In vitro and in vivo activity of cefiderocol against Achromobacter spp. and Burkholderia cepacia complex, including carbapenem-non-susceptible isolates

Abstract

Achromobacter spp. and Burkholderia cepacia complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the in vitro antibacterial activity of the siderophore antibiotic cefiderocol against Achromobacter spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 Achromobacter spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC)_50/90 of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) Achromobacter spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC_50/90 of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested in vitro against both Achromobacter spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant Achromobacter xylosoxidans strains compared with untreated controls (P < 0.05) and vehicle-treated controls (P < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by Achromobacter spp. and Bcc.

Keywords: Achromobacter spp.; Burkholderia cepacia complex; carbapenem non-susceptible; cefiderocol; multidrug resistant.

Fig 1

Cumulative percentage MIC distributions of cefiderocol and comparators against: (A) Achromobacter spp.; (B) carbapenem-non-susceptible Achromobacter spp.

Fig 2

Cumulative percentage MIC distributions of cefiderocol and comparators against: (A) Burkholderia cepacia complex; (B) carbapenem-non-susceptible Burkholderia cepacia complex.

Fig 3

In vivo efficacy in an immunocompetent rat respiratory infection model of humanized cefiderocol against: (A) meropenem-resistant Achromobacter xylosoxidans; (B) meropenem-susceptible Burkholderia cepacia ATCC 25416. *Significant reduction (P < 0.05) vs vehicle-treated control, Welch’s t test. ^#Significant difference (P < 0.05) vs cefiderocol, Welch’s t test. ^Significant reduction (P < 0.05) vs untreated control, Welch’s t test. Cefiderocol MIC: 0.5 µg/mL for A. xylosoxidans strain 1717914 and 2 µg/mL for A. xylosoxidans strain 1398044. Meropenem MIC: >16 µg/mL for A. xylosoxidans strain 1717914 and >16 µg/mL for A. xylosoxidans strain 1398044. Cefiderocol MIC: ≤0.03 µg/mL for Burkholderia cepacia ATCC 25416. Meropenem MIC: 4 µg/mL for Burkholderia cepacia ATCC 25416.

Fig 4

In vivo efficacy of cefiderocol against meropenem-resistant Achromobacter xylosoxidans in a neutropenic murine lung infection model. *Significant reduction (P < 0.05) vs untreated control, Dunnett’s multiple comparison test. ^#Significant difference (P < 0.05) vs equivalent dose of cefiderocol, Welch’s t test. Cefiderocol MIC: 0.5 µg/mL for A. xylosoxidans strain 1717914 and 2 µg/mL for A. xylosoxidans strain 1398044. Meropenem MIC: >16 µg/mL for A. xylosoxidans strain 1717914 and >16 µg/mL for A. xylosoxidans strain 1398044.