In vitro and in vivo activities of macrolides against Mycobacterium leprae

Abstract

We previously demonstrated the potent in vitro activity of erythromycin against Mycobacterium leprae as determined by its effect on ATP pools and rates of palmitate oxidation and phenolic glycolipid I synthesis. In the present study, the relative in vitro activities of a number of new macrolides with superior pharmacokinetic properties were assessed. In addition, for the most active compounds, concentrations in serum were determined by bioassay during continuous administration in the feed of mice, and in vivo activity against M. leprae was assessed by the kinetic mouse footpad technique. Both clarithromycin and roxithromycin were more potent than erythromycin in vitro, with the former showing the highest activity in accelerating rates of ATP decay and reducing rates of palmitate oxidation. In mice, concentrations of clarithromycin in serum were higher than those of roxithromycin and erythromycin, with the latter undetectable even when administered at 0.1% (wt/wt) in the diet. When administered at 0.01% (wt/wt) in the diet, erythromycin and roxithromycin were unable to inhibit growth of M. leprae in mouse footpads whereas clarithromycin demonstrated bactericidal-type activity. On the basis of these data and other properties of macrolides, a clinical trial of clarithromycin in leprosy is warranted.The existing armamentarium of antileprosy drugs is limited in number, and only one, rifampin, is rapidly bactericidal. In addition, drug-resistant strains of Mycobacterium leprae have been reported to the most commonly used agents (15). These factors among others have led to an ongoing search for new antileprosy agents.Because of the inability to cultivate the leprosy bacillus, primary drug screening has relied on the use of the mouse footpad system (MFP), which has, because of cost, time requirement, need for relatively large amounts of test drug, and necessity for favorable pharmacokinetic properties in mice, limited the number of drugs that can be evaluated. Therefore, a number of in vitro systems have been developed which rely on the inhibition of metabolic activity as an indicator of drug activity (8,10,11,13,14,17,19,25). We have demonstrated the potent direct activity of erythromycin against M. leprae as determined by measurement of intracellular ATP (11), radiorespirometric assay of palmitate oxidation (8), and measurement of the rate of phenolic glycolipid I synthesis (E. B. Harris, S. G. Franzblau, and R. C. Hastings, Int. J. Lepr., in press). We hypothesized that the failure of erythromycin to inhibit growth in the MFP (R. Gelber, personal communication) may be due to poor pharmacokinetics when the drug is administered in the feed of mice. Recently, a number of semisynthetic macrolides which have superior acid stability and serum half-lives compared with erythromycin have been developed (2,3,6,7,24). In this paper, we assess the in vitro and in vivo activities of some of these compounds against the leprosy bacillus. MATERIALS AND METHODSInoculum preparation. M. Ieprae suspensions were prepared from the footpad...

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

“…9-Oxime-substituted analogs were more active than erythromycin against erythromycin-resistant organisms, such as the M. avium complex, Staphylococcus aureus (23), and Mycobacterium leprae (11). Quantitative SAR studies revealed that the substitution of 9-oximes with short alkyl groups gives activity comparable to that of clarithromycin, while the introduction of more-bulky alkyl groups improves activity against S. aureus (23).…”

New directions for macrolide antibiotics: structural modifications and in vitro activity

“…However, synergistic effects have recently been reported for roxithromycin with either rifampin (15) or tumor necrosis factor and amikacin (10) against Mycobacterium avium; the activity of azithromycin against M. avium was also enhanced by tumor necrosis factor (10). In other studies, flurithromycin showed an additive effect with some other antibiotics against Mycobacterium species (37) and clarithromycin inhibited the growth of M. leprae in a mouse footpad infection model of leprosy (36).…”

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

“…There appears to be a general correlation between degree of bactericidal activity in vivo (1) and degree of activity in radiorespirometric systems (2,4). It was radiorespirometric systems which initially demonstrated the antileprosy activity of macrolides and further identified clarithromycin as the most active drug in this class (4); the latter has been confirmed in the mouse footpad system by my colleague and me (4) and others (17).…”