ANTIMICROBiAL AGENTS AND CHEMOTHERAPY, Nov. 1992, p. 2413-2417

Vol. 36, No. 11

0066-4804/92/112413-05$02.00/0 Copyright © 1992, American Society for Microbiology

Activity of Clarithromycin against Mycobacterium avium Complex Infection in Beige Mice S. P. KLEMENS,* M. S. DESTEFANO, AND M. H. CYNAMON State University of New York Health Science Center and Veterans Affairs Medical Center, Syracuse, New York 13210 Received 23 January 1992/Accepted 11 August 1992

The activity of clarithromycin alone and in combination with other antimycobacterial agents was evaluated in the beige (C57BV6J bg'/bg') mouse model of disseminated Mycobacterium avium complex (MAC) infection. A dose-response experiment was performed with clarithromycin at 50, 100, 200, or 300 mg/kg of body weight administered daily by gavage to mice infected with approximately 107 viable MAC. A dose-related reduction in spleen and liver cell counts was noted with treatment at 50, 100, and 200 mg/kg. The difference in cell counts between treatment at 200 and 300 mgtkg was not significant. Clarithromycin at 200 mg/kg of body weight was found to have activity against three additional MAC isolates (MICs for the isolates ranged from 1 to 4 pg/ml by broth dilution). Clarithromycin at 200 mg/kg in combination with amikacin, ethambutol, temafloxacin, or rifampin did not result in increased activity beyond that seen with clarithromycin alone. Clarithromycin in combination with clofazimine or rifabutin resulted in an increase in act'vity beyond that seen with clarithromycin alone. The combination of clarithromycin with clofazimine or rifabutin should be considered for evaluation in the treatment of human MAC infections.

Clarithromycin (CLA) is a new macrolide compound with enhanced in vitro activity against the Mycobacterium avium complex (MAC) (4, 7, 10, 18). The activities of clarithromycin in MAC-infected macrophage cultures (19, 27) and murine models of disseminated MAC infection (4, 12) have been demonstrated previously. After a single oral dose of 50 mg/kg of body weight in C57BL/6J mice, CILA achieves a peak level in serum of 2.6 ,ug/ml (4). After administration of 400 or 1,200 mg of CLA orally in humans, peak levels in serum are 2.1 tag/ml (15) and 4.4 ,ug/ml (22), respectively. Preliminary results of CLA-containing regimens in the treatment of disseminated MAC infection in persons with AIDS are encouraging (2, 3, 21). The purpose of the present study was to evaluate the activity of CILA alone and in combination with various antimycobacterial agents against several MAC isolates in the beige mouse model of disseminated MAC infection.

AIDS at the State University of New York Health Science Center in Syracuse. M. avium ATCC 49601, serotype 1, has been used previously in beige mouse studies in our laboratory and was designated isolate A (16, 17). MAC isolate 1408-3 was kindly provided by Leonid B. Heifets, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo. The MICs of CILA were determined in modified MuellerHinton broth (pH 7.4) (23) supplemented with 10% Middlebrook oleic acid-albumin-dextrose-catalase (OADC) enrichment (Difco Laboratories, Detroit, Mich.). The MICs of the remaining antimicrobial agents were determined in modified Middlebrook 7H10 broth (pH 6.6; 7H10 agar formulation with agar and malachite green omitted) (1) supplemented with 10% Middlebrook OADC enrichment. The MICs for M. avium ATCC 49601 (in micrograms per milliliter) are as follows: CLA, 4; TEM, 8; CFZ, 1; RBT, 0.06; AMK, 8; EMB, 4; and RIF, 1. The MICs of CIA for isolates G and F are 2 and 1 ,ug/ml, respectively. The MICs for MAC isolate 1408-3 (in micrograms per milliliter) are as follows: CLA, 1; CFZ, 0.25; EMB, 4; and RIF, 1. A cell suspension with a predominantly (>95%) transparent colony morphology was used for infection. Isolates were passaged through beige mice every 3 months to maintain virulence. Media. The organisms were grown in modified Middlebrook 7H10 broth with 10% Middlebrook OADC enrichment and 0.05% Tween 80 (25) on a rotary shaker at 37°C for 3 days. The culture suspension was diluted in 7H10 broth to yield 10 Klett units per ml (Klett-Summerson colorimeter; Klett Manufacturing, Brooklyn, N.Y.) or approximately 5 x 107 CFU/ml. The size of the inoculum was determined by titration and counting from duplicate 7H10 agar plates (BBL Microbiology Systems, Cockeysville, Md.) supplemented with 5% Middlebrook OADC enrichment. The plates were incubated at 37C for 3 weeks prior to counting. Infection studies. Six-week-old beige (C57BVJ6J bgi/bg') mice, bred at our facility, were infected intravenously through a caudal vein. Mice of the same sex were used in

MATERIALS AND METHODS Drugs. CILA and temafloxacin (TEM) were provided by Abbott Laboratories, Abbott Park, Ill. Clofazimine (CFZ) was provided by CIBA-GEIGY Pharmaceuticals, Summit, N.J. Rifabutin (RBT) was provided by Adria Laboratories, Dublin, Ohio. Amikacin (AMK), ethambutol (EMB), and rifampin (RIF) were obtained from Sigma Chemical Co., St. Louis, Mo. CLA and TEM were dissolved in absolute ethanol, with subsequent dilution in distilled water prior to administration. CFZ, RIF, and RBT were dissolved in dimethyl sulfoxide, with subsequent dilution in distilled water. The final concentration of ethanol or dimethyl sulfoxide in drug preparations was 0.5%. AMK and EMB were dissolved in distilled water. Drugs were freshly prepared each morning prior to administration. MAC isolates. M. avium ATCC 49601 and MAC isolates G and F were clinical isolates obtained from patients with *

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separate experiments. Each mouse received approximately 10' viable organisms suspended in 0.2 ml of 7H10 broth. There were five mice per group, unless otherwise noted. In each experiment, a control group of infected but untreated mice (late controls) was compared with treated groups of mice at the completion of the treatment period. In three of the combination studies, an additional group of control mice (early controls) was sacrificed at the initiation of therapy. Treatment was started 7 days after infection, and treatment was given daily for 10 days unless otherwise noted. All drugs except AMK and TEM were given orally by gavage; AMK and TEM were administered subcutaneously. Animals were sacrificed by cervical dislocation 2 days after the last dose of drug. Selected organs (spleens; spleens and lungs; or spleens, livers, and lungs) were aseptically removed and ground in a tissue homogenizer. The number of viable organisms was determined by titration on 7H10 agar plates. Statistical evaluation. The viable cell counts were converted to logarithms, which were then evaluated with one- or two-variable analyses of variance. Statistically significant effects from the analyses of variance were further evaluated by the Tukey honestly significant difference tests (14) to make pairwise comparisons among means. The results of the statistical evaluation for the organs are summarized below. RESULTS

CILA dose-response study. CLA at 50, 100, 200, or 300 mg/kg of body weight was given daily to female mice which had been infected with 1.4 x 107 viable M. avium ATCC 49601 (Fig. 1). CLA at all doses reduced organ cell counts compared with those in mice given no treatment (P < 0.01). Treatment at 100 mg/kg reduced cell counts in spleens and livers compared with the counts in the group treated with 50 mg/kg (P < 0.01). An increase in cell counts in the lungs of the group treated with 100 mg/kg compared with that in the lungs of the group treated with 50 mg/kg was noted (P < 0.05). Treatment with 200 mg/kg reduced the cell counts in spleens and livers compared with the counts in the spleens and livers of the group treated with 100 mg/kg (P < 0.01). A reduction in cell counts in lungs in the group treated with 200 mg/kg compared with that in the lungs of the group treated

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livers; (B) LU, lungs. with 100 mg/kg was significant (P < 0.01). The difference in cell counts in the lungs of the group treated with 200 mg/kg compared with that in the lungs of the group treated with 50 mg/kg was not significant (P > 0.05). The difference in cell counts between mice treated with 200 and 300 mg/kg was not significant for any organ (P > 0.05). Extended duration of therapy. CILA at 200 mg/kg was given daily to female mice which had been infected with 1.1 x 107 viable M. avium ATCC 49601. Mice received treatment for 10 or 20 days. Untreated control groups were sacrificed at the completion of each treatment period. The increase in cell counts between the control groups that received treatment for 10 and 20 days was significant for livers and lungs (P < 0.01) but not spleens (P > 0.05) (Fig. 2). Treatment with CLA reduced cell counts in organs at each time point compared with the counts in mice given no treatment (P < 0.01). Treatment for 20 days further reduced cell counts in each organ compared with the counts in mice treated for 10 days (P < 0.01).

CLARITHROMYCIN ACTIVITY AGAINST MAC

VOL. 36, 1992

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CILA alone and those treated with CLA-AMK or CLA-EMB not significant for organisms in spleens or lungs (P > 0.05). CLA alone was more active than the combination of CLA-RIF (P < 0.05 for organisms in spleens; P < 0.01 for organisms in lungs). The combination of CLA-CFZ was more active than CLA alone against organisms in spleens and lungs (P < 0.01). Combination of CLA with TEM or RBT. CLA (200 mg/kg) was given daily alone or in combination with TEM (100 mg/kg) or RBT (20 mg/kg) to female mice which had been infected with 1.9 x 107 viable M. avium ATCC 49601. A separate group received daily TEM alone at 100 mg/kg. A group of early control mice was sacrificed 7 days after infection. The difference in cell counts between early and late control groups was significant only for lungs (P < 0.01) (Fig. 5). Treatment with CILA alone reduced cell counts in spleens and lungs compared with the counts in the spleens and lungs of mice in the early and late control groups (P < 0.01). Treatment with TEM alone did not reduce cell counts in spleens compared with the counts in the spleens of mice in the early or late control groups (P > 0.05). Treatment with TEM alone reduced cell counts in lungs compared with the counts in the lungs of late controls (P < 0.01) but not in those of early controls. CIA alone was more active than the combination of CLA-TEM (P < 0.01 for organisms in spleens; P < 0.05 for organisms in lungs). The combination of CILA-RBT was more active than CILA alone against organisms in spleens and lungs (P < 0.01). Combination therapy against MAC isolate 1408-3. CLA (200 mg/kg) was given daily alone or in combination to female mice which had been infected with 6.2 x 106 viable MAC isolate 1408-3. Combination groups received either one or two additional agents, as follows: RIF (20 mg/kg), EMB (125 mg/kg), CFZ (20 mg/kg), RIF and EMB, RIF and CFZ, or CFZ and EMB. A group of early control mice was sacrificed 7 days after infection. The difference in cell counts between early and late control groups was not significant for organisms in spleens (P > 0.05) (Fig. 6). The reductions in cell counts seen with CIA alone and all combinations were significant compared with the reductions in the early and late control groups (P < 0.01). CLA alone was as active as the combinations of CLA-RIF, CLA-EMB, and CILA-RIF-EMB (P > 0.05). The reductions in cell counts seen with any of the CFZ-containing regimens (CLA-

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Activity of CIA against two additional isolates. In separate experiments, CLA at 200 mg/kg was given daily to mice which had been infected with 2.6 x 107 viable M. avium ATCC 49601 (males), 2.6 x 107 viable MAC isolate G (females), or 1.4 x 107 viable MAC isolate F (males). Treatment with CLA for 10 days reduced cell counts of each isolate in spleens compared with those in the spleens of mice given no treatment (P < 0.01) (Fig. 3). Combination of CIA with AMK, EMB, RIlF, or CFZ. CLA (200 mg/kg) was given daily alone or in combination with AMK (100 mg/kg), EMB (125 mg/kg), RIF (20 mg/kg), or CFZ (20 mg/kg) to male mice which had been infected with 3.3 x 107 viable M. avium ATCC 49601. A group of early control mice was sacrificed 7 days after infection. The increase in cell counts between early and late control groups was significant for spleens and lungs (P < 0.01) (Fig. 4). Treatment with CILA alone and all combinations reduced cell counts in spleens and lungs compared with those in the spleen and lungs of the early and late control groups (P < 0.01). The difference in cell counts between mice treated with O3 Early Control

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EMB, and CFZ against MAC isolate 1408-3. CFZ, CLA-RIF-CFZ or CLA-CFZ-EMB) wi ere significant compared with the reductions after treatme nt with CLA alone (P < 0.01). The differences in cell couints among the three CFZ-containing regimens were not sig,nificant (P > 0.05). DISCUSSION CLA mg/kg had activity against four MAC isolates tested in vivo. The reduction in log CFUs in sp leens between the late control and the CLA-treated group s in a 10-day treatment experiment ranged from 0.8 (MAC isolate G, for which the MIC was 1 ,g/ml) to 2.1 (M. avium ATCC 49601, for which the MIC was 4 ,g/ml). There was lit :tle correlation between in vitro MICs determined by the broth dilution method and the activity of CILA in the mouse model. In order to examine the interexperimenta .1 variation in CILA activity against a single MAC isolate (M. .avium ATCC 49601), we reviewed seven separate studies (four included in the current report; the others are not give n here). The reduction in log CFUs in spleens between th teie lateate%,UL.LLI controlJL and CLA (200 mg/kg)-treated groups occurred in a relatively narrow range (from 1.6 to 2.1; mean, 1.9). Initial inocula (range, 1.1 x 107 to 3.3 x 107 viable organtisms) did not appear to correlate with activity in vivo. Sinriilarly, mouse gender did not appear to influence CLA activi ty against this particular isolate. Drug preparation and admin Iistration were performed by the same investigator in a simil ar manner for each experiment. Previous studies of promising new agents in the beige mouse have often been limited by the use of a single MAC isolate (6, 16). Unlike wild-type strains of M. tuberculosis, MAC isolates have considerable variation in ini vitro susceptibility (9, 11, 26). Parallel testing of additioinralisolates in vitro and in vivo may help to determine whethe orin vitro data can be used to predict activity in the mouse n nodel. The rationale for combination chemotherap y in the treatment of mycobacterial infections is based on n ninimizing the emergence of drug resistance and, possibly, iincreasing the activity of agents which have only modest activity when used alone. Although the current studies do n(ot address the question of emergence of resistant organisms, the combination studies demonstrated various interactions vivo. in a decrease The addition of TEM or RIF to CLA resultec I in in activity compared with the activity of CLA aLlone. TEM as a single agent at 100 mg/kg had poor activil ty against M. at 200

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avium ATCC 49601. The activity of TEM alone against a second isolate, MAC 1408-3, for which the MIC was more favorable (1 ,ug/ml), was minimal in the beige mouse (data not shown). The in vitro activity of TEM has been variable. Khardori et al. (13) noted an MIC for 90% of strains tested (n

= 22) of 2.0 ,g/ml using a broth microdilution method, while Van Caekenberghe (24) reported an MIC for 90% of strains tested (n = 22) of 32 ,ug/ml (range, 1 to 64 ,g/ml) using an agar dilution method. Perrone et al. (20) reported activity of TEM at a concentration of 4 ,g/ml against one of two MAC isolates in human monocyte-derived macrophage cultures. Because the peak concentration of TEM in serum after a single subcutaneous dose of 100 mg/kg in CF-1 mice is 25.2 ,ug/ml (8), it is not clear why TEM alone did not have favorable activity against MAC in the beige mouse. The combination of TEM-CLA may have an antagonistic interaction against this particular MAC isolate. Different routes of administration were used for TEM and CLA in combination; therefore, decreased absorption of CLA was unlikely. The activities of RBT and CFZ as single agents against MAC ATCC 49601 infection in mice have been reported previously (16). The addition of CFZ or RBT to CLA in the current study resulted in an increase in activity compared with that of any of the agents alone. Although the addition of RIF or EMB to the combination of CLA-CFZ did not increase activity beyond that seen with the two-drug combination, the combination of CFZ with a newer rifamycin has been shown to have additive activity in MAC-infected beige mice (5, 16). Therefore, a study of CLA-CFZ-RBT would be of interest to determine whether an even more active regimen can be identified in the beige mouse model. Comparison of these agents singly and in combination would also be warranted to determine whether the emergence of resistant organisms is suppressed. Clinical trials of these promising combinations may lead to identification of an effective oral regimen for the treatment of human M. avium complex infections.

ACKNOWLEDGMENT This study was supported in part by a grant from Abbott Labo-

ratories.

REFERENCES 1. Cynamon, M. H. 1985. Comparative in vitro activities of MDL 473, rifampin, and ansamycin against Mycobacterium intracellulare. Antimicrob. Agents Chemother. 28:440 441. 2. Dautzenberg, B., T. St. Marc, V. Averous, C. Routkovky-Norval,

J. P. Breux, M. Kristetter, M. Eliazewitch, V. Mondain, S. Legris, and J. Grosset. 1991. Clarithromycin-containing regimens in the treatment of 54 AIDS patients with disseminated Mycobacterium avium-intracellulare infection. Program Abstr. 31st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 293. 3. Dautzenberg, B., C. Truffot, S. Legris, M.-C. Meyohas, H. C. Berlie, A. Mercat, S. Chevret, and J. Grosset. 1991. Activity of clarithromycin against Mycobacterium avium infection in patients with the acquired immune deficiency syndrome. Am. Rev. Respir. Dis. 144:564-569. 4. Fernandes, P. B., D. J. Hardy, D. McDaniel, C. W. Hanson, and R. N. Swanson. 1989. In vitro and in vivo activities of clarithro-

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VOL. 36, 1992 Kesavalu, and M. D. Iseman. 1988. In vivo activity of amikacin alone or in combination with clofazimine or rifabutin or both against acute experimental Mycobacterium avium complex infections in beige mice. Antimicrob. Agents Chemother. 32: 1400-1403. 7. Gorzynski, E. A., S. I. Gutman, and W. Allen. 1989. Comparative antimycobacterial activities of difloxacin, temafloxacin, enoxacin, pefloxacin, reference fluoroquinolones, and a new macrolide, clarithromycin. Antimicrob. Agents Chemother. 33: 591-592. 8. Hardy, D. J., R. N. Swanson, D. M. Hensey, N. R. Ramer, R. R. Bower, C. W. Hanson, D. T. W. Chu, and P. B. Fernandes. 1987. Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones. Antimicrob. Agents Chemother. 31:1768-1774. 9. Heifets, L. B. 1991. Dilemmas and realities in drug susceptibility testing of M. avium-M. intracellulare and other slowly growing nontuberculous mycobacteria. In L. B. Heifets (ed.), Drug susceptibility in the chemotherapy of mycobacterial infections. CRC Press, Inc., Boca Raton, Fla. 10. Inderlied, C. B., F. G. Sandoval, and L. S. Young. 1991. In vitro activity of clarithromycin and 14-hydroxy-clarithromycin against the Mycobactenium avium complex alone and in combination with other agents. Program Abstr. 31st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 239. 11. Inderlied, C. B., L. S. Young, and J. K. Yamada. 1987. Determination of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob. Agents Chemother. 31:1697-1702. 12. Ji, B., N. Lounis, C. Truffot-Pernot, and J. Grosset. 1991. Susceptibility of the immunocompetent, beige and nude mice to Mycobacterium avium infection and response to clarithromycin. Program Abstr. 31st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 291. 13. Khardori, N., K. Rolston, B. Rosenbaum, S. Hayat, and G. P. Bodey. 1989. Comparative in-vitro activity of twenty antimicrobial agents against clinical isolates of Afycobacterium avium complex. J. Antimicrob. Chemother. 24:667-673. 14. Kirk, R. E. 1986. Experimental design: procedures for the behavioral sciences. Brooks-Cole Publishing Co., Belmont, Calif. 15. Kirst, H. A., and G. D. Sides. 1989. New directions for macrolide antibiotics: pharmacokinetics and clinical efficacy. Antimicrob. Agents Chemother. 33:1419-1422. 16. Klemens, S. P., and M. H. Cynamon. 1991. In vivo activities of newer rifamycin analogs against Mycobactenium avium infection. Antimicrob. Agents Chemother. 35:2026-2030. 17. Klemens, S. P., M. H. Cynamon, C. E. Swenson, and R. S.

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Ginsberg. 1990. Liposome-encapsulated-gentamicin therapy of Mycobacterium avium complex infection in beige mice. Antimicrob. Agents Chemother. 34:967-970. 18. Naik, S., and R. Ruck. 1989. In vitro activities of several new macrolide antibiotics against Mycobacterium avium complex.

Antimicrob. Agents Chemother. 33:1614-1616. 19. Perronne, C., A. Gikas, C. Truffot-Pernot, J. Grosset, J.-J. Pocidalo, and J.-L. Vilde. 1990. Activities of clarithromycin, sulfisoxazole, and rifabutin against Mycobacterium avium complex multiplication within human macrophages. Antimicrob. Agents Chemother. 34:1508-1511. 20. Perronne, C., A. Gikas, C. Truffot-Pernot, J. Grosset, J.-L. Vilde, and J.-J. Pocidalo. 1991. Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobactenum avium complex within human macrophages. Antimicrob. Agents Chemother. 35:1356-1359. 21. Saint-Marc, T., and J. L. Touraine. 1991. Clinical experience with a combination of clarithromycin and clofazimine in the treatment of disseminated M. avium infections in AIDS patients. Program Abstr. 31st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 237. 22. Sennello, L. T., S.-Y. Chu, D. S. Wilson, K S. Laws, S. T. Bunnell, L. L. Varga, and K. Snyder. 1986. Single dose pharmacokinetics of ABBOTT-56268 (TE-031) after oral dosing. Program Abstr. 26th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 419. 23. Truffot-Pernot, C., B. Ji, and J. H. Grosset. 1991. Effect of pH on the in vitro potency of clarithromycin against Mycobactenium avium complex. Antimicrob. Agents Chemother. 35:16771678. 24. Van Caekenberghe, D. 1990. Comparative in-vitro activities of ten fluoroquiunolones and fusidic acid against Mycobacterium spp. J. Antimicrob. Chemother. 26:381-386. 25. Vestal, A. L. 1969. Procedures for the isolation and identification of mycobacteria, p. 113-115. Public Health Service publication no. 1995. Laboratory Division, National Communicable Disease Center, Atlanta. 26. Yajko, D. M., J. Kirihara, C. Sanders, P. Nassos, and W. K. Hadley. 1988. Antimicrobial synergism against Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome. Antimicrob. Agents Chemother.

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Activity of clarithromycin against Mycobacterium avium complex infection in beige mice.

The activity of clarithromycin alone and in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J bgj/bgj) mouse model ...
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