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Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study

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Abstract

Objectives

Multidrug chemotherapy is recommended for treating pulmonary Mycobacterium avium and Mycobacterium intracellulare disease. Although ethambutol has been demonstrated to inhibit macrolide resistance, the ethambutol dosage is sometimes decreased due to concerns about optic neuropathy. We aimed to assess whether lower ethambutol doses impact treatment outcomes.

Methods

Patients treated over 12 months between 2016 and 2020 were collected retrospectively. Clinical outcomes, including negative culture conversion, microbiological cure, adverse events, resistance to macrolides, and recurrence, were compared according to daily ethambutol dosage.

Results

Among 146 patients, 42 were treated with ethambutol dosages over 12.5 mg/kg/day, and 104 were treated with lower dosages. Negative culture conversion was achieved for 125 patients, and 90 patients achieved microbiological cure. Recurrence was identified in 16 patients who achieved microbiological cure. No macrolide resistance was observed, and no significant difference was observed in the percentage of negative culture conversion (P = 1.00) or microbiological cure (P = 0.67) between the high- and low-dosage ethambutol groups. Sputum smear positivity was associated with a lower adjusted odds ratio (aOR) of negative culture conversion (aOR: 0.48, 95% CI: 0.29–0.80). A lower aOR of microbiological cure was independently associated with sputum smear positivity (aOR: 0.52, 95% CI: 0.37–0.74) and with the use of an intermittent regimen (aOR: 0.60, 95% CI: 0.41–0.87). Daily ethambutol dosage was not identified as a prognostic factor for any of the outcomes. Optic neuropathy was observed in 7.1% of the high-dose ethambutol group and 1.0% of the low-dosage ethambutol group (P = 0.07).

Conclusion

An ethambutol dosage of 12.5 mg/kg/day or less in guideline-based chemotherapy may reduce optic neuropathy without worsening clinical outcomes.

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Abbreviations

aOR:

Adjusted odds ratio

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disease

FC:

Fibrocavitary

HIV:

Human immunodeficiency virus

M. avium :

Mycobacterium avium

M. intracellulare :

Mycobacterium intracellulare

NB:

Nodular bronchiectatic

NC-NB:

Noncavitary-nodular bronchiectatic

NTM:

Nontuberculous mycobacteria

TIW:

Three-times-weekly

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Funding

This study was supported by a Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan [No. N202704] (F. W) and the Japan Agency for Medical Research and Development [No. JP20fk0108129, 21fk0108129h0802] (K.M). These funding sources did not provide any input or contributions to the development of the research or manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, Tokyo, Japan

    Fumiya Watanabe & Kazuhiko Hanada

  2. Department of Pharmacy, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3–1-24, Matsuyama, Kiyose, Tokyo, 204–8522, Japan

    Fumiya Watanabe

  3. Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3–1-24, Matsuyama, Kiyose, Tokyo, 204–8522, Japan

    Shota Kaburaki, Koji Furuuchi, Fumiko Uesugi, Keiji Fujiwara, Yoshiaki Tanaka, Takashi Yoshiyama, Yuji Shiraishi, Atsuyuki Kurashima, Ken Ohta & Kozo Morimoto

  4. Division of Clinical Research, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3–1-24, Matsuyama, Kiyose, Tokyo, 204–8522, Japan

    Kozo Morimoto

Authors
  1. Fumiya Watanabe
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  2. Shota Kaburaki
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  10. Ken Ohta
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  12. Kozo Morimoto
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Contributions

FW and MK are the guarantors. FW was responsible for data collection, statistical analysis, and writing the manuscript. KM designed and conducted the study and assisted in writing the manuscript. SK, and FK contributed to the design of the study and data collection and supervised the conduct of the whole study. FU, KF, YT, TY, YS, AK, KH, and KO contributed to the interpretation of the results and critical revision of the manuscript for valuable intellectual content. All authors critically read and commented on the final manuscript.

Corresponding author

Correspondence to Kozo Morimoto.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The institutional review board of Fukujuji Hospital (#20044) approved this study.

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All authors have approved the publication of the manuscript.

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Watanabe, F., Kaburaki, S., Furuuchi, K. et al. Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study. Infection 50, 879–887 (2022). https://doi.org/10.1007/s15010-022-01757-3

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