinical data and biological samples have been collected from children and adolescents receiving treatment at The Children’s Obesity Clinic, Holbaek Hospital, using a population-based cohort as a reference group. Data have been collected on about 8,000 children and adolescents so far.

Jens-Christian Holm, PhD, along with colleague and research assistant Maria Frauland, both from Copenhagen University, Hospital Holbaek, presented a review of the HOLBAEK studies (2007-2021) at ECO 2022. They said the results highlight the importance of taking an integrated approach to managing children and adolescents with obesity.

The review, which included 82 papers, found a wide variety of obesity-related complications already present at a young age in some of the cross-sectional studies, including dyslipidemia in 28% of children with obesity, hepatic steatosis in 31%, obstructive sleep apnea in 45%, and prehypertension or hypertension in 52%.

The family-based interventional weight management programs adopted by HOLBAEK showed a 75% reduction in the “degree of obesity,” which comprised a measure of dyslipidemia, hypertension, hepatic steatosis, sleep apnea, and parental obesity.

“The HOLBAEK method is a holistic approach where we integrate everything,” Dr. Holm told this news organization.

Ms. Frauland said: “The HOLBAEK study has provided important insights into childhood overweight. It has highlighted that obesity is a serious multisystem disease that can be managed and treated effectively, reducing the degree of overweight and improving overweight-related complications.”

Dr. Kelly, the U.S. pediatrician, applauded the HOLBAEK philosophy, which emphasizes that obesity is not the fault of the child or parent, but rather the manifestation of dysregulated energy metabolism. “The recognition that obesity is a biologically driven, chronic, refractory, and relapsing disease is interwoven into the approach, which shifts the responsibility to the care provider for ensuring positive outcomes of treatment.

“Highlighting this fact to the parents and child can be game-changing since it removes the blame and shame associated with obesity and unburdens the family by framing the problem in a different light,” Dr. Kelly stressed.

Dr. Frithioff-Bøjsøe has reported no relevant financial relationships. Dr. Holm has an obesity management company called Holm. Dr. Kelly serves as an unpaid consultant for Novo Nordisk, Vivus, Eli Lilly, and Boehringer Ingelheim and receives donated drug/placebo from Vivus for a clinical trial funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Signs of cardiometabolic damage in children who are overweight appear as early as 6-8 years of age, but were not evident in preschoolers, providing a window of opportunity for intervention, show the latest results from a long-running Danish study of childhood weight.

The proportion of children who were overweight (nearly 14% in 2015) was similar between the two groups – those of preschool age (2-5 years) and school age (6-8 years) – but only the latter showed significant signs of cardiometabolic abnormalities.

The results, published in Obesity Research & Clinical Practice, are the latest in a series of many findings from the HOLBAEK study (formerly known as The Danish Childhood Obesity Biobank) that have emerged since it began in 2007. They were presented, along with a meta-analysis of much of their work, at the European Congress on Obesity (ECO) 2022.

“When comparing children with and without overweight, there were only barely significant differences among the preschool children,” said investigator Christine Frithioff-Bøjsøe, MD, but in contrast, “the school children with overweight exhibited significantly higher systolic blood pressure, glucose, insulin, and higher HDL cholesterol,” among other markers, she noted.

“Detection needs to start as early as age 2-5 years because if you wait just a few years longer these children will show early signs of disease starting to take hold. This could provide a critical window to detect and manage overweight,” said Frithioff-Bøjsøe, PhD, of the Children’s Obesity Clinic, Copenhagen University, Hospital Holbaek, Denmark.

Asked to comment, Aaron S. Kelly, PhD, professor of pediatrics, codirector, University of Minnesota Center for Pediatric Obesity Medicine in Minneapolis, said: “Recent results from HOLBAEK highlight the critical importance of identifying obesity early in life, before its complications spring up.

“Ideally, we should be in the business of managing and reducing excess adiposity as soon as it surfaces with the goal of preventing the onset of cardiometabolic risk factors, not watchful waiting and hoping for the best.”
 

Routine dental visits checked overweight

In the newest study, the researchers trained dental assistants to measure weight and height and carried out body mass index assessments during routine appointments.

A total of 335 preschool and 657 school-age children were recruited for the study. Of these, 40% attended additional hospital-based examinations including blood pressure measurement and a blood sample. Children were reexamined approximately 1 year later.

Systolic blood pressure, for example, was significantly higher in 6- to 8-year-olds with overweight compared to those of normal weight (P = .001). There was no significant difference between systolic blood pressure of 2.5- to 5-year-olds without and with overweight.

Likewise, with insulin resistance, there was no significant difference between preschoolers with and without overweight. However, in schoolchildren, homoeostasis model of assessment–insulin resistance (HOMA-IR) was significantly higher in those with overweight, at 2.2, compared to those without, at 0.9 (P < .001).

Also, during follow-up (around a year later), the prevalence of overweight did not change in preschool children but increased from 13.7% to 17.0% in schoolchildren.

The researchers noted that, in Europe, it is the primary health care sector that has continuous contact with the pediatric population, with the potential for early evaluation of children at risk. Their decision to use dental health care assistants to assess weight in this particular study is novel, but feasible, they observed.
 

Danish model for treating overweight and obesity is ‘game-changing’

As part of the HOLBAEK initiative, clinical data and biological samples have been collected from children and adolescents receiving treatment at The Children’s Obesity Clinic, Holbaek Hospital, using a population-based cohort as a reference group. Data have been collected on about 8,000 children and adolescents so far.

Jens-Christian Holm, PhD, along with colleague and research assistant Maria Frauland, both from Copenhagen University, Hospital Holbaek, presented a review of the HOLBAEK studies (2007-2021) at ECO 2022. They said the results highlight the importance of taking an integrated approach to managing children and adolescents with obesity.

The review, which included 82 papers, found a wide variety of obesity-related complications already present at a young age in some of the cross-sectional studies, including dyslipidemia in 28% of children with obesity, hepatic steatosis in 31%, obstructive sleep apnea in 45%, and prehypertension or hypertension in 52%.

The family-based interventional weight management programs adopted by HOLBAEK showed a 75% reduction in the “degree of obesity,” which comprised a measure of dyslipidemia, hypertension, hepatic steatosis, sleep apnea, and parental obesity.

“The HOLBAEK method is a holistic approach where we integrate everything,” Dr. Holm told this news organization.

Ms. Frauland said: “The HOLBAEK study has provided important insights into childhood overweight. It has highlighted that obesity is a serious multisystem disease that can be managed and treated effectively, reducing the degree of overweight and improving overweight-related complications.”

Dr. Kelly, the U.S. pediatrician, applauded the HOLBAEK philosophy, which emphasizes that obesity is not the fault of the child or parent, but rather the manifestation of dysregulated energy metabolism. “The recognition that obesity is a biologically driven, chronic, refractory, and relapsing disease is interwoven into the approach, which shifts the responsibility to the care provider for ensuring positive outcomes of treatment.

“Highlighting this fact to the parents and child can be game-changing since it removes the blame and shame associated with obesity and unburdens the family by framing the problem in a different light,” Dr. Kelly stressed.

Dr. Frithioff-Bøjsøe has reported no relevant financial relationships. Dr. Holm has an obesity management company called Holm. Dr. Kelly serves as an unpaid consultant for Novo Nordisk, Vivus, Eli Lilly, and Boehringer Ingelheim and receives donated drug/placebo from Vivus for a clinical trial funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

LISBON – A shift toward broader-spectrum antibiotics and increasing antibiotic resistance has led to high levels of mortality and neurodevelopmental impacts in surviving babies, according to a large international study conducted on four continents.

Results of the 3-year study were presented at this week’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).

The observational study, NeoOBS, conducted by the Global Antibiotic Research and Development Partnership (GARDP) and key partners from 2018 to 2020, explored the outcomes of more than 3,200 newborns, finding an overall mortality of 11% in those with suspected neonatal sepsis. The mortality rate increased to 18% in newborns in whom a pathogen was detected in blood culture.

More than half of infection-related deaths (59%) were due to hospital-acquired infections. Klebsiella pneumoniae was the most common pathogen isolated and is usually associated with hospital-acquired infections, which are increasingly resistant to existing antibiotic treatments, said a report produced by GARDP to accompany the results.

The study also identified a worrying trend: Hospitals are frequently using last-line agents such as carbapenems because of the high degree of antibiotic resistance in their facilities. Of note, 15% of babies with neonatal sepsis were given last-line antibiotics.

Pediatrician Julia Bielicki, MD, PhD, senior lecturer, Paediatric Infectious Diseases Research Group, St. George’s University of London, and clinician at the University of Basel Children’s Hospital, Switzerland, was a coinvestigator on the NeoOBS study.

In an interview, she explained that, as well as reducing mortality, the research is about managing infections better to prevent long-term events and improve the quality of life for survivors of neonatal sepsis. “It can have life-changing impacts for so many babies,” Dr. Bielicki said. “Improving care is much more than just making sure the baby survives the episode of sepsis – it’s about ensuring these babies can become children and adults and go on to lead productive lives.”

Also, only a minority of patients (13%) received the World Health Organization guidelines for standard of care use of ampicillin and gentamicin, and there was increasing use of last-line agents such as carbapenems and even polymyxins in some settings in low- and middle-income countries. “This is alarming and foretells the impending crisis of a lack of antibiotics to treat sepsis caused by multidrug-resistant organisms,” according to the GARDP report.

There was wide variability in antibiotic combinations used across sites in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Uganda, and Vietnam, and often such use was not supported by underlying data.

Dr. Bielicki remarked that there was a shift toward broad-spectrum antibiotic use. “In a high-income country, you have more restrictive patterns of antibiotic use, but it isn’t necessarily less antibiotic exposure of neonates to antibiotics, but on the whole, usually narrow-spectrum agents are used.”

In Africa and Asia, on the other hand, clinicians often have to use a broader-spectrum antibiotic empirically and may need to switch to another antibiotic very quickly. “Sometimes alternatives are not available,” she pointed out.

“Local physicians are very perceptive of this problem of antibiotic resistance in their daily practice, especially in centers with high mortality,” said Dr. Bielicki, emphasizing that it is not their fault, but is “due to the limitations in terms of the weapons available to treat these babies, which strongly demonstrates the growing problem of antimicrobial resistance affecting these babies on a global scale.”

Tim Jinks, PhD, Head of Drug Resistant Infections Priority Program at Wellcome Trust, commented on the study in a series of text messages to this news organization. “This research provides further demonstration of the urgent need for improved treatment of newborns suffering with sepsis and particularly the requirement for new antibiotics that overcome the burden of drug-resistant infections caused by [antimicrobial resistance].”

“The study is a hugely important contribution to our understanding of the burden of neonatal sepsis in low- and middle- income countries,” he added, “and points toward ways that patient treatment can be improved to save more lives.”
 

High-, middle-, and low-income countries

The NeoOBS study gathered data from 19 hospitals in 11 high-, middle-, and low-income countries and assessed which antibiotics are currently being used to treat neonatal sepsis, as well as the degree of drug resistance associated with them. Sites included some in Italy and Greece, where most of the neonatal sepsis data currently originate, and this helped to anchor the data, Dr. Bielicki said.

The study identified babies with clinical sepsis over a 4-week period and observed how these patients were managed, particularly with respect to antibiotics, as well as outcomes including whether they recovered, remained in hospital, or died. Investigators obtained bacterial cultures from the patients and grew them to identify which organisms were causing the sepsis.

Of note, mortality varied widely between hospitals, ranging from 1% to 27%. Dr. Bielicki explained that the investigators were currently exploring the reasons behind this wide range of mortality. “There are lots of possible reasons for this, including structural factors such as how care is delivered, which is complex to measure,” she said. “It isn’t trivial to measure why, in a certain setting, mortality is low and why in another setting of comparable income range, mortality is much higher.”

Aside from the mortality results, Dr. Bielicki also emphasized that the survivors of neonatal sepsis frequently experience neurodevelopmental impacts. “A hospital may have low mortality, but many of these babies may have neurodevelopment problems, and this has a long-term impact.”

“Even though mortality might be low in a certain hospital, it might not be low in terms of morbidity,” she added.

The researchers also collected isolates from the cohort of neonates to determine which antibiotic combinations work against the pathogens. “This will help us define what sort of antibiotic regimen warrants further investigation,” Dr. Bielicki said.

Principal Investigator, Mike Sharland, MD, also from St. George’s, University of London, who is also the Antimicrobial Resistance Program Lead at Penta Child Health Research, said, in a press release, that the study had shown that antibiotic resistance is now one of the major threats to neonatal health globally. “There are virtually no studies underway on developing novel antibiotic treatments for babies with sepsis caused by multidrug-resistant infections.”

“This is a major problem for babies in all countries, both rich and poor,” he stressed.
 

NeoSep-1 trial to compare multiple different treatments

The results have paved the way for a major new global trial of multiple established and new antibiotics with the goal of reducing mortality from neonatal sepsis – the NeoSep1 trial.

“This is a randomized trial with a specific design that allows us to rank different treatments against each other in terms of effectiveness, safety, and costs,” Dr. Bielicki explained.

Among the antibiotics in the study are amikacin, flomoxef and amikacin, or fosfomycin and flomoxef in babies with sepsis 28 days old or younger. Similar to the NeoOBS study, patients will be recruited from all over the world, and in particular from low- and middle-income countries such as Kenya, South Africa, and other countries in Africa and Southeast Asia.

Ultimately, the researchers want to identify modifiable risk factors and enact change in practice. But Dr. Bielicki was quick to point out that it was difficult to disentangle those factors that can easily be changed. “Some can be changed in theory, but in practice it is actually difficult to change them. One modifiable risk factor that can be changed is probably infection control, so when resistant bacteria appear in a unit, we need to ensure that there is no or minimal transmission between babies.”

Luregn Schlapbach, MD, PhD, Head, department of intensive care and neonatology, University Children’s Hospital Zurich, Switzerland, welcomed the study, saying recent recognition of pediatric and neonatal sepsis was an urgent problem worldwide.

She referred to the 2017 WHO resolution recognizing that sepsis represents a leading cause of mortality and morbidity worldwide, affecting patients of all ages, across all continents and health care systems but that many were pediatric. “At that time, our understanding of the true burden of sepsis was limited, as was our knowledge of current epidemiology,” she said in an email interview. “The Global Burden of Disease study in 2020 revealed that about half of the approximatively 50 million global sepsis cases affect pediatric age groups, many of those during neonatal age.”

The formal acknowledgment of this extensive need emphasizes the “urgency to design preventive and therapeutic interventions to reduce this devastating burden,” Dr. Schlapbach said. “In this context, the work led by GARDP is of great importance – it is designed to improve our understanding of current practice, risk factors, and burden of neonatal sepsis across low- to middle-income settings and is essential to design adequately powered trials testing interventions such as antimicrobials to improve patient outcomes and reduce the further emergence of antimicrobial resistance.”

Dr. Bielicki and Dr. Schlapbach have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – A shift toward broader-spectrum antibiotics and increasing antibiotic resistance has led to high levels of mortality and neurodevelopmental impacts in surviving babies, according to a large international study conducted on four continents.

Results of the 3-year study were presented at this week’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).

The observational study, NeoOBS, conducted by the Global Antibiotic Research and Development Partnership (GARDP) and key partners from 2018 to 2020, explored the outcomes of more than 3,200 newborns, finding an overall mortality of 11% in those with suspected neonatal sepsis. The mortality rate increased to 18% in newborns in whom a pathogen was detected in blood culture.

More than half of infection-related deaths (59%) were due to hospital-acquired infections. Klebsiella pneumoniae was the most common pathogen isolated and is usually associated with hospital-acquired infections, which are increasingly resistant to existing antibiotic treatments, said a report produced by GARDP to accompany the results.

The study also identified a worrying trend: Hospitals are frequently using last-line agents such as carbapenems because of the high degree of antibiotic resistance in their facilities. Of note, 15% of babies with neonatal sepsis were given last-line antibiotics.

Pediatrician Julia Bielicki, MD, PhD, senior lecturer, Paediatric Infectious Diseases Research Group, St. George’s University of London, and clinician at the University of Basel Children’s Hospital, Switzerland, was a coinvestigator on the NeoOBS study.

In an interview, she explained that, as well as reducing mortality, the research is about managing infections better to prevent long-term events and improve the quality of life for survivors of neonatal sepsis. “It can have life-changing impacts for so many babies,” Dr. Bielicki said. “Improving care is much more than just making sure the baby survives the episode of sepsis – it’s about ensuring these babies can become children and adults and go on to lead productive lives.”

Also, only a minority of patients (13%) received the World Health Organization guidelines for standard of care use of ampicillin and gentamicin, and there was increasing use of last-line agents such as carbapenems and even polymyxins in some settings in low- and middle-income countries. “This is alarming and foretells the impending crisis of a lack of antibiotics to treat sepsis caused by multidrug-resistant organisms,” according to the GARDP report.

There was wide variability in antibiotic combinations used across sites in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Uganda, and Vietnam, and often such use was not supported by underlying data.

Dr. Bielicki remarked that there was a shift toward broad-spectrum antibiotic use. “In a high-income country, you have more restrictive patterns of antibiotic use, but it isn’t necessarily less antibiotic exposure of neonates to antibiotics, but on the whole, usually narrow-spectrum agents are used.”

In Africa and Asia, on the other hand, clinicians often have to use a broader-spectrum antibiotic empirically and may need to switch to another antibiotic very quickly. “Sometimes alternatives are not available,” she pointed out.

“Local physicians are very perceptive of this problem of antibiotic resistance in their daily practice, especially in centers with high mortality,” said Dr. Bielicki, emphasizing that it is not their fault, but is “due to the limitations in terms of the weapons available to treat these babies, which strongly demonstrates the growing problem of antimicrobial resistance affecting these babies on a global scale.”

Tim Jinks, PhD, Head of Drug Resistant Infections Priority Program at Wellcome Trust, commented on the study in a series of text messages to this news organization. “This research provides further demonstration of the urgent need for improved treatment of newborns suffering with sepsis and particularly the requirement for new antibiotics that overcome the burden of drug-resistant infections caused by [antimicrobial resistance].”

“The study is a hugely important contribution to our understanding of the burden of neonatal sepsis in low- and middle- income countries,” he added, “and points toward ways that patient treatment can be improved to save more lives.”
 

High-, middle-, and low-income countries

The NeoOBS study gathered data from 19 hospitals in 11 high-, middle-, and low-income countries and assessed which antibiotics are currently being used to treat neonatal sepsis, as well as the degree of drug resistance associated with them. Sites included some in Italy and Greece, where most of the neonatal sepsis data currently originate, and this helped to anchor the data, Dr. Bielicki said.

The study identified babies with clinical sepsis over a 4-week period and observed how these patients were managed, particularly with respect to antibiotics, as well as outcomes including whether they recovered, remained in hospital, or died. Investigators obtained bacterial cultures from the patients and grew them to identify which organisms were causing the sepsis.

Of note, mortality varied widely between hospitals, ranging from 1% to 27%. Dr. Bielicki explained that the investigators were currently exploring the reasons behind this wide range of mortality. “There are lots of possible reasons for this, including structural factors such as how care is delivered, which is complex to measure,” she said. “It isn’t trivial to measure why, in a certain setting, mortality is low and why in another setting of comparable income range, mortality is much higher.”

Aside from the mortality results, Dr. Bielicki also emphasized that the survivors of neonatal sepsis frequently experience neurodevelopmental impacts. “A hospital may have low mortality, but many of these babies may have neurodevelopment problems, and this has a long-term impact.”

“Even though mortality might be low in a certain hospital, it might not be low in terms of morbidity,” she added.

The researchers also collected isolates from the cohort of neonates to determine which antibiotic combinations work against the pathogens. “This will help us define what sort of antibiotic regimen warrants further investigation,” Dr. Bielicki said.

Principal Investigator, Mike Sharland, MD, also from St. George’s, University of London, who is also the Antimicrobial Resistance Program Lead at Penta Child Health Research, said, in a press release, that the study had shown that antibiotic resistance is now one of the major threats to neonatal health globally. “There are virtually no studies underway on developing novel antibiotic treatments for babies with sepsis caused by multidrug-resistant infections.”

“This is a major problem for babies in all countries, both rich and poor,” he stressed.
 

NeoSep-1 trial to compare multiple different treatments

The results have paved the way for a major new global trial of multiple established and new antibiotics with the goal of reducing mortality from neonatal sepsis – the NeoSep1 trial.

“This is a randomized trial with a specific design that allows us to rank different treatments against each other in terms of effectiveness, safety, and costs,” Dr. Bielicki explained.

Among the antibiotics in the study are amikacin, flomoxef and amikacin, or fosfomycin and flomoxef in babies with sepsis 28 days old or younger. Similar to the NeoOBS study, patients will be recruited from all over the world, and in particular from low- and middle-income countries such as Kenya, South Africa, and other countries in Africa and Southeast Asia.

Ultimately, the researchers want to identify modifiable risk factors and enact change in practice. But Dr. Bielicki was quick to point out that it was difficult to disentangle those factors that can easily be changed. “Some can be changed in theory, but in practice it is actually difficult to change them. One modifiable risk factor that can be changed is probably infection control, so when resistant bacteria appear in a unit, we need to ensure that there is no or minimal transmission between babies.”

Luregn Schlapbach, MD, PhD, Head, department of intensive care and neonatology, University Children’s Hospital Zurich, Switzerland, welcomed the study, saying recent recognition of pediatric and neonatal sepsis was an urgent problem worldwide.

She referred to the 2017 WHO resolution recognizing that sepsis represents a leading cause of mortality and morbidity worldwide, affecting patients of all ages, across all continents and health care systems but that many were pediatric. “At that time, our understanding of the true burden of sepsis was limited, as was our knowledge of current epidemiology,” she said in an email interview. “The Global Burden of Disease study in 2020 revealed that about half of the approximatively 50 million global sepsis cases affect pediatric age groups, many of those during neonatal age.”

The formal acknowledgment of this extensive need emphasizes the “urgency to design preventive and therapeutic interventions to reduce this devastating burden,” Dr. Schlapbach said. “In this context, the work led by GARDP is of great importance – it is designed to improve our understanding of current practice, risk factors, and burden of neonatal sepsis across low- to middle-income settings and is essential to design adequately powered trials testing interventions such as antimicrobials to improve patient outcomes and reduce the further emergence of antimicrobial resistance.”

Dr. Bielicki and Dr. Schlapbach have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – A shift toward broader-spectrum antibiotics and increasing antibiotic resistance has led to high levels of mortality and neurodevelopmental impacts in surviving babies, according to a large international study conducted on four continents.

Results of the 3-year study were presented at this week’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).

The observational study, NeoOBS, conducted by the Global Antibiotic Research and Development Partnership (GARDP) and key partners from 2018 to 2020, explored the outcomes of more than 3,200 newborns, finding an overall mortality of 11% in those with suspected neonatal sepsis. The mortality rate increased to 18% in newborns in whom a pathogen was detected in blood culture.

More than half of infection-related deaths (59%) were due to hospital-acquired infections. Klebsiella pneumoniae was the most common pathogen isolated and is usually associated with hospital-acquired infections, which are increasingly resistant to existing antibiotic treatments, said a report produced by GARDP to accompany the results.

The study also identified a worrying trend: Hospitals are frequently using last-line agents such as carbapenems because of the high degree of antibiotic resistance in their facilities. Of note, 15% of babies with neonatal sepsis were given last-line antibiotics.

Pediatrician Julia Bielicki, MD, PhD, senior lecturer, Paediatric Infectious Diseases Research Group, St. George’s University of London, and clinician at the University of Basel Children’s Hospital, Switzerland, was a coinvestigator on the NeoOBS study.

In an interview, she explained that, as well as reducing mortality, the research is about managing infections better to prevent long-term events and improve the quality of life for survivors of neonatal sepsis. “It can have life-changing impacts for so many babies,” Dr. Bielicki said. “Improving care is much more than just making sure the baby survives the episode of sepsis – it’s about ensuring these babies can become children and adults and go on to lead productive lives.”

Also, only a minority of patients (13%) received the World Health Organization guidelines for standard of care use of ampicillin and gentamicin, and there was increasing use of last-line agents such as carbapenems and even polymyxins in some settings in low- and middle-income countries. “This is alarming and foretells the impending crisis of a lack of antibiotics to treat sepsis caused by multidrug-resistant organisms,” according to the GARDP report.

There was wide variability in antibiotic combinations used across sites in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Uganda, and Vietnam, and often such use was not supported by underlying data.

Dr. Bielicki remarked that there was a shift toward broad-spectrum antibiotic use. “In a high-income country, you have more restrictive patterns of antibiotic use, but it isn’t necessarily less antibiotic exposure of neonates to antibiotics, but on the whole, usually narrow-spectrum agents are used.”

In Africa and Asia, on the other hand, clinicians often have to use a broader-spectrum antibiotic empirically and may need to switch to another antibiotic very quickly. “Sometimes alternatives are not available,” she pointed out.

“Local physicians are very perceptive of this problem of antibiotic resistance in their daily practice, especially in centers with high mortality,” said Dr. Bielicki, emphasizing that it is not their fault, but is “due to the limitations in terms of the weapons available to treat these babies, which strongly demonstrates the growing problem of antimicrobial resistance affecting these babies on a global scale.”

Tim Jinks, PhD, Head of Drug Resistant Infections Priority Program at Wellcome Trust, commented on the study in a series of text messages to this news organization. “This research provides further demonstration of the urgent need for improved treatment of newborns suffering with sepsis and particularly the requirement for new antibiotics that overcome the burden of drug-resistant infections caused by [antimicrobial resistance].”

“The study is a hugely important contribution to our understanding of the burden of neonatal sepsis in low- and middle- income countries,” he added, “and points toward ways that patient treatment can be improved to save more lives.”
 

High-, middle-, and low-income countries

The NeoOBS study gathered data from 19 hospitals in 11 high-, middle-, and low-income countries and assessed which antibiotics are currently being used to treat neonatal sepsis, as well as the degree of drug resistance associated with them. Sites included some in Italy and Greece, where most of the neonatal sepsis data currently originate, and this helped to anchor the data, Dr. Bielicki said.

The study identified babies with clinical sepsis over a 4-week period and observed how these patients were managed, particularly with respect to antibiotics, as well as outcomes including whether they recovered, remained in hospital, or died. Investigators obtained bacterial cultures from the patients and grew them to identify which organisms were causing the sepsis.

Of note, mortality varied widely between hospitals, ranging from 1% to 27%. Dr. Bielicki explained that the investigators were currently exploring the reasons behind this wide range of mortality. “There are lots of possible reasons for this, including structural factors such as how care is delivered, which is complex to measure,” she said. “It isn’t trivial to measure why, in a certain setting, mortality is low and why in another setting of comparable income range, mortality is much higher.”

Aside from the mortality results, Dr. Bielicki also emphasized that the survivors of neonatal sepsis frequently experience neurodevelopmental impacts. “A hospital may have low mortality, but many of these babies may have neurodevelopment problems, and this has a long-term impact.”

“Even though mortality might be low in a certain hospital, it might not be low in terms of morbidity,” she added.

The researchers also collected isolates from the cohort of neonates to determine which antibiotic combinations work against the pathogens. “This will help us define what sort of antibiotic regimen warrants further investigation,” Dr. Bielicki said.

Principal Investigator, Mike Sharland, MD, also from St. George’s, University of London, who is also the Antimicrobial Resistance Program Lead at Penta Child Health Research, said, in a press release, that the study had shown that antibiotic resistance is now one of the major threats to neonatal health globally. “There are virtually no studies underway on developing novel antibiotic treatments for babies with sepsis caused by multidrug-resistant infections.”

“This is a major problem for babies in all countries, both rich and poor,” he stressed.
 

NeoSep-1 trial to compare multiple different treatments

The results have paved the way for a major new global trial of multiple established and new antibiotics with the goal of reducing mortality from neonatal sepsis – the NeoSep1 trial.

“This is a randomized trial with a specific design that allows us to rank different treatments against each other in terms of effectiveness, safety, and costs,” Dr. Bielicki explained.

Among the antibiotics in the study are amikacin, flomoxef and amikacin, or fosfomycin and flomoxef in babies with sepsis 28 days old or younger. Similar to the NeoOBS study, patients will be recruited from all over the world, and in particular from low- and middle-income countries such as Kenya, South Africa, and other countries in Africa and Southeast Asia.

Ultimately, the researchers want to identify modifiable risk factors and enact change in practice. But Dr. Bielicki was quick to point out that it was difficult to disentangle those factors that can easily be changed. “Some can be changed in theory, but in practice it is actually difficult to change them. One modifiable risk factor that can be changed is probably infection control, so when resistant bacteria appear in a unit, we need to ensure that there is no or minimal transmission between babies.”

Luregn Schlapbach, MD, PhD, Head, department of intensive care and neonatology, University Children’s Hospital Zurich, Switzerland, welcomed the study, saying recent recognition of pediatric and neonatal sepsis was an urgent problem worldwide.

She referred to the 2017 WHO resolution recognizing that sepsis represents a leading cause of mortality and morbidity worldwide, affecting patients of all ages, across all continents and health care systems but that many were pediatric. “At that time, our understanding of the true burden of sepsis was limited, as was our knowledge of current epidemiology,” she said in an email interview. “The Global Burden of Disease study in 2020 revealed that about half of the approximatively 50 million global sepsis cases affect pediatric age groups, many of those during neonatal age.”

The formal acknowledgment of this extensive need emphasizes the “urgency to design preventive and therapeutic interventions to reduce this devastating burden,” Dr. Schlapbach said. “In this context, the work led by GARDP is of great importance – it is designed to improve our understanding of current practice, risk factors, and burden of neonatal sepsis across low- to middle-income settings and is essential to design adequately powered trials testing interventions such as antimicrobials to improve patient outcomes and reduce the further emergence of antimicrobial resistance.”

Dr. Bielicki and Dr. Schlapbach have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Screening for Staphylococcus aureus, decolonization, and use of teicoplanin for surgical antimicrobial prophylaxis among patients with methicillin-resistant S. aureus (MRSA) lowered the number of prosthetic joint infections in elderly patients undergoing surgery for fracture of the femur.

The findings were presented in a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022, which was one of the few awarded the accolade of “top-rated poster.”

“We actually found that with our intervention, all prosthetic joint infections decreased, not just the Staphylococcus aureus but those due to MRSA, too,” Natividad Benito, MD, an infectious diseases specialist at Hospital de la Santa Creu i Sant Pau in Barcelona, said in an interview. “We’re pleased with these results because prosthetic joint infections present such a complicated situation for patients and surgeons. This is also a relatively easy intervention to use, and with time, even the PCR [polymerase chain reaction] technology will become cheaper. Now, in our hospital, prosthetic joint infections are rare.”

At Hospital de la Santa Creu i Sant Pau, around 200 hip hemiarthroplasties are performed per year. Preceding the intervention, the hospital recorded 11 prosthetic joint infections, with up to five infections due to S. aureus and up to four due to MRSA.

The intervention was introduced in 2016. After 2 years, there were no cases of prosthetic joint infections due to S. aureus; in 2018 there, was one case of prosthetic joint infection due to MRSA. In 2019, there was one case of prosthetic joint infection, but it was due neither to S. aureus nor MRSA. In 2020 and 2021, there was one infection each year that was due to MRSA.

Jesús Rodríguez Baño, MD, head of the infectious diseases division, Hospital Universitario Virgen Macarena at the University of Seville, Spain, who was not involved in the study, explained that for patients with hip fracture, “the time frame in which colonization can be studied is too short using traditional methods. Prosthetic joint infections in this population have a devastating effect, with not negligible mortality and very important morbidity and health care costs.”

Referring to the significant reduction in the rate of S. aureus prosthetic joint infections in the postintervention period, Dr. Rodríguez Baño said in an interview, “The results are sound, and the important reduction in infection risk invites for the development of a multicenter, randomized trial to confirm these interesting results.

“The authors are commended for measuring the impact of applying a well-justified preventive protocol,” Dr. Rodríguez Baño added. However, the study has some limitations: “It was performed in one center, it was not randomized, and control for potential confounders is needed.”
 

Decolonization in an emergency femur fracture

This study addressed a particular need in residents of Spain’s long-term care facilities. In 2016, the prevalence of MRSA was high.

Roughly one-third of the general population carry S. aureus in their noses. In care homes, the rate of MRSA is higher than in the general population, at around 30% of those with S. aureus. In Spain, recommendations for patients undergoing elective total joint arthroplasty advise S. aureus decolonization – which can take 5 days – to prevent surgical site infections.

“The problem with the elderly population is not only have they a higher incidence of MRSA but that the surgical prophylaxis is inadequate for MRSA,” Dr. Benito pointed out.

Many patients in long-term care facilities are elderly and frail and are at greater risk of fracture. Unlike elective hip surgery, in which patients are asked to undergo decolonization over the 5 days prior to their operation, with emergent femur fractures, there is insufficient time for such preparation. “These patients with femur fractures need surgery as soon as possible,” said Dr. Benito.

No studies have been conducted to determine the best way to minimize infection risk from S. aureus and MRSA for patients undergoing emergency hip hemiarthroplasty surgery to treat femoral fractures.

In the current study, Dr. Benito and coauthors assessed whether a bundle of measures – including rapid detection of S. aureus nasal carriage by PCR upon arrival in the emergency setting, followed by decolonization of carriers using a topical treatment in the nose and a prescription of surgical antimicrobial prophylaxis (adapted antibiotic prophylaxis for MRSA) – reduces the incidence of prosthetic joint infections after surgery.

The quasi-experimental single-center study included patients admitted to the emergency department at Hospital de la Santa Creu i Sant Pau. The PCR was rapid, with a turnaround of just 1.5 hours. Decolonization of S. aureus carriers was carried out using nasal mupirocin and chlorhexidine gluconate bathing, which was started immediately. It was used for a 5 days and was usually continued throughout and after surgery.

Patients carrying MRSA received teicoplanin as optimal surgical antimicrobial prophylaxis instead of cefazolin. The intervention did not interfere with the timing of surgery. The study’s principal outcomes were overall incidence of prosthetic joint infections and the incidence of those specifically caused by S. aureus and MRSA.

The researchers compared findings regarding these outcomes over 5 consecutive years of the intervention to outcomes during 4 consecutive years prior to the intervention, which started in 2016.

During 2016-2020, from 22% to 31% of the overall number of patients requiring hip hemiarthroplasty were referred from long-term care facilities. From 25% to 29% of these patients tested positive for S. aureus on PCR, and of these, 33%-64% had MRSA.

There were 772 surgical procedures from 2012 to 2015 and 786 from 2017 to 2020.

Prior to the intervention, over the years 2012-2014, S. aureus caused 36%-50% of prosthetic joint infections; 25%-100% of the S. aureus infections were MRSA. This decreased significantly after the intervention.

During 2016-2020, there was an average of 14 prosthetic joint infections (1.5%), compared to 36 (4.7%) in 2012-2015 (P < .001). Similarly, the incidence of prosthetic joint infections due to S. aureus dropped to 0.3% from 1.8% (P < .002). The incidence of MRSA prosthetic joint infections was 0.3% for 2016-2020, versus 1.2% for 2012-2015 (P = .012).

The years 2018, 2020, and 2021 each saw one case of infection due to MRSA. They were most likely due to “the intervention not being performed properly in all cases,” said Dr. Benito.

A prosthetic joint infection is very serious for the patient. “It means reoperating, because antibiotics are not enough to clear the infection. The biofilm and pus of the infection need to be cleaned out, a new prosthesis is needed, after which more antibiotics are needed for around 2 months, which can be hard to tolerate, and even then, the infection might not be eradicated,” explained Dr. Benito. “Many of these people are old and frail, and mortality can be significant. Getting a prosthetic joint infection is catastrophic for these patients.”

Dr. Benito and Dr. Rodríguez-Baño have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Screening for Staphylococcus aureus, decolonization, and use of teicoplanin for surgical antimicrobial prophylaxis among patients with methicillin-resistant S. aureus (MRSA) lowered the number of prosthetic joint infections in elderly patients undergoing surgery for fracture of the femur.

The findings were presented in a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022, which was one of the few awarded the accolade of “top-rated poster.”

“We actually found that with our intervention, all prosthetic joint infections decreased, not just the Staphylococcus aureus but those due to MRSA, too,” Natividad Benito, MD, an infectious diseases specialist at Hospital de la Santa Creu i Sant Pau in Barcelona, said in an interview. “We’re pleased with these results because prosthetic joint infections present such a complicated situation for patients and surgeons. This is also a relatively easy intervention to use, and with time, even the PCR [polymerase chain reaction] technology will become cheaper. Now, in our hospital, prosthetic joint infections are rare.”

At Hospital de la Santa Creu i Sant Pau, around 200 hip hemiarthroplasties are performed per year. Preceding the intervention, the hospital recorded 11 prosthetic joint infections, with up to five infections due to S. aureus and up to four due to MRSA.

The intervention was introduced in 2016. After 2 years, there were no cases of prosthetic joint infections due to S. aureus; in 2018 there, was one case of prosthetic joint infection due to MRSA. In 2019, there was one case of prosthetic joint infection, but it was due neither to S. aureus nor MRSA. In 2020 and 2021, there was one infection each year that was due to MRSA.

Jesús Rodríguez Baño, MD, head of the infectious diseases division, Hospital Universitario Virgen Macarena at the University of Seville, Spain, who was not involved in the study, explained that for patients with hip fracture, “the time frame in which colonization can be studied is too short using traditional methods. Prosthetic joint infections in this population have a devastating effect, with not negligible mortality and very important morbidity and health care costs.”

Referring to the significant reduction in the rate of S. aureus prosthetic joint infections in the postintervention period, Dr. Rodríguez Baño said in an interview, “The results are sound, and the important reduction in infection risk invites for the development of a multicenter, randomized trial to confirm these interesting results.

“The authors are commended for measuring the impact of applying a well-justified preventive protocol,” Dr. Rodríguez Baño added. However, the study has some limitations: “It was performed in one center, it was not randomized, and control for potential confounders is needed.”
 

Decolonization in an emergency femur fracture

This study addressed a particular need in residents of Spain’s long-term care facilities. In 2016, the prevalence of MRSA was high.

Roughly one-third of the general population carry S. aureus in their noses. In care homes, the rate of MRSA is higher than in the general population, at around 30% of those with S. aureus. In Spain, recommendations for patients undergoing elective total joint arthroplasty advise S. aureus decolonization – which can take 5 days – to prevent surgical site infections.

“The problem with the elderly population is not only have they a higher incidence of MRSA but that the surgical prophylaxis is inadequate for MRSA,” Dr. Benito pointed out.

Many patients in long-term care facilities are elderly and frail and are at greater risk of fracture. Unlike elective hip surgery, in which patients are asked to undergo decolonization over the 5 days prior to their operation, with emergent femur fractures, there is insufficient time for such preparation. “These patients with femur fractures need surgery as soon as possible,” said Dr. Benito.

No studies have been conducted to determine the best way to minimize infection risk from S. aureus and MRSA for patients undergoing emergency hip hemiarthroplasty surgery to treat femoral fractures.

In the current study, Dr. Benito and coauthors assessed whether a bundle of measures – including rapid detection of S. aureus nasal carriage by PCR upon arrival in the emergency setting, followed by decolonization of carriers using a topical treatment in the nose and a prescription of surgical antimicrobial prophylaxis (adapted antibiotic prophylaxis for MRSA) – reduces the incidence of prosthetic joint infections after surgery.

The quasi-experimental single-center study included patients admitted to the emergency department at Hospital de la Santa Creu i Sant Pau. The PCR was rapid, with a turnaround of just 1.5 hours. Decolonization of S. aureus carriers was carried out using nasal mupirocin and chlorhexidine gluconate bathing, which was started immediately. It was used for a 5 days and was usually continued throughout and after surgery.

Patients carrying MRSA received teicoplanin as optimal surgical antimicrobial prophylaxis instead of cefazolin. The intervention did not interfere with the timing of surgery. The study’s principal outcomes were overall incidence of prosthetic joint infections and the incidence of those specifically caused by S. aureus and MRSA.

The researchers compared findings regarding these outcomes over 5 consecutive years of the intervention to outcomes during 4 consecutive years prior to the intervention, which started in 2016.

During 2016-2020, from 22% to 31% of the overall number of patients requiring hip hemiarthroplasty were referred from long-term care facilities. From 25% to 29% of these patients tested positive for S. aureus on PCR, and of these, 33%-64% had MRSA.

There were 772 surgical procedures from 2012 to 2015 and 786 from 2017 to 2020.

Prior to the intervention, over the years 2012-2014, S. aureus caused 36%-50% of prosthetic joint infections; 25%-100% of the S. aureus infections were MRSA. This decreased significantly after the intervention.

During 2016-2020, there was an average of 14 prosthetic joint infections (1.5%), compared to 36 (4.7%) in 2012-2015 (P < .001). Similarly, the incidence of prosthetic joint infections due to S. aureus dropped to 0.3% from 1.8% (P < .002). The incidence of MRSA prosthetic joint infections was 0.3% for 2016-2020, versus 1.2% for 2012-2015 (P = .012).

The years 2018, 2020, and 2021 each saw one case of infection due to MRSA. They were most likely due to “the intervention not being performed properly in all cases,” said Dr. Benito.

A prosthetic joint infection is very serious for the patient. “It means reoperating, because antibiotics are not enough to clear the infection. The biofilm and pus of the infection need to be cleaned out, a new prosthesis is needed, after which more antibiotics are needed for around 2 months, which can be hard to tolerate, and even then, the infection might not be eradicated,” explained Dr. Benito. “Many of these people are old and frail, and mortality can be significant. Getting a prosthetic joint infection is catastrophic for these patients.”

Dr. Benito and Dr. Rodríguez-Baño have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Screening for Staphylococcus aureus, decolonization, and use of teicoplanin for surgical antimicrobial prophylaxis among patients with methicillin-resistant S. aureus (MRSA) lowered the number of prosthetic joint infections in elderly patients undergoing surgery for fracture of the femur.

The findings were presented in a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022, which was one of the few awarded the accolade of “top-rated poster.”

“We actually found that with our intervention, all prosthetic joint infections decreased, not just the Staphylococcus aureus but those due to MRSA, too,” Natividad Benito, MD, an infectious diseases specialist at Hospital de la Santa Creu i Sant Pau in Barcelona, said in an interview. “We’re pleased with these results because prosthetic joint infections present such a complicated situation for patients and surgeons. This is also a relatively easy intervention to use, and with time, even the PCR [polymerase chain reaction] technology will become cheaper. Now, in our hospital, prosthetic joint infections are rare.”

At Hospital de la Santa Creu i Sant Pau, around 200 hip hemiarthroplasties are performed per year. Preceding the intervention, the hospital recorded 11 prosthetic joint infections, with up to five infections due to S. aureus and up to four due to MRSA.

The intervention was introduced in 2016. After 2 years, there were no cases of prosthetic joint infections due to S. aureus; in 2018 there, was one case of prosthetic joint infection due to MRSA. In 2019, there was one case of prosthetic joint infection, but it was due neither to S. aureus nor MRSA. In 2020 and 2021, there was one infection each year that was due to MRSA.

Jesús Rodríguez Baño, MD, head of the infectious diseases division, Hospital Universitario Virgen Macarena at the University of Seville, Spain, who was not involved in the study, explained that for patients with hip fracture, “the time frame in which colonization can be studied is too short using traditional methods. Prosthetic joint infections in this population have a devastating effect, with not negligible mortality and very important morbidity and health care costs.”

Referring to the significant reduction in the rate of S. aureus prosthetic joint infections in the postintervention period, Dr. Rodríguez Baño said in an interview, “The results are sound, and the important reduction in infection risk invites for the development of a multicenter, randomized trial to confirm these interesting results.

“The authors are commended for measuring the impact of applying a well-justified preventive protocol,” Dr. Rodríguez Baño added. However, the study has some limitations: “It was performed in one center, it was not randomized, and control for potential confounders is needed.”
 

Decolonization in an emergency femur fracture

This study addressed a particular need in residents of Spain’s long-term care facilities. In 2016, the prevalence of MRSA was high.

Roughly one-third of the general population carry S. aureus in their noses. In care homes, the rate of MRSA is higher than in the general population, at around 30% of those with S. aureus. In Spain, recommendations for patients undergoing elective total joint arthroplasty advise S. aureus decolonization – which can take 5 days – to prevent surgical site infections.

“The problem with the elderly population is not only have they a higher incidence of MRSA but that the surgical prophylaxis is inadequate for MRSA,” Dr. Benito pointed out.

Many patients in long-term care facilities are elderly and frail and are at greater risk of fracture. Unlike elective hip surgery, in which patients are asked to undergo decolonization over the 5 days prior to their operation, with emergent femur fractures, there is insufficient time for such preparation. “These patients with femur fractures need surgery as soon as possible,” said Dr. Benito.

No studies have been conducted to determine the best way to minimize infection risk from S. aureus and MRSA for patients undergoing emergency hip hemiarthroplasty surgery to treat femoral fractures.

In the current study, Dr. Benito and coauthors assessed whether a bundle of measures – including rapid detection of S. aureus nasal carriage by PCR upon arrival in the emergency setting, followed by decolonization of carriers using a topical treatment in the nose and a prescription of surgical antimicrobial prophylaxis (adapted antibiotic prophylaxis for MRSA) – reduces the incidence of prosthetic joint infections after surgery.

The quasi-experimental single-center study included patients admitted to the emergency department at Hospital de la Santa Creu i Sant Pau. The PCR was rapid, with a turnaround of just 1.5 hours. Decolonization of S. aureus carriers was carried out using nasal mupirocin and chlorhexidine gluconate bathing, which was started immediately. It was used for a 5 days and was usually continued throughout and after surgery.

Patients carrying MRSA received teicoplanin as optimal surgical antimicrobial prophylaxis instead of cefazolin. The intervention did not interfere with the timing of surgery. The study’s principal outcomes were overall incidence of prosthetic joint infections and the incidence of those specifically caused by S. aureus and MRSA.

The researchers compared findings regarding these outcomes over 5 consecutive years of the intervention to outcomes during 4 consecutive years prior to the intervention, which started in 2016.

During 2016-2020, from 22% to 31% of the overall number of patients requiring hip hemiarthroplasty were referred from long-term care facilities. From 25% to 29% of these patients tested positive for S. aureus on PCR, and of these, 33%-64% had MRSA.

There were 772 surgical procedures from 2012 to 2015 and 786 from 2017 to 2020.

Prior to the intervention, over the years 2012-2014, S. aureus caused 36%-50% of prosthetic joint infections; 25%-100% of the S. aureus infections were MRSA. This decreased significantly after the intervention.

During 2016-2020, there was an average of 14 prosthetic joint infections (1.5%), compared to 36 (4.7%) in 2012-2015 (P < .001). Similarly, the incidence of prosthetic joint infections due to S. aureus dropped to 0.3% from 1.8% (P < .002). The incidence of MRSA prosthetic joint infections was 0.3% for 2016-2020, versus 1.2% for 2012-2015 (P = .012).

The years 2018, 2020, and 2021 each saw one case of infection due to MRSA. They were most likely due to “the intervention not being performed properly in all cases,” said Dr. Benito.

A prosthetic joint infection is very serious for the patient. “It means reoperating, because antibiotics are not enough to clear the infection. The biofilm and pus of the infection need to be cleaned out, a new prosthesis is needed, after which more antibiotics are needed for around 2 months, which can be hard to tolerate, and even then, the infection might not be eradicated,” explained Dr. Benito. “Many of these people are old and frail, and mortality can be significant. Getting a prosthetic joint infection is catastrophic for these patients.”

Dr. Benito and Dr. Rodríguez-Baño have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Two-thirds of antibiotic prescriptions written for Black patients and more than half of antibiotic prescriptions for Hispanic/Latinx patients are inappropriate, according to data from a study of antibiotic prescribing habits in U.S. doctors’ offices, hospital clinics, and emergency departments.

Eric Young, PharmD, PhD, from the University of Texas at Austin, and UT Health, San Antonio, presented his work as a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022.

“We were really surprised mainly by the racial findings, because Black patients have the highest overall and the highest inappropriate prescribing of antibiotics,” he told this news organization. “There was also a difference seen for age [across all ethnicities].”

Pediatric patients were found to have high overall prescribing but, notably, the lowest inappropriate prescribing among all the patient groups, reported Dr. Young. “This is interesting because oftentimes we think the more antibiotics are prescribed, then surely the greater the inappropriate prescribing would be too, but pediatricians actually have one of the lowest rates of inappropriate antibiotic prescribing. They do a great job.”

The study included more than 7 billion patient visits, 11.3% of which involved an antibiotic prescription.

The rate of antibiotic prescribing was 122 per 1,000 visits in Black patients and 139 per 1,000 visits in Hispanic patients, while in White patients, the rate was 109 per 1,000 visits. The rate was 114 per 1,000 visits in patients younger than 18 years and 170 per 1,000 visits in females.

Dr. Young found that almost 64% of antibiotic prescriptions written for Black patients and 58% for Hispanic patients were inappropriate. For White patients, the rate of inappropriate antibiotic prescribing was 56%. Similarly, 74% of prescriptions dispensed to patients aged 65 years and older and 58% to males were deemed inappropriate.

Kajal Bhakta, PharmD, BCACP, ambulatory care clinical pharmacist, University Health System, UT Health Science Center San Antonio, who was not involved in the study, pointed out that antibiotics are frequently prescribed without confirmation of an infection, owing to the fact that the verification process may delay care, especially in the outpatient setting.

Dr. Bhakta said that overprescribing in the elderly population and in certain ethnic groups was “likely due to socioeconomic and cultural factors. These prescribing methods may lead to unnecessary drug side effects and/or antimicrobial resistance.”

Regarding the patient-doctor consultation process, she pointed out that “older patients may have trouble describing their symptoms, and when those symptoms remain unresolved, providers may be more inclined to prescribe antibiotics to help.”

Sometimes overprescribing can occur because of the logistics involved in getting to the doctor’s office in the outpatient setting. “Sometimes patients struggle with transportation, as two separate trips to the doctor and pharmacy may not be feasible. Additionally, these same patients may have limited access to health care and therefore may use an urgent care facility for their acute infection–like symptoms,” Dr. Bhakta explained.

Dr. Young, who is of Asian descent, first became interested in disparities in health care when he noticed that ethnic minority groups showed greater hesitancy toward COVID-19 vaccination. “I noticed that there weren’t many Asians involved in previous trials and realized at this point that disparities were rampant.”

Dr. Young had been involved in investigating the overall use and the inappropriate use of antibiotics across the whole U.S. population when his interest in health disparities prompted him to study these patterns in specific demographic groups.

“Most previous data are derived from inpatient studies where the physician is giving the antibiotics,” said Dr. Young, who looked specifically at outpatient prescribing.

Dr. Young used prescribing data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Care Survey, which covers more than 5.7 billion adult (aged 18 and older) and 1.3 billion child visits to outpatient practices between 2009 and 2016 across all 50 U.S. states and Washington, D.C.

He gathered patient data on ICD-9-CM and ICD-10 diagnostic codes for infections and for diagnoses that “appeared like infections.” All of the patients who were included had received at least one oral antibiotic. Antibiotic prescribing was defined as visits that included an antibiotic per 1,000 total patient visits.

On the basis of previous research, Dr. Young and his colleagues then determined whether each antibiotic prescription was appropriate, possibly appropriate, or inappropriate. Patient demographics included age (younger than 18 years, 18-64 years, and older than 64 years), sex (male or female), race, and ethnicity (White, Black, more than one race, Hispanic/Latinx, and other). These data were used to evaluate overall and inappropriate use.

“The health care community needs to be really careful with the judicious use of antibiotics,” Dr. Young said. “We have good guidelines on antimicrobial stewardship both in the inpatient and outpatient settings, but sometimes we overlook the disparities and cultural implications held by some patients.”

Typical examples of socioeconomic and cultural factors at play included patients not being able to afford the antibiotics, having limited access to care, or not returning for a follow-up visit for whatever reason.

“Patients of Black and Hispanic descent often don’t have the same degree of established care that many White patients have,” Dr. Young noted.

In the future, Dr. Young wants to conduct research into whether patients are actually taking their prescribed antibiotics, as well as their outcomes. For example, he would like to investigate whether rates of antibiotic resistance or Clostridioides difficile infection are higher among Black patients.

Dr. Young and Dr. Bhakta have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Two-thirds of antibiotic prescriptions written for Black patients and more than half of antibiotic prescriptions for Hispanic/Latinx patients are inappropriate, according to data from a study of antibiotic prescribing habits in U.S. doctors’ offices, hospital clinics, and emergency departments.

Eric Young, PharmD, PhD, from the University of Texas at Austin, and UT Health, San Antonio, presented his work as a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022.

“We were really surprised mainly by the racial findings, because Black patients have the highest overall and the highest inappropriate prescribing of antibiotics,” he told this news organization. “There was also a difference seen for age [across all ethnicities].”

Pediatric patients were found to have high overall prescribing but, notably, the lowest inappropriate prescribing among all the patient groups, reported Dr. Young. “This is interesting because oftentimes we think the more antibiotics are prescribed, then surely the greater the inappropriate prescribing would be too, but pediatricians actually have one of the lowest rates of inappropriate antibiotic prescribing. They do a great job.”

The study included more than 7 billion patient visits, 11.3% of which involved an antibiotic prescription.

The rate of antibiotic prescribing was 122 per 1,000 visits in Black patients and 139 per 1,000 visits in Hispanic patients, while in White patients, the rate was 109 per 1,000 visits. The rate was 114 per 1,000 visits in patients younger than 18 years and 170 per 1,000 visits in females.

Dr. Young found that almost 64% of antibiotic prescriptions written for Black patients and 58% for Hispanic patients were inappropriate. For White patients, the rate of inappropriate antibiotic prescribing was 56%. Similarly, 74% of prescriptions dispensed to patients aged 65 years and older and 58% to males were deemed inappropriate.

Kajal Bhakta, PharmD, BCACP, ambulatory care clinical pharmacist, University Health System, UT Health Science Center San Antonio, who was not involved in the study, pointed out that antibiotics are frequently prescribed without confirmation of an infection, owing to the fact that the verification process may delay care, especially in the outpatient setting.

Dr. Bhakta said that overprescribing in the elderly population and in certain ethnic groups was “likely due to socioeconomic and cultural factors. These prescribing methods may lead to unnecessary drug side effects and/or antimicrobial resistance.”

Regarding the patient-doctor consultation process, she pointed out that “older patients may have trouble describing their symptoms, and when those symptoms remain unresolved, providers may be more inclined to prescribe antibiotics to help.”

Sometimes overprescribing can occur because of the logistics involved in getting to the doctor’s office in the outpatient setting. “Sometimes patients struggle with transportation, as two separate trips to the doctor and pharmacy may not be feasible. Additionally, these same patients may have limited access to health care and therefore may use an urgent care facility for their acute infection–like symptoms,” Dr. Bhakta explained.

Dr. Young, who is of Asian descent, first became interested in disparities in health care when he noticed that ethnic minority groups showed greater hesitancy toward COVID-19 vaccination. “I noticed that there weren’t many Asians involved in previous trials and realized at this point that disparities were rampant.”

Dr. Young had been involved in investigating the overall use and the inappropriate use of antibiotics across the whole U.S. population when his interest in health disparities prompted him to study these patterns in specific demographic groups.

“Most previous data are derived from inpatient studies where the physician is giving the antibiotics,” said Dr. Young, who looked specifically at outpatient prescribing.

Dr. Young used prescribing data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Care Survey, which covers more than 5.7 billion adult (aged 18 and older) and 1.3 billion child visits to outpatient practices between 2009 and 2016 across all 50 U.S. states and Washington, D.C.

He gathered patient data on ICD-9-CM and ICD-10 diagnostic codes for infections and for diagnoses that “appeared like infections.” All of the patients who were included had received at least one oral antibiotic. Antibiotic prescribing was defined as visits that included an antibiotic per 1,000 total patient visits.

On the basis of previous research, Dr. Young and his colleagues then determined whether each antibiotic prescription was appropriate, possibly appropriate, or inappropriate. Patient demographics included age (younger than 18 years, 18-64 years, and older than 64 years), sex (male or female), race, and ethnicity (White, Black, more than one race, Hispanic/Latinx, and other). These data were used to evaluate overall and inappropriate use.

“The health care community needs to be really careful with the judicious use of antibiotics,” Dr. Young said. “We have good guidelines on antimicrobial stewardship both in the inpatient and outpatient settings, but sometimes we overlook the disparities and cultural implications held by some patients.”

Typical examples of socioeconomic and cultural factors at play included patients not being able to afford the antibiotics, having limited access to care, or not returning for a follow-up visit for whatever reason.

“Patients of Black and Hispanic descent often don’t have the same degree of established care that many White patients have,” Dr. Young noted.

In the future, Dr. Young wants to conduct research into whether patients are actually taking their prescribed antibiotics, as well as their outcomes. For example, he would like to investigate whether rates of antibiotic resistance or Clostridioides difficile infection are higher among Black patients.

Dr. Young and Dr. Bhakta have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – Two-thirds of antibiotic prescriptions written for Black patients and more than half of antibiotic prescriptions for Hispanic/Latinx patients are inappropriate, according to data from a study of antibiotic prescribing habits in U.S. doctors’ offices, hospital clinics, and emergency departments.

Eric Young, PharmD, PhD, from the University of Texas at Austin, and UT Health, San Antonio, presented his work as a poster at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022.

“We were really surprised mainly by the racial findings, because Black patients have the highest overall and the highest inappropriate prescribing of antibiotics,” he told this news organization. “There was also a difference seen for age [across all ethnicities].”

Pediatric patients were found to have high overall prescribing but, notably, the lowest inappropriate prescribing among all the patient groups, reported Dr. Young. “This is interesting because oftentimes we think the more antibiotics are prescribed, then surely the greater the inappropriate prescribing would be too, but pediatricians actually have one of the lowest rates of inappropriate antibiotic prescribing. They do a great job.”

The study included more than 7 billion patient visits, 11.3% of which involved an antibiotic prescription.

The rate of antibiotic prescribing was 122 per 1,000 visits in Black patients and 139 per 1,000 visits in Hispanic patients, while in White patients, the rate was 109 per 1,000 visits. The rate was 114 per 1,000 visits in patients younger than 18 years and 170 per 1,000 visits in females.

Dr. Young found that almost 64% of antibiotic prescriptions written for Black patients and 58% for Hispanic patients were inappropriate. For White patients, the rate of inappropriate antibiotic prescribing was 56%. Similarly, 74% of prescriptions dispensed to patients aged 65 years and older and 58% to males were deemed inappropriate.

Kajal Bhakta, PharmD, BCACP, ambulatory care clinical pharmacist, University Health System, UT Health Science Center San Antonio, who was not involved in the study, pointed out that antibiotics are frequently prescribed without confirmation of an infection, owing to the fact that the verification process may delay care, especially in the outpatient setting.

Dr. Bhakta said that overprescribing in the elderly population and in certain ethnic groups was “likely due to socioeconomic and cultural factors. These prescribing methods may lead to unnecessary drug side effects and/or antimicrobial resistance.”

Regarding the patient-doctor consultation process, she pointed out that “older patients may have trouble describing their symptoms, and when those symptoms remain unresolved, providers may be more inclined to prescribe antibiotics to help.”

Sometimes overprescribing can occur because of the logistics involved in getting to the doctor’s office in the outpatient setting. “Sometimes patients struggle with transportation, as two separate trips to the doctor and pharmacy may not be feasible. Additionally, these same patients may have limited access to health care and therefore may use an urgent care facility for their acute infection–like symptoms,” Dr. Bhakta explained.

Dr. Young, who is of Asian descent, first became interested in disparities in health care when he noticed that ethnic minority groups showed greater hesitancy toward COVID-19 vaccination. “I noticed that there weren’t many Asians involved in previous trials and realized at this point that disparities were rampant.”

Dr. Young had been involved in investigating the overall use and the inappropriate use of antibiotics across the whole U.S. population when his interest in health disparities prompted him to study these patterns in specific demographic groups.

“Most previous data are derived from inpatient studies where the physician is giving the antibiotics,” said Dr. Young, who looked specifically at outpatient prescribing.

Dr. Young used prescribing data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Care Survey, which covers more than 5.7 billion adult (aged 18 and older) and 1.3 billion child visits to outpatient practices between 2009 and 2016 across all 50 U.S. states and Washington, D.C.

He gathered patient data on ICD-9-CM and ICD-10 diagnostic codes for infections and for diagnoses that “appeared like infections.” All of the patients who were included had received at least one oral antibiotic. Antibiotic prescribing was defined as visits that included an antibiotic per 1,000 total patient visits.

On the basis of previous research, Dr. Young and his colleagues then determined whether each antibiotic prescription was appropriate, possibly appropriate, or inappropriate. Patient demographics included age (younger than 18 years, 18-64 years, and older than 64 years), sex (male or female), race, and ethnicity (White, Black, more than one race, Hispanic/Latinx, and other). These data were used to evaluate overall and inappropriate use.

“The health care community needs to be really careful with the judicious use of antibiotics,” Dr. Young said. “We have good guidelines on antimicrobial stewardship both in the inpatient and outpatient settings, but sometimes we overlook the disparities and cultural implications held by some patients.”

Typical examples of socioeconomic and cultural factors at play included patients not being able to afford the antibiotics, having limited access to care, or not returning for a follow-up visit for whatever reason.

“Patients of Black and Hispanic descent often don’t have the same degree of established care that many White patients have,” Dr. Young noted.

In the future, Dr. Young wants to conduct research into whether patients are actually taking their prescribed antibiotics, as well as their outcomes. For example, he would like to investigate whether rates of antibiotic resistance or Clostridioides difficile infection are higher among Black patients.

Dr. Young and Dr. Bhakta have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LISBON – During the pandemic, critical and acute care hospitals with medium and high rates of antimicrobial resistance (AMR) showed significant increases in antibiotic prescriptions and longer durations of antibiotic treatment among all hospital admissions, and also in those patients who were bacterial culture negative, according to a large U.S.-based study.

The analysis across 271 U.S. hospitals also showed that AMR rates were significantly higher for pathogens during the pandemic period, compared with the prepandemic period in patients who were tested for SARS-CoV-2, and highest in SARS-CoV-2–positive patients.

More than a third of SARS-CoV-2–positive patients who were prescribed antibiotics were bacterial culture negative.

Findings of the study were presented by Vikas Gupta, PharmD, director of medical affairs at medical technology firm Becton Dickinson, at this year’s European Congress of Clinical Microbiology & Infectious Diseases. He conducted the study jointly with Karri Bauer, PharmD, from Merck Sharp & Dohme, Kenilworth, N.J., and colleagues.

“There are differences in AMR that go beyond COVID-positive admissions,” Dr. Gupta told this news organization. “There is opportunity for improvement especially with those hospitalized patients who had a negative culture result, or no culture collected.”

“We found a higher percentage of COVID-positive admissions that were prescribed antibacterial therapy even in those having [tested negative for bacteria] or no culture result,” said Dr. Gupta. “Our data also shows that the percentage of admissions with duration of antibacterial therapy over 3 days was significantly higher in COVID-positive but culture-negative/no culture patients, compared to other groups evaluated.”

Of all admissions prescribed antibiotics during the pandemic, 57.8% of SARS-CoV-2–positive patients were prescribed antibiotics whereas 88.1% of SARS-CoV-2–positive admissions were bacterial culture negative/no culture. Overall, prepandemic, 35% of admissions were prescribed antibiotics.

Duration of antibiotic therapy in the prepandemic era was an average of 3.5 days, compared with an average of 3.8 days overall in the pandemic and 5.7 days in patients who tested positive for SARS-CoV-2. Similarly, the percentage of patients who were bacterial culture negative or had no culture and received antibiotic therapy for more than 72 hours was 17.6% in the prepandemic era, compared with 19.2% overall in the pandemic era, and 41.1% in patients who tested positive for COVID-19.  

Dr. Gupta and Dr. Bauer wanted to look at all patients admitted to hospitals segmented by SARS-CoV-2 positive, negative, and not tested, to get a sense of how much antibiotic use there was and how long patients were on antibiotics. “We ultimately want to optimize and not overuse antibiotics and prescribe them for right period of time,” said Dr. Gupta.

“To date, there has been no conclusive evidence about the suggestion that the pandemic has led to increased AMR rates, so we aimed to evaluate the pandemic’s impact on AMR and antibiotic use across U.S. hospitals,” he explained.

The multicenter, retrospective cohort analysis made use of BD’s infection surveillance platform (BD HealthSight Infection Advisor with MedMined Insights) and was conducted across 271 U.S. critical access/acute care facilities, representing approximately 10%-13% of U.S. hospital admissions. It included all hospitalized patients with more than 1 day of in-patient admission. Patients were considered SARS-CoV-2 positive by polymerase chain reaction test or antigen test either 7 days or less prior to or within 14 days of admission.

Patients were categorized as hospitalized during the “prepandemic” period (July 1, 2019 through February 29, 2020) and the “pandemic” period (March 1, 2020 through Oct. 30, 2021) and were stratified based on their SARS-CoV-2 result. 

Investigators included all hospital admissions with an AMR event (first positive culture for select gram-negative or gram-positive pathogens that were reported as nonsusceptible across blood, urine, respiratory, intra-abdominal, skin/wound, and other sources).

The investigators calculated AMR rates at the patient-admission level and defined per 100 admissions. Also, they further evaluated AMR rates based on community onset (defined as culture collected ≤2 days from admission) or hospital onset (>2 days from admission). Finally, AMR rates were determined according to whether they related to prepandemic or pandemic periods. 

Hospitals were also categorized according to their AMR rates as low (<25%), medium (25%-75%), and high (>75%). 

Overall AMR rates were lower in the pandemic period, compared with the prepandemic period. However, reported Dr.Gupta, for hospital-onset pathogens specifically, AMR rates were significantly higher overall in the pandemic period and mostly driven by admissions tested for SARS-CoV-2 (whether positive or negative).

Hospitals with high AMR rates also tended to have more SARS-CoV-2 positive admissions (6.1% in high-AMR hospitals vs. 3% in low-AMR hospitals). The highest antibiotic-prescribing rates and highest duration of antibiotic use was also seen in those hospitals with highest AMR rates. 

Of the SARS-CoV-2 patients who were bacterial culture negative/no culture and were prescribed antibiotics, 36.5% were in hospitals with a high AMR rate. “Roughly one-third of patients without culture evidence of a bacterial infection were prescribed antibiotics in hospitals with a high AMR rate,” said Dr. Gupta.

The researchers wanted to tease out whether hospitals with high, moderate, or low AMR rates look different with respect to antibiotic-prescribing patterns. During the pandemic period, they found that hospitals with high and medium AMR rates experienced significant increases in antibiotic prescriptions and longer durations. Prepandemic, the overall hospital-onset AMR rate was 0.8 per 100 admissions, whereas during the pandemic this rose to 1.4 per 100 admissions in high-AMR hospitals and dropped to 0.4 in low-AMR hospitals.

SARS-CoV-2–positive admission rates were higher in facilities with medium (5.6%) and high AMR (6.1%) rates than those with low (3%) AMR rates. “We found that those with medium and high AMR rates were more likely to have COVID-positive admissions than facilities with low AMR rates,” Dr. Gupta said. “It appears as if COVID is contributing to AMR in the facilities.”

Asked for independent comment, Jason C. Gallagher, PharmD, BCPS, clinical professor at Temple University School of Pharmacy in Philadelphia, said in an interview, “It is not surprising that there was more antimicrobial resistance in patients with COVID than those without. Even though antibiotics do not work for COVID, they are often prescribed, and antibiotic use is a major risk factor for antimicrobial resistance. This is likely because clinicians are sometimes concerned about coinfections with bacteria (which are rare) and because hospitalized patients with severe COVID can acquire other infections as they are treated.”
 

Antibiotic stewardship programs

Antibiotic stewardship programs have been highly stressed during the pandemic, so the researchers hope their data support the need for better antibiotic stewardship practices during pandemic surges when control is more challenging.

Dr. Gupta explained that they were seeing interesting associations that can inform antimicrobial stewardship programs and teams. “We are not trying to imply causality,” he stressed.

It is a common practice for stewardship teams to evaluate the need for continuation of antibiotic therapy at 3 days, especially in patients who are culture negative or did not have a culture collected.

“Antibiotic time-out at 3 days is a recommended practice to evaluate for continuing antibiotic therapy based on the patient’s condition and culture results,” he said. “This is what made our study unique because we wanted to look at what percentage of admissions were prescribed antibiotics beyond 3 days and compare to the prepandemic period.”

Session moderator Evangelos J. Giamarellos-Bourboulis, MD, PhD, an assistant professor of internal medicine and infectious diseases, University of Athens, Greece, thanked Dr. Gupta for his “eloquent presentation” and sought to clarify whether the data “refer to antimicrobial use that was empirical or whether use was in hospitals with high AMR rates, or whether the approach was driven through microbiology?”

Dr. Gupta replied that this was why they evaluated the negative-culture and no-culture patients. “We wanted to get a measure of antibacterial use in this population too,” he said. “Definitely, there is empirical therapy as well as definitive therapy, but I think the negative and no-culture group provide a reference point where we see similar signals and trends to that of the overall population.”

An audience member also addressed a question to Dr. Gupta: “Did you look at the patient population, because in many cases, during COVID, these patients may have been more severe than in the prepandemic period?”

Dr. Gupta replied: “In our manuscript we’ve done an analysis where we adjusted for patient-level facility and regional-level factors. There are definitely differences in the patient populations but overall, these are pretty sick patients when we look at the level of severity overall.”

Dr. Gupta is an employee of and a shareholder in Becton Dickinson. Dr. Bauer is an employee of and a shareholder in Merck. Dr. Gallagher consults for many pharmaceutical companies including Merck.

Dr. Giamarellos-Bourboulis disclosed honoraria (paid to the University of Athens) from Abbott CH, Brahms Thermo Fisher GMBH Germany, GlaxoSmithKline, and Sobi; serving as a consultant for Abbott CH, Fab’nTech, InflaRx GmbH, UCB, Sobi, and Xbiotech; research grants (paid to the Hellenic Institute for the Study of Sepsis) from Abbott CH, BioMerieux France, Johnson & Johnson, MSD, Sobi, Thermo Fisher Brahms GmbH; and EU research funding: Horizon 2020 ITN European Sepsis Academy (granted to the University of Athens); Horizon 2020 ImmunoSep and RISinCOVID (granted to the Hellenic Institute for the Study of Sepsis); Horizon Health EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis).

A version of this article first appeared on Medscape.com.

LISBON – During the pandemic, critical and acute care hospitals with medium and high rates of antimicrobial resistance (AMR) showed significant increases in antibiotic prescriptions and longer durations of antibiotic treatment among all hospital admissions, and also in those patients who were bacterial culture negative, according to a large U.S.-based study.

The analysis across 271 U.S. hospitals also showed that AMR rates were significantly higher for pathogens during the pandemic period, compared with the prepandemic period in patients who were tested for SARS-CoV-2, and highest in SARS-CoV-2–positive patients.

More than a third of SARS-CoV-2–positive patients who were prescribed antibiotics were bacterial culture negative.

Findings of the study were presented by Vikas Gupta, PharmD, director of medical affairs at medical technology firm Becton Dickinson, at this year’s European Congress of Clinical Microbiology & Infectious Diseases. He conducted the study jointly with Karri Bauer, PharmD, from Merck Sharp & Dohme, Kenilworth, N.J., and colleagues.

“There are differences in AMR that go beyond COVID-positive admissions,” Dr. Gupta told this news organization. “There is opportunity for improvement especially with those hospitalized patients who had a negative culture result, or no culture collected.”

“We found a higher percentage of COVID-positive admissions that were prescribed antibacterial therapy even in those having [tested negative for bacteria] or no culture result,” said Dr. Gupta. “Our data also shows that the percentage of admissions with duration of antibacterial therapy over 3 days was significantly higher in COVID-positive but culture-negative/no culture patients, compared to other groups evaluated.”

Of all admissions prescribed antibiotics during the pandemic, 57.8% of SARS-CoV-2–positive patients were prescribed antibiotics whereas 88.1% of SARS-CoV-2–positive admissions were bacterial culture negative/no culture. Overall, prepandemic, 35% of admissions were prescribed antibiotics.

Duration of antibiotic therapy in the prepandemic era was an average of 3.5 days, compared with an average of 3.8 days overall in the pandemic and 5.7 days in patients who tested positive for SARS-CoV-2. Similarly, the percentage of patients who were bacterial culture negative or had no culture and received antibiotic therapy for more than 72 hours was 17.6% in the prepandemic era, compared with 19.2% overall in the pandemic era, and 41.1% in patients who tested positive for COVID-19.  

Dr. Gupta and Dr. Bauer wanted to look at all patients admitted to hospitals segmented by SARS-CoV-2 positive, negative, and not tested, to get a sense of how much antibiotic use there was and how long patients were on antibiotics. “We ultimately want to optimize and not overuse antibiotics and prescribe them for right period of time,” said Dr. Gupta.

“To date, there has been no conclusive evidence about the suggestion that the pandemic has led to increased AMR rates, so we aimed to evaluate the pandemic’s impact on AMR and antibiotic use across U.S. hospitals,” he explained.

The multicenter, retrospective cohort analysis made use of BD’s infection surveillance platform (BD HealthSight Infection Advisor with MedMined Insights) and was conducted across 271 U.S. critical access/acute care facilities, representing approximately 10%-13% of U.S. hospital admissions. It included all hospitalized patients with more than 1 day of in-patient admission. Patients were considered SARS-CoV-2 positive by polymerase chain reaction test or antigen test either 7 days or less prior to or within 14 days of admission.

Patients were categorized as hospitalized during the “prepandemic” period (July 1, 2019 through February 29, 2020) and the “pandemic” period (March 1, 2020 through Oct. 30, 2021) and were stratified based on their SARS-CoV-2 result. 

Investigators included all hospital admissions with an AMR event (first positive culture for select gram-negative or gram-positive pathogens that were reported as nonsusceptible across blood, urine, respiratory, intra-abdominal, skin/wound, and other sources).

The investigators calculated AMR rates at the patient-admission level and defined per 100 admissions. Also, they further evaluated AMR rates based on community onset (defined as culture collected ≤2 days from admission) or hospital onset (>2 days from admission). Finally, AMR rates were determined according to whether they related to prepandemic or pandemic periods. 

Hospitals were also categorized according to their AMR rates as low (<25%), medium (25%-75%), and high (>75%). 

Overall AMR rates were lower in the pandemic period, compared with the prepandemic period. However, reported Dr.Gupta, for hospital-onset pathogens specifically, AMR rates were significantly higher overall in the pandemic period and mostly driven by admissions tested for SARS-CoV-2 (whether positive or negative).

Hospitals with high AMR rates also tended to have more SARS-CoV-2 positive admissions (6.1% in high-AMR hospitals vs. 3% in low-AMR hospitals). The highest antibiotic-prescribing rates and highest duration of antibiotic use was also seen in those hospitals with highest AMR rates. 

Of the SARS-CoV-2 patients who were bacterial culture negative/no culture and were prescribed antibiotics, 36.5% were in hospitals with a high AMR rate. “Roughly one-third of patients without culture evidence of a bacterial infection were prescribed antibiotics in hospitals with a high AMR rate,” said Dr. Gupta.

The researchers wanted to tease out whether hospitals with high, moderate, or low AMR rates look different with respect to antibiotic-prescribing patterns. During the pandemic period, they found that hospitals with high and medium AMR rates experienced significant increases in antibiotic prescriptions and longer durations. Prepandemic, the overall hospital-onset AMR rate was 0.8 per 100 admissions, whereas during the pandemic this rose to 1.4 per 100 admissions in high-AMR hospitals and dropped to 0.4 in low-AMR hospitals.

SARS-CoV-2–positive admission rates were higher in facilities with medium (5.6%) and high AMR (6.1%) rates than those with low (3%) AMR rates. “We found that those with medium and high AMR rates were more likely to have COVID-positive admissions than facilities with low AMR rates,” Dr. Gupta said. “It appears as if COVID is contributing to AMR in the facilities.”

Asked for independent comment, Jason C. Gallagher, PharmD, BCPS, clinical professor at Temple University School of Pharmacy in Philadelphia, said in an interview, “It is not surprising that there was more antimicrobial resistance in patients with COVID than those without. Even though antibiotics do not work for COVID, they are often prescribed, and antibiotic use is a major risk factor for antimicrobial resistance. This is likely because clinicians are sometimes concerned about coinfections with bacteria (which are rare) and because hospitalized patients with severe COVID can acquire other infections as they are treated.”
 

Antibiotic stewardship programs

Antibiotic stewardship programs have been highly stressed during the pandemic, so the researchers hope their data support the need for better antibiotic stewardship practices during pandemic surges when control is more challenging.

Dr. Gupta explained that they were seeing interesting associations that can inform antimicrobial stewardship programs and teams. “We are not trying to imply causality,” he stressed.

It is a common practice for stewardship teams to evaluate the need for continuation of antibiotic therapy at 3 days, especially in patients who are culture negative or did not have a culture collected.

“Antibiotic time-out at 3 days is a recommended practice to evaluate for continuing antibiotic therapy based on the patient’s condition and culture results,” he said. “This is what made our study unique because we wanted to look at what percentage of admissions were prescribed antibiotics beyond 3 days and compare to the prepandemic period.”

Session moderator Evangelos J. Giamarellos-Bourboulis, MD, PhD, an assistant professor of internal medicine and infectious diseases, University of Athens, Greece, thanked Dr. Gupta for his “eloquent presentation” and sought to clarify whether the data “refer to antimicrobial use that was empirical or whether use was in hospitals with high AMR rates, or whether the approach was driven through microbiology?”

Dr. Gupta replied that this was why they evaluated the negative-culture and no-culture patients. “We wanted to get a measure of antibacterial use in this population too,” he said. “Definitely, there is empirical therapy as well as definitive therapy, but I think the negative and no-culture group provide a reference point where we see similar signals and trends to that of the overall population.”

An audience member also addressed a question to Dr. Gupta: “Did you look at the patient population, because in many cases, during COVID, these patients may have been more severe than in the prepandemic period?”

Dr. Gupta replied: “In our manuscript we’ve done an analysis where we adjusted for patient-level facility and regional-level factors. There are definitely differences in the patient populations but overall, these are pretty sick patients when we look at the level of severity overall.”

Dr. Gupta is an employee of and a shareholder in Becton Dickinson. Dr. Bauer is an employee of and a shareholder in Merck. Dr. Gallagher consults for many pharmaceutical companies including Merck.

Dr. Giamarellos-Bourboulis disclosed honoraria (paid to the University of Athens) from Abbott CH, Brahms Thermo Fisher GMBH Germany, GlaxoSmithKline, and Sobi; serving as a consultant for Abbott CH, Fab’nTech, InflaRx GmbH, UCB, Sobi, and Xbiotech; research grants (paid to the Hellenic Institute for the Study of Sepsis) from Abbott CH, BioMerieux France, Johnson & Johnson, MSD, Sobi, Thermo Fisher Brahms GmbH; and EU research funding: Horizon 2020 ITN European Sepsis Academy (granted to the University of Athens); Horizon 2020 ImmunoSep and RISinCOVID (granted to the Hellenic Institute for the Study of Sepsis); Horizon Health EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis).

A version of this article first appeared on Medscape.com.

LISBON – During the pandemic, critical and acute care hospitals with medium and high rates of antimicrobial resistance (AMR) showed significant increases in antibiotic prescriptions and longer durations of antibiotic treatment among all hospital admissions, and also in those patients who were bacterial culture negative, according to a large U.S.-based study.

The analysis across 271 U.S. hospitals also showed that AMR rates were significantly higher for pathogens during the pandemic period, compared with the prepandemic period in patients who were tested for SARS-CoV-2, and highest in SARS-CoV-2–positive patients.

More than a third of SARS-CoV-2–positive patients who were prescribed antibiotics were bacterial culture negative.

Findings of the study were presented by Vikas Gupta, PharmD, director of medical affairs at medical technology firm Becton Dickinson, at this year’s European Congress of Clinical Microbiology & Infectious Diseases. He conducted the study jointly with Karri Bauer, PharmD, from Merck Sharp & Dohme, Kenilworth, N.J., and colleagues.

“There are differences in AMR that go beyond COVID-positive admissions,” Dr. Gupta told this news organization. “There is opportunity for improvement especially with those hospitalized patients who had a negative culture result, or no culture collected.”

“We found a higher percentage of COVID-positive admissions that were prescribed antibacterial therapy even in those having [tested negative for bacteria] or no culture result,” said Dr. Gupta. “Our data also shows that the percentage of admissions with duration of antibacterial therapy over 3 days was significantly higher in COVID-positive but culture-negative/no culture patients, compared to other groups evaluated.”

Of all admissions prescribed antibiotics during the pandemic, 57.8% of SARS-CoV-2–positive patients were prescribed antibiotics whereas 88.1% of SARS-CoV-2–positive admissions were bacterial culture negative/no culture. Overall, prepandemic, 35% of admissions were prescribed antibiotics.

Duration of antibiotic therapy in the prepandemic era was an average of 3.5 days, compared with an average of 3.8 days overall in the pandemic and 5.7 days in patients who tested positive for SARS-CoV-2. Similarly, the percentage of patients who were bacterial culture negative or had no culture and received antibiotic therapy for more than 72 hours was 17.6% in the prepandemic era, compared with 19.2% overall in the pandemic era, and 41.1% in patients who tested positive for COVID-19.  

Dr. Gupta and Dr. Bauer wanted to look at all patients admitted to hospitals segmented by SARS-CoV-2 positive, negative, and not tested, to get a sense of how much antibiotic use there was and how long patients were on antibiotics. “We ultimately want to optimize and not overuse antibiotics and prescribe them for right period of time,” said Dr. Gupta.

“To date, there has been no conclusive evidence about the suggestion that the pandemic has led to increased AMR rates, so we aimed to evaluate the pandemic’s impact on AMR and antibiotic use across U.S. hospitals,” he explained.

The multicenter, retrospective cohort analysis made use of BD’s infection surveillance platform (BD HealthSight Infection Advisor with MedMined Insights) and was conducted across 271 U.S. critical access/acute care facilities, representing approximately 10%-13% of U.S. hospital admissions. It included all hospitalized patients with more than 1 day of in-patient admission. Patients were considered SARS-CoV-2 positive by polymerase chain reaction test or antigen test either 7 days or less prior to or within 14 days of admission.

Patients were categorized as hospitalized during the “prepandemic” period (July 1, 2019 through February 29, 2020) and the “pandemic” period (March 1, 2020 through Oct. 30, 2021) and were stratified based on their SARS-CoV-2 result. 

Investigators included all hospital admissions with an AMR event (first positive culture for select gram-negative or gram-positive pathogens that were reported as nonsusceptible across blood, urine, respiratory, intra-abdominal, skin/wound, and other sources).

The investigators calculated AMR rates at the patient-admission level and defined per 100 admissions. Also, they further evaluated AMR rates based on community onset (defined as culture collected ≤2 days from admission) or hospital onset (>2 days from admission). Finally, AMR rates were determined according to whether they related to prepandemic or pandemic periods. 

Hospitals were also categorized according to their AMR rates as low (<25%), medium (25%-75%), and high (>75%). 

Overall AMR rates were lower in the pandemic period, compared with the prepandemic period. However, reported Dr.Gupta, for hospital-onset pathogens specifically, AMR rates were significantly higher overall in the pandemic period and mostly driven by admissions tested for SARS-CoV-2 (whether positive or negative).

Hospitals with high AMR rates also tended to have more SARS-CoV-2 positive admissions (6.1% in high-AMR hospitals vs. 3% in low-AMR hospitals). The highest antibiotic-prescribing rates and highest duration of antibiotic use was also seen in those hospitals with highest AMR rates. 

Of the SARS-CoV-2 patients who were bacterial culture negative/no culture and were prescribed antibiotics, 36.5% were in hospitals with a high AMR rate. “Roughly one-third of patients without culture evidence of a bacterial infection were prescribed antibiotics in hospitals with a high AMR rate,” said Dr. Gupta.

The researchers wanted to tease out whether hospitals with high, moderate, or low AMR rates look different with respect to antibiotic-prescribing patterns. During the pandemic period, they found that hospitals with high and medium AMR rates experienced significant increases in antibiotic prescriptions and longer durations. Prepandemic, the overall hospital-onset AMR rate was 0.8 per 100 admissions, whereas during the pandemic this rose to 1.4 per 100 admissions in high-AMR hospitals and dropped to 0.4 in low-AMR hospitals.

SARS-CoV-2–positive admission rates were higher in facilities with medium (5.6%) and high AMR (6.1%) rates than those with low (3%) AMR rates. “We found that those with medium and high AMR rates were more likely to have COVID-positive admissions than facilities with low AMR rates,” Dr. Gupta said. “It appears as if COVID is contributing to AMR in the facilities.”

Asked for independent comment, Jason C. Gallagher, PharmD, BCPS, clinical professor at Temple University School of Pharmacy in Philadelphia, said in an interview, “It is not surprising that there was more antimicrobial resistance in patients with COVID than those without. Even though antibiotics do not work for COVID, they are often prescribed, and antibiotic use is a major risk factor for antimicrobial resistance. This is likely because clinicians are sometimes concerned about coinfections with bacteria (which are rare) and because hospitalized patients with severe COVID can acquire other infections as they are treated.”
 

Antibiotic stewardship programs

Antibiotic stewardship programs have been highly stressed during the pandemic, so the researchers hope their data support the need for better antibiotic stewardship practices during pandemic surges when control is more challenging.

Dr. Gupta explained that they were seeing interesting associations that can inform antimicrobial stewardship programs and teams. “We are not trying to imply causality,” he stressed.

It is a common practice for stewardship teams to evaluate the need for continuation of antibiotic therapy at 3 days, especially in patients who are culture negative or did not have a culture collected.

“Antibiotic time-out at 3 days is a recommended practice to evaluate for continuing antibiotic therapy based on the patient’s condition and culture results,” he said. “This is what made our study unique because we wanted to look at what percentage of admissions were prescribed antibiotics beyond 3 days and compare to the prepandemic period.”

Session moderator Evangelos J. Giamarellos-Bourboulis, MD, PhD, an assistant professor of internal medicine and infectious diseases, University of Athens, Greece, thanked Dr. Gupta for his “eloquent presentation” and sought to clarify whether the data “refer to antimicrobial use that was empirical or whether use was in hospitals with high AMR rates, or whether the approach was driven through microbiology?”

Dr. Gupta replied that this was why they evaluated the negative-culture and no-culture patients. “We wanted to get a measure of antibacterial use in this population too,” he said. “Definitely, there is empirical therapy as well as definitive therapy, but I think the negative and no-culture group provide a reference point where we see similar signals and trends to that of the overall population.”

An audience member also addressed a question to Dr. Gupta: “Did you look at the patient population, because in many cases, during COVID, these patients may have been more severe than in the prepandemic period?”

Dr. Gupta replied: “In our manuscript we’ve done an analysis where we adjusted for patient-level facility and regional-level factors. There are definitely differences in the patient populations but overall, these are pretty sick patients when we look at the level of severity overall.”

Dr. Gupta is an employee of and a shareholder in Becton Dickinson. Dr. Bauer is an employee of and a shareholder in Merck. Dr. Gallagher consults for many pharmaceutical companies including Merck.

Dr. Giamarellos-Bourboulis disclosed honoraria (paid to the University of Athens) from Abbott CH, Brahms Thermo Fisher GMBH Germany, GlaxoSmithKline, and Sobi; serving as a consultant for Abbott CH, Fab’nTech, InflaRx GmbH, UCB, Sobi, and Xbiotech; research grants (paid to the Hellenic Institute for the Study of Sepsis) from Abbott CH, BioMerieux France, Johnson & Johnson, MSD, Sobi, Thermo Fisher Brahms GmbH; and EU research funding: Horizon 2020 ITN European Sepsis Academy (granted to the University of Athens); Horizon 2020 ImmunoSep and RISinCOVID (granted to the Hellenic Institute for the Study of Sepsis); Horizon Health EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis).

A version of this article first appeared on Medscape.com.

An overall ninefold increase in COVID-19 antibody levels can be seen with a longer interval between first and second doses of the Pfizer/BioNTech (BNT162b2) vaccine in people without prior infection, according to data from the U.K. government’s SIREN (SARS-CoV-2 Immunity and Reinfection Evaluation) study.

This interval-dependent antibody level varied by age, with those aged 45-54 years showing an 11-fold increase with a longer dosing interval (greater than 10 weeks vs. 2-4 weeks). People younger than age 25 years showed a 13-fold increase with the longer interval, but participant numbers were low in this sub-group.

Overall antibody levels in infection-naive participants were 1,268.72 Binding Antibody Units (BAU)/mL (1,043.25-1,542.91) in those with a 2-4–week interval, compared with 11,479.73 BAU/mL (10,742.78-12,267.24) (P < .0001), in those with at least a 10-week interval between doses.

The work is the latest analysis from SIREN, which measured antibody levels in the blood from nearly 6,000 health care workers from across the United Kingdom. Study lead Ashley Otter, PhD, technical lead for SIREN serology at the UK Health Security Agency (UKHSA), will present the work on Tuesday at the 2022 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), Lisbon.

In an interview, Dr. Otter noted that, “it is important to remember that antibody levels are only one aspect of the immune response, and in our recent vaccine effectiveness analysis, we found that dosing intervals did not affect protection against infection.”

The study, which appeared in the March issue of the New England Journal of Medicine, also found that after the second dose of vaccine, there was about a 2.5–fold difference in antibody levels between those who had prior infection of 16.052 (14.071-18.312) BAU/mL, compared with 7.050 (6.634-7.491) BAU/mL in infection-naive individuals (P < .0001).

Following the first dose only, antibody levels were up to 10 times higher in participants who were previously infected, compared with infection-naive individuals. This effect lasted up to 8 months and then began to plateau.
 

Natural infection increased antibody levels

Dr. Otter remarked that, “COVID-19 antibody levels are high in those people who were previously naturally infected and vaccinated, highlighting that vaccination provides an additional benefit to these individuals.”

This news organization asked Charlotte Thålin, PhD, an immunologist from the Karolinska Institute, Stockholm, to comment on the study. Dr. Thålin studies a cohort similar to SIREN, called the Swedish COMMUNITY health care worker cohort. “The new data from the SIREN emphasizes the importance of the number of antigenic exposures and the time interval between them, whether it be exposure through vaccination or exposure through infection.” 

“We see similar data in our Swedish COMMUNITY health care worker cohort,” Dr. Thålin continued, “where infection prior to vaccination yields a more than twofold enhancement in antibodies, neutralizing breadth, and T cell responses, and an even larger increase with a longer time interval between infection and vaccination.”

However, she cautioned that they now see a high rate of Omicron vaccine breakthrough infections, and this is also true in people with previous infection and three vaccine doses.

“As we approach a second booster – a fourth vaccine dose – we need to consider that many individuals will have had up to five to six antigen exposures within a short period of time, sometimes within a year,” she pointed out. “This is a whole new scenario, with a lot of different combinations of vaccine and infection-induced immunity. We do not yet know the impact of these frequent immune exposures, and we now need to monitor immune responses following Omicron and booster doses closely.”

SIREN originally aimed to understand how much protection people got after developing a primary infection and why they might become reinfected with COVID-19. Following the rollout of the United Kingdom’s vaccination program, the protective effects of vaccination against COVID-19 were investigated, as well as why some people still become ill after being vaccinated, Dr. Otter explained.

In this latest analysis, Dr. Otter and colleagues assessed anti-spike binding antibodies in serum samples from a total of 5,871 health care workers, with 3,989 after one dose (at least 21 days) and 1,882 after two doses (at least 14 days).

Most participants were women (82.3%), of White ethnicity (87%), and came from across the United Kingdom.

Participants were also categorized into those who had evidence of natural COVID-19 infection (confirmed by a PCR test or assumed because of their antibody profile) or those who were infection-naive. Almost all (> 99%) of those who were infection-naive seroconverted after vaccination.

The primary outcome was anti-spike antibody levels assessed according to dose, previous infection, dosing interval, age, ethnicity, and comorbidities, including immunosuppressive disease such as immune system cancers, rheumatologic disease, chronic respiratory diseases, diabetes, obesity, and chronic neurologic disease. 

In the infection-naive group, the mean antibody (anti-S titer) was 75.48 BAU/mL after the first vaccine dose, and this rose to 7,049.76 BAU/mL after the second dose.

The much higher antibody titer with the second dose in infection-naive individuals “is what gives you the most protection, as your antibody titers are at their peak. They then start to gradually wane from this peak,” said Dr. Otter.

In the post-infection group, antibody titers also rose (2,111.08 BAU/mL after first dose and 16,052.39 BAU/mL after second dose), although less so than in the infection-naive group, because of the additional exposure of infection, added Dr. Otter.

Antibody levels also varied according to time elapsed between natural infection and dose 1 of vaccination. With a 3-month interval, antibody levels were 1,970.83 (1,506.01-2,579.1) BAU/mL, compared with 13,759.31 (8,097.78-23,379.09) BAU/mL after a 9-month interval. Antibody levels after one dose in those previously infected are higher than the infection-naive because “previous infection, then vaccination, is likely explained by T-cell expansion upon a boost with a second antigen exposure, and then a maturing memory B-cell response that has been demonstrated up to 6 months,” explained Dr. Otter.

 

Timing of fourth dose

By March of this year, 86.2% of the U.K. population aged over 12 years had received at least two doses, but with rises in disease prevalence and the spread of variants of concern, further work is ongoing to understand the waning of the immune response, level of protection, and why some individuals develop COVID-19 even when double-vaccinated.

This news organization asked Susanna Dunachie, BMChB, professor of infectious diseases, University of Oxford, U.K., what the interval findings might mean for the timing of the fourth dose of vaccine across the U.K. population.

In the United Kingdom, fourth doses are being given to people who are 75 years and older, residents in care homes for older people, and those with weakened immune systems. “To make decisions about fourth doses for healthy people, we need to see how quickly antibody and T-cell responses drop,” said Ms. Dunachie, who is part of the large SIREN study team but was not involved in the analysis led by Dr. Otter. “Current research suggests that the T-cell response may be better maintained than the antibody response, and less affected by variants like Omicron.”

She explained the balance between antibody and T-cell responses to vaccination. “It is likely that antibodies that neutralize the virus are important for preventing any infection at all, and these unfortunately do fall in time, but T-cell responses are better sustained and help keep people out of [the] hospital,” she said.

Ms. Dunachie added that it was necessary to wait and observe what happens next with SARS-CoV-2 evolution, as well as wait for longer follow-up after the third dose in healthy people. “On current evidence, my estimate is we postpone decisions on fourth doses in healthy people to late summer/autumn.”

A version of this article first appeared on Medscape.com.

An overall ninefold increase in COVID-19 antibody levels can be seen with a longer interval between first and second doses of the Pfizer/BioNTech (BNT162b2) vaccine in people without prior infection, according to data from the U.K. government’s SIREN (SARS-CoV-2 Immunity and Reinfection Evaluation) study.

This interval-dependent antibody level varied by age, with those aged 45-54 years showing an 11-fold increase with a longer dosing interval (greater than 10 weeks vs. 2-4 weeks). People younger than age 25 years showed a 13-fold increase with the longer interval, but participant numbers were low in this sub-group.

Overall antibody levels in infection-naive participants were 1,268.72 Binding Antibody Units (BAU)/mL (1,043.25-1,542.91) in those with a 2-4–week interval, compared with 11,479.73 BAU/mL (10,742.78-12,267.24) (P < .0001), in those with at least a 10-week interval between doses.

The work is the latest analysis from SIREN, which measured antibody levels in the blood from nearly 6,000 health care workers from across the United Kingdom. Study lead Ashley Otter, PhD, technical lead for SIREN serology at the UK Health Security Agency (UKHSA), will present the work on Tuesday at the 2022 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), Lisbon.

In an interview, Dr. Otter noted that, “it is important to remember that antibody levels are only one aspect of the immune response, and in our recent vaccine effectiveness analysis, we found that dosing intervals did not affect protection against infection.”

The study, which appeared in the March issue of the New England Journal of Medicine, also found that after the second dose of vaccine, there was about a 2.5–fold difference in antibody levels between those who had prior infection of 16.052 (14.071-18.312) BAU/mL, compared with 7.050 (6.634-7.491) BAU/mL in infection-naive individuals (P < .0001).

Following the first dose only, antibody levels were up to 10 times higher in participants who were previously infected, compared with infection-naive individuals. This effect lasted up to 8 months and then began to plateau.
 

Natural infection increased antibody levels

Dr. Otter remarked that, “COVID-19 antibody levels are high in those people who were previously naturally infected and vaccinated, highlighting that vaccination provides an additional benefit to these individuals.”

This news organization asked Charlotte Thålin, PhD, an immunologist from the Karolinska Institute, Stockholm, to comment on the study. Dr. Thålin studies a cohort similar to SIREN, called the Swedish COMMUNITY health care worker cohort. “The new data from the SIREN emphasizes the importance of the number of antigenic exposures and the time interval between them, whether it be exposure through vaccination or exposure through infection.” 

“We see similar data in our Swedish COMMUNITY health care worker cohort,” Dr. Thålin continued, “where infection prior to vaccination yields a more than twofold enhancement in antibodies, neutralizing breadth, and T cell responses, and an even larger increase with a longer time interval between infection and vaccination.”

However, she cautioned that they now see a high rate of Omicron vaccine breakthrough infections, and this is also true in people with previous infection and three vaccine doses.

“As we approach a second booster – a fourth vaccine dose – we need to consider that many individuals will have had up to five to six antigen exposures within a short period of time, sometimes within a year,” she pointed out. “This is a whole new scenario, with a lot of different combinations of vaccine and infection-induced immunity. We do not yet know the impact of these frequent immune exposures, and we now need to monitor immune responses following Omicron and booster doses closely.”

SIREN originally aimed to understand how much protection people got after developing a primary infection and why they might become reinfected with COVID-19. Following the rollout of the United Kingdom’s vaccination program, the protective effects of vaccination against COVID-19 were investigated, as well as why some people still become ill after being vaccinated, Dr. Otter explained.

In this latest analysis, Dr. Otter and colleagues assessed anti-spike binding antibodies in serum samples from a total of 5,871 health care workers, with 3,989 after one dose (at least 21 days) and 1,882 after two doses (at least 14 days).

Most participants were women (82.3%), of White ethnicity (87%), and came from across the United Kingdom.

Participants were also categorized into those who had evidence of natural COVID-19 infection (confirmed by a PCR test or assumed because of their antibody profile) or those who were infection-naive. Almost all (> 99%) of those who were infection-naive seroconverted after vaccination.

The primary outcome was anti-spike antibody levels assessed according to dose, previous infection, dosing interval, age, ethnicity, and comorbidities, including immunosuppressive disease such as immune system cancers, rheumatologic disease, chronic respiratory diseases, diabetes, obesity, and chronic neurologic disease. 

In the infection-naive group, the mean antibody (anti-S titer) was 75.48 BAU/mL after the first vaccine dose, and this rose to 7,049.76 BAU/mL after the second dose.

The much higher antibody titer with the second dose in infection-naive individuals “is what gives you the most protection, as your antibody titers are at their peak. They then start to gradually wane from this peak,” said Dr. Otter.

In the post-infection group, antibody titers also rose (2,111.08 BAU/mL after first dose and 16,052.39 BAU/mL after second dose), although less so than in the infection-naive group, because of the additional exposure of infection, added Dr. Otter.

Antibody levels also varied according to time elapsed between natural infection and dose 1 of vaccination. With a 3-month interval, antibody levels were 1,970.83 (1,506.01-2,579.1) BAU/mL, compared with 13,759.31 (8,097.78-23,379.09) BAU/mL after a 9-month interval. Antibody levels after one dose in those previously infected are higher than the infection-naive because “previous infection, then vaccination, is likely explained by T-cell expansion upon a boost with a second antigen exposure, and then a maturing memory B-cell response that has been demonstrated up to 6 months,” explained Dr. Otter.

 

Timing of fourth dose

By March of this year, 86.2% of the U.K. population aged over 12 years had received at least two doses, but with rises in disease prevalence and the spread of variants of concern, further work is ongoing to understand the waning of the immune response, level of protection, and why some individuals develop COVID-19 even when double-vaccinated.

This news organization asked Susanna Dunachie, BMChB, professor of infectious diseases, University of Oxford, U.K., what the interval findings might mean for the timing of the fourth dose of vaccine across the U.K. population.

In the United Kingdom, fourth doses are being given to people who are 75 years and older, residents in care homes for older people, and those with weakened immune systems. “To make decisions about fourth doses for healthy people, we need to see how quickly antibody and T-cell responses drop,” said Ms. Dunachie, who is part of the large SIREN study team but was not involved in the analysis led by Dr. Otter. “Current research suggests that the T-cell response may be better maintained than the antibody response, and less affected by variants like Omicron.”

She explained the balance between antibody and T-cell responses to vaccination. “It is likely that antibodies that neutralize the virus are important for preventing any infection at all, and these unfortunately do fall in time, but T-cell responses are better sustained and help keep people out of [the] hospital,” she said.

Ms. Dunachie added that it was necessary to wait and observe what happens next with SARS-CoV-2 evolution, as well as wait for longer follow-up after the third dose in healthy people. “On current evidence, my estimate is we postpone decisions on fourth doses in healthy people to late summer/autumn.”

A version of this article first appeared on Medscape.com.

An overall ninefold increase in COVID-19 antibody levels can be seen with a longer interval between first and second doses of the Pfizer/BioNTech (BNT162b2) vaccine in people without prior infection, according to data from the U.K. government’s SIREN (SARS-CoV-2 Immunity and Reinfection Evaluation) study.

This interval-dependent antibody level varied by age, with those aged 45-54 years showing an 11-fold increase with a longer dosing interval (greater than 10 weeks vs. 2-4 weeks). People younger than age 25 years showed a 13-fold increase with the longer interval, but participant numbers were low in this sub-group.

Overall antibody levels in infection-naive participants were 1,268.72 Binding Antibody Units (BAU)/mL (1,043.25-1,542.91) in those with a 2-4–week interval, compared with 11,479.73 BAU/mL (10,742.78-12,267.24) (P < .0001), in those with at least a 10-week interval between doses.

The work is the latest analysis from SIREN, which measured antibody levels in the blood from nearly 6,000 health care workers from across the United Kingdom. Study lead Ashley Otter, PhD, technical lead for SIREN serology at the UK Health Security Agency (UKHSA), will present the work on Tuesday at the 2022 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), Lisbon.

In an interview, Dr. Otter noted that, “it is important to remember that antibody levels are only one aspect of the immune response, and in our recent vaccine effectiveness analysis, we found that dosing intervals did not affect protection against infection.”

The study, which appeared in the March issue of the New England Journal of Medicine, also found that after the second dose of vaccine, there was about a 2.5–fold difference in antibody levels between those who had prior infection of 16.052 (14.071-18.312) BAU/mL, compared with 7.050 (6.634-7.491) BAU/mL in infection-naive individuals (P < .0001).

Following the first dose only, antibody levels were up to 10 times higher in participants who were previously infected, compared with infection-naive individuals. This effect lasted up to 8 months and then began to plateau.
 

Natural infection increased antibody levels

Dr. Otter remarked that, “COVID-19 antibody levels are high in those people who were previously naturally infected and vaccinated, highlighting that vaccination provides an additional benefit to these individuals.”

This news organization asked Charlotte Thålin, PhD, an immunologist from the Karolinska Institute, Stockholm, to comment on the study. Dr. Thålin studies a cohort similar to SIREN, called the Swedish COMMUNITY health care worker cohort. “The new data from the SIREN emphasizes the importance of the number of antigenic exposures and the time interval between them, whether it be exposure through vaccination or exposure through infection.” 

“We see similar data in our Swedish COMMUNITY health care worker cohort,” Dr. Thålin continued, “where infection prior to vaccination yields a more than twofold enhancement in antibodies, neutralizing breadth, and T cell responses, and an even larger increase with a longer time interval between infection and vaccination.”

However, she cautioned that they now see a high rate of Omicron vaccine breakthrough infections, and this is also true in people with previous infection and three vaccine doses.

“As we approach a second booster – a fourth vaccine dose – we need to consider that many individuals will have had up to five to six antigen exposures within a short period of time, sometimes within a year,” she pointed out. “This is a whole new scenario, with a lot of different combinations of vaccine and infection-induced immunity. We do not yet know the impact of these frequent immune exposures, and we now need to monitor immune responses following Omicron and booster doses closely.”

SIREN originally aimed to understand how much protection people got after developing a primary infection and why they might become reinfected with COVID-19. Following the rollout of the United Kingdom’s vaccination program, the protective effects of vaccination against COVID-19 were investigated, as well as why some people still become ill after being vaccinated, Dr. Otter explained.

In this latest analysis, Dr. Otter and colleagues assessed anti-spike binding antibodies in serum samples from a total of 5,871 health care workers, with 3,989 after one dose (at least 21 days) and 1,882 after two doses (at least 14 days).

Most participants were women (82.3%), of White ethnicity (87%), and came from across the United Kingdom.

Participants were also categorized into those who had evidence of natural COVID-19 infection (confirmed by a PCR test or assumed because of their antibody profile) or those who were infection-naive. Almost all (> 99%) of those who were infection-naive seroconverted after vaccination.

The primary outcome was anti-spike antibody levels assessed according to dose, previous infection, dosing interval, age, ethnicity, and comorbidities, including immunosuppressive disease such as immune system cancers, rheumatologic disease, chronic respiratory diseases, diabetes, obesity, and chronic neurologic disease. 

In the infection-naive group, the mean antibody (anti-S titer) was 75.48 BAU/mL after the first vaccine dose, and this rose to 7,049.76 BAU/mL after the second dose.

The much higher antibody titer with the second dose in infection-naive individuals “is what gives you the most protection, as your antibody titers are at their peak. They then start to gradually wane from this peak,” said Dr. Otter.

In the post-infection group, antibody titers also rose (2,111.08 BAU/mL after first dose and 16,052.39 BAU/mL after second dose), although less so than in the infection-naive group, because of the additional exposure of infection, added Dr. Otter.

Antibody levels also varied according to time elapsed between natural infection and dose 1 of vaccination. With a 3-month interval, antibody levels were 1,970.83 (1,506.01-2,579.1) BAU/mL, compared with 13,759.31 (8,097.78-23,379.09) BAU/mL after a 9-month interval. Antibody levels after one dose in those previously infected are higher than the infection-naive because “previous infection, then vaccination, is likely explained by T-cell expansion upon a boost with a second antigen exposure, and then a maturing memory B-cell response that has been demonstrated up to 6 months,” explained Dr. Otter.

 

Timing of fourth dose

By March of this year, 86.2% of the U.K. population aged over 12 years had received at least two doses, but with rises in disease prevalence and the spread of variants of concern, further work is ongoing to understand the waning of the immune response, level of protection, and why some individuals develop COVID-19 even when double-vaccinated.

This news organization asked Susanna Dunachie, BMChB, professor of infectious diseases, University of Oxford, U.K., what the interval findings might mean for the timing of the fourth dose of vaccine across the U.K. population.

In the United Kingdom, fourth doses are being given to people who are 75 years and older, residents in care homes for older people, and those with weakened immune systems. “To make decisions about fourth doses for healthy people, we need to see how quickly antibody and T-cell responses drop,” said Ms. Dunachie, who is part of the large SIREN study team but was not involved in the analysis led by Dr. Otter. “Current research suggests that the T-cell response may be better maintained than the antibody response, and less affected by variants like Omicron.”

She explained the balance between antibody and T-cell responses to vaccination. “It is likely that antibodies that neutralize the virus are important for preventing any infection at all, and these unfortunately do fall in time, but T-cell responses are better sustained and help keep people out of [the] hospital,” she said.

Ms. Dunachie added that it was necessary to wait and observe what happens next with SARS-CoV-2 evolution, as well as wait for longer follow-up after the third dose in healthy people. “On current evidence, my estimate is we postpone decisions on fourth doses in healthy people to late summer/autumn.”

A version of this article first appeared on Medscape.com.