James Albiero
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Josmar Mazucheli
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Juliana Pimenta dos Reis Barros
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Marcia Maria dos Anjos Szczerepa
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Sheila Alexandra Belini Nishiyama
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ABSTRACTFosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in bothin vitroand clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producingPseudomonas aeruginosastrains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producingP. aeruginosastrains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones ofP. aeruginosaisolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50and MIC90by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 μg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 μg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producingP. aeruginosastrains.