Ceftolozane/Tazobactam for the Treatment of Complicated Infections in Hospital Settings-A French Real-world Study.

Background: This study describes the conditions of use of ceftolozane/tazobactam (C/T) and associated outcomes in French hospital settings. Methods: This was a prospective, multicenter, French observational study. Patients who received at least 1 dose of C/T were included and followed up as per routine clinical practice, until stop of C/T. Results: A total of 260 patients were enrolled between October 2018 and December 2019 in 30 centers across France. Of these, 177 (68.0%) received C/T as per indication of usage following the results of the antibiogram (documented cases). Among documented patients, the mean age was 61.8 years, 73.4% were males, and 93.8% presented with multidrug-resistant (MDR) bacteria at inclusion. C/T was most frequently prescribed for pneumonia (48.6%), bacteremia (14.7%), complicated intra-abdominal infections (13.0%), or complicated urinary tract infections (9.6%). Pseudomonas aeruginosa was the species most frequently isolated with 212 strains from 155 patients, and 96.2% of these strains were susceptible to C/T. The median duration of C/T treatment was 16.1 days (1-115, n = 176). Complete or partial cure was achieved in 71.7% of patients, C/T was discontinued upon adaptation to microbiology results in 11.3% of patients for the following reasons: treatment failure in 2.8%, death in 4.0%, adverse events in 1.7%, and other in 8.5%. Conclusions: This is the first prospective observational study of C/T utilization in a health care setting enrolling many patients in France. C/T demonstrated a high rate of clinical effectiveness in MDR infections, confirming it as an effective treatment option for complicated infections in a high-risk population.

In vitro activity of ceftolozane/tazobactam against multidrug-resistant Pseudomonas aeruginosa from patients in Western Europe: SMART 2017-2020.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections compromise both empirical and definitive antimicrobial therapies. The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program identified 943 MDR P. aeruginosa (from a total of 4086 P. aeruginosa isolates [23.1%]) collected at 32 clinical laboratories in six countries in Western Europe from 2017 to 2020. Minimum inhibitory concentrations (MICs) for ceftolozane/tazobactam and 10 comparator agents were determined by broth microdilution and interpreted using 2021 EUCAST breakpoints. ß-lactamase genes were identified in selected isolate subsets. Most isolates of P. aeruginosa in Western Europe (93.3%) were ceftolozane/tazobactam-susceptible. A total of 23.1% of P. aeruginosa isolates were MDR. Of these, 72.0% were ceftolozane/tazobactam-susceptible, which is similar to that for ceftazidime/avibactam (73.6%) but >40% higher than for carbapenems, piperacillin/tazobactam, third- and fourth-generation cephalosporins, and levofloxacin. Metallo-ß-lactamases (MBLs) were carried by 8.8% of molecularly characterized MDR P. aeruginosa, and 7.6% of molecularly characterized MDR isolates carried Guiana Extended Spectrum (GES) carbapenemases. MBLs were identified in isolates from all six countries, ranging from 3.2% of all P. aeruginosa isolates from Italy to 0.4% of all isolates from the United Kingdom. Acquired ß-lactamases were not identified in 80.0% of molecularly characterized MDR P. aeruginosa isolates. Percentages of MDR isolates without detected ß-lactamases were higher in the United Kingdom (97.7%), Spain (88.2%), France (88.1%), and Germany (84.7%) than in Portugal (63.0%) and Italy (61.3%), where carbapenemases were more prevalent. Ceftolozane/tazobactam is an important treatment option for patients infected with MDR P. aeruginosa that are not susceptible to first-line antipseudomonal agents.

In vitro activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa collected from patients with bloodstream, intra-abdominal and urinary tract infections in Western Europe: SMART 2018-2020.

Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa; new agents with improved activity are needed.Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use.Aim. To describe the in vitro activity of IMR against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates.Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P. aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. ß-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020).Results. IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant (n=1601) and 73.7 % of meropenem-resistant (n=152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against P. aeruginosa; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant P. aeruginosa. In total, 1.6 % of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD-deficient.Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.

In vitro activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa collected from patients with lower respiratory tract infections in Western Europe: SMART 2018-20.

Objectives: To describe the in vitro activity of imipenem/relebactam against non-Morganellaceae Enterobacterales (NME) and Pseudomonas aeruginosa recently isolated from lower respiratory tract infection samples by hospital laboratories in Western Europe. Methods: From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 4414 NME and 1995 P. aeruginosa isolates. MICs were determined using the CLSI broth microdilution method and interpreted by EUCAST (2021) breakpoints. ß-Lactamase genes were identified in selected isolate subsets (2018-20) and oprD sequenced in molecularly characterized P. aeruginosa (2020). Results: Imipenem/relebactam (99.1% susceptible), amikacin (97.2%), meropenem (96.1%) and imipenem (95.9%) were the most active agents tested against NME; by country, relebactam increased imipenem susceptibility from <1% (France, Germany, UK) to 11.0% (Italy). A total of 96.0% of piperacillin/tazobactam-resistant (n = 990) and 81.1% of meropenem-resistant (n = 106) NME were imipenem/relebactam-susceptible. Only 0.5% of NME were MBL positive, 0.9% were OXA-48-like-positive (MBL negative) and 2.8% were KPC positive (MBL negative). Amikacin (91.5% susceptible) and imipenem/relebactam (91.4%) were the most active agents against P. aeruginosa; 72.3% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 34.4% (range by country, 39.1%-73.5%) in piperacillin/tazobactam-resistant and by 37.4% (3.1%-40.5%) in meropenem-resistant P. aeruginosa. Only 1.8% of P. aeruginosa isolates were MBL positive. Among molecularly characterized imipenem/relebactam-resistant P. aeruginosa isolates from 2020, 90.9% (30/33) were oprD deficient. Conclusions: Imipenem/relebactam appears to be a potential treatment option for lower respiratory tract infections caused by piperacillin/tazobactam- and meropenem-resistant NME and P. aeruginosa in Western Europe.

Collective assessment of antimicrobial susceptibility among the most common Gram-negative respiratory pathogens driving therapy in the ICU.

OBJECTIVES: To describe the pathogen predominance and to evaluate the probability of covering the most common Gram-negative pathogens collectively in both empirical and early adjustment prescribing scenarios in ICU patients with respiratory infections. METHODS: Data were collected from an international cohort of hospitals as part of the SMART Surveillance Program (2018). Susceptibility testing (mg/L) was performed by broth microdilution methods. RESULTS: 7171 Gram-negative respiratory isolates from adult ICU patients across 209 hospitals from 56 different countries were studied. Overall, the most common ICU respiratory pathogens isolated were Pseudomonas aeruginosa (25%), Klebsiella pneumoniae (18%), Acinetobacter baumannii (14%), and Escherichia coli (11%), with inter-regional differences among these pathogens. Among Enterobacterales, 36% were ESBL positive. When the collective susceptibility profile of this set of pathogens (P. aeruginosa plus Enterobacterales; comprising 78% of all organisms isolated) was performed, ceftolozane/tazobactam (84%), followed by meropenem (81%), provided the most reliable in vitro activity in the empirical prescribing scenario compared with other ß-lactam antibiotics. P. aeruginosa co-resistance was common among first-line ß-lactam antibiotics. If P. aeruginosa was non-susceptible to piperacillin/tazobactam, less than one-third were susceptible to meropenem or ceftazidime. In contrast, ceftolozane/tazobactam offered in vitro coverage in over two-thirds of these resistant pathogens. CONCLUSIONS: Ceftolozane/tazobactam demonstrated high cumulative susceptibility levels and in vitro activity in both empirical and adjustment antibiotic prescribing scenarios. High frequency of co-resistance undermines reliable coverage for Gram-negative pathogens already resistant to first-line agents. Ceftolozane/tazobactam would offer additional coverage in this setting.

Real-world evaluation of ceftolozane/tazobactam therapy and clinical outcomes in France.

OBJECTIVES: To describe the real-world clinical use of ceftolozane/tazobactam (C/T) and associated outcomes in France. PATIENTS AND METHODS: Multicenter, prospective cohort study conducted in 22 hospitals. All adult patients who received at least one dose of C/T were asked to participate (2018-2019). Patients were treated according to standard hospital practice and followed up until C/T stop. RESULTS: At the time of the analysis, 84 patients were evaluated. The median age was 64.8 years, and 67.9% (57/84) of patients were males. Fifty-seven patients (57/82, 69.5%) had one or more risk factors for multidrug-resistant (MDR) infections (missing MDR risk factor data for two patients). Most patients were critically ill and had several comorbidities. A majority (59/84, 70.2%) of patients had nosocomial infections. Half of all patients (n=42) had a diagnosis of pneumonia, of which 69% (29/42) were hospital acquired. Overall, 90.5% (76/84) of patients had MDR bacteria. Pseudomonas aeruginosa was the most frequently isolated bacterium (71/80, 88.8%), including 93% (80/86) of C/T-susceptible strains. C/T was prescribed as the first-line treatment to 29.8% (25/84) of patients. A concomitant antibiotic treatment was prescribed to 48.8% (41/84) of patients, of whom 65.9% (27/41) were prescribed concomitant antibiotics at the same time as C/T initiation. Empirical C/T prescription was microbiologically appropriate in 11/16 patients after susceptibility testing. Most patients (44/72, 61.1%) were cured and four (4/72, 5.6%) deaths were reported. CONCLUSIONS: The results showed that C/T was most frequently prescribed for documented cases of P. aeruginosa infections. Most outcomes were positive, including among pneumonia patients.