Feasibility of routine synergy testing using antibiotic gradient diffusion strips in the clinical laboratory

Feasibility of routine synergy testing using antibiotic gradient diffusion strips in the clinical... Sir, We recently reported synergistic activity between ceftolozane/tazobactam and colistin, as well as between ceftolozane/tazobactam and fosfomycin, against MDR Pseudomonas aeruginosa (MDRP) by time–kill experiments.1 These are important observations as combination therapy against P. aeruginosa is frequently employed in clinical practice, especially for patients at high risk of mortality.2 Although time–kill analyses are revered as the ‘gold standard’ for synergy assessments, they are typically only performed in the research setting versus the clinical laboratory given the time-intensive procedure involved. The chequerboard method is useful and a simplified ‘breakpoint chequerboard method’ has also been described,3,4 though both are cumbersome and not easily adaptable to the clinical laboratory for testing of multiple isolates. However, given the increasing prevalence of MDRP and the need to avoid delay in the initiation of potent, optimized combination antibacterial regimens, clinicians will find routine synergy testing an asset to patient care. Thus, we performed synergy tests using antibiotic gradient diffusion strips (GDSs) on the four MDRP strains used in our previous time–kill experiments to assess the clinical feasibility of performing these tests and their concordance with the gold standard synergy testing method. The MICs of ceftolozane/tazobactam, fosfomycin, colistin and amikacin were determined by Etest® (bioMérieux, Durham, NC, USA) and MIC Test Strip (MTS) (Liofilchem®, Waltham, MA, USA). Synergy assessments were performed by crossing ceftolozane/tazobactam with fosfomycin, colistin and amikacin Etest® strips (i.e. Method 1) and Liofilchem® MTSs (i.e. Method 2) at a 90° angle at the respective MICs of each agent. The Etest® MIC:MIC method (i.e. Method 3) was also performed as described by Pankey et al.5 Synergy assessments were performed in duplicate with a separately prepared inoculum from the second subculture. The mean fractional inhibitory concentration index (FICI) was calculated by dividing the mean MIC of each drug in combination by the MIC of each drug alone and adding the results. Synergy was defined as FICI ≤0.50, no interaction was defined as FICI >0.50 to ≤4.00 and antagonism was defined as FICI >4.00.6 In total, 12 different ceftolozane/tazobactam-drug combinations were assessed among the four P. aeruginosa isolates tested previously by time–kill experiments. Concordance across all three GDS methods was frequently observed, with 10 (83.3%) ceftolozane/tazobactam-drug combinations producing identical qualitative results, indicating the absence of antibiotic interaction (Table 1). Synergistic interactions were recorded by time–kill analysis for seven combinations;1 however, only GDS Method 1 produced concordant results for one (14.3%) combination and Methods 2 and 3 indicated absence of antibiotic interaction for all seven combinations. Synergy was identified by Methods 1 and 3 (Etest® methods) for one combination that produced additive results (i.e. 1–2 log10 cfu/mL decrease in bacterial burden compared with the most active agent alone) by time–kill analysis. For the four remaining combinations, the FICIs resulting from all three GDS methods indicated ‘no interaction’, which is similar to the ‘indifference’ interpretation from the time–kill results. The presence of some discordance between time–kill experiments and Etest® methods has been reported previously.5,7 Table 1. Synergy testing results P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  a Synergistic interaction assessed by a GDS method. b Concordance with time–kill results. Table 1. Synergy testing results P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  a Synergistic interaction assessed by a GDS method. b Concordance with time–kill results. While these GDS synergy methods did not detect all synergistic interactions by time–kill analyses, they did identify an MIC-lowering effect equivalent to at least a one-dilution reduction for one or both agents in six (50%) combinations by each crossing method (Methods 1 and 2) and in seven (58%) combinations by Method 3. Importantly, this MIC-lowering effect may indicate opportunities to optimize pharmacodynamic exposures in vivo and may be especially valuable to a clinician when MICs of multiple antibiotics approach or just barely exceed the susceptibility breakpoint. With regard to time, ∼12–15 min was required to complete Methods 1 and 2. This included a waiting period of 10 min to allow for plates to dry prior to GDS placement, and therefore only 2–5 min was spent performing the technical procedure. Method 3 requires an extra hour of incubation at room temperature; thus a total of ∼75 min was required. As the MICs of each agent alone must be determined prior to synergy testing, the procedure is usually carried out over a span of 2 days, which is not practical in the clinical setting. In order to provide results to clinicians in <24 h, it would be ideal if GDS synergy tests could be performed with MICs determined by the reference antimicrobial susceptibility testing (AST) method utilized in the clinical laboratory. For this reason, a sensitivity analysis was performed using Method 1 but crossing both strips at 1–2 dilutions higher or lower than determined by the GDS to account for expected discordance between the reference AST method and the GDS-derived MIC. The qualitative interpretation of the FICI was identical in 16 of 24 (67%) additional tests completed in this manner. However, agreement was 100% if the original GDS-derived MIC was used to calculate the FICI. Thus, performance of the standard GDS procedure simultaneously with the synergy test at MICs produced from AST improves concordance while still allowing results in <24 h. It would be prudent to perform a similar sensitivity analysis should a laboratory prefer to adopt either Method 2 or 3 using MICs derived from reference AST for routine GDS synergy studies. In summary, synergy testing with GDSs performed on four MDRP isolates supported our previous findings of synergy between ceftolozane/tazobactam and fosfomycin by time–kill analysis. These data provide additional support for use of this combination against MDRP. Ceftolozane/tazobactam-colistin and ceftolozane/tazobactam-amikacin combinations warrant additional study owing to the observed discordance between time–kill and GDS synergy testing methods. Notwithstanding the presence of some degree of expected discordance with the gold standard synergy testing method, we determined GDS crossing methods to be quick, simple methods that are feasible to implement in the clinical setting, especially if conducting these studies with MICs derived from reference testing. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Monogue ML, Nicolau DP. Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa. J Antimicrob Chemother  2018; 73: 942– 52. Google Scholar CrossRef Search ADS PubMed  2 Kalil AC, Metersky ML, Klompas M et al.   Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis  2016; 63: e61– 111. Google Scholar CrossRef Search ADS PubMed  3 Tateda K, Ishii Y, Matsumoto T et al.   ‘Break-point Checkerboard Plate’ for screening of appropriate antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa. Scand J Infect Dis  2006; 38: 268– 72. Google Scholar CrossRef Search ADS PubMed  4 Tunney MM, Scott EM. Use of breakpoint combination sensitivity testing as a simple and convenient method to evaluate the combined effects of ceftazidime and tobramycin on Pseudomonas aeruginosa and Burkholderia cepacia complex isolates in vitro. J Microbiol Methods  2004; 57: 107– 14. Google Scholar CrossRef Search ADS PubMed  5 Pankey GA, Ashcraft DS, Dornelles A. Comparison of 3 Etest® methods and time-kill assay for determination of antimicrobial synergy against carbapenemase-producing Klebsiella species. Diagn Microbiol Infect Dis  2013; 77: 220– 6. Google Scholar CrossRef Search ADS PubMed  6 Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother  2003; 52: 1. Google Scholar CrossRef Search ADS PubMed  7 White RL, Burgess DS, Manduru M et al.   Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother  1996; 40: 1914– 8. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Feasibility of routine synergy testing using antibiotic gradient diffusion strips in the clinical laboratory

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Abstract

Sir, We recently reported synergistic activity between ceftolozane/tazobactam and colistin, as well as between ceftolozane/tazobactam and fosfomycin, against MDR Pseudomonas aeruginosa (MDRP) by time–kill experiments.1 These are important observations as combination therapy against P. aeruginosa is frequently employed in clinical practice, especially for patients at high risk of mortality.2 Although time–kill analyses are revered as the ‘gold standard’ for synergy assessments, they are typically only performed in the research setting versus the clinical laboratory given the time-intensive procedure involved. The chequerboard method is useful and a simplified ‘breakpoint chequerboard method’ has also been described,3,4 though both are cumbersome and not easily adaptable to the clinical laboratory for testing of multiple isolates. However, given the increasing prevalence of MDRP and the need to avoid delay in the initiation of potent, optimized combination antibacterial regimens, clinicians will find routine synergy testing an asset to patient care. Thus, we performed synergy tests using antibiotic gradient diffusion strips (GDSs) on the four MDRP strains used in our previous time–kill experiments to assess the clinical feasibility of performing these tests and their concordance with the gold standard synergy testing method. The MICs of ceftolozane/tazobactam, fosfomycin, colistin and amikacin were determined by Etest® (bioMérieux, Durham, NC, USA) and MIC Test Strip (MTS) (Liofilchem®, Waltham, MA, USA). Synergy assessments were performed by crossing ceftolozane/tazobactam with fosfomycin, colistin and amikacin Etest® strips (i.e. Method 1) and Liofilchem® MTSs (i.e. Method 2) at a 90° angle at the respective MICs of each agent. The Etest® MIC:MIC method (i.e. Method 3) was also performed as described by Pankey et al.5 Synergy assessments were performed in duplicate with a separately prepared inoculum from the second subculture. The mean fractional inhibitory concentration index (FICI) was calculated by dividing the mean MIC of each drug in combination by the MIC of each drug alone and adding the results. Synergy was defined as FICI ≤0.50, no interaction was defined as FICI >0.50 to ≤4.00 and antagonism was defined as FICI >4.00.6 In total, 12 different ceftolozane/tazobactam-drug combinations were assessed among the four P. aeruginosa isolates tested previously by time–kill experiments. Concordance across all three GDS methods was frequently observed, with 10 (83.3%) ceftolozane/tazobactam-drug combinations producing identical qualitative results, indicating the absence of antibiotic interaction (Table 1). Synergistic interactions were recorded by time–kill analysis for seven combinations;1 however, only GDS Method 1 produced concordant results for one (14.3%) combination and Methods 2 and 3 indicated absence of antibiotic interaction for all seven combinations. Synergy was identified by Methods 1 and 3 (Etest® methods) for one combination that produced additive results (i.e. 1–2 log10 cfu/mL decrease in bacterial burden compared with the most active agent alone) by time–kill analysis. For the four remaining combinations, the FICIs resulting from all three GDS methods indicated ‘no interaction’, which is similar to the ‘indifference’ interpretation from the time–kill results. The presence of some discordance between time–kill experiments and Etest® methods has been reported previously.5,7 Table 1. Synergy testing results P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  a Synergistic interaction assessed by a GDS method. b Concordance with time–kill results. Table 1. Synergy testing results P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  P. aeruginosa strain and ceftolozane/tazobactam- drug combination  Time–kill results  Method 1, Etest® crossing method, mean FICI  Method 2, MTS crossing method, mean FICI  Method 3, Etest® MIC: MIC method, mean FICI  P. aeruginosa C8-21           ceftolozane/tazobactam-fosfomycin  additive  0.26a  0.78  0.07a   ceftolozane/tazobactam-colistin  synergy  1.03  1.21  0.56   ceftolozane/tazobactam-amikacin  indifference  0.63  0.81  0.63  P. aeruginosa C14-22           ceftolozane/tazobactam-fosfomycin  synergy  0.74  0.78  0.52   ceftolozane/tazobactam-colistin  synergy  2.00  1.13  1.83   ceftolozane/tazobactam-amikacin  indifference  1.33  0.67  1.08  P. aeruginosa C28-5           ceftolozane/tazobactam-fosfomycin  synergy  0.50a,b  0.58  0.53   ceftolozane/tazobactam-colistin  synergy  1.76  1.71  1.38   ceftolozane/tazobactam-amikacin  indifference  0.88  1.54  0.88  P. aeruginosa C45-10           ceftolozane/tazobactam-fosfomycin  indifference  0.79  0.79  0.77   ceftolozane/tazobactam-colistin  synergy  2.00  1.17  2.00   ceftolozane/tazobactam-amikacin  synergy  1.21  1.00  1.02  a Synergistic interaction assessed by a GDS method. b Concordance with time–kill results. While these GDS synergy methods did not detect all synergistic interactions by time–kill analyses, they did identify an MIC-lowering effect equivalent to at least a one-dilution reduction for one or both agents in six (50%) combinations by each crossing method (Methods 1 and 2) and in seven (58%) combinations by Method 3. Importantly, this MIC-lowering effect may indicate opportunities to optimize pharmacodynamic exposures in vivo and may be especially valuable to a clinician when MICs of multiple antibiotics approach or just barely exceed the susceptibility breakpoint. With regard to time, ∼12–15 min was required to complete Methods 1 and 2. This included a waiting period of 10 min to allow for plates to dry prior to GDS placement, and therefore only 2–5 min was spent performing the technical procedure. Method 3 requires an extra hour of incubation at room temperature; thus a total of ∼75 min was required. As the MICs of each agent alone must be determined prior to synergy testing, the procedure is usually carried out over a span of 2 days, which is not practical in the clinical setting. In order to provide results to clinicians in <24 h, it would be ideal if GDS synergy tests could be performed with MICs determined by the reference antimicrobial susceptibility testing (AST) method utilized in the clinical laboratory. For this reason, a sensitivity analysis was performed using Method 1 but crossing both strips at 1–2 dilutions higher or lower than determined by the GDS to account for expected discordance between the reference AST method and the GDS-derived MIC. The qualitative interpretation of the FICI was identical in 16 of 24 (67%) additional tests completed in this manner. However, agreement was 100% if the original GDS-derived MIC was used to calculate the FICI. Thus, performance of the standard GDS procedure simultaneously with the synergy test at MICs produced from AST improves concordance while still allowing results in <24 h. It would be prudent to perform a similar sensitivity analysis should a laboratory prefer to adopt either Method 2 or 3 using MICs derived from reference AST for routine GDS synergy studies. In summary, synergy testing with GDSs performed on four MDRP isolates supported our previous findings of synergy between ceftolozane/tazobactam and fosfomycin by time–kill analysis. These data provide additional support for use of this combination against MDRP. Ceftolozane/tazobactam-colistin and ceftolozane/tazobactam-amikacin combinations warrant additional study owing to the observed discordance between time–kill and GDS synergy testing methods. Notwithstanding the presence of some degree of expected discordance with the gold standard synergy testing method, we determined GDS crossing methods to be quick, simple methods that are feasible to implement in the clinical setting, especially if conducting these studies with MICs derived from reference testing. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Monogue ML, Nicolau DP. Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa. J Antimicrob Chemother  2018; 73: 942– 52. Google Scholar CrossRef Search ADS PubMed  2 Kalil AC, Metersky ML, Klompas M et al.   Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis  2016; 63: e61– 111. Google Scholar CrossRef Search ADS PubMed  3 Tateda K, Ishii Y, Matsumoto T et al.   ‘Break-point Checkerboard Plate’ for screening of appropriate antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa. Scand J Infect Dis  2006; 38: 268– 72. Google Scholar CrossRef Search ADS PubMed  4 Tunney MM, Scott EM. Use of breakpoint combination sensitivity testing as a simple and convenient method to evaluate the combined effects of ceftazidime and tobramycin on Pseudomonas aeruginosa and Burkholderia cepacia complex isolates in vitro. J Microbiol Methods  2004; 57: 107– 14. Google Scholar CrossRef Search ADS PubMed  5 Pankey GA, Ashcraft DS, Dornelles A. Comparison of 3 Etest® methods and time-kill assay for determination of antimicrobial synergy against carbapenemase-producing Klebsiella species. Diagn Microbiol Infect Dis  2013; 77: 220– 6. Google Scholar CrossRef Search ADS PubMed  6 Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother  2003; 52: 1. Google Scholar CrossRef Search ADS PubMed  7 White RL, Burgess DS, Manduru M et al.   Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother  1996; 40: 1914– 8. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 9, 2018

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