key: cord-0844455-5kpccjpy
authors: Meschiari, Marianna; Volpi, Sara; Faltoni, Matteo; Dolci, Giovanni; Orlando, Gabriella; Franceschini, Erica; Menozzi, Marianna; Sarti, Mario; Del Fabro, Giovanni; Fumarola, Benedetta; Guarneri, Francesco; Lanza, Paola; Lorenzotti, Silvia; Saccani, Barbara; Signorini, Liana; Van Hauwermeiren, Evelyn; Gatti, Milo; Pea, Federico; Castelli, Francesco; Mussini, Cristina
title: Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections
date: 2021-12-11
journal: JAC Antimicrob Resist
DOI: 10.1093/jacamr/dlab188
sha: a9b209258941c6178761c782162eab64fdcacd00
doc_id: 844455
cord_uid: 5kpccjpy

OBJECTIVES: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. METHODS: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. RESULTS: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58–73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3–10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. CONCLUSIONS: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

Cefiderocol is a new siderophore cephalosporin that exploits iron transport systems to penetrate bacterial cells and that has been developed to meet the treatment challenge of carbapenemresistant Gram-negative bacteria (CRGNB). 1 It has shown potent in vitro activity against carbapenem-resistant Enterobacteriaceae (CRE), such as strains producing KPC and metallo-b-lactamases (NDM, VIM and IMP), and against carbapenem-resistant nonfermenting Gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia). 2 Two randomized controlled trials (RCTs) have highlighted the efficacy of cefiderocol compared with regimens including carbapenems in complicated urinary tract infections (cUTI; APEKS-cUTI) 3 and nosocomial pneumonia (APEKS-NP), 4 while the CREDIBLE-CR study demonstrated its efficacy in the treatment of CRGNB when compared with best available therapy (BAT). 5, 6 Nevertheless, in this latter randomized study, the prevalence of P. aeruginosa in the cefiderocol group was only 15%, and real-life studies exploring this specific setting are currently limited. Our aim was to further evaluate the role of cefiderocol in extensively drug resistant (XDR) and difficult-to-treat V C The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecom mons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com resistant P. aeruginosa (DTR-P) infections 7 unresponsive to the BAT or without any other available treatment options.

We conducted a prospective, observational study enrolling all the patients treated with compassionate use of cefiderocol admitted to two large tertiary-care hospitals in Northern Italy (the University Hospitals of Modena and Brescia) from February 2020 to May 2021. We included patients with a proven infection due to an XDR/DTR-P who failed previous treatment regimens or without any other available antibiotic option. Cefiderocol was administered at a standard dose of 2 g every 8 h, each given as a 3 h infusion, with a renal adjustment dose according to the manufacturer recommendations, unless otherwise noted. The patients were prospectively followed from start of cefiderocol to day 90 or until hospital discharge or death. Clinical cure was defined as a resolution, or an improvement of baseline signs and symptoms related to the infection; microbiological cure was defined as the absence of the same CRGNB isolates, both assessed after 7 days from the end of treatment (EOT) with cefiderocol. We also evaluated the occurrence and the time onset of relapse of the clinical signs and/or symptoms (referred to hereafter as 'relapse') or the microbiological recurrence of the baseline pathogen from an appropriate specimen (referred to hereafter as 'recurrence'), in those patients who previously reached clinical and microbiological cure. Thirty and 90 day all-cause mortality rates were also recorded.

All collected isolates were identified by MALDI-TOF MS using VITEK MS (bioMérieux, Marcy lEtoile, France) following the manufacturer's instructions. Antimicrobial susceptibility testing was performed by VITEK MS (bioMérieux) and for cefiderocol by broth microdilution panel YEUMDROF [Thermo Fisher Diagnostics S.p.A., Rodano (MI), Italia]. P. aeruginosa ATCC 27853 was used as QC strain. MICs were interpreted according to the EUCAST breakpoints, Version 11.0, 2021. 8 Each P. aeruginosa isolate was classified according to the Magiorakos et al. 9 criteria as MDR, XDR or pandrug resistant (PDR) and further characterized according to Kadri et al. 7 as difficult-to-treat resistance (DTR).

Finally, we performed therapeutic drug monitoring (TDM) in the case of meningitis. Cefiderocol concentrations were determined by means of a validated liquid chromatography-tandem mass spectrometry method, using cefiderocol-d12 at a concentration of 10 ppm as internal standard working solution. 10 The lower limit of quantification for cefiderocol was 0.25 mg/L.

According to the Early Access Program of Shionogi & Co. Ltd (closed on 26 April 2021), each single request for cefiderocol compassionate use was approved by the Institutional Ethics Committee of Modena and Brescia University hospitals. Table 1 shows the MIC values of the P. aeruginosa isolates.

A total of 17 patients were treated for .72 h with cefiderocol, 14 with combination regimens (82.4%) and 3 with monotherapy (17.6%). All the XDR/DTR-P were susceptible to cefiderocol (MIC 2 mg/L, MIC was not available for three strains). The median duration of therapy was 14 days (IQR 12-21). Cefiderocol was administered in all but one patient as a rescue therapy after experiencing failure of previous treatment regimens. Median time to switch was 3 days (IQR 2-5).

Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to ICU, five had septic shock (29%) and 13/17 (76.5%) underwent endotracheal intubation (ETI). Seven cases (41.2%) were ventilator-associated pneumonia (VAP) of which 71% (5/7) occurred in COVID-19 patients, one of them complicated with bacteraemia. Four cases were complicated intrabdominal infections: two peritonitis with retroperitoneal abscess following an acute necrotic-haemorrhagic pancreatitis and a pancreatectomy, one cholangitis in cholangiocarcinoma and one aortic graft infection with associated tertiary peritonitis. Finally, there was one osteomyelitis, one ecthyma gangrenosum, one nosocomial pneumonia, one recurrent thoracic empyema, one primary bacteraemia and one nosocomial external ventricular drainage meningitis. Patient characteristics, type of infections, pathogens and therapies are described in Table 2 .

In most cases XDR/DTR P. aeruginosa was the only pathogen isolated, while three cases were polymicrobial: one with a PDR A. baumannii, one with S. maltophilia and one with a carbapenem and ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae.

In the whole population, clinical cure was observed in 12/17 patients (70.6%), all but one of them also obtained microbiological cure (13/17; 76.5%). We did not observe breakthrough infections during therapy with cefiderocol. Clinical relapse was observed in three patients (17.6%). The median time from cefiderocol discontinuation to relapse/recurrence was 10 days (IQR 10-12). Unfortunately, we were able to re-test cefiderocol in only one case (P3), in which the MIC increased from 0.25 to 1 mg/L.

Considering only patients with XDR/DRT-P HAP or VAP, the clinical and microbiological cure rates were respectively 62.5% (5/8) and 75% (6/8).

The 30 day and 90 day all-cause mortality rates were respectively 23.5% and 35.3%. The median time to death was 8 days (IQR 3-10) from the EOT. Importantly, only two deaths were associated with both clinical and microbiological failures.

There was no evidence of mild-to-moderate side effects, except for one case (P13) with a possible neurological drug-related adverse event (encephalopathy) requiring the discontinuation of cefiderocol (and amikacin) after 5 days of therapy.

Concerning the TDM for the meningitis case (P10), trough and peak cefiderocol serum levels were collected immediately before (-0.25 h) administration and at the end of 3 h infusion, respectively, resulting in concentrations of 105 mg/L (C min ) and 170 mg/L (C max ). CSF levels (13 mg/L) were measured 25 min before cefiderocol administration, concomitantly with serum trough concentrations, accounting for a C min CSF/serum ratio of 12.4%. It is important to remark that P10 showed moderate renal impairment (creatinine clearance 44.8 mL/min) and was treated with high-dose cefiderocol (2000 mg q6h by 3 h infusion), to optimize drug penetration into the CSF, without developing adverse events despite the high dosage.

Our study described a successful experience with the compassionate use of cefiderocol as rescue therapy in a series of 17 patients with severe infection due to XDR/DRT-P with no other antibiotic options available. We report a rate of clinical and microbiological success respectively of 70.6% and 76.5%. Although the rate of clinical cure reported in our study is in line with those previously reported in the larger RCTs, this result is relevant considering the Meschiari et al.

peculiarity of our population. First of all, the prevalence of DRT-P infections was much higher than in previous studies: the rate was only 15% in the CREDIBLE-CR (including also MDR P. aeruginosa) 5, 6 and in the study by Bavaro et al., 11 while no cases were reported by Falcone et al. 12 Only Bleibtreu et al. 13 reported 9 of 12 cases (75%) of XDR P. aeruginosa, and 5 of them were non-susceptible to cefiderocol at baseline, contributing to the 55% overall clinical failure. Second, the clinical pictures of patients included were particularly challenging. Indeed, our series included difficult-to-treatinfections (meningitis, aortic prosthetic graft infections, osteomyelitis with prosthetic joint infection, acute necrotic-haemorrhagic pancreatitis and thoracic empyema) that are characterized by poor penetration of antibiotics, inadequate source control and inadequate host defence/cellular response. All these factors could affect the antibiotic pharmacodynamic and pharmacokinetic aspects and may influence clinical outcome. Finally, these favourable outcomes are even more relevant since almost 90% of the patients were admitted to intensive care and they all had an extended follow-up of 90 days, significantly longer than other published case series, 11, 13 and 30% of our cases were critically ill COVID-19 patients with a VAP due to XDR/DRT-P, associated per se with a significantly increased 28 day mortality rate. 14 Concerning mortality, there is still an open debate after the alarming results reported by the CREDIBLE-CR study, in which the authors reported numerically more deaths in the cefiderocol group, especially in patients affected by Acinetobacter spp. infections. 5, 6 In our series, six patients died (35.3%) but only two of them reported both clinical and microbiological failure. The first case was a COVID-19 patient (P4) with a DTR-P VAP who died during cefiderocol therapy after 18 days and after 40 days of extracorporeal membrane oxygenation (ECMO). The second one, P9, with a prosthetic joint infection and osteomyelitis, died while waiting for joint replacement.

Therefore, our study, in agreement with previous studies, 12,13 confirms that inadequate source control together with failing to achieve adequate drug exposure still represents a crucial risk factor for death related to infection. To date, no real-world evidence regarding the administration of cefiderocol during ECMO exists and optimizing the drug dosage in this emerging clinical scenario could be extremely difficult.

Notably, this is the first study providing real-life data on CSF and plasma cefiderocol concentrations. Our findings suggest that highdose cefiderocol could allow adequate CSF concentrations to be achieved. However, further confirmation through the assessment of AUC CSF:plasma ratio will be required.

Lastly, in our series, cefiderocol has been mostly used in combination therapy. The main combinations were with colistin (often by inhalation for VAP), fosfomycin, ceftazidime/avibactam and amikacin. It is important to highlight that two out of three patients treated with cefiderocol monotherapy experienced microbiological relapse and one of them (P3) reported an MIC creep. Currently, there is still no agreement about how to use cefiderocol, whether in monotherapy 12 or in combinations, 11, 15 and further studies are needed. Our study has several limitations. The limited sample size from only two Italian centres does not allow us to draw universal and definitive conclusions. Moreover, information about molecular mechanisms of P. aeruginosa resistance and about in vivo development of cefiderocol resistance observed in other real-life series are lacking in our study and need future investigations. [11] [12] [13] 16 In conclusion, our experience describing a large number of cases of DTR-P susceptible to cefiderocol allows us to provide promising data that may help clinicians with the use of cefiderocol in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage.

In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria

In vitro activity of cefiderocol against a broad range of clinically important Gram-negative bacteria

Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, doubleblind, non-inferiority trial

Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial

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Simple and accurate quantitative analysis of cefiderocol and ceftobiprole in human plasma using liquid chromatography-isotope dilution tandem mass spectrometry: interest for their therapeutic drug monitoring and pharmacokinetic studies

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Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in intensive care unit patients

Susceptibility testing is key for the success of cefiderocol treatment: a retrospective cohort study

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The authors gratefully acknowledge Prof Inge C. Gyssens MD (Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands) for her manuscript revision.

This study was carried out as part of our routine work.

None to declare.