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Am. J. Trop. Med. Hyg., 77(1), 2007, pp. 99-101
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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Efficacy of Azithromycin versus Systemic Meglumine Antimoniate (Glucantime) in the Treatment of Cutaneous Leishmaniasis

Pouran Layegh*, Mohammad Javad Yazdanpanah, Elham Mohammadi Vosugh, Fakhrozaman Pezeshkpoor, Mohamad Taghi Shakeri, AND Toktam Moghiman
Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cutaneous leishmaniasis (CL) treatment is painful, and cosmetic results are often unsatisfying. Azithromycin has been reported to be effective in treatment of CL caused by Leishmania viannia braziliensis. The efficacy of azithromycin was compared with Glucantime in treatment of Old World leishmaniasis. Of 49 patients, 22 received 500 mg/day azithromycin for 5 days/month. Treatment cycles were repeated monthly to a maximum of 4 months; 27 patients received 60 mg/kg intramuscular meglumine antimoniate for 20 days. Both groups were followed up for 16 weeks. In the azithromycin group, 2 patients withdrew because of GI symptoms. The response rates of 20 patients (29 lesions) were as follows: full improvement, 10.3%; partial improvement, 27.6%; and 62.1%, no response. In the glucantime group with 27 patients (58 lesions), these rates were 34.4%, 13.8%, and 51.7%, respectively (P = 0.036). Azithromycin was determined to be not as effective as Glucantime in treatment of Old World CL.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Treatment of leishmaniasis has classically been based on pentavalent antimoniates, such as meglumine antimoniate (Glucantime) or sodium stibogluconate (Pentostam). Other therapeutic options of proven efficacy are amphotericin B, pentamidine, and aminosidine.1–3 All of these drugs are administered through the parenteral route, but they present several side and toxic effects and must be used for several weeks. Oral medications, such as imidazole, triazole derivatives, and allopurinol, have been used, among others, with variable responses.4

The availability of an effective medication that could be administered by the oral route and which is effective against leishmaniasis would be highly relevant. Azithromycin is a macrolide derivative structurally related to erythromycin,5 and it has been used in clinical practice for the treatment of various infections.6 Its administration by the oral route, rapid passage into the intracellular compartments, slow release (a half-life of 2–6 days), and accumulation in various organs and tissues at high concentrations—especially in phagocytic cells—make this drug an attractive option for the treatment of microorganisms that cause intracellular infections.7 In addition, therapeutic levels of this medication are maintained up to 5 days after administration of the last dose.8,9 Azithromycin shows good oral tolerance in both children and adults and has been successfully used in clinical practice administered as a single dose for the treatment of infections of the respiratory tract and skin and of sexually transmitted diseases, especially non-gonococcal urethritis, as well as of ocular infections, especially trachoma.10,11

The in vitro and in vivo activity against Leishmania major was reported by Krolewiecki and others.12 Prata and others reported a cure rate of 85% in CL caused by Leishmania viannia braziliensis (LvB) in an open pilot study.13 These preliminary results encouraged us to perform this study, to assess the efficacy of azithromycin in the treatment of Old World CL and to compare its clinical effect with meglumine antimoniate.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This prospective study was conducted from October 2004 through November 2005 at the dermatology department of Qaem University Hospital, Mashhad, Iran, where CL is endemic and L. tropica and, less commonly, L. major are the most prevalent species. Inclusion criteria were as follows:

  1. Patients older than 2 years with cutaneous leishmaniasis of <6-months’ duration;
  2. No treatment of the current infection during the last 3 months; and
  3. No history of a renal or liver disease.

Exclusion criteria were as follows:

  1. Pregnant women;
  2. History of intolerance or allergy to Glucantime or macrolides; and
  3. Simultaneous use of antacids containing Al and Mg, theophyline, phenytoin, barbiturates, carbamazepine, and cyclosporin.

Diagnosis of CL was confirmed by direct examination of the ulcer smear or slit–skin-smear stained by Giemsa, and all patients were submitted to clinical examination and photography of the lesions.

The 49 patients who met our criteria were randomly divided into two groups. The first group included 22 patients (35 lesions) who received a daily oral dose of 500 mg of azithromycin for 5 days/month in adults (according to the study by Prata and others13) and 10 mg/kg in children; treatment cycles were repeated monthly when no favorable response was achieved, up to a maximum duration of 4 months. The second group included 27 patients (58 lesions) who received 60 mg/kg of meglumine antimoniate for 20 days. Patients in the azithromycin group were evaluated monthly up to a maximum of 4 months, but patients in the Glucantime group were evaluated both at the end of the treatment period (day 20) and 45 days later. The patients’ evaluation and clinical response were determined on the basis of the lesions’ size, border, induration, and infiltration of papulonodular lesions; ulcerative lesions were evaluated on the basis of the ulcer depth, diameter, crusting, and the extent of re-epithelialization.

At each visit, clinical response was determined on the basis of the following criteria:

  1. Complete or significant improvement: decrease in the induration size >75% or full re-epithelialization of the lesions and a negative direct skin smear (absence of parasites in the lesion).
  2. No improvement: decrease in induration size <30%.
  3. Partial improvement: any changes between criteria a and b above.

It was decided that patients showing no favorable response after 4 months of azithromycin therapy would receive Glucantime at the same dose as the other group, at the end of the study.

Study goals were explained to the patients, and a signed consent form was obtained from the patients or their guardian before entering the study, which was also approved by the Ethics Committee of the Faculty of Medicine of Mashhad.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Forty-nine patients diagnosed with CL were enrolled in our study. Among them, two patients (6 lesions) from the azithromycin group were excluded because they experienced GI symptoms a few days after administration.

The demographic characteristics of our patients in both groups are shown in Table 1Go; 65% of the patients in the azithromycin and 44.4% of the Glucantime group were younger than 20 years of age. The most common lesion type was papulonodular, while ulceration and crusting were noted in 4 lesions (8.6%). Results of the final evaluation of clinical response in both groups are shown in Table 2Go. Comparison of these results between the two groups showed a significant statistical difference ({chi}2 = 6.636, P = 0.036), in which systemic Glucantime was proved to have a higher efficacy in the treatment of Old World CL than azithromycin.


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TABLE 1
Demographic and CL characteristics of the study population
 

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TABLE 2
Improvement rate in CL lesions treated with azithromycin and Glucantime*
 
Three patients in the Glucantime group complained of myalgia, and one showed erythema at the injection site, but they all completed the treatment course. In the azithromycin group, 2 patients had complaints of nausea and vomiting a few days after administration and stopped the treatment course. After the 16-week follow-up period, none of the lesions with a complete response in either group showed any sign of recurrence.


DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Treatment regimens of CL in the Old World are scarce, fragmentary,14 and vary in dosage, total number of applications and intervals.15 Chronicity and resistance rates are increasing due to insufficient treatment, and the cosmetic results are often unsatisfying,14,15 thus, new treatment protocols are required.

In experimental and clinical assays, azithromycin has shown efficacy in combined therapy for treatment and prophylaxis of infections caused by Mycobacterium avium intra-cellulare in AIDS patients.6 The drug has also proved to be effective in vitro against Toxoplasma gondii and in the prophylaxis of Plasmodium falciparum malaria, among other infections.16,17

The in vitro and in vivo activity against L. major was reported by Krolewiecki and others.18 According to this study, the azithromycin mode of action against Leishmania species is not yet known. It could be due to a direct drug effect on the parasite or modulated immune and inflammatory responses.18 Furthermore, other effects of this medication have been described, such as stimulation of phagocytosis, chemotaxis, and cytotoxic activity in addition to its immunomodulating action.19 Tanyuksel and others showed that azithromycin is able to kill intracellular amastigotes and has anti- Leishmania activity.20

Prata and others reported a cure rate of 85% in CL cases caused by LvB in an open pilot study that took place in Ar-guai and Varzelandia (MG), where American tegmental leishmaniasis (ATL) is endemic and LvB is the most common species.13

Silva-Vergara and others also reported on the efficacy of azithromycin in the treatment of mucosal leishmaniasis in three elderly Brazilian patients. The favorable response obtained in these cases again may support the anti-Leishmania activity of this macrolide on mucosal leishmaniasis.21

The results of our study concerning the efficacy of azithromycin on Old World CL were not satisfactory, and disparities might be due to differences in the pathogenic species (especially L. tropica and, less commonly, L. major) in our area (Hajjaran and others, unpublished data).

However, partial improvement of the lesions in our study was higher in the azithromycin group than in the Glucantime group (27.6% vs. 13.8%, Table 2Go); moreover, we must indicate that these results cannot be due to spontaneous response because we elected patients who had a lesion appearance of <6-months’ duration. In our region, the usual spontaneous recovery is {approx}1 year in CL with L. tropica and <1 year with L. major. Thus, modification in dosage or duration of the azithromycin regimen may be required to achieve a more effective response, or the drug could be administered in a combined therapy. Further in vitro studies are recommended to determine the intracellular efficacies of this drug against L. tropica.

Received December 10, 2006. Accepted for publication April 9, 2007.

* Address correspondence to Pouran Layegh, Qaem Hospital, Mash-had University of Medical Sciences, Mashhad, Iran. E-mail: Pouran_layegh{at}yahoo.com Back

Authors’ addresses: Pouran Layegh, Mohammad Javad Yazdan-panah, Elham Mohammadi Vosugh, Fakhrozaman Pezeshkpoor, Mohamad Taghi Shakeri, and Toktam Moghiman, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran, Telephone: +98-511-8814988, Fax: +98-511-8409612, E-mail: pouran_layegh{at}yahoo.com.

Reprint requests: Pouran Layegh, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran, Telephone: +98-511-8814988, Fax: +98-511-8409612, E-mail: pouran_layegh{at}yahoo.com.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Marsden PD, 1985. Pentavalent antimonials: old drug for new disease. Rev Soc Bras Med Trop 18: 187–198.
  2. Navin TR, Arana BA, Arana FE, Berman JD, Chajon JF, 1992. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 165: 528–534.[Web of Science][Medline]
  3. Romero GAS, Guerra MVF, Paes MG, Macedo VO, 2001. Comparison of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guaynensis in Brazil. Am J Trop Med Hyg 65: 456–465.[Abstract]
  4. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, Maguire JH, 2002. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 346: 891–895.[Abstract/Free Full Text]
  5. Foulds G, Shepard RM, Johnson RB, 1990. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 25 (Suppl A): 73–82.[Abstract/Free Full Text]
  6. Koletar SL, Berry AJ, Cynamon MH, Jacobson J, Currier JS, MacGregor RR, Dunne MW, Williams DJ, 1999. Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients. Antimicrob Agents Chemother 43: 2869–2872.[Abstract/Free Full Text]
  7. Wildfleuer A, Laufen H, Zimmermann T, 1996. Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions. Antimicrob Agents Chemother 40: 75–79.[Abstract]
  8. Neu HC, 1991. Clinical microbiology of azithromycin. Am J Med 91: 12S–18S.[Medline]
  9. Peters DH, Friedel HA, McTavish D, 1992. Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs 44: 750–799.[Web of Science][Medline]
  10. Stamm WE, Hicks CB, Martin DH, Leone P, Hood EW 3rd, Cooper RH, Cohen MS, Batteiger BE, Workowski K, McCormack WM, 1995. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study. JAMA 274: 545–549.[Abstract/Free Full Text]
  11. Tabbara KF, Abu-el-Asrar A, al-Omar O, Choudhury AH, al-Faisal Z. 1996. Single-dose azithromycin in the treatment of trachoma. A randomized controlled study. Ophthalmology 103: 842–846..[Web of Science][Medline]
  12. Krolewiecki AJ, Scott P, Abraham D, 1999. The anti-leishmania activity of azithromycin in an in vitro model. Rev Soc Bras Med Trop 32: 137.
  13. Prata A, Silva-Vergara ML, Costa L, Rocha A, Krolewiecki A, Silva JC, Paula EV, Pimenta FG Jr, Giraldo LE, 2003. Efficacy of azithromycin in the treatment of cutaneous leishmaniasis. Rev Soc Bras Med Trop 36: 65–69.[Medline]
  14. Herwaldt BL, 1999. Leishmaniasis. Lancet 354: 1191–1199.[Web of Science][Medline]
  15. Hepburn NC, 2000. Cutaneous leishmaniasis. Clin Exp Dermatol 25: 363–370.[Web of Science][Medline]
  16. Anderson SL, Berman J, Kuschner R, Wesche D, Magill A, Wellde B, Schneider J, Dunne M, Schuster BG, 1995. Prophy-laxis of Plasmodium falciparum malaria with azithromycin administered to volunteers. Ann Intern Med 123: 771–773.[Abstract/Free Full Text]
  17. Chang HR, Pechere JC, 1988. In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,693], and A-56268) on Toxoplasma gondii. Antimicrob Agents Chemother 32: 524–529.[Abstract/Free Full Text]
  18. Krolewiecki AJ, Leon S, Scott P, Abraham D, 2002. Activity of azithromycin against Leishmania major in vitro and in vivo. Am J Trop Med Hyg 67: 273–277.[Abstract]
  19. Xu G, Fujita J, Negayama K, Yuube K, Hojo S, Yamaji Y, Kawanishi K, Takahara J, 1996. Effect of macrolide antibiotics on macrophage functions. Microb Immunol 40: 473–479.
  20. Tanyuksel M, Bas AL, Araz E, Aybay C, 2003. Determination of intracellular efficacies of azithromycin against Leishmania major infection in human neutrophils in vitro. Cell Biochem Funct 21: 93–96.[Web of Science][Medline]
  21. Silva-Vergara ML, Silva L de A, Maneira FR, da Silva AG, Prata A, 2004. Azithromycin in treatment of mucosal leishmaniasis. Med Trop Sao Paulo 46: 175–177.



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