Amoxicillin, Ertapenem Increase Antibiotic-Resistance Genes

Oral amoxicillin and intravenous ertapenem kill commensal bacteria and increase risk for antibiotic resistance in Clostridium difficile.

Sheila Connelly, PhD

In a study published in Anaerobe, investigators found that amoxicillin and ertapenem, distinct beta-lactam antibiotics which are delivered orally and intravenously, result in significant changes in the microbiome as well as noticeable increases in pathogen overgrowth and emergent antibiotic resistance genes, indicating for the presence of antibiotic-resistant bacteria. Although this was an animal study, these findings may be helpful in improving understanding of the effects of these 2 antibiotics in patients affected with common hospital-acquired infections, including Clostridium difficile (C. difficile).

Antibiotics offer protection against the progression of potentially deadly bacterial infections, such as C. difficile. These life-saving medications, however, can sometimes result in collateral damage and the subsequent eradication of commensal microbiota residing in the gastrointestinal tract. Consequently, this eradication of the commensal bacteria can result in the proliferation of C. difficile opportunistic pathogens.

“Different antibiotics have distinct consequences on the gut microbiome, and understanding the effects of individual antibiotics on the microbiome may help to mitigate adverse outcomes,” lead investigator Sheila Connelly, PhD, vice president of research, Synthetic Biologics, told MD Magazine. “For example, if the effect of each antibiotic on the microbiome is known, an alternative antibiotic may be chosen that is equally effective against the infectious agent but limits damage to the gut microbiome.”

In their study, investigators Connelly et al. used a porcine model to assess modifications that occur in the gut following the administering of 2 beta-lactam antibiotics: amoxicillin and ertapenem. Amoxicillin, which was delivered orally, is a broad-spectrum antibiotic that is commonly used in young children affected by C. difficile and other pathogenic bacteria. Ertapenem, which belongs in the carbapenem class and is delivered intravenously, is a “last-resort” antibiotic that is infrequently used in humans.

A total of 5 normal pigs without infection were given twice-daily 20 mg/kg oral amoxicillin or once-daily 30 mg/kg intravenous ertapenem for 7 days. The investigators used whole genome shotgun metagenomics analyses of the cohort’s fecal DNA to assess microbiome changes before, during, and following treatment with the antibiotics.

Both treatments were associated with significant and prominent microbiome modifications as well as eradication of key commensal bacteria and increase in the overgrowth of taxa with pathogenic potential. In the pigs provided amoxicillin treatment, the investigators observed an increase in the growth of broad-range antibiotic resistance genes. The majority of the antibiotic-resistance genes encoded beta-lactamases and efflux pump components. Comparatively, treatment with ertapenem was associated with an increase in genes which encoded for vancomycin resistance and beta-lactamases.

According to Connelly, similar studies which examine human subjects exposed to oral amoxicillin and intravenous ertapenem are minimal.

“There is a surprising dearth of data regarding the damage caused by individual antibiotics,” Connelly added, “However, studies of antibiotic effects in humans rarely focus on the effects of a single agent.”

Despite the lack of human data, Connelly hints toward future trials that may be focused on human participants, thanks in part to the new research by her and her fellow investigators.

“Understanding the effects of individual antibiotics on the microbiome may allow clinicians to choose antibiotics that are effective against the pathogen and limit damage to the gut microbiome,” explained Connelly.

The porcine antibiotic-mediated dysbiosis models developed in this study may ultimately be utilized “to evaluate strategic interventions to protect and maintain the gut microbiome in animals and humans.”

REFERENCE

Connelly S, Subramanian P, Hasan NA, Colwell RR, Kaleko M. Distinct consequences of amoxicillin and ertapenem exposure in the porcine gut microbiome [published online April 21, 2018]. Anaerobe. doi: 10.1016/j.anaerobe.2018.04.012.