In Vitro and In Vivo Activity of Cefiderocol against Stenotrophomonas maltophilia Clinical Isolates

Background: Cefiderocol (S-649266, CFDC) is a novel siderophore cephalosporin against Gram-negatives including carbapenem (CR)-resistant strains. Its spectrum includes both the Enterobacteriaceae but also non-fermenters, including Stenotrophomonas maltophilia—an opportunistic pathogen with intrinsic resistance to carbapenem antibiotics. In this study, in vitro activity and in vivo efficacy of CFDC and comparators against S. maltophilia were determined.

Methods: MICs of CFDC and comparators (trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), tigecycline (TGC), ciprofloxacin (CPFX), cefepime (CFPM), meropenem (MEPM), and colistin (CL)) were determined by broth microdilution method as recommended by CLSI. The MIC against CFDC was determined using iron-depleted cation-adjusted Mueller-Hinton broth. In vivo efficacy of CFDC, CFPM, ceftazidime-avibactam (CAZ/AVI), MEPM, and CL was evaluated using neutropenic murine systemic infection model caused by strain SR21970. The 50% effective doses (ED₅₀s) were calculated by the logit method using the survival number at each dose 7 days after infection.

Results: MIC₉₀ of CFDC and comparators against the 216 clinical isolates from global countries collected in SIDERO-CR 2014/2016 study are shown in the Table. CFDC, TMP/SMX, MINO, and TGC showed good activity with MIC₉₀ of 0.5, 0.25/4.75, 1, and 2µg/mL, respectively. CFDC, MINO and TGC inhibited growth of all tested strains at ≤1, ≤4, ≤8 µg/mL although 2 strains showed resistance to TMP/SMX. MICs of CFPM, CAZ/AVI, MEPM, and CL were ≥32 µg/mL. The ED₅₀ of CFDC against S. maltophilia SR21970 with MIC of 0.125 mg/mL was 1.17 mg/kg/dose. Conversely, MICs of CFPM, CAZ/AVI, MEPM/CS, and CL against SR21970 were 32 μg/mL or higher, and ED₅₀s were >100 mg/kg/dose, showing that CFDC had potent in vivo efficacy against S. maltophilia strain which was resistant to other antibiotics.

	MIC range (µg/mL)	MIC50 (µg/mL)	MIC90 (µg/mL)
CFDC	≤ 0.031 – 1	0.063	0.5
TMP/SMX	≤ 0.031/≤ 0.589 – 16/304	0.125/2.375	0.25/4.75
MINO	0.063 – 4	0.25	1
TGC	0.125 – 8	1	2
CPFX	0.5 – >32	2	16
CFPM	2 – >32	32	>32
MEPM	0.25 – >32	>32	>32
CL	0.125 – >32	4	16

Conclusion: CFDC showed potent in vitro activity against S. maltophilia including TMP/SMX resistant isolates. CFDC also showed potent in vivo efficacy reflecting in vitro activity against S. maltophilia in murine systemic infection model.