Macrolide-resistant Mycobacterium Avium Complex Research Articles

In vitro and intracellular activities of novel thiopeptide derivatives against macrolide-susceptible and macrolide-resistant Mycobacterium avium complex.

Unsatisfactory outcomes following long-term multidrug treatment in patients with Mycobacterium avium complex (MAC) pulmonary disease have urged us to develop novel antibiotics. Thiopeptides, a class of peptide antibiotics derived from natural products, have potential as drug candidates that target bacterial ribosomes, but drug development has been hampered due to their extremely poor solubility. Here, we evaluated three new compounds (AJ-037, AJ-039, and AJ-206) derived from the thiopeptide micrococcin P2 with enhanced aqueous solubility; the derivatives were generated based on structure-activity relationship analysis. We conducted in vitro drug susceptibility and intracellular antimycobacterial activity testing of the three thiopeptide derivatives against various MAC strains, including macrolide-resistant MAC clinical isolates. These compounds showed low MICs against MAC, similar to that of clarithromycin (CLR). In particular, two compounds, AJ-037 and AJ-206, had intracellular antimycobacterial activities, along with synergistic effects with CLR, and inhibited the growth of MAC inside macrophages. Moreover, these two compounds showed in vitro and intracellular anti-MAC activities against macrolide-resistant MAC strains without showing cross-resistance with CLR. Taken together, the results of the current study suggest that AJ-037 and AJ-206 can be promising anti-MAC agents for the treatment of MAC infection, including for macrolide-resistant MAC strains. IMPORTANCE Novel antibiotics for the treatment of MAC infection are urgently needed because the treatment outcomes using the standard regimen for Mycobacterium avium complex (MAC) pulmonary disease remain unsatisfactory. Here, we evaluated three novel thiopeptide derivatives (AJ-037, AJ-039, and AJ-206) derived from the thiopeptide micrococcin P2, and they were confirmed to be effective against macrolide-susceptible and macrolide-resistant MAC. Our thiopeptide derivatives have enhanced aqueous solubility through structural modifications of poorly soluble thiopeptides. The thiopeptide derivatives showed minimal inhibitory concentrations against MAC that were comparable to clarithromycin (CLR). Notably, two compounds, AJ-037 and AJ-206, exhibited intracellular antimycobacterial activities and acted synergistically with CLR to hinder the growth of MAC within macrophages. Additionally, these compounds demonstrated in vitro and intracellular anti-MAC activities against macrolide-resistant MAC strains without showing any cross-resistance with CLR. We believe that AJ-037 and AJ-206 can be promising anti-MAC agents for the treatment of MAC infections, including macrolide-resistant MAC strains.

Monotherapy: Key cause of macrolide-resistant Mycobacterium avium complex disease

BackgroundMacrolide-resistant Mycobacterium avium complex (MAC) disease is very difficult to cure. Macrolide-resistance emerges in patients and is largely preventable by appropriate screening and treatment practices. MethodsPatients with macrolide-resistant MAC isolates between March 2019 and March 2022 were retrieved from the mycobacteriology reference laboratory database at Radboudumc, Nijmegen, the Netherlands. Clinical consultation reports were extracted from the database to assess the cause of macrolide resistance. ResultsSixteen patients with macrolide-resistant MAC disease were included, from a total of 815 patients with MAC isolates (2%); Macrolide monotherapy in bronchiectasis or CF was the most frequent cause of development of macrolide-resistance MAC disease (n = 8; 50%). Short (n = 3; mean duration 9 months, range 6–12) or guideline non-compliant (n = 2) treatment regimens and patient non-adherence (n = 2) were other key causes of macrolide-resistance. ConclusionsMacrolide monotherapy after inappropriate screening is the most frequent cause of macrolide-resistant Mycobacterium avium complex disease in the Netherlands. Educational efforts are needed to prevent this.

A Rapid Screening Assay for Clarithromycin-Resistant Mycobacterium avium Complex Using Melting Curve Analysis with Nonfluorescent Labeled Probes.

Mycobacterium avium complex (MAC) thrives in various environments and mainly causes lung disease in humans. Because macrolide antibiotics such as clarithromycin or azithromycin are key drugs for MAC lung disease, the emergence of macrolide-resistant strains prevents the treatment of MAC. More than 95% of macrolide-resistant MAC strains are reported to have a point mutation in 23S rRNA domain V. This study successfully developed a melting curve assay using nonfluorescent labeled probes to detect the MAC mutation at positions 2058 to 2059 of the 23S rRNA gene (AA genotype, clarithromycin susceptible; TA, GA, AG, CA, AC, and AT genotypes, clarithromycin resistant). In the AA-specific probe assay, the melting peak of the DNA fragment of the AA genotype was higher than that of DNA fragments of other genotypes. Melting temperature (Tm) values of the AA genotype and the other genotypes were about 80°C and 77°C, respectively. DNA fragments of each genotype were identified correctly in six other genotype-specific probes (TA, GA, AG, CA, AC, and AT) assays. Using genomic DNA from six genotype strains of M. avium and four genotype strains of M. intracellulare, we confirmed that all genomic DNAs could be correctly identified as individual genotypes according to the highest Tm values among the same probe assays. These results indicate that this melting curve-based assay is able to determine MAC genotypes at positions 2058 to 2059 of the 23S rRNA gene. This simple method could contribute to the rapid detection of clarithromycin-resistant MAC strains and help to provide accurate drug therapy for MAC lung disease. IMPORTANCE Since macrolide antibiotics such as clarithromycin or azithromycin are key drugs in multidrug therapy for Mycobacterium avium complex (MAC) lung diseases, the rapid detection of macrolide-resistant MAC strains has important implications for the treatment of MAC. Previous studies have reported a correlation between drug susceptibility testing and the mutation of macrolide resistance genes. In this study, we developed a novel melting curve-based assay using nonfluorescent labeled probes to identify both clarithromycin-resistant M. avium and M. intracellulare with mutations in the 23S rRNA gene, which is the clarithromycin or azithromycin resistance gene. This assay contributed to not only the detection of MAC mutations but also the determination of all genotypes at positions 2058 to 2059 of the 23S rRNA gene. Furthermore, because nonfluorescent labeled probes are used, this assay is more easily and more immediately available than other methods.

The Association of Long-term Macrolide Therapy and Nontuberculous Mycobacterial Culture Positivity in Patients With Bronchiectasis

The Association of Long-term Macrolide Therapy and Nontuberculous Mycobacterial Culture Positivity in Patients With Bronchiectasis

Macrolide resistant Mycobacterium avium complex pulmonary disease following clarithromycin and ethambutol combination therapy.

Whether two-drug therapy (clarithromycin and ethambutol) for Mycobacterium avium complex (MAC) pulmonary disease contributes to the development of macrolide-resistant MAC is unclear. To compare the incidence of macrolide-resistant MAC between patients treated with two-drug therapy (clarithromycin and ethambutol) and the standard three-drug therapy (clarithromycin, ethambutol, and rifampicin) for MAC pulmonary disease. We retrospectively reviewed 147 patients with treatment-naive MAC pulmonary disease who had received two-drug therapy (n=47) or three-drug therapy (n=100) between 1997 and 2016at National Hospital Organization, Tenryu Hospital, Hamamatsu, Japan. The risk of development of macrolide-resistant MAC was evaluated by calculating the cumulative incidence rate using Gray's test. The median follow-up period was 74.5 months. During the follow-up period, one of the 47 patients (2.1%) in the two-drug group developed macrolide-resistant MAC, compared to 12 of the 100 patients (12.0%) in the three-drug group. The cumulative incidence rate of macrolide-resistant MAC was lower in the two-drug group than in the three-drug group (0.0023; 95% confidence interval, 0.002 to 0.107 versus 0.200; 95% confidence interval, 0.100 to 0.324, p=0.0593). These results suggest that two-drug treatment with clarithromycin and ethambutol for MAC pulmonary disease does not lead to a higher incidence of resistance acquisition to clarithromycin than the standard three-drug treatment.

Effective treatment for clarithromycin-resistant Mycobacterium avium complex lung disease

Clinical management of macrolide-resistant Mycobacterium avium complex (MR-MAC) lung disease is difficult. To date, there only exist a limited number of reports on the treatment of clarithromycin-resistant MAC (CR-MAC) lung disease. This study aimed to evaluate prognostic factors and identify effective treatments in CR-MAC lung disease. We retrospectively collected clinical data of patients newly diagnosed with CR-MAC lung disease at the Kinki-Chuo Chest Medical Center between August 2010 and June 2018. Altogether, 37 patients with CR-MAC lung disease were enrolled. The median age was 69 years; 30, 22, and 21 patients received clarithromycin, ethambutol, and rifampicin, respectively, on their own or in drug combination. The observed sputum culture conversion rate was 29.7% (11/37 patients). In univariate analysis, ethambutol significantly increased the rate of sputum culture conversion (p = 0.027, odds ratio (OR) 10; 95% confidence interval (CI) 1.11–89.77). Multivariate analysis confirmed that ethambutol increased sputum culture conversion rate (p = 0.026; OR 21.8; 95% CI 1.45–329) while the existence of lung cavities decreased it (p = 0.04; OR 0.088; 95% CI 0.009–0.887). The combined use of ethambutol with other drugs may improve sputum culture conversion rate in CR-MAC lung disease.

Clinical characteristics and treatment outcomes of patients with macrolide-resistant Mycobacterium avium complex pulmonary disease: a systematic review and meta-analysis

BackgroundMacrolide is a key drug in the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). Macrolide-resistant MAC is gaining importance, but there are little data in clinical characteristics and treatment outcomes of macrolide-resistant MAC-PD (MR-MAC-PD).MethodsWe performed a systematic review and meta-analysis of published studies reporting clinical characteristics and treatment outcomes of patients with MR-MAC-PD. Risk of bias was assessed using the modified Newcastle-Ottawa Scale.ResultsNine studies (seven retrospective and two prospective) comprising 319 patients were identified through a database search. Around 73% were women, and 52% had the fibrocavitary form. Pooled sputum culture conversion rate after combined multiple antibiotics or surgical resection was 21% (95% confidence interval [CI], 14–30%), and the one-year all-cause mortality was 10% (95% CI, 5–20%). There was no significant difference in treatment outcomes between nodular bronchiectatic and fibrocavitary types.ConclusionsEven combination therapy with fluoroquinolone, aminoglycoside, and surgical resection, the treatment outcomes of MR-MAC-PD were poor. The investigation of new treatment modalities is urgent.

Treatment of Mycobacterium avium Complex Pulmonary Disease.

The pathogen Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial pulmonary disease worldwide. The decision to initiate long-term antibiotic treatment is difficult for the physician due to inconsistent disease progression and adverse effects associated with the antibiotic treatment. The prognostic factors for the progression of MAC pulmonary disease are low body mass index, poor nutritional status, presence of cavitary lesion(s), extensive disease, and a positive acid-fast bacilli smear. A regimen consisting of macrolides (clarithromycin or azithromycin) with rifampin and ethambutol has been recommended; this regimen significantly improves the treatment of MAC pulmonary disease and should be maintained for at least 12 months after negative sputum culture conversion. However, the rates of default and disease recurrence after treatment completion are still high. Moreover, treatment failure or macrolide resistance can occur, although in some refractory cases, surgical lung resection can improve treatment outcomes. However, surgical resection should be carefully performed in a well-equipped center and be based on a rigorous risk-benefit analysis in a multidisciplinary setting. New therapies, including clofazimine, inhaled amikacin, and bedaquiline, have shown promising results for the treatment of MAC pulmonary disease, especially in patients with treatment failure or macrolide-resistant MAC pulmonary disease. However, further evidence of the efficacy and safety of these new treatment regimens is needed. Also, a new consensus is needed for treatment outcome definitions as widespread use of these definitions could increase the quality of evidence for the treatment of MAC pulmonary disease.

Macrolide-Resistant Mycobacterium avium Complex Lung Disease: Analysis of 102 Consecutive Cases.

The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital. Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

Clinical Characteristics, Treatment Outcomes, and Resistance Mutations Associated with Macrolide-Resistant Mycobacterium avium Complex Lung Disease.

Macrolide antibiotics are key components of the multidrug treatment regimen for treating lung disease (LD) due to Mycobacterium avium complex (MAC). Despite the emergence of macrolide resistance, limited data are available on macrolide-resistant MAC-LD. This study evaluated the clinical features and treatment outcomes of patients with macrolide-resistant MAC-LD and the molecular characteristics of the macrolide-resistant isolates. A retrospective review of the medical records of 34 patients with macrolide-resistant MAC-LD who were diagnosed between January 2002 and December 2014 was performed, along with genetic analysis of 28 clinical isolates. Nineteen (56%) patients had the fibrocavitary form of MAC-LD, and 15 (44%) had the nodular bronchiectatic form. M. intracellulare was the etiologic organism in 21 (62%) patients. Approximately two-thirds (22/34 [65%]) of the patients had been treated with currently recommended multidrug regimens that included macrolide, ethambutol, and rifamycin prior to the emergence of macrolide resistance, and none had been treated with macrolide monotherapy. The median duration of treatment after the detection of macrolide resistance was 23.0 months (interquartile range, 16.8 to 45.3 months). Treatment outcomes were poor after the development of macrolide resistance, with favorable treatment outcomes achieved in only five (15%) patients, including two patients who underwent surgical resection. One-, 3-, and 5-year mortality rates were 9, 24, and 47%, respectively. Molecular analysis of 28 clinical isolates revealed that 96% (27/28) had point mutations at position 2058 or 2059 of the 23S rRNA gene. Our analyses indicate that more effective therapy is needed to treat macrolide-resistant MAC-LD and prevent its development.

Current Opinions in the Treatment of Pulmonary Nontuberculous Mycobacteria in Non-Cystic Fibrosis Patients: Mycobacterium abscessus Group, Mycobacterium avium Complex, and Mycobacterium kansasii

Treatment of pulmonary infections caused by Mycobacterium avium complex (MAC) and Mycobacterium kansasii involves multidrug oral therapy with a macrolide (azithromycin or clarithromycin), ethambutol, and a rifamycin (rifampin or rifabutin). Patients with M. kansasii rapidly respond to a regimen of intermittent (three times weekly) or daily administration of this three-drug regimen. Patients with MAC respond more slowly and often require adjustment of the multidrug regimen because of drug intolerance. The usual treatment for patients with MAC nodular disease takes 15–18 months, with a goal of 12 months of negative cultures. Recent studies support the use of a three-times weekly oral treatment regimen for patients with macrolide-susceptible nodular MAC disease. Patients with upper lobe fibro-cavitary MAC, macrolide-resistant MAC, or severe nodular bronchiectatic disease are usually treated with a daily multidrug regimen supplemented with an injectable antibiotic (amikacin or streptomycin) or, most recently, inhaled preparations of amikacin. Patients with cavitary changes and/or those with macrolide-resistant isolates are often associated with poor treatment response and may require surgical resection in addition to their drug therapy. In contrast to patients with lung disease due to MAC and M. kansasii, the presence of a functional erythromycin ribosomal methylase (erm) gene in the majority of isolates of Mycobacterium abscessus (M. abscessus subsp. abscessus) blocks the activity of macrolides and precludes an effective oral drug regimen for most of these patients. Treatment regimens for macrolide-resistant M. abscessus require long-term intravenous access and parenteral drug combinations of amikacin, cefoxitin, imipenem, and/or tigecycline. Because of the inconvenience of dosing cefoxitin, a regimen of imipenem and amikacin may be preferred. Cure with these agents is infrequent because of the long-term toxicity and expense of these agents. Other treatment options are currently dismal. The role of newer antimicrobials such as tedizolid and bedaquiline has not been evaluated. Approximately 15 % of isolates of subsp. abscessus and all isolates of subsp. massiliense (infrequent in the USA) have a nonfunctional erm gene and are macrolide susceptible, making an oral macrolide an important treatment component and increasing the likelihood of long-term cure of the infection.

Short Course Antimicrobial Therapy for Adult Patients with Mycobacterium Avium Complex (MAC) Pulmonary Infection: A Pilot Study

Rationale: Patients with pulmonary infections due to Mycobacterium avium complex (MAC) are treated with multiple antimicrobial agents administered simultaneously for a period of at least one year after conversion of sputum cultures from positive to negative. However, this therapy is often poorly tolerated. Additionally, repeat infections upon discontinuation of therapy commonly occur and often necessitate subsequent prolonged courses of therapy. Shorter courses of drug therapy would likely diminish the morbidity of treatment but could potentially result in the development of antibiotic resistance. We hypothesized that a 3 months course of antimicrobial therapy for MAC would not induce macrolide resistance and be well tolerated, while providing clinical benefit to patients. This pilot study was conducted to test this hypothesis in a small number of patients. Methods: We treated adults with MAC pulmonary disease associated with multifocal bronchiectasis and multiple small nodules with a 3 months course of triple antibiotic therapy including a macrolide antibiotic (clarithromycin or azithromycin). The development of macrolide resistance was the primary outcome assessed. Secondary outcomes included drug tolerability, quality of life (QOL) assessments, and temporal changes in pulmonary function tests (PFT) and high resolution computerized tomography (HRCT) scans. Measurements and main results: Thirteen adult patients with MAC pulmonary infection were recruited and begun on antimicrobial therapy; 12 completed 3 months of treatment; 11 had 6 month follow-up. No participant developed evidence of macrolide resistant MAC. HRCT findings at 6 months were stable or improved relative to baseline in most participants (8/11 and 9/11, respectively). The symptom score on the St. George Respiratory Questionnaire (SGRQ) improved at the conclusion of drug administration at 3 months in 10 of 12 patients and there was improvement on the mental subscale of the SF-12 at 6 months. Conclusions: We demonstrated preliminary supporting evidence that a 3 months course of triple drug therapy in adult patients with MAC pulmonary infections does not induce macrolide resistance and that it may be associated with improved QOL and radiographic stability. Implications: A three month course of multiple drug therapy for patients with MAC pulmonary infections may offer an alternative to standard prolonged drug therapy. Subsequent periodic, short courses of therapy may be needed if re-infection occurs.

Therapy of refractory nontuberculous mycobacterial lung disease

The prevalence of nontuberculous mycobacterial (NTM) lung disease is increasing in the USA. Clinicians are therefore encountering these patients with increasing frequency, with the attendant multiple therapeutic challenges presented by NTM lung disease including relatively frequent (compared with tuberculosis) treatment failure. Critical elements for the successful treatment of Mycobacterium avium complex (MAC) lung disease include aggressive first therapeutic attempts and avoidance of the emergence of macrolide-resistant MAC strains, which are associated with worse treatment response and increased mortality. Reliably effective therapy for M. abscessus lung disease remains elusive but still usually requires parenteral agents. Lung resection surgery for selected patients is an important adjunct for both MAC and M. abscessus lung disease. Aside from surgery and parenteral antibiotics, there are very few data to support the efficacy of other drugs or interventions for patients who have failed the first-line therapy. Clinicians who manage NTM lung disease will inevitably encounter patients who fail the first-line therapy. The choices for effective treatment of these patients are depressingly sparse. It is critically important to avoid creation of macrolide-resistant MAC strains and to carefully choose those NTM lung disease patients who will benefit from surgery.

Use of mefloquine in multidrug-resistant Mycobacterium avium complex pulmonary disease in an HIV-negative patient

Mycobacterium avium complex (MAC) is a leading cause of pulmonary disease (PD), even in those with intact immunity, representing about 30% of the cases of pleuropulmonary mycobacterial infection. Based on previous studies, macrolides are the only agents used in the treatment of MAC disease for which there is a correlation between in vitro susceptibility and in vivo (clinical) response. However, resistance develops rapidly if single-agent treatment is used. Data regarding treatment of macrolide-resistant MAC (MRMAC) and multidrug-resistant MAC (MDRMAC) are sparse. A 50-year-old, HIV-negative white man, weighing 53.6 kg, with severe chronic obstructive pulmonary disease and bronchiectasis was initially on treatment for MAC-PD and MRMAC. The patient was followed between 1999 and 2006. His treatment history revealed that in addition to the multiple drugs administered during the course of his illness, thalidomide, interferon-γ, and mefloquine were also administered. The patient died ~7 years later due to respiratory failure and overwhelming infection This case report describes the use of mefloquine as adjunct treatment in an HIV-negative patient with MDRMAC-PD and discusses the associated outcomes of drug resistance.

Therapy of nontuberculous mycobacterial disease

Nontuberculous mycobacterial disease, especially pulmonary disease, is increasingly encountered by clinicians. Therapy of the most common nontuberculous mycobacterial pathogen, Mycobacterium avium complex, improved with the introduction of macrolide-containing regimens, but treatment for this and most other nontuberculous mycobacterial pathogens remains difficult. Treatment trials with macrolide-containing regimens for Mycobacterium avium complex lung disease have yielded generally favorable outcomes. Studies consistently show that in-vitro susceptibility to macrolides remains the only in-vitro susceptibility for Mycobacterium avium complex that correlates with in-vivo response. Patients who have macrolide-resistant Mycobacterium avium complex isolates are much harder to treat and have higher mortality than patients with macrolide-susceptible isolates. Studies also consistently show that patients who fail therapy, even those who remain macrolide susceptible in vitro, are more difficult to treat than patients without previous therapy. There have been no significant treatment advances for Mycobacterium avium complex lung disease, and nontuberculous mycobacterial disease in general, since the advent of the newer macrolides. It has become clear that the best opportunity for treatment success is the first treatment effort. It is also clear that protection against the emergence of macrolide-resistant Mycobacterium avium complex isolates is critically important. For further progress in the treatment of these pathogens, new and more active drugs must be developed.

EDP-420, a bicyclolide (bridged bicyclic macrolide), is active against Mycobacterium avium.

Infection caused by Mycobacterium avium complex (MAC) is common in patients with immunosuppression, such as AIDS, and deficiencies of gamma interferon and interleukin-12, as well as patients with chronic lung diseases. Treatment of MAC disease is limited since few drugs show in vivo activity. We tested a new bridged bicyclic macrolide, EDP-420, against MAC in vitro and in beige mice. EDP-420 was inhibitory in vitro at a concentration ranging from 2 to 8 microg/ml (MIC(50) of 4 microg/ml and MIC(90) of 8 microg/ml). In macrophages, EDP-420 was inhibitory at 0.5 microg/ml, suggesting that the drug concentrates intracellularly. Mice infected with macrolide-susceptible MAC strain 101 were given 100 mg of EDP-420/kg of body weight daily for 4 weeks and showed a significant reduction in the number of bacteria in both liver and spleen which was greater than the reduction observed with clarithromycin treatment at the same dose (P < 0.05). However, macrolide-resistant MAC 101 did not respond to EDP-420 treatment. A combination of EDP-420 with mefloquine was shown to be indifferent; mefloquine alone was active against macrolide-resistant MAC. The frequency of resistance to EDP-420 in MAC 101 was 10(-9), which is significantly less than the emergence of resistance to clarithromycin, approximately 10(-7) (P < 0.05). Further evaluation of EDP-420 in the treatment of MAC disease is warranted.

Clinical and Molecular Analysis of Macrolide Resistance in Mycobacterium avium Complex Lung Disease

The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known. Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease. Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates. We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted). Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.

Effect of ethambutol on emergence of clarithromycin-resistant Mycobacterium avium complex in the beige mouse model.

An animal model was developed for studying macrolide-resistant Mycobacterium avium complex (MAC) and to measure the effect of ethambutol on resistance. MAC-infected beige mice were given clarithromycin daily; the frequency of clarithromycin-resistant MAC after 8 and 12 weeks was 10(-3) and 10(-2), respectively. Combined ethambutol plus clarithromycin did not increase anti-MAC activity, but clarithromycin-resistant MAC was less frequent (P < .05). The frequency of clarithromycin-resistant MAC in mice receiving the combination was significantly higher than that in untreated mice. These results are consistent with two human trials, which showed that adding ethambutol reduced the frequency of clarithromycin-resistant MAC. Results of the present study suggest that with an initially high level of MAC infection, the addition of ethambutol may only delay resistance. This mouse test system will be useful for investigating the influence of the level of MAC infection and the effect of other drugs on the frequency of resistant MAC.