The choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and metaanalysis of studies that assessed the risk of CDI with tetracyclines compared to other antibiotics.
We conducted a systematic search of Medline, Embase, and Web of Science from January 1978 through December 2016 to include studies that assessed the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale.
Six studies (4 case control, 2 cohort) with patient recruitment between 1993 and 2012 were included. Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47–0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40–0.75; P < .001).
Metaanalyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease CDI associated with antibiotic use.
The strengths of our study include a comprehensive literature search with well-defined inclusion criteria and multiple subgroup analyses, with no subgroup analysis showing an increased risk of CDI with the use of tetracyclines. Limitations of our meta-analysis include that the individual studies varied in several ways, including study design, patient population (age, sex, inpatient vs outpatient status), method of CDI diagnosis, time period for prior antibiotic exposure, and dose and duration of tetracycline use. These variations led to substantial heterogeneity. Although all the studies controlled for some potential confounders, each individual study controlled for different variables. Hence, we were unable to perform analyses in which all confounding factors could be accounted or controlled for, including duration of exposure and dose of tetracyclines, indication for tetracycline use, adherence to infection-control practices, use of administrative diagnosis codes, and the possibility that a positive stool assay represented colonization rather than active infection. None of the studies included outpatients only; hence, we could not perform analyses separating inpatients vs outpatients only. We also could not perform analyses separating patients with hospital-acquired vs community-acquired CDI. All studies assessed the risk of primary CDI and excluded patients with recurrent CDI.