In vivo efficacy & resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam or meropenem using human-simulated regimens versus Acinetobacter baumannii.

OBJECTIVE: Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model. METHODS: In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking. RESULTS: Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA -3.75 ±â€Š0.37 reduction in log10 cfu/thigh, C-SAM produced -3.55 ±â€Š0.50 and C-MEM produced -2.18 ±â€Š1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy. CONCLUSIONS: Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates.

Cefiderocol: EUCAST criteria for disc diffusion and broth microdilution for antimicrobial susceptibility testing.

OBJECTIVES: The reproducibility of cefiderocol MIC determination using broth microdilution (BMD) in iron-depleted CAMHB (ID-CAMHB) was investigated, and the EUCAST disc diffusion (DD) method for cefiderocol susceptibility testing was developed and validated against reference BMD. METHODS: Cefiderocol values were determined for wild-type (WT) and non-WT isolates using BMD plates with ID-CAMHB (Thermo Scientific, Oakwood, USA) per EUCAST guidelines. DD was performed using standard EUCAST methodology on unsupplemented Mueller-Hinton agar with cefiderocol 30 µg discs. Control agents were included in all tests. MICs were correlated with zone diameters (ZD), and ZD breakpoints (BP) best corresponding to the MIC BPs were determined. Areas of technical uncertainty (ATU) were included where appropriate. External laboratory validation of cefiderocol DD was performed per the EUCAST SOP 9.2. RESULTS: MIC and ZD distributions for cefiderocol against WT isolates were established. Cefiderocol ZD BPs were set at susceptible ≥22 mm, resistant <22 mm for Enterobacterales and Pseudomonas aeruginosa and ATUs were decided. For Acinetobacter baumannii and Stenotrophomonas maltophilia, ZD cut-off values of ≥17 mm and ≥20 mm corresponded to MIC values of ≤2 and ≤0.5 mg/L, respectively. Cefiderocol ZDs for Escherichia coli ATCC 25922 (target 27 mm) and P. aeruginosa ATCC 27853 (target 26 mm) were within ±3 mm of the target values. For DD, there was no problematic variation between discs, media or laboratories. CONCLUSIONS: DD is a robust and easy-to-perform method for cefiderocol susceptibility testing. For isolates with results in the ATU, an MIC test should be performed to confirm the results.

Are resistance rates among bloodstream isolates a good proxy for other infections? Analysis from the BSAC Resistance Surveillance Programme.

BACKGROUND: Bacteraemia data are often used as a general measure of resistance prevalence but may poorly represent other infection types. We compared resistance prevalence between bloodstream infection (BSI) and lower respiratory tract infection (LRTI) isolates collected by the BSAC Resistance Surveillance Programme. METHODS: BSI isolates (n = 8912) were collected during 2014-18 inclusive and LRTI isolates (n = 6280) between October 2013 to September 2018 from participating laboratories in the UK and Ireland, to a fixed annual quota per species group. LRTI isolates, but not BSI, were selected by onset: community for Streptococcus pneumoniae; hospital for Staphylococcus aureus, Pseudomonas aeruginosa and Enterobacterales. MICs were determined centrally by agar dilution; statistical modelling adjusted for ICU location and possible clustering by collection centre. RESULTS: Resistance was more prevalent among the LRTI isolates, even after adjusting for a larger proportion of ICU patients. LRTI P. aeruginosa and S. pneumoniae were more often resistant than BSI isolates for most antibiotics, and the proportion of MRSA was higher in LRTI. For S. pneumoniae, the observation reflected different serotype distributions in LRTI and BSI. Relationships between LRTI and resistance were less marked for Enterobacterales, but LRTI E. coli were more often resistant to ß-lactams, particularly penicillin/ß-lactamase inhibitor combinations, and LRTI K. pneumoniae to piperacillin/tazobactam. For E. cloacae there was a weak association between LRTI, production of AmpC enzymes and cephalosporin resistance. CONCLUSIONS: Estimates of resistance prevalence based upon bloodstream isolates underestimate the extent of the problem in respiratory isolates, particularly for P. aeruginosa, S. pneumoniae, S. aureus and, less so, for Enterobacterales.

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

OBJECTIVES: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications. METHODS: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed. RESULTS: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)]. CONCLUSIONS: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.

Diversity of Clostridium difficile PCR ribotypes in Europe: results from the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), 2012 and 2013.

Clostridium difficile infection (CDI) is the major cause of infective diarrhoea in healthcare environments. As part of the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), the largest C. difficile epidemiological study of its type, PCR ribotype distribution of C. difficile isolates in Europe was investigated. PCR ribotyping was performed on 1,196 C. difficile isolates from diarrhoeal samples sent to the European coordinating laboratory in 2012-13 and 2013 (from two sampling days) by 482 participating hospitals from 19 European countries. A total of 125 ribotypes were identified, of which ribotypes 027 (19%, n =222), 001/072 (11%, n = 134) and 014/020 (10%, n = 119) were the most prevalent. Distinct regional patterns of ribotype distribution were noted. Of 596 isolates from patients with toxin-positive stools (CDI cases), ribotype 027 accounted for 22% (32/144) of infections in cases aged from 18 to less than 65 years, but the prevalence decreased in those aged ≥ 65 years (14% (59/412)) and further decreased in those aged ≥ 81 years (9% (18/195)). The prevalence of ribotype 027 and 176, but not other epidemic strains, was inversely proportional to overall ribotype diversity (R(2) = 0.717). This study highlights an increased diversity of C. difficile ribotypes across Europe compared with previous studies, with considerable intercountry variation in ribotype distribution. Continuous surveillance programmes are necessary to monitor the changing epidemiology of C. difficile.

In vitro activity of cefiderocol against Gram-negative pathogens isolated from people with cystic fibrosis and bronchiectasis.

OBJECTIVES: Gram-negative pathogens causing respiratory infection in people with cystic fibrosis and bronchiectasis are becoming progressively more resistant to conventional antibiotics. Although cefiderocol is licenced for the treatment of infections due to Gram-negative organisms, there are limited data on the activity of cefiderocol against pathogens associated with chronic respiratory diseases. The aim of this study was to determine the susceptibility of Gram-negative pathogens from cystic fibrosis and bronchiectasis to cefiderocol and comparator antibiotics. METHODS: Minimal inhibitory concentrations (MICs) of cefiderocol and 15 comparator antibiotics were determined by broth microdilution against 300 respiratory isolates: Burkholderia spp., Stenotrophomonas spp., Achromobacter spp., Ralstonia spp. and Pandoraea spp., and used to calculate the MIC of each antibiotic required to inhibit 50% (MIC50) and 90% (MIC90) of isolates. RESULTS: The MIC50 and MIC90 of cefiderocol for all 300 isolates tested was 0.25 and 32 mg/L, with 232 (77.3%) isolates having an MIC value ≤2 mg/L. In addition, cefiderocol demonstrated excellent activity against Stenotrophomonas spp. and Achromobacter spp. isolates, with 86.7% and 87.2%, respectively, exhibiting an MIC of 2 mg/L. Tigecycline also demonstrated good activity against all isolates with an MIC50 of <0.5 mg/L. CONCLUSIONS: These in vitro data demonstrated that cefiderocol had greater activity than most comparator antibiotics and could be an alternative treatment option for respiratory infection caused by these pathogens that has not responded to first-line therapy.

In vitro activity of cefiderocol against European Enterobacterales, including isolates resistant to meropenem and recentß-lactam/ß-lactamase inhibitor combinations.

Carbapenem-resistant Enterobacterales represent a major health threat and have few approved therapeutic options. Enterobacterales isolates were collected from hospitalized inpatients from 49 sites in six European countries (1 January-31 December 2020) and underwent susceptibility testing to cefiderocol and ß-lactam/ß-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L) and cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-|resistant isolates by whole-genome sequencing, to identify resistance mechanisms. Overall, 1,909 isolates (including 970 Klebsiella spp., 382 Escherichia coli, and 244 Enterobacter spp.) were collected, commonly from bloodstream infections (43.6%). Cefiderocol susceptibility was higher than approved ß-lactam/ß-lactamase inhibitor combinations and largely comparable to cefepime-taniborbactam and aztreonam-avibactam against all Enterobacterales (98.1% vs 78.1%-|97.4% and 98.7%-99.1%, respectively) and Enterobacterales resistant to meropenem (n = 148, including 125 Klebsiella spp.; 87.8% vs 0%-71.6% and 93.2%-98.6%, respectively), ß-lactam/ß-lactamase inhibitor combinations (66.7%-|92.1% vs 0%-|88.1% and 66.7%-97.9%, respectively), and to both meropenem and ß-|lactam/ß-lactamase inhibitor combinations (61.9%-65.9% vs 0%-|20.5% and 76.2%-97.7%, respectively). Susceptibilities to approved and developmental ß-lactam/ß-lactamase inhibitor combinations against cefiderocol-resistant Enterobacterales (n = 37) were 10.8%-|56.8% and 78.4%-94.6%, respectively. Most meropenem-resistant Enterobacterales harbored Klebsiella pneumoniae carbapenemase (110/148) genes, although metallo-ß-lactamase (35/148) and oxacillinase (OXA) carbapenemase (6/148) genes were less common; cefiderocol susceptibility was retained in ß-lactamase producers, other than NDM, AmpC, and non-carbapenemase OXA producers. Most cefiderocol-resistant Enterobacterales had multiple resistance mechanisms, including ≥1 iron uptake-related mutation (37/37), carbapenemase gene (33/37), and ftsI mutation (24/37). The susceptibility to cefiderocol was higher than approved ß-lac|tam/ß-lactamase inhibitor combinations against European Enterobacterales, including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates. IMPORTANCE: This study collected a notably large number of Enterobacterales isolates from Europe, including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates against which the in vitro activities of cefiderocol and developmental ß-lactam/ß-lactamase inhibitor combinations were directly compared for the first time. The MIC breakpoint for high-dose meropenem was used to define meropenem resistance, so isolates that would remain meropenem resistant with doses clinically available to patients were included in the data. Susceptibility to cefiderocol, as a single active compound, was high against Enterobacterales and was higher than or comparable to available ß-lactam/ß-lactamase inhibitor combinations. These results provide insights into the treatment options for infections due to Enterobacterales with resistant phenotypes. Early susceptibility testing of cefiderocol in parallel with ß-lactam/ß-lactamase inhibitor combinations will allow patients to receive the most appropriate treatment option(s) available in a timely manner. This is particularly important when options are more limited, such as against metallo-ß-lactamase-producing Enterobacterales.

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.

In vitro activity of telavancin in combination with colistin versus Gram-negative bacterial pathogens.

The treatment of Gram-negative infections is increasingly compromised by the spread of resistance. With few agents currently in development, clinicians are now considering the use of unorthodox combination therapies for multidrug-resistant strains. Here we assessed the in vitro activity of the novel lipoglycopeptide telavancin (TLV) when combined with colistin (COL) versus 13 Gram-negative type strains and 66 clinical isolates. Marked synergy was observed in either checkerboard (fractional inhibitory concentration index [FICI], <0.5; susceptibility breakpoint index [SBPI], >2) or time-kill assays (>2-log reduction in viable counts compared with starting inocula at 24 h) versus the majority of COL-susceptible enterobacteria, Stenotrophomonas maltophilia, and Acinetobacter baumannii isolates, but only limited effects were seen against Pseudomonas aeruginosa or strains with COL resistance. Using an Etest/agar dilution method, the activity of TLV was potentiated by relatively low concentrations of COL (0.25 to 0.75 µg/ml), reducing the MIC of TLV from >32 µg/ml to ≤ 1 µg/ml for 35% of the clinical isolates. This provides further evidence that glycopeptide-polymyxin combinations may be a useful therapeutic option in the treatment of Gram-negative infections.

Assessment of In Vitro Cefiderocol Susceptibility and Comparators against an Epidemiologically Diverse Collection of Acinetobacter baumannii Clinical Isolates.

Cefiderocol is a catechol-substituted siderophore cephalosporin combining rapid penetration into the periplasmic space with increased stability against ß-lactamases. This study provides additional data on the in vitro antimicrobial activity of cefiderocol and commercially available comparators against an epidemiologically diverse collection of Acinetobacter baumannii clinical isolates. Antimicrobial susceptibility was tested using pre-prepared frozen 96-well microtiter plates containing twofold serial dilutions of: cefepime, ceftazidime/avibactam, imipenem/relebactam, ampicillin/sulbactam, meropenem, meropenem/vaborbactam, ciprofloxacin, minocycline, tigecycline, trimethoprim/sulfamethoxazole and colistin using the standard broth microdilution procedure in cation-adjusted Mueller-Hinton broth (CAMHB). For cefiderocol, iron-depleted CAMHB was used. A collection of 113 clinical strains of A. baumannii isolated from Argentina, Azerbaijan, Croatia, Greece, Italy, Morocco, Mozambique, Peru and Spain were included. The most active antimicrobial agents against our collection were colistin and cefiderocol, with 12.38% and 21.23% of non-susceptibility, respectively. A high proportion of multidrug-resistant (76.77%) and carbapenem-resistant (75.28%) A. baumannii isolates remained susceptible to cefiderocol, which was clearly superior to novel ß-lactam/ß-lactamase inhibitor combinations. Cefiderocol-resistance was higher among carbapenem-resistant isolates and isolates belonging to ST2, but could not be associated with any particular resistance mechanism or clonal lineage. Our data suggest that cefiderocol is a good alternative to treat infections caused by MDR A. baumanni, including carbapenem-resistant strains.

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 against Gram-negative bacterial pathogens in Germany.

OBJECTIVES: Widespread antimicrobial resistance in Gram-negative bacteria (GNB), particularly carbapenem resistance, represents a major clinical challenge. Cefiderocol is a novel siderophore cephalosporin active against all carbapenemase classes. METHODS: We evaluated the in vitro activity of cefiderocol and other antibacterial agents (ceftazidime/avibactam, ceftolozane/tazobactam, colistin and meropenem) against GNB isolates collected in Germany (2013-2018) as part of two multinational studies. Antimicrobial susceptibility testing was performed by broth microdilution. Minimum inhibitory concentrations were interpreted according to EUCAST breakpoints. RESULTS: Cefiderocol had high activity against GNB isolates (N = 2298), encompassing both Enterobacterales (n = 1562) and non-fermenter species (n = 736), and maintained high activity against carbapenem-resistant strains (n = 211). The activity of cefiderocol against Enterobacterales was equivalent to that of ceftazidime/avibactam and colistin, while ceftolozane/tazobactam was somewhat less active. Against non-fermenter species, cefiderocol displayed equivalent activity to colistin; both of these agents were more active than ceftazidime/avibactam and ceftolozane/tazobactam. Colistin had similar activity to cefiderocol against the majority of species. These patterns of activity were echoed in carbapenem-resistant isolates. The high activity of cefiderocol was independent of infection site, whereas other antibacterial agents demonstrated slightly lower activity against isolates causing pneumonia compared with those from other key infection sites. CONCLUSION: Cefiderocol exhibited consistently high in vitro activity against a variety of GNB isolates collected in Germany, including resistant phenotypes, across multiple infection sites. These data suggest that cefiderocol is an effective choice of antibacterial agent in patients with GNB infection, regardless of species and resistance phenotype to other agents.

In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium.

Infections with carbapenem-resistant (CR) Gram-negative (GN) pathogens have increased in many countries worldwide, leaving only few therapeutic options. Cefiderocol (CFDC) 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 multidrug-resistant (MDR) bacteria including meropenem-resistant (MR) or pandrug-resistant (PR) GN clinical isolates from France and Belgium. The minimum inhibitory concentrations (MICs) of CFDC were determined by broth microdilution, using iron-depleted cation-adjusted Mueller-Hinton broth, and were compared to those of 10 last-line antibiotics. The MICs were interpreted according to EUCAST and CLSI breakpoints, and in the absence of species-specific breakpoints, non-species-related pharmacokinetic/pharmacodynamic breakpoints were used. Among the 476 isolates tested, 322 were carbapenemase producers (CP), 58 non-CP-CRs, 52 intrinsically CR, 41 expanded-spectrum cephalosporin resistant and 5 were multi-susceptible. Susceptibility to CFDC was high using EUCAST breakpoints 81%, 99% and 84%, and was even higher using CLSI breakpoints to 93%, 100% and 88% for Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii, respectively. Susceptibility to cefiderocol using non-species-related breakpoints for Stenotrophomonas maltophilia, Achromobacter xylosoxydans and Burkholderia cepacia, was 100%, 100% and 92.3%, respectively. The susceptibility rates were lower with the NDM producers, with values of 48% and 30% using EUCAST breakpoints and 81% and 50% using CLSI breakpoints for Enterobacterales and Acinetobacter spp, respectively. CFDC demonstrated high in vitro susceptibility rates against a wide range of MDR GN pathogens, including MR and PR isolates.

Epidemiology, Outcomes and Resource Utilisation in Patients with Carbapenem Non-susceptible Gram-Negative Bacteria in the UK: A Retrospective, Observational Study (CARBAR UK).

INTRODUCTION: Antimicrobial resistance is an urgent medical challenge. In this two-part study, we investigated the epidemiology and management of carbapenem non-susceptible (Carb-NS) Gram-negative bacteria (GNB) in the UK. METHODS: We conducted a retrospective review of data from UK hospitals (ten in part 1, nine in part 2). In part 1, epidemiological data were collected from patients hospitalised between April 2017 and March 2018 with any laboratory detection of Carb-NS GNB, encompassing both colonisation and infection. In part 2, diagnosis and management pathways in a randomly selected population of adults from part 1 with confirmed Carb-NS GNB infection were assessed. Data were obtained from a detailed medical chart review for ≥ 3 months from index (collection date of first positive Carb-NS GNB sample). RESULTS: Of 42,340 GNB isolates from 36,098 patients colonised/infected with GNB in part 1, 7% were Carb-NS. In 157 patients included in part 2, 234 GNB index samples were collected, of which 197 (82%) were Carb-NS (median number of Carb-NS pathogens per patient, 1; range 1-3). The most frequent Carb-NS isolates were Pseudomonas aeruginosa (36%), Stenotrophomonas maltophilia (29%) and Klebsiella pneumoniae (10%). Median length of hospitalisation was 34 days. Median time from index to appropriate therapy was 3 days, with empirical therapy initiated a median of 1 day before index. Carb-NS infection was believed to contribute to 21 (28%) of 76 deaths during the study. CONCLUSIONS: This study highlights the high incidence of Carb-NS GNB colonisation and infection in the UK and the need for improved management of patients with Carb-NS GNB infection.

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.

Erratum to: 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.

[This corrects the article DOI: 10.1093/jacamr/dlab081.].