Original Article
The association between erythromycin monotherapy for Mycobacterium avium complex lung disease and cross-resistance to clarithromycin: A retrospective case-series study

https://doi.org/10.1016/j.jiac.2017.12.008Get rights and content

Abstract

Long-term, low-dose erythromycin monotherapy, based on the anti-inflammatory effects of macrolides, has been reported to have the potential to suppress the exacerbation of Mycobacterium avium complex (MAC) lung disease with less toxicity. It remains unclear whether erythromycin monotherapy induces cross-resistance to clarithromycin, a key drug for MAC. To clarify this point, we conducted a retrospective, single-center, case-series study on patients with MAC lung disease who underwent erythromycin monotherapy for at least 6 months. Drug susceptibility tests, before and after erythromycin treatment initiation, were analyzed. Thirty-three patients were included in our study. All 33 patients showed susceptibility to clarithromycin for MAC both before and after erythromycin monotherapy. There was no significant difference in clarithromycin minimum inhibitory concentrations between before and after erythromycin treatment (median difference = 0 μg/ml; P = .313, Wilcoxon's signed-rank test). We conclude that erythromycin monotherapy for MAC lung disease may not induce cross-resistance to clarithromycin.

Introduction

Mycobacterium avium complex (MAC) can cause chronic and progressive lung infection, and MAC lung disease (MAC-LD) is increasing worldwide [1], [2]. Although multidrug chemotherapy, including clarithromycin, is the standard treatment for MAC-LD, this requires a long treatment period and often causes drug-related toxicities. The efficacy of standard therapy is not sufficient to cure MAC-LD completely, but rather, is mainly prescribed to suppress exacerbation in clinical practice. Moreover, some patients with MAC-LD show a long-term stable or slowly progressive course without intensive chemotherapy. For these reasons, the timing of multidrug chemotherapy initiation is controversial. For mild MAC-LD patients, treatments less intensive than the standard multidrug treatment, and alternative, well-tolerated chemotherapies may be useful to control symptoms and suppress exacerbation for MAC-LD in clinical practice.

Macrolides have anti-inflammatory effects and are often used to treat chronic pulmonary inflammatory diseases such as diffuse panbronchiolitis, cystic fibrosis, asthma, bronchiectasis, and chronic obstructive pulmonary disease, conferring beneficial effects to patients [3], [4], [5]. A retrospective study reported that long-term, low-dose erythromycin monotherapy may potentially suppress the exacerbation of MAC-LD, with well-tolerated adverse events [6].

To date, clarithromycin and azithromycin are the only antimicrobial agents demonstrated to be effective in treating MAC-LD, both in vitro and in clinical practice [7]. Macrolides are known to produce cross-resistance among pathogens such as Streptococcus pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori [8], [9], [10]. A randomized prospective study among MAC patients with autoimmune deficiency syndrome (AIDS) treated by clarithromycin monotherapy showed that 46% of these patients acquired resistance to clarithromycin 4 months after treatment [11]. Once MAC patients acquire clarithromycin-resistance, the treatment prognosis becomes poor [12]. Consequently, clarithromycin monotherapy is strictly prohibited. In contrast, erythromycin monotherapy is highly unlikely to induce cross-resistance to clarithromycin. A study reported that the rate of response to multidrug regimens after erythromycin monotherapy for MAC-LD was comparable to control patients naïve to erythromycin treatment [6]. Among them, 4 out of 31 patients showed susceptibility to clarithromycin after erythromycin monotherapy. Drug susceptibility tests after erythromycin monotherapy have not been widely investigated. It remains unclear whether the clarithromycin minimum inhibitory concentrations (MICs) for MAC after erythromycin treatment change.

Therefore, in the present study, we aimed to clarify whether erythromycin monotherapy for MAC-LD induces cross-resistance to clarithromycin, by reviewing the clarithromycin MICs for MAC reported before and after erythromycin monotherapy in a select group of Japanese patients.

Section snippets

Study subjects

A retrospective, single-center, case-series study was conducted between July 2008 and April 2017 at the Department of Respiratory Medicine, National Hospital Organization, National Toneyama Hospital (Osaka, Japan). The study included patients who met the diagnostic criteria for MAC-LD of the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) of 2007, and had received oral erythromycin monotherapy for at least 6 months. Moreover, patients who twice received drug

Enrolment of study subjects and characteristics

A total of 110 MAC-LD patients received erythromycin monotherapy at a dose of 200–600 mg/day for more than 6 months during the study period. Of them, 41 patients were tested twice for drug susceptibility to clarithromycin for MAC. Among them, 8 patients were excluded because they showed resistance to clarithromycin at the first drug susceptibility test. Ultimately, 33 patients were investigated (Fig. 1). The baseline characteristics of the study subjects are shown in Table 1. Nineteen patients

Discussion

This is the first study to investigate the association between erythromycin monotherapy for MAC-LD and cross-resistance to clarithromycin by comparing MICs before and after treatment initiation. As expected, our results suggest that erythromycin monotherapy does not induce cross-resistance to clarithromycin for treatment of MAC. Another study had reported that the rate of response to standard chemotherapy, including clarithromycin for MAC-LD, after erythromycin monotherapy was comparable to

Authorship statement

All authors meet the ICMJE authorship criteria.

Conflicts of interest

None.

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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