Journal Club

Impact of Bioavailability of Antibiotics for Gram-Negative Bacteremia: Dose Those Beta-Lactams Appropriately!

By Christopher J. Graber, MD, MPH, FIDSA

As shorter treatment and early transition to oral antibiotic therapy for Gram-negative bacteremia has gained more attention of late, concerns have been raised regarding the efficacy of oral beta-lactams and cephalosporins when used to complete an antibiotic course for Gram-negative bacteremia due to their lower bioavailability than fluoroquinolones and trimethoprim-sulfamethoxazole.

In a study recently published in Clinical Microbiology and Infection, authors affiliated with the University of Toronto addressed this issue by identifying 1,006 patients throughout Ontario from 2017-2019 who had Gram-negative bacteremia susceptible to at least one less-bioavailable oral antibiotic (e.g., beta-lactam, cephalosporin) and at least one high-bioavailable oral antibiotic (e.g., fluoroquinolone or trimethoprim-sulfamethoxazole) who were discharged to complete their course with a less-bioavailable antibiotic, matched 1:1 on sex, pathogen (Escherichia coli or not), and urinary source to patients discharged with a high-bioavailable antibiotic. Mean duration of hospitalization was 4.2 days, and mean total duration of therapy was 7.0 days in the less-bioavailable group vs. 8.1 days in the high-bioavailable group. Amoxicillin-clavulanate was most prescribed (31.2%) in the less-bioavailable group, and ciprofloxacin was most prescribed (80.5%) in the high-bioavailable group.

The primary composite outcome of 90-day all-cause mortality, recurrent bacteremia with the same species, and readmission to any Ontario hospital was reached in 171 (17%) in the group receiving high-bioavailable therapy vs. 216 (21.5%) in the less-bioavailable group (adjusted odds ratio [aOR], 0.74; 95% confidence interval [CI], 0.60-0.92), with recurrent bacteremia being the primary driver of the difference in the composite outcome: 62 (6.2%) and 100 (9.9%) in the high and less-bioavailable groups, respectively (aOR, 0.59; 95% CI, 0.42-0.82). However, when high doses of the less-bioavailable agents were given (e.g., > 875 mg q12h for amoxicillin, > 500 mg q6h for cephalexin, > 500 mg q12h for cefuroxime), aOR for the primary outcome was only 0.97 (95% CI, 0.59-1.60) for high vs. less-bioavailable agents.

This work provides an important perspective to completion of antibiotic treatment for Gram-negative bacteremia with oral agents, suggesting that if an oral beta-lactam or cephalosporin is used, that it be dosed on the higher side for the patient’s renal function. Prospective randomized studies that also explore pharmacokinetics and pharmacodynamics of these agents are warranted.

(Mponponsuo et al. Clin Microbiol Infect. Published online: Oct. 7, 2022.)