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Brief Report
20 December 2019

Intermittent Treatment with Azithromycin and Ethambutol for Noncavitary Mycobacterium avium Complex Pulmonary Disease

ABSTRACT

We evaluated the efficacy of intermittent azithromycin and ethambutol therapy for noncavitary Mycobacterium avium complex pulmonary disease (MAC-PD). Twenty-nine (76%) of 38 patients achieved sputum culture conversion after 12 months of treatment, and sputum smear positivity was an independent factor for failure to achieve culture conversion (adjusted odds ratio, 26.7; 95% confidence interval, 2.1 to 339.9; P = 0.011). Intermittent azithromycin and ethambutol may be an optional treatment regimen for noncavitary MAC-PD.

INTRODUCTION

The incidence of Mycobacterium avium complex pulmonary disease (MAC-PD) is increasing worldwide (1, 2), and the current guidelines recommend a macrolide, ethambutol, and rifamycin as the standard three-drug treatment regimen (3, 4). Daily treatment is recommended for cavitary MAC-PD, and an intermittent (3 times/week) regimen is recommended for noncavitary MAC-PD (3, 4). However, treatment discontinuation or modification because of drug toxicity is common (5, 6).
The drug-drug interactions between macrolides and rifamycin are an important issue in the treatment of MAC-PD (7, 8) and may be associated with unsuccessful outcomes (9). Moreover, rifamycin is related to several adverse effects, such as hepatitis, gastrointestinal symptoms, and hematological toxicities, which hinder long-term multidrug treatment for MAC-PD (10); the guidelines indicate that a daily regimen consisting of a macrolide with ethambutol would be acceptable for some patients with mild nodular bronchiectatic MAC-PD and medication intolerance (3). In clinical practice, many patients treated with the three-drug intermittent regimen cannot maintain rifamycin because of drug-drug interactions or other adverse events. However, no data are available on the clinical efficacy of two-drug intermittent treatment with a macrolide and ethambutol for noncavitary MAC-PD. Therefore, we evaluated the treatment outcomes of a two-drug (azithromycin and ethambutol) intermittent treatment regimen for noncavitary MAC-PD.
A total of 38 patients with noncavitary MAC-PD treated with intermittent azithromycin and ethambutol for ≥12 months between January 2011 and June 2017 in Samsung Medical Center (a 1,961-bed referral hospital in Seoul, South Korea) were retrospectively reviewed. Treatment outcomes, including the rates of symptomatic radiological improvement and sputum culture conversion at 12-month follow-up visits, were analyzed. Sputum specimens were obtained at 1, 3, and 6 months after treatment initiation and then at 2- to 3-month intervals during treatment (6), and sputum cultures obtained from treatment initiation to the 12-month time point were evaluated in this study. In patients with persistently positive cultures, drug susceptibility testing was repeated every 6 months during antibiotic treatment (11). Data were accessed in August 2018. The institutional review board approved this study (IRB no. 2018-10-035-001), and informed consent was waived for the use of patient medical data.
All data are presented as the median and interquartile range (IQR) and as the number and percentage. To identify the related factors for failure to achieve sputum culture conversion, univariate and multivariate logistic regression analyses were used. All statistical analyses were performed using SPSS software, version 24 (IBM, Armonk, NY).
Among the 38 patients with noncavitary MAC-PD, 28 patients (74%) were female, and 31 patients (82%) were never smokers. The median body mass index (BMI) of the patients was 21.4 kg/m2 (IQR, 20.0 to 22.7 kg/m2), and M. avium and Mycobacterium intracellulare were isolated in 22 (58%) and 16 (42%) patients, respectively. Nine patients (24%) had a history of tuberculosis. The major phenotype in most patients (n = 36 [95%]) was the nodular bronchiectatic form, and the other patients (n = 2) had multiple nodular lesions. Sputum acid-fast bacilli (AFB) smears were positive in 15 patients (40%). The median follow-up duration was 32.7 months (IQR, 21.7 to 49.0 months) from treatment initiation.
All of the patients were treated with an intermittent therapy regimen of azithromycin (500 mg) and ethambutol (25 mg/kg), and rifamycin was either not used because of interactions with other drugs (n = 13 [34%]), such as warfarin or other anticoagulants (n = 5), immunosuppressive agents (n = 4), chemotherapy (n = 2), and levothyroxine (n = 2), or discontinued because of gastrointestinal disturbances (n = 18 [48%]), leukopenia (n = 3 [8%]), hepatotoxicity (n = 2 [5%]), or urticaria (n = 2 [5%]). In the patients who previously discontinued rifamycin, median duration of rifamycin administration was 0.8 months (IQR, 0 to 1.8 months).
Of 38 patients treated for 12 months, 35 (92%) described symptomatic improvement, and 30 (79%) showed radiological improvement on chest computed tomography. Sputum culture conversion was achieved in 29 patients (76%), and the median time to culture conversion was 1.2 months (IQR, 1.0 to 4.1 months). None of the 9 patients who failed culture conversion acquired additional drug resistance to macrolide. The 9 patients were kept on two-drug intermittent therapy without regimen changes. Of these patients, 8 failed culture conversion and discontinued treatment after a median of 20.4 months (IQR, 15.2 to 27.5 months) of treatment, and 1 patient achieved culture conversion after surgical resection (right middle lobectomy with wedge resection of right upper lobe) and a total of 41.6 months of treatment. The factor associated with failure to achieve sputum culture conversion within 12 months was AFB smear positivity (odds ratio [OR], 9.2; 95% confidence interval [CI], 1.6 to 53.9; P = 0.014), and this factor was still significant after adjusting for confounders, including age, sex, BMI, smoking history, and previous tuberculosis (adjusted OR, 26.7; 95% CI, 2.1 to 339.9; P = 0.011) (Table 1).
TABLE 1
TABLE 1 Univariate and multivariate analyses for failure to achieve culture conversion after 12 months of treatment in 38 patients with noncavitary Mycobacterium avium complex pulmonary disease
VariableUnivariate analysisMultivariate analysis
OR (95% CI)P valueAdjusted OR (95% CI)P value
Age1.0 (0.9–1.1)0.30622.4 (0.4–1188.4)0.125
Male3.1 (0.6–15.1)0.1680.9 (0.9–1.1)0.986
Body mass index1.0 (0.8–1.3)0.9240.8 (0.5–1.2)0.279
Never smoker1.4 (0.2–8.7)0.7370.1 (0.003–6.4)0.303
Previous tuberculosis0.3 (0.03–3.1)0.3280.2 (0.01–2.4)0.178
Sputum AFBa smear positivity9.2 (1.6–53.9)0.01426.7 (2.1–339.9)0.011
a
AFB, acid-fast bacilli.
This study evaluated the treatment outcomes of a two-drug (azithromycin and ethambutol) intermittent therapy regimen for noncavitary MAC-PD. After 12 months of treatment, sputum culture conversion was achieved in 76% (29/38) of the patients, and AFB smear positivity was the independent risk factor for failure to achieve sputum culture conversion.
Intermittent treatment has been recommended for the noncavitary nodular bronchiectatic form of MAC-PD (3), and a three-drug intermittent regimen showed higher treatment adherence than and similar treatment outcomes to a daily regimen (5). In the current study, the culture conversion rate of two-drug intermittent therapy was 76% (29/38), which was comparable with three-drug daily (76% [75/99]) and three-drug intermittent (67% [79/118]) treatment outcomes from a previous study (5). Our study suggested that sputum smear positivity was associated with unfavorable outcomes, and the result was consistent with a previous three-drug intermittent treatment study (5).
The role of rifampin in the treatment of MAC-PD is controversial. The cornerstones of MAC-PD treatment were a macrolide plus ethambutol, and rifampin was recommended as a usual companion drug (3). However, evidence showed that coadministration of rifampin was associated with a lower macrolide concentration (8, 9, 12, 13), and one study suggested that a higher peak plasma concentration of azithromycin was associated with favorable outcomes in MAC-PD (12). A previous study on the efficacy of two-drug (clarithromycin and ethambutol) daily treatment suggested that it was not inferior to daily treatment with three drugs and had fewer drug adverse events (14). Similarly, our study showed the efficacy of two-drug (azithromycin and ethambutol) intermittent treatment in noncavitary MAC-PD, and further studies of two-drug treatment without rifampin are needed.
In conclusion, two-drug (azithromycin and ethambutol) intermittent treatment may be an optional regimen in the treatment of noncavitary MAC-PD, especially in patients who cannot tolerate rifamycin. Furthermore, large-cohort and long-term comparative studies are warranted.

ACKNOWLEDGMENTS

This work was supported by the National Research Foundation of Korea (NRF) funded by the South Korean government (MSIT) (NRF-2018R1A2A1A05018309).
We have no conflicts of interest to declare.

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Jeong BH, Jeon K, Park HY, Moon SM, Kim SY, Lee SY, Shin SJ, Daley CL, Koh WJ. 2016. Peak plasma concentration of azithromycin and treatment responses in Mycobacterium avium complex lung disease. Antimicrob Agents Chemother 60:6076–6083.
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Information & Contributors

Information

Published In

cover image Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Volume 64Number 120 December 2019
eLocator: 10.1128/aac.01787-19

History

Received: 31 August 2019
Returned for modification: 26 September 2019
Accepted: 10 October 2019
Published online: 20 December 2019

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Keywords

  1. macrolide
  2. ethambutol
  3. intermittent therapy
  4. Mycobacterium avium complex

Contributors

Authors

Seong Mi Moon
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
In Young Yoo
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Hee Jae Huh
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Nam Yong Lee
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Byung Woo Jhun
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Notes

Address correspondence to Byung Woo Jhun, [email protected].

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