In vitro activity of cefiderocol against European Pseudomonas aeruginosa and Acinetobacter spp., including isolates resistant to meropenem and recent ß-lactam/ß-lactamase inhibitor combinations.

Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. represent major threats and have few approved therapeutic options. Non-|fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and ß-lactam/ß-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 P. aeruginosa; 501 Acinetobacter spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than |ß|-|l|a|c|t|a|m|/|ß|-|l|a|c|t|a|mase| inhibitor combinations against P. aeruginosa (98.9% vs 83.3%-91.4%), and P. |aeruginosa resistant to meropenem (n = 139; 97.8% vs 12.2%-59.7%), ß-lactam/ß-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-||45.0%) or |ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against Acinetobacter spp. (92.4% and 97.0%) and meropenem-resistant Acineto|bacter |spp. (n = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- (n |= 15; 13.3%) and cefiderocol- (n = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant P. aeruginosa and Acinetobacter spp., the most common ß-||lactamase genes were metallo-ß-lactamases [30/139; blaVIM-2 (15/139)] and oxacillinases [215/227; blaOXA-23 (194/227)], respectively. Acquired ß-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant P. aeruginosa and Acinetobacter spp., and pirA-like or piuA mutations in 10/10 and 37/38, respectively. Conclusion: cefiderocol susceptibility was high against P. aeruginosa and Acinetobacter spp., including meropenem-resistant isolates and those resistant to recent ß-lactam/ß-lactamase inhibitor combinations common in first-line treatment of European non-fermenters. IMPORTANCE: This was the first study in which the in vitro activity of cefiderocol and non-licensed ß-lactam/ß-lactamase inhibitor combinations were directly compared against Pseudomonas aeruginosa and Acinetobacter spp., including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and ß-lactam/ß-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant P. aeruginosa and Acinetobacter spp. and indicate how early susceptibility testing of cefiderocol in parallel with ß-lactam/ß-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.

Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis.

IMPORTANCE: The population analysis profiling (PAP) test is considered the "gold standard" method to detect heteroresistance. It exposes bacteria to increasing concentrations of antibiotics at high cell densities to detect any minority resistant subpopulations that might be missed by the low inoculums used for reference susceptibility tests. However, its clinical relevance has not been well established. In the CREDIBLE-CR study, a numerically increased all-cause mortality was observed in the cefiderocol arm relative to the best available therapy arm for patients with Acinetobacter spp. infections. Heteroresistance has independently been proposed by another research group as a potential explanation of the mortality difference. An analysis of the baseline carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from patients treated with cefiderocol in the CREDIBLE-CR study showed the highest clinical cure rate and the lowest mortality for patients with PAP-heteroresistant isolates compared with PAP-susceptible or PAP-resistant isolates. These findings contradict the abovementioned hypothesis that heteroresistance contributed to the increased mortality.

Carbapenem-Resistant Acinetobacter spp Infection in Critically Ill Patients With Limited Treatment Options: A Descriptive Study of Cefiderocol Therapy During the COVID-19 Pandemic.

Background: Carbapenem-resistant Acinetobacter baumannii infections are difficult to treat and are a significant public health threat due to intrinsic/acquired resistance and limited treatment options. Methods: A retrospective, observational cohort study in patients receiving cefiderocol via Shionogi's early access program for Acinetobacter spp infections (1 April 2020-30 April 2021; 27 sites; Italy, Spain, Germany, France). Primary outcome was clinical success, defined as clinical resolution of infection at day 14 or day 28 survival. Results: Overall, 147 patients were included. Primary infection sites were respiratory (65.3%) and bloodstream (unknown source [15.6%]; catheter-related [10.9%]); 24.5% of patients had polymicrobial infection. Of 136 patients in intensive care (92.5%), 85.3% (116/136) received mechanical ventilation. Septic shock (55.6% [70/126]) and coronavirus disease 2019 (COVID-19) (81.6%) were prevalent. Prior to cefiderocol, 85.0% of patients received gram-negative treatment, 61.2% received ≥2 antimicrobials, and most received colistin (58.5%; median duration, 11.5 days). Cefiderocol monotherapy was used in 30.6% of patients. Clinical success rate was 53.1% and was higher in patients without septic shock (62.5%), without COVID-19 (77.8%), and with lower Sequential Organ Failure Assessment (SOFA) scores (quartile 1 [median, 3; range, 0-5]: 82.9%). Day 28 survival was 44.9% and was higher in patients without septic shock (60.7%), without COVID-19 (59.3%), with lower SOFA score (quartile 1: 82.9%), and receiving first-line cefiderocol (68.2% [15/22]). Resolution of infection at day 14 occurred in 39.5% of patients. Conclusions: Despite use in complex patients with limited treatment options and high septic shock/COVID-19 rates, cefiderocol treatment was associated with an overall clinical success rate of 53%.

In vitro activity of ceftobiprole and comparator antibiotics against contemporary European isolates (2016-19).

Objectives: To evaluate the susceptibility to ceftobiprole of clinical bacterial isolates obtained from hospitalized patients in Europe. Methods: A total of 20 000 non-duplicate bacterial isolates were collected in 2016-19 from patients with documented infections at medical centres located in 17 countries in Europe. Bacterial identification was confirmed and susceptibility to ceftobiprole and comparator agents was tested using the EUCAST broth microdilution methodology and interpretive criteria by a central microbiology laboratory. Results: Of the 20 000 isolates, 10 007 (50.0%) were Gram-positive and 9993 (50.0%) were Gram-negative. The most common species was Staphylococcus aureus (35.0%), followed by Streptococcus pneumoniae (15.0%), Klebsiella pneumoniae (11.1%), Pseudomonas aeruginosa (11.0%), Escherichia coli (9.7%) and Haemophilus influenzae (3.0%). Overall, 99.7% (6981/7000) of S. aureus, including 99.5% (3483/3502) of MRSA, 97.8% (2941/3007) of S. pneumoniae, 100% (605/605) of H. influenzae and 76.3% (5492/7197) of Enterobacterales isolates were susceptible to ceftobiprole. Susceptibility to ceftobiprole was higher for isolates from northern and western Europe as compared with eastern and southern Europe. Conclusions: Ceftobiprole continues to exhibit potent and broad-spectrum activity against Gram-positive and Gram-negative clinical isolates from Europe, and as expected, with a slight north-to-south and west-to-east susceptibility gradient.

In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection.

OBJECTIVES: We assessed the activity of the novel siderophore cephalosporin, cefiderocol and selected other antibacterial agents against Gram-negative bacterial isolates in Europe. METHODS: Isolates were obtained between 2013 and 2018 from European countries participating in the SIDERO-WT and SIDERO-Proteeae multinational surveillance studies. Isolates were categorised by infection site, focusing on bloodstream infections, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infections and complicated urinary tract infections. Cefiderocol activity was compared with ceftazidime-avibactam, ceftolozane-tazobactam, colistin and meropenem using standard susceptibility testing methods. European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used to interpret susceptibility data. RESULTS: Isolates (n = 20 911) were collected from 145 sites in 24 countries in Europe, the highest proportion (34%) being from patients with HABP/VABP. Enterobacterales (66.6% of isolates) were more frequent than glucose non-fermenting species (33.4%) overall, with some differences between infection sites. Across all infection sites, the MIC50/MIC90 for cefiderocol was ≤0.5/≤2 mg/L for Enterobacter spp., ≤0.25/<2 mg/L for Klebsiella spp., 0.12/2 mg/L for Acinetobacter spp., ≤0.25/1 mg/L for Pseudomonas aeruginosa and ≤0.12/≤0.5 mg/L for Stenotrophomonas maltophilia. Across all infection sites, cefiderocol MICs were ≤2 mg/L for ≥96% of Enterobacter spp., ≥95% of Klebsiella spp., ≥90% of Acinetobacter spp. and ≥99% of Pseudomonas aeruginosa and Stenotrophomonas maltophilia isolates. Cefiderocol maintained high activity in carbapenem-resistant isolates, and the difference in activity between carbapenem-resistant (percentage susceptibility at EUCAST breakpoint: E. coli 77.8%, Klebsiella spp. 69.2%, Pseudomonas aeruginosa 97.5%, Acinetobacter spp. 90.7%, Stenotrophomonas maltophilia 99.6%) and carbapenem-susceptible (percentage susceptibility at EUCAST breakpoint: E. coli 99.4%, Klebsiella spp. 98.0%, Pseudomonas aeruginosa 99.7%, Acinetobacter spp. 94.9%) isolates was lower for cefiderocol than other agents. CONCLUSIONS: Cefiderocol had excellent activity against all Gram-negative species, independent of key infection site and carbapenem MIC. Cefiderocol is a useful addition to the therapeutic options available for these difficult-to-treat infections.

In vitro activity of cefiderocol and comparators against isolates of Gram-negative pathogens from a range of infection sources: SIDERO-WT-2014-2018 studies in France.

OBJECTIVES: Over recent years, France has experienced an increase of infections caused by carbapenem-resistant Gram-negative (GN) pathogens. Cefiderocol is approved in Europe for the treatment of aerobic GN infections in adults with limited treatment options. This study evaluated the in vitro activity of cefiderocol and comparators against GN clinical isolates from France. METHODS: MICs were determined by broth microdilution, according to International Organization for Standardization guidelines. Cefiderocol was tested using iron-depleted CAMHB. Susceptibility rates were based on EUCAST breakpoints. In the absence of a species-specific breakpoint, pharmacokinetic/pharmacodynamic breakpoints were used. RESULTS: Of 2027 isolates, 1344 (66.3%) were Enterobacterales and 683 (33.7%) were non-fermenters. The most common pathogen was Pseudomonas aeruginosa (16.8%), followed by Escherichia coli (16.0%), Klebsiella pneumoniae (13.1%), Acinetobacter baumannii (7.9%) and Stenotrophomonas maltophilia (5.1%). Isolates represented a range of infection sources including nosocomial pneumonia (33.6%), complicated urinary tract infection (24.3%), bloodstream infection (13.1%) and complicated intra-abdominal infection (18.0%). In total, 135/2027 (6.7%) isolates were meropenem resistant (MIC >8 mg/L); 133/135 (98.5%) were non-fermenters. Overall, 1330/1344 (99.0%) Enterobacterales and 681/683 (99.7%) non-fermenters were cefiderocol susceptible, including 100% of meropenem-resistant S. maltophilia (n = 98) and P. aeruginosa (n = 18) isolates. Susceptibility to cefiderocol was significantly higher (P < 0.01) in nosocomial pneumonia isolates (681/682 [99.9%]) than susceptibility to meropenem (586/682 [85.9%]), ceftolozane/tazobactam (593/682 [87.0%]), ceftazidime/avibactam (612/682 [89.7%]) and colistin (538/682 [78.9%]). CONCLUSIONS: Cefiderocol demonstrated high in vitro susceptibility rates against a wide range of Gram-negative pathogens, including meropenem-resistant strains, and was significantly more active than comparators against pneumonia isolates.

Staphylococcus aureus from hospital-acquired pneumonia from an Italian nationwide survey: activity of ceftobiprole and other anti-staphylococcal agents, and molecular epidemiology of methicillin-resistant isolates.

OBJECTIVES: To determine the prevalence of Staphylococcus aureus from hospital-acquired pneumonia (HAP) in Italy and the susceptibility to ceftobiprole and comparators of MSSA and MRSA isolates. A secondary objective was to characterize the clonality and acquired resistance and virulence genes of MRSA. METHODS: Consecutive non-replicate isolates from HAP were collected from 13 laboratories distributed across Italy, from January to May 2016. Antimicrobial susceptibility testing was performed by broth microdilution, and results were interpreted according to the EUCAST breakpoints. All MRSA isolates were subjected to WGS using an Illumina platform. Clonality and resistance and virulence gene content were investigated with bioinformatics tools. RESULTS: Among 333 isolates from HAP, S. aureus was the third most common pathogen (18.6%). The proportion of MRSA was 40.3%. Susceptibility to ceftobiprole was 100% for MSSA and 95.5% for MRSA. Lower susceptibility rates of 78.4% and 94.6% in MSSA and 36.4% and 12.1% in MRSA isolates were observed for erythromycin and levofloxacin, respectively. The MRSA from HAP mostly belonged to clonal complex (CC) 22 (47.0%), CC5 (25.8%) and CC8 (15.2%), with a minority of other lineages (ST1, ST6, ST7, ST30, ST152 and ST398). Acquired resistance and virulence genes in most cases exhibited a clonal distribution. The three ceftobiprole-resistant isolates exhibited an MIC of 4 mg/L and belonged to ST228-MRSA-I of CC5. CONCLUSIONS: S. aureus is an important cause of HAP in Italy. Ceftobiprole exhibited good in vitro activity against S. aureus isolated from HAP, including MRSA. A trend to replacement of ST228 with ST22 was noticed compared with previous studies.

Early improvement in severely ill patients with pneumonia treated with ceftobiprole: a retrospective analysis of two major trials.

BACKGROUND: Patients with pneumonia who are elderly or severely ill are at a particularly high risk of mortality. This post hoc retrospective analysis of data from two Phase III studies evaluated early improvement outcomes in subgroups of high-risk patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia [VAP]). METHODS: One study included hospitalised CAP patients randomised to ceftobiprole or ceftriaxone ± linezolid treatment. The other study included HAP patients, who were randomised to ceftobiprole or ceftazidime plus linezolid treatment. The primary outcome was rate of early clinical response (Day 3 in CAP and Day 4 in HAP patients). Additional outcome measures included clinical cure at a test-of-cure visit, 30-day all-cause mortality and safety. RESULTS: The overall high-risk group comprised 398 CAP patients and 307 HAP patients with risk factors present at baseline. The rate of early response was numerically higher in ceftobiprole-treated patients vs comparator-treated patients in the following high-risk groups: CAP patients aged ≥75 years (16.3% difference, 95% confidence interval [CI]: 1.8, 30.8); CAP patients with COPD (20.1% difference, 95% CI: 8.8, 31.1); all high-risk HAP patients (12.5% difference, 95% CI: 3.5, 21.4); HAP patients with >10 baseline comorbidities (15.3% difference, 95% CI: 0.3, 30.4). CONCLUSIONS: Previous studies show that ceftobiprole is an efficacious therapy for patients with pneumonia who are at high risk of poor outcomes. This post hoc analysis provides preliminary evidence that ceftobiprole treatment may have advantages over other antibiotics in terms of achieving early improvement in high-risk patients with HAP (excluding VAP) and in some subgroups of high-risk CAP patients. TRIAL REGISTRATION: NCT00210964 : registered September 21, 2005; NCT00229008 : registered September 29, 2005; NCT00326287 : registered May 16, 2006.

Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.

Susceptibility to ceftobiprole of respiratory-tract pathogens collected in the United Kingdom and Ireland during 2014-2015.

PURPOSE: Lower respiratory tract infections (LRTIs) can cause significant morbidity and mortality and are becoming increasingly difficult to treat because of the growing prevalence of resistance to conventional antimicrobial agents. This study aimed to assess the current in vitro susceptibility of respiratory tract pathogens collected from the UK and Ireland to ceftobiprole, an advanced-generation cephalosporin, as compared with other antibiotics. METHODS: Pathogens isolated from patients with LRTIs were analyzed as part of the British Society for Antimicrobial Chemotherapy Antimicrobial Resistance Surveillance Programme during 2014-2015. Antibiotic susceptibility was evaluated using European Committee on Antimicrobial Susceptibility Testing breakpoints, including the ceftobiprole pharmacokinetic/pharmacodynamic non-species-specific breakpoint when species-specific breakpoints were not available. RESULTS: One thousand one hundred and sixty-eight isolates from community-onset LRTIs and 1,264 isolates from hospital-onset LRTIs were analyzed. The ceftobiprole susceptibility rate was 99.8% (428/429) for Streptococcus pneumoniae, 100% (502/502) for Haemophilus influenzae, and 99.6% (236/237) for Moraxella catarrhalis. All Staphylococcus aureus isolates, including methicillin-susceptible S. aureus (MSSA; N=181) and methicillin-resistant S. aureus (MRSA; N=35), were susceptible to ceftobiprole. Overall, ceftobiprole susceptibility was observed in 88.1% (215/244) of Escherichia coli isolates, 83.4% (156/187) of Klebsiella pneumoniae isolates and 86.7% (98/113) of Enterobacter spp. isolates. CONCLUSION: Ceftobiprole had in vitro activity against all S. aureus (both MSSA and MRSA) isolates, and almost all S. pneumoniae isolates, as well as against Gram-negative bacteria associated with community-onset or hospital-onset LRTIs. Based on this analysis, ceftobiprole is a good treatment option when broad-spectrum antibiotic coverage is needed for LRTIs.