Predicting the limit to ceftriaxone's use in gonorrhea treatment: impending resistance and logistical challenges

The increasing prevalence of antimicrobial resistance in Neisseria gonorrhoeae threatens the efficacy of ceftriaxone, the last widely effective treatment for gonorrhea. Resistance mechanisms challenge the adequacy of current dosing strategies and minimum inhibitory concentration (MIC) thresholds, with treatment failures documented at MICs as low as 0.125 mcg/mL. Limited clinical and pharmacodynamic data complicate efforts to define optimal dosing and resistance breakpoints.

This review examines the evolution of ceftriaxone dosing recommendations in response to resistance trends, explores the genetic and pharmacokinetic factors driving reduced susceptibility, and critically evaluates the CDC's MIC 'alert value' of 0.125 mcg/mL. Surveillance data are analyzed alongside pharmacokinetic/pharmacodynamic (PK/PD) models, including Monte Carlo simulations and hollow fiber infection models (HFIM). Practical challenges, including injection site tolerability, lidocaine safety, and dosing limits for intramuscular administration, are reviewed.

Current PK/PD data and IV tolerability studies support ceftriaxone dose escalation up to 3.5 g IM as a feasible outpatient limit for strains with MICs up to 0.5 mcg/mL. However, the MIC at which even high-dose regimens fail remains unknown. Urgent priorities include validating higher doses through clinical pharmacokinetic and outcomes studies, refining MIC thresholds by anatomical site, and evaluating novel agents for reliable pharyngeal eradication.