Meta-Analysis Links Classes of Antibiotics to latrogenic C difficile Infections

Carbapenems and third- and fourth-generation cephalosporin were the antibiotic classes most strongly associated withClostridioides difficile infection arising in healthcare facilities, in a new systematic review and meta-analysis.

The review and analysis of studies of hospitalized patients publishedin English between January 2013 and April 2020 was conducted by Claudia Slimings, PhD, School of Pathology and Laboratory Medicine, The University of Western Australia, Crowley, Western Australia, Australia, and Thomas Riley, PhD, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia.

In their previous review of studies of antibiotic usage linked to iatrogenic C difficle infection published in 2014, Slimings and Riley had found that use of cephalosporings or clindamycin were the most likely antibiotics to precede C difficile infection (CDI).In that earlier review, the investigators suggested that concern with fluoquinolones might have been overemphasized, particularly if fluoroquinolone-resistant epidemic strains of C difficile are absent.

In the current review, Slimings and Riley find that iatrogenic C difficile infection is more than twice as likely after recent exposure to carbapenems or third- and fourth-generation cephalosporins; and that there are "modest" associations with fluoroquinolones, clindamycin andß-lactamase inhibitor combination penicillin antibiotics.

For non-ß-lactam antibiotic classes, the strongest evidence for association with healthcare facility-associated (HCFA)-CDI infections was found for quinolones (fluoroquinolones) and lincosamides (clindamycin).Overall, quinolones were associated with 34% increased odds of HCFA-CDI (OR 1.34; 95% CI 1.13-1.60).Lincosamides were associated with 56% increased odds of HCFA-CDI (OR 1.56; 95% CI 1.13-2.14).The reviewers also found associations for antibiotics used to treat CDI, particularly vancomycin(OR 1.91; 95% CI 1.32-2.78).

The incidence rates of HCFA-CDI have been increasing, according to Slimings and Riley.They suggest several factors for the increase, including increased testing and more sensitive diagnostic tests, increased use of broad-spectrum antibiotics, inadequate prevention measures, aging populations, and emergence of community strains.

"Antibiotic use is the most important modifiable risk factor for CDI," Slimings and Riley assert."Other important risk factors include advanced age, increased number of comorbidities or severe underlying diseases and duration of healthcare exposure."

The multiple contributing factors and the different methodologies and populations of the 21 studies that met inclusion criteria posed challenges for the current meta-analysis. Slimings and Riley found that a more diverse range of patient populations had been studied since 2013, with increased focus on particular patient subgroups such as surgical and ICU patients and patients with particular conditions, rather than the general inpatient populations of the earlier studies.

"Studies using patient subgroups tended to have weaker associations," they observed."A potential explanation is that studies of patient subgroups had shorter periods of antibiotic exposure measurement."

The reviewers found that few studies marked dose-response relationships, or examined HCFA-CDI in relation to timing and duration of antibiotic exposure.They noted the substantial increase in computing power that has become available since their last review, and urged investigators to apply that to their patient cohort studies to clearly report surveillance definitions, criteria and laboratory methods for diagnosis of CDI in their institutions, and how these align with relevant current guidelines.

"Future studies should clearly report the parameters of exposure measurement, including all sources of information on exposure, as it was often unclear," Slimings and Riley indicated."Particularly in studies with a longer exposure window, when in-hospital prescription only was recorded, or whether prescription in the community setting was included."