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 isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated 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 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.

Trends and Risk Factors for Antimicrobial-Resistant Neisseria gonorrhoeae , Melbourne, Australia, 2007 to 2018

“…genitalium exceeds 60% in Melbourne (16), with previous work demonstrating the potential for azithromycin exposure to be associated with macrolide-resistant isolates posttreatment (17). Although it is possible that increasing the dose of azithromycin from 1 to 2 g (as recently recommended in Australian guidelines for oropharyngeal gonorrhea) (8) may overcome the potential for gonorrhea treatment failures caused by low-level-resistant azithromycin isolates (18), it remains to be seen what further “collateral damage” may result from increasing azithromycin exposure, both at the patient and population levels. Of note, and unlike low-level azithromycin resistance, the majority of HLR azithromycin isolates in our study were from people with recent sexual contact (direct and indirect) in Asia, further highlighting this region as a potential reservoir for MDR-N.…”

Updates on Sexually Transmitted Urethro-cystitis

“…It is currently recommended to use the 250 mg rather than the 125 mg dosage of ceftriaxone as the lower dosage has a lower efficacy in treating concomitant pharyngeal infections and higher treatment failure rates [9]. It is also recommended to use the single oral dose of azithromycin rather than the 1-week course of twice daily doxycycline 200 mg due to better compliance and lower risk of tetracycline resistance [9,11,12]. Although up to 10% of patients with penicillin allergies have cross-reactivity to cephalosporins, the only after starting therapy 2.…”

Molecular Epidemiology, Antimicrobial Surveillance, and PK/PD Analysis to Guide the Treatment of Neisseria gonorrhoeae Infections

“…In order to predict the probability of PK/PD target attainment, different antibiotics and dosing regimens were evaluated (Table 1). From the published pharmacokinetic parameters listed in Table 1 [15][16][17][18][19], and from the study sample MIC distribution, we estimated the probability of target attainment (PTA, defined as the probability that at least a specific value of a PK/PD index is achieved at a certain minimum inhibitory concentration) and calculated the cumulative fraction of response (CFR, defined as the expected population probability of target attainment for a specific drug dose and a specific population of microorganisms). PK/PD indices and values related to efficacy are also listed in Table 1.…”