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Role of prophylactic antibiotics for recurrent C. difficile prevention
Should patients who have suffered from a recent Clostridium difficile infection, or CDI, receive secondary CDI prophylaxis to reduce the risk for relapse when they require treatment with antibiotics?
This is a question not fully answered from current clinical trials. Even though most patients with primary CDI are successfully treated, 10% to 30% will experience a CDI recurrence. In those who have one recurrence, the risk for a subsequent CDI is even greater. In clinical practice, it is not uncommon for patients who have had recent CDI to receive prophylactic oral vancomycin or metronidazole for secondary prevention while they are taking antibiotics for a non-CDI indication, despite current clinical practice guidelines stating that recommendations cannot be made regarding prevention of recurrent CDI in patients who require continued antimicrobial therapy due to lack of data to support its use.
C. difficile has been reported as one of the most common causes of health care-associated infections in U.S. hospitals, thus it is important to know if the practice of providing these patients prophylactic CDI therapy is effective. CDI is expensive to treat and more importantly, it is associated with significant morbidity and mortality. Attributable mortality ranges between 5% and 10%. Furthermore, it was recently estimated that the inpatient cost of one episode of recurrent CDI was $11,631, with an overall cost to the health care system of $4.8 billion annually.
Evidence supporting secondary CDI prophylaxis
Literature evaluating the role of secondary prophylaxis in high-risk patients is sparse. There is one published study in addition to abstracts presented at the 2014 and 2015 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
Van Hise and colleagues presented a poster at ICAAC 2014 that evaluated whether secondary prophylaxis with oral vancomycin had an impact on the incidence of recurrent CDI. There were 203 patients with a history of CDI meeting criteria as high risk included in the study. The primary outcome was the absolute difference in the rate of CDI within the first 4 weeks following completion of antibiotic therapy with and without prophylactic oral vancomycin. This study demonstrated a reduction in CDI recurrence in patients taking oral vancomycin (1%) compared with those who did not (37%; P = .0001).
Similarly, Wong and colleagues presented a study at ICAAC 2015 looking at secondary prophylaxis of CDI in high-risk patients. This study included patients who were treated with antibiotics for a non-CDI indication 14 to 90 days following an initial CDI diagnosis. Patients receiving prophylaxis relapsed less often than the control group (6.25% vs. 19.3%; P = .003) — a 67.6% risk reduction. There were no reported significant differences in baseline characteristics between the two groups. Despite the significantly reduced relapse rate, the prophylaxis group had a higher 90-day death rate (33% vs. 19%; P = .008), though these were deemed to be due to noninfectious complications.
Conversely, King and colleagues, who also presented their study during ICAAC 2015, did not find a significant difference in patients receiving CDI prophylaxis. This was a retrospective cohort study that compared either oral vancomycin, or metronidazole (IV or oral) with no prophylaxis. Patients were included if they had a positive PCR for C. difficile toxin between 2011 and 2013 and subsequently received a minimum 5 days of broad-spectrum antibiotics at least 2 weeks after completion of CDI therapy. The study included 339 eligible patients. The patients who received prophylaxis had a CDI relapse rate of 1.8% vs. 5.7% for the control group. There was no difference in relapse rates between vancomycin- and metronidazole-treated patients. In addition, the researchers did not find a correlation between CDI recurrence and the number of months from initial episode.
A retrospective cohort analysis done at hospitals associated with Cleveland Clinic found success looking at prophylaxis for high-risk patients. The study included 12,026 patients aged older than 55 years who received piperacillin-tazobactam or ciprofloxacin and either a proton pump inhibitor or a histamine-2 receptor blocker. These patients were then divided into two groups during hospitalization — those who received metronidazole before antibiotic therapy and those who did not receive metronidazole before antibiotic therapy. For inclusion, metronidazole was required to begin 1 to 3 days prior to the piperacillin-tazobactam or ciprofloxacin to ensure patients were not being started on empiric CDI treatment. The primary outcome was the rate of CDI between days 1 and 7 after starting the piperacillin-tazobactam or ciprofloxacin. The CDI rate among those receiving metronidazole was 1.4%, while the rate was 6.5% among those not on metronidazole. Duration, dose and route of administration of metronidazole were not examined in the study.
Unanswered questions
While we lack robust, randomized, clinical trial evidence supporting the role of secondary prophylaxis, these studies begin to paint a promising picture. Many questions remain, such as, ‘How long should prophylaxis continue after the course of antibiotic therapy, and what is the definition of recent CDI?’ However, there are two new trials looking at oral vancomycin and metronidazole for recurrent CDI that are currently recruiting patients. These trials should provide even more valuable data. More information about these trials can be found at www.clinicaltrials.gov.
In March, the White House in its National Action Plan for Combating Antibiotic-resistant Bacteria set a goal for the U.S. to reduce the incidence of CDI by 50% by 2020. To achieve this ambitious goal we must reinforce known interventions to reduce CDI such as performing proper hand hygiene, adhering to contact precautions and using effective environmental decontamination. Although there is a potential benefit of using secondary prophylaxis, clinicians should still utilize other proven preventive methods of reducing CDI, such as decreasing unnecessary antibiotic use through antimicrobial stewardship. Since up to 50% of antimicrobials are being used inappropriately, it is likely that some of the patients being retreated with antimicrobials after experiencing CDI may be taking antimicrobials they do not need in the first place.
- References:
- CDC. Antibiotic Resistance Threats in the United States, 2013. www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed October 16, 2015.
- Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;doi:10.1086/651706.
- Dubberke ER, et al. Infect Control Hosp Epidemiol. 2014;doi:10.1086/676023.
- Dubberke ER, et al. Infect Control Hosp Epidemiol. 2014;doi:10.1086/678428.
- King M, et al. Utility of Secondary Prophylaxis with Oral Vancomycin or Metronidazole to Prevent Recurrent Clostridium Difficile Infection (CDI) in Patients Receiving Broad-spectrum Antibiotics. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.
- Rodriguez S, et al. Clin Gastroenterol Hepatol. 2014;doi:10.1016/j.cgh.2014.02.040.
- Van Hise NW, et al. Abstract K367. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 5-9, 2014; Washington, D.C.
- The White House. National Action Plan for Combating Antibiotic-Resistant Bacteria. www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Accessed October 12, 2015.
- Wong D, et al. Secondary Prophylaxis in High Risk Patients Reduces the Risk of Clostridium difficile Recurrence. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.
- For more information:
- Jeff Brock, PharmD, MBA, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: JBrock@mercydesmoines.org.
- Nathan Peterson, PharmD, is a PGY-2 infectious diseases resident at Mercy Medical Center.
Disclosures: Brock and Peterson report no relevant financial disclosures.