Antimicrobials May Be Associated with Spread of Drug-Resistant C. Difficile Strains


Cephalosporin treatment is a risk factor of Clostridioides difficile infection.

Penicillin binding protein (PBP) substitutions may raise the minimal inhibitory concentration (MIC) of the antimicrobial cephalosporin—a risk factor for Clostridioides difficile (C. diff) infection (CDI). This may lead to more drug-resistant epidemic C. diff lineages, according to new research published in ASM.

Credit: Yurii Kibalnik -

Credit: Yurii Kibalnik -

CDI outbreaks carry a high risk of mortality, and outbreaks can be prevented or resolved with antimicrobial stewardship, according to the study.

“Greater numbers of PBP substitutions were significantly associated with the highest cephalosporin MICs,” the study authors wrote in the paper.

C. diff is one of the leading causes of health care-associated infection. CDI in humans is often caused by the uncontrolled prescribing of antimicrobials such as fluoroquinolones and cephalosporins. Since the 1990s, a growing number of C. diff strains have become multidrug-resistant (MDR), identifiable by multilocus sequence type (ST) and/or PCR ribotype.

Investigators do not understand the exact mechanisms in C. diff that make it resistant to β-lactam cephalosporin and raises its MIC. But through studying other species, they learned that PBP substitutions cause increased cephalosporin MICs.

In other words, PBP substitutions reduced a bacterium’s susceptibility to cephalosporin, thus increasing its drug resistance, according to the study. PBPs are enzymes that conduct peptidoglycan in bacterial cell walls.

In the current study, investigators studied the substitutions of 5 C. diff PBP peptides (PBP1 to PBP5), cephalosporin MICs, and fluoroquinolone resistance to better understand the mechanism responsible for MDR C. diff lineages. They also studied the relationship between PBP-substituted strains in cephalosporin MIC and wild-type controls.

The study included 16 genetic lineages of C. diff, 14 of which are associated with CDI in the health care setting. The team compared PBP substitutions with the occurrence of fluoroquinolone resistance, measured and compared cephalosporin MICs containing these substitutions with wild-type ancestors, and timed/sequenced the PBP substitution and fluoroquinolone resistance.

In the absence of fluoroquinolone resistance, investigators discovered that PBP substitutions occurred at a lower frequency in the clinically important C. diff lineages. They also found that PBP substitutions of transpeptides PBP1 and PBP3 were associated with raised cephalosporin MICs in C. diff. The investigators hypothesize that the number uncontrolled cephalosporin and fluoroquinolone prescriptions determined the prevalence of C. diff MDR strains.

In addition, the study authors identified that the cephalosporin MICs of wild-type bacterial strains were different, depending on when they acquired PBP substitutions.

“It suggests that wild-type precursors of PBP-substituted clades are better adapted to cephalosporin exposure and therefore perhaps more likely to acquire PBP substitutions,” the study authors wrote.

Investigators note that the bacterium’s adaption to antibiotics, called acquired antimicrobial resistance (AMR), could be an important factor in driving the epidemic as well—possibly more so than the strain’s wild-type genetic virulence.

Antimicrobial stewardship of cephalosporins and fluoroquinolones can control C. diff outbreaks, and has been successful in the UK, among other parts of the world. Investigators have yet to fully understand how PBP substitutions and fluoroquinolone resistance propel the C. diff epidemic, suggesting the need for further controlled studies of cephalosporin and fluoroquinolone stewardship.


Dingle K, Freeman J, Didelot X, et al. Penicillin Binding Protein Substitutions Cooccur with Fluoroquinolone Resistance in Epidemic Lineages of Multidrug-Resistant Clostridioides difficile. ASM Microbe. April 5, 2023. DOI:

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