Impact of bacterial load on pharmacodynamics and susceptibility breakpoints for tigecycline and Klebsiella pneumoniae

Abstract

Objectives: In the absence of other therapeutic options, tigecycline is used to treat bloodstream infections and pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp). In this study, the standard and high tigecycline dosing regimens were simulated and tested against different inocula of CP-Kp isolates in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model. Methods: Four susceptible isolates (EUCAST MICs of 0.125-1 mg/L) and two intermediately susceptible CP-Kp clinical isolates (MICs of 2 mg/L) were tested at three different inocula (107, 105 and 103 cfu/mL), simulating tigecycline serum and lung fCmax concentrations of 0.15 and 1.5 mg/L, respectively, of 50 mg tigecycline every 12 h for 48 h. The exposure-effect relationships were described and the probability of target attainment was calculated for each inoculum in order to determine PK/PD susceptibility breakpoints. Results: No cfu reduction was observed at serum concentrations. At lung concentrations and low inocula, a bacteriostatic and killing effect was found for isolates with MICs of 0.25 and 0.125 mg/L, respectively. The fAUC0-24/MIC (tAUC0-24/MIC) associated with half-maximal activity was 16 (150) with 103 cfu/mL, 28 (239) with 105 cfu/mL and 79 (590) with 107 cfu/mL. A PK/PD susceptibility breakpoint of ≤0.06 and ≤0.125 mg/L for bacteraemia with ≤101 cfu/mL and ≤0.25 and ≤0.5 mg/L for pneumonia with ≤103 cfu/g was determined for the standard tigecycline dose of 50 mg and the higher dose of 100 mg, respectively. Conclusions: Tigecycline monotherapy with either 50 or 100 mg would not be sufficient for most patients with bacteraemia, though the higher dose of 100 mg could be effective for patients with pneumonia with low bacterial load.