In Vitro Susceptibility Testing Limitations in NTM Lung Disease

In vitro susceptibility testing is the cornerstone of effective tuberculosis therapy. Patients with tuberculosis predictably have favorable clinical responses to antibiotics that have susceptible minimum inhibitory concentrations (MICs) to the patient’s Mycobacterium tuberculosis clinical isolate.

By contrast, nontuberculous mycobacteria (NTM) possess mechanisms of drug resistance that are not reflected in usual microbiologic measurements, such as MICs. This form of drug resistance, termed “natural drug resistance,” is a likely explanation of the limited efficacy of current treatment regimens for NTM disease. Testing the susceptibility of individual clinical isolates is of limited value for drugs to which natural resistance is expected. Moreover, for most drugs there is no clear correlation between in vitro activity of the drug and the outcome of treatment in vivo. This disparity is perhaps the most frustrating and misunderstood aspect of NTM disease management.

Mycobacterium avium complex (MAC)
In vitro susceptibility testing for Mycobacterium avium complex (MAC) is encountered most often, and it provides an important example of how “natural drug resistance” affects treatment choices. Whereas multiple antibiotic MICs are sometimes reported on MAC in vitro susceptibility reports, the only antibiotic MICs that predict treatment outcome are those for macrolides and amikacin. For both macrolides and amikacin, clear MIC cutoffs are associated with treatment response and/or failure. Each is associated with mutations (23S rRNA for macrolides and 16S rRNA for amikacin) that result in drug resistance and clinical failure.

These associations are demonstrable for macrolides and amikacin only but for no other agents (including fluoroquinolones). As such, the Clinical and Laboratory Standards Institute recommends that MAC isolates should be tested for in vitro susceptibility only to macrolides and amikacin. There are no other antibiotics where in vitro susceptibility results predict treatment response. Therefore, MICs for those drugs should not be reported and should not be used to construct MAC treatment regimens.  

To further complicate MAC treatment decisions, the most important drug for protecting against the emergence of acquired macrolide resistance is ethambutol, which is uniformly associated with high MICs for MAC. Ethambutol is an essential element of MAC treatment, despite high MICs, because it preserves macrolide susceptibility. Preventing the emergence of macrolide resistance is a priority in the management of MAC lung disease. Macrolide resistance is associated with treatment failure and excess mortality in comparison with macrolide-susceptible MAC lung disease. The 2 most important risk factors for developing macrolide resistance are macrolide monotherapy and the combination of macrolide and fluoroquinolone in the absence of ethambutol. Discontinuing ethambutol and/or adding fluoroquinolone in a MAC regimen based on in vitro susceptibility results are both inappropriate.  

M abscessus and M kansasii
In vitro susceptibilities for macrolide and amikacin also yield the only MICs for M abscessus that are associated with clinical response. Somewhat ironically, the 2020 NTM Treatment Guidelines suggest basing M abscessus treatment regimens on M abscessus in vitro susceptibilities without evidence that in vitro susceptibilities for agents other than macrolide and amikacin are associated with favorable treatment response. For M kansasii, in vitro susceptibilities for rifampin and macrolides (and probably fluoroquinolones) predict treatment response.

Conclusion
The principles of tuberculosis therapy, with reliance on in vitro susceptibilities to guide therapy, have limited applicability for NTM species; therefore, healthcare professionals must understand and apply the sometimes frustrating and counterintuitive principles required for effective NTM disease management.

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For more information on NTM resources to share with patients, please visit the NTM Info & Research website.