TY - JOUR
T1 - Towards clinical breakpoints for non-tuberculous mycobacteria – Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution
AU - EUCAST AMST study group
AU - ESCMYC study group
AU - Fröberg, Gabrielle
AU - Maurer, Florian P.
AU - Chryssanthou, Erja
AU - Fernström, Louise
AU - Benmansour, Hanaa
AU - Boarbi, Samira
AU - Mengshoel, Anne Torunn
AU - Keller, Peter Michael
AU - Viveiros, Miguel
AU - Machado, Diana
AU - Fitzgibbon, Margaret M.
AU - Mok, Simone
AU - Werngren, Jim
AU - Cirillo, Daniela Maria
AU - Alcaide, Fernando
AU - Hyyryläinen, Hanne Leena
AU - Aubry, Alexandra
AU - Andres, Sönke
AU - Nadarajan, Darshaalini
AU - Svensson, Erik
AU - Turnidge, John
AU - Giske, Christian G.
AU - Kahlmeter, Gunnar
AU - Cambau, Emmanuelle
AU - van Ingen, Jakko
AU - Schön, Thomas
N1 - 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)
PY - 2023/6
Y1 - 2023/6
N2 - Objective: For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints. Methods: We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TECOFFs) were determined by EUCAST methodology including quality control (QC) strains. Results: The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For QC M. avium and M. peregrinum, ≥95% of MIC values were well within recommended QC ranges. Conclusion: As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs.
AB - Objective: For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints. Methods: We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TECOFFs) were determined by EUCAST methodology including quality control (QC) strains. Results: The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For QC M. avium and M. peregrinum, ≥95% of MIC values were well within recommended QC ranges. Conclusion: As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs.
KW - Broth microdilution
KW - Drug susceptibility testing
KW - ECOFF
KW - Mycobacterium
KW - Mycobacterium abscessus
KW - Mycobacterium avium
KW - Non-tuberculous mycobacteria
UR - http://www.scopus.com/inward/record.url?scp=85149856029&partnerID=8YFLogxK
U2 - 10.1016/j.cmi.2023.02.007
DO - 10.1016/j.cmi.2023.02.007
M3 - Article
C2 - 36813087
AN - SCOPUS:85149856029
SN - 1198-743X
VL - 29
SP - 758
EP - 764
JO - Clinical Microbiology and Infection
JF - Clinical Microbiology and Infection
IS - 6
ER -
