Letter to the Editor In Vitro Activity of Amikacin against Mycobacterium avium In a recent article by L. Heifets and P. Lindholm-Levy (Antimicrob. Agents Chemother. 33:1298-1301, 1989), the authors contend that they could not confirm our conclusions about the in vitro activity of amikacin against the Mycobacterium avium complex (C. B. Inderlied, L. S. Young, and J. K. Yamada, Antimicrob. Agents Chemother. 31:16971701, 1987) and found our observations on the clinical efficacy of amikacin paradoxical (C. B. Inderlied, P. T. Kolonoski, M. Wu, and L. S. Young, Antimicrob. Agents Chemother. 33:176-180, 1989). We disagree with these statements. Heifets and Lindholm-Levy reported amikacin MICs for 50 and 90% of isolates tested of 2.65 and 6.75 ,ug/ml, respectively. These values are quite similar to our values of 4.8 and 13.4 ,ug/ml using a similar method but a more exacting endpoint (99.9% inhibition). When amikacin was tested in an animal model of disseminated M. avium infection, we found it to be effective, and the addition of ciprofloxacin and/or imipenem did not improve the efficacy of amikacin. Heifets and Lindholm-Levy interpreted our results as suggesting evidence for a synergistic interaction between the drugs. We disagree and continue to interpret our results as evidence for the efficacy of amikacin alone. Criteria for the definition of susceptibility of M. avium are neither clearly established nor generally accepted by the community of scientists studying the M. avium complex. Drug concentrations that can be achieved in serum provide only one criterion, and even this criterion must be interpreted in light of the nature of the infection and drug pharmacokinetics. The rather arbitrary interpretive criteria used by Heifets and Lindholm-Levy need to be assessed in terms of clinical efficacy and until substantiated should be regarded as conjecture and potentially misleading.
and therefore we could not refer to this paper as a clinical observation. (iii) Is amikacin active alone or in combination when tested in beige mice? The authors concluded in the abstract (2) that "Imipenem and ciprofloxacin had little or no activity alone .. ., but when they were combined with amikacin there was bactericidal activity" (p. 176). In the Discussion section the authors stated (p. 179), "When amikacin was combined with ciprofloxacin and imipenem, there was no clear improvement in therapeutic effectiveness [in mice], although there was a significant decrease in bacteremia in the three-drug-treated group compared with the groups treated by the other regimens." These and other statements gave us enough ground to suggest, by referring to the paper by Inderlied et al., that "amikacin can enhance a therapeutic effect in beige mice treated with amikacin plus imipenem and ciprofloxacin." We did not express any doubts about the authors' experiments with amikacin alone in beige mice, and we did not discuss whether these experiments could be considered "as evidence for the efficacy of amikacin alone." But in response to Dr. Inderlied's letter we can say that we are not convinced, since his conclusion is based on testing of only one strain in a model in which predictability for the clinical outcome is unknown. Is amikacin effective in the treatment of M. avium disease in humans? Maybe, but more likely it is effective only in combination with other drugs, as suggested in the report by B. J. Baron and L. S. Young, the only clinical observation which we quoted in our paper. (iv) In the last paragraph of his letter, Dr. Inderlied criticizes the "interpretive criteria" used in our paper, but he does not say which exact data are "potentially misleading." It is true that, in the absence of any controlled clinical trials with M. avium, we compared MICs and MBCs with concentrations in human serum. And so did Inderlied with colleagues in regard to MIC. However, we suggested the tentative interpretation "susceptible" only for those strains for which the MICs were not just below the maximum concentration in serum but lower than the MICs found for wild M. tuberculosis strains. Dr. Inderlied did not use the world "tentative" at all for interpretation of his results. The most important fact is that our paper is not about the inhibitory but rather the bactericidal activity of the four drugs (MICs are given for comparison with MBCs). Dr. Inderlied with his colleagues did not test the bactericidal activity of amikacin in vitro at all. We found that MBCs of amikacin, as well as MBCs of streptomycin and kanamycin, for M. avium were very much higher than concentrations achievable in human serum, in contrast to the very low MBCs found for M. tuberculosis. The low bactericidal activity of these drugs against M. avium is a fact, whether the MBCs were compared with the peak concentrations in serum or with MBCs of the same drugs for M. tuberculosis. In conclusion, we would like to thank Dr. Inderlied for his letter, which gave us an opportunity to clarify our view. We only regret that Dr. Inderlied did not acknowledge that our paper is about the bactericidal activity of the four injectable drugs and that we came to the conclusion that none of them (when tested alone) is reasonably bactericidal against M.
Clark B. Inderlied Department of Pathology and Laboratory Medicine Children's Hospital 4650 Sunset Boulevard Post Office Box 54700 Los Angeles, California 90054-0700
Author's Reply (i) Dr. Inderlied says that the MICs of amikacin found in our study for 50 and 90% of isolates were similar to those he reported (3). This is correct, but we did not say in our paper (1) that we could not confirm his conclusion about the activity of amikacin. In fact, we only stated that he "indicated that a higher percentage of M. avium strains . . . was susceptible to amikacin than to streptomycin at 4.0 ,ug or less per ml." We could not confirm this conclusion by testing 100 versus 15 strains in the paper by Inderlied et al. Other authors quoted in our paper could not find differences in activity of various aminoglycosides against Mycobacterium avium either. (ii) Another point in Dr. Inderlied's letter is that we allegedly found his and his colleagues' (2) "observations on the clinical efficacy of amikacin paradoxical." We did discuss the controversy over the low bactericidal activity of amikacin and its efficacy in a clinical situation, but we did not doubt the conclusions made from the clinical observations. Besides, Dr. Inderlied's paper (2) is a study on mice,
avium.
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VOL. 34, 1990 LITERATURE CITED 1. Heifets, L., and P. Lindholm-Levy. 1989. Comparison of bactericidal activities of streptomycin, amikacin, kanamycin, and capreomycin against Mycobacterium avium and M. tuberculosis. Antimicrob. Agents Chemother. 33:1298-1301. 2. Inderlied, C. B., P. T. Kolonoski, M. Wu, and L. S. Young. 1989. Amikacin, ciprofloxacin, and imipenem treatment for disseminated Mycobacterium avium complex infection of beige mice. Antimicrob. Agents Chemother. 33:176-180. 3. Inderlied, C. B., L. S. Young, and J. K. Yamada. 1987. Determi-
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nation of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob. Agents Chemother. 31:1697-1702. Leonid Heifets Pamela Lindholm-Levy National Jewish Center for Immunology and Respiratory Medicine 1400 Jackson Street Denver, Colorado 80206
and therefore we could not refer to this paper as a clinical observation. (iii) Is amikacin active alone or in combination when tested in beige mice? The authors concluded in the abstract (2) that "Imipenem and ciprofloxacin had little or no activity alone .. ., but when they were combined with amikacin there was bactericidal activity" (p. 176). In the Discussion section the authors stated (p. 179), "When amikacin was combined with ciprofloxacin and imipenem, there was no clear improvement in therapeutic effectiveness [in mice], although there was a significant decrease in bacteremia in the three-drug-treated group compared with the groups treated by the other regimens." These and other statements gave us enough ground to suggest, by referring to the paper by Inderlied et al., that "amikacin can enhance a therapeutic effect in beige mice treated with amikacin plus imipenem and ciprofloxacin." We did not express any doubts about the authors' experiments with amikacin alone in beige mice, and we did not discuss whether these experiments could be considered "as evidence for the efficacy of amikacin alone." But in response to Dr. Inderlied's letter we can say that we are not convinced, since his conclusion is based on testing of only one strain in a model in which predictability for the clinical outcome is unknown. Is amikacin effective in the treatment of M. avium disease in humans? Maybe, but more likely it is effective only in combination with other drugs, as suggested in the report by B. J. Baron and L. S. Young, the only clinical observation which we quoted in our paper. (iv) In the last paragraph of his letter, Dr. Inderlied criticizes the "interpretive criteria" used in our paper, but he does not say which exact data are "potentially misleading." It is true that, in the absence of any controlled clinical trials with M. avium, we compared MICs and MBCs with concentrations in human serum. And so did Inderlied with colleagues in regard to MIC. However, we suggested the tentative interpretation "susceptible" only for those strains for which the MICs were not just below the maximum concentration in serum but lower than the MICs found for wild M. tuberculosis strains. Dr. Inderlied did not use the world "tentative" at all for interpretation of his results. The most important fact is that our paper is not about the inhibitory but rather the bactericidal activity of the four drugs (MICs are given for comparison with MBCs). Dr. Inderlied with his colleagues did not test the bactericidal activity of amikacin in vitro at all. We found that MBCs of amikacin, as well as MBCs of streptomycin and kanamycin, for M. avium were very much higher than concentrations achievable in human serum, in contrast to the very low MBCs found for M. tuberculosis. The low bactericidal activity of these drugs against M. avium is a fact, whether the MBCs were compared with the peak concentrations in serum or with MBCs of the same drugs for M. tuberculosis. In conclusion, we would like to thank Dr. Inderlied for his letter, which gave us an opportunity to clarify our view. We only regret that Dr. Inderlied did not acknowledge that our paper is about the bactericidal activity of the four injectable drugs and that we came to the conclusion that none of them (when tested alone) is reasonably bactericidal against M.
Clark B. Inderlied Department of Pathology and Laboratory Medicine Children's Hospital 4650 Sunset Boulevard Post Office Box 54700 Los Angeles, California 90054-0700
Author's Reply (i) Dr. Inderlied says that the MICs of amikacin found in our study for 50 and 90% of isolates were similar to those he reported (3). This is correct, but we did not say in our paper (1) that we could not confirm his conclusion about the activity of amikacin. In fact, we only stated that he "indicated that a higher percentage of M. avium strains . . . was susceptible to amikacin than to streptomycin at 4.0 ,ug or less per ml." We could not confirm this conclusion by testing 100 versus 15 strains in the paper by Inderlied et al. Other authors quoted in our paper could not find differences in activity of various aminoglycosides against Mycobacterium avium either. (ii) Another point in Dr. Inderlied's letter is that we allegedly found his and his colleagues' (2) "observations on the clinical efficacy of amikacin paradoxical." We did discuss the controversy over the low bactericidal activity of amikacin and its efficacy in a clinical situation, but we did not doubt the conclusions made from the clinical observations. Besides, Dr. Inderlied's paper (2) is a study on mice,
avium.
378
VOL. 34, 1990 LITERATURE CITED 1. Heifets, L., and P. Lindholm-Levy. 1989. Comparison of bactericidal activities of streptomycin, amikacin, kanamycin, and capreomycin against Mycobacterium avium and M. tuberculosis. Antimicrob. Agents Chemother. 33:1298-1301. 2. Inderlied, C. B., P. T. Kolonoski, M. Wu, and L. S. Young. 1989. Amikacin, ciprofloxacin, and imipenem treatment for disseminated Mycobacterium avium complex infection of beige mice. Antimicrob. Agents Chemother. 33:176-180. 3. Inderlied, C. B., L. S. Young, and J. K. Yamada. 1987. Determi-
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nation of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob. Agents Chemother. 31:1697-1702. Leonid Heifets Pamela Lindholm-Levy National Jewish Center for Immunology and Respiratory Medicine 1400 Jackson Street Denver, Colorado 80206
