Our antibiotic susceptibility testing results supported the current recommendation of using macrolides, rifamycins, and aminoglycosides to treat MAC infections. In our study, clarithromycin showed good inhibitory activity against all MAC isolates, consistent with previous studies[19, 20]. The resistance rate of MAC isolates against rifampin was 82.9% (92/111), which was in agreement (78.9%; 216/274) with a previous study[21]. Unlike rifampin, rifabutin showed a better antimicrobial activity and was recommended as an alternative to rifampicin, especially for disseminated MAC infections, for patients infected with MAC[22]. However, in a recent study, neither rifampin or rifabutin inhibited MAC growth in vitro[23]. Therefore, further clinical trials are still needed to determine the best choice among different rifamycins for treating MAC diseases. The intermediate resistance against ethambutol was comparable with that of a previous study (58.1%;159/274)[21]. These results do not support the usage of ethambutol for MAC. Among the aminoglycosides, amikacin may be better for treating MAC infections than streptomycin, with an overall low resistant rate of 2.7% (24/111), which is as low as shown in previous studies[24, 25]. Streptomycin is a potentially good choice for treatment of MAC isolates. In a study in a Taiwanese district, the resistance rate of MAC isolates against streptomycin was even lower (4.8%; 4/83)[26]. This difference may be regional (different geographies) or may be due to the inconsistent proportions of MAC subspecies collected in the studies.
As second-line drugs for MAC disease, the clinical efficacy of moxifloxacin and linezolid remains uncertain[27]. In our study, both had limited activity against MAC isolates, which is comparable with previous studies in Korea[28], Sweden[25], and China[29]. However, unlike the poor activity in vitro, a recent study has shown that fluoroquinolone-containing regimens could achieve similar clinical improvement with the standard regimen and could be an alternative for patients who cannot tolerate the standard regimen[30]. As for the other tested anti-tuberculosis drugs, such as isoniazid, ciprofloxacin, doxycycline, and ethionamide, the MAC isolates showed high resistance, which supported the consensus that these drugs should not be used in the treatment of MAC diseases as shown in a previous study[20]. The comparison of drug resistance rate of recommended agents for MAC isolates from different studies were shown in Table 3.
Table 3
The comparison of drug resistance rate of recommended agents for MAC isolates from different studies.
Nation/district | Year | Isolate | CLA | RIF | EMB | MXF | RFB | AMI | LZD | STR | Source |
This study | 2021 | 111 | 5(4.5%) | 92(82.9%) | 60(54.1%) | 67(60.4%) | 24(21.6%) | 3(2.7%) | 80(72.1%) | 19(17.1%) | |
Germany | 2020 | 98 | 1(1.2%) | - | - | 38(44.7%) | - | 0(0%) | 57(67.1%) | - | [19] |
Germany | 2019 | 683 | 17(2.5%) | - | - | 430(63.1%) | - | - | 511(75.0%) | - | [19] |
Korea | 2018 | 1883 | 95(5.0%) | 1080(57.4%) | 1691(89.8%) | 1054(56.0%) | - | 166(8.8%) | 805(42.8%) | - | [28] |
Sweden | 2017 | 229 | 6(2.6%) | 210(91.7%) | - | 112(48.9%) | - | 11(4.8%) | 118(51.5%) | - | [25] |
Taiwan | 2018 | 83 | 0(0%) | - | - | 72(86.7%) | - | 2(2.4%) | 61(73.5%) | 4(4.8%) | [26] |
UK | 2016 | - | 248(19.9%) | 686(55.7%) | 391(31.9%) | - | 58(5.9%) | 100(8.2%) | - | 498(53.0%) | [45] |
In our study, the new oxazolidinone, tedizolid, had a significantly lower resistance rate than linezolid, supporting the previous results which indicated that tedizolid has enhanced in vitro activities against several NTM species[31]. In addition, it has less side effects in long-term therapy, compared with linezolid and has a concentration-dependent activity against M. avium. Its efficacy can be enhanced by ethambutol, which suggests its potential role in the treatment of MAC diseases[32].
Clofazimine, which also had a low resistance rate in our study, has been recently proven to be an effective agent for the treatment of MAC both in patients and mouse models[33, 34]. A recent study conducted in Korea found that a lower MIC value of clofazimine (≤ 0.25 mg/L) was associated with negative conversion of sputum culture in patients with NTM lung diseases[35]. Another study in Korea demonstrated that clofazimine, together with inhaled amikacin, could provide favorable outcomes in patients with refractory MAC-LD[36]. Nevertheless, the adverse effects of clofazimine are a major concern that affects its application in patients.
Bedaquiline is a diarylquinoline antibiotic, acting through an antimicrobial mechanism by inhibiting F1Fo-ATP synthase, an enzyme that is essential in Mycobacterium tuberculosis[36]. Although several clinical studies have found increased sputum conversion rates with bedaquiline in patients with multidrug-resistant tuberculosis, its efficacy in the treatment of MAC-LD is currently controversial. In some studies, bedaquiline is considered to be a good candidate for refractory or relapsing diseases caused by MAC[38, 39], while in other studies, bedaquiline treatment in patients with MAC-LD were not favorable due to the emergence of resistance and the decreased systemic exposure caused by rifamycin through the induction of cytochrome P450[40, 41]. In our study, most MAC isolates showed low MIC values (0.015–0.12 µg/mL) for bedaquiline, which is in agreement with previous studies[42–44]. Clinical trials are warranted to correlate the in vitro susceptibility of MAC to bedaquiline with the clinical outcome.
Cycloserine is mainly used to treat drug-resistant M. tuberculosis, and there are few reports on its effect on NTM. MAC isolates were completely sensitive to cycloserine in several studies[45], with an MIC breakpoint of 80 µg/mL. However, in our study, the resistant rates (≥64µg/mL) are 28.9% and 42.9% for M. intracellulare and M. avium, respectively. Considering the side effects of long-term use of cycloserine and the intermediate resistance rate in vitro, it is necessary to be cautious and more data are needed to test its effect upon clinical application as a candidate drug.
In this study, drug susceptibilities of M. avium and M. intracellulare (which has been less reported) to several agents were different. M. avium had a higher resistance rate than M. intracellulare for clarithromycin, ethambutol, trimethoprim/sulfamethoxazole, amikacin, linezolid, clofazimine, and cycloserine. However, since the number of resistant M. avium isolates was small in our study, the calculations of the resistance rates of clarithromycin and amikacin using only two isolates might be inaccurate. In another study in Germany[20], higher resistance rates of M. avium to trimethoprim/sulfamethoxazole and linezolid were also reported. Contrary to our results, in a recent study in Shanghai[46], M. intracellulare had higher resistance rates than M. avium for most tested antimicrobials. The difference may be related to different identification methods between these studies. As for the other subspecies, few studies have reported their resistance profiles and more research is needed in the future.