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.

Cefiderocol susceptibility of Achromobacter spp.: study of an accurately identified collection of 230 strains

“…strains accurately identified by nrdA gene sequencing and providing a full comparison to TZP, MEM and SXT susceptibility data. To date, only eight studies [ 32 – 39 ] have focused on determining susceptibility to cefiderocol of a series of Achromobacter spp., and only four of them [ 34 – 36 , 38 ] used the BMD reference method (ID-CAMHB) (Table 3 ). Compared to the present study of 230 isolates, most of published articles have presented a limited number of strains ranging from one [ 37 ] to 74 strains [ 39 ], except for Takemura et al .…”

“…Compared to the present study of 230 isolates, most of published articles have presented a limited number of strains ranging from one [ 37 ] to 74 strains [ 39 ], except for Takemura et al . , who recently studied a larger panel of 334 strains [ 36 ]. However, none of these articles used nrdA gene sequencing as the identification method except for Takemura et al .…”

“…However, none of these articles used nrdA gene sequencing as the identification method except for Takemura et al . who performed whole-genome sequencing and MLST characterization on eight Achromobacter strains only (seven A. xylosoxidans and one Achromobacter sp., including six strains resistant to cefiderocol) [ 36 ]. When specified, the identification method was MALDI-TOF MS, suggesting low reliability of species identification and potentially explaining the low diversity of species identified ( A. xylosoxidans , A. insolitus , A. denitrificans , A. piechaudii and Achromobacter sp.)…”

“… MALDI-TOF MS (Bruker) MIC with EUMDROXF® plate Sensititre (standard CAMHB) – ≤ 0.03 to > 8 0.25 1 91 EUCAST [ 33 ] 8 – A. xylosoxidans MALDI-TOF MS (Bruker) MIC with Sensititre lyophilized BMD panel (standard CAMHB) – 0.06 to 1 0.25 1 100 EUCAST [ 34 ] 12 – A. xylosoxidans MALDI-TOF MS (NS brand) MIC with BMD reference method (ID-CAMHB) – 0.25 to 2 0.5 1 100 EUCAST, CLSI [ 35 ] 15 Blood (> 90%) (cancer patients) Achromobacter sp. – MIC with BMD reference method (ID-CAMHB) – – – 0.125 100 CLSI [ 36 ] 334 Respiratory tract (76.6%) Blood (7.2%) Skin (6%), gastrointestinal (4.8%) and urinary (3.9%) tract, unknown (1.5%) A. xylosoxidans (93.1%) A. insolitus (3.3%), Achromobacter sp. (2.7%) A. denitrificans (0.6%) A. piechaudii (0.3%) MALDI-TOF MS (Bruker) + WGS and MLST characterization for 8 strains (2.4%) MIC with BMD reference method (ID-CAMHB) – ≤ 0.03 to > 64...…”

“…Taking all these studies together, 22 strains (4.6%) were resistant to cefiderocol: two strains (one A. xylosoxidans and one A. insolitus ) from sputum of CF patients with MICs ≥ 8 mg/L with EUMDROXF® plate Sensititre (standard CAMHB) [ 32 ], six strains (five A. xylosoxidans and one Achromobacter sp.) with MICs ≥ 16 mg/L with BMD reference method (origin not specified) and 14 other strains with no available associated information on species or origin [ 36 , 39 ]. Among these 22 strains resistant to cefiderocol, at least seven isolates (≥ 31.8%) were non-susceptible to MEM (no data given on both TZP and SXT susceptibilities).…”