The combined effect of systemic antibiotics and proton pump inhibitors on Clostridioides difficile infection and recurrence

Abstract

Background: Antibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear.

Objectives: To assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence.

Methods: Population-based study including all 43 152 patients diagnosed with CDI in Sweden (2006-2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0-30 days) and preceding (31-180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs.

Results: Compared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48-17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83-15.93); ORPPI = 2.65 (2.54-2.76)]. Results were less pronounced for exposure during the preceding months. Dose-response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15-6.49); ORPPI = 1.65 (1.62-1.68) per prescription increase].Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23-1.38)] and preceding [ORAB = 1.23 (1.16-1.31); ORPPI = 1.12 (1.03-1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes.

Conclusion: Recent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.

Figure 1.

Flowchart describing the selection of participants in the case-control design to assess CDI risk, and the cohort design to assess CDI recurrence. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Effect of (combined) use of antibiotics and PPI on (a) the risk of CDI and (b) CDI recurrence, expressed as OR. All models were adjusted for region of birth, chronic comorbidity score (continuous variable), inflammatory bowel disease, haematological diseases, aspirin, NSAID use and H2-receptor antagonist use. The recurrence model was additionally adjusted for sex and age (continuously).