Real-life experience with use of cefiderocol in non-critically ill patients in a tertiary care hospital

Abstract

Background

Clinical experience with cefiderocol is limited to a few patients with multidrug-resistant (MDR) infections. Moreover, the data has been collected primarily in critically ill patients. Thus, there is a need to increase the information regarding the use of cefiderocol in clinical practice in more types of patients.

Objectives

To evaluate the effectiveness and safety of cefiderocol in clinical practice in non-critical patients.

Methods

A retrospective observational study including all adult patients treated with cefiderocol between January 2020 and March 2023 in a tertiary hospital. Patients with a prescription at an intensive care unit were excluded. Effectiveness was measured in terms of clinical and microbiological cure seven days after the end of treatment. To assess safety, adverse effects potentially associated with cefiderocol were collected.

Results

A total of 17 patients (80% men) with a median age of 57 (IQR 53–64) years were included. The predominant focus of infection was urinary (47%). The main causal microorganism of the infection was Pseudomonas aeruginosa (59%). Eleven isolates (65%) were carbapenemase-producing gram-negative bacilli (GNB); the rest (35%) was classified as extensively-drug resistant GNB (XDR-GNB) with other resistance mechanisms. The isolated carbapenemases were one GES, one KPC, eight metallobetalactamases (seven VIM type and one NDM), and one carbapenemase without type identification. Treatment with cefiderocol was completed in all the patients. Fifteen (88%) patients were clinically cured. Regarding microbiological cure, 12 (70%) had negative cultures. No patient presented adverse effects potentially associated with cefiderocol.

Conclusion

Cefiderocol achieves clinical and microbiological improvement in non-critical patients with infections with limited therapeutic options while maintaining a good safety profile.

Resumen

Antecedentes

La experiencia clínica con cefiderocol en el tratamiento de infecciones multiresistentes se limita principalmente a pacientes críticos. Es necesario aumentar la información con respecto al uso de cefiderocol en la práctica clínica en otros tipos de pacientes.

Objetivos

Evaluar la eficacia y seguridad de cefiderocol en la práctica clínica habitual en pacientes no críticos.

Métodos

Estudio observacional retrospectivo que incluye todos los pacientes adultos no críticos tratados con cefiderocol entre enero de 2020 y marzo de 2023 en un hospital terciario. La eficacia del tratamiento se midió en términos de curación clínica y microbiológica siete días después de finalizar el tratamiento. Para evaluar la seguridad, se recogieron los efectos adversos potencialmente asociados a cefiderocol.

Resultados

Se incluyeron 17 pacientes con una mediana de edad de 57 (IQR 53-64) años. El foco predominante fue el urinario (47%). El principal microorganismo causal fue Pseudomonas aeruginosa (59%). Once aislados (65%) eran bacilos gramnegativos (BGN) productores de carbapenemasas; el resto (35%) se clasificaron como BGN extremadamente resistentes a fármacos (XDR-BGN) con otros mecanismos de resistencia. Las carbapenemasas aisladas fueron una GES, una KPC, ocho metalobetalactamasas (siete tipos VIM y un tipo NDM) y una con tipo de carbapenemasa sin identificar. Todos los pacientes completaron el tratamiento. Quince (88%) pacientes alcanzaron la curación clínica y 12 (70%) la microbiológica. Ningún paciente presentó efectos adversos potencialmente asociados a cefiderocol.

Conclusiones

Cefiderocol consigue mejoría clínica y microbiológica en pacientes no críticos con infecciones con opciones terapéuticas limitadas manteniendo un buen perfil de seguridad.

Introduction

Antimicrobial resistance is an emerging global health problem for the World Health Organization (WHO), which establishes as a priority objective the development of new antibiotics for emerging multi-drug resistant (MDR) and extensively-drug resistant (XDR) bacteria.¹ Another issue of concern is bacteria with difficult-to-treat resistance (DTR), defined as those strains that do not show sensitivity to highly effective low-toxicity agents.²

The pathogens with the highest priority for the WHO in the research and development of new drugs are the Enterobacterales group, Pseudomonas aeruginosa and Acinetobacter baumannii. Recently, new combinations of β-lactam/β-lactamase inhibitors (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, imipenem/cilastatin–relebactam) and non-β-lactam antibacterials have appeared. Those combinations overcome some of these resistance mechanisms. However, none of the new combinations of β-lactams/β-lactamase inhibitors are stable against metallo-β-lactamases. Therefore, none of these treatments would cover all classes of β-lactamases, and it is necessary to use antibacterials that do have this activity.³

Cefiderocol is the first siderophore cephalosporin for treating adults with gram-negative bacterial infections with a unique cell entry mechanism, an excellent in vitro activity, a good tolerability and a good safety profile.⁴ The periplasmic concentration of cefiderocol is increased by forming a ferric iron chelate with the hydroxyl groups of the catechol moiety, thereby taking advantage of bacterial iron transport systems.⁵ Furthermore, this structure confers additional stability against all classes of carbapenemases, including serine-carbapenemases (KPC, OXA) and metallo-β-lactamases (NDM, VIM and IMP). It has also demonstrated potent in vitro activity against a wide range of gram-negative bacteria, including those expressing extended-spectrum beta-lactamases (ESBL) and non-fermenting gram-negative bacteria such as DTR-P. aeruginosa (DTR-PA) and carbapenem-resistant A. baumannii (CRAB).^6,7

However, there are still unresolved questions about the efficacy of cefiderocol, its use as a single agent or in combination therapy, and recommendations for its use in certain situations. Therefore, clinical experience is limited to multidrug-resistant infection cases series after the failure of previous treatments, mostly in critical care settings.⁸ So far, the efficacy of cefiderocol has been demonstrated in two Phase III randomized clinical trials (RCT), but clinical data evaluating efficacy and safety in clinical practice settings are scarce and limited to a few case reports and small case series in specific patient groups.^9,10

This study aims to evaluate the effectiveness and safety of cefiderocol in clinical practice in non-critically ill patients (not admitted to intensive care units) in a tertiary care hospital.

Methods

Design

A retrospective observational study was conducted at the Hospital Universitario Ramón y Cajal in Madrid, a tertiary-care hospital. All adult patients (>18 years) admitted to inpatient units treated with cefiderocol were included from January 2020 to April 2023. Patients whose prescription of cefiderocol was initiated at an intensive care unit (ICU) were excluded.

This study was approved by the Ethics Committee on Investigation with Medicines (CEIm) of the Hospital Universitario Ramón y Cajal (219/23).

Data collection

Patient clinical variables and microbiological variables about the episode were collected.

Clinical variables at admission: sex, age, admission department, Charlson Comorbidity Index, risk factors for being a carrier of gram-negative bacilli (GNB), presence of bloodstream infection (BSI), use in monotherapy (single antigram-negative agent) or in combination (use of one or more antibiotics in addition to cefiderocol), administration pattern (dose, frequency). The following were considered risk factors for being a carrier of GNB¹¹: hospital admission lasting more than five days in the last three months, being institutionalized (health center, nursing home, prison), presenting known colonization or infection by multi-drug resistant GNB (MDR-GNB), having been on antibiotic treatment for more than seven days in the previous month, presenting chronic renal failure on hemodialysis (HD) or peritoneal dialysis (PD), or suffering from a colonizable chronic pathology (bronchiectasis, cystic fibrosis, chronic ulcer).

Microbiological variables: indication, source of infection, acquisition of infection, type of culture in which isolation of the causal microorganism is confirmed and presence of MDR (bacteria that are resistant to at least one agent in three or more antimicrobial categories).

Clinical variables at discharge: clinical cure (CC), microbiological cure (CM), source control, the outcome of admission (admission to ICU, death, transfer to another center), recurrence (recurrence of infection by the same bacterial specie), reinfection (recurrence of infection by a different bacterial specie), persistence (non clinical or microbiological cure), adverse effects potentially associated with cefiderocol, and re-admissions after 30 days from discharge, differentiation between all-cause re-admissions and re-admissions due to the infection.

All data were collected anonymously in an electronic database.

Microbiological analysis

Bacterial identification was confirmed by MALDI-TOF MS (Bruker Daltonics GmbH, Leipzig, Germany). Antimicrobial susceptibility was performed by an automated microdilution method (MicroScan; Siemens, CA) and interpreted using EUCAST-2023 clinical breakpoints (https://www.eucast.org/clinical_breakpoints/). Carbapenemase production was investigated using O.K.N.V.I. RESIST-5 immunochromatography test (CORIS BioConcept, Gembloux, Belgium) and further molecular characterization was routinely performed using eazyplex® SuperBug-CRE and SuperBug-expert (Amplex-Biosystems, Delaware). Cefiderocol susceptibility was assessed by disk diffusion method (30 μg, ThermoFisher Scientific, US). In those isolates with inhibition zones within the ATU range, the cefiderocol susceptibility was further studied by standard broth microdilution using SensititreTM EUMDROXF (Thermo Fisher Scientific, US).

Evaluation of effectiveness

Effectiveness was measured in terms of clinical cure and microbiological cure. Clinical cure was considered as the disappearance of signs and symptoms and microbiological cure as the presence of negative cultures for the microorganism treated with cefiderocol seven days after treatment, based on CREDIBLE-CR clinical trial design.⁹ Peer review was performed in a blinded fashion.

Safety assessment

Adverse effects potentially associated with cefiderocol were collected.

Documentary source and statistical analysis

The information was obtained from the Electronic Medical Record. The results were expressed in median (interquartile range or IQR) for continuous variables and absolute frequency and percentages for categorical variables. The Kolmogorov–Smirnov test was used to determine normality. The association between categorical variables was studied using the chi-square test or Fisher's exact test, as appropriate. The relationship between quantitative variables was studied using the Student's t-test or Mann–Whitney U test.

Results

A total of 43 patients were selected, of which 23 (46.5%) were excluded because they were critically ill and cefiderocol was prescribed at an ICU. Three other patients were excluded from the analysis because information on clinical and microbiological response was unavailable. A total of 17 patients were evaluated, and fourteen of them (82%) were men. The median age was 57 (IQR 53–64) years. They had a median Charlson Comorbidity Index of 3 (1–4) points. The admission service was surgical in nine of the cases (53%) and medical in eight (47%). All patients were followed up by the Infectious Diseases Service, who made recommendations through an inter-consultation.

In 10 patients (41%), risk factors for being a carrier of GNB were found, primarily due to hospital admission for more than five days in the last three months (90%) and to a lesser extent due to antibiotic use for more than seven days in the previous month (80%), colonization or infection by MDR-GNB (50%) and chronic renal failure on HD or PD (20%). In most cases (94%), the indication for treatment was targeted, i.e., with microbiological confirmation, and in only one patient (6%), it was prescribed empirically due to a history of MDR-GNB infection.

The predominant focus of infection was urinary (47%), five of them were catheter-associated infection (62.5%); minority focus of infection are presented in Table 1. The acquisition was nosocomial in 11 cases (65%) and community-acquired in 6 cases (35%). BSI occurred in 6patients (35%). Description of patient characteristics, admission service, type of infection and therapies are also shown in Table 1.

Table 1.

Description of patient characteristics, admission service, type of infection and therapies.

Patient	Age (years)/sex	Admission department	Diagnosis	Source	Culture	BSI	Type of infection	Cefiderocol dosage	Cefiderocol duration (days)	Combination therapy for BGN
P1	77/M	NEPHROLOGY	cUTI	URINARY	URINE	No	CA	1.5 g/8 h	7	No
P2	55/M	UROLOGY	PNA	URINARY	BLOOD	Yes	N	2 g/8 h	15	No
P3	75/M	GENERAL SURGERY	IAI	ABDOMINAL	ASCITIC FLUIDNo		CA	2g/8 h	27	No
P4	38/M	NEPHROLOGY	cUTI	URINARY	URINE	No	N	2 g/8 h	19	No
P5	64/F	GENERAL SURGERY	IAI	ABDOMINAL	ASCITIC FLUID	No	N	2 g/8 h	11	Tobramycin
P6	59/M	UROLOGY	cUTI	URINARY	URINE	No	N	1.5 g/8 h	29	No
P7	68/M	CARDIOLOGY	SSTI	CATHETER	BLOOD	Yes	CA	1 g/8 h	13	Tigecycline
P8	55/F	SURGERY	IAI	ABDOMINAL	BLOOD	Yes	CA	2 g/8 h	7	Tigecycline
P9	74/M	UROLOGY	cUTI	URINARY	URINE	No	N	1 g/8 h	14	No
P10	57/M	HEMATOLOGY	FN	BLOOD	BLOOD	Yes	N	2 g/8 h	11	Ciprofloxacin
P11	53/M	SURGERY	BTI	BILIARY	BILE	No	N	2 g/8 h	37	Meropenem
P12	40/M	PLASTIC SURGERY	SSTI	SKIN AND SOFT-TISSUE	SURGICAL WOUND	No	N	2 g/6 h	15	Colistin
P13	44/M	GASTROENTE-ROLOGY	IAI	ABDOMINAL	IA ABSCESS	No	N	2 g/8 h	29	ColistinMeropenem
P14	41/M	INFECTIOUS DISEASES	TB	RESPIRATORY	TRACHEAL ASPIRATE	No	CA	2 g/6 h	15	Colistin
P15	57/M	NEPHROLOGY	PNA	URINARY	URINEBLOOD	Yes	CA	2 g/8 h	14	No
P16	64/F	NEUROSUR-GERY	PNA	URINARYRESPIRATORYRECTAL CARRIER	URINERECTALTRACHEO-BRONQUIAL	Yes	N	2 g/8 h	14	No
P17	62/M	GENERAL SURGERY	cUTI	URINARY	URINE	No	N	2 g/8 h	6	No

BTI = biliary tract infection. CA = community-acquired. F = female. FN = febrile neutropenia. IAI = intra-abdominal infection. M = male. N = nosocomial. PNA = pyelonephritis. SSTI = skin and soft tissue infection. TB = tracheobronchitis. cUTI = complicated urinary tract infection.

In eight patients (47%), cefiderocol was used in combination with other antibiotics, while in 9 patients (53%) it was used in monotherapy. When used in combination, it was mainly with colistin (37.5%). Other drugs were used in combination with cefiderocol, as reflected in Table 1. The starting dose of cefiderocol was 2 g/8 h in 11 patients (64%); in four patients, the dose was adjusted according to renal function to 1.5 g/8 h (12%) or 1 g/8 h (12%), and in two patients (12%) the dosage was 2 g/6 h due to high glomerular filtration rates, in all cases following the indications of the technical data sheet.

Microbiological tests were requested in all patients before starting cefiderocol and in all of them the species were identified. Isolation was mainly confirmed in urine cultures (41%) followed by blood cultures (29%). The main causative microorganism was P. aeruginosa in 10 patients (59%). The rest of the isolated microorganisms are shown in Table 2. In most of the patients (94%), the bacteria causing the infection were multiresistant. In 11 patients (65%), carbapenemase-producing GNB were isolated. The rest (35%) was classified as XDR (bacteria that are resistant to at least one agent in most antimicrobial categories, except for two or less categories) GNB with other resistance mechanisms. The types of carbapenemases isolated were GES (one), KPC (one), metallobetalactamases (seven VIM type and one NDM), and one type of carbapenemase was not identified.

Table 2.

Description of pathogen characteristics, clinical and microbiological outcomes and mortality.

Patient	Pathogen	MRO	Other isolates	Clinical cure (after 7 days from EOT)	Microbiological cure (after 7 days from EOT)	30 day mortality
P1	K. oxytoca	KPCVIM	No	Yes	Yes	No
P2	P. aeruginosa	XDR	No	Yes	No assessable	No
P3	P. aeruginosa	XDR	K. aerogenesC. albicans	Yes	Yes	No
P4	P. aeruginosa	C	No	Yes	Yes	No
P5	P. aeruginosa	XDR	No	No	Yes	No
P6	P. putida	VIM	E. faeciumC. guillermondii	Yes	Yes	No
P7	E. cloacae	VIM	K. aerogenes	Yes	Yes	No
P8	P. aeruginosa	XDR	No	Yes	Yes	No
P9	P. fluorescens	VIM	No	Yes	Yes	No
P10	S. maltophilia	–	No	Yes	Yes	No
P11	K. oxytoca	VIM	E. faecium	Yes	No assessable	No
P12	P. aeuruginosa	NDM	K. pneumoniae	No	No	No
P13	P. aeruginosa	XDR	C. glabrata	Yes	No assessable	No
P14	P. aeruginosa	GES	No	Yes	Yes	No
P15	P. aeruginosa	VIM	No	Yes	Yes	No
P16	E. cloacae	VIM	No	Yes	Yes	No
P17	A. baumannii	XDR	No	Yes	No assessable	No

C = carbapenemase. EOT = end of treatment. MRO = multidrug-resistant organisms.

The sensitivity of cefiderocol against the different isolates and those of the other antimicrobials used is included as supplementary material.

The median number of days of treatment was 14 (7–19). Treatment with cefiderocol was completed in all the patients. Fifteen patients (88%) were clinically cured seven days after the end of treatment, and two (10%) suffered a recurrence. Regarding microbiological cure, seven days after the end of treatment, 12 patients (70%) had negative cultures, one (6%) had recurrence, and four (24%) were not evaluable due to lack of cultures. Three patients (18%) required surgical intervention to control the focus and remove the surgical drainage. None of the patients died during admission, nor did they require admission to the ICU. Fourteen (82%) were discharged, and three (18%) were transferred to another center. Five patients (29%) were readmitted within 30 days of discharge, with only one case due to infectious disease.

No patient presented adverse effects potentially associated with cefiderocol nor Clostridioides difficile infection.

Discussion

This article describes the efficacy and safety of cefiderocol to treat multidrug-resistant gram-negative bacteria. Data from our center suggests that cefiderocol could be a treatment option in patients with severe infections caused by resistant microorganisms, since most patients have shown good results. Clinical cure and microbiological cure were achieved in 88% and 70% of the patients who completed the treatment respectively. Furthermore, cefiderocol was well tolerated; no patient presented adverse effects potentially associated with cefiderocol nor C. difficile infection.

Cefiderocol is a siderophore cephalosporin approved for treating infections due to aerobic gram-negative organisms in adults with limited treatment options.⁵ The use of cefiderocol in non-critically ill patients has not been expressly described. In most studies, the majority of patients are in critical condition. In studies conducted in Spain by C. de la Fuente et al.¹² and A.M. Fendian et al.,¹³ 76.9% and 70% of patients are in intensive care units. We did not include patients whose cefiderocol prescription was performed at an intensive care unit.

The most frequently carbapenem-resistant pathogen found in this study was P. aeruginosa (59% of patients). This is consistent with the European Centre for Disease Prevention and Control (ECDC) epidemiological report for 2022, that explained that carbapenem resistance is common in P. aeruginosa and Acinetobacter spp., with a higher EU/EEA population-weighted mean percentage than in Klebsiella pneumoniae.¹⁴ This is also consistent with the real-world evidence published in the literature.¹⁵

Our results for clinical cure (88%) and microbiological cure (70%) were in concordance with other clinical practice studies.^12,13,16,17 Therefore, clinical and microbiological cure were higher than in the clinical trial that led to the drug's approval. In the CREDIBLE⁹ trial, clinical cure is 53% and microbiological cure is 31%. This may be due to a higher percentage of urinary focus in our study and a higher prevalence of critically ill patients and A. baumannii isolates in the CREDIBLE trial.

In our study, cefiderocol was used in combination with other antibiotics in 60% of patients. This combination was mainly with colistin (37.5%). In other clinical practice studies, one of the most commonly used antibiotics in combination with cefiderocol is also colistin.¹⁶ As in other similar retrospective studies, the use of combined treatment and the small number of patients do not allow conclusions to be drawn about the benefit of combined therapy.

The safety of cefiderocol that can be described thanks to this study is in line with that present in the literature, concluding that cefiderocol is a well-tolerated drug.^15,16 No patient required dose adjustment or early discontinuation of the drug due to adverse effects. In addition, no infections due to C. difficile were found. The absence of adverse effects could be a bias due to the retrospective review, whose data is limited to the information found in the clinical record.

The limitations of this study are the usual ones derived from a retrospective design carried out in a single center. The information was collected from the Electronic Medical Record, which could lead to a loss of information if it is not adequately collected. To minimize this, a blinded peer review was performed. However, despite the small sample size, the results, both microbiological and clinical, are very positive and are in line with what was observed in clinical trials. In addition, this is a clinical practice study with subsequent follow-up of patients.

In our experience, cefiderocol achieves both clinical and microbiological improvement in non-critical patients with infections due to gram-negative microorganisms with limited therapeutic options, with low non-response or recurrence. It has a good safety profile, with no potential adverse effects associated with it.

Conflict of interest

The authors report that there are no competing interests to declare.