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Antimicrobial Agents and Chemotherapy, August 1998, p. 2070-2073, Vol. 42, No. 8
Department of Microbiology, Institute of
Tropical Medicine, Antwerp, Belgium,1 and
Armed Forces Institute of Pathology, Washington, D.C.
20306-60002
Received 9 March 1998/Returned for modification 13 April
1998/Accepted 1 June 1998
Buruli ulcer (BU), caused by Mycobacterium ulcerans,
was recently recognized by the World Health Organization as an
important emerging disease. While antimycobacterial therapy is often
effective for the earliest nodular or ulcerative lesions, medical
management of BU lesions in patients presenting for treatment is
usually disappointing, leaving wide surgical excision the only
alternative. Advanced ulcerated lesions of BU rarely respond to
antimycobacterial agents; however, perioperative administration of such
drugs may prevent relapses or disseminated infections. Clarithromycin
possesses strong activity in vitro and in vivo against most
nontuberculous mycobacteria. In this study we determined the
antimycobacterial activity of this drug in vitro against 46 strains of
M. ulcerans isolated from 11 countries. The MIC of
clarithromycin was determined at pH 6.6 (on 7H11 agar) and at pH 7.4 (on Mueller-Hinton agar). The MICs ranged from 0.125 to 2 µg/ml at pH
6.6 and from <0.125 to 0.5 µg/ml at pH 7.4. For the majority of the
strains, geographic origin did not play a significant role.
Thirty-eight strains (83%) were inhibited by 0.5 µg/ml at pH 7.4. These MICs are below peak therapeutic concentrations of clarithromycin
obtainable in blood. These results suggest that clarithromycin is a
promising drug both for the treatment of early lesions of M. ulcerans and for the prevention of hematogenous dissemination of
the etiologic agent during and after surgery. Studies should be
initiated to evaluate the effects of clarithromycin in combination with
ethambutol and rifampin on M. ulcerans both in vitro and in
experimentally infected mice. Multidrug regimens containing
clarithromycin may also help control the secondary bacterial infections
sometimes seen in BU patients, most importantly osteomyelitis.
Mycobacterium ulcerans
causes necrotizing, relatively nonpainful lesions known variously as
Buruli ulcer (BU), Bairnsdale ulcer, or more precisely, M. ulcerans infection. BU was recently recognized by the World Health
Organization as an important emerging disease. The disease has been
reported in many countries, mostly tropical, in Africa, North America
(Mexico), South America, Southeast Asia, and Australia. Recent reports
have suggested increased incidences of BU in, for example, some areas
of Benin (21), Australia (13), and Côte
d'Ivoire (24).
Medical treatment of these ulcers is usually disappointing, leaving
wide surgical excision followed by skin grafting the only alternative
(4). Preulcerative nodular lesions and early small ulcerated
lesions can be effectively treated by excision and primary closure, by
rifampin alone, or possibly by heating at 40°C without prior excision
(26). Rifampin, however, is usually not effective against
advanced ulcers. Even though currently the best therapeutic approach is
surgery, it is possible that postsurgical antimycobacterial treatment
would prevent relapses or metastatic infections. Disseminated infections with involvement of bone and cartilage have been observed (3, 10).
Among the new macrolides, clarithromycin possesses strong activity in
vitro and in vivo against most nontuberculous mycobacteria. Clarithromycin is effective for the treatment of infections caused by
Mycobacterium avium complex in AIDS patients (8,
11), Mycobacterium genavense (5) and
Mycobacterium haemophilum (22) infections,
lymphadenitis caused by nontuberculous mycobacteria (36),
and Mycobacterium marinum infections in both human
immunodeficiency virus-seronegative and -seropositive patients
(6). Numerous investigations have shown clarithromycin to be
active in the treatment of infections caused by rapidly growing
mycobacteria (7, 25, 28, 30, 37, 38), and it is active in
vitro and in vivo against M. avium (12) and
Mycobacterium leprae (14).
Several reports suggest that the susceptibilities of some mycobacterial
species to clarithromycin depend on the pH of the medium and that the
MIC of clarithromycin for these species is lower at pH 7.4 than at pH
6.6 (20, 32).
Based on the reported efficacy of clarithromycin for the treatment of
leprosy and some other nontuberculous mycobacterial infections, we
determined the antimycobacterial activities of this drug in vitro at pH
6.6 and at pH 7.4 against strains of M. ulcerans of
different geographic origins. We chose to assess the MIC at pH 6.6 and
7.4 because pH 6.6 is the standard pH of 7H11 medium, which is commonly
used for drug sensitivity tests and determination of the MIC for
mycobacteria (19), and because the physiological pH of
plasma is 7.4.
Antimicrobial agent.
Clarithromycin was kindly provided by
Abbott Laboratories Ltd. (Queenborough, Kent, England). The stock
solution (2 mg/ml) and working solutions were prepared as described by
Mor and Heifets (27).
MIC determination.
Because the antimycobacterial efficacy of
clarithromycin depends on the pH of the medium, the MIC of
clarithromycin was determined on two different media: 7H11 agar (pH
6.6) and Mueller-Hinton agar (pH 7.4) supplemented with 10% (vol/vol)
OADC (oleic acid, albumin, dextrose, and catalase; Difco Laboratories,
Detroit, Mich.) (20, 32). Both media contained twofold
dilutions of clarithromycin from 0.125 to 4 µg/ml. Media without
antibiotics added served as controls. The inocula were 0.1 ml of
10 Bacterial strains.
A total of 46 M. ulcerans
strains isolated from patients from 11 countries were studied (see
Table 1). One ATCC reference strain, ATCC 19423, from Australia, was
studied. A total of 41 strains were isolated at the Institute of
Tropical Medicine from tissue fragments transported to Antwerp
(31), and 5 strains were obtained from other laboratories: 4 (1 from Papua New Guinea and 3 from Malaysia) were contributed by K. Jackson (Fairfield Hospital, Melbourne, Australia), and 1 (from French
Guiana) was contributed by V. Vincent, Institut Pasteur, Paris, France.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Susceptibility of Mycobacterium
ulcerans to Clarithromycin
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
1 and 103 dilutions of bacterial
suspensions of 1 mg/ml in phosphate-buffered saline. The tubes were
incubated at 33°C and were read after 28 and 42 days of incubation.
The MIC was defined as the lowest concentration of clarithromycin
inhibiting 
99% of the bacterial population in the 101
dilution. Only tests with growth in the tubes inoculated with the
103 dilution were considered valid.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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As indicated in Table 1, the MICs of clarithromycin for the 44 M. ulcerans strains tested on 7H11 medium (pH 6.6) ranged from 0.125 to 2 µg/ml and the MICs for the 29 strains tested on Mueller-Hinton medium (pH 7.4) ranged from <0.125 to 0.5 µg/ml. All tested strains were inhibited by 2 µg of clarithromycin per ml, and all but one Australian and one Malaysian strain were inhibited by 1 µg/ml (at pH 6.6).
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Of the 46 strains tested at pH 6.6 and/or pH 7.4, 38 strains (83%) were inhibited by 0.5 µg/ml. For six Australian strains and one strain each from Benin and the Democratic Republic of Congo (formerly Zaire), the MICs were >0.5 µg/ml.
For some of the strains, the MICs obtained at pH 7.4 were 1 or more
dilutions lower than those obtained at pH 6.6. MICs for 11 strains (7 from Australia, 2 from Benin, 1 from the Democratic Republic of Congo,
and 1 from Togo) were 
0.125 µg/ml when these strains were tested at
pH 7.4. The MICs obtained on 7H11 agar (pH 6.6) for the Australian and
Malaysian strains were higher by 1 to 2 dilutions than those for
strains from other countries.
The MIC of clarithromycin for the ATCC reference strain, ATCC 19423, was 0.5 µg/ml on 7H11 medium (pH 6.6) and <0.125 µg/ml on Mueller-Hinton agar (pH 7.4).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
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The MICs for the 46 M. ulcerans strains tested at pH
6.6 and/or at pH 7.4 varied from 0.125 to 2 µg of clarithromycin
per ml. For 1 Australian and 1 Malaysian strain (the latter tested at
pH 6.6 only), the MIC was 2 µg/ml, while the other 44 strains were
inhibited by concentrations lower than 2 µg/ml. These MICs are below
peak plasma concentrations of clarithromycin obtainable in humans.
Administration of 500 mg of clarithromycin twice daily for up to 3.5 days to volunteers resulted in mean peak plasma concentrations between
2.4 and 3.5 µg/ml (9).
For the majority of strains, geographic origin did not seem to play a significant role in sensitivity to clarithromycin. The Australian and the Malaysian strains, nevertheless, were more resistant; MICs for these strains ranged from 0.5 to 2 µg/ml. Genetic and phenotypic differences have been demonstrated between different strains of M. ulcerans (31). Whether these genetic and phenotypic differences (28) are related to susceptibility to antimycobacterial agents is unknown.
Low clarithromycin MICs have been obtained in vitro for other mycobacterial species; for example, with the BACTEC system, Rastogi and Goh (32) found low MICs for three Mycobacterium bovis BCG strains (0.25 to 0.5 µg/ml at pH 6.8 and 0.1 to 0.2 µg/ml at pH 7.4). These authors found MICs lower than 1 µg/ml at pH 6.8 and 7.4 for several other mycobacterial pathogens, including Mycobacterium xenopi, Mycobacterium scrofulaceum, Mycobacterium kansasii, Mycobacterium chelonae, and M. marinum. Using the broth microdilution method with Mueller-Hinton medium (pH 7.4), Brown et al. (7) found that 90% of Mycobacterium chelonae subsp. chelonae organisms and 90% of Mycobacterium chelonae subsp. abscessus organisms were inhibited by 0.25 and 0.5 µg of clarithromycin/ml, respectively. Rastogi and colleagues (33) also have reported clarithromycin activity against M. marinum and Mycobacterium paratuberculosis (MICs, 0.25 to 0.5 µg/ml). MICs at pH 7.4 in liquid media were 2 µg/ml or lower for M. avium strains (20). These results strongly suggest that clarithromycin is a promising chemotherapeutic agent for infections caused by a variety of mycobacterial species.
Because the inhibitory activity of clarithromycin is higher at pH 7.4 than at an acid pH, this drug may be especially effective for the elimination of extracellular bacteria and suppression of mycobacterial bacteremia. Heifets et al. (20) suggested that the elimination of M. avium from the blood of patients with AIDS under clarithromycin therapy was most likely related to the increased inhibitory activity of this drug at pH 7.4.
Clinical studies have repeatedly revealed that antimycobacterial agents are not effective for the treatment of advanced ulcerated lesions of BU. This is believed to be related to the low drug levels obtainable in the necrotic tissues of advanced BU in the skin. Extensive histopathologic studies demonstrate that M. ulcerans is essentially an extracellular parasite largely confined to areas of necrosis in skin; however, the bacillus often spreads to local and regional lymph nodes and causes metastatic disease in bone (1). In our report on 867 BU patients treated at Zangnanado (3), we observed disseminated lesions following the appearance of the primary lesion. In some instances the disseminated lesions appeared after complete healing of the initial lesion. Such lesions probably represent hematogenous spread that may be preventable by effective antimycobacterial agents.
The present study demonstrates that levels of clarithromycin that are obtainable in blood are inhibitory for M. ulcerans in vitro. Thus, clarithromycin offers promise, not only for the treatment of early lesions of M. ulcerans, but also as an adjunct treatment for the prevention of hematogenous dissemination of the etiologic agent. The efficacy of rifampin against M. ulcerans in vitro and in vivo in the mouse has been established. The in vitro susceptibility of M. ulcerans to rifampin was found to be similar to that of Mycobacterium tuberculosis (18, 29, 34). Early nodular lesions and early limited ulcerated lesions in humans respond favorably to rifampin monotherapy (23). Rifampin, thus, could also be a useful drug for the prevention of dissemination.
Combined therapy is generally recommended for the treatment of mycobacterial infections in order to prevent the development of resistance when the infection is caused by a sufficiently large number of bacilli to allow for the selection of resistant mutants. Most BU patients, at some stage of the disease, have massive bacillary burdens. Multiple-drug therapy may also produce additive or mutually synergistic effects between the antibacterial agents. Although M. ulcerans is resistant in vitro to ethambutol (data not shown), several reports indicate that ethambutol is synergistic with other antimycobacterial agents (16, 33). Clarithromycin shows synergism with rifampin in combined therapy of M. avium complex infections, and ethambutol enhances the bactericidal activity of rifampin against the same M. avium strains (35, 39). It was, however, recently demonstrated that rifabutin in combination with clarithromycin substantially reduced clarithromycin levels (17). Although rifampin or clarithromycin alone may be used in the treatment of patients with BU, studies should be initiated to evaluate the effects of clarithromycin alone and in combination with ethambutol and rifampin on M. ulcerans, both in vitro and in vivo in experimentally infected mice. Such studies would give valuable information for the formulation of recommendations for an optimal antimycobacterial regimen for use (i) as a treatment of certain stages of M. ulcerans infection, (ii) for the prevention of dissemination during or after surgery, and (iii) as an adjunct to other therapeutic approaches. Secondary bacterial infections are common in BU patients, especially in patients with osteomyelitis (2). Multidrug regimens containing clarithromycin might help control the complications of BU, which are often mutilating and sometimes life threatening.
Finally, regimens containing rifampin and ethambutol would avoid the selection of resistant mutants in patients who may have undiagnosed M. tuberculosis infection.
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ACKNOWLEDGMENTS |
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This study was supported by the Damien Foundation (Brussels, Belgium).
We are grateful to K. Jackson for providing strains of M. ulcerans from Papua New Guinea and Malaysia and to V. Vincent for providing the strains from French Guiana. We thank R. Womersley, Abbott Laboratories Ltd., for kindly providing clarithromycin.
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FOOTNOTES |
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* Corresponding author. Mailing address: Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium. Phone: 32 3 247 63 24. Fax: 32 3 247 63 33. E-mail: portaels{at}itg.be.
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Antimicrobial Agents and Chemotherapy, August 1998, p. 2070-2073, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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