Pharmacodynamics of plazomicin and a comparator aminoglycoside, amikacin, studied in an in vitro pharmacokinetic model of infection.

• The pharmacodynamics of plazomicin were studied in a pre-clinical model of infection. • Plazomicin AUC/MIC ratios for 24-h static and bactericidal effects were determined for E. coli and K. pneumoniae. • Plazomicin AUC/MIC targets align with amikacin. The new aminoglycoside plazomicin shows in vitro potency against multidrug-resistant Enterobacteriales. The exposure–response relationship of plazomicin and the comparator aminoglycoside amikacin was determined for Escherichia coli , while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic model was used. Five E. coli strains (two meropenem-resistant) and five K. pneumoniae strains (two meropenem-resistant) with plazomicin MICs of 0.5–4 mg/L were used. Antibacterial effect was assessed by changes in bacterial load and bacterial population profile. The correlation between change in initial inoculum after 24 h of drug exposure and the AUC/MIC ratio was good (plazomicin R 2 ≥ 0.8302; amikacin R 2 ≥ 0.9520). Escherichia coli plazomicin AUC/MIC ratios for 24-h static, –1, –2 and –3 log drop were 36.1 ± 18.4, 39.3 ± 20.9, 41.2 ± 21.9 and 44.8 ± 24.3, respectively, and for amikacin were 49.5 ± 12.7, 55.7 ± 14.8, 64.1 ± 19.2 and 73.3 ± 25.3. Klebsiella pneumoniae plazomicin AUC/MIC ratios for 24-h static, –1, –2 and –3 log drop were 34.0 ± 15.2, 46.8 ± 27.8, 67.4 ± 46.5 and 144.3 ±129.8. Plazomicin AUC/MIC ratios >66 and amikacin AUC/MIC ratios >57.7 were associated with suppression of E. coli growth on 4 × or 8 × MIC recovery plates. The equivalent plazomicin AUC/MIC to suppress resistance emergence with K. pneumoniae was >132. The plazomicin AUC/MIC for 24-h static effect and –1 log reduction in E. coli and K. pneumoniae bacterial load was in the range 30–60. Plazomicin AUC/MIC targets aligned with those of amikacin for E. coli. [ABSTRACT FROM AUTHOR]