Doxycycline May Protect Against Clostridium Difficile Infection

By Betty Tran, MD, MS, Assistant Professor of Medicine, Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago

Dr. Tran reports no financial relationships relevant to this field of study.

Synopsis: This retrospective study of hospitalized patients receiving ceftriaxone found that additional treatment with doxycycline compared to other antibiotics was associated with a lower risk of Clostridium difficile infection.

Source: Doernberg SB, et al. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis 2012;55:615-620.

Doernberg and colleagues sought to determine whether receipt of doxycycline was associated with protection from development of Clostridium difficile infection (CDI) in hospitalized patients being treated with ceftriaxone, a known high-risk antibiotic for CDI. They retrospectively identified 2734 hospitalizations involving 2305 adult patients at San Francisco General Hospital who received ceftriaxone during their hospitalization. Of these, 1066 (39%) patients also received doxycycline; these patients tended to be older, were more likely to have pneumonia on admission, were less likely to be surgical patients, had higher Charlson Comorbidity Index scores, and received shorter courses of additional antibiotics. The duration of treatment with ceftriaxone, the number of hospital days before development of CDI, and total length of hospital stay, however, were similar between the group that received doxycycline and the group that did not. The primary outcome of interest was development of CDI within 30 days of receiving ceftriaxone.

During the 2005-2010 study period, the overall incidence of CDI was 5.60 per 10,000 patient-days, a rate that is lower than reported in other studies. The incidence of CDI in patients who received doxycycline was 1.67 per 10,000 patient-days compared to 8.11 per 10,000 patient-days in patients who did not receive doxycycline. For each day that a patient received doxycycline, there was a 27% lower risk of CDI compared to a patient who was not receiving doxycycline (95% confidence interval [CI], 0.56-0.96; P = 0.03). When the authors directly compared common therapies for community-acquired pneumonia (CAP), a 5-day course of ceftriaxone plus doxycycline was associated with an 85% lower rate of CDI (95% CI, 0.03-0.77) compared to a 5-day course of ceftriaxone plus a macrolide, and an 87% lower rate of CDI (95% CI, 0.03-0.62) compared to a 5-day course of ceftriaxone plus a fluoroquinolone. Because of the uncertainty of capturing all data on antibiotic exposure and CDI cases after discharge, a sensitivity analysis was performed using only hospital data up until discharge with similar results, according to the authors.


Given the increasing morbidity and mortality of CDI, especially among hospitalized patients, and the high prevalence with which inpatients receive at least one dose of antibiotics, this article poses a fascinating question and springboard for further clinical and laboratory investigations.

San Francisco General Hospital, the study site, presented a unique opportunity for investigators as doxycycline was the recommended first-line therapy for CAP in non-ICU inpatients. Current American Thoracic Society and Infectious Diseases Society of America guidelines, however, recommend doxycycline as an alternative to either a macrolide or a fluoroquinolone as part of a treatment regimen for CAP based only on level III evidence. Findings from this study suggest that further research is needed to revisit the use of doxycycline as a preferred antibiotic in CAP treatment. Doxycycline may reduce the burden of CDI in already vulnerable patient populations, but widespread recommendations for its use may be tempered by differences in clinical outcomes of CAP depending on the setting (outpatient vs inpatient vs ICU).

The mechanisms to explain the association between receiving doxycycline and having a lower risk of CDI also need to be explored. The authors posit a few possibilities, including doxycycline’s in vitro activity against C. difficile, its attenuation of C. difficile toxin production, and its minimal effects on bowel flora due to maximal absorption in the upper gastrointestinal tract. These hypotheses sound plausible, although further data will be informative, especially to ensure that doxycycline use does not result in inadvertent but unwanted outcomes such as the selection of rarer but more virulent strains of C. difficile.

Although further data are needed to support the findings reported, this study is encouraging and also highlights an approach to reducing the rate of CDI by using “lower-risk” antibiotics, a method that may prove to be a valuable weapon in the antibiotic stewardship arsenal.