Antimicrobial Stewardship and C. difficile Therapy: It's Complicated

The CDC's Get Smart About Antibiotics Week (November 16-22, 2015) is upon us. To do our part, we bloggers are using 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 November 15 issue of JID 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 C. difficile specific therapies and how does antibiotic selection alter colonization resistance to C. difficile, VRE, CRE and E. 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. As you can see in the figure below, most metronidazole-treated mice could not support C. difficile growth (red circles) after seven 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 (See figure below - click to enlarge), 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 (see figure below) found that mice treated with vancomycin (pink circles) were far more susceptible to VRE, carbapenem-resistant K. pneumoniae and E. coli than metronidazole treated (black circles) or untreated mice (open circles) for at least two 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, CRKP 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 PO 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 CDI...and so it goes.

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It's been a crazy couple weeks out here on the edge of the prairie. Clinical service, grants, papers, holidays, Ebola?, the ESCMID-SHEA course in Phuket and SHEA2015 have swallowed up my fall. Get those SHEA abstracts ready folks - the deadline is fast approaching - January 16th.

In the middle of this chaos, the CDC's Get Smart About Antibiotics Week seemingly appeared out of nowhere and CDDEP investigators just published a very nice antibiotic use point prevalence study in 6 US hospitals in this month's Lancet ID to coincide with the 'Get Smart' Campaign. Nikolay Braykov and Dan Morgan led the study and Nikolay wrote up a nice post describing what they found, which I've excerpted below:

We undertook a chart review study at six institutions – two teaching centers, three community hospitals and one VA – looking at the indications for starting antimicrobials, the use of culture and radiology results and the patterns of modifying empiric therapy in the first five days of treatment. We found nearly two-thirds of inpatients were receiving antibiotics, with empiric starts dominated by combinations of vancomycin, piperacillin/tazobactam and fluoroquinolones. It is likely that a lot of those initial prescriptions were unnecessary, as 30% of patients lacked fever or abnormal white blood cell counts at the start.

Appropriate cultures (on or before start of therapy) were collected from 59% of patients, and although 60% came back negative, only 22% of all evaluated patients and had their antibiotics narrowed or stopped (Figure). More specifically, 22/59 (37%) of patients with negative urine culture and 11/22 (50%) of those with negative blood culture had antimicrobials stopped or narrowed. Of pneumonia patients with negative chest imaging that proportion was 12/50 (24%).

Narrowing or discontinuation (of antibiotic therapy) was more likely when cultures were collected at the start of therapy and no infection was noted on an initial radiological study. In turn, escalation was associated with multiple infection sites and a positive culture (see table below).

It seems like diagnostic uncertainty drives a lot of possibly unnecessary antibiotic use. These results underscore not only the need for rapid diagnostics, but also the importance of mechanisms to assure tests are ordered in time and their results are actually used to optimize therapy – goals attainable through better stewardship programs and physician education.

A great point made recently is that the government’s resistance action plans should include steps to incentivize and expand the training of more ID physicians. Although the threat of drug resistance gets more public attention each year, “getting smart” about antibiotics, including their timely withdrawal and adjustment, ultimately requires the buy-in of current and future prescribers. 

CDC's Get Smart for Healthcare program

Arjun Srinivasan, Medical Director for CDC’s “Get Smart for Healthcare” campaign, and Ramanan Laxminarayan, Director of Extending the Cure, co-authored a recent piece in the Health Care Blog. It describes the current crisis with carbepenem-resistant Enterobacteriaceae and how the CDC and partners are responding. For example, this week, they launched the “Get Smart for Healthcare” program which complements the existing “Get Smart: Know When Antibiotics Work” program. I will let you read what Arjun and Ramaman have to say...

link: The Health Care Blog

h/t: Mark Vander Weg

Post #610: Happy "Get Smart About Antibiotics Week" (November 15-21, 2010)

Man, have we done a lot of posting in the past 1.5 years.  I think Dan and Mike will agree with me here when I say that none of our posts have been as important as this one.  None.  The reason for this is that I'm announcing a whole 7 days of celebrating and not just one day. The world has witnessed Global Handwashing Day,  World Hand Hygiene Day, and World MRSA Day this past year.

But notice, these were just on single days.  Thus, we can officially announce that the smart use of antibiotics is 7 times more important than MRSA and 7/2 or 3.5 times more important than the domain of handwashing/hand hygiene. These are two questions that as an epidemiologist I've been struggling to answer for 10+ years and now I finally know.  While it is true that this is the 3rd annual "Get Smart About Antibiotics Week" and I should have officially known this two years ago, I do like to wait for "replication of results" or reproducibility before drawing a firm conclusion on such important questions. Alright everybody, get ready and Get Smart about antibiotics!