Evaluation of the activity of cefepime/enmetazobactam against Enterobacterales bacteria collected in Europe from 2019 to 2021, including third-generation cephalosporin-resistant isolates.

OBJECTIVES: This study was performed to investigate the activity of the novel ß-lactam/ß-lactamase inhibitor combination cefepime/enmetazobactam, against recently circulating Enterobacterales isolates from Europe from 2019 to 2021. METHODS: A total of 2627 isolates were collected, and antimicrobial susceptibility was determined according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem) and isolates nonsusceptible to meropenem were screened for the presence of ß-lactamases. RESULTS: Overall, susceptibility to third-generation cephalosporins was 77%, and 97.3% were susceptible to meropenem. Cefepime/enmetazobactam susceptibility was 97.9% (72% of these isolates were Klebsiella pneumoniae from Italy), compared with 80.0% susceptibility to piperacillin/tazobactam and 99.4% to ceftazidime/avibactam. A total of 320 isolates (12.2%) were resistant to third-generation cephalosporins but susceptible to meropenem, and virtually all (96.3%) carried an extended-spectrum ß-lactamase with or without an AmpC and these were all susceptible to cefepime/enmetazobactam. Most meropenem-nonsusceptible isolates carried a KPC (68%), which were not inhibited by cefepime/enmetazobactam but were inhibited by ceftazidime/avibactam. Additionally, most meropenem-nonsusceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam. CONCLUSIONS: Cefepime/enmetazobactam was highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins. These data suggest that cefepime/enmetazobactam could be used as a carbapenem-sparing agent to replace piperacillin/tazobactam.

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.

US-Focused Conceptual Health Care Decision-Analytic Models Examining the Value of Pivmecillinam Relative to Current Standard-of-Care Agents Among Adult Patients With Uncomplicated Urinary Tract Infections due to Enterobacterales.

BACKGROUND: Pivmecillinam is approved for the treatment of adults with uncomplicated urinary tract infection (uUTI) in Canada and Europe and is pending United States (US) Food and Drug Administration submission for consideration for approval. US-focused health care decision-analytics were developed to define the value of an agent like pivmecillinam relative to current standard-of-care (SOC) agents among adult patients with Enterobacterales uUTIs based on its improved microbiologic activity against common Enterobacterales. METHODS: The model population was 100 theoretical adult outpatients with Enterobacterales uUTIs under 4 different uUTI first-line empiric treatment scenarios (ie, pivmecillinam, nitrofurantoin, trimethoprim-sulfamethoxazole [SXT], or fluoroquinolones). The total mean uUTI-related 30-day costs, including inappropriate treatment costs, were calculated for each regimen. The range of pivmecillinam regimen costs that conferred cost savings relative to the current SOC agents based on its potentially improved microbiologic activity against common Enterobacterales was determined. RESULTS: The 30-day uUTI-related costs associated with nitrofurantoin, SXT, and fluoroquinolones were $655.61, $687.57, and $659.69, respectively. The pivmecillinam neutral regimen cost thresholds that resulted in the same uUTI-related 30-day per-patient costs for nitrofurantoin, SXT, and fluoroquinolones were $83.50, $115.45, and $87.58, respectively. The overall antimicrobial susceptibility improvement required with pivmecillinam fixed at $200/regimen, for it to be cost savings relative to SOC agents, was 28%. CONCLUSIONS: The analyses suggests that an agent like pivmecillinam, if approved in the US, has the potential to reduce the economic burden associated with inappropriate treatment of adult outpatients with uUTIs, especially in patients at high risk for an Enterobacterales uUTI that is resistant to SOC agents.

In vitro activity of cefiderocol and comparators against isolates of Gram-negative bacterial pathogens from a range of infection sources: SIDERO­WT­2014-2018 studies in Spain.

OBJECTIVES: The incidence of antimicrobial resistance in Europe is rising. Cefiderocol is approved in Europe for treatment of aerobic Gram-negative bacterial (GNB) infections in adults with limited treatment options. We report the in vitro activity of cefiderocol versus comparators against GNB clinical isolates from Spain. METHODS: MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol was tested using iron-depleted cation-adjusted Mueller-Hinton broth. Susceptibility rates were based on EUCAST breakpoints; if a species-specific breakpoint was unavailable, pharmacokinetic/pharmacodynamic breakpoints were used. RESULTS: Of 2303 isolates [1502 (65.2%) Enterobacterales and 801 (34.8%) non-fermenters], 2260 (98.1%) were susceptible to cefiderocol compared with 80.8-86.9% for comparators. By infection source, susceptibility to cefiderocol ranged from 97.3% (721/741) in isolates from patients with nosocomial pneumonia to 98.9% (349/353) in bloodstream infection isolates and was greater than susceptibility to comparators (70.7-93.6% across infection sources). Overall, 368/2303 isolates (16.0%) were meropenem-resistant. A high proportion of meropenem-resistant Acinetobacter baumannii [169/175 (96.6%)] and Pseudomonas aeruginosa [48/50 (96.0%)] were cefiderocol-susceptible, similar to colistin [169/175 (96.6%) and 47/50 (94.0%), respectively] but higher than ceftazidime/avibactam [26/175 (14.9%) and 20/50 (40.0%), respectively] and ceftolozane/tazobactam [17/175 (9.7%) and 25/50 (50.0%), respectively]. All meropenem-resistant Stenotrophomonas maltophilia isolates [120/120 (100%)] were cefiderocol-susceptible, including one trimethoprim/sulfamethoxazole-resistant isolate, with fewer susceptible to colistin [86/120 (71.7%)], ceftazidime/avibactam [42/120 (35.0%)] and ceftolozane/tazobactam [35/120 (29.2%)]. CONCLUSION: A high proportion of clinical isolates from Spain, representing a wide range of pathogens across multiple infection sources, were susceptible to cefiderocol. Cefiderocol retained activity against meropenem-resistant 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.].

In vitro activity of cefiderocol and comparators against Gram-negative bacterial isolates from a series of surveillance studies in England: 2014-2018.

OBJECTIVES: The prevalence of Gram-negative bacteria (GNB) demonstrating extensive, multiple antimicrobial resistance is increasing in England, leaving few treatment choices. Cefiderocol is a novel siderophore cephalosporin approved in Europe for the treatment of aerobic GNB infections in adults with limited treatment options. We report pooled data for a clinical isolate set collected in England between 2014-2018. METHODS: MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol susceptibility was tested using iron-depleted cation-adjusted Muller-Hinton broth. Susceptibility rates were based on EUCAST breakpoints. In the absence of a species-specific breakpoint, pharmacokinetic/pharmacodynamic breakpoints were used. RESULTS: Of 1886 isolates from England [74.1% Enterobacterales (18.7% Escherichia coli, 17.2% Klebsiella pneumoniae), 25.9% non-fermenters (18.4% Pseudomonas aeruginosa, 3.7% Acinetobacter baumannii)], 98.7% were cefiderocol-susceptible. Cefiderocol susceptibility in Enterobacterales (99.0%) was significantly (P < 0.01) greater than ceftolozane/tazobactam (94.3%), but similar to meropenem (99.3%) and ceftazidime/avibactam (99.4%). Overall, cefiderocol susceptibility (98.0%) in non-fermenters was significantly (P < 0.01) higher than comparators (range, 84.5-92.4%). Susceptibility to cefiderocol was 98.3-99.6% by infection source and was significantly (P < 0.01) greater than comparators for isolates from patients with nosocomial pneumonia (cefiderocol, 98.3%; comparators range, 79.8-93.8%). Excluding intrinsically meropenem-resistant Stenotrophomonas maltophilia, 47/1846 isolates (2.5%) were meropenem-resistant. A high proportion of meropenem-resistant P. aeruginosa were susceptible to cefiderocol (95.0%). All S. maltophilia isolates (40/40) were cefiderocol-susceptible. CONCLUSION: A substantial proportion of clinical isolates from England, representing a wide range of pathogens across multiple infection sources, was cefiderocol-susceptible. Cefiderocol retained activity against meropenem-resistant strains.

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 Italy.

OBJECTIVES: Antimicrobial resistance, particularly carbapenem resistance, in Gram-negative pathogens poses a significant healthcare threat. Carbapenem resistance rates in Italy are among the highest in Europe. We report the in vitro activity of cefiderocol, a novel siderophore cephalosporin, and comparator antibiotics against Gram-negative isolates from Italy as part of the SIDERO-WT studies. METHODS: Isolates were collected between 2014 and 2018. Minimum inhibitory concentrations (MICs) were determined using International Organization for Standardization and EUCAST guidelines. Antimicrobial susceptibilities were interpreted using EUCAST breakpoints; pharmacodynamic/pharmacokinetic breakpoints were used if EUCAST breakpoints were not specified. RESULTS: The 2472 isolates [1545 (62.5%) Enterobacterales and 927 (37.5%) non-fermenters] represented a range of infection sources, including nosocomial pneumonia (902; 36.5%), complicated urinary tract infection (374; 15.1%), bloodstream infection (596; 24.1%), complicated intra-abdominal infection (257; 10.4%) and other infection sources (343; 13.9%). Cefiderocol was active against the majority of isolates, regardless of infection source (susceptibility, 94.2-97.3%). A high proportion of non-fermenters (97.6%) and Enterobacterales (95.6%) were cefiderocol-susceptible, although susceptibility was lower in Klebsiella pneumoniae (88.1%). Susceptibility to cefiderocol was significantly (P < 0.01) greater than comparators overall (96.4% vs. 71.3-81.6%) and in non-fermenters (97.6% vs. 44.3-90.3%) across infection sources. Overall 612/2472 isolates (24.8%) were meropenem-resistant (MIC > 8 mg/L), comprising 516/927 (55.7%) non-fermenters and 96/1545 (6.2%) Enterobacterales. Cefiderocol (499/516; 96.7%) activity was greater than colistin (440/516; 85.3%), ceftazidime/avibactam (123/516; 23.8%) and ceftolozane/tazobactam (89/516; 17.2%) in meropenem-resistant non-fermenter isolates. CONCLUSION: Susceptibility to cefiderocol was significantly greater than meropenem, colistin, ceftazidime/avibactam and ceftolozane/tazobactam overall, regardless of infection source.

Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins.

BACKGROUND: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.

Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC Bacteraemia Surveillance Programme, 2013-2015.

Coagulase-negative staphylococci (CoNS) are a significant cause of bacteraemia, the treatment of which is becoming increasingly complex due to the emergence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of ceftobiprole, an advanced-generation cephalosporin, as compared with other antimicrobial agents against CoNS from patients with bacteraemia. As part of the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme, 650 blood isolates of CoNS were obtained from patients with bacteraemia at 74 centres throughout the UK and Ireland for the years 2013-2015. Minimum inhibitory concentrations (MICs) of ceftobiprole and other antimicrobial agents were determined using the BSAC agar dilution method. Susceptibility was assessed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The majority of the isolates (63.2%) were Staphylococcus epidermidis. Overall, methicillin resistance, as determined by oxacillin susceptibility testing, was observed in 64.2% of isolates. The MIC50/90 of ceftobiprole was 1/2 mg/L, and 100% of CoNS isolates were inhibited at the EUCAST ceftobiprole non-species-specific pharmacokinetic/pharmacodynamic breakpoint of 4 mg/L. Only one isolate was resistant to vancomycin. Overall rates of resistance to ciprofloxacin, clindamycin, erythromycin and teicoplanin were 50.5, 25.1, 68.2 and 20.9%, respectively. In S. epidermidis, resistance to oxacillin was associated with increased resistance to other antimicrobials. Ceftobiprole demonstrated in vitro activity against all CoNS species isolated from patients with bacteraemia and was active against species resistant to other antistaphylococcal antimicrobials. The collection of clinical data regarding the efficacy of ceftobiprole in treating CoNS bacteraemia is warranted.