In the JournalsPerspective

Study: Fidaxomicin ‘better’ option than vancomycin in many C. difficile cases

Based on a systematic review and network meta-analysis, researchers said fidaxomicin is a “better” option than vancomycin for the treatment of Clostridium difficile in all patients except those with severe infections and that metronidazole “should not be recommended” to treat the infection.

Venkataraman Subramanian, MD, clinical associate professor and honorary consultant gastroenterologist at the Leeds Institute of Biomedical and Clinical Studies in Leeds, England, and colleagues compared and ranked treatments for non-multiply recurrent C. difficile infections and reported that fidaxomicin “provides a sustained symptomatic cure most frequently.”

In new guidelines published last year, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America recommended vancomycin and fidaxomicin as first-line treatments for C. difficile over metronidazole.

“For more than three decades, metronidazole and vancomycin have been the principal treatment options for C. difficile infections. However, sub-optimal numbers of sustained cures and the increasing prevalence and associated morbidity and mortality from infections with C. difficile have warranted the development and evaluation of new therapeutic drugs,” Subramanian and colleagues wrote in The Lancet Infectious Diseases. “After showing a higher number of sustained clinical cures than vancomycin, fidaxomicin was approved for treatment of infections with C. difficile in 2011. However, a long-term response was not achieved in 29% of patients, and research to develop several drugs to provide a lasting cure are ongoing.”

Photo of Herbert DuPont
Herbert DuPont

In a related comment published in The Lancet Infectious Diseases, Herbert DuPont, MD, director of the Center for Infectious Diseases at the University of Texas School of Public Health and an Infectious Disease News Editorial Board member, said the frequency of C. difficile infections have steadily increased over the past 2 decades.

“An optimal drug that is selected for treatment of C. difficile infections should target as many of the pathogenic factors associated with C. difficile as possible,” DuPont wrote.

Subramanian and colleagues screened 23,004 published and unpublished trials from numerous databases until June 30, 2017. Study inclusion criteria included any randomized controlled trials that evaluated treatments for non-multiply recurrent infections with C. difficile in adults aged 18 years or older and provided primary cure and recurrence rates.

Sustained symptomatic cure was the primary outcome, which researchers calculated as the number of patients whose diarrhea was resolved minus the number of patients who sustained a recurrent infection or death.

Subramanian and colleagues selected 24 trials for the analysis, which included 5,361 patients and 13 different treatments with a moderate to low rating for overall quality of evidence.

Fidaxomicin (OR = 0.67; 95% CI, 0.55-0.82) and teicoplanin (OR = 0.37; 95% CI, 0.14-0.94) had a sustained symptomatic cure rate that was significantly better than vancomycin, they reported. Furthermore, metronidazole’s sustained symptomatic cure was not as favorable as teicoplanin (OR = 0.27; 95% CI, 0.10–0.70), ridinilazole (OR = 0.41; 95% CI, 0.19–0.88), fidaxomicin (OR = 0.49; 95% CI, 0.35–0.68), surotomycin (OR = 0.66; 95% CI, 0.45–0.97) or vancomycin (OR = 0.73; 95% CI, 0.56–0.95), which is why the researchers do not recommend the drug for treatment of C. difficile infection.

DuPont agreed that oral metronidazole should not be recommended for mild, moderate or severe cases of C. difficile, but said the drug still provides relevant treatment options.

“Intravenous use of metronidazole still has a role in treatment of severe C. difficile infections in patients who are unable to take oral drugs but should be combined with intracolonic vancomycin treatment,” he wrote.

According to the study, fidaxomicin was evaluated in almost 900 patients in six randomized controlled trials. In achieving a sustained cure, the researchers found that fidaxomicin was significantly better than vancomycin, metronidazole, bacitracin and tolevamer.

They also found that bacitracin was inferior to both teicoplanin (OR = 0.22; 95% CI, 00.6-0.77) and fidaxomicin (OR = 0.40; 95% CI, 0.17-0.94). Moreover, the systematic review showed that although tolevamer was better than bacitracin (OR = 0.67; 95% CI, 0.28-1.58) and LFF571 (OR = 0.5; 95% CI, 0.18-1.39), it was inferior to all other drugs.

DuPont pointed to cost as a reason why, in the 2018 guidelines,, vancomycin was still a recommended first-line treatment.

“Studies that showed the benefits of fidaxomicin versus vancomycin in direct comparisons were available to the authors of these guidelines, suggesting that they considered drug costs when developing their recommendations,” he wrote.

“The findings of this network meta-analysis suggest that, of the currently approved treatments, fidaxomicin has the strongest evidence for being the most effective treatment in providing a long-term cure against C. difficile,” Subramanian and colleagues concluded. “Apart from affordability, there is little evidence to support use of metronidazole as a first-line treatment against infections with C. difficile.” – by Marley Ghizzone

Editor’s note: In the United States, fidaxomicin is marketed as Dificid (Merck).

References:

Dupont H. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30308-6.

Disclosures: Subramanian reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Based on a systematic review and network meta-analysis, researchers said fidaxomicin is a “better” option than vancomycin for the treatment of Clostridium difficile in all patients except those with severe infections and that metronidazole “should not be recommended” to treat the infection.

Venkataraman Subramanian, MD, clinical associate professor and honorary consultant gastroenterologist at the Leeds Institute of Biomedical and Clinical Studies in Leeds, England, and colleagues compared and ranked treatments for non-multiply recurrent C. difficile infections and reported that fidaxomicin “provides a sustained symptomatic cure most frequently.”

In new guidelines published last year, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America recommended vancomycin and fidaxomicin as first-line treatments for C. difficile over metronidazole.

“For more than three decades, metronidazole and vancomycin have been the principal treatment options for C. difficile infections. However, sub-optimal numbers of sustained cures and the increasing prevalence and associated morbidity and mortality from infections with C. difficile have warranted the development and evaluation of new therapeutic drugs,” Subramanian and colleagues wrote in The Lancet Infectious Diseases. “After showing a higher number of sustained clinical cures than vancomycin, fidaxomicin was approved for treatment of infections with C. difficile in 2011. However, a long-term response was not achieved in 29% of patients, and research to develop several drugs to provide a lasting cure are ongoing.”

Photo of Herbert DuPont
Herbert DuPont

In a related comment published in The Lancet Infectious Diseases, Herbert DuPont, MD, director of the Center for Infectious Diseases at the University of Texas School of Public Health and an Infectious Disease News Editorial Board member, said the frequency of C. difficile infections have steadily increased over the past 2 decades.

“An optimal drug that is selected for treatment of C. difficile infections should target as many of the pathogenic factors associated with C. difficile as possible,” DuPont wrote.

Subramanian and colleagues screened 23,004 published and unpublished trials from numerous databases until June 30, 2017. Study inclusion criteria included any randomized controlled trials that evaluated treatments for non-multiply recurrent infections with C. difficile in adults aged 18 years or older and provided primary cure and recurrence rates.

Sustained symptomatic cure was the primary outcome, which researchers calculated as the number of patients whose diarrhea was resolved minus the number of patients who sustained a recurrent infection or death.

Subramanian and colleagues selected 24 trials for the analysis, which included 5,361 patients and 13 different treatments with a moderate to low rating for overall quality of evidence.

PAGE BREAK

Fidaxomicin (OR = 0.67; 95% CI, 0.55-0.82) and teicoplanin (OR = 0.37; 95% CI, 0.14-0.94) had a sustained symptomatic cure rate that was significantly better than vancomycin, they reported. Furthermore, metronidazole’s sustained symptomatic cure was not as favorable as teicoplanin (OR = 0.27; 95% CI, 0.10–0.70), ridinilazole (OR = 0.41; 95% CI, 0.19–0.88), fidaxomicin (OR = 0.49; 95% CI, 0.35–0.68), surotomycin (OR = 0.66; 95% CI, 0.45–0.97) or vancomycin (OR = 0.73; 95% CI, 0.56–0.95), which is why the researchers do not recommend the drug for treatment of C. difficile infection.

DuPont agreed that oral metronidazole should not be recommended for mild, moderate or severe cases of C. difficile, but said the drug still provides relevant treatment options.

“Intravenous use of metronidazole still has a role in treatment of severe C. difficile infections in patients who are unable to take oral drugs but should be combined with intracolonic vancomycin treatment,” he wrote.

According to the study, fidaxomicin was evaluated in almost 900 patients in six randomized controlled trials. In achieving a sustained cure, the researchers found that fidaxomicin was significantly better than vancomycin, metronidazole, bacitracin and tolevamer.

They also found that bacitracin was inferior to both teicoplanin (OR = 0.22; 95% CI, 00.6-0.77) and fidaxomicin (OR = 0.40; 95% CI, 0.17-0.94). Moreover, the systematic review showed that although tolevamer was better than bacitracin (OR = 0.67; 95% CI, 0.28-1.58) and LFF571 (OR = 0.5; 95% CI, 0.18-1.39), it was inferior to all other drugs.

DuPont pointed to cost as a reason why, in the 2018 guidelines,, vancomycin was still a recommended first-line treatment.

“Studies that showed the benefits of fidaxomicin versus vancomycin in direct comparisons were available to the authors of these guidelines, suggesting that they considered drug costs when developing their recommendations,” he wrote.

“The findings of this network meta-analysis suggest that, of the currently approved treatments, fidaxomicin has the strongest evidence for being the most effective treatment in providing a long-term cure against C. difficile,” Subramanian and colleagues concluded. “Apart from affordability, there is little evidence to support use of metronidazole as a first-line treatment against infections with C. difficile.” – by Marley Ghizzone

Editor’s note: In the United States, fidaxomicin is marketed as Dificid (Merck).

References:

Dupont H. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30308-6.

Disclosures: Subramanian reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

PAGE BREAK

    Perspective

    Photo of Brad Spellberg

    I disagree with the findings of Beinortas and colleagues and think that the researchers simply reinforce pre-existing expert opinion bias. C. difficile is overdiagnosed because of reliance on overly sensitive nucleic acid amplification methodologies. As a result, many patients who get treated do not actually have C. difficile infection. The continued persistent push to get clinicians to prescribe expensive branded drugs in lieu of cheaper generics is not in the public’s best interest. There are no randomized controlled trial data that demonstrate that metronidazole is ineffective for patients with mild illness. That is based on expert opinion. Nor do I see any reason why an expensive branded drug should be used at this point in lieu of inexpensive generic options (eg, generic vancomycin powder compounded to administer orally).

    Brad Spellberg, MD

    Chief Medical Officer, Los Angeles County-University of Southern California Medical Center
    Professor of clinical medicine and associate dean for clinical affairs, Keck School of Medicine

    Disclosure: Infectious Disease News was unable to confirm relevant financial disclosures at the time of publication.