Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis

Abstract

The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.

Keywords: Monte Carlo simulation; Neisseria gonorrhoeae; PK/PD; azithromycin; gonococcal urethritis.

FIG 1

Typical AZM LC-MS/MS chromatograms and goodness-of-fit plots for the final PK model. (A) Chromatograms showing the results for plasma AZM concentrations of 300 (i), 100 (ii), 30 (iii), and 10 (iv) ng/ml; (B) scatter plots of observed plasma AZM concentrations (Cobs) versus individual model predictions (IPRED); (C) conditional weighted residuals (CWRES) versus population predictions (PRED); (D) CWRES versus time after dose.

FIG 2

Comparison of AZM PK parameters (AUC, MIC, and AUC/MIC) in 36 patients with gonococcal urethritis. (A) AUC; (B) MIC; (C) AUC/MIC. Each line represents the median. P values were calculated by the Mann-Whitney U test.

FIG 3

Probability of cure following AZM-SR administration. The solid line shows the logistic regression curve, and open circles represent clinical data.

FIG 4

Probability of target attainment achieved with 2 g AZM-SR, 2 g AZM, and 1 g AZM at each MIC and the cumulative probability of AUC/MIC distributions calculated by Monte Carlo simulation. (A) The plots show data for 2 g AZM-SR (open circles, solid lines), 1 g AZM (open triangles, dashed lines), and 2 g AZM (open diamonds, dotted lines). (B) Each line represents 2 g AZM-SR (solid lines), 1 g AZM (dashed lines), and 2 g AZM (dotted lines).