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

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 R2 ≥ 0.8302; amikacin R2 ≥ 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.