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Antibiotic prophylaxis for artificial joints
A 66-year-old woman 3 years status post hip replacement is seen for dental work. The dentist contacts the clinic for an antibiotic prescription. The patient has a penicillin allergy (rash). What do you recommend?
A. Clindamycin one dose before dental work.
B. Amoxicillin one dose before dental work.
C. Amoxicillin one dose before, one dose 4 hours after dental work.
D. Clindamycin one dose before dental work, one dose 4 hours after dental work.
E. No antibiotics.
Many patients with prosthetic joints will request antibiotics to take prior to dental procedures. Sometimes this request comes from the dental office.
When I ask patients why they feel they need antibiotics, they often reply that they were told by their orthopedic surgeons or their dentist that they would need to take antibiotics before dental procedures.
In an era when Clostridium difficile infection is a common and dangerous complication in the elderly, avoidance of unnecessary antibiotics is critical. In the United States, it is estimated that there are 240,000 patients infected with C. difficile annually, with 24,000 deaths at a cost of $6 billion.1
Is there compelling evidence to justify giving antibiotic prophylaxis for dental procedures to patients with prosthetic joints?
This information has called into question the wisdom of giving antibiotic prophylaxis for dental procedures when the same patients have transient bacteremias as a regular part of day-to-day life, and mouth organisms were infrequent causes of prosthetic joint infections.
The American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA) released an advisory statement 20 years ago on antibiotic prophylaxis for patients with dental replacements, which concluded: “Antibiotic prophylaxis is not indicated for dental patients with pins, plates, and screws, nor is it routinely indicated for most dental patients with total joint replacements.”4
In 2003, the AAOS and the ADA released updated guidelines that stated: “Presently, no scientific evidence supports the position that antibiotic prophylaxis to prevent hematogenous infections is required prior to dental treatment in patients with total joint prostheses. The risk/benefit and cost/effectiveness ratios fail to justify the administration of routine antibiotics.”5
Great confusion arose in 2009 when the AAOS published a position paper on its website that reversed this position.6 Interestingly, the statement was done by the AAOS alone, and not done in conjunction with the ADA.
In this position paper, the AAOS recommended that health care providers consider antibiotic prophylaxis prior to invasive procedures on all patients who had prosthetic joints, regardless of how long those joints have been in place. This major change in recommendations was not based on any new evidence that had been reviewed since the 2003 guidelines.
There are two studies that address outcome of patients with prosthetic joints who have and have not received prophylactic antibiotics.
Elie Berbari, MD, and colleagues reported on the results of a prospective case-control study comparing patients with prosthetic joints hospitalized with hip or knee infections with patients who had prosthetic joints hospitalized at the same time who did not have hip or knee infections.7
There was no increased risk of prosthetic hip or knee infection for patients undergoing a dental procedure who were not receiving antibiotic prophylaxis (odds ratio, 0.8; 95% confidence interval, 0.4-1.6), compared with the risk for patients not undergoing a dental procedure (OR, 0.6; 95% CI, 0.4-1.1). Antibiotic prophylaxis in patients undergoing high and low risk dental procedures did not decrease the risk of prosthetic joint infections.
In 2012, the AAOS and the ADA published updated guidelines with the following summary recommendation: “The practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures.”8 They referenced the Berbari study as the best available evidence.
Feng-Chen Kao, MD, and colleagues published a study this year with a design very similar to the Berbari study, with similar results.9 All Taiwanese residents who had received hip or knee replacements over a 12-year period were screened. Those who had received dental procedures were matched with individuals who had not had dental procedures. The dental procedure group was subdivided into a group that received antibiotics and one that didn’t.
There was no difference in infection rates between the group that had received dental procedures and the group that did not, and no difference in infection rates between those who received prophylactic antibiotics and those who didn’t.
I think this myth can be put to rest. There is no evidence to give patients with joint prostheses prophylactic antibiotics before dental procedures.
References
1. Steckelberg J.M., Osmon D.R. Prosthetic joint infections. In: Bisno A.L., Waldvogel F.A., eds. Infections associated with indwelling medical devices. Third ed., Washington, D.C.: American Society of Microbiology Press, 2000:173-209.
2. J Dent Res. 2004 Feb;83(2):170-4.
3. J Clin Periodontol. 2006 Feb;33(6):401-7.
4. J Am Dent Assoc. 1997 Jul;128(7):1004-8.
5. J Am Dent Assoc. 2003 Jul;134(7):895-9.
6. Spec Care Dentist. 2009 Nov-Dec;29(6):229-31.
7. Clin Infect Dis. 2010 Jan 1;50(1):8-16.
8. J Dent (Shiraz). 2013 Mar;14(1):49-52.
9. Infect Control Hosp Epidemiol. 2017 Feb;38(2):154-61.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
A 66-year-old woman 3 years status post hip replacement is seen for dental work. The dentist contacts the clinic for an antibiotic prescription. The patient has a penicillin allergy (rash). What do you recommend?
A. Clindamycin one dose before dental work.
B. Amoxicillin one dose before dental work.
C. Amoxicillin one dose before, one dose 4 hours after dental work.
D. Clindamycin one dose before dental work, one dose 4 hours after dental work.
E. No antibiotics.
Many patients with prosthetic joints will request antibiotics to take prior to dental procedures. Sometimes this request comes from the dental office.
When I ask patients why they feel they need antibiotics, they often reply that they were told by their orthopedic surgeons or their dentist that they would need to take antibiotics before dental procedures.
In an era when Clostridium difficile infection is a common and dangerous complication in the elderly, avoidance of unnecessary antibiotics is critical. In the United States, it is estimated that there are 240,000 patients infected with C. difficile annually, with 24,000 deaths at a cost of $6 billion.1
Is there compelling evidence to justify giving antibiotic prophylaxis for dental procedures to patients with prosthetic joints?
This information has called into question the wisdom of giving antibiotic prophylaxis for dental procedures when the same patients have transient bacteremias as a regular part of day-to-day life, and mouth organisms were infrequent causes of prosthetic joint infections.
The American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA) released an advisory statement 20 years ago on antibiotic prophylaxis for patients with dental replacements, which concluded: “Antibiotic prophylaxis is not indicated for dental patients with pins, plates, and screws, nor is it routinely indicated for most dental patients with total joint replacements.”4
In 2003, the AAOS and the ADA released updated guidelines that stated: “Presently, no scientific evidence supports the position that antibiotic prophylaxis to prevent hematogenous infections is required prior to dental treatment in patients with total joint prostheses. The risk/benefit and cost/effectiveness ratios fail to justify the administration of routine antibiotics.”5
Great confusion arose in 2009 when the AAOS published a position paper on its website that reversed this position.6 Interestingly, the statement was done by the AAOS alone, and not done in conjunction with the ADA.
In this position paper, the AAOS recommended that health care providers consider antibiotic prophylaxis prior to invasive procedures on all patients who had prosthetic joints, regardless of how long those joints have been in place. This major change in recommendations was not based on any new evidence that had been reviewed since the 2003 guidelines.
There are two studies that address outcome of patients with prosthetic joints who have and have not received prophylactic antibiotics.
Elie Berbari, MD, and colleagues reported on the results of a prospective case-control study comparing patients with prosthetic joints hospitalized with hip or knee infections with patients who had prosthetic joints hospitalized at the same time who did not have hip or knee infections.7
There was no increased risk of prosthetic hip or knee infection for patients undergoing a dental procedure who were not receiving antibiotic prophylaxis (odds ratio, 0.8; 95% confidence interval, 0.4-1.6), compared with the risk for patients not undergoing a dental procedure (OR, 0.6; 95% CI, 0.4-1.1). Antibiotic prophylaxis in patients undergoing high and low risk dental procedures did not decrease the risk of prosthetic joint infections.
In 2012, the AAOS and the ADA published updated guidelines with the following summary recommendation: “The practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures.”8 They referenced the Berbari study as the best available evidence.
Feng-Chen Kao, MD, and colleagues published a study this year with a design very similar to the Berbari study, with similar results.9 All Taiwanese residents who had received hip or knee replacements over a 12-year period were screened. Those who had received dental procedures were matched with individuals who had not had dental procedures. The dental procedure group was subdivided into a group that received antibiotics and one that didn’t.
There was no difference in infection rates between the group that had received dental procedures and the group that did not, and no difference in infection rates between those who received prophylactic antibiotics and those who didn’t.
I think this myth can be put to rest. There is no evidence to give patients with joint prostheses prophylactic antibiotics before dental procedures.
References
1. Steckelberg J.M., Osmon D.R. Prosthetic joint infections. In: Bisno A.L., Waldvogel F.A., eds. Infections associated with indwelling medical devices. Third ed., Washington, D.C.: American Society of Microbiology Press, 2000:173-209.
2. J Dent Res. 2004 Feb;83(2):170-4.
3. J Clin Periodontol. 2006 Feb;33(6):401-7.
4. J Am Dent Assoc. 1997 Jul;128(7):1004-8.
5. J Am Dent Assoc. 2003 Jul;134(7):895-9.
6. Spec Care Dentist. 2009 Nov-Dec;29(6):229-31.
7. Clin Infect Dis. 2010 Jan 1;50(1):8-16.
8. J Dent (Shiraz). 2013 Mar;14(1):49-52.
9. Infect Control Hosp Epidemiol. 2017 Feb;38(2):154-61.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
A 66-year-old woman 3 years status post hip replacement is seen for dental work. The dentist contacts the clinic for an antibiotic prescription. The patient has a penicillin allergy (rash). What do you recommend?
A. Clindamycin one dose before dental work.
B. Amoxicillin one dose before dental work.
C. Amoxicillin one dose before, one dose 4 hours after dental work.
D. Clindamycin one dose before dental work, one dose 4 hours after dental work.
E. No antibiotics.
Many patients with prosthetic joints will request antibiotics to take prior to dental procedures. Sometimes this request comes from the dental office.
When I ask patients why they feel they need antibiotics, they often reply that they were told by their orthopedic surgeons or their dentist that they would need to take antibiotics before dental procedures.
In an era when Clostridium difficile infection is a common and dangerous complication in the elderly, avoidance of unnecessary antibiotics is critical. In the United States, it is estimated that there are 240,000 patients infected with C. difficile annually, with 24,000 deaths at a cost of $6 billion.1
Is there compelling evidence to justify giving antibiotic prophylaxis for dental procedures to patients with prosthetic joints?
This information has called into question the wisdom of giving antibiotic prophylaxis for dental procedures when the same patients have transient bacteremias as a regular part of day-to-day life, and mouth organisms were infrequent causes of prosthetic joint infections.
The American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA) released an advisory statement 20 years ago on antibiotic prophylaxis for patients with dental replacements, which concluded: “Antibiotic prophylaxis is not indicated for dental patients with pins, plates, and screws, nor is it routinely indicated for most dental patients with total joint replacements.”4
In 2003, the AAOS and the ADA released updated guidelines that stated: “Presently, no scientific evidence supports the position that antibiotic prophylaxis to prevent hematogenous infections is required prior to dental treatment in patients with total joint prostheses. The risk/benefit and cost/effectiveness ratios fail to justify the administration of routine antibiotics.”5
Great confusion arose in 2009 when the AAOS published a position paper on its website that reversed this position.6 Interestingly, the statement was done by the AAOS alone, and not done in conjunction with the ADA.
In this position paper, the AAOS recommended that health care providers consider antibiotic prophylaxis prior to invasive procedures on all patients who had prosthetic joints, regardless of how long those joints have been in place. This major change in recommendations was not based on any new evidence that had been reviewed since the 2003 guidelines.
There are two studies that address outcome of patients with prosthetic joints who have and have not received prophylactic antibiotics.
Elie Berbari, MD, and colleagues reported on the results of a prospective case-control study comparing patients with prosthetic joints hospitalized with hip or knee infections with patients who had prosthetic joints hospitalized at the same time who did not have hip or knee infections.7
There was no increased risk of prosthetic hip or knee infection for patients undergoing a dental procedure who were not receiving antibiotic prophylaxis (odds ratio, 0.8; 95% confidence interval, 0.4-1.6), compared with the risk for patients not undergoing a dental procedure (OR, 0.6; 95% CI, 0.4-1.1). Antibiotic prophylaxis in patients undergoing high and low risk dental procedures did not decrease the risk of prosthetic joint infections.
In 2012, the AAOS and the ADA published updated guidelines with the following summary recommendation: “The practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures.”8 They referenced the Berbari study as the best available evidence.
Feng-Chen Kao, MD, and colleagues published a study this year with a design very similar to the Berbari study, with similar results.9 All Taiwanese residents who had received hip or knee replacements over a 12-year period were screened. Those who had received dental procedures were matched with individuals who had not had dental procedures. The dental procedure group was subdivided into a group that received antibiotics and one that didn’t.
There was no difference in infection rates between the group that had received dental procedures and the group that did not, and no difference in infection rates between those who received prophylactic antibiotics and those who didn’t.
I think this myth can be put to rest. There is no evidence to give patients with joint prostheses prophylactic antibiotics before dental procedures.
References
1. Steckelberg J.M., Osmon D.R. Prosthetic joint infections. In: Bisno A.L., Waldvogel F.A., eds. Infections associated with indwelling medical devices. Third ed., Washington, D.C.: American Society of Microbiology Press, 2000:173-209.
2. J Dent Res. 2004 Feb;83(2):170-4.
3. J Clin Periodontol. 2006 Feb;33(6):401-7.
4. J Am Dent Assoc. 1997 Jul;128(7):1004-8.
5. J Am Dent Assoc. 2003 Jul;134(7):895-9.
6. Spec Care Dentist. 2009 Nov-Dec;29(6):229-31.
7. Clin Infect Dis. 2010 Jan 1;50(1):8-16.
8. J Dent (Shiraz). 2013 Mar;14(1):49-52.
9. Infect Control Hosp Epidemiol. 2017 Feb;38(2):154-61.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
Small study: Drug combo achieves negative bacterial culture in all TB patients
SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.
The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.
The mortality rate among study participants was less than 6%.
“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.
Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.
Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.
Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.
Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.
Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.
Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.
The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.
Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.
SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.
The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.
The mortality rate among study participants was less than 6%.
“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.
Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.
Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.
Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.
Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.
Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.
Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.
The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.
Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.
SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.
The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.
The mortality rate among study participants was less than 6%.
“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.
Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.
Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.
Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.
Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.
Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.
Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.
The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.
Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.
AT CROI
Key clinical point: An oral, three-drug combination led to undetectable bacteria levels.
Major finding: All of the patients in the study were culture negative at 4 months.
Data source: Open-label trial of 72 patients at two centers.
Disclosures: Dr. Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.
C. auris forms biofilms, enhancing its virulence, resistance
The emerging multidrug-resistant yeast organism Candida auris forms biofilms that enhance both its resistance and its virulence, according to in vitro analyses.
C. auris first attracted attention in 2009 because of its resistance to azoles and amphotericin B. Since then, it has been identified as the cause of life-threatening invasive infections worldwide, including hospital outbreaks across Asia and South America, wrote Leighann Sherry, PhD, a medical mycologist at the University of Glasgow, and her associates.
To determine whether the pathogen has the capacity to form biofilms, the investigators propagated several different strains in the laboratory and examined their development. In three separate trials, eight samples of each strain grew biofilms, which constitute “a key driver of candida pathogenicity.” In antifungal susceptibility tests, caspofungin was completely ineffective, an unexpected finding because the agent usually is highly effective against other candida species. Amphotericin B, liposomal amphotericin B, and fluconazole also were ineffective; micafungin and chlorhexidine were the most effective at clearing C. auris.
Biofilm formation “contributes not only to C. auris virulence but also to its [resistance] in hospital environments, increasing its ability to cause outbreaks,” Dr. Sherry and her associates said (Emerg. Infect. Dis. 2017 Feb;23[2]:328-31).
“Our findings suggest it is improbable that the spread and prevalence of C. auris can be controlled with antifungal stewardship approaches alone,” they noted, adding that “infection-prevention measures targeting C. auris biofilms in patients, on medical devices, and in the hospital environment will be required,” they noted.
The emerging multidrug-resistant yeast organism Candida auris forms biofilms that enhance both its resistance and its virulence, according to in vitro analyses.
C. auris first attracted attention in 2009 because of its resistance to azoles and amphotericin B. Since then, it has been identified as the cause of life-threatening invasive infections worldwide, including hospital outbreaks across Asia and South America, wrote Leighann Sherry, PhD, a medical mycologist at the University of Glasgow, and her associates.
To determine whether the pathogen has the capacity to form biofilms, the investigators propagated several different strains in the laboratory and examined their development. In three separate trials, eight samples of each strain grew biofilms, which constitute “a key driver of candida pathogenicity.” In antifungal susceptibility tests, caspofungin was completely ineffective, an unexpected finding because the agent usually is highly effective against other candida species. Amphotericin B, liposomal amphotericin B, and fluconazole also were ineffective; micafungin and chlorhexidine were the most effective at clearing C. auris.
Biofilm formation “contributes not only to C. auris virulence but also to its [resistance] in hospital environments, increasing its ability to cause outbreaks,” Dr. Sherry and her associates said (Emerg. Infect. Dis. 2017 Feb;23[2]:328-31).
“Our findings suggest it is improbable that the spread and prevalence of C. auris can be controlled with antifungal stewardship approaches alone,” they noted, adding that “infection-prevention measures targeting C. auris biofilms in patients, on medical devices, and in the hospital environment will be required,” they noted.
The emerging multidrug-resistant yeast organism Candida auris forms biofilms that enhance both its resistance and its virulence, according to in vitro analyses.
C. auris first attracted attention in 2009 because of its resistance to azoles and amphotericin B. Since then, it has been identified as the cause of life-threatening invasive infections worldwide, including hospital outbreaks across Asia and South America, wrote Leighann Sherry, PhD, a medical mycologist at the University of Glasgow, and her associates.
To determine whether the pathogen has the capacity to form biofilms, the investigators propagated several different strains in the laboratory and examined their development. In three separate trials, eight samples of each strain grew biofilms, which constitute “a key driver of candida pathogenicity.” In antifungal susceptibility tests, caspofungin was completely ineffective, an unexpected finding because the agent usually is highly effective against other candida species. Amphotericin B, liposomal amphotericin B, and fluconazole also were ineffective; micafungin and chlorhexidine were the most effective at clearing C. auris.
Biofilm formation “contributes not only to C. auris virulence but also to its [resistance] in hospital environments, increasing its ability to cause outbreaks,” Dr. Sherry and her associates said (Emerg. Infect. Dis. 2017 Feb;23[2]:328-31).
“Our findings suggest it is improbable that the spread and prevalence of C. auris can be controlled with antifungal stewardship approaches alone,” they noted, adding that “infection-prevention measures targeting C. auris biofilms in patients, on medical devices, and in the hospital environment will be required,” they noted.
FROM EMERGING INFECTIOUS DISEASES
Key clinical point: The emerging multidrug-resistant yeast organism Candida auris forms biofilms that enhance both its resistance and its virulence.
Major finding: In three separate trials, eight samples of each strain of C. auris grew biofilms that constitute “a key driver of Candida pathogenicity.”
Data source: In-vitro analyses of C. auris growth.
Disclosures: No funding source(s) or financial disclosures were provided.
Postdischarge antibiotics for complicated pneumonia
Clinical question: Are oral antibiotics as effective as intravenous (IV) antibiotics in the treatment of complicated pneumonia after discharge to home?
Background: Pneumonia is the most common illness among hospitalized children and adolescents (excluding neonates). Among children admitted with community acquired pneumonia, 15% may develop a complicated pneumonia (one with a pleural effusion or empyema). Treatment for these complicated pneumonias may include a variety of invasive procedures, such as video-assisted thorascopic surgery or chest tube placement.
Typically, a long course of antibiotics is prescribed on discharge, which may be oral or parenterally administered via a peripherally inserted central catheter (PICC). Previous studies have shown that oral antibiotics are equivalent to parenteral antibiotics for outpatient treatment of osteomyelitis. However, little evidence exists comparing the effectiveness of the two routes in treating complicated pneumonia. 
The rate of PICC complications in complicated pneumonia also has not been well studied.
Study design: Retrospective cohort study.
Setting: Thirty-eight children’s hospitals affiliated with the Children’s Hospital Association.
Synopsis: Over 4 years, 7,820 encounters were identified with 2,123 patients ultimately being included in the cohort. Inclusion criteria were age 2 months to 18 years, and discharge diagnoses of pneumonia and pleural effusion. The authors excluded patients with chronic medical conditions, length of stay (LOS) less than 4 and more than 14 days, patients transferred to or from other institutions, and patients receiving no antibiotics on hospital day 1. The final criteria attempted to avoid inclusion of patients with nosocomial pneumonia. After application of these criteria, individual patient records were reviewed.
Patients were categorized as PICC or oral antibiotics based upon antibiotic route at their initial discharge. Treatment failure was defined as an ED revisit or rehospitalization that led to a change in antibiotic, lengthening of antibiotic course, or pleural drainage. Records were searched for evidence of PICC complications, adverse drug reactions, and other illness-related revisits. Patients in the PICC arm and oral arm were matched by age, race, insurance, LOS, positive vs. negative blood culture, ICU admission, and timing and type of pleural drainage.
Fifty-seven patients had treatment failure (2.7%). In matched analysis, there was no difference in treatment failure between PICC and oral routes (PICC treatment failure OR, 1.26 95% CI, 0.54-2.94). PICC complications were found in 7.1% of patients. Patients with PICC had significantly higher rates of adverse drug reactions (OR, 19.1 95% CI, 4.2-87.3) and illness-related revisits (OR 3.27 95% CI, 1.65-6.48), and all revisits (OR, 4.71 95% CI, 2.97-7.46).
PICC use varied markedly across geographic regions and institutions, with rates varying from less than 10% of cases to approximately 70%. Of geographic regions, the Mid-Atlantic used PICCs least often while the East North Central used them the most.
Bottom line: Treatment failure with both oral and PICC treatment of complicated pneumonia occur at the same rate, and are uncommon. Patients with PICCs had an increased rate of complications, including adverse drug reactions and revisits.
Citation: Shah SS, Srivastava R, Wu S, et al. Intravenous versus oral antibiotics for postdischarge treatment of complicated pneumonia. Pediatrics. 2016;138(6):e20161692. doi: 10.1542/peds.2016-1692.
Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.
Clinical question: Are oral antibiotics as effective as intravenous (IV) antibiotics in the treatment of complicated pneumonia after discharge to home?
Background: Pneumonia is the most common illness among hospitalized children and adolescents (excluding neonates). Among children admitted with community acquired pneumonia, 15% may develop a complicated pneumonia (one with a pleural effusion or empyema). Treatment for these complicated pneumonias may include a variety of invasive procedures, such as video-assisted thorascopic surgery or chest tube placement.
Typically, a long course of antibiotics is prescribed on discharge, which may be oral or parenterally administered via a peripherally inserted central catheter (PICC). Previous studies have shown that oral antibiotics are equivalent to parenteral antibiotics for outpatient treatment of osteomyelitis. However, little evidence exists comparing the effectiveness of the two routes in treating complicated pneumonia.
The rate of PICC complications in complicated pneumonia also has not been well studied.
Study design: Retrospective cohort study.
Setting: Thirty-eight children’s hospitals affiliated with the Children’s Hospital Association.
Synopsis: Over 4 years, 7,820 encounters were identified with 2,123 patients ultimately being included in the cohort. Inclusion criteria were age 2 months to 18 years, and discharge diagnoses of pneumonia and pleural effusion. The authors excluded patients with chronic medical conditions, length of stay (LOS) less than 4 and more than 14 days, patients transferred to or from other institutions, and patients receiving no antibiotics on hospital day 1. The final criteria attempted to avoid inclusion of patients with nosocomial pneumonia. After application of these criteria, individual patient records were reviewed.
Patients were categorized as PICC or oral antibiotics based upon antibiotic route at their initial discharge. Treatment failure was defined as an ED revisit or rehospitalization that led to a change in antibiotic, lengthening of antibiotic course, or pleural drainage. Records were searched for evidence of PICC complications, adverse drug reactions, and other illness-related revisits. Patients in the PICC arm and oral arm were matched by age, race, insurance, LOS, positive vs. negative blood culture, ICU admission, and timing and type of pleural drainage.
Fifty-seven patients had treatment failure (2.7%). In matched analysis, there was no difference in treatment failure between PICC and oral routes (PICC treatment failure OR, 1.26 95% CI, 0.54-2.94). PICC complications were found in 7.1% of patients. Patients with PICC had significantly higher rates of adverse drug reactions (OR, 19.1 95% CI, 4.2-87.3) and illness-related revisits (OR 3.27 95% CI, 1.65-6.48), and all revisits (OR, 4.71 95% CI, 2.97-7.46).
PICC use varied markedly across geographic regions and institutions, with rates varying from less than 10% of cases to approximately 70%. Of geographic regions, the Mid-Atlantic used PICCs least often while the East North Central used them the most.
Bottom line: Treatment failure with both oral and PICC treatment of complicated pneumonia occur at the same rate, and are uncommon. Patients with PICCs had an increased rate of complications, including adverse drug reactions and revisits.
Citation: Shah SS, Srivastava R, Wu S, et al. Intravenous versus oral antibiotics for postdischarge treatment of complicated pneumonia. Pediatrics. 2016;138(6):e20161692. doi: 10.1542/peds.2016-1692.
Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.
Clinical question: Are oral antibiotics as effective as intravenous (IV) antibiotics in the treatment of complicated pneumonia after discharge to home?
Background: Pneumonia is the most common illness among hospitalized children and adolescents (excluding neonates). Among children admitted with community acquired pneumonia, 15% may develop a complicated pneumonia (one with a pleural effusion or empyema). Treatment for these complicated pneumonias may include a variety of invasive procedures, such as video-assisted thorascopic surgery or chest tube placement.
Typically, a long course of antibiotics is prescribed on discharge, which may be oral or parenterally administered via a peripherally inserted central catheter (PICC). Previous studies have shown that oral antibiotics are equivalent to parenteral antibiotics for outpatient treatment of osteomyelitis. However, little evidence exists comparing the effectiveness of the two routes in treating complicated pneumonia.
The rate of PICC complications in complicated pneumonia also has not been well studied.
Study design: Retrospective cohort study.
Setting: Thirty-eight children’s hospitals affiliated with the Children’s Hospital Association.
Synopsis: Over 4 years, 7,820 encounters were identified with 2,123 patients ultimately being included in the cohort. Inclusion criteria were age 2 months to 18 years, and discharge diagnoses of pneumonia and pleural effusion. The authors excluded patients with chronic medical conditions, length of stay (LOS) less than 4 and more than 14 days, patients transferred to or from other institutions, and patients receiving no antibiotics on hospital day 1. The final criteria attempted to avoid inclusion of patients with nosocomial pneumonia. After application of these criteria, individual patient records were reviewed.
Patients were categorized as PICC or oral antibiotics based upon antibiotic route at their initial discharge. Treatment failure was defined as an ED revisit or rehospitalization that led to a change in antibiotic, lengthening of antibiotic course, or pleural drainage. Records were searched for evidence of PICC complications, adverse drug reactions, and other illness-related revisits. Patients in the PICC arm and oral arm were matched by age, race, insurance, LOS, positive vs. negative blood culture, ICU admission, and timing and type of pleural drainage.
Fifty-seven patients had treatment failure (2.7%). In matched analysis, there was no difference in treatment failure between PICC and oral routes (PICC treatment failure OR, 1.26 95% CI, 0.54-2.94). PICC complications were found in 7.1% of patients. Patients with PICC had significantly higher rates of adverse drug reactions (OR, 19.1 95% CI, 4.2-87.3) and illness-related revisits (OR 3.27 95% CI, 1.65-6.48), and all revisits (OR, 4.71 95% CI, 2.97-7.46).
PICC use varied markedly across geographic regions and institutions, with rates varying from less than 10% of cases to approximately 70%. Of geographic regions, the Mid-Atlantic used PICCs least often while the East North Central used them the most.
Bottom line: Treatment failure with both oral and PICC treatment of complicated pneumonia occur at the same rate, and are uncommon. Patients with PICCs had an increased rate of complications, including adverse drug reactions and revisits.
Citation: Shah SS, Srivastava R, Wu S, et al. Intravenous versus oral antibiotics for postdischarge treatment of complicated pneumonia. Pediatrics. 2016;138(6):e20161692. doi: 10.1542/peds.2016-1692.
Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.
In ICU, pair MRSA testing method with isolation protocol
An ICU’s method of testing for methicillin-resistant Staphylococcus aureus (MRSA) should be paired with its patient isolation policy, according to researchers at the University of Colorado at Denver.
In an ICU with all patients preemptively isolated, it is worth the added expense to opt for the polymerase chain reaction (PCR) test – which generates results in a few hours – so that patients negative for the infection can be moved out of isolation more quickly, wrote Melanie D. Whittington, PhD, and her coauthors. But if the ICU is only isolating MRSA-positive patients, the authors instead recommend the less expensive but slower chromogenic agar 24-hour testing.
The other two MRSA tests the researchers assessed – conventional culture and chromogenic agar 48-hour testing – are less expensive. But when paired with either ICU isolation policy, those tests lead to excessive inappropriate isolation costs while waiting for the results, the study investigators cautioned (Am J Infect Control. 2017 Jan 23. doi: 10.1016/j.ajic.2016.12.014).
Adding together the cost per patient of the test, the “appropriate isolation costs,” and “inappropriate isolation costs,” the universal isolation policy is least expensive per patient with PCR, at $82.51 per patient. With conventional culture, which can take several days, this cost ballooned to $290.11 per patient, with high inappropriate isolation costs.
Doing the same math with the more targeted isolation policy, the least expensive screening method was the 24-hour chromogenic agar, at $8.54 per patient, while the expense of the PCR test made it the most expensive method when paired with this isolation policy, at $30.95 per patient.
“With knowledge of the screening test that minimizes inappropriate and total costs, hospitals can maximize the efficiency of their resource use and improve the health of their patients,” Dr. Whittington and her coauthors wrote.
The authors reported no conflicts of interest.
An ICU’s method of testing for methicillin-resistant Staphylococcus aureus (MRSA) should be paired with its patient isolation policy, according to researchers at the University of Colorado at Denver.
In an ICU with all patients preemptively isolated, it is worth the added expense to opt for the polymerase chain reaction (PCR) test – which generates results in a few hours – so that patients negative for the infection can be moved out of isolation more quickly, wrote Melanie D. Whittington, PhD, and her coauthors. But if the ICU is only isolating MRSA-positive patients, the authors instead recommend the less expensive but slower chromogenic agar 24-hour testing.
The other two MRSA tests the researchers assessed – conventional culture and chromogenic agar 48-hour testing – are less expensive. But when paired with either ICU isolation policy, those tests lead to excessive inappropriate isolation costs while waiting for the results, the study investigators cautioned (Am J Infect Control. 2017 Jan 23. doi: 10.1016/j.ajic.2016.12.014).
Adding together the cost per patient of the test, the “appropriate isolation costs,” and “inappropriate isolation costs,” the universal isolation policy is least expensive per patient with PCR, at $82.51 per patient. With conventional culture, which can take several days, this cost ballooned to $290.11 per patient, with high inappropriate isolation costs.
Doing the same math with the more targeted isolation policy, the least expensive screening method was the 24-hour chromogenic agar, at $8.54 per patient, while the expense of the PCR test made it the most expensive method when paired with this isolation policy, at $30.95 per patient.
“With knowledge of the screening test that minimizes inappropriate and total costs, hospitals can maximize the efficiency of their resource use and improve the health of their patients,” Dr. Whittington and her coauthors wrote.
The authors reported no conflicts of interest.
An ICU’s method of testing for methicillin-resistant Staphylococcus aureus (MRSA) should be paired with its patient isolation policy, according to researchers at the University of Colorado at Denver.
In an ICU with all patients preemptively isolated, it is worth the added expense to opt for the polymerase chain reaction (PCR) test – which generates results in a few hours – so that patients negative for the infection can be moved out of isolation more quickly, wrote Melanie D. Whittington, PhD, and her coauthors. But if the ICU is only isolating MRSA-positive patients, the authors instead recommend the less expensive but slower chromogenic agar 24-hour testing.
The other two MRSA tests the researchers assessed – conventional culture and chromogenic agar 48-hour testing – are less expensive. But when paired with either ICU isolation policy, those tests lead to excessive inappropriate isolation costs while waiting for the results, the study investigators cautioned (Am J Infect Control. 2017 Jan 23. doi: 10.1016/j.ajic.2016.12.014).
Adding together the cost per patient of the test, the “appropriate isolation costs,” and “inappropriate isolation costs,” the universal isolation policy is least expensive per patient with PCR, at $82.51 per patient. With conventional culture, which can take several days, this cost ballooned to $290.11 per patient, with high inappropriate isolation costs.
Doing the same math with the more targeted isolation policy, the least expensive screening method was the 24-hour chromogenic agar, at $8.54 per patient, while the expense of the PCR test made it the most expensive method when paired with this isolation policy, at $30.95 per patient.
“With knowledge of the screening test that minimizes inappropriate and total costs, hospitals can maximize the efficiency of their resource use and improve the health of their patients,” Dr. Whittington and her coauthors wrote.
The authors reported no conflicts of interest.
Sterile fecal filtrate effectively treated recurrent CDI
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Sterile fecal filtrate transplantation effectively treated symptomatic chronic-relapsing Clostridium difficile infection.
Major finding: For all patients, transplantation restored normal bowel habits within 2-4 days and eliminated symptoms for at least 6 months.
Data source: A single-center cases series of five patients with recurrent symptomatic CDI.
Disclosures: The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
Carbapenem-resistant K. pneumoniae occurs in 25% of long-term acute care hospital cultures
Nearly one-quarter of Klebsiella pneumoniae cultures in a network of U.S. long-term acute care hospitals are resistant to carbapenem, according to Jennifer H. Han, MD, and her associates.
From a sample of 3,846 K. pneumoniae cultures taken from 64 long-term acute care hospitals in 16 states, 946, or 24.6%, of the cultures were carbapenem-resistant, and were taken from 821 patients. Just under 54% of CRKP isolates were taken from a respiratory source, with 37% coming from urine and the remaining 9.4% coming from blood. Nearly all CRKP isolates were resistant to fluoroquinolones, and 59.2% were resistant to amikacin.
Of the 16 states where cultures were taken from, California had the highest rate of carbapenem resistance, with 45.5% of K. pneumoniae cultures showing resistance. Other states with high rates of CRKP included South Carolina, Kentucky, and Indiana.
“Given the chronically, critically ill population, with convergence of at-risk patients from multiple facilities, future studies of optimal infection prevention strategies are urgently needed for this setting. In addition, expansion of national surveillance efforts and improved communication between [long-term acute care hospitals] and acute care hospitals will be critical for reducing the continued emergence and dissemination of CRKP across the health care continuum,” Dr. Han and her associates concluded.
Find the full study in Clinical Infectious Diseases (doi: 10.1 LTACHs 093/cid/ciw856)
Nearly one-quarter of Klebsiella pneumoniae cultures in a network of U.S. long-term acute care hospitals are resistant to carbapenem, according to Jennifer H. Han, MD, and her associates.
From a sample of 3,846 K. pneumoniae cultures taken from 64 long-term acute care hospitals in 16 states, 946, or 24.6%, of the cultures were carbapenem-resistant, and were taken from 821 patients. Just under 54% of CRKP isolates were taken from a respiratory source, with 37% coming from urine and the remaining 9.4% coming from blood. Nearly all CRKP isolates were resistant to fluoroquinolones, and 59.2% were resistant to amikacin.
Of the 16 states where cultures were taken from, California had the highest rate of carbapenem resistance, with 45.5% of K. pneumoniae cultures showing resistance. Other states with high rates of CRKP included South Carolina, Kentucky, and Indiana.
“Given the chronically, critically ill population, with convergence of at-risk patients from multiple facilities, future studies of optimal infection prevention strategies are urgently needed for this setting. In addition, expansion of national surveillance efforts and improved communication between [long-term acute care hospitals] and acute care hospitals will be critical for reducing the continued emergence and dissemination of CRKP across the health care continuum,” Dr. Han and her associates concluded.
Find the full study in Clinical Infectious Diseases (doi: 10.1 LTACHs 093/cid/ciw856)
Nearly one-quarter of Klebsiella pneumoniae cultures in a network of U.S. long-term acute care hospitals are resistant to carbapenem, according to Jennifer H. Han, MD, and her associates.
From a sample of 3,846 K. pneumoniae cultures taken from 64 long-term acute care hospitals in 16 states, 946, or 24.6%, of the cultures were carbapenem-resistant, and were taken from 821 patients. Just under 54% of CRKP isolates were taken from a respiratory source, with 37% coming from urine and the remaining 9.4% coming from blood. Nearly all CRKP isolates were resistant to fluoroquinolones, and 59.2% were resistant to amikacin.
Of the 16 states where cultures were taken from, California had the highest rate of carbapenem resistance, with 45.5% of K. pneumoniae cultures showing resistance. Other states with high rates of CRKP included South Carolina, Kentucky, and Indiana.
“Given the chronically, critically ill population, with convergence of at-risk patients from multiple facilities, future studies of optimal infection prevention strategies are urgently needed for this setting. In addition, expansion of national surveillance efforts and improved communication between [long-term acute care hospitals] and acute care hospitals will be critical for reducing the continued emergence and dissemination of CRKP across the health care continuum,” Dr. Han and her associates concluded.
Find the full study in Clinical Infectious Diseases (doi: 10.1 LTACHs 093/cid/ciw856)
FROM CLINICAL INFECTIOUS DISEASES
Asymptomatic carriage of carbapenem-resistant Enterobacteriaceae ‘considerable’
Asymptomatic carriage of carbapenem-resistant Enterobacteriaceae is “considerable,” according to genetic analyses of bacterial isolates obtained from patients at four large U.S. hospitals.
To better understand the “urgent threat” of carbapenem resistance – specifically, to obtain a “snapshot” of how the resistant enterobacteria evolve, diversify, and spread – the researchers performed genetic analyses on 122 carbapenem-resistant and 141 carbapenem-susceptible bacterial isolates from patients hospitalized during a 16-month period at three Boston and one California medical centers. The isolates were obtained from urine (44%), respiratory tract (16%), blood (11%), wound (11%), and other samples, said Gustavo C. Cerqueira, PhD, of the Broad Institute of MIT and Harvard University in Cambridge, Mass., and his associates.
They found 8 species of bacteria that exhibited carbapenem resistance, chiefly Klebsiella pneumoniae. There also was a significant degree of diversity among resistant Enterobacteria. Most importantly, the investigators found evidence of substantial asymptomatic carriage of resistant bacteria and discovered several previously unrecognized mechanisms that produced resistance. Taken together, the findings indicate “continued innovation by these organisms to thwart the action of this important class of antibiotics,” reported Dr. Cerqueira, also affiliated with Massachusetts General Hospital in Boston, and his associates (Proc Nat Acad Sci USA. 2017 Jan 16 [doi:10.1073/pnas.1616248114]).
The study findings underscore the need for “an aggressive approach to surveillance and isolation” to control this continuing threat, they added.
This work was supported by the National Institute of Allergy and Infectious Diseases. Dr. Cerqueira and his associates reported having no relevant financial disclosures.
Asymptomatic carriage of carbapenem-resistant Enterobacteriaceae is “considerable,” according to genetic analyses of bacterial isolates obtained from patients at four large U.S. hospitals.
To better understand the “urgent threat” of carbapenem resistance – specifically, to obtain a “snapshot” of how the resistant enterobacteria evolve, diversify, and spread – the researchers performed genetic analyses on 122 carbapenem-resistant and 141 carbapenem-susceptible bacterial isolates from patients hospitalized during a 16-month period at three Boston and one California medical centers. The isolates were obtained from urine (44%), respiratory tract (16%), blood (11%), wound (11%), and other samples, said Gustavo C. Cerqueira, PhD, of the Broad Institute of MIT and Harvard University in Cambridge, Mass., and his associates.
They found 8 species of bacteria that exhibited carbapenem resistance, chiefly Klebsiella pneumoniae. There also was a significant degree of diversity among resistant Enterobacteria. Most importantly, the investigators found evidence of substantial asymptomatic carriage of resistant bacteria and discovered several previously unrecognized mechanisms that produced resistance. Taken together, the findings indicate “continued innovation by these organisms to thwart the action of this important class of antibiotics,” reported Dr. Cerqueira, also affiliated with Massachusetts General Hospital in Boston, and his associates (Proc Nat Acad Sci USA. 2017 Jan 16 [doi:10.1073/pnas.1616248114]).
The study findings underscore the need for “an aggressive approach to surveillance and isolation” to control this continuing threat, they added.
This work was supported by the National Institute of Allergy and Infectious Diseases. Dr. Cerqueira and his associates reported having no relevant financial disclosures.
Asymptomatic carriage of carbapenem-resistant Enterobacteriaceae is “considerable,” according to genetic analyses of bacterial isolates obtained from patients at four large U.S. hospitals.
To better understand the “urgent threat” of carbapenem resistance – specifically, to obtain a “snapshot” of how the resistant enterobacteria evolve, diversify, and spread – the researchers performed genetic analyses on 122 carbapenem-resistant and 141 carbapenem-susceptible bacterial isolates from patients hospitalized during a 16-month period at three Boston and one California medical centers. The isolates were obtained from urine (44%), respiratory tract (16%), blood (11%), wound (11%), and other samples, said Gustavo C. Cerqueira, PhD, of the Broad Institute of MIT and Harvard University in Cambridge, Mass., and his associates.
They found 8 species of bacteria that exhibited carbapenem resistance, chiefly Klebsiella pneumoniae. There also was a significant degree of diversity among resistant Enterobacteria. Most importantly, the investigators found evidence of substantial asymptomatic carriage of resistant bacteria and discovered several previously unrecognized mechanisms that produced resistance. Taken together, the findings indicate “continued innovation by these organisms to thwart the action of this important class of antibiotics,” reported Dr. Cerqueira, also affiliated with Massachusetts General Hospital in Boston, and his associates (Proc Nat Acad Sci USA. 2017 Jan 16 [doi:10.1073/pnas.1616248114]).
The study findings underscore the need for “an aggressive approach to surveillance and isolation” to control this continuing threat, they added.
This work was supported by the National Institute of Allergy and Infectious Diseases. Dr. Cerqueira and his associates reported having no relevant financial disclosures.
FROM THE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES
Key clinical point: Asymptomatic carriage of carbapenem-resistant Enterobacteriaceae is “considerable.”
Major finding: Researchers found eight species of bacteria that exhibited carbapenem resistance, a significant degree of diversity among resistant enterobacteria, evidence of substantial asymptomatic carriage of resistant bacteria, and several previously unrecognized mechanisms that produced resistance.
Data source: Genetic analyses of 122 carbapenem-resistant and 141 carbapenem-susceptible bacterial isolates obtained from patients at 4 large U.S. hospitals.
Disclosures: This work was supported by the National Institute of Allergy and Infectious Diseases. Dr. Cerqueira and his associates reported having no relevant financial disclosures.
Bezlotoxumab prevents recurrent C. difficile infection
Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.
As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.
The primary efficacy endpoint – the proportion of patients with recurrent C. difficile infection during 12 weeks of follow-up – was substantially lower with bezlotoxumab (17%) than with placebo (28%) in the first trial and in the second trial (16% vs. 26%). This treatment benefit was evident as early as 2 weeks after infusion and persisted throughout follow-up, the investigators said (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMoa1602615).
The agent’s persistent effect through 12 weeks is important to note because approximately 30% of the recurrences in this study “occurred beyond the conventional 4-week assessment period for treatment efficacy. The number needed to treat to prevent one episode of recurrent C. difficile infection was 10; it was 6 among participants 65 years of age or older and those with previous C. difficile infection,” Dr. Wilcox and his associates noted.
Bezlotoxumab was consistently effective in several sensitivity analyses. It also was effective in both trials individually as well as in pooled results. And the choice of oral antibiotic appeared to have no effect on bezlotoxumab’s efficacy.
In a post hoc analysis, bezlotoxumab was also effective in the subgroup of 1,964 patients at highest risk for C. difficile recurrence because they were elderly, had compromised immunity, had the most severe infections, had a history of C. difficile infection, or carried a strain of the organism associated with particularly poor outcomes. In this subgroup, 17% of patients given bezlotoxumab and 16% of those given bezlotoxumab plus actoxumab developed recurrences, compared with 30% of those given placebo.
Regarding adverse events, the agent had “a generally favorable safety profile,” and the rates of adverse events “were generally as expected, given the underlying disease severity, baseline coexisting conditions, and ages of the participants.” Two participants discontinued the infusion because of an adverse event. Drug-related adverse events occurred in 7% of the entire study population, serious drug-related adverse events occurred in 1%, and both occurred at similar rates across the study groups.
Both trials were funded by Merck, which also was involved in study design, data analysis and interpretation, and writing the reports. Dr. Wilcox and his associates reported ties to Merck and numerous other industry sources.
Bezlotoxumab must be placed in perspective, seen within the context of alternative options currently being evaluated in clinical trials.
These include recently developed drugs such as ridinilazole, surotomycin, cadazolid, RBX2660, and SER-109. Also under assessment is the oral administration of nontoxigenic C. difficile strains to compete with toxigenic strains, as well as three vaccines against the organism. Stool transplantation also is known to be highly successful in preventing recurrent C. difficile infection.
In addition, the cost-effectiveness of bezlotoxumab, especially in relation to these alternative treatments, hasn’t yet been determined.
John G. Bartlett, MD, is in the department of medicine at Johns Hopkins University, Baltimore. He reported having no relevant financial disclosures. Dr. Bartlett made these remarks in an editorial accompanying Dr. Wilcox’s report (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMe1614726).
Bezlotoxumab must be placed in perspective, seen within the context of alternative options currently being evaluated in clinical trials.
These include recently developed drugs such as ridinilazole, surotomycin, cadazolid, RBX2660, and SER-109. Also under assessment is the oral administration of nontoxigenic C. difficile strains to compete with toxigenic strains, as well as three vaccines against the organism. Stool transplantation also is known to be highly successful in preventing recurrent C. difficile infection.
In addition, the cost-effectiveness of bezlotoxumab, especially in relation to these alternative treatments, hasn’t yet been determined.
John G. Bartlett, MD, is in the department of medicine at Johns Hopkins University, Baltimore. He reported having no relevant financial disclosures. Dr. Bartlett made these remarks in an editorial accompanying Dr. Wilcox’s report (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMe1614726).
Bezlotoxumab must be placed in perspective, seen within the context of alternative options currently being evaluated in clinical trials.
These include recently developed drugs such as ridinilazole, surotomycin, cadazolid, RBX2660, and SER-109. Also under assessment is the oral administration of nontoxigenic C. difficile strains to compete with toxigenic strains, as well as three vaccines against the organism. Stool transplantation also is known to be highly successful in preventing recurrent C. difficile infection.
In addition, the cost-effectiveness of bezlotoxumab, especially in relation to these alternative treatments, hasn’t yet been determined.
John G. Bartlett, MD, is in the department of medicine at Johns Hopkins University, Baltimore. He reported having no relevant financial disclosures. Dr. Bartlett made these remarks in an editorial accompanying Dr. Wilcox’s report (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMe1614726).
Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.
As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.
The primary efficacy endpoint – the proportion of patients with recurrent C. difficile infection during 12 weeks of follow-up – was substantially lower with bezlotoxumab (17%) than with placebo (28%) in the first trial and in the second trial (16% vs. 26%). This treatment benefit was evident as early as 2 weeks after infusion and persisted throughout follow-up, the investigators said (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMoa1602615).
The agent’s persistent effect through 12 weeks is important to note because approximately 30% of the recurrences in this study “occurred beyond the conventional 4-week assessment period for treatment efficacy. The number needed to treat to prevent one episode of recurrent C. difficile infection was 10; it was 6 among participants 65 years of age or older and those with previous C. difficile infection,” Dr. Wilcox and his associates noted.
Bezlotoxumab was consistently effective in several sensitivity analyses. It also was effective in both trials individually as well as in pooled results. And the choice of oral antibiotic appeared to have no effect on bezlotoxumab’s efficacy.
In a post hoc analysis, bezlotoxumab was also effective in the subgroup of 1,964 patients at highest risk for C. difficile recurrence because they were elderly, had compromised immunity, had the most severe infections, had a history of C. difficile infection, or carried a strain of the organism associated with particularly poor outcomes. In this subgroup, 17% of patients given bezlotoxumab and 16% of those given bezlotoxumab plus actoxumab developed recurrences, compared with 30% of those given placebo.
Regarding adverse events, the agent had “a generally favorable safety profile,” and the rates of adverse events “were generally as expected, given the underlying disease severity, baseline coexisting conditions, and ages of the participants.” Two participants discontinued the infusion because of an adverse event. Drug-related adverse events occurred in 7% of the entire study population, serious drug-related adverse events occurred in 1%, and both occurred at similar rates across the study groups.
Both trials were funded by Merck, which also was involved in study design, data analysis and interpretation, and writing the reports. Dr. Wilcox and his associates reported ties to Merck and numerous other industry sources.
Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.
As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.
The primary efficacy endpoint – the proportion of patients with recurrent C. difficile infection during 12 weeks of follow-up – was substantially lower with bezlotoxumab (17%) than with placebo (28%) in the first trial and in the second trial (16% vs. 26%). This treatment benefit was evident as early as 2 weeks after infusion and persisted throughout follow-up, the investigators said (N Engl J Med. 2017 Jan 25. doi: 10.1056/NEJMoa1602615).
The agent’s persistent effect through 12 weeks is important to note because approximately 30% of the recurrences in this study “occurred beyond the conventional 4-week assessment period for treatment efficacy. The number needed to treat to prevent one episode of recurrent C. difficile infection was 10; it was 6 among participants 65 years of age or older and those with previous C. difficile infection,” Dr. Wilcox and his associates noted.
Bezlotoxumab was consistently effective in several sensitivity analyses. It also was effective in both trials individually as well as in pooled results. And the choice of oral antibiotic appeared to have no effect on bezlotoxumab’s efficacy.
In a post hoc analysis, bezlotoxumab was also effective in the subgroup of 1,964 patients at highest risk for C. difficile recurrence because they were elderly, had compromised immunity, had the most severe infections, had a history of C. difficile infection, or carried a strain of the organism associated with particularly poor outcomes. In this subgroup, 17% of patients given bezlotoxumab and 16% of those given bezlotoxumab plus actoxumab developed recurrences, compared with 30% of those given placebo.
Regarding adverse events, the agent had “a generally favorable safety profile,” and the rates of adverse events “were generally as expected, given the underlying disease severity, baseline coexisting conditions, and ages of the participants.” Two participants discontinued the infusion because of an adverse event. Drug-related adverse events occurred in 7% of the entire study population, serious drug-related adverse events occurred in 1%, and both occurred at similar rates across the study groups.
Both trials were funded by Merck, which also was involved in study design, data analysis and interpretation, and writing the reports. Dr. Wilcox and his associates reported ties to Merck and numerous other industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduced recurrences by 38% (10 percentage points).
Major finding: The number needed to treat to prevent one episode of recurrent C. difficile infection was 10; it was 6 among high-risk participants who were 65 years of age or older or who had previous C. difficile infection.
Data source: Two parallel randomized double-blind placebo-controlled international trials involving 2,655 adults followed for 12 weeks.
Disclosures: Both trials were funded by Merck, which also was involved in study design, data analysis and interpretation, and writing the reports. Dr. Wilcox and his associates reported ties to Merck and numerous other industry sources.
VA MRSA Prevention Initiative reports continued health care–associated infection declines
The U.S. Department of Veterans Affairs MRSA Prevention Initiative, implemented in October 2007, has shown progress at limiting health care–associated infections of methicillin-resistant Staphylococcus aureus through 2011 and 2012.
A new report published in the January 2017 issue of the American Journal of Infection Control tracks continued declines in infection through September 2015.
Monthly rates of health care–associated infections fell significantly in all settings from October 2007 to September 2015: an 87% decrease in ICUs, 80.1% in non-ICUs, 80.9% in spinal cord injury units, and 49.4% in long-term care facilities (P for all less than .0001).
“The VA data suggest that active surveillance followed by contact precautions (with or without decolonization) may be most useful when MRSA [health care–associated infection] rates are unacceptably high (as they were in VA facilities during 2007) or to decrease infections in high-risk units such as ICUs,” Dr. Evans and his colleagues concluded.
Details about the implementation of the initiative were previously published in the New England Journal of Medicine in 2011, including the initiative’s goal to promote “a change in the institutional culture whereby infection control would become the responsibility of everyone who had contact with patients” (N Engl J Med. 2011;364:1419-30).
Dr. Evans and his colleagues had no relevant financial disclosures.
The U.S. Department of Veterans Affairs MRSA Prevention Initiative, implemented in October 2007, has shown progress at limiting health care–associated infections of methicillin-resistant Staphylococcus aureus through 2011 and 2012.
A new report published in the January 2017 issue of the American Journal of Infection Control tracks continued declines in infection through September 2015.
Monthly rates of health care–associated infections fell significantly in all settings from October 2007 to September 2015: an 87% decrease in ICUs, 80.1% in non-ICUs, 80.9% in spinal cord injury units, and 49.4% in long-term care facilities (P for all less than .0001).
“The VA data suggest that active surveillance followed by contact precautions (with or without decolonization) may be most useful when MRSA [health care–associated infection] rates are unacceptably high (as they were in VA facilities during 2007) or to decrease infections in high-risk units such as ICUs,” Dr. Evans and his colleagues concluded.
Details about the implementation of the initiative were previously published in the New England Journal of Medicine in 2011, including the initiative’s goal to promote “a change in the institutional culture whereby infection control would become the responsibility of everyone who had contact with patients” (N Engl J Med. 2011;364:1419-30).
Dr. Evans and his colleagues had no relevant financial disclosures.
The U.S. Department of Veterans Affairs MRSA Prevention Initiative, implemented in October 2007, has shown progress at limiting health care–associated infections of methicillin-resistant Staphylococcus aureus through 2011 and 2012.
A new report published in the January 2017 issue of the American Journal of Infection Control tracks continued declines in infection through September 2015.
Monthly rates of health care–associated infections fell significantly in all settings from October 2007 to September 2015: an 87% decrease in ICUs, 80.1% in non-ICUs, 80.9% in spinal cord injury units, and 49.4% in long-term care facilities (P for all less than .0001).
“The VA data suggest that active surveillance followed by contact precautions (with or without decolonization) may be most useful when MRSA [health care–associated infection] rates are unacceptably high (as they were in VA facilities during 2007) or to decrease infections in high-risk units such as ICUs,” Dr. Evans and his colleagues concluded.
Details about the implementation of the initiative were previously published in the New England Journal of Medicine in 2011, including the initiative’s goal to promote “a change in the institutional culture whereby infection control would become the responsibility of everyone who had contact with patients” (N Engl J Med. 2011;364:1419-30).
Dr. Evans and his colleagues had no relevant financial disclosures.
FROM THE AMERICAN JOURNAL OF INFECTION CONTROL