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Does Doxycycline Protect Against Development of Clostridium difficile Infection?

Doernberg SB, Winston LG, Deck DH, Chambers HF
Clin Infect Dis. 2012;55:615-620.

C difficile Infection and Antibiotic Exposure

When used in combination with ceftriaxone, doxycycline appears to lower the risk of developing C difficileinfection compared with ceftriaxone alone. C difficile is a major hospital pathogen, and risk for C difficile infection increases with antibiotic exposure (number of antibiotics and duration of antibiotic use). A previous case-controlled study found that doxycycline reduced the risk for C difficile infection, although other studies have not corroborated this finding.

Doernberg and colleagues sought to evaluate the effect of doxycycline exposure on risk for C difficile infection by evaluating their practice of using ceftriaxone and doxycycline as a preferred treatment for community-acquired pneumonia.

Study Summary

Over a 4.5-year period, adult inpatients who had received ceftriaxone were compared with those who had received both ceftriaxone and doxycycline. The primary measurement was the development of C difficileinfection during the next 30 days. Exposure to and duration of treatment with other antimicrobials were measured, along with demographics and comorbidity data, but no severity-of-illness data were acquired.

Doxycycline was used in 39% of the patients who received ceftriaxone. Rates of C difficile infection were much lower in those receiving the ceftriaxone/doxycycline combination compared with those receiving ceftriaxone alone (1.67/10,000 patient-days vs 8.11/10,000 patient-days). In addition, 29% of patients received another antibiotic and 16% received at least 2 additional antibiotics.

A multivariate analysis that adjusted for multiple factors, including duration of hospitalization, demographics, surgical admission, comorbid conditions, and duration of ceftriaxone and other antibiotics, indicated that each day of doxycycline therapy was associated with a 27% reduction in the rate of C difficile infection. Duration of ceftriaxone or other antibiotic therapy was not associated with increased risk for C difficile infection, and the strongest predictor of this risk by far was duration of hospitalization (adjusted hazard ratio, 15.1 [5.73-39.6]). When specific antimicrobial regimens for community-acquired pneumonia were compared, risk for C difficileinfection in the ceftriaxone/doxycycline group was significantly lower than combinations containing either macrolides or fluoroquinolones.

Viewpoint

This study suggests that doxycycline may protect against the development of C difficile infection, although the mechanism of this effect is unknown. Doxycycline might directly inhibit C difficile, and small studies have shown that a similar agent (tigecycline) could be efficacious in treating C difficile infection. Doxycycline might also produce less disruption of enteric flora than other antimicrobials such as fluoroquinolones or carbapenems.

Limitations of this study must be considered. First, there were major differences between the comparator groups. Although the investigators attempted to adjust for possible confounders, unrecognized or unmeasured differences may have predisposed the doxycycline group to a lower risk for C difficile infection. Severity of illness may be one of these confounders because macrolides and fluoroquinolones were preferred for the treatment of severe pneumonia.

Indication bias could also be present because indications for which clinicians avoided doxycycline may have been those that carried a higher risk for C difficile infection. Furthermore, neither hospital location nor strain relatedness was evaluated for possible effect on C difficile infection. It may be that certain services or hospital locations where doxycycline use was low had higher C difficile infection pressure.

A final issue to consider is that very few data exist on the efficacy of doxycycline-containing combinations for the treatment of community-acquired pneumonia. Despite these limitations, the role of doxycycline in prevention of C difficile infection needs to be further explored.