In vitro activity between linezolid and other antimicrobial agents against Mycobacterium abscessus complex

Highlights

• Linezolid and amikacin show the most potent activity against Mycobacterium abscessus complex

• The frequent synergism is observed in linezolid-amikacin and linezolid-tigecycline combinations

• Linezolid rarely exhibits in vitro synergy with moxifloxacin and cefoxitin when tested against Mycobacterium abscessus complex.

Abstract

Linezolid (LZD) serves as an effective option in the treatment of Mycobacterium abscessus complex (MABC) infection. Unfortunately, the combined activities of LZD with other antimicrobial agents against MABC have not been evaluated systemically. In this study, we randomly selected 32 Mycobacterium abscessus and 32 Mycobacterium massiliense isolates for the determination of in vitro synergistic effect between LZD and other antimicrobial agents, including amikacin (AMK), moxifloxacin (MOX), cefoxitin (CFX) and tigecycline (TGC). Out of 64 MABC isolates tested, only one (1.6%, 1/64) and two (3.2%, 2/64) exhibited resistance to AMK and LZD, respectively. Statistical analysis revealed that the percentage of TGC-resistant isolates was significantly lower among M. massiliense (9.4%, 3/32) than that among M. abscessus (25.0%, 8/32, P < 0.001). In addition, LZD and AMK showed synergy for 29 MABC isolates (45.3%), whereas no antagonism was noted for this combination. The second mostly frequent synergistic effect was found in LZD plus TGC combination, and 26.6% (17/64) of the strains tested exhibited synergy. In contrast, LZD-CFX and LZD-MOX combinations appeared antagonistic for half of the isolates (48.4%, 31/64 for CFX and 51.6%, 33/64), and almost no synergistic effect was reported in any of the strains for these two combinations. In conclusion, our data reveal that LZD and AMK show the most potent activity against MABC. The frequent synergism is observed in LZD-AMK and LZD-TGC combinations, while LZD rarely exhibits in vitro synergy with MOX and CFX when tested against MABC.

Introduction

Diseases caused by nontuberculous mycobacteria (NTM) have attracted more attention due to their increasing incidence worldwide (Hoefsloot et al., 2013). Of these NTM species, Mycobacterium abscessus complex (MABC) is one of the most important human pathogens causing a wide spectrum of diseases such as pulmonary infection, soft tissue infection, and other infections (Griffith et al., 2007, Nessar et al., 2012). Remarkably, this species represents the most resistant mycobacteria to chemotherapeutic agents, and is often associated with a poor treatment outcome (Kasperbauer and De Groote, 2015). In view of its impressive natural and acquired resistance, the treatment for M. abscessus infection always relies on extended therapy with extremely limited combination antibiotics (Kasperbauer and De Groote, 2015). Hence, there is an urgent need to develop new antimicrobial agents and their combinations for improving treatment outcome of patients infected with M. abscessus complex.

Linezolid (LZD), a member of oxazolidinone antibiotics, has been approved for the treatment of infections due to various gram-positive bacteria (Kearney et al., 1999, Zhang et al., 2014). Previous evidences have repeatedly demonstrated that LZD has good antimycobacterial activity against Mycobacterium tuberculosis and several NTM species (Wallace et al., 2001, Zhang et al., 2014). For MABC, the prevalence of LZD resistance ranged from 7% in India to 63% in UK (Broda et al., 2013, Singh et al., 2014), which probably reflects the geographic diversity of MABC in LZD susceptibility. Despite conflicting data from different studies, the clinical trials revealed that the regimens containing LZD exhibit favorable outcome in the treatment of MABC infection, indicating the promising prospects of this agent (Brown-Elliott et al., 2001, Kyle and Porter, 2004). Unfortunately, the combined activities of LZD with other antimicrobial agents against MABC have not been evaluated systemically in previous studies.

On the basis of the rpoB sequence, M. abscessus complex is differentiated into 3 subspecies: M. abscessus subsp. abscessus (M. abscessus), M. abscessus subsp. massiliense (M. massiliense), and M. abscessus subsp. bolletii (Lee et al., 2015). Further in vitro drug susceptibility testing has revealed that these three subspecies can differ from each other in their antibiotic resistance profiles, especially for the two major subspecies, M. abscessus and M. massiliense (Nessar et al., 2012). The prominent distinction between M. abscessus and M. massilliense is that a functional erm(41) gene conferring inducible resistance to macrolides exists in M. abscessus rather than M. massilliense, which limits the clinical application of macrolides for M. abscessus infection (Nessar et al., 2012). In addition, M. massilliense exhibits significance difference in in vitro activity of clarithromycin (CLA) in combination with moxifloxcin (MOX) compared with M. abscessus (Zhang et al., 2017). Therefore, it is meaningful to investigate whether these two subspecies show different in vitro synergistic effect in combination with other antibiotics, which will provide important insights for the application of LZD in clinical practice. In this study, our objective was to gather results from in vitro drug susceptibility testing (DST) of MABC against the combination of LZD with various other antimicrobial agents, including amikacin (AMK), MOX, cefoxitin (CFX) and tigecycline (TGC).