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Scientists use mRNA technology for universal flu vaccine
Two years ago, when the first COVID-19 vaccines were administered, marked a game-changing moment in the fight against the pandemic. But it also was a significant moment for messenger RNA (mRNA) technology, which up until then had shown promise but had never quite broken through.
It’s the latest advance in a new age of vaccinology, where vaccines are easier and faster to produce, as well as more flexible and customizable.
“It’s all about covering the different flavors of flu in a way the current vaccines cannot do,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program at Boston Children’s Hospital, who is not involved with the UPenn research. “The mRNA platform is attractive here given its scalability and modularity, where you can mix and match different mRNAs.”
A recent paper, published in Science, reports successful animal tests of the experimental vaccine, which, like the Pfizer-BioNTech and Moderna COVID vaccines, relies on mRNA. But the idea is not to replace the annual flu shot. It’s to develop a primer that could be administered in childhood, readying the body’s B cells and T cells to react quickly if faced with a flu virus.
It’s all part of a National Institutes of Health–funded effort to develop a universal flu vaccine, with hopes of heading off future flu pandemics. Annual shots protect against flu subtypes known to spread in humans. But many subtypes circulate in animals, like birds and pigs, and occasionally jump to humans, causing pandemics.
“The current vaccines provide very little protection against these other subtypes,” says lead study author Scott Hensley, PhD, a professor of microbiology at UPenn. “We set out to make a vaccine that would provide some level of immunity against essentially every influenza subtype we know about.”
That’s 20 subtypes altogether. The unique properties of mRNA vaccines make immune responses against all those antigens possible, Dr. Hensley says.
Old-school vaccines introduce a weakened or dead bacteria or virus into the body, but mRNA vaccines use mRNA encoded with a protein from the virus. That’s the “spike” protein for COVID, and for the experimental vaccine, it’s hemagglutinin, the major protein found on the surface of all flu viruses.
Mice and ferrets that had never been exposed to the flu were given the vaccine and produced high levels of antibodies against all 20 flu subtypes. Vaccinated mice exposed to the exact strains in the vaccine stayed pretty healthy, while those exposed to strains not found in the vaccine got sick but recovered quickly and survived. Unvaccinated mice exposed to the flu strain died.
The vaccine seems to be able to “induce broad immunity against all the different influenza subtypes,” Dr. Hensley says, preventing severe illness if not infection overall.
Still, whether it could truly stave off a pandemic that hasn’t happened yet is hard to say, Dr. Levy cautions.
“We are going to need to better learn the molecular rules by which these vaccines protect,” he says.
But the UPenn team is forging ahead, with plans to test their vaccine in human adults in 2023 to determine safety, dosing, and antibody response.
A version of this article first appeared on WebMD.com.
Two years ago, when the first COVID-19 vaccines were administered, marked a game-changing moment in the fight against the pandemic. But it also was a significant moment for messenger RNA (mRNA) technology, which up until then had shown promise but had never quite broken through.
It’s the latest advance in a new age of vaccinology, where vaccines are easier and faster to produce, as well as more flexible and customizable.
“It’s all about covering the different flavors of flu in a way the current vaccines cannot do,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program at Boston Children’s Hospital, who is not involved with the UPenn research. “The mRNA platform is attractive here given its scalability and modularity, where you can mix and match different mRNAs.”
A recent paper, published in Science, reports successful animal tests of the experimental vaccine, which, like the Pfizer-BioNTech and Moderna COVID vaccines, relies on mRNA. But the idea is not to replace the annual flu shot. It’s to develop a primer that could be administered in childhood, readying the body’s B cells and T cells to react quickly if faced with a flu virus.
It’s all part of a National Institutes of Health–funded effort to develop a universal flu vaccine, with hopes of heading off future flu pandemics. Annual shots protect against flu subtypes known to spread in humans. But many subtypes circulate in animals, like birds and pigs, and occasionally jump to humans, causing pandemics.
“The current vaccines provide very little protection against these other subtypes,” says lead study author Scott Hensley, PhD, a professor of microbiology at UPenn. “We set out to make a vaccine that would provide some level of immunity against essentially every influenza subtype we know about.”
That’s 20 subtypes altogether. The unique properties of mRNA vaccines make immune responses against all those antigens possible, Dr. Hensley says.
Old-school vaccines introduce a weakened or dead bacteria or virus into the body, but mRNA vaccines use mRNA encoded with a protein from the virus. That’s the “spike” protein for COVID, and for the experimental vaccine, it’s hemagglutinin, the major protein found on the surface of all flu viruses.
Mice and ferrets that had never been exposed to the flu were given the vaccine and produced high levels of antibodies against all 20 flu subtypes. Vaccinated mice exposed to the exact strains in the vaccine stayed pretty healthy, while those exposed to strains not found in the vaccine got sick but recovered quickly and survived. Unvaccinated mice exposed to the flu strain died.
The vaccine seems to be able to “induce broad immunity against all the different influenza subtypes,” Dr. Hensley says, preventing severe illness if not infection overall.
Still, whether it could truly stave off a pandemic that hasn’t happened yet is hard to say, Dr. Levy cautions.
“We are going to need to better learn the molecular rules by which these vaccines protect,” he says.
But the UPenn team is forging ahead, with plans to test their vaccine in human adults in 2023 to determine safety, dosing, and antibody response.
A version of this article first appeared on WebMD.com.
Two years ago, when the first COVID-19 vaccines were administered, marked a game-changing moment in the fight against the pandemic. But it also was a significant moment for messenger RNA (mRNA) technology, which up until then had shown promise but had never quite broken through.
It’s the latest advance in a new age of vaccinology, where vaccines are easier and faster to produce, as well as more flexible and customizable.
“It’s all about covering the different flavors of flu in a way the current vaccines cannot do,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program at Boston Children’s Hospital, who is not involved with the UPenn research. “The mRNA platform is attractive here given its scalability and modularity, where you can mix and match different mRNAs.”
A recent paper, published in Science, reports successful animal tests of the experimental vaccine, which, like the Pfizer-BioNTech and Moderna COVID vaccines, relies on mRNA. But the idea is not to replace the annual flu shot. It’s to develop a primer that could be administered in childhood, readying the body’s B cells and T cells to react quickly if faced with a flu virus.
It’s all part of a National Institutes of Health–funded effort to develop a universal flu vaccine, with hopes of heading off future flu pandemics. Annual shots protect against flu subtypes known to spread in humans. But many subtypes circulate in animals, like birds and pigs, and occasionally jump to humans, causing pandemics.
“The current vaccines provide very little protection against these other subtypes,” says lead study author Scott Hensley, PhD, a professor of microbiology at UPenn. “We set out to make a vaccine that would provide some level of immunity against essentially every influenza subtype we know about.”
That’s 20 subtypes altogether. The unique properties of mRNA vaccines make immune responses against all those antigens possible, Dr. Hensley says.
Old-school vaccines introduce a weakened or dead bacteria or virus into the body, but mRNA vaccines use mRNA encoded with a protein from the virus. That’s the “spike” protein for COVID, and for the experimental vaccine, it’s hemagglutinin, the major protein found on the surface of all flu viruses.
Mice and ferrets that had never been exposed to the flu were given the vaccine and produced high levels of antibodies against all 20 flu subtypes. Vaccinated mice exposed to the exact strains in the vaccine stayed pretty healthy, while those exposed to strains not found in the vaccine got sick but recovered quickly and survived. Unvaccinated mice exposed to the flu strain died.
The vaccine seems to be able to “induce broad immunity against all the different influenza subtypes,” Dr. Hensley says, preventing severe illness if not infection overall.
Still, whether it could truly stave off a pandemic that hasn’t happened yet is hard to say, Dr. Levy cautions.
“We are going to need to better learn the molecular rules by which these vaccines protect,” he says.
But the UPenn team is forging ahead, with plans to test their vaccine in human adults in 2023 to determine safety, dosing, and antibody response.
A version of this article first appeared on WebMD.com.
FROM SCIENCE
COVID booster shot poll: People ‘don’t think they need one’
Now, a new poll shows why so few people are willing to roll up their sleeves again.
The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation.
The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.
Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling.
So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.
Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.
Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.
“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.
Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.
Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.
“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”
A version of this article first appeared on WebMD.com.
Now, a new poll shows why so few people are willing to roll up their sleeves again.
The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation.
The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.
Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling.
So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.
Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.
Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.
“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.
Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.
Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.
“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”
A version of this article first appeared on WebMD.com.
Now, a new poll shows why so few people are willing to roll up their sleeves again.
The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation.
The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.
Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling.
So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.
Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.
Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.
“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.
Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.
Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.
“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”
A version of this article first appeared on WebMD.com.
40-year-old woman • fever • rash • arthralgia • Dx?
THE CASE
A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8
The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.
At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 103/µL (normal range, 4.0-10.0 × 103/µL) with an absolute neutrophil count of 9.7 × 103/µL (normal, 1.7-7.0 × 103/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.
THE DIAGNOSIS
The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).1 She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.
A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.
DISCUSSION
Sweet syndrome is considered rare, and incidence numbers are elusive.2 It has a worldwide distribution and no racial bias.3 Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.
Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–stimulating factor treatment.4 Our patient had the most common subtype: classical Sweet syndrome.
Continue to: What you'll see
What you’ll see.
Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.5 If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.5 Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.
There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.5 Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.5
The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.
THE TAKEAWAY
On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]
1. Gewitz MH, Baltimore SR, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806-1818. doi: 10.1161/CIR.0000000000000205
2. Joshi TP, Friske SK, Hsiou DA, Duvic M. New practical aspects of Sweet syndrome. Am J Clin Dermatol. 2022;23:301-318. doi: 10.1007/s40257-022-00673-4
3. Cohen PR, Kurzrock R. Sweets syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42:761-778. doi: 10.1046/j.1365-4362.2003.01891.x
4. Merola JF. Sweet syndrome (acute febrile neutrophilic dermatosis): pathogenesis, clinical manifestations, and diagnosis. UpToDate. August 9, 2020. Accessed October 27, 2022. www.uptodate.com/contents/sweet-syndrome-acute-febrile-neutrophilic-dermatosis-pathogenesis-clinical-manifestations-and-diagnosis
5. Cohen PR. Sweets syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. doi: 10.1186/1750-1172-2-34
THE CASE
A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8
The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.
At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 103/µL (normal range, 4.0-10.0 × 103/µL) with an absolute neutrophil count of 9.7 × 103/µL (normal, 1.7-7.0 × 103/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.
THE DIAGNOSIS
The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).1 She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.
A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.
DISCUSSION
Sweet syndrome is considered rare, and incidence numbers are elusive.2 It has a worldwide distribution and no racial bias.3 Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.
Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–stimulating factor treatment.4 Our patient had the most common subtype: classical Sweet syndrome.
Continue to: What you'll see
What you’ll see.
Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.5 If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.5 Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.
There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.5 Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.5
The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.
THE TAKEAWAY
On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]
THE CASE
A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8
The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.
At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 103/µL (normal range, 4.0-10.0 × 103/µL) with an absolute neutrophil count of 9.7 × 103/µL (normal, 1.7-7.0 × 103/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.
THE DIAGNOSIS
The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).1 She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.
A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.
DISCUSSION
Sweet syndrome is considered rare, and incidence numbers are elusive.2 It has a worldwide distribution and no racial bias.3 Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.
Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–stimulating factor treatment.4 Our patient had the most common subtype: classical Sweet syndrome.
Continue to: What you'll see
What you’ll see.
Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.5 If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.5 Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.
There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.5 Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.5
The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.
THE TAKEAWAY
On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]
1. Gewitz MH, Baltimore SR, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806-1818. doi: 10.1161/CIR.0000000000000205
2. Joshi TP, Friske SK, Hsiou DA, Duvic M. New practical aspects of Sweet syndrome. Am J Clin Dermatol. 2022;23:301-318. doi: 10.1007/s40257-022-00673-4
3. Cohen PR, Kurzrock R. Sweets syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42:761-778. doi: 10.1046/j.1365-4362.2003.01891.x
4. Merola JF. Sweet syndrome (acute febrile neutrophilic dermatosis): pathogenesis, clinical manifestations, and diagnosis. UpToDate. August 9, 2020. Accessed October 27, 2022. www.uptodate.com/contents/sweet-syndrome-acute-febrile-neutrophilic-dermatosis-pathogenesis-clinical-manifestations-and-diagnosis
5. Cohen PR. Sweets syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. doi: 10.1186/1750-1172-2-34
1. Gewitz MH, Baltimore SR, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806-1818. doi: 10.1161/CIR.0000000000000205
2. Joshi TP, Friske SK, Hsiou DA, Duvic M. New practical aspects of Sweet syndrome. Am J Clin Dermatol. 2022;23:301-318. doi: 10.1007/s40257-022-00673-4
3. Cohen PR, Kurzrock R. Sweets syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42:761-778. doi: 10.1046/j.1365-4362.2003.01891.x
4. Merola JF. Sweet syndrome (acute febrile neutrophilic dermatosis): pathogenesis, clinical manifestations, and diagnosis. UpToDate. August 9, 2020. Accessed October 27, 2022. www.uptodate.com/contents/sweet-syndrome-acute-febrile-neutrophilic-dermatosis-pathogenesis-clinical-manifestations-and-diagnosis
5. Cohen PR. Sweets syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. doi: 10.1186/1750-1172-2-34
What length antibiotic course for prostatitis?
PARIS – To date, studies of antibiotic course length for treating urinary tract infections in men have been patchy and retrospective.
Through recent randomized trials, guidelines can now be based on more solid data.
In sum, to maximize clinical and microbiologic success, a nonfebrile urinary tract infection is treated for 7 days, and a febrile urinary tract infection is treated for a minimum of 14 days.
At the 116th conference of the French urology association, Matthieu Lafaurie, MD, of the Multidisciplinary Infectious Diseases Unit U21, Saint Louis Hospital, Paris, reviewed the literature on this subject.
Guidelines for men
The European Association of Urology made its position clear in a text updated in 2022. It stated: Therefore, treatment with antimicrobial drugs that penetrate the prostate tissue is needed in men presenting with symptoms of a urinary tract infection.” In its classification of prostatitis, the National Institutes of Health distinguishes between acute prostatitis (symptoms of a urinary tract infection; stage I) and chronic prostatitis (recurrent infection with the same microorganism; stage II).
Although the French-language Society of Infectious Diseases distinguishes between febrile and nonfebrile urinary tract infections in males, the academic body does not take into account whether the patient has a fever when determining which antibiotic should be given and how long the course should be: A minimum of 14 days’ treatment is recommended when opting for fluoroquinolones, trimethoprim-sulfamethoxazole (cotrimoxazole), or injectable beta-lactam antibiotics, and at least 21 days is recommended for other drugs or in cases in which there is an underlying urologic condition that has not been treated.
Yet the EAU recommends treating cystitis with antibiotics for at least 7 days, preferably with cotrimoxazole or fluoroquinolone, depending on the results of sensitivity testing. For acute prostatitis, the length of treatment with fluoroquinolones should be at least 14 days.
Nonfebrile infections
Participation of men in studies of the treatment of complicated cystitis is variable; at most only 10% of patients in such trials are men. There are few data specific to men with nonfebrile urinary tract infections, and most studies are retrospective and involve small cohorts. One of these is a community-based study that involved 422 men aged 18-104 years who presented with nonfebrile urinary tract infection (acute dysuria, frequency of urination and/or urgency of urination, temperature < 38° C, no general symptoms). Antibiotic treatment was prescribed in 60% of cases. In more than 55% of cases, the length of the course of treatment was 1–7 days. Treatment was with cotrimoxazole, quinolones, and nitrofurantoin.
Another observational retrospective study showed benefit with nitrofurantoin (50 mg/8 h in 94% of cases; 69 patients) and pivmecillinam (200 mg/8 h in 65% of cases; 200 mg/12 h in 30% of patients; 57 patients) in treating lower urinary tract infections in men. The median treatment duration was 7 days. The failure rate was 1.4% and 12%, respectively, for these treatments. Compared to the so-called gold-standard treatment, trimethoprim (10 days/800 mg/12 h; 45 patients), the recurrence rate was 11% and 26% for nitrofurantoin and pivmecillinam versus 7% for trimethoprim. The most significant relapse rate with pivmecillinam was when treatment was given for fewer than 7 days.
This is the only risk factor for further antibiotic treatment and/or recurrence. There was no significant difference between the three drugs with regard to other parameters (urinary tract infection symptoms, benign prostatic hypertrophy, prostate cancer, gram-positive bacteria, etc).
Another retrospective, European study of nitrofurantoin that was published in 2015 included 485 patients (100 mg twice daily in 71% of cases). Clinical cure was defined as an absence of signs or symptoms of a urinary tract infection for 14 days after stopping nitrofurantoin, without use of other antibiotics. The cure rate was 77%. Better efficacy was achieved for patients with gram-negative (vs. gram-positive) bacteria. The treatment duration did not differ significantly (clinical success was achieved when the treatment was taken for 8.6 ± 3.6 days; clinical failure occurred when the treatment was taken for 9.3 ± 6.9 days; P = .28).
Regarding pivmecillinam, a retrospective 2010-2016 study involved 21,864 adults and included 2,524 men who had been treated empirically with pivmecillinam (400 mg three times daily) for significant bacteriuria (Escherichia coli) and a lower urinary tract infection. The researchers concluded that for men, the success rate was identical whether the treatment lasted 5 or 7 days.
An American community-based (urologists, primary care physicians, general medicine services) retrospective cohort study involving 573 men with nonfebrile lower urinary tract infections was conducted from 2011 to 2015. The patients received antibiotic treatment with fluoroquinolones (69.7%), cotrimoxazole (21.2%), nitrofurantoin (5.3%), trimethoprim, beta-lactam antibiotics, or aminoglycosides. No clinical advantage was seen in treating men with urinary tract infections for longer than 7 days.
There are some data on the use of fosfomycin. In an observational retrospective study, 25 men of 52 male adults with leukocyturia and E. coli greater than 105, ESBL, were treated with fosfomycin trometamol 3 g on days 1, 3, 5. Clinical and microbiologic success was achieved for 94% and 78.5%, respectively. No distinction was made between the sexes.
These results were confirmed in a retrospective, observational study involving 18 men (of a total of 75 adults) with no fever or hyperleukocytosis who received the same fosfomycin trometamol regimen. The rate of clinical cure or sterile urine microscopy and culture was 69% at 13 days. The risk failure factor was, as expected, infection with Klebsiella pneumoniae, which was slightly susceptible to fosfomycin, unlike E. coli.
The most recent study in this field was published in 2021. It was also the first randomized, double-blind, placebo-controlled study. In all, 272 men older than 18 years were prescribed either ciprofloxacin or cotrimoxazole for 7-14 days to treat a nonfebrile urinary tract infection. To be eligible for the trial, patients were required to have disease of new onset with at least one of the following symptoms: dysuria, frequency of urination, urgency of urination, hematuria, costovertebral angle tenderness, or perineal, flank, or suprapubic pain. Urine microscopy and culture were not necessary; the approach was wholly symptomatic. Treatment was prescribed for 7 days. Patients were randomly allocated on day 8 to receive treatment for the following 7 days (molecule or placebo). The primary outcome was resolution of clinical symptoms of urinary tract infection by 14 days after completion of active antibiotic treatment. In an intention-to-treat or per-protocol analysis, the difference in efficacy between the two molecules was largely below the required 10%. The treatment duration noninferiority margin was 7 days, compared with 14 days.
“In 2022, with regard to the duration of treatment of nonfebrile urinary tract infections in men, the not completely irrefutable evidence does, however, stack up in favor of the possibility of a 7-day or even 5-day course,” pointed out Dr. Lafaurie. “Fluoroquinolones [such as] ofloxacin, levofloxacin, ciprofloxacin, as well as cotrimoxazole and other antibiotics, such as pivmecillinam, nitrofurantoin, or fosfomycin trometamol, can be used, despite the fact that they pass less easily into the prostate – a not-so-obvious benefit.”
Febrile infections
In terms of febrile urinary tract infections, a single-center, prospective, open-label study from 2003 involved 72 male inpatients who were randomly to receive treatment either for 2 weeks or 4 weeks. Treatment consisted of ciprofloxacin 500 mg twice daily. This study provided most of the evidence to justify the recommended 14-day antibiotic course.
Another noninferiority, randomized, placebo-controlled study published in 2017 compared 7- and 14-day treatment with ciprofloxacin 500 mg to placebo twice per week. In men, 7 days of antibiotic therapy was inferior to 14 days during a short-term follow-up but was not inferior during a longer follow-up.
A decisive study, which is currently in the submission phase, could silence debate. “In our noninferiority, multicenter, randomized, double-blind, placebo-controlled study, we have enrolled 240 men over the age of 18 years with a febrile infection documented by a fever of 38° C or more, clinical signs of infection, and leukocyturia at least above 10/mm3 and with symptoms lasting less than 3 months,” said Dr. Lafaurie, the trial coordinator.
The primary outcome for efficacy was microbiologic and clinical success after 6 weeks. Patients received either ofloxacin, ceftriaxone, or cefotaxime (two third-generation cephalosporins in the beta-lactam family).
“We clearly show that, for a 7-day course, the clinical success rate is 55.7%, and for a 14-day course, this goes up to 77.6%, with no difference in terms of adverse effects or selection of resistant bacteria. The predictive factors for success are a 14-day treatment and being under the age of 50 years,” said Dr. Lafaurie.
“Unlike nonfebrile urinary tract infections in men, a 7-day course is insufficient for patients with febrile urinary tract infections, and a minimum of 14 days is required to achieve clinical and microbiological success,” he concluded.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
PARIS – To date, studies of antibiotic course length for treating urinary tract infections in men have been patchy and retrospective.
Through recent randomized trials, guidelines can now be based on more solid data.
In sum, to maximize clinical and microbiologic success, a nonfebrile urinary tract infection is treated for 7 days, and a febrile urinary tract infection is treated for a minimum of 14 days.
At the 116th conference of the French urology association, Matthieu Lafaurie, MD, of the Multidisciplinary Infectious Diseases Unit U21, Saint Louis Hospital, Paris, reviewed the literature on this subject.
Guidelines for men
The European Association of Urology made its position clear in a text updated in 2022. It stated: Therefore, treatment with antimicrobial drugs that penetrate the prostate tissue is needed in men presenting with symptoms of a urinary tract infection.” In its classification of prostatitis, the National Institutes of Health distinguishes between acute prostatitis (symptoms of a urinary tract infection; stage I) and chronic prostatitis (recurrent infection with the same microorganism; stage II).
Although the French-language Society of Infectious Diseases distinguishes between febrile and nonfebrile urinary tract infections in males, the academic body does not take into account whether the patient has a fever when determining which antibiotic should be given and how long the course should be: A minimum of 14 days’ treatment is recommended when opting for fluoroquinolones, trimethoprim-sulfamethoxazole (cotrimoxazole), or injectable beta-lactam antibiotics, and at least 21 days is recommended for other drugs or in cases in which there is an underlying urologic condition that has not been treated.
Yet the EAU recommends treating cystitis with antibiotics for at least 7 days, preferably with cotrimoxazole or fluoroquinolone, depending on the results of sensitivity testing. For acute prostatitis, the length of treatment with fluoroquinolones should be at least 14 days.
Nonfebrile infections
Participation of men in studies of the treatment of complicated cystitis is variable; at most only 10% of patients in such trials are men. There are few data specific to men with nonfebrile urinary tract infections, and most studies are retrospective and involve small cohorts. One of these is a community-based study that involved 422 men aged 18-104 years who presented with nonfebrile urinary tract infection (acute dysuria, frequency of urination and/or urgency of urination, temperature < 38° C, no general symptoms). Antibiotic treatment was prescribed in 60% of cases. In more than 55% of cases, the length of the course of treatment was 1–7 days. Treatment was with cotrimoxazole, quinolones, and nitrofurantoin.
Another observational retrospective study showed benefit with nitrofurantoin (50 mg/8 h in 94% of cases; 69 patients) and pivmecillinam (200 mg/8 h in 65% of cases; 200 mg/12 h in 30% of patients; 57 patients) in treating lower urinary tract infections in men. The median treatment duration was 7 days. The failure rate was 1.4% and 12%, respectively, for these treatments. Compared to the so-called gold-standard treatment, trimethoprim (10 days/800 mg/12 h; 45 patients), the recurrence rate was 11% and 26% for nitrofurantoin and pivmecillinam versus 7% for trimethoprim. The most significant relapse rate with pivmecillinam was when treatment was given for fewer than 7 days.
This is the only risk factor for further antibiotic treatment and/or recurrence. There was no significant difference between the three drugs with regard to other parameters (urinary tract infection symptoms, benign prostatic hypertrophy, prostate cancer, gram-positive bacteria, etc).
Another retrospective, European study of nitrofurantoin that was published in 2015 included 485 patients (100 mg twice daily in 71% of cases). Clinical cure was defined as an absence of signs or symptoms of a urinary tract infection for 14 days after stopping nitrofurantoin, without use of other antibiotics. The cure rate was 77%. Better efficacy was achieved for patients with gram-negative (vs. gram-positive) bacteria. The treatment duration did not differ significantly (clinical success was achieved when the treatment was taken for 8.6 ± 3.6 days; clinical failure occurred when the treatment was taken for 9.3 ± 6.9 days; P = .28).
Regarding pivmecillinam, a retrospective 2010-2016 study involved 21,864 adults and included 2,524 men who had been treated empirically with pivmecillinam (400 mg three times daily) for significant bacteriuria (Escherichia coli) and a lower urinary tract infection. The researchers concluded that for men, the success rate was identical whether the treatment lasted 5 or 7 days.
An American community-based (urologists, primary care physicians, general medicine services) retrospective cohort study involving 573 men with nonfebrile lower urinary tract infections was conducted from 2011 to 2015. The patients received antibiotic treatment with fluoroquinolones (69.7%), cotrimoxazole (21.2%), nitrofurantoin (5.3%), trimethoprim, beta-lactam antibiotics, or aminoglycosides. No clinical advantage was seen in treating men with urinary tract infections for longer than 7 days.
There are some data on the use of fosfomycin. In an observational retrospective study, 25 men of 52 male adults with leukocyturia and E. coli greater than 105, ESBL, were treated with fosfomycin trometamol 3 g on days 1, 3, 5. Clinical and microbiologic success was achieved for 94% and 78.5%, respectively. No distinction was made between the sexes.
These results were confirmed in a retrospective, observational study involving 18 men (of a total of 75 adults) with no fever or hyperleukocytosis who received the same fosfomycin trometamol regimen. The rate of clinical cure or sterile urine microscopy and culture was 69% at 13 days. The risk failure factor was, as expected, infection with Klebsiella pneumoniae, which was slightly susceptible to fosfomycin, unlike E. coli.
The most recent study in this field was published in 2021. It was also the first randomized, double-blind, placebo-controlled study. In all, 272 men older than 18 years were prescribed either ciprofloxacin or cotrimoxazole for 7-14 days to treat a nonfebrile urinary tract infection. To be eligible for the trial, patients were required to have disease of new onset with at least one of the following symptoms: dysuria, frequency of urination, urgency of urination, hematuria, costovertebral angle tenderness, or perineal, flank, or suprapubic pain. Urine microscopy and culture were not necessary; the approach was wholly symptomatic. Treatment was prescribed for 7 days. Patients were randomly allocated on day 8 to receive treatment for the following 7 days (molecule or placebo). The primary outcome was resolution of clinical symptoms of urinary tract infection by 14 days after completion of active antibiotic treatment. In an intention-to-treat or per-protocol analysis, the difference in efficacy between the two molecules was largely below the required 10%. The treatment duration noninferiority margin was 7 days, compared with 14 days.
“In 2022, with regard to the duration of treatment of nonfebrile urinary tract infections in men, the not completely irrefutable evidence does, however, stack up in favor of the possibility of a 7-day or even 5-day course,” pointed out Dr. Lafaurie. “Fluoroquinolones [such as] ofloxacin, levofloxacin, ciprofloxacin, as well as cotrimoxazole and other antibiotics, such as pivmecillinam, nitrofurantoin, or fosfomycin trometamol, can be used, despite the fact that they pass less easily into the prostate – a not-so-obvious benefit.”
Febrile infections
In terms of febrile urinary tract infections, a single-center, prospective, open-label study from 2003 involved 72 male inpatients who were randomly to receive treatment either for 2 weeks or 4 weeks. Treatment consisted of ciprofloxacin 500 mg twice daily. This study provided most of the evidence to justify the recommended 14-day antibiotic course.
Another noninferiority, randomized, placebo-controlled study published in 2017 compared 7- and 14-day treatment with ciprofloxacin 500 mg to placebo twice per week. In men, 7 days of antibiotic therapy was inferior to 14 days during a short-term follow-up but was not inferior during a longer follow-up.
A decisive study, which is currently in the submission phase, could silence debate. “In our noninferiority, multicenter, randomized, double-blind, placebo-controlled study, we have enrolled 240 men over the age of 18 years with a febrile infection documented by a fever of 38° C or more, clinical signs of infection, and leukocyturia at least above 10/mm3 and with symptoms lasting less than 3 months,” said Dr. Lafaurie, the trial coordinator.
The primary outcome for efficacy was microbiologic and clinical success after 6 weeks. Patients received either ofloxacin, ceftriaxone, or cefotaxime (two third-generation cephalosporins in the beta-lactam family).
“We clearly show that, for a 7-day course, the clinical success rate is 55.7%, and for a 14-day course, this goes up to 77.6%, with no difference in terms of adverse effects or selection of resistant bacteria. The predictive factors for success are a 14-day treatment and being under the age of 50 years,” said Dr. Lafaurie.
“Unlike nonfebrile urinary tract infections in men, a 7-day course is insufficient for patients with febrile urinary tract infections, and a minimum of 14 days is required to achieve clinical and microbiological success,” he concluded.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
PARIS – To date, studies of antibiotic course length for treating urinary tract infections in men have been patchy and retrospective.
Through recent randomized trials, guidelines can now be based on more solid data.
In sum, to maximize clinical and microbiologic success, a nonfebrile urinary tract infection is treated for 7 days, and a febrile urinary tract infection is treated for a minimum of 14 days.
At the 116th conference of the French urology association, Matthieu Lafaurie, MD, of the Multidisciplinary Infectious Diseases Unit U21, Saint Louis Hospital, Paris, reviewed the literature on this subject.
Guidelines for men
The European Association of Urology made its position clear in a text updated in 2022. It stated: Therefore, treatment with antimicrobial drugs that penetrate the prostate tissue is needed in men presenting with symptoms of a urinary tract infection.” In its classification of prostatitis, the National Institutes of Health distinguishes between acute prostatitis (symptoms of a urinary tract infection; stage I) and chronic prostatitis (recurrent infection with the same microorganism; stage II).
Although the French-language Society of Infectious Diseases distinguishes between febrile and nonfebrile urinary tract infections in males, the academic body does not take into account whether the patient has a fever when determining which antibiotic should be given and how long the course should be: A minimum of 14 days’ treatment is recommended when opting for fluoroquinolones, trimethoprim-sulfamethoxazole (cotrimoxazole), or injectable beta-lactam antibiotics, and at least 21 days is recommended for other drugs or in cases in which there is an underlying urologic condition that has not been treated.
Yet the EAU recommends treating cystitis with antibiotics for at least 7 days, preferably with cotrimoxazole or fluoroquinolone, depending on the results of sensitivity testing. For acute prostatitis, the length of treatment with fluoroquinolones should be at least 14 days.
Nonfebrile infections
Participation of men in studies of the treatment of complicated cystitis is variable; at most only 10% of patients in such trials are men. There are few data specific to men with nonfebrile urinary tract infections, and most studies are retrospective and involve small cohorts. One of these is a community-based study that involved 422 men aged 18-104 years who presented with nonfebrile urinary tract infection (acute dysuria, frequency of urination and/or urgency of urination, temperature < 38° C, no general symptoms). Antibiotic treatment was prescribed in 60% of cases. In more than 55% of cases, the length of the course of treatment was 1–7 days. Treatment was with cotrimoxazole, quinolones, and nitrofurantoin.
Another observational retrospective study showed benefit with nitrofurantoin (50 mg/8 h in 94% of cases; 69 patients) and pivmecillinam (200 mg/8 h in 65% of cases; 200 mg/12 h in 30% of patients; 57 patients) in treating lower urinary tract infections in men. The median treatment duration was 7 days. The failure rate was 1.4% and 12%, respectively, for these treatments. Compared to the so-called gold-standard treatment, trimethoprim (10 days/800 mg/12 h; 45 patients), the recurrence rate was 11% and 26% for nitrofurantoin and pivmecillinam versus 7% for trimethoprim. The most significant relapse rate with pivmecillinam was when treatment was given for fewer than 7 days.
This is the only risk factor for further antibiotic treatment and/or recurrence. There was no significant difference between the three drugs with regard to other parameters (urinary tract infection symptoms, benign prostatic hypertrophy, prostate cancer, gram-positive bacteria, etc).
Another retrospective, European study of nitrofurantoin that was published in 2015 included 485 patients (100 mg twice daily in 71% of cases). Clinical cure was defined as an absence of signs or symptoms of a urinary tract infection for 14 days after stopping nitrofurantoin, without use of other antibiotics. The cure rate was 77%. Better efficacy was achieved for patients with gram-negative (vs. gram-positive) bacteria. The treatment duration did not differ significantly (clinical success was achieved when the treatment was taken for 8.6 ± 3.6 days; clinical failure occurred when the treatment was taken for 9.3 ± 6.9 days; P = .28).
Regarding pivmecillinam, a retrospective 2010-2016 study involved 21,864 adults and included 2,524 men who had been treated empirically with pivmecillinam (400 mg three times daily) for significant bacteriuria (Escherichia coli) and a lower urinary tract infection. The researchers concluded that for men, the success rate was identical whether the treatment lasted 5 or 7 days.
An American community-based (urologists, primary care physicians, general medicine services) retrospective cohort study involving 573 men with nonfebrile lower urinary tract infections was conducted from 2011 to 2015. The patients received antibiotic treatment with fluoroquinolones (69.7%), cotrimoxazole (21.2%), nitrofurantoin (5.3%), trimethoprim, beta-lactam antibiotics, or aminoglycosides. No clinical advantage was seen in treating men with urinary tract infections for longer than 7 days.
There are some data on the use of fosfomycin. In an observational retrospective study, 25 men of 52 male adults with leukocyturia and E. coli greater than 105, ESBL, were treated with fosfomycin trometamol 3 g on days 1, 3, 5. Clinical and microbiologic success was achieved for 94% and 78.5%, respectively. No distinction was made between the sexes.
These results were confirmed in a retrospective, observational study involving 18 men (of a total of 75 adults) with no fever or hyperleukocytosis who received the same fosfomycin trometamol regimen. The rate of clinical cure or sterile urine microscopy and culture was 69% at 13 days. The risk failure factor was, as expected, infection with Klebsiella pneumoniae, which was slightly susceptible to fosfomycin, unlike E. coli.
The most recent study in this field was published in 2021. It was also the first randomized, double-blind, placebo-controlled study. In all, 272 men older than 18 years were prescribed either ciprofloxacin or cotrimoxazole for 7-14 days to treat a nonfebrile urinary tract infection. To be eligible for the trial, patients were required to have disease of new onset with at least one of the following symptoms: dysuria, frequency of urination, urgency of urination, hematuria, costovertebral angle tenderness, or perineal, flank, or suprapubic pain. Urine microscopy and culture were not necessary; the approach was wholly symptomatic. Treatment was prescribed for 7 days. Patients were randomly allocated on day 8 to receive treatment for the following 7 days (molecule or placebo). The primary outcome was resolution of clinical symptoms of urinary tract infection by 14 days after completion of active antibiotic treatment. In an intention-to-treat or per-protocol analysis, the difference in efficacy between the two molecules was largely below the required 10%. The treatment duration noninferiority margin was 7 days, compared with 14 days.
“In 2022, with regard to the duration of treatment of nonfebrile urinary tract infections in men, the not completely irrefutable evidence does, however, stack up in favor of the possibility of a 7-day or even 5-day course,” pointed out Dr. Lafaurie. “Fluoroquinolones [such as] ofloxacin, levofloxacin, ciprofloxacin, as well as cotrimoxazole and other antibiotics, such as pivmecillinam, nitrofurantoin, or fosfomycin trometamol, can be used, despite the fact that they pass less easily into the prostate – a not-so-obvious benefit.”
Febrile infections
In terms of febrile urinary tract infections, a single-center, prospective, open-label study from 2003 involved 72 male inpatients who were randomly to receive treatment either for 2 weeks or 4 weeks. Treatment consisted of ciprofloxacin 500 mg twice daily. This study provided most of the evidence to justify the recommended 14-day antibiotic course.
Another noninferiority, randomized, placebo-controlled study published in 2017 compared 7- and 14-day treatment with ciprofloxacin 500 mg to placebo twice per week. In men, 7 days of antibiotic therapy was inferior to 14 days during a short-term follow-up but was not inferior during a longer follow-up.
A decisive study, which is currently in the submission phase, could silence debate. “In our noninferiority, multicenter, randomized, double-blind, placebo-controlled study, we have enrolled 240 men over the age of 18 years with a febrile infection documented by a fever of 38° C or more, clinical signs of infection, and leukocyturia at least above 10/mm3 and with symptoms lasting less than 3 months,” said Dr. Lafaurie, the trial coordinator.
The primary outcome for efficacy was microbiologic and clinical success after 6 weeks. Patients received either ofloxacin, ceftriaxone, or cefotaxime (two third-generation cephalosporins in the beta-lactam family).
“We clearly show that, for a 7-day course, the clinical success rate is 55.7%, and for a 14-day course, this goes up to 77.6%, with no difference in terms of adverse effects or selection of resistant bacteria. The predictive factors for success are a 14-day treatment and being under the age of 50 years,” said Dr. Lafaurie.
“Unlike nonfebrile urinary tract infections in men, a 7-day course is insufficient for patients with febrile urinary tract infections, and a minimum of 14 days is required to achieve clinical and microbiological success,” he concluded.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
Flu hospitalizations drop amid signs of an early peak
It’s beginning to look less like an epidemic as seasonal flu activity “appears to be declining in some areas,” according to the Centers for Disease Control and Prevention.
Declines in a few states and territories were enough to lower national activity, as measured by outpatient visits for influenza-like illness, for the second consecutive week. This reduced the weekly number of hospital admissions for the first time in the 2022-2023 season, according to the CDC influenza division’s weekly FluView report.
Flu-related hospital admissions slipped to about 23,500 during the week of Dec. 4-10, after topping 26,000 the week before, based on data reported by 5,000 hospitals from all states and territories.
which was still higher than any other December rate from all previous seasons going back to 2009-10, CDC data shows.
Visits for flu-like illness represented 6.9% of all outpatient visits reported to the CDC during the week of Dec. 4-10. The rate reached 7.5% during the last full week of November before dropping to 7.3%, the CDC said.
There were 28 states or territories with “very high” activity for the latest reporting week, compared with 32 the previous week. Eight states – Colorado, Idaho, Kentucky, Nebraska, New Mexico, Oklahoma, Tennessee, and Washington – and New York City were at the very highest level on the CDC’s 1-13 scale of activity, compared with 14 areas the week before, the agency reported.
So far for the 2022-2023 season, the CDC estimated there have been at least 15 million cases of the flu, 150,000 hospitalizations, and 9,300 deaths. Among those deaths have been 30 reported in children, compared with 44 for the entire 2021-22 season and just 1 for 2020-21.
A version of this article first appeared on WebMD.com.
It’s beginning to look less like an epidemic as seasonal flu activity “appears to be declining in some areas,” according to the Centers for Disease Control and Prevention.
Declines in a few states and territories were enough to lower national activity, as measured by outpatient visits for influenza-like illness, for the second consecutive week. This reduced the weekly number of hospital admissions for the first time in the 2022-2023 season, according to the CDC influenza division’s weekly FluView report.
Flu-related hospital admissions slipped to about 23,500 during the week of Dec. 4-10, after topping 26,000 the week before, based on data reported by 5,000 hospitals from all states and territories.
which was still higher than any other December rate from all previous seasons going back to 2009-10, CDC data shows.
Visits for flu-like illness represented 6.9% of all outpatient visits reported to the CDC during the week of Dec. 4-10. The rate reached 7.5% during the last full week of November before dropping to 7.3%, the CDC said.
There were 28 states or territories with “very high” activity for the latest reporting week, compared with 32 the previous week. Eight states – Colorado, Idaho, Kentucky, Nebraska, New Mexico, Oklahoma, Tennessee, and Washington – and New York City were at the very highest level on the CDC’s 1-13 scale of activity, compared with 14 areas the week before, the agency reported.
So far for the 2022-2023 season, the CDC estimated there have been at least 15 million cases of the flu, 150,000 hospitalizations, and 9,300 deaths. Among those deaths have been 30 reported in children, compared with 44 for the entire 2021-22 season and just 1 for 2020-21.
A version of this article first appeared on WebMD.com.
It’s beginning to look less like an epidemic as seasonal flu activity “appears to be declining in some areas,” according to the Centers for Disease Control and Prevention.
Declines in a few states and territories were enough to lower national activity, as measured by outpatient visits for influenza-like illness, for the second consecutive week. This reduced the weekly number of hospital admissions for the first time in the 2022-2023 season, according to the CDC influenza division’s weekly FluView report.
Flu-related hospital admissions slipped to about 23,500 during the week of Dec. 4-10, after topping 26,000 the week before, based on data reported by 5,000 hospitals from all states and territories.
which was still higher than any other December rate from all previous seasons going back to 2009-10, CDC data shows.
Visits for flu-like illness represented 6.9% of all outpatient visits reported to the CDC during the week of Dec. 4-10. The rate reached 7.5% during the last full week of November before dropping to 7.3%, the CDC said.
There were 28 states or territories with “very high” activity for the latest reporting week, compared with 32 the previous week. Eight states – Colorado, Idaho, Kentucky, Nebraska, New Mexico, Oklahoma, Tennessee, and Washington – and New York City were at the very highest level on the CDC’s 1-13 scale of activity, compared with 14 areas the week before, the agency reported.
So far for the 2022-2023 season, the CDC estimated there have been at least 15 million cases of the flu, 150,000 hospitalizations, and 9,300 deaths. Among those deaths have been 30 reported in children, compared with 44 for the entire 2021-22 season and just 1 for 2020-21.
A version of this article first appeared on WebMD.com.
Patient With Severe Headache After IV Immunoglobulin
A 35-year-old woman with a history of hypothyroidism and idiopathic small fiber autonomic and sensory neuropathy presented to the emergency department (ED) 48 hours after IV immunoglobulin (IG) infusion with a severe headache, nausea, neck stiffness, photophobia, and episodes of intense positional eye pressure. The patient reported previous episodes of headaches post-IVIG infusion but not nearly as severe. On ED arrival, the patient was afebrile with vital signs within normal limits. Initial laboratory results were notable for levels within reference range parameters: 5.9 × 109/L white blood cell (WBC) count, 13.3 g/dL hemoglobin, 38.7% hematocrit, and 279 × 109/L platelet count; there were no abnormal urinalysis findings, and she was negative for human chorionic gonadotropin.
Due to the patient’s symptoms concerning for an acute intracranial process, a brain computed tomography (CT) without contrast was ordered. The CT demonstrated no intracranial abnormalities, but the patient’s symptoms continued to worsen. The patient was started on IV fluids and 1 g IV acetaminophen and underwent a lumbar puncture (LP). Her opening pressure was elevated at 29 cm H2O (reference range, 6-20 cm), and the fluid was notably clear. During the LP, 25 mL of cerebrospinal fluid (CSF) was collected for laboratory analysis to include a polymerase chain reaction (PCR) panel and cultures, and a closing pressure of 12 cm H2O was recorded at the end of the procedure with the patient reporting some relief of pressure. The patient was admitted to the medicine ward for further workup and observations.The patient’s meningitis/encephalitis PCR panel detected no pathogens in the CSF, but her WBC count was 84 × 109/L (reference range, 4-11) with 30 segmented neutrophils (reference range, 0-6) and red blood cell count of 24 (reference range, 0-1); her normal glucose at 60 mg/dL (reference range, 40-70) and protein of 33 mg/dL (reference range, 15-45) were within normal parameters. Brain magnetic resonance images with and without contrast was inconsistent with any acute intracranial pathology to include subarachnoid hemorrhage or central nervous system neoplasm (Figure 1). Bacterial and fungal cultures were negative.
- What is your diagnosis?
- How would you treat this patient?
Discussion
Aseptic meningitis presents with a typical clinical picture of meningitis to include headache, stiffened neck, and photophobia. In the event of negative CSF bacterial and fungal cultures and negative viral PCR, a diagnosis of aseptic meningitis is considered.1 Though the differential for aseptic meningitis is broad, in the immunocompetent patient, the most common etiology of aseptic meningitis in the United States is by far viral, and specifically, enterovirus (50.9%). It is less commonly caused by herpes simplex virus (8.3%), varicella zoster virus, and finally, the mosquito-borne St. Louis encephalitis and West Nile viruses typically acquired in the summer or early fall months. Other infectious agents that can present with aseptic meningitis are spirochetes (Lyme disease and syphilis), tuberculous meningitis, fungal infections (cryptococcal meningitis), and other bacterial infections that have a negative culture.
The patient’s history, physical examination, vital signs, imaging, and lumbar puncture findings were most concerning for drug-induced aseptic meningitis (DIAM) secondary to her recent IVIG infusion. An algorithm can be used to work through the diagnostic approach (Figure 2).3,4
Immediate and delayed adverse reactions to IVIG are known risks for IVIG therapy. About 1% to 15% of patients who receive IVIG will experience mild immediate reactions to the infusion.6 These immediate reactions include fever (78.6%), acrocyanosis (71.4%), rash (64.3%), headache (57.1%), shortness of breath (42.8%), hypotension (35.7%), and chest pain (21.4%).
IVIG is an increasingly used biologic pharmacologic agent used for a variety of medical conditions. This can be attributed to its multifaceted properties and ability to fight infection when given as replacement therapy and provide immunomodulation in conjunction with its more well-known anti-inflammatory properties.8 The number of conditions that can potentially benefit from IVIG is so vast that the American Academy of Allergy, Asthma and Immunology had to divide the indication for IVIG therapy into definitely beneficial, probably beneficial, may provide benefit, and unlikely to provide benefit categories.8
Conclusions
We encourage heightened clinical suspicion of DIAM in patients who have recently undergone IVIG infusion and present with meningeal signs (stiff neck, headache, photophobia, and ear/eye pressure) without any evidence of infection on physical examination or laboratory results. With such, we hope to improve clinician suspicion, detection, as well as patient education and outcomes in cases of DIAM.
1. Kareva L, Mironska K, Stavric K, Hasani A. Adverse reactions to intravenous immunoglobulins—our experience. Open Access Maced J Med Sci. 2018;6(12):2359-2362. doi:10.3889/oamjms.2018.513
2. Mount HR, Boyle SD. Aseptic and bacterial meningitis: evaluation, treatment, and prevention. Am Fam Physician. 2017;96(5):314-322.
3. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician. 2003;68(6):1103-1108.
4. Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am. 1990;4(4):599-622.
5. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22(3):215-226. doi:10.2165/00002018-200022030-00005
6. Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol. 2018;32(3):252-260. doi:10.1111/fcp.12349
7. Kepa L, Oczko-Grzesik B, Stolarz W, Sobala-Szczygiel B. Drug-induced aseptic meningitis in suspected central nervous system infections. J Clin Neurosci. 2005;12(5):562-564. doi:10.1016/j.jocn.2004.08.024
8. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46. doi:10.1016/j.jaci.2016.09.023
9. Kaarthigeyan K, Burli VV. Aseptic meningitis following intravenous immunoglobulin therapy of common variable immunodeficiency. J Pediatr Neurosci. 2011;6(2):160-161. doi:10.4103/1817-1745.92858
A 35-year-old woman with a history of hypothyroidism and idiopathic small fiber autonomic and sensory neuropathy presented to the emergency department (ED) 48 hours after IV immunoglobulin (IG) infusion with a severe headache, nausea, neck stiffness, photophobia, and episodes of intense positional eye pressure. The patient reported previous episodes of headaches post-IVIG infusion but not nearly as severe. On ED arrival, the patient was afebrile with vital signs within normal limits. Initial laboratory results were notable for levels within reference range parameters: 5.9 × 109/L white blood cell (WBC) count, 13.3 g/dL hemoglobin, 38.7% hematocrit, and 279 × 109/L platelet count; there were no abnormal urinalysis findings, and she was negative for human chorionic gonadotropin.
Due to the patient’s symptoms concerning for an acute intracranial process, a brain computed tomography (CT) without contrast was ordered. The CT demonstrated no intracranial abnormalities, but the patient’s symptoms continued to worsen. The patient was started on IV fluids and 1 g IV acetaminophen and underwent a lumbar puncture (LP). Her opening pressure was elevated at 29 cm H2O (reference range, 6-20 cm), and the fluid was notably clear. During the LP, 25 mL of cerebrospinal fluid (CSF) was collected for laboratory analysis to include a polymerase chain reaction (PCR) panel and cultures, and a closing pressure of 12 cm H2O was recorded at the end of the procedure with the patient reporting some relief of pressure. The patient was admitted to the medicine ward for further workup and observations.The patient’s meningitis/encephalitis PCR panel detected no pathogens in the CSF, but her WBC count was 84 × 109/L (reference range, 4-11) with 30 segmented neutrophils (reference range, 0-6) and red blood cell count of 24 (reference range, 0-1); her normal glucose at 60 mg/dL (reference range, 40-70) and protein of 33 mg/dL (reference range, 15-45) were within normal parameters. Brain magnetic resonance images with and without contrast was inconsistent with any acute intracranial pathology to include subarachnoid hemorrhage or central nervous system neoplasm (Figure 1). Bacterial and fungal cultures were negative.
- What is your diagnosis?
- How would you treat this patient?
Discussion
Aseptic meningitis presents with a typical clinical picture of meningitis to include headache, stiffened neck, and photophobia. In the event of negative CSF bacterial and fungal cultures and negative viral PCR, a diagnosis of aseptic meningitis is considered.1 Though the differential for aseptic meningitis is broad, in the immunocompetent patient, the most common etiology of aseptic meningitis in the United States is by far viral, and specifically, enterovirus (50.9%). It is less commonly caused by herpes simplex virus (8.3%), varicella zoster virus, and finally, the mosquito-borne St. Louis encephalitis and West Nile viruses typically acquired in the summer or early fall months. Other infectious agents that can present with aseptic meningitis are spirochetes (Lyme disease and syphilis), tuberculous meningitis, fungal infections (cryptococcal meningitis), and other bacterial infections that have a negative culture.
The patient’s history, physical examination, vital signs, imaging, and lumbar puncture findings were most concerning for drug-induced aseptic meningitis (DIAM) secondary to her recent IVIG infusion. An algorithm can be used to work through the diagnostic approach (Figure 2).3,4
Immediate and delayed adverse reactions to IVIG are known risks for IVIG therapy. About 1% to 15% of patients who receive IVIG will experience mild immediate reactions to the infusion.6 These immediate reactions include fever (78.6%), acrocyanosis (71.4%), rash (64.3%), headache (57.1%), shortness of breath (42.8%), hypotension (35.7%), and chest pain (21.4%).
IVIG is an increasingly used biologic pharmacologic agent used for a variety of medical conditions. This can be attributed to its multifaceted properties and ability to fight infection when given as replacement therapy and provide immunomodulation in conjunction with its more well-known anti-inflammatory properties.8 The number of conditions that can potentially benefit from IVIG is so vast that the American Academy of Allergy, Asthma and Immunology had to divide the indication for IVIG therapy into definitely beneficial, probably beneficial, may provide benefit, and unlikely to provide benefit categories.8
Conclusions
We encourage heightened clinical suspicion of DIAM in patients who have recently undergone IVIG infusion and present with meningeal signs (stiff neck, headache, photophobia, and ear/eye pressure) without any evidence of infection on physical examination or laboratory results. With such, we hope to improve clinician suspicion, detection, as well as patient education and outcomes in cases of DIAM.
A 35-year-old woman with a history of hypothyroidism and idiopathic small fiber autonomic and sensory neuropathy presented to the emergency department (ED) 48 hours after IV immunoglobulin (IG) infusion with a severe headache, nausea, neck stiffness, photophobia, and episodes of intense positional eye pressure. The patient reported previous episodes of headaches post-IVIG infusion but not nearly as severe. On ED arrival, the patient was afebrile with vital signs within normal limits. Initial laboratory results were notable for levels within reference range parameters: 5.9 × 109/L white blood cell (WBC) count, 13.3 g/dL hemoglobin, 38.7% hematocrit, and 279 × 109/L platelet count; there were no abnormal urinalysis findings, and she was negative for human chorionic gonadotropin.
Due to the patient’s symptoms concerning for an acute intracranial process, a brain computed tomography (CT) without contrast was ordered. The CT demonstrated no intracranial abnormalities, but the patient’s symptoms continued to worsen. The patient was started on IV fluids and 1 g IV acetaminophen and underwent a lumbar puncture (LP). Her opening pressure was elevated at 29 cm H2O (reference range, 6-20 cm), and the fluid was notably clear. During the LP, 25 mL of cerebrospinal fluid (CSF) was collected for laboratory analysis to include a polymerase chain reaction (PCR) panel and cultures, and a closing pressure of 12 cm H2O was recorded at the end of the procedure with the patient reporting some relief of pressure. The patient was admitted to the medicine ward for further workup and observations.The patient’s meningitis/encephalitis PCR panel detected no pathogens in the CSF, but her WBC count was 84 × 109/L (reference range, 4-11) with 30 segmented neutrophils (reference range, 0-6) and red blood cell count of 24 (reference range, 0-1); her normal glucose at 60 mg/dL (reference range, 40-70) and protein of 33 mg/dL (reference range, 15-45) were within normal parameters. Brain magnetic resonance images with and without contrast was inconsistent with any acute intracranial pathology to include subarachnoid hemorrhage or central nervous system neoplasm (Figure 1). Bacterial and fungal cultures were negative.
- What is your diagnosis?
- How would you treat this patient?
Discussion
Aseptic meningitis presents with a typical clinical picture of meningitis to include headache, stiffened neck, and photophobia. In the event of negative CSF bacterial and fungal cultures and negative viral PCR, a diagnosis of aseptic meningitis is considered.1 Though the differential for aseptic meningitis is broad, in the immunocompetent patient, the most common etiology of aseptic meningitis in the United States is by far viral, and specifically, enterovirus (50.9%). It is less commonly caused by herpes simplex virus (8.3%), varicella zoster virus, and finally, the mosquito-borne St. Louis encephalitis and West Nile viruses typically acquired in the summer or early fall months. Other infectious agents that can present with aseptic meningitis are spirochetes (Lyme disease and syphilis), tuberculous meningitis, fungal infections (cryptococcal meningitis), and other bacterial infections that have a negative culture.
The patient’s history, physical examination, vital signs, imaging, and lumbar puncture findings were most concerning for drug-induced aseptic meningitis (DIAM) secondary to her recent IVIG infusion. An algorithm can be used to work through the diagnostic approach (Figure 2).3,4
Immediate and delayed adverse reactions to IVIG are known risks for IVIG therapy. About 1% to 15% of patients who receive IVIG will experience mild immediate reactions to the infusion.6 These immediate reactions include fever (78.6%), acrocyanosis (71.4%), rash (64.3%), headache (57.1%), shortness of breath (42.8%), hypotension (35.7%), and chest pain (21.4%).
IVIG is an increasingly used biologic pharmacologic agent used for a variety of medical conditions. This can be attributed to its multifaceted properties and ability to fight infection when given as replacement therapy and provide immunomodulation in conjunction with its more well-known anti-inflammatory properties.8 The number of conditions that can potentially benefit from IVIG is so vast that the American Academy of Allergy, Asthma and Immunology had to divide the indication for IVIG therapy into definitely beneficial, probably beneficial, may provide benefit, and unlikely to provide benefit categories.8
Conclusions
We encourage heightened clinical suspicion of DIAM in patients who have recently undergone IVIG infusion and present with meningeal signs (stiff neck, headache, photophobia, and ear/eye pressure) without any evidence of infection on physical examination or laboratory results. With such, we hope to improve clinician suspicion, detection, as well as patient education and outcomes in cases of DIAM.
1. Kareva L, Mironska K, Stavric K, Hasani A. Adverse reactions to intravenous immunoglobulins—our experience. Open Access Maced J Med Sci. 2018;6(12):2359-2362. doi:10.3889/oamjms.2018.513
2. Mount HR, Boyle SD. Aseptic and bacterial meningitis: evaluation, treatment, and prevention. Am Fam Physician. 2017;96(5):314-322.
3. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician. 2003;68(6):1103-1108.
4. Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am. 1990;4(4):599-622.
5. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22(3):215-226. doi:10.2165/00002018-200022030-00005
6. Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol. 2018;32(3):252-260. doi:10.1111/fcp.12349
7. Kepa L, Oczko-Grzesik B, Stolarz W, Sobala-Szczygiel B. Drug-induced aseptic meningitis in suspected central nervous system infections. J Clin Neurosci. 2005;12(5):562-564. doi:10.1016/j.jocn.2004.08.024
8. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46. doi:10.1016/j.jaci.2016.09.023
9. Kaarthigeyan K, Burli VV. Aseptic meningitis following intravenous immunoglobulin therapy of common variable immunodeficiency. J Pediatr Neurosci. 2011;6(2):160-161. doi:10.4103/1817-1745.92858
1. Kareva L, Mironska K, Stavric K, Hasani A. Adverse reactions to intravenous immunoglobulins—our experience. Open Access Maced J Med Sci. 2018;6(12):2359-2362. doi:10.3889/oamjms.2018.513
2. Mount HR, Boyle SD. Aseptic and bacterial meningitis: evaluation, treatment, and prevention. Am Fam Physician. 2017;96(5):314-322.
3. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician. 2003;68(6):1103-1108.
4. Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am. 1990;4(4):599-622.
5. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22(3):215-226. doi:10.2165/00002018-200022030-00005
6. Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol. 2018;32(3):252-260. doi:10.1111/fcp.12349
7. Kepa L, Oczko-Grzesik B, Stolarz W, Sobala-Szczygiel B. Drug-induced aseptic meningitis in suspected central nervous system infections. J Clin Neurosci. 2005;12(5):562-564. doi:10.1016/j.jocn.2004.08.024
8. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46. doi:10.1016/j.jaci.2016.09.023
9. Kaarthigeyan K, Burli VV. Aseptic meningitis following intravenous immunoglobulin therapy of common variable immunodeficiency. J Pediatr Neurosci. 2011;6(2):160-161. doi:10.4103/1817-1745.92858
Oral Therapy for Aerococcus urinae Bacteremia and Thoracic Spondylodiscitis of Presumed Urinary Origin
Aerococcus urinae (A urinae), a gram-positive coccus readily mistaken for a Staphylococcus species, was first identified in 1992.1-3 It now reportedly accounts for 0.2% to 0.8% of clinical urine isolates.4-6A urinae bacteriuria is typically asymptomatic and mainly occurs in women.7-9 Symptomatic A urinae urinary tract infection (UTI) occurs predominantly in older men with underlying urologic abnormalities.4-10
Serious A urinae infections are rare. The first 2 reported cases involved men with A urinae endocarditis, one of whom died.11,12 To date, only 8 cases of spondylodiscitis due to A urinae have been reported.13-20 Optimal treatment for invasive A urinae infection is undefined; however, the reported cases were treated successfully with diverse antibiotic regimen combinations; all including a β-lactam and beginning with at least 2 weeks of IV antibiotics.13-20 We describe a man with A urinae bacteremia and spondylodiscitis, presumably arising from a urinary source in the setting of bladder outlet obstruction, who was treated successfully.
Case Presentation
A 74-year-old man with morbid obesity, type 2 diabetes mellitus, stage 2 chronic kidney disease, and tobacco use presented to the emergency department after 2 weeks of progressive, nonradiating, midthoracic back pain, lower extremity weakness, gait imbalance, fatigue, anorexia, rigors, and subjective fevers. On presentation, he was afebrile and hemodynamically stable. A physical examination revealed point tenderness of the midthoracic vertebrae, nontender costovertebral angles, diffusely decreased strength, nonsustained clonus in both lower extremities, inguinal intertrigo, and a buried penis with purulent meatal discharge.
Laboratory results indicated a white blood cell (WBC) count of 13.5 K/μL (reference range, 4.0-11.0), absolute neutrophil count of 11.48 K/μL (reference range, 2.0-7.7), C-reactive protein (CRP) level of 225.3 mg/L (reference range, ≤ 5.0), erythrocyte sedimentation rate of 85 mm/h (reference range, 5-15), serum blood urea nitrogen of 76 mg/dL (reference range, 8-26), and serum creatinine (SCr) of 1.9 mg/dL (reference range, 1.1-1.4). A urinalysis showed positive leukocyte esterase, WBC clumps, and little bacteria. Abdominal/pelvic computed tomography showed spondylodiscitis-like changes at T7-T8, bilateral perinephric fat stranding, bladder distension, and bladder wall thickening.
The patient was presumed to have discitis secondary to a UTI, with possible pyelonephritis, and was given empiric vancomycin and ceftriaxone. Spinal magnetic resonance imaging with contrast supported spondylodiscitis at T7-T8, extending to T8-T9. Preliminary results from the admission blood and urine cultures showed gram-positive cocci in clusters, which were presumed initially to be Staphylococcus aureus (S aureus).
The final urine culture report listed multiple organisms, predominantly A urinae (Table 1); 
On hospital day 6, the patient’s back pain had resolved, micturition was normal, appetite had normalized, and SCr was minimally above baseline (1.4 mg/dL). He insisted on completing antibiotic treatment at home and had no other medical indication for continued hospitalization. Thus, antibiotic therapy was changed to an all-oral regimen of amoxicillin 1 g 3 times daily for 10 days and levofloxacin 750 mg daily for 6 weeks, and the patient was discharged to home.
The patient returned 5 days postdischarge due to anuria. Investigation showed severe acute kidney injury (SCr, 6.8 mg/dL) and bladder outlet obstruction due to phimosis and urethral meatal stenosis. Urinalysis was unremarkable. His CRP had declined from 225 mg/L (initial admission) to 154 mg/L. A urinae culture and 2 sets of blood cultures were finalized as no growth. He was diagnosed with postrenal acute kidney injury and underwent meatal dilation and Foley catheterization but declined surgical correction. When seen in the clinic 2 months postantimicrobial therapy, the patient had normal micturition, no symptoms or signs of infection, and steadily down-trending inflammatory markers.
Discussion
A urinae, historically considered a rare pathogen, has been identified with increasing frequency in urine cultures due to improved microbiologic diagnostic techniques. However, there are only 8 reported cases of A urinae spondylodiscitis. Urinary pathology is an accepted risk factor for A urinae infections; consequently, we suspect that our patient’s urinary outflow obstruction and poor genitourinary hygiene were related to his invasive A urinae infection.10,21,22 We surmise that he had a chronic urinary outflow obstruction contributing to his infection, as evidenced by imaging findings, while the phimosis and urethral meatal stenosis were most likely infectious sequelae considering his anuria and acute kidney injury 5 days postdischarge. Indeed, the correlation between A urinae and urinary tract pathology may justify an evaluation for urinary pathology in any man with A urinae infection, regardless of the presence of symptoms.
By contrast, the implications of A urinae bacteriuria remain unclear. From a public health perspective, A urinae bacteriuria is rare, but the infectious mechanism remains undetermined with a case report suggesting the possibility of sexual transmission.4-6,23 In our case, the patient was not sexually active and had no clear origin of infection. Considering the potential severity of infection, more studies are needed to determine the infectious mechanism of A urinae.
In terms of infectious morbidity, the results seem to vary by sex. In a retrospective study of about 30,000 clinical urine samples, 62 (58 from women, 4 from men) yielded A urinae. The 62 corresponding patients lacked systemic infectious complications, leading the authors to conclude that A urinae is a relatively avirulent organism.24 Although possibly true in women, we are wary of drawing conclusions, especially regarding men, from a study that included only 62 urine samples were A urinae–positive, with only 4 from men. More evidence is needed to define the prognostic implications of A urinae bacteriuria in men.
As illustrated by the present case and previous reports, severe A urinae infections can occur, and the contributory factors deserve consideration. In our patient, the actual mechanism for bacteremia remains unclear. The initial concern for acute pyelonephritis was prompted by a computed tomography finding of bilateral perinephric fat stranding. This finding was questioned because it is common in older patients without infection, hence, is highly nonspecific. A correlation with urinary outflow obstruction may be an important clue in cases like this one.25,26
Furthermore, whether the urinary tract truly was the source of the patient’s bacteremia is clouded by the differing antimicrobial susceptibility patterns of the A urinae blood and urine isolates. The simplest explanation for this discordance may be that all the isolates shared a common initial origin but adapted to different environments in the host (perhaps over time) or laboratory, producing phenotypic variation. Alternatively, the infection could have been polyclonal from the onset, with sampling error leading to the differing detected susceptibility patterns, or the blood and urine isolates may have represented independent acquisition events, involving distinct A urinae strains. Unfortunately (from an academic perspective), given patient preferences and recommendations from the infectious disease consultant, no bone biopsy was done for histology and culture to confirm infection and to allow comparative strain identification if A urinae was isolated.
Optimal treatment for A urinae spondylodiscitis has yet to be established. β-lactams have shown good clinical efficacy despite being bacteriostatic in vitro.27 Early in vitro studies showed synergistic bactericidal synergistic activity with penicillin plus aminoglycoside combination therapies.27-30 Cases of endocarditis have been successfully treated mainly with the combination of a β-lactam plus aminoglycoside combination therapy.30,31 Previous cases of spondylodiscitis have been treated successfully with diverse antimicrobial agents, including clindamycin, β-lactams, cephalosporins, fluoroquinolones, and aminoglycosides.14
Our patient improved rapidly while receiving empiric therapy with vancomycin and ceftriaxone and tolerated a rapid transition to oral amoxicillin and levofloxacin. This is the shortest IV treatment course for A urinae spondylodiscitis reported to date. We suspect that such rapid IV-to-oral transitions will suffice in most stable patients with A urinae spondylodiscitis or other invasive A urinae infections in line with the results of the OVIVA and POET trials.32,33
Conclusions
We believe A urinae UTI in the absence of obvious predisposing factors should prompt evaluation for urinary outflow obstruction. Despite improved laboratory diagnostic techniques, spondylodiscitis related to A urinae remains a rare entity and thus definitive treatment recommendations are difficult to make. However, we suspect that in many cases it is reasonable to extrapolate from the results of the POET and OVIVA trials and rapidly transition therapy of A urinae spondylodiscitis from IV to oral antibiotics. We suspect a review of the US Department of Veterans Affairs population might uncover a higher incidence of A urinae infection than previously estimated due to the population demographics and the epidemiology of A urinae.
1. Christensen JJ, Korner B, Kjaergaard H. Aerococcus-like organism—an unnoticed urinary tract pathogen. APMIS. 1989;97(6):539-546. doi:10.1111/j.1699-0463.1989.tb00828.x
2. Aguirre M, Collins MD. Phylogenetic analysis of some Aerococcus-like organisms from urinary tract infections: description of Aerococcus urinae sp. nov. J Gen Microbiol. 1992;138(2):401-405. doi:10.1099/00221287-138-2-401
3. Williams RE, Hirch A, Cowan ST. Aerococcus, a new bacterial genus. J Gen Microbiol. 1953;8(3):475-480. doi:10.1099/00221287-8-3-475
4. Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol Spectr. 2016;4(2). doi:10.1128/microbiolspec.UTI-0012-2012
5. Schuur PM, Kasteren ME, Sabbe L, Vos MC, Janssens MM, Buiting AG. Urinary tract infections with Aerococcus urinae in the south of The Netherlands. Eur J Clin Microbiol Infect Dis. 1997;16(12):871-875. doi:10.1007/BF01700552
6. Grude N, Tveten Y. Aerococcus urinae og urinveisinfeksjon [Aerococcus urinae and urinary tract infection]. Tidsskr Nor Laegeforen. 2002;122(2):174-175.
7. Narayanasamy S, King K, Dennison A, Spelman DW, Aung AK. Clinical characteristics and laboratory identification of Aerococcus infections: an Australian tertiary centre perspective. Int J Microbiol. 2017;2017. doi:10.1155/2017/5684614
8. Hilt EE, McKinley K, Pearce MM, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871-876. doi:10.1128/JCM.02876-13
9. Pearce MM, Hilt EE, Rosenfeld AB, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5(4):e01283-14. doi:10.1128/mBio.01283-14
10. Sahu KK, Lal A, Mishra AK, Abraham GM. Aerococcus-related infections and their significance: a 9-year retrospective study. J Microsc Ultrastruct. 2021;9(1):18-25. doi:10.4103/JMAU.JMAU_61_19
11. Skov RL, Klarlund M, Thorsen S. Fatal endocarditis due to Aerococcus urinae. Diagn Microbiol Infect Dis. 1995;21(4):219-221. doi:10.1016/0732-8893(95)00037-b
12. Kristensen B, Nielsen G. Endocarditis caused by Aerococcus urinae, a newly recognized pathogen. Eur J Clin Microbiol Infect Dis. 1995;14(1):49-51. doi:10.1007/BF02112619
13. Astudillo L, Sailler L, Porte L, Lefevre JC, Massip P, Arlet-Suau E. Spondylodiscitis due to Aerococcus urinae: a first report. Scand J Infect Dis. 2003;35(11-12):890-891. doi:10.1080/00365540310016664
14. Lyagoubi A, Souffi C, Baroiller V, Vallee E. Spondylodiscitis: an increasingly described localization. EJIFCC. 2020;31(2):169-173.
15. Jerome M, Slim J, Sison R, Marton R. A case of Aerococcus urinae vertebral osteomyelitis. J Glob Infect Dis. 2015;7(2):85-86. doi:10.4103/0974-777X.157246
16. Tekin A, Tekin G, Turunç T, Demiroğlu Z, Kizilkiliç O. Infective endocarditis and spondylodiscitis in a patient due to Aerococcus urinae: first report. Int J Cardiol. 2007;115(3):402-403. doi:10.1016/j.ijcard.2006.01.046
17. Rougier E, Braud A, Argemi X, et al. Spondylodiscitis due to Aerococcus urinae and literature review. Infection. 2018;46(3):419-421. doi:10.1007/s15010-017-1106-0
18. Degroote E, Yildiz H, Lecouvet F, Verroken A, Belkhir L. Aerococcus urinae: an underestimated cause of spine infection? Case report and review of the literature. Acta Clin Belg. 2018;73(6):444-447. doi:10.1080/17843286.2018.1443003
19. Torres-Martos E, Pérez-Cortés S, Sánchez-Calvo JM, López-Prieto MD. Spondylodiscitis due to Aerococcus urinae infection in an elderly immunocompetent patient. Enferm Infecc Microbiol Clin. 2017;35(10):682-684. doi:10.1016/j.eimc.2017.02.005
20. Senneby E, Petersson AC, Rasmussen M. Clinical and microbiological features of bacteraemia with Aerococcus urinae. Clin Microbiol Infect. 2012;18(6):546-550. doi:10.1111/j.1469-0691.2011.03609.x
21. Sunnerhagen T, Nilson B, Olaison L, Rasmussen M. Clinical and microbiological features of infective endocarditis caused by aerococci. Infection. 2016;44(2):167-173. doi:10.1007/s15010-015-0812-8
22. de Jong MF, Soetekouw R, ten Kate RW, Veenendaal D. Aerococcus urinae: severe and fatal bloodstream infections and endocarditis. J Clin Microbiol. 2010;48(9):3445-3447. doi:10.1128/JCM.00835-10
23. Babaeer AA, Nader C, Iacoviello V, Tomera K. Necrotizing urethritis due to Aerococcus urinae. Case Rep Urol. 2015;2015:136147. doi:10.1155/2015/136147
24. Sierra-Hoffman M, Watkins K, Jinadatha C, Fader R, Carpenter JL. Clinical significance of Aerococcus urinae: a retrospective review. Diagn Microbiol Infect Dis. 2005;53(4):289-292. doi:10.1016/j.diagmicrobio.2005.06.021
25. Fukami H, Takeuchi Y, Kagaya S, et al. Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis. Int J Gen Med. 2017;10:137-144. doi:10.2147/IJGM.S133685
26. Han NY, Sung DJ, Kim MJ, Park BJ, Sim KC, Cho SB. Perirenal fat stranding on CT: is there an association with bladder outlet obstruction? Br J Radiol. 2016;89(1063):20160195. doi:10.1259/bjr.20160195
27. Hirzel C, Hirzberger L, Furrer H, Endimiani A. Bactericidal activity of penicillin, ceftriaxone, gentamicin and daptomycin alone and in combination against Aerococcus urinae. Int J Antimicrob Agents. 2016;48(3):271-276. doi:10.1016/j.ijantimicag.2016.05.007
28. Zbinden R, Santanam P, Hunziker L, Leuzinger B, von Graevenitz A. Endocarditis due to Aerococcus urinae: diagnostic tests, fatty acid composition and killing kinetics. Infection. 1999;27(2):122-124. doi:10.1007/BF02560511
29. Skov R, Christensen JJ, Korner B, Frimodt-Møller N, Espersen F. In vitro antimicrobial susceptibility of Aerococcus urinae to 14 antibiotics, and time-kill curves for penicillin, gentamicin and vancomycin. J Antimicrob Chemother. 2001;48(5):653-658. doi:10.1093/jac/48.5.653
30. Ebnöther C, Altwegg M, Gottschalk J, Seebach JD, Kronenberg A. Aerococcus urinae endocarditis: case report and review of the literature. Infection. 2002;30(5):310-313. doi:10.1007/s15010-002-3106-x
31. Tai DBG, Go JR, Fida M, Saleh OA. Management and treatment of Aerococcus bacteremia and endocarditis. Int J Infect Dis. 2021;102:584-589. doi:10.1016/j.ijid.2020.10.096
32. Li H-K, Rombach I, Zambellas R, et al; OVIVA Trial Collaborators. Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med. 2019;380(5):425-436. doi:10.1056/NEJMoa1710926
33. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med. 2019;380(5):415-424. doi:10.1056/NEJMoa1808312
Aerococcus urinae (A urinae), a gram-positive coccus readily mistaken for a Staphylococcus species, was first identified in 1992.1-3 It now reportedly accounts for 0.2% to 0.8% of clinical urine isolates.4-6A urinae bacteriuria is typically asymptomatic and mainly occurs in women.7-9 Symptomatic A urinae urinary tract infection (UTI) occurs predominantly in older men with underlying urologic abnormalities.4-10
Serious A urinae infections are rare. The first 2 reported cases involved men with A urinae endocarditis, one of whom died.11,12 To date, only 8 cases of spondylodiscitis due to A urinae have been reported.13-20 Optimal treatment for invasive A urinae infection is undefined; however, the reported cases were treated successfully with diverse antibiotic regimen combinations; all including a β-lactam and beginning with at least 2 weeks of IV antibiotics.13-20 We describe a man with A urinae bacteremia and spondylodiscitis, presumably arising from a urinary source in the setting of bladder outlet obstruction, who was treated successfully.
Case Presentation
A 74-year-old man with morbid obesity, type 2 diabetes mellitus, stage 2 chronic kidney disease, and tobacco use presented to the emergency department after 2 weeks of progressive, nonradiating, midthoracic back pain, lower extremity weakness, gait imbalance, fatigue, anorexia, rigors, and subjective fevers. On presentation, he was afebrile and hemodynamically stable. A physical examination revealed point tenderness of the midthoracic vertebrae, nontender costovertebral angles, diffusely decreased strength, nonsustained clonus in both lower extremities, inguinal intertrigo, and a buried penis with purulent meatal discharge.
Laboratory results indicated a white blood cell (WBC) count of 13.5 K/μL (reference range, 4.0-11.0), absolute neutrophil count of 11.48 K/μL (reference range, 2.0-7.7), C-reactive protein (CRP) level of 225.3 mg/L (reference range, ≤ 5.0), erythrocyte sedimentation rate of 85 mm/h (reference range, 5-15), serum blood urea nitrogen of 76 mg/dL (reference range, 8-26), and serum creatinine (SCr) of 1.9 mg/dL (reference range, 1.1-1.4). A urinalysis showed positive leukocyte esterase, WBC clumps, and little bacteria. Abdominal/pelvic computed tomography showed spondylodiscitis-like changes at T7-T8, bilateral perinephric fat stranding, bladder distension, and bladder wall thickening.
The patient was presumed to have discitis secondary to a UTI, with possible pyelonephritis, and was given empiric vancomycin and ceftriaxone. Spinal magnetic resonance imaging with contrast supported spondylodiscitis at T7-T8, extending to T8-T9. Preliminary results from the admission blood and urine cultures showed gram-positive cocci in clusters, which were presumed initially to be Staphylococcus aureus (S aureus).
The final urine culture report listed multiple organisms, predominantly A urinae (Table 1);
On hospital day 6, the patient’s back pain had resolved, micturition was normal, appetite had normalized, and SCr was minimally above baseline (1.4 mg/dL). He insisted on completing antibiotic treatment at home and had no other medical indication for continued hospitalization. Thus, antibiotic therapy was changed to an all-oral regimen of amoxicillin 1 g 3 times daily for 10 days and levofloxacin 750 mg daily for 6 weeks, and the patient was discharged to home.
The patient returned 5 days postdischarge due to anuria. Investigation showed severe acute kidney injury (SCr, 6.8 mg/dL) and bladder outlet obstruction due to phimosis and urethral meatal stenosis. Urinalysis was unremarkable. His CRP had declined from 225 mg/L (initial admission) to 154 mg/L. A urinae culture and 2 sets of blood cultures were finalized as no growth. He was diagnosed with postrenal acute kidney injury and underwent meatal dilation and Foley catheterization but declined surgical correction. When seen in the clinic 2 months postantimicrobial therapy, the patient had normal micturition, no symptoms or signs of infection, and steadily down-trending inflammatory markers.
Discussion
A urinae, historically considered a rare pathogen, has been identified with increasing frequency in urine cultures due to improved microbiologic diagnostic techniques. However, there are only 8 reported cases of A urinae spondylodiscitis. Urinary pathology is an accepted risk factor for A urinae infections; consequently, we suspect that our patient’s urinary outflow obstruction and poor genitourinary hygiene were related to his invasive A urinae infection.10,21,22 We surmise that he had a chronic urinary outflow obstruction contributing to his infection, as evidenced by imaging findings, while the phimosis and urethral meatal stenosis were most likely infectious sequelae considering his anuria and acute kidney injury 5 days postdischarge. Indeed, the correlation between A urinae and urinary tract pathology may justify an evaluation for urinary pathology in any man with A urinae infection, regardless of the presence of symptoms.
By contrast, the implications of A urinae bacteriuria remain unclear. From a public health perspective, A urinae bacteriuria is rare, but the infectious mechanism remains undetermined with a case report suggesting the possibility of sexual transmission.4-6,23 In our case, the patient was not sexually active and had no clear origin of infection. Considering the potential severity of infection, more studies are needed to determine the infectious mechanism of A urinae.
In terms of infectious morbidity, the results seem to vary by sex. In a retrospective study of about 30,000 clinical urine samples, 62 (58 from women, 4 from men) yielded A urinae. The 62 corresponding patients lacked systemic infectious complications, leading the authors to conclude that A urinae is a relatively avirulent organism.24 Although possibly true in women, we are wary of drawing conclusions, especially regarding men, from a study that included only 62 urine samples were A urinae–positive, with only 4 from men. More evidence is needed to define the prognostic implications of A urinae bacteriuria in men.
As illustrated by the present case and previous reports, severe A urinae infections can occur, and the contributory factors deserve consideration. In our patient, the actual mechanism for bacteremia remains unclear. The initial concern for acute pyelonephritis was prompted by a computed tomography finding of bilateral perinephric fat stranding. This finding was questioned because it is common in older patients without infection, hence, is highly nonspecific. A correlation with urinary outflow obstruction may be an important clue in cases like this one.25,26
Furthermore, whether the urinary tract truly was the source of the patient’s bacteremia is clouded by the differing antimicrobial susceptibility patterns of the A urinae blood and urine isolates. The simplest explanation for this discordance may be that all the isolates shared a common initial origin but adapted to different environments in the host (perhaps over time) or laboratory, producing phenotypic variation. Alternatively, the infection could have been polyclonal from the onset, with sampling error leading to the differing detected susceptibility patterns, or the blood and urine isolates may have represented independent acquisition events, involving distinct A urinae strains. Unfortunately (from an academic perspective), given patient preferences and recommendations from the infectious disease consultant, no bone biopsy was done for histology and culture to confirm infection and to allow comparative strain identification if A urinae was isolated.
Optimal treatment for A urinae spondylodiscitis has yet to be established. β-lactams have shown good clinical efficacy despite being bacteriostatic in vitro.27 Early in vitro studies showed synergistic bactericidal synergistic activity with penicillin plus aminoglycoside combination therapies.27-30 Cases of endocarditis have been successfully treated mainly with the combination of a β-lactam plus aminoglycoside combination therapy.30,31 Previous cases of spondylodiscitis have been treated successfully with diverse antimicrobial agents, including clindamycin, β-lactams, cephalosporins, fluoroquinolones, and aminoglycosides.14
Our patient improved rapidly while receiving empiric therapy with vancomycin and ceftriaxone and tolerated a rapid transition to oral amoxicillin and levofloxacin. This is the shortest IV treatment course for A urinae spondylodiscitis reported to date. We suspect that such rapid IV-to-oral transitions will suffice in most stable patients with A urinae spondylodiscitis or other invasive A urinae infections in line with the results of the OVIVA and POET trials.32,33
Conclusions
We believe A urinae UTI in the absence of obvious predisposing factors should prompt evaluation for urinary outflow obstruction. Despite improved laboratory diagnostic techniques, spondylodiscitis related to A urinae remains a rare entity and thus definitive treatment recommendations are difficult to make. However, we suspect that in many cases it is reasonable to extrapolate from the results of the POET and OVIVA trials and rapidly transition therapy of A urinae spondylodiscitis from IV to oral antibiotics. We suspect a review of the US Department of Veterans Affairs population might uncover a higher incidence of A urinae infection than previously estimated due to the population demographics and the epidemiology of A urinae.
Aerococcus urinae (A urinae), a gram-positive coccus readily mistaken for a Staphylococcus species, was first identified in 1992.1-3 It now reportedly accounts for 0.2% to 0.8% of clinical urine isolates.4-6A urinae bacteriuria is typically asymptomatic and mainly occurs in women.7-9 Symptomatic A urinae urinary tract infection (UTI) occurs predominantly in older men with underlying urologic abnormalities.4-10
Serious A urinae infections are rare. The first 2 reported cases involved men with A urinae endocarditis, one of whom died.11,12 To date, only 8 cases of spondylodiscitis due to A urinae have been reported.13-20 Optimal treatment for invasive A urinae infection is undefined; however, the reported cases were treated successfully with diverse antibiotic regimen combinations; all including a β-lactam and beginning with at least 2 weeks of IV antibiotics.13-20 We describe a man with A urinae bacteremia and spondylodiscitis, presumably arising from a urinary source in the setting of bladder outlet obstruction, who was treated successfully.
Case Presentation
A 74-year-old man with morbid obesity, type 2 diabetes mellitus, stage 2 chronic kidney disease, and tobacco use presented to the emergency department after 2 weeks of progressive, nonradiating, midthoracic back pain, lower extremity weakness, gait imbalance, fatigue, anorexia, rigors, and subjective fevers. On presentation, he was afebrile and hemodynamically stable. A physical examination revealed point tenderness of the midthoracic vertebrae, nontender costovertebral angles, diffusely decreased strength, nonsustained clonus in both lower extremities, inguinal intertrigo, and a buried penis with purulent meatal discharge.
Laboratory results indicated a white blood cell (WBC) count of 13.5 K/μL (reference range, 4.0-11.0), absolute neutrophil count of 11.48 K/μL (reference range, 2.0-7.7), C-reactive protein (CRP) level of 225.3 mg/L (reference range, ≤ 5.0), erythrocyte sedimentation rate of 85 mm/h (reference range, 5-15), serum blood urea nitrogen of 76 mg/dL (reference range, 8-26), and serum creatinine (SCr) of 1.9 mg/dL (reference range, 1.1-1.4). A urinalysis showed positive leukocyte esterase, WBC clumps, and little bacteria. Abdominal/pelvic computed tomography showed spondylodiscitis-like changes at T7-T8, bilateral perinephric fat stranding, bladder distension, and bladder wall thickening.
The patient was presumed to have discitis secondary to a UTI, with possible pyelonephritis, and was given empiric vancomycin and ceftriaxone. Spinal magnetic resonance imaging with contrast supported spondylodiscitis at T7-T8, extending to T8-T9. Preliminary results from the admission blood and urine cultures showed gram-positive cocci in clusters, which were presumed initially to be Staphylococcus aureus (S aureus).
The final urine culture report listed multiple organisms, predominantly A urinae (Table 1);
On hospital day 6, the patient’s back pain had resolved, micturition was normal, appetite had normalized, and SCr was minimally above baseline (1.4 mg/dL). He insisted on completing antibiotic treatment at home and had no other medical indication for continued hospitalization. Thus, antibiotic therapy was changed to an all-oral regimen of amoxicillin 1 g 3 times daily for 10 days and levofloxacin 750 mg daily for 6 weeks, and the patient was discharged to home.
The patient returned 5 days postdischarge due to anuria. Investigation showed severe acute kidney injury (SCr, 6.8 mg/dL) and bladder outlet obstruction due to phimosis and urethral meatal stenosis. Urinalysis was unremarkable. His CRP had declined from 225 mg/L (initial admission) to 154 mg/L. A urinae culture and 2 sets of blood cultures were finalized as no growth. He was diagnosed with postrenal acute kidney injury and underwent meatal dilation and Foley catheterization but declined surgical correction. When seen in the clinic 2 months postantimicrobial therapy, the patient had normal micturition, no symptoms or signs of infection, and steadily down-trending inflammatory markers.
Discussion
A urinae, historically considered a rare pathogen, has been identified with increasing frequency in urine cultures due to improved microbiologic diagnostic techniques. However, there are only 8 reported cases of A urinae spondylodiscitis. Urinary pathology is an accepted risk factor for A urinae infections; consequently, we suspect that our patient’s urinary outflow obstruction and poor genitourinary hygiene were related to his invasive A urinae infection.10,21,22 We surmise that he had a chronic urinary outflow obstruction contributing to his infection, as evidenced by imaging findings, while the phimosis and urethral meatal stenosis were most likely infectious sequelae considering his anuria and acute kidney injury 5 days postdischarge. Indeed, the correlation between A urinae and urinary tract pathology may justify an evaluation for urinary pathology in any man with A urinae infection, regardless of the presence of symptoms.
By contrast, the implications of A urinae bacteriuria remain unclear. From a public health perspective, A urinae bacteriuria is rare, but the infectious mechanism remains undetermined with a case report suggesting the possibility of sexual transmission.4-6,23 In our case, the patient was not sexually active and had no clear origin of infection. Considering the potential severity of infection, more studies are needed to determine the infectious mechanism of A urinae.
In terms of infectious morbidity, the results seem to vary by sex. In a retrospective study of about 30,000 clinical urine samples, 62 (58 from women, 4 from men) yielded A urinae. The 62 corresponding patients lacked systemic infectious complications, leading the authors to conclude that A urinae is a relatively avirulent organism.24 Although possibly true in women, we are wary of drawing conclusions, especially regarding men, from a study that included only 62 urine samples were A urinae–positive, with only 4 from men. More evidence is needed to define the prognostic implications of A urinae bacteriuria in men.
As illustrated by the present case and previous reports, severe A urinae infections can occur, and the contributory factors deserve consideration. In our patient, the actual mechanism for bacteremia remains unclear. The initial concern for acute pyelonephritis was prompted by a computed tomography finding of bilateral perinephric fat stranding. This finding was questioned because it is common in older patients without infection, hence, is highly nonspecific. A correlation with urinary outflow obstruction may be an important clue in cases like this one.25,26
Furthermore, whether the urinary tract truly was the source of the patient’s bacteremia is clouded by the differing antimicrobial susceptibility patterns of the A urinae blood and urine isolates. The simplest explanation for this discordance may be that all the isolates shared a common initial origin but adapted to different environments in the host (perhaps over time) or laboratory, producing phenotypic variation. Alternatively, the infection could have been polyclonal from the onset, with sampling error leading to the differing detected susceptibility patterns, or the blood and urine isolates may have represented independent acquisition events, involving distinct A urinae strains. Unfortunately (from an academic perspective), given patient preferences and recommendations from the infectious disease consultant, no bone biopsy was done for histology and culture to confirm infection and to allow comparative strain identification if A urinae was isolated.
Optimal treatment for A urinae spondylodiscitis has yet to be established. β-lactams have shown good clinical efficacy despite being bacteriostatic in vitro.27 Early in vitro studies showed synergistic bactericidal synergistic activity with penicillin plus aminoglycoside combination therapies.27-30 Cases of endocarditis have been successfully treated mainly with the combination of a β-lactam plus aminoglycoside combination therapy.30,31 Previous cases of spondylodiscitis have been treated successfully with diverse antimicrobial agents, including clindamycin, β-lactams, cephalosporins, fluoroquinolones, and aminoglycosides.14
Our patient improved rapidly while receiving empiric therapy with vancomycin and ceftriaxone and tolerated a rapid transition to oral amoxicillin and levofloxacin. This is the shortest IV treatment course for A urinae spondylodiscitis reported to date. We suspect that such rapid IV-to-oral transitions will suffice in most stable patients with A urinae spondylodiscitis or other invasive A urinae infections in line with the results of the OVIVA and POET trials.32,33
Conclusions
We believe A urinae UTI in the absence of obvious predisposing factors should prompt evaluation for urinary outflow obstruction. Despite improved laboratory diagnostic techniques, spondylodiscitis related to A urinae remains a rare entity and thus definitive treatment recommendations are difficult to make. However, we suspect that in many cases it is reasonable to extrapolate from the results of the POET and OVIVA trials and rapidly transition therapy of A urinae spondylodiscitis from IV to oral antibiotics. We suspect a review of the US Department of Veterans Affairs population might uncover a higher incidence of A urinae infection than previously estimated due to the population demographics and the epidemiology of A urinae.
1. Christensen JJ, Korner B, Kjaergaard H. Aerococcus-like organism—an unnoticed urinary tract pathogen. APMIS. 1989;97(6):539-546. doi:10.1111/j.1699-0463.1989.tb00828.x
2. Aguirre M, Collins MD. Phylogenetic analysis of some Aerococcus-like organisms from urinary tract infections: description of Aerococcus urinae sp. nov. J Gen Microbiol. 1992;138(2):401-405. doi:10.1099/00221287-138-2-401
3. Williams RE, Hirch A, Cowan ST. Aerococcus, a new bacterial genus. J Gen Microbiol. 1953;8(3):475-480. doi:10.1099/00221287-8-3-475
4. Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol Spectr. 2016;4(2). doi:10.1128/microbiolspec.UTI-0012-2012
5. Schuur PM, Kasteren ME, Sabbe L, Vos MC, Janssens MM, Buiting AG. Urinary tract infections with Aerococcus urinae in the south of The Netherlands. Eur J Clin Microbiol Infect Dis. 1997;16(12):871-875. doi:10.1007/BF01700552
6. Grude N, Tveten Y. Aerococcus urinae og urinveisinfeksjon [Aerococcus urinae and urinary tract infection]. Tidsskr Nor Laegeforen. 2002;122(2):174-175.
7. Narayanasamy S, King K, Dennison A, Spelman DW, Aung AK. Clinical characteristics and laboratory identification of Aerococcus infections: an Australian tertiary centre perspective. Int J Microbiol. 2017;2017. doi:10.1155/2017/5684614
8. Hilt EE, McKinley K, Pearce MM, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871-876. doi:10.1128/JCM.02876-13
9. Pearce MM, Hilt EE, Rosenfeld AB, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5(4):e01283-14. doi:10.1128/mBio.01283-14
10. Sahu KK, Lal A, Mishra AK, Abraham GM. Aerococcus-related infections and their significance: a 9-year retrospective study. J Microsc Ultrastruct. 2021;9(1):18-25. doi:10.4103/JMAU.JMAU_61_19
11. Skov RL, Klarlund M, Thorsen S. Fatal endocarditis due to Aerococcus urinae. Diagn Microbiol Infect Dis. 1995;21(4):219-221. doi:10.1016/0732-8893(95)00037-b
12. Kristensen B, Nielsen G. Endocarditis caused by Aerococcus urinae, a newly recognized pathogen. Eur J Clin Microbiol Infect Dis. 1995;14(1):49-51. doi:10.1007/BF02112619
13. Astudillo L, Sailler L, Porte L, Lefevre JC, Massip P, Arlet-Suau E. Spondylodiscitis due to Aerococcus urinae: a first report. Scand J Infect Dis. 2003;35(11-12):890-891. doi:10.1080/00365540310016664
14. Lyagoubi A, Souffi C, Baroiller V, Vallee E. Spondylodiscitis: an increasingly described localization. EJIFCC. 2020;31(2):169-173.
15. Jerome M, Slim J, Sison R, Marton R. A case of Aerococcus urinae vertebral osteomyelitis. J Glob Infect Dis. 2015;7(2):85-86. doi:10.4103/0974-777X.157246
16. Tekin A, Tekin G, Turunç T, Demiroğlu Z, Kizilkiliç O. Infective endocarditis and spondylodiscitis in a patient due to Aerococcus urinae: first report. Int J Cardiol. 2007;115(3):402-403. doi:10.1016/j.ijcard.2006.01.046
17. Rougier E, Braud A, Argemi X, et al. Spondylodiscitis due to Aerococcus urinae and literature review. Infection. 2018;46(3):419-421. doi:10.1007/s15010-017-1106-0
18. Degroote E, Yildiz H, Lecouvet F, Verroken A, Belkhir L. Aerococcus urinae: an underestimated cause of spine infection? Case report and review of the literature. Acta Clin Belg. 2018;73(6):444-447. doi:10.1080/17843286.2018.1443003
19. Torres-Martos E, Pérez-Cortés S, Sánchez-Calvo JM, López-Prieto MD. Spondylodiscitis due to Aerococcus urinae infection in an elderly immunocompetent patient. Enferm Infecc Microbiol Clin. 2017;35(10):682-684. doi:10.1016/j.eimc.2017.02.005
20. Senneby E, Petersson AC, Rasmussen M. Clinical and microbiological features of bacteraemia with Aerococcus urinae. Clin Microbiol Infect. 2012;18(6):546-550. doi:10.1111/j.1469-0691.2011.03609.x
21. Sunnerhagen T, Nilson B, Olaison L, Rasmussen M. Clinical and microbiological features of infective endocarditis caused by aerococci. Infection. 2016;44(2):167-173. doi:10.1007/s15010-015-0812-8
22. de Jong MF, Soetekouw R, ten Kate RW, Veenendaal D. Aerococcus urinae: severe and fatal bloodstream infections and endocarditis. J Clin Microbiol. 2010;48(9):3445-3447. doi:10.1128/JCM.00835-10
23. Babaeer AA, Nader C, Iacoviello V, Tomera K. Necrotizing urethritis due to Aerococcus urinae. Case Rep Urol. 2015;2015:136147. doi:10.1155/2015/136147
24. Sierra-Hoffman M, Watkins K, Jinadatha C, Fader R, Carpenter JL. Clinical significance of Aerococcus urinae: a retrospective review. Diagn Microbiol Infect Dis. 2005;53(4):289-292. doi:10.1016/j.diagmicrobio.2005.06.021
25. Fukami H, Takeuchi Y, Kagaya S, et al. Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis. Int J Gen Med. 2017;10:137-144. doi:10.2147/IJGM.S133685
26. Han NY, Sung DJ, Kim MJ, Park BJ, Sim KC, Cho SB. Perirenal fat stranding on CT: is there an association with bladder outlet obstruction? Br J Radiol. 2016;89(1063):20160195. doi:10.1259/bjr.20160195
27. Hirzel C, Hirzberger L, Furrer H, Endimiani A. Bactericidal activity of penicillin, ceftriaxone, gentamicin and daptomycin alone and in combination against Aerococcus urinae. Int J Antimicrob Agents. 2016;48(3):271-276. doi:10.1016/j.ijantimicag.2016.05.007
28. Zbinden R, Santanam P, Hunziker L, Leuzinger B, von Graevenitz A. Endocarditis due to Aerococcus urinae: diagnostic tests, fatty acid composition and killing kinetics. Infection. 1999;27(2):122-124. doi:10.1007/BF02560511
29. Skov R, Christensen JJ, Korner B, Frimodt-Møller N, Espersen F. In vitro antimicrobial susceptibility of Aerococcus urinae to 14 antibiotics, and time-kill curves for penicillin, gentamicin and vancomycin. J Antimicrob Chemother. 2001;48(5):653-658. doi:10.1093/jac/48.5.653
30. Ebnöther C, Altwegg M, Gottschalk J, Seebach JD, Kronenberg A. Aerococcus urinae endocarditis: case report and review of the literature. Infection. 2002;30(5):310-313. doi:10.1007/s15010-002-3106-x
31. Tai DBG, Go JR, Fida M, Saleh OA. Management and treatment of Aerococcus bacteremia and endocarditis. Int J Infect Dis. 2021;102:584-589. doi:10.1016/j.ijid.2020.10.096
32. Li H-K, Rombach I, Zambellas R, et al; OVIVA Trial Collaborators. Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med. 2019;380(5):425-436. doi:10.1056/NEJMoa1710926
33. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med. 2019;380(5):415-424. doi:10.1056/NEJMoa1808312
1. Christensen JJ, Korner B, Kjaergaard H. Aerococcus-like organism—an unnoticed urinary tract pathogen. APMIS. 1989;97(6):539-546. doi:10.1111/j.1699-0463.1989.tb00828.x
2. Aguirre M, Collins MD. Phylogenetic analysis of some Aerococcus-like organisms from urinary tract infections: description of Aerococcus urinae sp. nov. J Gen Microbiol. 1992;138(2):401-405. doi:10.1099/00221287-138-2-401
3. Williams RE, Hirch A, Cowan ST. Aerococcus, a new bacterial genus. J Gen Microbiol. 1953;8(3):475-480. doi:10.1099/00221287-8-3-475
4. Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol Spectr. 2016;4(2). doi:10.1128/microbiolspec.UTI-0012-2012
5. Schuur PM, Kasteren ME, Sabbe L, Vos MC, Janssens MM, Buiting AG. Urinary tract infections with Aerococcus urinae in the south of The Netherlands. Eur J Clin Microbiol Infect Dis. 1997;16(12):871-875. doi:10.1007/BF01700552
6. Grude N, Tveten Y. Aerococcus urinae og urinveisinfeksjon [Aerococcus urinae and urinary tract infection]. Tidsskr Nor Laegeforen. 2002;122(2):174-175.
7. Narayanasamy S, King K, Dennison A, Spelman DW, Aung AK. Clinical characteristics and laboratory identification of Aerococcus infections: an Australian tertiary centre perspective. Int J Microbiol. 2017;2017. doi:10.1155/2017/5684614
8. Hilt EE, McKinley K, Pearce MM, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871-876. doi:10.1128/JCM.02876-13
9. Pearce MM, Hilt EE, Rosenfeld AB, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5(4):e01283-14. doi:10.1128/mBio.01283-14
10. Sahu KK, Lal A, Mishra AK, Abraham GM. Aerococcus-related infections and their significance: a 9-year retrospective study. J Microsc Ultrastruct. 2021;9(1):18-25. doi:10.4103/JMAU.JMAU_61_19
11. Skov RL, Klarlund M, Thorsen S. Fatal endocarditis due to Aerococcus urinae. Diagn Microbiol Infect Dis. 1995;21(4):219-221. doi:10.1016/0732-8893(95)00037-b
12. Kristensen B, Nielsen G. Endocarditis caused by Aerococcus urinae, a newly recognized pathogen. Eur J Clin Microbiol Infect Dis. 1995;14(1):49-51. doi:10.1007/BF02112619
13. Astudillo L, Sailler L, Porte L, Lefevre JC, Massip P, Arlet-Suau E. Spondylodiscitis due to Aerococcus urinae: a first report. Scand J Infect Dis. 2003;35(11-12):890-891. doi:10.1080/00365540310016664
14. Lyagoubi A, Souffi C, Baroiller V, Vallee E. Spondylodiscitis: an increasingly described localization. EJIFCC. 2020;31(2):169-173.
15. Jerome M, Slim J, Sison R, Marton R. A case of Aerococcus urinae vertebral osteomyelitis. J Glob Infect Dis. 2015;7(2):85-86. doi:10.4103/0974-777X.157246
16. Tekin A, Tekin G, Turunç T, Demiroğlu Z, Kizilkiliç O. Infective endocarditis and spondylodiscitis in a patient due to Aerococcus urinae: first report. Int J Cardiol. 2007;115(3):402-403. doi:10.1016/j.ijcard.2006.01.046
17. Rougier E, Braud A, Argemi X, et al. Spondylodiscitis due to Aerococcus urinae and literature review. Infection. 2018;46(3):419-421. doi:10.1007/s15010-017-1106-0
18. Degroote E, Yildiz H, Lecouvet F, Verroken A, Belkhir L. Aerococcus urinae: an underestimated cause of spine infection? Case report and review of the literature. Acta Clin Belg. 2018;73(6):444-447. doi:10.1080/17843286.2018.1443003
19. Torres-Martos E, Pérez-Cortés S, Sánchez-Calvo JM, López-Prieto MD. Spondylodiscitis due to Aerococcus urinae infection in an elderly immunocompetent patient. Enferm Infecc Microbiol Clin. 2017;35(10):682-684. doi:10.1016/j.eimc.2017.02.005
20. Senneby E, Petersson AC, Rasmussen M. Clinical and microbiological features of bacteraemia with Aerococcus urinae. Clin Microbiol Infect. 2012;18(6):546-550. doi:10.1111/j.1469-0691.2011.03609.x
21. Sunnerhagen T, Nilson B, Olaison L, Rasmussen M. Clinical and microbiological features of infective endocarditis caused by aerococci. Infection. 2016;44(2):167-173. doi:10.1007/s15010-015-0812-8
22. de Jong MF, Soetekouw R, ten Kate RW, Veenendaal D. Aerococcus urinae: severe and fatal bloodstream infections and endocarditis. J Clin Microbiol. 2010;48(9):3445-3447. doi:10.1128/JCM.00835-10
23. Babaeer AA, Nader C, Iacoviello V, Tomera K. Necrotizing urethritis due to Aerococcus urinae. Case Rep Urol. 2015;2015:136147. doi:10.1155/2015/136147
24. Sierra-Hoffman M, Watkins K, Jinadatha C, Fader R, Carpenter JL. Clinical significance of Aerococcus urinae: a retrospective review. Diagn Microbiol Infect Dis. 2005;53(4):289-292. doi:10.1016/j.diagmicrobio.2005.06.021
25. Fukami H, Takeuchi Y, Kagaya S, et al. Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis. Int J Gen Med. 2017;10:137-144. doi:10.2147/IJGM.S133685
26. Han NY, Sung DJ, Kim MJ, Park BJ, Sim KC, Cho SB. Perirenal fat stranding on CT: is there an association with bladder outlet obstruction? Br J Radiol. 2016;89(1063):20160195. doi:10.1259/bjr.20160195
27. Hirzel C, Hirzberger L, Furrer H, Endimiani A. Bactericidal activity of penicillin, ceftriaxone, gentamicin and daptomycin alone and in combination against Aerococcus urinae. Int J Antimicrob Agents. 2016;48(3):271-276. doi:10.1016/j.ijantimicag.2016.05.007
28. Zbinden R, Santanam P, Hunziker L, Leuzinger B, von Graevenitz A. Endocarditis due to Aerococcus urinae: diagnostic tests, fatty acid composition and killing kinetics. Infection. 1999;27(2):122-124. doi:10.1007/BF02560511
29. Skov R, Christensen JJ, Korner B, Frimodt-Møller N, Espersen F. In vitro antimicrobial susceptibility of Aerococcus urinae to 14 antibiotics, and time-kill curves for penicillin, gentamicin and vancomycin. J Antimicrob Chemother. 2001;48(5):653-658. doi:10.1093/jac/48.5.653
30. Ebnöther C, Altwegg M, Gottschalk J, Seebach JD, Kronenberg A. Aerococcus urinae endocarditis: case report and review of the literature. Infection. 2002;30(5):310-313. doi:10.1007/s15010-002-3106-x
31. Tai DBG, Go JR, Fida M, Saleh OA. Management and treatment of Aerococcus bacteremia and endocarditis. Int J Infect Dis. 2021;102:584-589. doi:10.1016/j.ijid.2020.10.096
32. Li H-K, Rombach I, Zambellas R, et al; OVIVA Trial Collaborators. Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med. 2019;380(5):425-436. doi:10.1056/NEJMoa1710926
33. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med. 2019;380(5):415-424. doi:10.1056/NEJMoa1808312
HIV vaccine trial makes pivotal leap toward making ‘super antibodies’
The announcement comes from the journal Science, which published phase 1 results of a small clinical trial for a vaccine technology that aims to cause the body to create a rare kind of cell.
“At the most general level, the trial results show that one can design vaccines that induce antibodies with prespecified genetic features, and this may herald a new era of precision vaccines,” William Schief, PhD, a researcher at the Scripps Research Institute and study coauthor, told the American Association for the Advancement of Science.
The study was the first to test the approach in humans and was effective in 97% – or 35 of 36 – participants. The vaccine technology is called “germline targeting.” Trial results show that “one can design a vaccine that elicits made-to-order antibodies in humans,” Dr. Schief said in a news release.
In addition to possibly being a breakthrough for the treatment of HIV, the vaccine technology could also impact the development of treatments for flu, hepatitis C, and coronaviruses, study authors wrote.
There is no cure for HIV, but there are treatments to manage how the disease progresses. HIV attacks the body’s immune system, destroys white blood cells, and increases susceptibility to other infections, AAAS summarized. More than 1 million people in the United States and 38 million people worldwide have HIV.
Previous HIV vaccine attempts were not able to cause the production of specialized cells known as “broadly neutralizing antibodies,” CNN reported.
“Call them super antibodies, if you want,” University of Minnesota HIV researcher Timothy Schacker, MD, who was not involved in the research, told CNN. “The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses that we’ve had a very hard time designing vaccines for that are effective. So this is an important step forward.”
Study authors said this is just the first step in the multiphase vaccine design, which so far is a theory. Further study is needed to see if the next steps also work in humans, and then if all the steps can be linked together and can be effective against HIV.
A version of this article first appeared on WebMD.com.
The announcement comes from the journal Science, which published phase 1 results of a small clinical trial for a vaccine technology that aims to cause the body to create a rare kind of cell.
“At the most general level, the trial results show that one can design vaccines that induce antibodies with prespecified genetic features, and this may herald a new era of precision vaccines,” William Schief, PhD, a researcher at the Scripps Research Institute and study coauthor, told the American Association for the Advancement of Science.
The study was the first to test the approach in humans and was effective in 97% – or 35 of 36 – participants. The vaccine technology is called “germline targeting.” Trial results show that “one can design a vaccine that elicits made-to-order antibodies in humans,” Dr. Schief said in a news release.
In addition to possibly being a breakthrough for the treatment of HIV, the vaccine technology could also impact the development of treatments for flu, hepatitis C, and coronaviruses, study authors wrote.
There is no cure for HIV, but there are treatments to manage how the disease progresses. HIV attacks the body’s immune system, destroys white blood cells, and increases susceptibility to other infections, AAAS summarized. More than 1 million people in the United States and 38 million people worldwide have HIV.
Previous HIV vaccine attempts were not able to cause the production of specialized cells known as “broadly neutralizing antibodies,” CNN reported.
“Call them super antibodies, if you want,” University of Minnesota HIV researcher Timothy Schacker, MD, who was not involved in the research, told CNN. “The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses that we’ve had a very hard time designing vaccines for that are effective. So this is an important step forward.”
Study authors said this is just the first step in the multiphase vaccine design, which so far is a theory. Further study is needed to see if the next steps also work in humans, and then if all the steps can be linked together and can be effective against HIV.
A version of this article first appeared on WebMD.com.
The announcement comes from the journal Science, which published phase 1 results of a small clinical trial for a vaccine technology that aims to cause the body to create a rare kind of cell.
“At the most general level, the trial results show that one can design vaccines that induce antibodies with prespecified genetic features, and this may herald a new era of precision vaccines,” William Schief, PhD, a researcher at the Scripps Research Institute and study coauthor, told the American Association for the Advancement of Science.
The study was the first to test the approach in humans and was effective in 97% – or 35 of 36 – participants. The vaccine technology is called “germline targeting.” Trial results show that “one can design a vaccine that elicits made-to-order antibodies in humans,” Dr. Schief said in a news release.
In addition to possibly being a breakthrough for the treatment of HIV, the vaccine technology could also impact the development of treatments for flu, hepatitis C, and coronaviruses, study authors wrote.
There is no cure for HIV, but there are treatments to manage how the disease progresses. HIV attacks the body’s immune system, destroys white blood cells, and increases susceptibility to other infections, AAAS summarized. More than 1 million people in the United States and 38 million people worldwide have HIV.
Previous HIV vaccine attempts were not able to cause the production of specialized cells known as “broadly neutralizing antibodies,” CNN reported.
“Call them super antibodies, if you want,” University of Minnesota HIV researcher Timothy Schacker, MD, who was not involved in the research, told CNN. “The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses that we’ve had a very hard time designing vaccines for that are effective. So this is an important step forward.”
Study authors said this is just the first step in the multiphase vaccine design, which so far is a theory. Further study is needed to see if the next steps also work in humans, and then if all the steps can be linked together and can be effective against HIV.
A version of this article first appeared on WebMD.com.
FROM SCIENCE
CAB-LA’s full potential for HIV prevention hits snags
, say authors of a new review article.
CAB-LA “represents the most important breakthrough in HIV prevention in recent years,” write Geoffroy Liegeon, MD, and Jade Ghosn, MD, PhD, with Université Paris Cité, in this month’s HIV Medicine.
It has been found to be safe, and more effective in phase 3 trials than oral PrEP, and is well-accepted in men who have sex with men, and transgender and cisgender women.
Reductions in stigma
Surveys show patients at high risk for HIV – especially those who see PrEP as burdensome – are highly interested in long-acting injectable drugs. Reduced stigma with the injections also appears to steer the choice toward a long-acting agent and may attract more people to HIV prevention programs.
The first two injections are given 4 weeks apart, followed by an injection every 8 weeks.
Models designed to increase uptake, adherence, and persistence when on and after discontinuing CAB-LA will be important for wider rollout, as will better patient education and demonstrated efficacy and safety in populations not included in clinical trials, Dr. Liegeon and Dr. Ghosn note.
Still, they point out that its broader integration into clinical routine is held back by factors including breakthrough infections despite timely injections, complexity of follow-up, logistical considerations, and its cost-effectiveness compared with oral PrEP.
A hefty price tag
“[T]he cost effectiveness compared with TDF-FTC [tenofovir/emtricitabine] generics may not support its use at the current price in many settings,” the authors write.
For low- and middle-income countries, the TDF/FTC price is about $55, according to the World Health Organization’s Global Price Reporting, while the current price of CAB-LA in the United States is about $22,000, according to Dr. Ghosn. He said in an interview that because the cost of generics can reach $400-$500 per year in the United States, depending on the pharmaceutical companies, the price for CAB-LA is almost 60 times higher than TDF/FTC in the Untied States.
The biggest hope for the price reduction, at least in lower-income countries, he said, is a new licensing agreement.
ViiV Healthcare signed a new voluntary licensing agreement with the Medicines Patent Pool in July to help access in low-income, lower-middle-income, and sub-Saharan African countries, he explained.
The authors summarize: “[E]stablishing the effectiveness of CAB-LA does not guarantee its uptake into clinical routine.”
Because of the combined issues, the WHO recommended CAB-LA as an additional prevention choice for PrEP in its recent guidelines, pending further studies.
Barriers frustrate providers
Lauren Fontana, DO, assistant professor at the University of Minnesota, Minneapolis, and infectious disease physician at M Health Fairview, said in an interview that “as a health care provider, cost and insurance barriers can be frustrating, especially when CAB-LA is identified as the best option for a patient.”
Lack of nonphysician-led initiatives, such as nurse- or pharmacy-led services for CAB-LA, may limit availability to marginalized and at-risk populations, she said.
“If a clinic can acquire CAB-LA, clinic protocols need to be developed and considerations of missed visits and doses must be thought about when implementing a program,” Dr. Fontana said.
Clinics need resources to engage with patients to promote retention in the program with case management and pharmacy support, she added.
“Simplification processes need to be developed to make CAB-LA an option for more clinics and patients,” she continued. “We are still learning about the incidence of breakthrough HIV infections, patterns of HIV seroconversion, and how to optimize testing so that HIV infections are detected early.”
Dr. Liegeon, Dr. Ghosn, and Dr. Fontana report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, say authors of a new review article.
CAB-LA “represents the most important breakthrough in HIV prevention in recent years,” write Geoffroy Liegeon, MD, and Jade Ghosn, MD, PhD, with Université Paris Cité, in this month’s HIV Medicine.
It has been found to be safe, and more effective in phase 3 trials than oral PrEP, and is well-accepted in men who have sex with men, and transgender and cisgender women.
Reductions in stigma
Surveys show patients at high risk for HIV – especially those who see PrEP as burdensome – are highly interested in long-acting injectable drugs. Reduced stigma with the injections also appears to steer the choice toward a long-acting agent and may attract more people to HIV prevention programs.
The first two injections are given 4 weeks apart, followed by an injection every 8 weeks.
Models designed to increase uptake, adherence, and persistence when on and after discontinuing CAB-LA will be important for wider rollout, as will better patient education and demonstrated efficacy and safety in populations not included in clinical trials, Dr. Liegeon and Dr. Ghosn note.
Still, they point out that its broader integration into clinical routine is held back by factors including breakthrough infections despite timely injections, complexity of follow-up, logistical considerations, and its cost-effectiveness compared with oral PrEP.
A hefty price tag
“[T]he cost effectiveness compared with TDF-FTC [tenofovir/emtricitabine] generics may not support its use at the current price in many settings,” the authors write.
For low- and middle-income countries, the TDF/FTC price is about $55, according to the World Health Organization’s Global Price Reporting, while the current price of CAB-LA in the United States is about $22,000, according to Dr. Ghosn. He said in an interview that because the cost of generics can reach $400-$500 per year in the United States, depending on the pharmaceutical companies, the price for CAB-LA is almost 60 times higher than TDF/FTC in the Untied States.
The biggest hope for the price reduction, at least in lower-income countries, he said, is a new licensing agreement.
ViiV Healthcare signed a new voluntary licensing agreement with the Medicines Patent Pool in July to help access in low-income, lower-middle-income, and sub-Saharan African countries, he explained.
The authors summarize: “[E]stablishing the effectiveness of CAB-LA does not guarantee its uptake into clinical routine.”
Because of the combined issues, the WHO recommended CAB-LA as an additional prevention choice for PrEP in its recent guidelines, pending further studies.
Barriers frustrate providers
Lauren Fontana, DO, assistant professor at the University of Minnesota, Minneapolis, and infectious disease physician at M Health Fairview, said in an interview that “as a health care provider, cost and insurance barriers can be frustrating, especially when CAB-LA is identified as the best option for a patient.”
Lack of nonphysician-led initiatives, such as nurse- or pharmacy-led services for CAB-LA, may limit availability to marginalized and at-risk populations, she said.
“If a clinic can acquire CAB-LA, clinic protocols need to be developed and considerations of missed visits and doses must be thought about when implementing a program,” Dr. Fontana said.
Clinics need resources to engage with patients to promote retention in the program with case management and pharmacy support, she added.
“Simplification processes need to be developed to make CAB-LA an option for more clinics and patients,” she continued. “We are still learning about the incidence of breakthrough HIV infections, patterns of HIV seroconversion, and how to optimize testing so that HIV infections are detected early.”
Dr. Liegeon, Dr. Ghosn, and Dr. Fontana report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, say authors of a new review article.
CAB-LA “represents the most important breakthrough in HIV prevention in recent years,” write Geoffroy Liegeon, MD, and Jade Ghosn, MD, PhD, with Université Paris Cité, in this month’s HIV Medicine.
It has been found to be safe, and more effective in phase 3 trials than oral PrEP, and is well-accepted in men who have sex with men, and transgender and cisgender women.
Reductions in stigma
Surveys show patients at high risk for HIV – especially those who see PrEP as burdensome – are highly interested in long-acting injectable drugs. Reduced stigma with the injections also appears to steer the choice toward a long-acting agent and may attract more people to HIV prevention programs.
The first two injections are given 4 weeks apart, followed by an injection every 8 weeks.
Models designed to increase uptake, adherence, and persistence when on and after discontinuing CAB-LA will be important for wider rollout, as will better patient education and demonstrated efficacy and safety in populations not included in clinical trials, Dr. Liegeon and Dr. Ghosn note.
Still, they point out that its broader integration into clinical routine is held back by factors including breakthrough infections despite timely injections, complexity of follow-up, logistical considerations, and its cost-effectiveness compared with oral PrEP.
A hefty price tag
“[T]he cost effectiveness compared with TDF-FTC [tenofovir/emtricitabine] generics may not support its use at the current price in many settings,” the authors write.
For low- and middle-income countries, the TDF/FTC price is about $55, according to the World Health Organization’s Global Price Reporting, while the current price of CAB-LA in the United States is about $22,000, according to Dr. Ghosn. He said in an interview that because the cost of generics can reach $400-$500 per year in the United States, depending on the pharmaceutical companies, the price for CAB-LA is almost 60 times higher than TDF/FTC in the Untied States.
The biggest hope for the price reduction, at least in lower-income countries, he said, is a new licensing agreement.
ViiV Healthcare signed a new voluntary licensing agreement with the Medicines Patent Pool in July to help access in low-income, lower-middle-income, and sub-Saharan African countries, he explained.
The authors summarize: “[E]stablishing the effectiveness of CAB-LA does not guarantee its uptake into clinical routine.”
Because of the combined issues, the WHO recommended CAB-LA as an additional prevention choice for PrEP in its recent guidelines, pending further studies.
Barriers frustrate providers
Lauren Fontana, DO, assistant professor at the University of Minnesota, Minneapolis, and infectious disease physician at M Health Fairview, said in an interview that “as a health care provider, cost and insurance barriers can be frustrating, especially when CAB-LA is identified as the best option for a patient.”
Lack of nonphysician-led initiatives, such as nurse- or pharmacy-led services for CAB-LA, may limit availability to marginalized and at-risk populations, she said.
“If a clinic can acquire CAB-LA, clinic protocols need to be developed and considerations of missed visits and doses must be thought about when implementing a program,” Dr. Fontana said.
Clinics need resources to engage with patients to promote retention in the program with case management and pharmacy support, she added.
“Simplification processes need to be developed to make CAB-LA an option for more clinics and patients,” she continued. “We are still learning about the incidence of breakthrough HIV infections, patterns of HIV seroconversion, and how to optimize testing so that HIV infections are detected early.”
Dr. Liegeon, Dr. Ghosn, and Dr. Fontana report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HIV MEDICINE
Pregnancy outcomes on long-acting antiretroviral
In a cautiously optimistic report,
Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.
“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.
“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”
The study was published in HIV Medicine.
“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
Pregnancies in trials excluding pregnant women
In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.
Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
Pregnancy outcomes
Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.
The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.
Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.
Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.
“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
Planned studies during pregnancy
Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.
“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.
“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”
Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.
“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”
Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”
Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.
This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a cautiously optimistic report,
Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.
“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.
“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”
The study was published in HIV Medicine.
“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
Pregnancies in trials excluding pregnant women
In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.
Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
Pregnancy outcomes
Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.
The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.
Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.
Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.
“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
Planned studies during pregnancy
Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.
“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.
“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”
Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.
“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”
Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”
Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.
This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a cautiously optimistic report,
Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.
“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.
“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”
The study was published in HIV Medicine.
“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
Pregnancies in trials excluding pregnant women
In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.
Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
Pregnancy outcomes
Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.
The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.
Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.
Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.
“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
Planned studies during pregnancy
Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.
“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.
“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”
Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.
“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”
Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”
Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.
This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HIV MEDICINE