Challenges in the Management of Mycobacterium abscessus Complex

A group of mycobacteria that usually produce mature growth on media plates within 7 days are collectively called rapidly growing mycobacteria (RGM). Mycobacterium abscessus complex (MABC) is one of the most commonly isolated RGM in respiratory specimens and also the most pathogenic organism in the group.^1,2,3 Since the discovery of M abscessus in 1952, the taxonomy and nomenclature has been changed multiple times. Now there are 3 proposed subspecies based on genomic sequencing: M abscessus subspecies (subsp) abscessus, M abscessus subsp bolletii, and M abscessus subsp massiliense. Because they are closely related, these entities are not distinguished at the subspecies level in clinical laboratories; as a result, the 3 subspecies are often reported combined as MABC, not individual subspecies. M abscessus is the third most frequently isolated nontuberculous mycobacteria (NTM) pulmonary pathogen in the United States.⁴ Of the complex subspecies, subsp abscessus is generally most common; however, considerable geographic variations exist, with subsp massiliense being more prevalent in South Korea and Taiwan.⁵

MABC causes pulmonary and extrapulmonary diseases including skin and soft tissue infections, bacteremia, and disseminated disease in immunocompromised hosts. It is highly resistant to most oral antimicrobials, which makes long-term treatment complex and difficult.

PRESENTATION

1. Pulmonary

The lungs are most commonly affected by NTM, with M abscessus being the most common cause of lung disease.⁶ MABC is seen in patients with underlying structural lung disease such as cystic fibrosis, bronchiectasis, prior tuberculosis, pulmonary alveolar proteinosis, and esophageal motility disorders.^4,7 Alpha-1 antitrypsin phenotypes and abnormal cystic fibrosis genotypes increase the risk for NTM infection.⁷ The median age of onset is around 50 years, with women being more often affected. The most common symptoms seen are chronic cough, sputum production, fatigue, weight loss, and hemoptysis.⁷ The common findings in chest x-ray are reticulonodular, mixed interstitial-alveolar opacities with a right upper lobe predominance; multilobar patchy opacities; and, less frequently, cavitation.^4,7 High-resolution CT can show cylindrical bronchiectasis and small nodules of less than 5 mm.⁷

The diagnosis based on American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines from 2007 requires the fulfillment of clinical (clinical symptoms, radiological evidence, and exclusion of other diseases) and microbiological criteria. Isolation of the species from the respiratory specimen culture from at least 2 separate cultures is collected over an interval of a week or more.^7,8 Bronchoscopy is offered to patients with high suspicion of having NTM lung disease from whom the respiratory culture cannot be obtained.⁸ Treatment with antimicrobials with surgical resection of the localized disease has been shown to elicit more sustained microbiologic response than antimicrobials alone.^4,7 MABC infection can cause complications (soft tissue and mediastinal abscess) in patients who undergo lung transplant, thereby requiring assessment for NTM pulmonary disease before lung transplant evaluation.⁹ Pretransplant MABC isolation can be a risk factor for posttransplant MABC lung disease.⁴ Persistent MABC infection despite treatment is not an absolute contraindication for lung transplant.

2. Skin and soft tissue infections

Skin and soft tissue infection (SSTI) caused by MABC usually follows accidental trauma or surgery in a variety of clinical settings. The manifestation can range from simple nodules, ulcer, and abscess to deep-seated infections.⁴ These can occur through direct contact of areas with skin breakdown with contaminated sources or through metastatic deposit from disseminated disease.⁴ More common presentation is a nosocomial infection after a surgical procedure, including cosmetic procedures, augmentation mammaplasty, tattooing, acupuncture, and corneal infections after laser in situ keratomileusis.^4,6 M abscessus subsp massiliense is the most common isolate in postsurgical SSTIs.⁴

3. Disseminated disease and bacteremia

Bacteremia caused by MABC is most often associated with intravenous catheter placement.⁴ Intravenous drug use has also been associated with endocarditis and disseminated disease, specifically in patients with prosthetic valves, and it portends a high mortality.^10-12 Disseminated disease could be a manifestation of immunologic defect, either acquired, such as through HIV and anti–interferon-γ antibody formation, or genetic, caused by defects in the interferon-γ or IL-12 pathway genes.^7,13

DIAGNOSIS

Diagnosis of infection is straightforward when MABC is recovered from a normally sterile site such as blood, whereas isolation of MABC in respiratory specimens does not necessarily indicate disease. NTM/MABC are ubiquitous in the environment. Isolation of NTM in respiratory specimens can be due to environmental contamination or respiratory colonization, hence the significance of MABC isolated in sputum should be carefully evaluated. The ATS/IDSA guidelines include the criteria for diagnosis of NTM pulmonary disease (see pulmonary section).

DRUG RESISTANCE AND SUSCEPTIBILITY TEST

Identification to the subspecies level is critical, for it is generally correlated with treatment outcomes.8 Although MABC can be identified by DNA/DNA hybridization or single gene sequencing, a wide-array genomic sequencing is more discriminative.⁸ A drug susceptibility test is also essential to guide treatment, as there is heterogeneity in the resistance profile.⁸ M abscessus subsp abscessus and bolletii possess 2 mechanisms that confer resistance to macrolides: inducible erythromycin ribosomal methylase, or the erm (41) gene, and the acquired mutational resistance in the 23S ribosomal RNA gene. Both subsp abscessus and bolletii carry a functional erm(41) gene, whereas subsp massiliense has a nonfunctional copy of the gene, thereby rendering this subspecies susceptible to macrolides.14 The inducible macrolide resistance can be screened by prolonged incubation in the presence of a macrolide for up to 14 days or through molecular detection and characterization of the erm (41) gene.^7,8,14 The ATS/IDSA guidelines recommend susceptibility test panels including amikacin, cefoxitin, imipenem, clarithromycin, linezolid, doxycycline, tigecycline, ciprofloxacin, and moxifloxacin for MABC. The Clinical and Laboratory Standards Institute set minimal inhibitory concentration cutoffs for RGM in general, and the AST/IDSA guidelines recommend choosing antibiotics based on the in vitro susceptibility tests. However, strong clinical relevance of such strategy was established only for macrolides.^8,14

TREATMENT

MABC isolates are uniformly resistant to standard antituberculous drugs and to most oral antibiotics. Macrolides are a cornerstone of therapy as they possess potent activity against MABC as well as immunomodulatory effects. The ATS/ IDSA guidelines for treatment of NTM pulmonary disease recommend a macrolide-containing multidrug treatment regimen for MABC strains without inducible or mutational macrolide resistance. A macrolide-containing regimen is also recommended for strains with macrolide resistance for its immunomodulatory properties, although a macrolide is not counted as an active drug in the multidrug regimen.⁸ Macrolide-containing multidrug regimens demonstrated higher sputum culture conversion rates: 34% with M abscessus subsp abscessus compared with 54% with subsp massiliense.⁸ Therefore, a critical step is the differentiation of the MABC into its subspecies, as this informs treatment decisions.^4,8

The multidrug regimen should include at least 3 active drugs guided by in vitro susceptibility. The regimen includes combination therapy of 1 or 2 intravenous agents (amikacin 10-15 mg/kg/day, cefoxitin 2-4 g two to three times/day, imipenem 500-1000 mg every 6-12 hours, or tigecycline 50 mg/day) and 2 oral agents (azithromycin 250 mg/day, clofazimine 100-200 mg/day, omadacycline 300 mg/day, linezolid 600 mg/day or tedizolid 200 mg/day, bedaquiline 400 mg/day for 2 weeks, then 200 mg 3 times a week).¹⁴ Clarithromycin 1000 mg/day can also be used, but there is evidence that azithromycin is more effective.¹⁵ Amikacin is generally the most active parenteral drug but its use is limited by nephrotoxicity and ototoxicity. Notably, MABC has low MICs to tigecycline but there are no established cutoffs for susceptibility.¹⁶ Clofazimine has also been found to be useful as it saturates the reticuloendothelial system while having low MICs; however, clofazimine is not commercially available in the United States, and its procurement restrictions hamper widespread usage.^17,18 Omadacycline showed a favorable outcome in the recent retrospective review that included 36 participants. Omadacycline monotherapy for 4 months was well tolerated and achieved microbiologic cure in 25% of the patients.¹⁹ Tedizolid demonstrated lower MICs for MABC, but its clinical efficacy and safety have not been established. Surgical resection can be used in select patients with MABC pulmonary disease.

DURATION

Due to data scarcity, the optional duration of therapy for MABC has not yet been established. The ATS/IDSA guidelines suggest that either a shorter or longer treatment regimen be used and expert consultation obtained.⁸ The British Thoracic Society recommends a 4-week intensive induction phase with amikacin, tigecycline, and imipenem followed by a 12-month continuation phase, depending on susceptibilities.²⁰ Duration of therapy is currently based on expert opinion and type of infection (more prolonged for cerebral or disseminated infection). Notably, longer treatment regimens become difficult to tolerate with certain antibiotics such as amikacin as previously described, tigecycline (considerable nausea and vomiting), and linezolid (bone marrow suppression).¹⁷ Some experts use intermittent courses of multidrug therapy instead of transitioning to a longer continuation phase. For pulmonary infections, one article describes 12 months for negative cultures, 4 months for soft tissue infection, 12 months for cerebral infection, 4 weeks for bacteremia in central line–associated blood stream infection, and 6 weeks to 6 months for ocular infections.²¹ MABC are ubiquitous in soil and water environments. Patients with underlying structural lung abnormalities are at high risk for reinfection after adequate treatment. Long-term monitoring after discontinuation of the therapy is warranted.

FUTURE DIRECTIONS

MABC mechanisms of resistance continue to be elucidated. For example, β-lactam resistance is mediated by BlaMab, which is not inhibited by the classic β-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam. Avibactam is a new, non–β-lactam, β-lactamase inhibitor, active against BlaMab. Data from in vitro studies show BlaMab is inhibited by avibactam, so combining imipenem with the β-lactamase inhibitors could be a future option. M abscessus subsp Massiliense harbors BlaMmas, which exhibits not only β-lactamase activity but also mild carbapenemase activity. It is structurally similar to other carbapenemases found in Klebsiella pneumoniae carbapenemase-2 (KPC-2) and Serratia fonticola carbapenemase (SFC-1).²² In addition, less toxic members of the tetracycline class including oral omadacycline could also represent a new option. Bedaquiline, which is used as a mycobacterial ATP synthase inhibitor for drug-resistant tuberculosis, is another potential treatment, but data are scant. And, there are reports of antagonism between bedaquiline and β-lactams.¹⁷


References

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