Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria

Abstract

Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacterium kansasii) and rapid growers (e.g. Mycobacterium abscessus, Mycobacterium fortuitum). In general, drug treatment is long, costly, and often associated with drug-related toxicities; outcome of drug treatment is poor and is likely related to the high levels of natural antibiotic resistance in NTM. The role of drug susceptibility testing (DST) in the choice of agents for antimicrobial treatment of NTM disease, mainly that by slow growers, remains subject of debate. There are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo. In part, these discrepancies derive from laboratory technical issues. There is still no consensus on a standardized method. With the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. This review provides a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods for testing susceptibility in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance.

Introduction

Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. Pulmonary infections are most frequent and tend to affect patients with pre-existing pulmonary diseases. Cervicofacial lymphadenitis is the second most common and relatively benign manifestation and affects immunocompetent children. In severely immunocompromised patients, NTM can cause localized extrapulmonary or disseminated disease. NTM can be acquired by inhalation, ingestion or direct inoculation in the skin (Griffith et al., 2007).

Treatment of infections caused by NTM is either by surgery, drug therapy, or both. Drug therapy of NTM disease is long, costly, and often associated with drug-related toxicities. The treatment regimens differ by species with the most important distinction being that between slow and rapid growing NTM (see Table 1). For most slow growers, the recommended regimen consists of rifampicin (or rifabutin), ethambutol and a macrolide antibiotic and is given for 18–24 months; amikacin or streptomycin can be added in the initial 3–6 months in cases of severe disease. For the rapid growers, regimens are primarily based on in vitro drug susceptibility test (DST) results. For Mycobacterium abscessus, the most notorious causative agent of disease among rapid growers, these regimens often include a macrolide antibiotic, amikacin and either cefoxitin, imipenem or tigecycline (Jarand et al., 2011). Treatment for NTM disease, in particular pulmonary NTM disease, can be disappointing and clinical improvement and prolonged culture conversion is not achievable for all patients. Cure rates of pulmonary NTM disease differ by species, ranging from 30–50% in M. abscessus disease, to 50–70% in Mycobacterium avium complex and 80–90% in Mycobacterium malmoense and Mycobacterium kansasii disease (Hoefsloot et al., 2009, Jarand et al., 2011, van Ingen et al., 2009).

The exact role of DST remains subject of debate, in particular for slow growers. One of the reason is that there are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo (Griffith et al., 2007, Society, 2001). In part, these discrepancies derive from laboratory technical difficulties of DST, standardization of methods and a lack of clinical validation. Yet, with the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. In this review we provide a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance. We also discuss the usefulness of these tests in clinical practice. This review is limited to susceptibility and susceptibility testing to antimicrobial compounds in past or current clinical use; susceptibility to disinfectants or non-medical substances falls outside the scope of this review.