The new diazabicyclooctane-based β-lactamase inhibitors avibactam and relebactam improve the in vitro activity of β-lactam antibiotics against bacteria of the Mycobacterium abscessus complex (MABC). Here, we evaluated the in vitro activities of two newer diazabicyclooctane-based β-lactamase inhibitors in clinical development, nacubactam and zidebactam, with β-lactams against clinical isolates of MABC.
KEYWORDS: β-lactamase inhibitors, β-lactams, Mycobacterium abscessus, cefepime, diazabicyclooctane, drug susceptibility assay, meropenem, nacubactam, zidebactam
ABSTRACT
The new diazabicyclooctane-based β-lactamase inhibitors avibactam and relebactam improve the in vitro activity of β-lactam antibiotics against bacteria of the Mycobacterium abscessus complex (MABC). Here, we evaluated the in vitro activities of two newer diazabicyclooctane-based β-lactamase inhibitors in clinical development, nacubactam and zidebactam, with β-lactams against clinical isolates of MABC. Both inhibitors lowered the MICs of their partner β-lactams, meropenem (8-fold) and cefepime (2-fold), respectively, and those of other β-lactams, similar to prior results with avibactam and relebactam.
INTRODUCTION
The Mycobacterium abscessus complex (MABC) is composed of subspecies M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii (1). These rapidly growing nontuberculous mycobacteria are responsible for chronic difficult-to-treat lung, skin, and wound infections that are increasing in prevalence (2–4). Both intrinsic and acquired drug resistance contribute to the recalcitrance of MABC lung infections (5). Despite the outstanding contribution of β-lactam antibiotics to the treatment of infectious diseases, their utility against MABC organisms is limited by a chromosomally encoded broad-spectrum Ambler class A β-lactamase, BlaMab, which is the major determinant of intrinsic β-lactam resistance in MABC (6). While older β-lactam-based β-lactamase inhibitors (BLIs), such as clavulanate, tazobactam, and sulbactam, are ineffective against BlaMab and do not improve the in vitro activity of β-lactam antibiotics against MABC organisms (7, 8), we and others have shown that the new diazabicyclooctane-based BLIs avibactam and relebactam, developed to treat multidrug-resistant Gram-negative bacteria (9), do improve the in vitro activity of many β-lactam antibiotics against MABC organisms, particularly carbapenems and cephalosporins (8, 10–12). Avibactam and relebactam have been developed with ceftazidime and imipenem, respectively. However, ceftazidime has poor intrinsic activity against MABC organisms, as evidenced by high MICs despite combination with avibactam or relebactam (10, 12), while imipenem has relatively high intrinsic activity and the MICs are only modestly lower in the presence of these BLIs (8, 10). Newer diazabicyclooctane-based BLIs being developed for the treatment of challenging Gram-negative infections, including nacubactam and zidebactam (13, 14), may offer advantages over avibactam and relebactam. Both nacubactam (OP0595, RG6080) coformulated with meropenem and zidebactam (WCK 5107) coformulated with cefepime (coformulation WCK 5222) have completed clinical safety, tolerability, pharmacokinetics, and lung penetration studies (ClinicalTrials.gov identifiers NCT02972255, NCT03182504, NCT02674347, and NCT03630094) and received Fast Track and Qualified Infectious Disease Product (QIDP) designations from the U.S. Food and Drug Administration (15, 16).
The aim of our study was to evaluate the activity of nacubactam or zidebactam in combination with β-lactams against drug-resistant clinical isolates of MABC. This study is available in bioRxiv (17). Nacubactam and zidebactam were procured from MedKoo Biosciences, Inc., NC, USA (purity >98%). A total of 26 β-lactam antibiotics (Table 1), including penicillins, cephalosporins, and carbapenems, were purchased from commercial sources, as previously described (10). The purity of all β-lactams was >95%. All drugs were stored and dissolved either in dimethyl sulfoxide (DMSO) or water prior to drug susceptibility testing (DST), according to the manufacturers’ recommendations.
TABLE 1.
MIC values of β-lactams with without β-lactamase inhibitors against M. abscessus subsp. abscessus strain ATCC 19977T in Middlebrook 7H9 medium and CAMHB
| β-lactam tested by class | MIC (μg/ml) in: |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Middlebrook 7H9 |
CAMHB |
|||||||||
| Alone | With nacubactam at: |
With zidebactam at: |
Alone | With nacubactam at: |
With zidebactam at: |
|||||
| 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | |||
| Oral carbapenems | ||||||||||
| Faropenem | 128 | 32 | 32 | 32 | 32 | 128 | 32 | 32 | 128 | 64 |
| Tebipenem | 256 | 8 | 4 | 16 | 16 | 128 | 16 | 16 | 64 | 16 |
| Parenteral carbapenems | ||||||||||
| Biapenem | 16 | 4 | 4 | 4 | 4 | 64 | 16 | 16 | 32 | 32 |
| Doripenem | 16 | 4 | 2 | 4 | 4 | 32 | 16 | 8 | 16 | 8 |
| Ertapenem | >256 | 16 | 16 | 64 | 64 | 256 | 32 | 32 | 256 | 32 |
| Imipenem | 8 | 4 | 2 | 2 | 2 | 8 | 4 | 4 | 8 | 8 |
| Meropenem | 16 | 4 | 2 | 8 | 8 | 32 | 16 | 8 | 16 | 8 |
| Oral cephalosporins | ||||||||||
| Cefdinir | 32 | 16 | 16 | 16 | 16 | 32 | 16 | 8 | 32 | 16 |
| Cefixime | >256 | 128 | 128 | 256 | 128 | >256 | 128 | 128 | >256 | >256 |
| Cefpodoxime | >256 | 64 | 64 | 128 | 64 | >256 | 128 | 128 | >256 | >256 |
| Cefuroximea | 128 | 8 | 8 | 16 | 16 | 256 | 32 | 16 | 64 | 32 |
| Cephalexin | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Parenteral cephalosporins | ||||||||||
| Cefazolin | >256 | >256 | 256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Cefepime | 32 | 32 | 16 | 16 | 16 | 64 | 32 | 32 | 32 | 32 |
| Cefoperazone | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Cefotaxime | 128 | 64 | 32 | 64 | 64 | 64 | 64 | 64 | 128 | 128 |
| Cefoxitin | 32 | 32 | 32 | 32 | 32 | 32 | 32 | 16 | 16 | 16 |
| Ceftaroline | >256 | 8 | 8 | 64 | 32 | 128 | 32 | 16 | 128 | 64 |
| Ceftazidime | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Ceftriaxone | >256 | 32 | 16 | 128 | 32 | >256 | 128 | 64 | >256 | >256 |
| Cephalothin | >256 | 256 | 128 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Moxalactam | 128 | 128 | 128 | 128 | 128 | 128 | 128 | 128 | 128 | 128 |
| Penicillins | ||||||||||
| Amoxicillin | >256 | 16 | 16 | 256 | 256 | >256 | 64 | 8 | >256 | >256 |
| Cloxacillin | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Dicloxacillin | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
| Oxacillin | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 | >256 |
Cefuroxime is available in both oral and parenteral formulations.
Twenty-eight clinical isolates of MABC were collected at Johns Hopkins Hospital, Baltimore, MD, USA, from 2005 to 2015 and were described previously (8, 10, 18). M. abscessus ATCC 19977T was purchased from the American Type Culture Collection (Manassas, VA, USA) and used as a reference strain. Middlebrook 7H9 broth supplemented with 10% Middlebrook oleic acid-albumin-dextrose-catalase (OADC) enrichment, 0.5% glycerol, and 0.05% Tween 80 was used as the growth medium. Middlebrook 7H9 broth supplemented with 10% OADC and 0.5% glycerol was used primarily for MIC determination instead of cation-adjusted Mueller-Hinton broth (CAMHB), because the growth of clinical isolates is faster in Middlebrook 7H9 broth than in CAMHB, thus limiting the potential for overestimation of MICs due to β-lactam instability in the medium, as discussed previously (10).
MICs were determined using the broth microdilution method in round-bottom wells in 96-well plates, as previously described (8, 10). In brief, 100 μl of medium was dispensed in the wells. Drugs were dissolved, and 2-fold dilutions were prepared, ranging from 2 to 256 μg/ml. Wells were prepared with β-lactams alone or in combination with a fixed concentration of 4 or 8 μg/ml either nacubactam or zidebactam or either BLI alone. A total of 100 μl of a log-phase culture containing 1 × 104 to 5 × 104 CFU was added to each well except the negative-control well (which had medium only). Plates were incubated at 30°C for 3 days for Middlebrook 7H9 broth and 5 days for CAMHB. The MIC was defined as the lowest concentration of β-lactam that prevented growth as observed by the naked eye. The MIC50 and MIC90 were defined as the MICs at which at least 50% and at least 90%, respectively, of the clinical MABC isolates were inhibited. DST was repeated to confirm the MICs.
Initially, we studied the effect of β-lactams in the presence and absence of nacubactam and zidebactam against M. abscessus ATCC 19977T. Both BLIs improved the activities of carbapenems and some cephalosporins (Table 1). The potentiating effects were greatest with tebipenem, ertapenem, cefuroxime, ceftaroline, and, to a lesser extent, meropenem. However, nacubactam was generally slightly more effective than zidebactam, and it uniquely potentiated the effects of amoxicillin. Nacubactam at 8 μg/ml resulted in 2-fold lower MICs than with 4 μg/ml for some β-lactams, while the zidebactam results were similar irrespective of the concentration tested. Specifically, nacubactam at 8 μg/ml and zidebactam at 4 to 8 μg/ml improved the activities of their partner β-lactams, meropenem and cefepime, by 8-fold and 2-fold, respectively. As previously observed with avibactam and relebactam, the MICs of cefoxitin remained unchanged in the presence of nacubactam and zidebactam, reflecting the stability of cefoxitin to MABC β-lactamase activity (19). The MICs of nacubactam and zidebactam against M. abscessus 19977T were >256 μg/ml, suggesting that their potentiation of β-lactam activity was due to β-lactamase inhibition rather than any intrinsic antibacterial effects.
We chose 8 μg/ml for nacubactam and 4 μg/ml for zidebactam as fixed concentrations to screen against the clinical isolates. On average, the clinical isolates were more resistant than was M. abscessus 19977T. However, both BLIs improved the activity of selected β-lactams (Table 2). Nacubactam and zidebactam lowered the MIC50 values of their partner β-lactams, meropenem and cefepime, by 8-fold and 2-fold, respectively, as well as those of the carbapenems, several cephalosporins (ceftaroline, cefuroxime, and cefdinir), and, in the case of nacubactam, amoxicillin, consistent with their effects against ATCC 19977T.
TABLE 2.
MIC values of β-lactams with and without nacubactam or zidebactam against 28 drug-resistant MABC clinical isolates in Middlebrook 7H9 medium
| β-lactam tested by class | MIC (μg/ml)a
|
||||||||
|---|---|---|---|---|---|---|---|---|---|
| Alone |
With nacubactam |
With zidebactam |
|||||||
| Range | MIC50 | MIC90 | Range | MIC50 | MIC90 | Range | MIC50 | MIC90 | |
| Oral carbapenems | |||||||||
| Tebipenem | 64 to >256 | 256 | >256 | 4 to 32 | 8 | 16 | 16 to 256 | 32 | 128 |
| Parenteral carbapenems | |||||||||
| Biapenem | 8 to 256 | 16 | 64 | 4 to 8 | 8 | 8 | 4 to 64 | 8 | 32 |
| Doripenem | 8 to 128 | 32 | 64 | 4 to 16 | 8 | 8 | 4 to 64 | 8 | 32 |
| Ertapenem | 128 to >256 | 256 | >256 | 8 to 64 | 16 | 64 | 16 to >256 | 64 | 256 |
| Imipenem | 8 to 64 | 16 | 32 | 4 to 16 | 8 | 16 | 4 to 32 | 8 | 16 |
| Meropenem | 8 to 256 | 32 | 256 | 4 to 16 | 4 | 8 | 4 to 128 | 8 | 64 |
| Oral cephalosporins | |||||||||
| Cefdinir | 32 to 256 | 64 | 128 | 16 to 32 | 16 | 32 | 16 to 64 | 32 | 64 |
| Cefuroximeb | 64 to >256 | 256 | >256 | 8 to 32 | 16 | 32 | 16 to 256 | 32 | 64 |
| Parenteral cephalosporins | |||||||||
| Cefepime | 16 to 128 | 32 | 64 | 8 to 64 | 16 | 32 | 8 to 64 | 16 | 32 |
| Cefoxitin | 32 to 64 | 32 | 64 | 32 to 64 | 32 | 64 | 32 to 64 | 32 | 64 |
| Ceftaroline | 64 to >256 | >256 | >256 | 4 to 32 | 8 | 16 | 16 to >256 | 64 | 256 |
| Oral penicillin | |||||||||
| Amoxicillin | >256 | >256 | >256 | 8 to 256 | 16 | 64 | 64 to >256 | 256 | >256 |
Nacubactam and zidebactam were used at fixed concentrations of 8 and 4 μg/ml, respectively.
Cefuroxime is available in both oral and parenteral formulations.
Against the clinical isolates, the addition of 8 μg/ml nacubactam reduced the meropenem MIC50 from 32 μg/ml to 4 μg/ml, thus changing the interpretation from resistant to susceptible, according to CLSI breakpoints for M. abscessus (albeit using 7H9 broth rather than the CAMHB medium recommended by the CLSI, for reasons we explained previously) (10). Indeed, all 28 clinical isolates had MICs within the susceptible-to-intermediate range when meropenem was combined with nacubactam. These results are somewhat better than those observed in our previous study when meropenem was combined with 4 μg/ml vaborbactam (10). For β-lactams, the percentage of the dosing interval for which free drug concentrations exceed the MIC (%fT>MIC) is the pharmacokinetic/pharmacodynamic parameter best correlated with antibacterial effect (20). The target values for the %fT>MIC vary among subclasses of β-lactams and by organism. Although such targets are not established for β-lactams against MABC organisms, the target %fT>MIC values against other bacteria are ≈40% for carbapenems and ≈40% to 60% for cephalosporins (21, 22). Monogue et al. showed that nacubactam plasma concentrations exceed 8 μg/ml for about 60% of the dosing interval when dosed intravenously at 1.5 g every 8 h (0.5-h infusion) (13), suggesting that β-lactam MICs in the presence of 8 μg/ml nacubactam may predict clinical efficacy if the β-lactam dosing regimen meets the %fT>MIC target for MIC in the presence of the BLI. Likewise, susceptibility breakpoints based on such targets should be predictive of clinical efficacy. Although no breakpoint has been established for cefepime against MABC organisms, the addition of 4 μg/ml zidebactam (or 8 μg/ml nacubactam) reduced the cefepime MIC50 from the resistant to the intermediate susceptibility range when considering the CLSI breakpoints for cefepime against Pseudomonas aeruginosa (23, 24). A 2-fold reduction in MIC was observed among 17/28 clinical isolates, as well as the ATCC 19977 strain, using cefepime-zidebactam compared to cefepime alone. Zidebactam plasma and alveolar epithelial lining fluid concentrations exceed 4 μg/ml for at least 75% and at least 50%, respectively, of the dosing interval when cefepime and zidebactam are dosed intravenously at 2 g and 1 g, respectively, every 8 h (1-h infusion) in healthy subjects (16).
In conclusion, this study demonstrates that nacubactam and zidebactam improve the anti-MABC activities of carbapenems, several cephalosporins, and, in the case of nacubactam, amoxicillin. Specifically, the addition of nacubactam lowered meropenem MICs 8-fold, resulting in all isolates being susceptible or intermediately susceptible by the CLSI interpretive criteria for meropenem. In our previous study (10), the meropenem-vaborbactam combination was not quite as potent as the meropenem-nacubactam combination studied here against the same isolates, suggesting that meropenem-nacubactam, if approved, could have an advantage for the treatment of MABC infections. However, further head-to-head comparisons with larger numbers of clinical isolates are required before drawing a more confident conclusion. Zidebactam had a more modest effect on cefepime MICs, and cefepime has lower intrinsic activity against MABC than does meropenem. However, emerging evidence suggests that combinations of two β-lactams with an effective BLI could be synergistic against M. abscessus (12, 25, 26). Our study identified β-lactams belonging to several subclasses that are potentiated by new BLIs and could be combined with a fixed β-lactam–BLI combination to pursue such synergistic effects.
ACKNOWLEDGMENTS
We gratefully acknowledge Gyanu Lamichhane (Johns Hopkins University) for providing the MABC clinical isolates.
Funding was provided by the National Institutes of Health grant R21AI137814 (to E.L.N.).
REFERENCES
- 1.Tortoli E, Kohl TA, Brown-Elliott BA, Trovato A, Leão SC, Garcia MJ, Vasireddy S, Turenne CY, Griffith DE, Philley JV, Baldan R, Campana S, Cariani L, Colombo C, Taccetti G, Teri A, Niemann S, Wallace RJ Jr, Cirillo DM. 2016. Emended description of Mycobacterium abscessus, Mycobacterium abscessus subsp. abscessus and Mycobacterium abscessus subsp. bolletii and designation of Mycobacterium abscessus subsp. massiliense comb. nov. Int J Syst Evol Microbiol 66:4471–4479. doi: 10.1099/ijsem.0.001376. [DOI] [PubMed] [Google Scholar]
- 2.Prevots DR, Shaw PA, Strickland D, Jackson LA, Raebel MA, Blosky MA, Montes de Oca R, Shea YR, Seitz AE, Holland SM, Olivier KN. 2010. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med 182:970–976. doi: 10.1164/rccm.201002-0310OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Adjemian J, Frankland TB, Daida YG, Honda JR, Olivier KN, Zelazny A, Honda S, Prevots DR. 2017. Epidemiology of nontuberculous mycobacterial lung disease and tuberculosis, Hawaii, USA. Emerg Infect Dis 23:439–447. doi: 10.3201/eid2303.161827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ringshausen FC, Apel RM, Bange FC, de Roux A, Pletz MW, Rademacher J, Suhling H, Wagner D, Welte T. 2013. Burden and trends of hospitalisations associated with pulmonary non-tuberculous mycobacterial infections in Germany, 2005–2011. BMC Infect Dis 13:231. doi: 10.1186/1471-2334-13-231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. 2012. Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother 67:810–818. doi: 10.1093/jac/dkr578. [DOI] [PubMed] [Google Scholar]
- 6.Soroka D, Dubée V, Soulier-Escrihuela O, Cuinet G, Hugonnet JE, Gutmann L, Mainardi JL, Arthur M. 2014. Characterization of broad-spectrum Mycobacterium abscessus class A β-lactamase. J Antimicrob Chemother 69:691–696. doi: 10.1093/jac/dkt410. [DOI] [PubMed] [Google Scholar]
- 7.Kaushik A, Makkar N, Pandey P, Parrish N, Singh U, Lamichhane G. 2015. Carbapenems and rifampin exhibit synergy against Mycobacterium tuberculosis and Mycobacterium abscessus. Antimicrob Agents Chemother 59:6561–6567. doi: 10.1128/AAC.01158-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kaushik A, Gupta C, Fisher S, Story-Roller E, Galanis C, Parrish N, Lamichhane G. 2017. Combinations of avibactam and carbapenems exhibit enhanced potencies against drug-resistant Mycobacterium abscessus. Future Microbiol 12:473–480. doi: 10.2217/fmb-2016-0234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagacé-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP III, Karlowsky JA. 2018. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. Drugs 78:65–98. doi: 10.1007/s40265-017-0851-9. [DOI] [PubMed] [Google Scholar]
- 10.Kaushik A, Ammerman NC, Lee J, Martins O, Kreiswirth BN, Lamichhane G, Parrish NM, Nuermberger EL. 2019. In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates. Antimicrob Agents Chemother 63:e02623-18. doi: 10.1128/AAC.02623-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dubée V, Bernut A, Cortes M, Lesne T, Dorchene D, Lefebvre AL, Hugonnet JE, Gutmann L, Mainardi JL, Herrmann JL, Gaillard JL, Kremer L, Arthur M. 2015. β-Lactamase inhibition by avibactam in Mycobacterium abscessus. J Antimicrob Chemother 70:1051–1058. doi: 10.1093/jac/dku510. [DOI] [PubMed] [Google Scholar]
- 12.Pandey R, Chen L, Manca C, Jenkins S, Glaser L, Vinnard C, Stone G, Lee J, Mathema B, Nuermberger EL, Bonomo RA, Kreiswirth BN. 2019. Dual β-lactam combinations highly active against Mycobacterium abscessus complex in vitro. mBio 10:e02895-18. doi: 10.1128/mBio.02895-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Monogue ML, Giovagnoli S, Bissantz C, Zampaloni C, Nicolau DP. 2018. In vivo efficacy of meropenem with a novel non-β-lactam–β-lactamase inhibitor, nacubactam, against Gram-negative organisms exhibiting various resistance mechanisms in a murine complicated urinary tract infection model. Antimicrob Agents Chemother 62:e02596-17. doi: 10.1128/AAC.02596-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sader HS, Rhomberg PR, Flamm RK, Jones RN, Castanheira M. 2017. WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant β-lactamases. J Antimicrob Chemother 72:1696–1703. doi: 10.1093/jac/dkx050. [DOI] [PubMed] [Google Scholar]
- 15.NacuGen Therapeutics, Inc. 2019. Fedora Pharmaceuticals and Meiji Seika Pharma sign basic agreement to establish NacuGen Therapeutics, Inc., a joint venture to develop and commercialize nacubactam for bacterial infections. GlobeNewswire News Room. https://www.globenewswire.com/news-release/2019/01/07/1681316/0/en/Fedora-Pharmaceuticals-and-Meiji-Seika-Pharma-Sign-Basic-Agreement-to-Establish-NacuGen-Therapeutics-Inc-a-Joint-Venture-to-Develop-and-Commercialize-Nacubactam-for-Bacterial-Infec.html (Accessed 29 March 2019).
- 16.Rodvold KA, Gotfried MH, Chugh R, Gupta M, Patel A, Chavan R, Yeole R, Friedland HD, Bhatia A. 2018. Plasma and intrapulmonary concentrations of cefepime and zidebactam following intravenous administration of WCK 5222 to healthy adult subjects. Antimicrob Agents Chemother 62:e00682-18. doi: 10.1128/AAC.00682-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kaushik A, Ammerman NC, Parrish NM, Nuermberger EL. 2019. New β-lactamase inhibitors nacubactam and zidebactam improve the in vitro activity of β-lactam antibiotics against Mycobacterium abscessus complex clinical isolates. bioRxiv doi: 10.1101/597765. [DOI] [PMC free article] [PubMed]
- 18.Kaushik A, Ammerman NC, Martins O, Parrish NM, Nuermberger EL. 2019. In vitro activity of new tetracycline analogs omadacycline and eravacycline against drug-resistant clinical isolates of Mycobacterium abscessus. Antimicrob Agents Chemother 63:e00470-19. doi: 10.1128/AAC.00470-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Dubée V, Soroka D, Cortes M, Lefebvre AL, Gutmann L, Hugonnet JE, Arthur M, Mainardi JL. 2015. Impact of β-lactamase inhibition on the activity of ceftaroline against Mycobacterium tuberculosis and Mycobacterium abscessus. Antimicrob Agents Chemother 59:2938–2941. doi: 10.1128/AAC.05080-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Mouton JW, Brown DF, Apfalter P, Cantón R, Giske CG, Ivanova M, MacGowan AP, Rodloff A, Soussy CJ, Steinbakk M, Kahlmeter G. 2012. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 18:E37–E45. doi: 10.1111/j.1469-0691.2011.03752.x. [DOI] [PubMed] [Google Scholar]
- 21.Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, Drusano GL. 2007. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis 44:79–86. doi: 10.1086/510079. [DOI] [PubMed] [Google Scholar]
- 22.Craig WA. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10. doi: 10.1086/516284. [DOI] [PubMed] [Google Scholar]
- 23.Nakamura T, Shimizu C, Kasahara M, Nakata C, Munakata M, Takahashi H, Nakamura T. 2007. Differences in antimicrobial susceptibility breakpoints for Pseudomonas aeruginosa, isolated from blood cultures, set by the Clinical and Laboratory Standards Institute (CLSI) and the Japanese Society of Chemotherapy. J Infect Chemother 13:24–29. doi: 10.1007/s10156-006-0493-4. [DOI] [PubMed] [Google Scholar]
- 24.CLSI. 2017. Performance standards for antimicrobial susceptibility testing. 27th ed CLSI supplement M100. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 25.Story-Roller E, Maggioncalda EC, Lamichhane G. 2019. Select β-lactam combinations exhibit synergy against Mycobacterium abscessus in vitro. Antimicrob Agents Chemother 63:e02613-18. doi: 10.1128/AAC.02613-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kumar P, Chauhan V, Silva JRA, Lameira J, d’Andrea FB, Li SG, Ginell SL, Freundlich JS, Alves CN, Bailey S, Cohen KA, Lamichhane G. 2017. Mycobacterium abscessus l,d-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins. Antimicrob Agents Chemother 61:e00866-17. doi: 10.1128/AAC.00866-17. [DOI] [PMC free article] [PubMed] [Google Scholar]