By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: In a retrospective study from the VA, doxycycline was associated with a lower risk of C. difficile infection compared to azithromycin in hospitalized patients with community-acquired pneumonia.
SOURCE: O’Leary AL, Chan AK, Wattengel BA, et al. Impact of doxycycline on Clostridioides difficile infection in patients hospitalized with community-acquired pneumonia. Am J Infect Control 2023; Nov. 2:S0196-6553(23)00628-4. doi: 10.1016/j.ajic.2023.09.007. [Online ahead of print].
For most cases of community-acquired pneumonia (CAP), current Infectious Diseases Society of America treatment guidelines recommend a beta-lactam antibiotic plus a macrolide for atypical coverage.1 Doxycycline is suggested as an alternative to azithromycin in certain circumstances, such as a prolonged QTc interval or the presence of a drug allergy. Because of an increasing rate of Clostridioides difficile infection (CDI) at their institution, O’Leary and colleagues sought to determine whether using doxycycline as an alternative to azithromycin in CAP would lead to a reduction in CDI cases.
The study was a retrospective cohort analysis that used information from a Veterans Affairs (VA) database. Patients were included who were hospitalized for CAP at a VA healthcare facility between Jan. 1, 2009, and Aug. 25, 2022. All patients had to have received intravenous (IV) ceftriaxone. The comparator groups were IV or oral doxycycline vs. azithromycin. Exclusion criteria were receipt of both doxycycline and azithromycin, or diagnosis of Legionella or viral pneumonia. Legionella pneumonia was excluded because tetracyclines are not recommended for treatment because of resistance concerns. For the study, CDI was diagnosed if the patient was positive by C. difficile polymerase chain reaction (PCR) testing within 30 days of receiving antibiotics. The primary outcome of the study was the development of CDI within 30 days of initiation of doxycycline or azithromycin for CAP.
A total of 156,107 patients were included in the analysis, of whom 135,703 (86.9%) received azithromycin and 20,404 (13.1%) received doxycycline. The mean age was 72 years and 96% were male. There were 1,234 patients who developed CDI within 30 days of starting antibiotic therapy: 1,085 patients in the azithromycin group (0.8%) and 149 patients in the doxycycline group (0.7%). The risk for CDI was 17% less with doxycycline compared to azithromycin when combined with ceftriaxone (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.70-0.99; P = 0.03).
Overall, the risk for CDI was low (0.7%) for patients who never had a previous episode. However, those who had CDI in the previous year had an 18.5% higher risk for a recurrence in the 30 days after being hospitalized for CAP (P < 0.0001). In those patients, 12.2% developed CDI again after at least one dose of ceftriaxone and doxycycline or azithromycin. Doxy-cycline decreased the incidence of CDI by 45% (OR, 0.55; P = 0.02).
A Charlson Comorbidity Index of 6 to 23 was associated with a higher incidence of CDI (OR, 1.22; 95% CI, 1.1-1.4). A greater percentage of patients who developed CDI received a proton pump inhibitor (47.3%) compared to those who did not after CAP treatment (42.2%; P = 0.0003). Chronic renal disease and chronic liver disease also were associated with a higher risk for recurrent CDI. Furthermore, the risk for CDI increased with more ceftriaxone doses (OR, 1.029; 95% CI, 1.01-1.04).
COMMENTARY
The main take-home point from this study is that doxycycline reduced the risk of CDI by 17% compared to azithromycin. The reduction was even more substantial for patients with a prior history of CDI (45%). The underlying biological mechanism may be the ability of doxycycline to attenuate C. difficile toxin production through protein synthesis inhibition. Alternatively, or perhaps concurrently, doxycycline has minimal impact on gut flora, thereby preventing overgrowth of C. difficile.
The study had a few limitations. First, the patients primarily were elderly men, so the results might not be generalizable to other populations. Second, there was no information about patients who may have developed CDI after CAP therapy and were admitted to a non-VA hospital. Third, the observational design may have allowed unmeasured confounding variables to affect the results. Finally, PCR was used to diagnose CDI and no toxin testing was performed. This could have led to false-positive results by detecting patients colonized with C. difficile.
Does the study by O’Leary and colleagues signal that it is time to change the CAP guidelines and abandon azithromycin for doxycycline? Not yet. As the authors mentioned, doxycycline may not be as effective as a fluoroquinolone or azithromycin for Legionella pneumonia because of antibiotic resistance. However, if Legionella has been ruled out, and the patient has a history of CDI, then using doxycycline instead of azithromycin along with ceftriaxone would be a reasonable treatment regimen. Further studies are needed to confirm these findings and assess for any esoteric consequences of using doxycycline instead of azithromycin for CAP.
Reference
- Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019;200:45-67.
