Interactions of dirithromycin with human polymorphonuclear leukocytes

Hand, W. Lee; Hand, D L

doi:10.1128/aac.37.12.2557

Cited by 29 publications

(24 citation statements)

References 25 publications

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“…By contrast, as we and others have already observed (16,39), dirithromycin uptake increased as a function of time; a similar but less striking phenomenon was observed with erythromycylamine.…”

Section: Methodsmentioning

confidence: 40%

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Mtairag

Abdelghaffar

Douhet

et al. 1995

Antimicrob Agents Chemother

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We compared the uptakes and intracellular locations of four 14-membered-ring macrolides (roxithromycin, dirithromycin, erythromycin, and erythromycylamine) in human polymorphonuclear neutrophils (PMNs) in vitro. Intracellular location was assessed by cell fractionation and uptake kinetics in cytoplasts (granule-poor PMNs). Trapping of dirithromycin within PMN granules (up to 80% at 30 min) was significantly more marked than the intracellular trapping of the other drugs (erythromycylamine, 45% ؎ 5.1%; erythromycin, 42% ؎ 3.7%; roxithromycin, 35% ؎ 3.0%). A new finding was that, in the absence of extracellular calcium, the uptakes of all of the macrolides by PMNs and cytoplasts were significantly impaired, by about 50% (PMN) and 90% (cytoplasts). Furthermore, inorganic Ca 2؉ channel blockers inhibited macrolide uptake in a concentrationdependent manner, with 50% inhibitory concentrations of 1.6 to 2.0 mM and 29 to 35 M, respectively, for Ni The organic Ca 2؉ channel blocker nifedipine had no effect on macrolide uptake, whereas verapamil inhibited it in a time-and concentration-dependent manner. These data show the importance of extracellular Ca 2؉ in macrolide uptake by phagocytes and suggest a link with Ca 2؉ channels or a Ca 2؉ channel-operated mechanism.Infections caused by organisms which survive and multiply within host cells, such as Legionella spp., Chlamydia spp., and Mycobacteria spp., are difficult to cure, partly because of the intracellular locations of these pathogens, which are protected from the antimicrobial activities of non-cell-penetrating agents (20). However, the abilities of antibiotics to enter and concentrate within host cells, generally estimated from the intracellular concentration-to-extracellular concentration ratio, may not actually reflect their overall intracellular bactericidal activities (17). Another factor of importance is the respective intracellular locations of the drug and the pathogen. Possible interactions between the drug and host cell factors (inactivation, binding, synergy) may also result from the particular location of the drug. In addition, intracellular accumulation of antibacterial agents or the mechanism used for this cellular transport may in turn affect host cell metabolism and functions, ultimately modifying the overall course of infectious diseases. Among those cell-penetrating agents, macrolide antibiotics have been much studied (14,27). Many publications examine their intracellular (particularly intraphagocytic) accumulation (for a review, see reference 29) and their possible interference with phagocyte activities (for a review, see reference 28). Despite abundant data, the mechanism underlying macrolide uptake by host cells is poorly understood. Various hypotheses have been put forward. These hypotheses involve liposolubility and active transport systems, particularly those used by nucleosides (18, 21). A likely mechanism for their intracellular accumulation involves the weakly basic nature of macrolides and the possibility of trapping by protonation within ...

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Section: Methodsmentioning

confidence: 40%

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Mtairag

Abdelghaffar

Douhet

et al. 1995

Antimicrob Agents Chemother

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“…In previous studies, we showed that certain antibiotics (clindamycin, several macrolides, and trimethoprim) are highly concentrated by human PMNs (16,19,21,32,37). Like pentoxifylline, these drugs inhibit the respiratory burst response in PMNs (16,17,29).…”

mentioning

confidence: 99%

“…Pentoxifylline inhibited the zymosan-stimulated increase in the uptake of adenosine but, surprisingly, actually augmented the phagocytosisinduced increase in clindamycin uptake by PMNs (14). Ingestion of microbial particles inhibits the accumulation of macrolide antibiotics (erythromycin, roxithromycin, and dirithromycin) by phagocytic cells (16,19,21,37).…”

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confidence: 99%

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Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells

Hand

1995

Antimicrob Agents Chemother

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Pentoxifylline modulates multiple activities of stimulated polymorphonuclear neutrophils (PMNs), including the respiratory burst response and membrane transport of certain substances (e.g., nucleosides). We found that several weakly basic antibiotics are highly concentrated by human PMNs and that these drugs also inhibit the respiratory burst response (by a mechanism different from that of pentoxifylline). Since both pentoxifylline and antibiotics will be administered to some patients with serious infections, we have evaluated several types of interactions between these drugs and human PMNs and have attempted to identify the mechanisms that produce alterations in cellular function. Roxithromycin, dirithromycin, and clindamycin were avidly concentrated by PMNs. Pentoxifylline and two derivatives (HWA-448 [torbafylline] and HWA-138 [albifylline]) increased the uptake of these antibiotics by PMNs, both in the resting state and during phagocytosis. Pentoxifylline, HWA-448, HWA-138, and the highly concentrated antibiotics each exerted an inhibitory effect on the stimulated respiratory burst response in PMNs. The combination of both pentoxifylline and a modulatory antibiotic (roxithromycin or clindamycin) inhibited superoxide production to a greater extent than either agent alone. This additive effect might be expected, since pentoxifylline and the modulatory antibiotics influence the respiratory burst activation pathway at different sites. The ability of pentoxifylline to augment the entry of antibiotics into neutrophils has important therapeutic implications. The consequences of this phenomenon might include improved intracellular bactericidal activity as well as efficient antibiotic delivery and release at sites of infection.

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“…Dirithromycin has been shown to have higher intracellular retention [26,29], probably because this molecule contains two basic sites for protonation, one on the desosamine sugar and the other at the C9 position of the lactone ring. Its long persistence in the cells may be attributable to this second amino group.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease

Matera¹,

Tufano²,

Polverino³

et al. 1997

Eur Respir J

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Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease. M.G. Matera, M.A. Tufano, M. Polverino, F. Rossi, M. Cazzola. ©ERS Journals Ltd 1997. ABSTRACT: We compared the concentrations of dirithromycin and erythromycin at steady state in serum and the intrapulmonary region in patients suffering from acute exacerbation of mild chronic obstructive pulmonary disease.Twenty patients received dirithromycin, 500 mg given orally once daily for five consecutive days. The other 20 patients were treated with erthromycin base, which was administered orally four times daily at a total daily dose of 1000 mg for seven days. All patients were divided into eight groups, with five subjects in each group, according to sampling times (2, 4, 8, and 24 hrs after the last dose) and treatment.After the erthromycin treatment mean serum concentrations were higher than those of dirithromycin treatment mean serum concentrations were higher than those of dirithromycin for upto 4 hours, but they were undetectable 24 hours after the last dose. At all time periods, the concentrations of dirithromycin in bronchial secretion, bronchial mucosa and epithelial lining fluid were greater than the concentration in serum. Concentrations of erythromycin were always lower than those of dirithromycin in the explored pulmonary sites.Our data demonstrated that a five day course of 500 mg of dirithromycin once daily induced higher concentrations and longer persistence in the various potential sites of pulmonary infection than a seven day course of 250 mg of erythromycin every 6 hrs. The shorter duration of therapy and the once daily dosing with good efficacy against common respiratory pathogens would be advantageous for patients and would be likely to promote better patient compliance and acceptability. Eur Respir J., 1997; 10: 98-103 Many factors influence the choice of antibiotic and determine the optimum regimen. One such factor is tissue penetration. It is of primary importance to have a dosing regimen that maintains the free drug concentration above the minimum inhibitory concentration (MICs) for a reasonable period of time, in order to target the pathogens of the common lower respiratory tract infections with antimicrobials. The potential efficacy of an antibiotic in the treatment of chest infections may be estimated by measuring the concentration of the drug at potential sites of infection, other than serum [1].Dirithromycin is a new macrolide antibiotic with unusual pharmacokinetics, characterized by a rapid and extensive distribution to the extravascular tissues and a slow but constant elimination from these tissues into the vascular spaces [2,3]. It possesses antimicrobial activity comparable to that of erythromycin in vitro, but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissues [4,5]. Dirithromycin serum half-life is longer than that of erythromycin, and some lines of evidence have indicated tiss...

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Interactions of dirithromycin with human polymorphonuclear leukocytes

Cited by 29 publications

References 25 publications

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells

Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease

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