Blog | Thursday, December 3, 2015

Antimicrobial stewardship and C. difficile therapy are complicated


The CDC's Get Smart About Antibiotics Week was November 16-22. To do our part, bloggers used this (and hopefully other) posts to “Highlight Get Smart Week on your website” as CDC suggested as an Activity Idea. Of course, the problem with getting smart about antibiotics is that it's really complicated. Sure, reducing unnecessary antibiotic use (e.g. don't treat viruses) seems simple, but the toolkits necessary to assist primary care physicians aren't yet fully developed (e.g. improved rapid diagnostics).

And don't even think about inpatient stewardship. I've yet to see antibiotic selection guided by the existence of bacterial multidrug efflux pumps, for example, but hopefully that's coming too. This is not meant to be discouraging, it's just to say that we have a long road ahead and we must keep pushing forward with stewardship-focused basic science studies and clinical trials including implementation science.

With all that in mind, I came across what appears to be an important paper in the Nov. 15 issue of the Journal of Infectious Diseases by Brittany Lewis and colleagues at Memorial Sloan-Kettering. The authors asked a fairly simple question. What happens to gut flora when it's treated with Clostridium difficile specific therapies and how does antibiotic selection alter colonization resistance to C. difficile, vancomycin-resistant Enterococci, carbapenem-resistant Enterococci, and Escherichia coli challenges. The authors designed their study around a typical antimicrobial stewardship question: Should we treat C. difficile infection (CDI) with metronidazole, vancomycin, or both?

Using a mouse model (9 mice per treatment-time point), each was treated for 3 days with metronidazole, vancomycin or both. Fecal samples were then tested for bacterial population diversity (16s sequencing) and susceptibility to C. difficile spore inoculation at 1, 3, 7, 14 and 21 days. Most metronidazole-treated mice could not support C. difficile growth (red circles) after 7 days, while many who received vanco or vanco+metro remained susceptible to infection out to 3 weeks. At 7 days and 14 days, 11% and 0% of metronidazole-treated mice were susceptible, respectively. In those treated with vanco, 89% were susceptible at day 3 and 100% were susceptible at day 7. This suggests that vancomycin might increase risk for recurrent infection compared to metronidazole.

Given those findings, it is not surprising that mice treated with metronidazole alone maintained a relatively stable microbiota, which could explain their reduced susceptibility to C. difficile. Among those treated with vanco or vanco+metro, mice with higher levels of disrupted microbial communities were less able to suppress C. difficile growth.

Perhaps more importantly in our fight against antibacterial resistance, a second aim of their study found that mice treated with vancomycin (pink circles) were far more susceptible to VRE, carbapenem-resistant Klebsiella pneumoniae and E. coli than metronidazole treated or untreated mice for at least 2 weeks post therapy.

In summary, in this sophisticated mouse model, exposure to oral vancomycin was associated with higher risk of C. difficile, a prolonged highly disrupted microbiota and an elevated risk of VRE, carbapenem-resistant K. Pneumoniae and E. coli colonization compared to those treated with metronidazole alone. There seems to be an increased push to treat CDI patients with oral vancomycin, but given these findings, one wonders if increased utilization of per orem vancomycin might be right for an individual patient (although there might be higher recurrence), but wrong for society with increased emergence of VRE, CRKP and other pathogens. After reviewing this study, I'm surely a bit smarter about antibiotics, but unsure of how to treat patients with C. difficile infections … and so it goes.

Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands). This post originally appeared at the blog Controversies in Hospital Infection Prevention.