Evidence for Efficacy of Cefiderocol against OXA-48-Containing Isolates from the APEKS-NP and CREDIBLE-CR Trials.

LETTER

We were very interested to read the minireview by Boyd et al. (1) on the classification, identification, epidemiology, and treatment of OXA-48-like carbapenemase-producing Enterobacterales. In their discussion of cefiderocol, the authors were correct to point out “it is unclear how many patients had OXA-48-like producers” with regard to the CREDIBLE-CR study (2). Aside from a single poster describing the outcomes of specific carbapenemases from the CREDIBLE-CR study (3), we have not published data specific to clinical efficacy in OXA-48-producing infections except for two cases of bacteremia (4). The authors also point out that registrational clinical trials that usually exclude patients with known carbapenem-resistant infections due to the inactivity of the control antibiotics provide limited high-quality information pertaining to molecularly characterized clinical data on OXA-48- and OXA-48-like pathogens.

Shionogi reviewed both the CREDIBLE-CR and APEKS-NP (5) clinical trial databases, where all pathogens were molecularly characterized. A total of 10 patients with OXA-48-positive Enterobacterales who received cefiderocol were identified (Table 1). Seven were from CREDIBLE-CR, and three were from APEKS-NP. All characterized pathogens were Klebsiella pneumoniae species. Of note, three contained OXA-48 along with NDM-1 carbapenemase, and all contained other extended-spectrum (ESBL) and original-spectrum (OSBL) type beta-lactamases. All but two isolates had high-level resistance to meropenem (MIC > 8 μg/mL). All patients but one received cefiderocol as monotherapy, 7 of 10 (70%) patients were judged to have clinical cure at the test-of-cure assessment (cefiderocol MIC range, 0.12 to 4 mg/L), and all survived through day 28.

TABLE 1

Summary of CREDIBLE-CR and APEKS-NP database results for Klebsiella pneumoniae

Clinical study	Cefiderocol MIC (μg/mL)	Meropenem MIC (μg/mL)	Site of infectiona	Country	Clinical outcome at TOC	Beta-lactamase profileb
CREDIBLE-CR	2	4	BSI/sepsis	Spain	Clinical failure	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-48
	4	>64	cUTI	Turkey	Clinical cure	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-48; NDM-1
	0.12	32	cUTI	Turkey	Clinical cure	CTX-M-9-group; SHV-OSBL; TEM-OSBL; OXA-48
	1	16	cUTI	Turkey	Clinical cure	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-232
	1	8	cUTI	Turkey	Clinical cure	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-48
	4	>64	cUTI	Korea	Indeterminate	CTX-M-55; SHV-OSBL; OXA-232; NDM-1
	1	>64	BSI/sepsis	Thailand	Clinical cure	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-232; NDM-1
APEKS-NP	2	64	RTI	Ukraine	Clinical cure	CTX-M-1-TYPE; SHV-OSBL; TEM-OSBL; OXA-48
	1	64	RTI	Russia	Clinical cure	CTX-M-15; SHV-OSBL; OXA-48
	0.5	32	RTI	Georgia	Indeterminate	CTX-M-15; SHV-OSBL; TEM-OSBL; OXA-48

BSI, bloodstream infection; cUTI, complicated urinary tract infection; RTI, respiratory tract infection.

Beta-lactamases in bold type are carbapenemases.

Although these numbers are small, the clinical and microbiological outcomes were consistent with the studies’ overall findings of efficacy against Enterobacterales. Together with the demonstrated in vitro stability of cefiderocol to OXA-48 hydrolysis (6) and the in vitro activity against OXA-48 producers (7–9), we are confident of the potential benefit of cefiderocol treatment for OXA-48-producing Enterobacterales.