In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae

Abstract

Objectives: Colistin is still a "last-resort" antibiotic used to manage human infections due to multidrug-resistant (MDR) Klebsiella pneumoniae. However, colistin-resistant K. pneumoniae (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro.

Methods: Three clinical CR-Kp isolates from three patients were collected. Whole-genome sequencing and bioinformatics analysis were performed. The Pharmacokinetics Auto Simulation System 400, by simulating human pharmacokinetics in vitro, was employed to simulate FM, AMK, and COL alone and in combination. Different pharmacodynamic parameters were calculated for determining the antimicrobial effect.

Results: Whole-genome sequencing revealed that none of the three isolates contain mcr gene and that no insertion was found in pmrAB, phoPQ, or mgrB genes. We found the antibacterial activity of AMK alone was more efficient than FM or COL against CR-Kp. The area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was higher than 170 LogCFU/mL·h^-1. In addition, the area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with COL (75,000 IU/kg every12 hours) was higher than that of monotherapies (>100 LogCFU/mL·h^-1 vs <80 LogCFU/mL·h^-1).

Conclusion: FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was effective at maximizing bacterial killing against CR-Kp.

Keywords: Pharmacokinetics; colistin-resistant Klebsiella pneumoniae; combination therapy; monotherapy; pharmacodynamics.

Figure 1

The sketch of PD parameters. Abbreviations: −1KT, −1Log kill time; −2KT, −2Log kill time; −3KT, −3Log kill time; SRT, regrowth recovery time; +1RT, +1Log growth time; AAKC, area above kill curve; AST, analysis start time; MKD, maximum kill down; MKT, maximum kill time; PD, pharmacodynamics; RT, bacterial growth recovery time; TAAKC, total area above kill curve; T−1KT, total −1Log kill time.

Figure 2

In vitro dynamic model time–kill assays using concentrations of FM, AMK, and COL (either alone or in combination) against three CR-Kp strains. Notes: (A) and (B) monotherapy or combination therapy, respectively, against isolate 2887; (C) and (D) monotherapy or combination therapy, respectively, against isolate 3155; (E) and (F) monotherapy and combination therapy, respectively, against isolate 18253. The dotted lines indicate monotherapy, and the solid lines indicate combination therapy. Antibiotic concentrations are denoted by different symbols. Abbreviations: AMK, amikacin; COL, colistin; CR-Kp, colistin-resistant Klebsiella pneumoniae; FM, fosfomycin; q8h, every 8 hours; q12h, every 12 hours; qd, once daily.