Pharmacodynamics of Ceftriaxone, Ertapenem, Fosfomycin and Gentamicin in Neisseria gonorrhoeae

Abstract

Objectives: To assess the in vitro effect of select antimicrobials on the growth of N. gonorrhoeae and its pharmacodynamic parameters.

Methods: Time-kill assays were performed on two reference N. gonorrhoeae strains (ceftriaxone-resistant WHO X and ceftriaxone-susceptible WHO F) and one clinical N. gonorrhoeae strain (ceftriaxone-susceptible CS03307). Time-kill curves were constructed for each strain by measuring bacterial growth rates at doubling antimicrobial concentrations of ceftriaxone, ertapenem, fosfomycin and gentamicin. Inputs from these curves were used to estimate minimal bacterial growth rates at high antimicrobial concentrations (ψ_min), maximum bacterial growth rates in the absence of antimicrobials (ψ_max), pharmacodynamic minimum inhibitory concentrations (zMIC), and Hill's coefficients (κ).

Results: Ceftriaxone, ertapenem and fosfomycin showed gradual death overtime at higher antimicrobial concentrations with a relatively high ψ_min, demonstrating time-dependent activity. Compared to WHO F, the ψ_min for WHO X was significantly increased, reflecting decreased killing activity for ceftriaxone, ertapenem and fosfomycin. At high ceftriaxone concentrations, WHO X was still efficiently killed. CS03307 also showed a high ψ_min for ceftriaxone in spite of a low MIC and no difference in ψ_min for fosfomycin in spite of significant MIC and zMIC differences. Gentamicin showed rapid killing for all three strains at high concentrations, demonstrating concentration-dependent activity.

Conclusions: Based on time-kill assays, high-dosage ceftriaxone could be used to treat N. gonorrhoeae strains with MIC above breakpoint, with gentamicin as a potential alternative. Whether ertapenem or fosfomycin would be effective to treat strains with a high MIC to ceftriaxone is questionable.

Keywords: Neisseria gonorrhoeae; antimicrobial resistance; ceftriaxone; ertapenem; fosfomycin; gentamicin; pharmacodynamics; time–kill curves.

Figure 1

Selected time–kill curves (TKC) for three different strains of Neisseria gonorrhoeae using ceftriaxone. For each combination of antibiotic and strain, the TKC from one of the three independent experiments is shown: WHO F (A), WHO X (B), CS03307 (C). For each figure, eleven doubling dilutions are plotted. The black line corresponds to the highest concentration of antibiotics used in the assay (16× the minimum inhibitory concentration (MIC)). The yellow line represents the concentration corresponding to 1× MIC, while the red line represents growth in the absence of antimicrobials. The number of colony-forming units (CFU)/ml was measured from 4 h before until 6 h after the addition of antimicrobials. The limit of detection was 200 CFU/mL.

Figure 2

Selected time–kill curves (TKC) for three different strains of Neisseria gonorrhoeae using ertapenem. For each combination of antibiotic and strain, the TKC from one of the three independent experiments is shown: WHO F (A), WHO X (B), CS03307 (C). See the legend for Figure 1 for further explanation.

Figure 3

Selected time–kill curves (TKC) for three different strains of Neisseria gonorrhoeae using fosfomycin. For each combination of antibiotic and strain, the TKC from one of the three independent experiments is shown: WHO F (A), WHO X (B), CS03307 (C). See the legend for Figure 1 for further explanation.

Figure 4

Selected time–kill curves (TKC) for three different strains of Neisseria gonorrhoeae using gentamicin. For each combination of antibiotic and strain, the TKC from one of the three independent experiments is shown: WHO F (A), WHO X (B), CS03307 (C). See the legend for Figure 1 for further explanation.

Figure 5

Curves representing the pharmacodynamic functions of specific antimicrobials (i.e., ceftriaxone (A), ertapenem (B), fosfomycin (C) and gentamicin (D)) for the three different strains of Neisseria gonorrhoeae. Curves for the WHO F strain (ceftriaxone susceptible, high fosfomycin MIC) are presented in yellow lines, WHO X (ceftriaxone resistant, high fosfomycin MIC) in brown lines and CS03307 (ceftriaxone susceptible, low fosfomycin MIC) in navy blue lines. Curves from the three independent experiments with each combination of antibiotic and strain are presented. Abbreviations: CRO, ceftriaxone; ERT, ertapenem; FOS, fosfomycin; GEN, gentamicin.