Simplified LC–MS/MS method enabling the determination of azithromycin in human plasma after a low 100 mg dose administration

Filist, Monika; Buś-Kwaśnik, Katarzyna; Ksycińska, Hanna; Rudzki, Piotr J.

doi:10.1016/j.jpba.2014.07.015

Cited by 25 publications

(16 citation statements)

References 22 publications

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“…The assay for AZM in plasma, tissues, and ISF was performed by using a previously reported method, with minor modifications (18)(19)(20). Briefly, to determine AZM levels, 5 l of ISF was diluted with 95 l of distilled water.…”

Section: Methodsmentioning

confidence: 99%

Transport of Azithromycin into Extravascular Space in Rats

Kobuchi

Aoki

Inoue

et al. 2016

Antimicrob Agents Chemother

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f Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent proteinunbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.

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Section: Methodsmentioning

confidence: 99%

Transport of Azithromycin into Extravascular Space in Rats

Kobuchi

Aoki

Inoue

et al. 2016

Antimicrob Agents Chemother

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“…A simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of AZM was established. In this method, solid-phase extraction (SPE) instead of liquid-liquid extraction was used, unlike in previous studies (20,21). Plasma AZM concentrations were measured within 5 min, with good validation.…”

Section: Discussionmentioning

confidence: 99%

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

Soda

Ito

Matsumaru

et al. 2018

Antimicrob Agents Chemother

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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.

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“…The assay for EM or CAM was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS), according to a previously-reported method with minor modifications [30,31]. Briefly, 5 µL of ISF was diluted with 95 µL of distilled water.…”

Section: Macrolides Assaymentioning

confidence: 99%

Pharmacokinetics of Macrolide Antibiotics and Transport into the Interstitial Fluid: Comparison among Erythromycin, Clarithromycin, and Azithromycin

et al. 2020

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Recent research has found higher levels and longer total exposure of azithromycin, a macrolide antibiotic agent, in the interstitial fluid of the skin than in the plasma. This unique distribution is expected to contribute to its antimicrobial activity at the primary infection site. However, it remains unclear whether this characteristic distribution in the extracellular tissue space is common to macrolide antibiotics or if it is azithromycin-specific, with most macrolides largely localized intracellularly. In this study, we investigated pharmacokinetic characteristics of erythromycin and clarithromycin in the interstitial fluid of the skin of rats after intravenous drug administration, and compared the results with our previously reported results on azithromycin. Interstitial fluid samples were directly collected from a pore on the skin using a dissolving microneedle array. We found that the total macrolide concentrations in the interstitial fluid were significantly different among three macrolides. The rank order of the interstitial fluid-plasma concentration ratio was azithromycin (3.8 to 4.9) > clarithromycin (1.2 to 1.5) > erythromycin (0.27 to 0.39), and this ratio was stable after dosing, whereas higher drug levels in the skin tissue than in the plasma were observed for all three macrolides. Our results suggest that lower erythromycin concentrations in the interstitial fluid than in the plasma contributes to the emergence of bacterial resistance in the extracellular tissue space. Monitoring of total macrolide concentrations in interstitial fluid may provide valuable information regarding antimicrobial effects and the emergence of bacterial resistance for the development of an appropriate pharmacokinetics–pharmacodynamics-based dosing strategy.

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Simplified LC–MS/MS method enabling the determination of azithromycin in human plasma after a low 100 mg dose administration

Cited by 25 publications

References 22 publications

Transport of Azithromycin into Extravascular Space in Rats

Transport of Azithromycin into Extravascular Space in Rats

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

Pharmacokinetics of Macrolide Antibiotics and Transport into the Interstitial Fluid: Comparison among Erythromycin, Clarithromycin, and Azithromycin

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