Towards clinical breakpoints for non-tuberculous mycobacteria – Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution

• Autor(a) principal: for the EUCAST AMST and ESCMYC study groups
• Data de Publicação: 2023
• Outros Autores: Viveiros, Miguel, Machado, Diana
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/155415
• topic: Broth microdilution; Drug susceptibility testing; ECOFF; Mycobacterium; Mycobacterium abscessus; Mycobacterium avium; Non-tuberculous mycobacteria; RA0421 Public health. Hygiene. Preventive Medicine; QR Microbiology; RM Therapeutics. Pharmacology; Microbiology (medical); Infectious Diseases; SDG 3 - Good Health and Well-being

Funding Information: FPM; Mukoviszidose Institut gGmbH, Bonn, the German Cystic Fibrosis Association Mukoviszidose e.V. TS; Swedish Heart and Lung Foundation and the Swedish research council. Funding Information: The Clinical and Laboratory Standards Institute (CLSI) recommends using broth microdilution (BMD) in cation adjusted Mueller Hinton broth (CAMHB) for AST of most NTM [10,11]. There is limited data in support of the current CLSI breakpoints in terms of wild-type (WT) MIC distributions, epidemiological cut-off values (ECOFFs), PK/PD and clinical outcome [13,15]. So far, single laboratory studies using commercial BMD plates, such as Sensititre SLOMYCOI and RAPMYCOI (Thermo Fisher Scientific Inc., US) have suggested putative ECOFFs representing the highest MIC value for the phenotypic WT distribution [12,15]. However, to define ECOFFs, valid WT distributions from at least five separate laboratories are required according to European Committee of Antimicrobial Susceptibility Testing (EUCAST) to capture intra- and interlaboratory technical variability [16]. Thus, the aim of this study was to define EUCAST ECOFFs for drugs against MAC and MAB in a widely used commercial BMD method as a first step towards EUCAST NTM breakpoints.Our data support previous single laboratory studies of MIC determinations which showed WT distributions in the same range as in the present study [12,15,23,24]. However, the broad MIC distributions indicate a need for refinement of both species identification and methodology used for MIC determination for NTM. This is the case in particular for the key drug clarithromycin, where MAB subspecies identification is crucial regarding inducible resistance and MIC testing is dependent on the pH [25]. Future development of the EUCAST AMST reference method for NTM should take this into account, but also include proper MIC ranges, standardized preparation of the inoculum and a more thorough growth control like in the EUCAST AMST reference method for M. tuberculosis [26]. An additional point for discussion is whether clarithromycin is the most suitable macrolide representative, given that current treatment guidelines specifically advocate the use of azithromycin [2] and therapeutic drug monitoring including MIC determination for azithromycin may help to predict and improve treatment outcome although the stability of azithromycin during AST may need consideration [27].We found that the CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For both MAC and MAB, the WT distributions expanded well above these breakpoints, splitting the WT distributions and causing substantial reproducibility concerns due to the inherent technical variability of MIC testing of up to ± one MIC dilution step. Consequently, the SIR-classification of “susceptible, at standard dosing (S)”, “susceptible at increased exposure (I)” and “resistant (R)” based on these breakpoints is dependent on method variability rather than a prediction of the efficacy of the drug. This is further substantiated by a very low categorical agreement (54%) between laboratories in the SIR classification of linezolid for MAB in quality assessment studies for NTM [19]. For moxifloxacin and linezolid, clinical efficacy data for both MAC and MAB in support of the current CLSI breakpoints (1 and 8 mg/L, respectively) are very scarce [2,11]. Additionally, the CLSI breakpoints for moxifloxacin and linezolid were both two MIC dilution steps higher than the non-species related PK/PD breakpoints as defined by EUCAST (0.25 and 2 mg/L, respectively). This is of particular concern for linezolid because of the potential severe side effects from long term use such as anemia and polyneuropathy. We strongly suggest that current breakpoints for moxifloxacin and linezolid against MAC and MAB should be removed until a reproducible AST is in place supported by both PK/PD and clinical outcome data (Table 1).GF; Stockholm Region and Karolinska Institute clinical research grant. Funding Information: GF; Stockholm Region and Karolinska Institute clinical research grant. Publisher Copyright: © 2023 The Author(s)