Is Doxycycline Protective Against the Development of C. difficile infection?

By Richard R. Watkins, MD, MS, FACP, Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH, is Associate Editor for Infectious Disease Alert.

Dr. Watkins reports no financial relationships in this field of study.

Synopsis: A historical cohort study from San Francisco General Hospital evaluated patients ≥18 years old that were hospitalized and received at least one dose of ceftriaxone. In a multivariable analysis, for every day a patient also received doxycycline the rate of Clostridium difficile infection was 27% lower than for those who did not receive doxycycline (hazard ratio, 0.73%; 95% confidence interval, 0.56-0.96).

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

Clostridium difficile infection (CDI) is a major complication associated with antibiotic usage, and its incidence continues to increase. Management of CDI remains challenging despite new therapies and many patients suffer from recurrences. Interventions to limit acquisition of the disease are therefore urgently needed. Not all antibiotics predispose to CDI equally, and there is some clinical evidence that certain antibiotics may be associated with a lower risk or even prevent it. Investigators sought to determine if doxycycline could avert CDI among patients who received ceftriaxone, a high-risk antibiotic. They performed a historical cohort study between June 1, 2005 and December 31, 2010 that included hospitalized patients ≥ 18 years of age who received at least one dose of ceftriaxone. Patients were excluded who were diagnosed with CDI in the 30 days prior to admission through 2 days after admission, or if diagnosed with CDI before they received ceftriaxone. The main outcome of interest was the onset of CDI within 30 days of initiation of ceftriaxone. The cohort consisted of 2,734 hospitalizations, with 2,305 different patients.

The results of the study were that 39% of patients (1,066) received doxycycline during their hospitalization, and 5 developed CDI for an incidence rate of 1.67 per 10,000 patient-days. Of the patients who did not receive doxycycline, 38 developed CDI, an incidence rate of 8.11 per 10,000 patient days. Unadjusted analysis found white race to be associated with a 2.67-fold higher hazard of CDI compared with nonwhite race (95% confidence interval, 1.46-4.89; P = 0.001). There was a trend toward a protective effect with male gender (P = 0.06). On bivariate analysis, for every day of additional antibiotic receipt besides ceftriaxone, the hazard for acquiring CDI increased by 4%. For every day of doxycycline receipt the unadjusted hazard was 0.67-fold lower for developing CDI compared to patients not receiving doxycycline.

On multivariable analysis, for each additional day that a patient received doxycycline the rate of CDI was 27% lower compared to a patient not receiving it when adjusted for age, gender, race, comorbidities, duration of hospitalization, pneumonia diagnosis, surgical admission, and duration of ceftriaxone and other antibiotics. When a patient received a 5 day course of doxycycline the hazard for developing CDI was 0.21 fold that of a patient not receiving it when adjusted for other factors in the model (95% confidence interval, 0.05-0.82). The hazard ratio for developing CDI in a patient who received a 5 day course of doxycycline and ceftriaxone compared to a macrolide and ceftriaxone was 0.15 (95% confidence interval, 0.03-0.77), and was 0.13 compared to a 5 day course of a fluoroquinolones and ceftriaxone (95% confidence interval, 0.03-0.62). The strongest predictor of developing CDI was time spent in the hospital and the hazard for each day was 15.1 fold higher than for an outpatient.

The study had several limitations. First, all patients in the cohort were given ceftriaxone which would have increased their baseline risk for CDI. This made it difficult for the investigators to determine the increased risk of CDI specifically due to the duration of ceftriaxone. Second, trauma patients could have caused confounding of the results as they were commonly male and nonwhite, two groups shown in the study to have lower incidence of CDI. Third, measurement bias may have occurred since hospitalized patients who develop diarrhea are more likely to be tested for CDI than those who have been discharged. Fourth, antibiotics received before hospitalization were not recorded and could underestimate the subsequent risk for developing CDI. Finally, the authors did not identify the strain(s) of C. difficile present during the study.

Commentary

Doxycycline plus a β-lactam antibiotic is an alternative recommendation for the treatment of patients hospitalized for community-acquired pneumonia (CAP) in the current IDSA/ATS guidelines.1 The majority of patients with CAP admitted to the general floor at my hospital (which is similar in size to the authors') receive either levofloxacin or ceftriaxone plus azithromycin, while those admitted to the ICU receive levofloxacin or azithromycin plus ceftriaxone. The recent report on the cardiovascular risks associated with macrolides makes doxycycline look appealing.2 It will be interesting to see if doxycycline usage in clinical practice increases in light of this study, especially for CAP. Furthermore, if doxycycline decreases the risk of developing CDI there would be even more reason to use it over macrolides and possibly quinolones, the latter of which carry a high risk for CDI.

The mechanism behind the possible protective effect of doxycycline is unknown. Several theories have been proposed, including its in vitro activity against anaerobic bacteria (including C. difficile), attenuating C. difficile toxin production, and the fact that doxycycline is mostly absorbed in the upper gastrointestinal tract which would spare the normal flora in the colon.3,4 Tigecycline, a derivative of minocycline, has been used successfully in refractory cases of CDI.5

In the present study, patients who received doxycycline had shorter courses of antibiotics overall, which would intuitively decrease their risk for CDI. It was not randomized, which could predispose to confounding and uncertainty as to whether the observed association was due to the treatment or the type of patient to whom the treatment was administered. For instance, the cohort patients who received doxycycline were more likely to have had pneumonia on admission, less likely to have been admitted to a surgery service, had higher Charlson comorbidity indices, and received shorter courses of additional antibiotics. Moreover, the authors did not determine whether patients in the cohort had an episode of CDI more than 30 days prior to hospitalization, as this may have led to increased risk. The incidence of CDI in this study was lower compared to prior studies. This might have been due to the enzyme immunoassay testing method used, which has poor sensitivity. Whether it impacted the results is uncertain.

The incidence of CDI shows no sign of abating, and current infection control practices and antimicrobials are unlikely to curtail the epidemic. Novel and innovative solutions are required and will likely be the key to controlling the disease. Despite its limitations, this study has an important finding: hospitalized patients treated with ceftriaxone who also received doxycycline had a lower risk for developing CDI. Indeed, it could lead to adjustment of the paradigm for treating CAP by making doxycycline plus ceftriaxone first-line therapy. However, additional studies that verify the favorable association between CDI and doxycycline should be performed before changes to the current guidelines can be recommended.

References

  1. Mandell LA, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(suppl 2):S27-72.
  2. Ray WA, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-1890.
  3. Noren T, et al. In vitro susceptibility to 17 antimicrobials of clinical Clostridium Difficile isolates collected in 1993-2007 in Sweden. Clin Microbiol Infec 2010; 16:1104-1110.
  4. Joshi N, et al. Doxycycline revisited. Arch Intern Med 1997;157:1421-1428.
  5. Venugopal AA, et al. Current state of Clostridium difficile treatment options. Clin Infect Dis 2012;55 Suppl 2:S71-76.