Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Abstract

cAlthough azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC 0 -24 )/MIC 90 ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

Transport of Azithromycin into Extravascular Space in Rats

“…After AZM is distributed to the acidic compartment in the cell, it is protonated and thus becomes trapped in the cell. This ion-trapping mechanism is responsible for the long retention of AZM in tissues and the very slow release of AZM from intracellular compartments, which are characteristics consistent with its large distribution volume and long half-life (4,8,9).…”

“…The interstitial fluid (ISF), i.e., the extracellular tissue space, is the primary site of most bacterial infections (8,10). However, most studies have focused on the AZM concentration in WBCs, different tissue-specific phagocytes (i.e., the intracellular tissue space), and tissue homogenates (8,(11)(12)(13).…”

“…However, most studies have focused on the AZM concentration in WBCs, different tissue-specific phagocytes (i.e., the intracellular tissue space), and tissue homogenates (8,(11)(12)(13). The AZM concentration in tissue homogenates represents a mixture of AZM concentrations in the intracellular and extracellular tissue spaces; estimation of drug concentrations in the infection site is not possible.…”

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

“…Considered collectively, the findings of these preclinical studies indicate that azithromycin is a weak hERG blocker and even under conditions where it has been seen to delay repolarization, it did not share proarrhythmic features with other macrolides. In healthy volunteers receiving short-term azithromycin (500 mg daily for 3 days), peak plasma levels close to 400 ng/ml ($0.5 mM) have been reported [Matzneller et al 2013] that are $2000-fold less than the estimated hERG IC 50 of >1000 mM [Thomsen et al 2006]. Although it has been reported that tissue concentrations of azithromycin can significantly exceed those in plasma (with muscle concentrations of $1 mg/kg, in excess of 1 mM), it is not clear that these are indicative of possible cardiac levels commensurate with significant hERG block [Foulds et al 1990].…”

Limited Azithromycin Localization to Rabbit Meibomian Glands Revealed by LC-MS-Based Bioanalysis and DESI Imaging

“…Indeed, azithromycin levels accumulated somewhat following multiple administrations not only in the conjunctiva but also in soft tissues such as muscle and subcutaneous adipose tissue. 22,27) Therefore, we cannot exclude the possibility that azithromycin might eventually reach meaningful concentrations in the meibomian glands. It is important, however, to recognize the limited penetration of azithromycin into the meibomian glands.…”