Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro

doi:10.1016/j.actatropica.2006.10.008

Acta Tropica

Volume 100, Issue 3, December 2006, Pages 185-191

https://doi.org/10.1016/j.actatropica.2006.10.008 Get rights and content

Abstract

Azithromycin, an azalide analog of erythromycin was assayed for its in vitro activity against multidrug-resistant Plasmodium falciparum K1 strain by measuring the ³H-hypoxanthine incorporation. Azithromycin caused inhibitory effects on the parasite growth with IC₅₀ and IC₉₀ values of 8.4 ± 1.2 μM and 26.0 ± 0.9 μM, respectively. Erythromycin inhibited growth of P. falciparum with IC₅₀ and IC₉₀ values of 58.2 ± 7.7 μM and 104.0 ± 10.8 μM, respectively. The activity of antimalarial drugs in combination with azithromycin or erythromycin against P. falciparum K1 were compared. Combinations of chloroquine with azithromycin or erythromycin showed synergistic effects against parasite growth in vitro. Combinations of quinine–azithromycin and quinine–erythromycin showed potentiation. Additive effects were observed in mefloquine–azithromycin and mefloquine–erythromycin combinations. Similar results were also produced by pyronaridine in combination with azithromycin or erythromycin. However, artesunate–azithromycin and artesunate–erythromycin combinations had antagonistic effects. The in vitro data suggest that azithromycin and erythromycin will have clinical utility in combination with chloroquine and quinine. The worldwide spread of chloroquine-resistant P. falciparum might inhibit the ability to treat malaria patients with chloroquine–azithromycin and chloroquine–erythromycin in areas of drug-resistant. The best drug combinations against multidrug-resistant P. falciparum are quinine–azithromycin and quinine–erythromycin.

Introduction

Some antibiotics have antimalarial activity that can be used for the treatment of malaria. Combination therapy is one method of overcoming the global challenge of drug-resistance Plasmodium falciparum malaria. Antibiotics are used in combination with antimalarial drug against multidrug-resistant P. falciparum. Combination of the tetracycline group of antibiotics with quinine and mefloquine has been used successful in Southeast Asia to treat multidrug-resistant P. falciparum cases (Watt et al., 1992, Looareesuwan et al., 1994a). The artesunate–tetracycline combination has been shown to be a useful alternative (Duarte et al., 1996, Looareesuwan et al., 1994b). The drugs of the tetracycline group should not be used in pregnant women and young children.

Quinine–clindamycin has been shown to be effective in pregnancy (Mc Gready et al., 2001). Clindamycin is used in combination with either chloroquine or quinine to treat children with uncomplicated falciparum malaria (Kremsner et al., 1994). Side effects of clindamycin are diarrhea and colitis. New combinations that are safe and effective against drug-resistant P. falciparum in children and pregnant women are clearly needed.

Erythromycin has been shown to have antimalarial activity against P. falciparum in vitro and Plasmodium berghei in vivo (Gingras and Jensen, 1992, Gingras and Jensen, 1993). Azithromycin is a semisynthetic derivative of erythromycin that differs from erythromycin by possessing a methyl-substituted nitrogen in the macrolide ring. This alteration allows for greater bioavailability, increased tissue penetration and longer elimination half-life compared with those of erythromycin (Dunn and Barradell, 1996). Azithromycin has antimalarial activity against P. falciparum in vitro, P. berghei and Plasmodium yoelii in vivo (Gingras and Jensen, 1992, Gingras and Jensen, 1993, Puri and Singh, 2000). The clinical trial of daily oral azithromycin in adults is effective for prevention of Plasmodium vivax malaria (Heppner et al., 2005). Azithromycin is approved for the use in children (Zithromax product information, 1999; Pfizer Inc., New York), and is safe for pregnant women (Gray et al., 2001, Wawer et al., 1999). The objective of this in vitro study is to determine the best drug combination between azithromycin or erythromycin and standard antimalarial drugs against multidrug-resistant P. falciparum that will be clinically useful.

Section snippets

Methods for testing drug combination on the P. falciparum growth

Multidrug-resistant P. falciparum K1 strain was obtained from an infected individual in Kanchanaburi province, Thailand. They routinely can be maintained in human group O red blood cells in a medium RPMI 1640 supplemented with 10% human serum using the candle jar method (Trager and Jensen, 1976). Antimalarial drugs in combination with azithromycin or erythromycin (Fig. 1) were tested against P. falciparum in vitro by ³H-hypoxanthine incorporation (Desjardin et al., 1979). In the experiment, 200

Effects of antimalarial drugs and antibiotic combinations on the P. falciparum growth

Multidrug-resistant P. falciparum K1 growth were inhibited by azithromycin with IC₅₀ and IC₉₀ values of 8.4 ± 1.2 μM and 26.0 ± 0.9 μM, respectively. The IC₅₀ and IC₉₀ values for erythromycin against P. falciparum K1 were 58.2 ± 7.7 μM and 104.0 ± 10.8 μM, respectively. To determine the effect of drug combinations between antimalarial drugs and azithromycin or erythromycin, isobolograms were constructed. The isobologram of an additive combination of two agents lies on a straight line. The isobologram of

Discussion

The most common antibiotics used against malaria are tetracycline and doxycycline. A standard treatment for patients with infections by chloroquine-resistant P. falciparum strains is a 7-day course of quinine–tetracycline combinations (Bunnag et al., 1996). Quinine–doxycycline and chloroquine–doxycycline were effective in treating chloroquine-resistant uncomplicated falciparum malaria patients (Taylor et al., 2001). Drug of tetracycline class however cannot be used in pregnant women and young

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Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro

Abstract

Introduction

Section snippets

Methods for testing drug combination on the P. falciparum growth

Effects of antimalarial drugs and antibiotic combinations on the P. falciparum growth

Discussion

Eur. J. Pharmacol.

Pharmacol. Ther.

Am. J. Obstet. Gynecol.

Acta Trop.

Trans. R. Soc. Trop. Med. Hyg.

Acta Trop.

Lancet

Exp. Parasitol.

Lancet

Lancet

Prophylaxis of Plasmodium falciparum malaria with azithromycin administered to volunteers

Ann. Intern. Med.

A method for testing synergy with any number of agents

J. Infect. Dis.

Inhibition of Toxoplasma gondii protein synthesis by azithromycin

Antimicrob. Agents. Chemother.

Quinine-tetracycline for multidrug-resistant falciparum malaria

Southeast Asian J. Trop. Med. Publ. Health

Lack of a pharmacokinetic interaction between azithromycin and chloroquine

Am. J. Trop. Med. Hyg.

Quantitative assessment of antimalarial activity in vitro by semiautomated microdilution technique

Antimicrob. Agents Chemother.

Short course of azithromycin–artesunate against falciparum malaria: no full protection against recrudescence

Trop. Med. Intern. Health

Randomized controlled trial of artesunate plus tetracycline versus standard treatment (quinine plus tetracycline) for uncomplicated Plasmodium falciparum malaria in Brazil

Am. J. Trop. Med. Hyg.

Azithromycin: a review of its pharmacological properties and use as a 3-day therapy in respiratory tract infection

Drugs

A multicenter study of azithromycin alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India

J. Infect. Dis.