LETTER
Mycobacterium avium and M. intracellulare are referred as the M. avium complex (MAC) (1) and are known as causative agents of opportunistic infections in humans (1–3). The first-line recommended treatment consists of a combination of either clarithromycin or azithromycin with rifampin and ethambutol, the two latter drugs being considered companion drugs to prevent the emergence of macrolide resistance (4, 5). Amikacin is an alternative to macrolides for the treatment of MAC lung cavitary disease or in case of macrolide resistance (6). To date, the treatment guidelines have referred to MAC as a complex (4), but there are no clear data regarding the antibiotic susceptibility of each species separately. Therefore, we sought to delineate the clarithromycin and amikacin susceptibility profiles of both species (4, 5).
All of the clinically relevant MAC isolates sent to the French National Reference Center for Mycobacteria between 2009 and 2011 were routinely identified by using GenoType Mycobacterium CM/AS line probe assays (Hain, Lifescience) as recommended by the manufacturer, leading to the identification of M. avium or M. intracellulare (7). After the exclusion of duplicates, only isolates from patients with no history of previous antibiotic treatment were selected to be representative of a wild population. MICs were determined by the broth microdilution method with Sensititre SLOMYCO (Biocentric) (8). The Kruskal-Wallis test was used for statistical comparisons. Epidemiological cutoff (ECOFF) values were determined as values larger than the modal MIC plus one 2-fold dilution (variability of the test) and including at least 95% of the isolates tested.
One hundred eighty-six M. avium and 154 M. intracellulare isolates were studied. The distributions of clarithromycin and amikacin MICs were unimodal for both species (Fig. 1). Clarithromycin MICs were lower for M. intracellulare than for M. avium isolates (MIC50, 2 versus 8 mg/liter, respectively; P < 0.001) (Table 1). The same observation was made for amikacin MICs, although the difference was not as drastic (MIC50, 8 versus 16 mg/liter, respectively; P < 0.001). Consequently, the tentative ECOFFs were slightly lower for M. intracellulare than for M. avium (Table 1).
FIG 1.
Distribution of clarithromycin (a) and amikacin (b) MICs for M. avium and M. intracellulare and box plots of MIC distribution (c).
TABLE 1.
Statistical analysis of MICs of clarithromycin and amikacin for MAC
| Drug and species no. of isolates) | Modal MIC | MIC50 | MIC90 | Geometric mean MIC | MIC range | ECOFF |
|---|---|---|---|---|---|---|
| Clarithromycin | ||||||
| M. avium (186) | 8a | 8 | 16 | 6.7 | 1–16 | 16 |
| M. intracellulare (154) | 2 | 2 | 4 | 1.7 | ≤0.25–16 | 8 |
| Amikacin | ||||||
| M. avium (186) | 16 | 16 | 16 | 10.7 | 2–32 | 32 |
| M. intracellulare (154) | 8 | 8 | 16 | 7.4 | 2–32 | 16 |
Values are in milligrams per liter.
Many studies report MAC as a single entity. Our results demonstrate that M. avium and M. intracellulare have different patterns of clarithromycin and amikacin susceptibility. Such a difference has been previously reported (9, 10), but recent data considering both clarithromycin and standardized methods (recommended by CLSI [8]) were lacking at the time of those publications. Considering that (i) clarithromycin and amikacin MICs have been linked to treatment outcomes (6, 11) and (ii) the MICs for M. avium are higher, one could expect more therapeutic failures and a higher rate of selection of resistant mutants of this species if it is associated with a large mutant selection window (which remains to be determined). A limitation of the present study is, however, the use the GenoType Mycobacterium CM/AS line probe assay to identify M. avium and M. intracellulare. Other MAC species, such as M. chimaera, may have been misidentified as one of the two main species by this assay, although the impact on the results is likely to be limited because the other species are less frequently encountered (7, 12). In fine, our results need to be further confirmed by a definitive species identification method, such as sequencing.
In conclusion, there are differences in antibiotic susceptibility between MAC species in terms of MIC50s and ECOFFs. Whether these differences are clinically relevant remains to be determined; indeed, there are not a wide variety of drugs and dosage options for the treatment of MAC infections, and the choice of the antibiotic regimen could be based on MICs determination despite definite species identification. On the other hand, these differences will be of interest in determining the correlation between in vitro results and clinical and bacteriological outcomes.
ACKNOWLEDGMENTS
We are grateful to Stanley Pang for editing the manuscript and to Anton Granzhan for his help in preparing the manuscript.
We have no conflict of interest to declare.
This work was supported by an annual grant from the Institut National de Veille Sanitaire to the French National Reference Center for Mycobacteria and Antimycobacterial Resistance.
Footnotes
Published ahead of print 1 October 2014
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