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Int J Antimicrob Agents. 2019 Jul 9. pii: S0924-8579(19)30181-5. doi: 10.1016/j.ijantimicag.2019.07.001. [Epub ahead of print]

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

Author information

1
Bristol Centre for Antimicrobial Research & Evaluation (BCARE), Severn Infection Sciences Partnership, Southmead Hospital, BRISTOL BS10 5NB UK.
2
Achaogen, 1 Tower Place, Suite 300, South San Francisco, CA 94080, USA.

Abstract

Plazomicin, an aminoglycoside, overcomes aminoglycoside modifying enzymes with in vitro potency against multidrug resistant Enterobacteriales. The exposure response relationship of plazomicin and comparator aminoglycoside amikacin was determined for Escherichia coli while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic (PK) model was used. Five strains of E.coli (2 meropenem resistant) and 5 strains of K.pneumoniae (2 meropenem resistant) plazomicin MICs 0.5-4mg/L were used. Antibacterial effect was assessed by changes in bacterial load and changes in bacterial population profile. The correlation between change in initial inoculum after 24h drug exposure and area under the concentration curve to MIC ratio (AUC/MIC) was good (plazomicin R2 ≥0.8302, amikacin R2 ≥0.9520). E.coli plazomicin AUC/MIC ratios for 24h static, -1 log drop, -2 log drop and -3 log drop were 36.1±18.4, 39.3±20.9, 41.2±21.9 and 44.8±24.4 respectively, and for amikacin were 49.5±12.7, 55.7±14.8, 64.1±19.2 and 73.3±25.3. K.pneumoniae plazomicin AUC/MIC ratios for 24h static, -1 log drop, -2 log drop 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 MICx4 or x8 recovery plates. The equivalent plazomicin AUC/MIC to suppress emergence of resistance with K.pneumoniae was >132. The plazomicin AUC/MIC for 24h 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.

KEYWORDS:

In vitro model; Pharmacodynamics; Pharmacokinetics; Plazomicin

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