Accumulation of Clarithromycin in Macrophages Infected With <i>Mycobacterium avium</i>

Mor, N; Vanderkolk, J.; Heifets, Leonid

doi:10.1002/j.1875-9114.1994.tb02793.x

Cited by 22 publications

(11 citation statements)

References 11 publications

(3 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We confirmed previously that clarithromycin concentrations in macrophages can be 15-to 17-fold greater than those in the extracellular fluid (14). In spite of this, the concentrations in the extracellular fluid that were required to inhibit the intracellular bacterial growth were in the same range as those that were active against the extracellular bacteria.…”

Section: Discussionsupporting

confidence: 89%

Effects of clarithromycin and rifabutin alone and in combination on intracellular and extracellular replication of Mycobacterium avium

Mor

Vanderkolk

Mezo

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The combined effect of clarithromycin and rifabutin against Mycobacterium avium multiplying either within human monocyte-derived macrophages or extracellularly in a liquid medium was additive: both MICs and MBCs were twofold lower for the combination than they were for each drug alone. Prolonged exposure for 4 weeks of M. avium-infected macrophages to combined concentrations that were only twofold greater than the MICs resulted in a 100-fold decrease in the number of viable bacteria, while in the drug-free controls a 100-fold or greater increase in comparison with the initial viable counts took place. Comparison of this effect with the results of the prolonged exposure to each drug alone suggested that under these experimental conditions rifabutin enhanced the antimicrobial activity of clarithromycin against intracellular bacteria. At the same time, inhibition of intracellular growth by a 2-h pulsed exposure of the infected macrophages to the combination of the two drugs was not different from the effect induced by clarithromycin alone. In conclusion, clarithromycin played the major role in the antimicrobial activity of the tested combination, while rifabutin may have enhanced this effect during a prolonged exposure of the intracellular bacteria to these two agents.Combinations of clarithromycin with a variety of other drugs have been investigated in vitro in cell-free culture media and macrophages (3,7,9,10,16,17). The overall analyses of these data indicated that the interaction in these combinations tested against Mycobacterium avium was additive rather than synergistic (2). The effect of this combination for the treatment and prevention of disseminated M. avium infection in patients with AIDS is under investigation. The aim of the present study was to evaluate the activity of clarithromycin in combination with rifabutin against M. avium in a cell-free culture medium and human monocyte-derived macrophages. The study included an evaluation of the antimicrobial activity during prolonged exposure and the effect of a drug combination given to infected macrophages by pulsed exposure.MATERUILS AND METHODS Antimicrobial agents. Rifabutin (Adria Laboratories, Pharmacia, Columbus, Ohio) was dissolved first in methanol (640 jig/ml) and was then diluted further in distilled water to make appropriate working solutions. Clarithromycin (Abbott Laboratories, Abbott Park, Ill.) was first dissolved in dimethyl sulfoxide (1,280 jig/ml) and was then diluted further in phosphate buffer (pH 6.5).Test strains. Three strains identified as M. avium by the Gen-Probe (San Diego, Calif.) technique were used for the studies. These strains, isolated from blood samples obtained from patients with AIDS, were used in our previous studies (8,12,13). They were preserved in frozen 7H9 broth culture aliquots at -70°C. For each experiment, a subculture in 7H9 broth was made from a frozen aliquot.Antimicrobial activity against extracellular bacteria. The MIC was defined as the lowest drug concentration that inhibited more than 99% of the bacteria...

show abstract

Section: Discussionsupporting

confidence: 89%

Effects of clarithromycin and rifabutin alone and in combination on intracellular and extracellular replication of Mycobacterium avium

Mor

Vanderkolk

Mezo

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In parallel, erythromycin and azithromycin are capable of inhibiting the transport of various substrates of the P-glycoprotein in epithelial cells in vitro as well as in vivo (9,12,13,23,30,31,39). Yet, little is known about the role of efflux transporters in the handling of macrolides by macrophages, in which these drugs are known to accumulate in large amounts (2,3,20,24).In the present study, we have examined directly in macrophages the potential influence of P-glycoprotein and MRP on the accumulation and efflux of five macrolides of clinical interest. We used both broad-spectrum, nonspecific inhibitors of P-glycoprotein (verapamil and cyclosporine) and MRP (probenecid and gemfibrozil) and the specific P-glycoprotein modulator GF120918 (11, 15).…”

mentioning

confidence: 98%

mentioning

confidence: 99%

Influence of P-Glycoprotein Inhibitors on Accumulationof Macrolides in J774 MurineMacrophages

Seral

Michot

Chanteux

et al. 2003

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2-to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally. At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three-to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation ( 1). P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes). The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.Active drug transporters have been described in both procaryotic and eucaryotic cells. Originally described as conferring resistance to anticancer agents in cancer cells, antibiotics in bacteria, or antifungal agents in fungi, these proteins appear today to be part of a very general mechanism that cells have developed to protect themselves from invasion by diffusible, foreign molecules (for a review, see reference 37). In this context, the occurrence of antibiotic transporters in eucaryotic cells has become a common observation (7, 33). More specifically, P-glycoprotein (also referred to as MDR1) and MRP, which are expressed in most cell types and which transport a large variety of drugs, have received much attention. These two types of transporters belong to the superfamily of ATP binding cassette transporters and use ATP hydrolysis as an energy source (28). They play a key role in drug disposition by modulating drug transport through epithelia and other biological barriers to an extent that was completely unsuspected only a few years ago (1).Focusing on macrolides, erythromycin has been shown to be transported by P-glycoprotein in Caco-2 intestinal cells (29, 34). In parallel, erythromycin and azithromycin are capable of inhibiting the transport of various substrates of the P-glycoprotein in epithelial cells in vitro as well as in vivo (9,12,13,23,30,31,39). Yet, little is known about the role of efflux transporters in the handling of macrolides by macrophages, in which these drugs are known to accumulate in large amounts (2,3,20,24).In the present study, we have examined directly in macrophages the potential influence of P-glycoprotein and MRP on the accumulation and efflux of five macrolides of clinical interest. We used both broad-spectrum, nonspecific inhibitors of P-glycoprotein (verapamil and cyclosporine) and MRP (probenecid and gemfibrozil) and the specific P-glycoprotein modulator GF120918 (11, 15). We selected the murine J774 murine macrophage line since much is already known about the dispositions of macrolides in these cells (2,3,36). MATERIALS AND METHODS Cells.We used J77...

show abstract

“…In intracellular susceptibility studies CLR resulted in reduction of CFU counts [39,48,49]. This effect can be explained by other studies describing the ability of CLR to accumulate in phagocytic cells, resulting in high intracellular to extracellular concentration ratios [77,78].…”

Section: Discussionmentioning

confidence: 80%

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

et al. 2015

View full text Add to dashboard Cite

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen. @ERSpublications Macrolides deserve more research interest for use against MDR-TB as results appear to be more promising than thought http://ow.ly/LDFjp

show abstract

Accumulation of Clarithromycin in Macrophages Infected With Mycobacterium avium

Cited by 22 publications

References 11 publications

Effects of clarithromycin and rifabutin alone and in combination on intracellular and extracellular replication of Mycobacterium avium

Effects of clarithromycin and rifabutin alone and in combination on intracellular and extracellular replication of Mycobacterium avium

Influence of P-Glycoprotein Inhibitors on Accumulationof Macrolides in J774 MurineMacrophages

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

Contact Info

Product

Resources

About