ABSTRACT
BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.
Subject(s)
Anti-Bacterial Agents , Continuous Renal Replacement Therapy , Cross-Over Studies , Meropenem , Renal Dialysis , Shock, Septic , Humans , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/blood , Male , Female , Middle Aged , Aged , Shock, Septic/therapy , Shock, Septic/drug therapy , Shock, Septic/blood , Pilot Projects , Continuous Renal Replacement Therapy/methods , Renal Dialysis/methods , Meropenem/therapeutic use , Meropenem/administration & dosage , Meropenem/pharmacokinetics , Tazobactam/therapeutic use , Tazobactam/pharmacokinetics , Piperacillin/pharmacokinetics , Piperacillin/therapeutic use , Piperacillin/administration & dosage , Hemodiafiltration/methodsABSTRACT
OBJECTIVES: To investigate clinical outcomes of patients with Pseudomonas endocarditis and identify factors associated with treatment failure. METHODS: Adult patients meeting definitive Duke's criteria for Pseudomonas endocarditis at 11 hospitals were identified between May 2000 and February 2024. Failure was defined as death or microbiological failure by day 42. First-line therapy consisted of cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam alone or in combination. RESULTS: Forty-eight patients met inclusion criteria; 29% were persons who inject drugs and 13% were organ transplant recipients. Pseudomonas aeruginosa was the causative species in 98% of cases. Patients who experienced 42 day cure were more likely to be initially managed with first-line ß-lactam agents compared with those who experienced clinical failure (97% versus 62%, Pâ=â0.004). Treatment with first-line ß-lactams was associated with shorter time to treatment initiation and a lower likelihood of infection due to MDR Pseudomonas spp. In the univariate model, patients who experienced 90 day mortality were more likely to have prosthetic valve endocarditis (57% versus 24%, Pâ=â0.02), an intracardiac complication (36% versus 9%, Pâ=â0.04) and a higher median (IQR) Pitt bacteraemia score [2.5 (2-3.8) versus 1 (0-2), Pâ=â0.048]. Combination therapy did not improve clinical outcomes but did increase the rate of adverse effects resulting in drug discontinuation compared with monotherapy, (21% versus 0%, Pâ=â0.08). CONCLUSIONS: This is the largest study of Pseudomonas endocarditis to date. We identified improved clinical outcomes when cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam were used for initial treatment. We did not identify a clinical benefit for combination treatment.
Subject(s)
Anti-Bacterial Agents , Endocarditis, Bacterial , Pseudomonas Infections , Pseudomonas aeruginosa , Humans , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas Infections/mortality , Male , Female , Middle Aged , Anti-Bacterial Agents/therapeutic use , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/microbiology , Endocarditis, Bacterial/mortality , Adult , Aged , Pseudomonas aeruginosa/drug effects , Treatment Outcome , Tazobactam/therapeutic use , Retrospective Studies , Treatment Failure , Piperacillin, Tazobactam Drug Combination/therapeutic use , CephalosporinsABSTRACT
BACKGROUND: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. OBJECTIVE: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). DESIGN: Retrospective cohort. SETTING: 619 U.S. hospitals. PARTICIPANTS: Adult inpatients. MEASUREMENTS: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. RESULTS: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. LIMITATION: Residual confounding. CONCLUSION: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration; NIH Intramural Research Program.
Subject(s)
Anti-Bacterial Agents , Gram-Negative Bacterial Infections , Practice Patterns, Physicians' , Humans , Gram-Negative Bacterial Infections/drug therapy , Anti-Bacterial Agents/therapeutic use , Retrospective Studies , United States , Practice Patterns, Physicians'/statistics & numerical data , Drug Combinations , Male , Tazobactam/therapeutic use , Female , Middle Aged , Cephalosporins/therapeutic use , Cefiderocol , Azabicyclo Compounds/therapeutic use , Drug Approval , Sisomicin/analogs & derivatives , Sisomicin/therapeutic use , Gram-Negative Bacteria/drug effects , United States Food and Drug Administration , Ceftazidime , TetracyclinesABSTRACT
BACKGROUND: Novel ß-lactams have in vitro activity against Pseudomonas aeruginosa (PA), but their clinical performances and the selection criteria for practical use are still not clear. We aimed to evaluate the efficacy of novel ß-lactams for PA infection in various sites and to compare the efficacy of each agent. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science for randomized controlled trials that used novel ß-lactams to treat PA infection. The primary outcomes were clinical cure and favorable microbiological response. Subgroup analyses were performed based on drug type, drug resistance of pathogens, and site of infection. Network meta-analysis was carried out within a Bayesian framework. RESULTS: In all studies combined (16 randomized controlled trials), novel ß-lactams indicated comparable performance to other treatment regimens in both outcome measures (relative risk = 1.04; 95% confidence interval 0.94-1.15; P = .43) (relative risk = 0.97; 95% confidence interval 0.81-1.17; P = .76). Subgroup analyses showed that the efficacy of ceftolozane-tazobactam (TOL-TAZ), ceftazidime-avibactam (CAZ-AVI), imipenem-cilastatin-relebactam, and cefiderocol had no apparent differences compared to control groups among different infection sites, drug types and drug resistance of PA. In network meta-analysis, the results showed no statistically significant differences between TOL-TAZ, CAZ-AVI, and cefiderocol. CONCLUSIONS: TOL-TAZ, CAZ-AVI, imipenem-cilastatin-relebactam, and cefiderocol are not inferior to other agents in the treatment of PA infection. Their efficacy is also comparable between TOL-TAZ, CAZ-AVI, and cefiderocol.
Subject(s)
Anti-Bacterial Agents , Pseudomonas Infections , Pseudomonas aeruginosa , beta-Lactams , Humans , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , beta-Lactams/therapeutic use , beta-Lactams/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Treatment Outcome , Randomized Controlled Trials as Topic , Drug Combinations , Azabicyclo Compounds/therapeutic use , Tazobactam/therapeutic use , Tazobactam/pharmacology , Ceftazidime/therapeutic use , Cephalosporins/therapeutic useABSTRACT
OBJECTIVES: WCK 4282 is a novel combination of cefepime 2â g and tazobactam 2â g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. METHODS: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16â mg/L, a dosing regimen of 2â g q8h infused over 1.5â h resulted in a combined PTA of 99% for the mean murine 1â log10-kill target for the cefepime/tazobactam combination. RESULTS: We found that to adjust for renal function, doses need to be reduced to 1â g q8h, 500â mg q8h and 500â mg q12h for patients with CLCR of 30-59, 15-29 and 8-14â mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180â mL/min), a prolonged 4â h infusion of standard dose is required. CONCLUSIONS: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16â mg/L.
Subject(s)
Anti-Bacterial Agents , Cefepime , Cephalosporins , Microbial Sensitivity Tests , Piperacillin, Tazobactam Drug Combination , Renal Dialysis , Humans , Cefepime/administration & dosage , Cefepime/pharmacokinetics , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Piperacillin, Tazobactam Drug Combination/administration & dosage , Piperacillin, Tazobactam Drug Combination/pharmacokinetics , Cephalosporins/administration & dosage , Cephalosporins/pharmacokinetics , Cephalosporins/therapeutic use , Male , Female , Tazobactam/administration & dosage , Tazobactam/therapeutic use , Middle Aged , beta-Lactamases , Adult , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/administration & dosage , Penicillanic Acid/pharmacokinetics , Healthy Volunteers , Young Adult , Piperacillin/administration & dosage , Piperacillin/pharmacokinetics , Piperacillin/pharmacology , AnimalsABSTRACT
BACKGROUND: Resistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropenem in patients with ventilated hospital-acquired bacterial pneumonia in the ASPECT-NP study. One cost-effectiveness analysis in the United States revealed that ceftolozane/tazobactam was cost effective, but no Japanese studies have been conducted. Therefore, the objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam compared to meropenem for patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia from a health care payer perspective. METHODS: A hybrid decision-tree Markov decision-analytic model with a 5-year time horizon were developed to estimate costs and quality-adjusted life-years and to calculate the incremental cost-effectiveness ratio associated with ceftolozane/tazobactam and meropenem in the treatment of patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Clinical outcomes were based on the ASPECT-NP study, costs were based on the national fee schedule of 2022, and utilities were based on published data. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to assess the robustness of our modeled estimates. RESULTS: According to our base-case analysis, compared with meropenem, ceftolozane/tazobactam increased the total costs by 424,731.22 yen (£2,626.96) and increased the quality-adjusted life-years by 0.17, resulting in an incremental cost-effectiveness ratio of 2,548,738 yen (£15,763.94) per quality-adjusted life-year gained for ceftolozane/tazobactam compared with meropenem. One-way sensitivity analysis showed that although the incremental cost-effectiveness ratio remained below 5,000,000 yen (£30,925) for most of the parameters, the incremental net monetary benefit may have been less than 0 depending on the treatment efficacy outcome, especially the cure rate and mortality rate for MEPM and mortality rate for CTZ/TAZ. 53.4% of the PSA simulations demonstrated that CTZ/TAZ was more cost-effective than MEPM was. CONCLUSION: Although incremental cost-effectiveness ratio was below ï¿¥5,000,000 in base-case analysis, whether ceftolozane/tazobactam is a cost-effective alternative to meropenem for ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in Japan remains uncertain. Future research should examine the unobserved heterogeneity across patient subgroups and decision-making settings, to characterise decision uncertainty and its consequences so as to assess whether additional research is required.
Subject(s)
Anti-Bacterial Agents , Cephalosporins , Pneumonia, Bacterial , Humans , United States , Anti-Bacterial Agents/therapeutic use , Meropenem/therapeutic use , Cost-Effectiveness Analysis , Japan/epidemiology , Tazobactam/therapeutic use , Pneumonia, Bacterial/drug therapy , HospitalsABSTRACT
AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.
Subject(s)
Administration, Intravenous , Anti-Bacterial Agents , Cephalosporins , Drug Resistance, Multiple, Bacterial , Drug Therapy, Combination , Fosfomycin , Gram-Negative Bacterial Infections , Fosfomycin/therapeutic use , Fosfomycin/administration & dosage , Humans , Retrospective Studies , Male , Female , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/mortality , Aged , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Middle Aged , Gram-Negative Bacteria/drug effects , Treatment Outcome , Aged, 80 and over , Tazobactam/therapeutic use , Adult , Drug Combinations , Pseudomonas aeruginosa/drug effects , Risk FactorsABSTRACT
Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common healthcare-associated infections linked to high morbidity and mortality. Gram-negative pathogens, such as Pseudomonas aeruginosa, exhibit multidrug resistance and are recognized as major public health concerns, particularly among critically ill patients with HABP/VABP. Ceftolozane/tazobactam is a novel combination antibacterial agent comprising ceftolozane (a potent antipseudomonal cephalosporin) and tazobactam (a ß-lactamase inhibitor). Phase III trials have demonstrated non-inferiority of ceftolozane/tazobactam to comparators, leading to the approval of ceftolozane/tazobactam for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. In this article, we review the clinical trial evidence and key real-world effectiveness data of ceftolozane/tazobactam for the treatment of serious healthcare-associated Gram-negative infections, focusing on patients with HABP/VABP.
Highlights from a review of ceftolozane/tazobactam for the treatment of serious infectionsSerious infections that can affect people in hospitals can cause serious illness or loss of life. Antibiotics are a type of medicine designed to kill the bacteria that cause these infections. However, bacteria have evolved over time, which means that antibiotics are not as effective at killing the bacteria and treating the infection. This is known as antibiotic resistance. To treat serious infections in hospital, there is a need for new antibiotics that can overcome this resistance and successfully fight off bacteria. This paper looks at an antibiotic known as ceftolozane/tazobactam (C/T), which can be used to treat people with serious infections that are picked up in hospitals. Clinical and laboratory studies have been reviewed to evaluate how effective, safe, and suitable C/T is for patients. The studies discussed in this paper highlight how well C/T works in people with serious infections, including those who are already ill and have been put on a ventilator to help with their breathing. Some of these studies showed that C/T worked well against lots of different types of bacteria that are known to cause serious infections in hospital and are linked to a high risk of death. Antibiotic resistance is a major problem all over the world. There is a need for effective antibiotics that can treat a range of infections caused by resistant bacteria. The results of this paper show that there is a lot of evidence to support the use of C/T in hospitals for people with serious bacterial infections.
Subject(s)
Anti-Bacterial Agents , Cephalosporins , Tazobactam , Humans , Cephalosporins/therapeutic use , Tazobactam/therapeutic use , Anti-Bacterial Agents/therapeutic use , Cross Infection/drug therapy , Cross Infection/microbiology , Pneumonia, Ventilator-Associated/drug therapy , Pneumonia, Ventilator-Associated/microbiology , Pseudomonas aeruginosa/drug effects , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Clinical Trials as Topic , Drug Resistance, Multiple, Bacterial , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/microbiology , Healthcare-Associated Pneumonia/drug therapy , Healthcare-Associated Pneumonia/microbiology , Urinary Tract Infections/drug therapy , Urinary Tract Infections/microbiology , beta-Lactamase Inhibitors/therapeutic use , Clinical Trials, Phase III as TopicABSTRACT
In intensive care units (ICUs), infection rates range from 18 to 54%, which is five to ten times higher than those observed in other hospital units, with a mortality rate of 9% to 60%. In recent decades, the susceptibility pattern has changed and Gram-Negative Bacteria (GNB) have become a threat due to their high frequency of multidrug resistance associated with a scarcity of therapeutic options. However, the drugs Ceftolozane/Tazobactam (C/T) and Ceftazidime/Avibactam (C/A) are demonstrating good clinical and microbiological response in the treatment of severe nosocomial infections. Therefore, this study aims to evaluate the clinical outcome of patients with severe infections caused by Multidrug-Resistant (MDR) GNB treated with C/T and C/A. Our study evaluates a total of 131 patients who received treatment with C/T and C/A due to infections caused by MDR GNB within the period from 2018 to 2021. The main infections were urinary tract (46,6%) and respiratory (26,7%) infections. Pseudomonas aeruginosa was the prevailing agent in the sample evaluation (34.3%), followed by Klebsiella pneumoniae (30,1%). About 54,9% of patients showed a favorable response, with culture negativation in 66,4% of the samples, with no discrepancy in negativations when comparing ages: 67,7% in young and 66% in elderly patients. Among the patients, 62,6% received monotherapy with C/T and C/A with a better response observed with monotherapy compared to combination therapy (58,6% vs 41,4%). The overall mortality rate was 45%, with MDR GNB infections responsible for 33,9% of these deaths, and the others (66,1%) due to factors such as oncological, hematological, and degenerative neurological diseases. In regards to hematological aspect, 35,1% of patients showed changes, with 28,2% of them presenting anemia, 4,5% thrombocytopenia, and 2,5% thrombocytosis. Concerning the use of invasive devices, higher mortality was observed in patients on mechanical ventilation (52%). In this manner, it was possible to observe that therapy with C/T and C/A yielded a favorable clinical outcome in patients with severe infections caused by MDR GNB in the study. These drugs also demonstrated good tolerability regardless of age or the presence of preexisting comorbidities and were deemed safe when assessing adverse effects. Our data also demonstrate the importance of determining the mechanism of resistance to carbapenems so that these drugs can be used more effectively and rationally.
Subject(s)
Anti-Bacterial Agents , Azabicyclo Compounds , Ceftazidime , Humans , Aged , Ceftazidime/therapeutic use , Ceftazidime/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Tazobactam/therapeutic use , Tazobactam/pharmacology , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria , Intensive Care Units , Microbial Sensitivity Tests , Pseudomonas aeruginosaABSTRACT
BACKGROUND: Temporal changes in the microbiological resistance profile have been reported in several life-threatening infections. However, no data have ever assessed this issue in postoperative peritonitis (POP). Our purpose was to assess the rate of multidrug-resistant organisms (MDROs) in POP over a two-decade period and to analyse their influence on the adequacy of empirical antibiotic therapy (EAT). METHODS: This retrospective monocentric analysis (1999-2019) addressed the changes over time in microbiologic data, including the emergence of MDROs and the adequacy of EAT for all intensive care unit adult patients treated for POP. The in vitro activities of 10 antibiotics were assessed to determine the most adequate EAT in the largest number of cases among 17 antibiotic regimens in patients with/without MDRO isolates. Our primary endpoint was to determine the frequency of MDRO and their temporal changes. Our second endpoint assessed the impact of MDROs on the adequacy of EAT per patient and their temporal changes based on susceptibility testing. In this analysis, the subgroup of patients with MDRO was compared with the subgroup of patients free of MDRO. RESULTS: A total of 1,318 microorganisms were cultured from 422 patients, including 188 (45%) patients harbouring MDROs. The growing proportions of MDR Enterobacterales were observed over time (p = 0.016), including ESBL-producing strains (p = 0.0013), mainly related to Klebsiella spp (p < 0.001). Adequacy of EAT was achieved in 305 (73%) patients. Decreased adequacy rates were observed when MDROs were cultured [p = 0.0001 vs. MDRO-free patients]. Over the study period, decreased adequacy rates were reported for patients receiving piperacillin/tazobactam in monotherapy or combined with vancomycin and imipenem/cilastatin combined with vancomycin (p < 0.01 in the three cases). In patients with MDROs, the combination of imipenem/cilastatin + vancomycin + amikacin or ciprofloxacin reached the highest adequacy rates (95% and 91%, respectively) and remained unchanged over time. CONCLUSIONS: We observed high proportions of MDRO in patients treated for POP associated with increasing proportions of MDR Enterobacterales over time. High adequacy rates were only achieved in antibiotic combinations involving carbapenems and vancomycin, while piperacillin/tazobactam is no longer a drug of choice for EAT in POP in infections involving MDRO.
Subject(s)
Peritonitis , Vancomycin , Adult , Humans , Retrospective Studies , Vancomycin/therapeutic use , Drug Resistance, Multiple, Bacterial , Anti-Bacterial Agents/therapeutic use , Cilastatin, Imipenem Drug Combination/therapeutic use , Peritonitis/drug therapy , Piperacillin/therapeutic use , Tazobactam/therapeutic useABSTRACT
OBJECTIVES: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project. METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability. RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children. CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.
Subject(s)
Anti-Bacterial Agents , Sepsis , Humans , Child , Animals , Swine , Anti-Bacterial Agents/therapeutic use , Microdialysis , Piperacillin, Tazobactam Drug Combination/therapeutic use , Piperacillin/therapeutic use , Tazobactam/therapeutic use , Sepsis/drug therapy , Penicillanic Acid/therapeutic useABSTRACT
Ceftolozane-tazobactam (C/T) recommended dosing in patients undergoing renal replacement therapies (RRT) is lacking evidence. The objective of this study was to evaluate the clinical outcomes of C/T dosing in patients on RRT. MATERIALS AND METHODS: A retrospective descriptive study conducted at our institution between May 1, 2017, and March 15, 2022. The primary endpoint was to determine the clinical cure for patients who received C/T for documented infection while on RRT. The secondary endpoints were the microbiologic cure, 30-day infection recurrence, and 30-day crude mortality. RESULTS: Of the 27 patients who met the inclusion criteria, 17 (63%) were males, median age was 69 (62 - 82) years, and weight 67 (57 - 79) kg. The majority of patients had pneumonia 19 (70.4%) followed by bacteremia 5 (18.5%). Multidrug resistant Pseudomonas spp. was the causative organism of infection in 22 subjects (81.5%). Clinical cure was achieved in 17 subjects (63%). Of the 14 subjects who had their culture repeated, 10 (71.4%) patients had microbiologic cure vs. 4 (28.5%) patients who had a microbiologic failure (p = 0.327). 30-day infection recurrence occurred in 6 (35.3%) patients of the clinical cure group and 2 (20%) patients in the clinical failure group (p = 0.362), while mortality occurred in 5 (29.4%) subjects vs. 7 (70%) in both groups, respectively (p = 0.049). The most frequently used doses of C/T were 1.5 g IV q8h while undergoing continuous venovenous hemodiafiltration and 0.75 g IV q8h while undergoing hemodialysis (p = 0.209). The median duration of therapy was 9 (4.5 - 13) days in the clinically cured group vs. 5 (3.75 - 5.5) days in those who had clinical failure (p = 0.038). There was no adverse event reported using these doses during the study period. CONCLUSION: The used doses of C/T in this study were higher than those approved by the U.S. FDA, while clinical success is uncertain. Larger outcomes and pharmacokinetics studies are needed to establish effective dosing and therapy duration.
Subject(s)
Bacteremia , Continuous Renal Replacement Therapy , Male , Humans , Aged , Female , Anti-Bacterial Agents/therapeutic use , Retrospective Studies , Tazobactam/pharmacokinetics , Tazobactam/therapeutic use , Bacteremia/drug therapyABSTRACT
Ceftolozane-tazobactam (C-T) and ceftazidime-avibactam (CAZ-AVI) are two novel antimicrobials that retain activity against resistant Pseudomonas aeruginosa. The comparative effectiveness and safety of C-T versus CAZ-AVI remain unknown. A retrospective, multicenter cohort study was performed in six tertiary centers in Saudi Arabia and included patients who received either C-T or CAZ-AVI for infections due to multidrug-resistant (MDR) P. aeruginosa. Overall in-hospital mortality, 30-day mortality, and clinical cure were the main study outcomes. Safety outcomes were also evaluated. A multivariate analysis using logistic regression was used to determine the independent impact of treatment on the main outcomes of interest. We enrolled 200 patients in the study (100 in each treatment arm). A total of 56% were in the intensive care unit, 48% were mechanically ventilated, and 37% were in septic shock. Approximately 19% of patients had bacteremia. Combination therapy was administered to 41% of the patients. The differences between the C-T and CAZ-AVI groups did not reach statistical significance in the overall in-hospital mortality (44% versus 37%; P = 0.314; OR, 1.34; 95% CI, 0.76 to 2.36), 30-day mortality (27% versus 23%; P = 0.514; OR, 1.24; 95% CI, 0.65 to 2.35), clinical cure (61% versus 66%; P = 0.463; OR, 0.81; 95% CI, 0.43 to 1.49), or acute kidney injury (23% versus 17%; P = 0.289; OR, 1.46; 95% CI, 0.69 to 3.14), even after adjusting for differences between the two groups. C-T and CAZ-AVI did not significantly differ in terms of safety and effectiveness, and they serve as potential options for the treatment of infections caused by MDR P. aeruginosa.
Subject(s)
Pseudomonas Infections , Pseudomonas aeruginosa , Humans , Anti-Bacterial Agents/therapeutic use , Retrospective Studies , Cohort Studies , Ceftazidime/therapeutic use , Cephalosporins/therapeutic use , Tazobactam/therapeutic use , Azabicyclo Compounds/therapeutic use , Drug Combinations , Pseudomonas Infections/drug therapy , Microbial Sensitivity TestsABSTRACT
Ceftolozane-tazobactam is a new ß-lactam/ß-lactamase inhibitor combination approved by the U.S. Food and Drug Administration in 2019 for the treatment of hospital-acquired and ventilator-associated pneumonia. The combination is a particularly potent inhibitor of penicillin-binding proteins with higher affinity than other ß-lactam agents. Persons with cystic fibrosis (pwCF) often harbour resistant Gram-negative bacteria in the airways and need antibiotics to prevent declining lung function. To test whether the introduction of ceftolozane-tazobactam in the period 2015-2020 led to a bacterial population level increase in cephalosporin resistance in a Danish CF population. In vitro, activity of ceftolozane-tazobactam was evaluated by susceptibility testing of clinical Pseudomonas aeruginosa isolated from pwCF from January 1, 2015, to June 1, 2020. Six thousand three hundred thirty two isolates collected from 210 adult pwCF were included. Thirty pwCF were treated with ceftolozane-tazobactam at least once. Ceftolozane-tazobactam exposure did not increase cephalosporin resistance on an individual or population level. However, resistance to ceftolozane-tazobactam was recorded despite no prior exposure in four pwCF. Compared to ceftazidime, ceftolozane-tazobactam had a better in vitro activity on P. aeruginosa. The percentage of non-mucoid P. aeruginosa isolates susceptible to ceftolozane-tazobactam were higher or equal to 5 other ß-lactams. Ceftolozane-tazobactam expands the armamentaria against P. aeruginosa with acceptable levels for a selection of drug resistance.
Subject(s)
Cystic Fibrosis , Pseudomonas Infections , Humans , Adult , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , beta-Lactamase Inhibitors/pharmacology , beta-Lactamase Inhibitors/therapeutic use , Pseudomonas aeruginosa , Cystic Fibrosis/microbiology , Cephalosporinase/pharmacology , Cephalosporinase/therapeutic use , Drug Resistance, Bacterial , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Tazobactam/pharmacology , Tazobactam/therapeutic use , Monobactams/pharmacology , Monobactams/therapeutic use , Microbial Sensitivity Tests , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Drug Resistance, Multiple, BacterialABSTRACT
OBJECTIVE: Acute exacerbations of biofilm-associated Pseudomonas aeruginosa infections in cystic fibrosis (CF) have limited treatment options. Ceftolozane/tazobactam (alone and with a second antibiotic) has not yet been investigated against hypermutable clinical P. aeruginosa isolates in biofilm growth. This study aimed to evaluate, using an in vitro dynamic biofilm model, ceftolozane/tazobactam alone and in combination with tobramycin at simulated representative lung fluid pharmacokinetics against free-floating (planktonic) and biofilm states of two hypermutable P. aeruginosa epidemic strains (LES-1 and CC274) from adolescents with CF. METHODS: Regimens were intravenous ceftolozane/tazobactam 4.5 g/day continuous infusion, inhaled tobramycin 300 mg 12-hourly, intravenous tobramycin 10 mg/kg 24-hourly, and both ceftolozane/tazobactam-tobramycin combinations. The isolates were susceptible to both antibiotics. Total and less-susceptible free-floating and biofilm bacteria were quantified over 120-168 h. Ceftolozane/tazobactam resistance mechanisms were investigated by whole-genome sequencing. Mechanism-based modelling of bacterial viable counts was performed. RESULTS: Monotherapies of ceftolozane/tazobactam and tobramycin did not sufficiently suppress emergence of less-susceptible subpopulations, although inhaled tobramycin was more effective than intravenous tobramycin. Ceftolozane/tazobactam resistance development was associated with classical (AmpC overexpression plus structural modification) and novel (CpxR mutations) mechanisms depending on the strain. Against both isolates, combination regimens demonstrated synergy and completely suppressed the emergence of ceftolozane/tazobactam and tobramycin less-susceptible free-floating and biofilm bacterial subpopulations. CONCLUSION: Mechanism-based modelling incorporating subpopulation and mechanistic synergy well described the antibacterial effects of all regimens against free-floating and biofilm bacterial states. These findings support further investigation of ceftolozane/tazobactam in combination with tobramycin against biofilm-associated P. aeruginosa infections in adolescents with CF.
Subject(s)
Pseudomonas Infections , Tobramycin , Humans , Adolescent , Tobramycin/pharmacology , Tobramycin/therapeutic use , Pseudomonas aeruginosa , Cephalosporins/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Tazobactam/therapeutic use , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Biofilms , Microbial Sensitivity Tests , Drug Resistance, Multiple, BacterialABSTRACT
INTRODUCTION: This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice. METHODS: This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients. RESULTS: The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation. CONCLUSIONS: This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients.
Subject(s)
Intraabdominal Infections , Metronidazole , Humans , Tazobactam/therapeutic use , Metronidazole/adverse effects , Penicillanic Acid/adverse effects , Cephalosporins/therapeutic use , Anti-Bacterial Agents/adverse effects , Intraabdominal Infections/drug therapy , Intraabdominal Infections/microbiologyABSTRACT
BACKGROUND: Carbapenem-sparing antibiotics are needed urgently for patients with complicated intra-abdominal infections (cIAIs). Although several novel antibiotics - novel ß-lactam/ß-lactamase inhibitor combinations (e.g. ceftolozane-tazobactam and ceftazidime-avibactam) and a novel tetracycline derivative (eravacycline) - have been developed for cIAIs, it remains unclear whether these antibiotics are comparable to carbapenems for the treatment of cIAIs. METHODS: A comprehensive search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov was conducted until 1 October 2022. Only randomized controlled trials (RCTs) that compared the clinical efficacy and safety of novel antibiotics against carbapenems for patients with cIAIs were included. RESULTS: Among the 11 selected RCTs, no significant differences in clinical cure rate at the test-of-cure visit were observed between the study group and the control group on analysis of the clinically evaluable population [93.6% vs 93.7%, risk ratio (RR) 1.00, 95% confidence interval (CI) 0.98-1.01; P=0.84], microbiologically evaluable population (93.0% vs 94.5%, RR 0.98, 95% CI 0.96-1.00; P=0.10) and modified intention-to-treat population (85.9% vs 87.7%, RR 0.98, 95% CI 0.95-1.01; P=0.13). All findings were consistent across the subgroup analyses and sensitivity tests. Similarly, no significant difference in microbiological eradication was observed between the study group and the control group (87.8% vs 89.7%, RR 0.98, 95% CI 0.96-1.01; P=0.18). The risk of adverse events was similar in both groups. CONCLUSIONS: Clinical efficacy, microbiological response and safety of the novel antibiotics, including ceftazidime-avibactam, ceftolozane-tazobactam and eravacycline, are comparable to carbapenems for the treatment of patients with cIAIs. These agents can be potential therapeutic options as carbapenem-sparing antibiotics for cIAIs.
Subject(s)
Anti-Bacterial Agents , Intraabdominal Infections , Humans , Anti-Bacterial Agents/adverse effects , Carbapenems/adverse effects , Randomized Controlled Trials as Topic , Ceftazidime/adverse effects , Intraabdominal Infections/drug therapy , Intraabdominal Infections/microbiology , Tazobactam/therapeutic use , beta-Lactamase Inhibitors/adverse effects , Drug Combinations , Azabicyclo Compounds/therapeutic useABSTRACT
The role of novel ß-lactam/ß-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the in vitro activity of novel ß-lactam/ß-lactamase inhibitor combinations against Pseudomonas aeruginosa clinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producing P. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596 P. aeruginosa clinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired ß-lactamases with KPC-2 predominant (n = 19), and 45.3% (34/75) presented overexpression of chromosomal ß-lactamase ampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation of oprD gene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity against P. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producing P. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC. IMPORTANCE The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with "difficult-to-treat" resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three ß-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance in P. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producing P. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NS P. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.
Subject(s)
Ceftazidime , Pseudomonas Infections , Humans , Ceftazidime/pharmacology , Ceftazidime/therapeutic use , Pseudomonas aeruginosa/genetics , beta-Lactamase Inhibitors/pharmacology , Pseudomonas Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cephalosporins/pharmacology , Tazobactam/pharmacology , Tazobactam/therapeutic use , beta-Lactamases/genetics , Imipenem/pharmacology , Imipenem/therapeutic use , Microbial Sensitivity TestsABSTRACT
BACKGROUND: Which antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains unclear but is paramount in the context of evolving antimicrobial resistance. Therefore, updated meta-analyses on this issue are warranted. METHODS: We systematically searched four major electronic databases from their inception through October 2022. Randomized controlled trials examining antimicrobial agents for cIAI treatment were included. Two reviewers independently assessed the quality of included studies utilizing the Cochrane Collaboration's risk of bias tool as described in the updated version 1 of the Cochrane Collaboration Handbook and extracted data from all manuscripts according to a predetermined list of topics. All meta-analyses were conducted using R software. The primary outcome was clinical success rate in patients with cIAIs. RESULTS: Forty-five active-controlled trials with low to medium methodological quality and involving 14,267 adults with cIAIs were included in the network meta-analyses. The vast majority of patients with an acute physiology and chronic health evaluation II score < 10 had low risk of treatment failure or death. Twenty-one regimens were investigated. In the network meta-analyses, cefepime plus metronidazole was more effective than tigecycline and ceftolozane/tazobactam plus metronidazole (odds ratio [OR] = 1.96, 95% credibility interval [CrI] 1.05 ~ 3.79; OR = 3.09, 95% CrI 1.02 ~ 9.79, respectively). No statistically significant differences were found among antimicrobial agents regarding microbiological success rates. Cefepime plus metronidazole had lower risk of all-cause mortality than tigecycline (OR = 0.22, 95% CrI 0.05 ~ 0.85). Statistically significant trends were observed favoring cefotaxime plus metronidazole, which exhibited fewer discontinuations because of adverse events (AEs) when compared with eravacycline, meropenem and ceftolozane/tazobactam plus metronidazole (OR = 0.0, 95% CrI 0.0 ~ 0.8; OR = 0.0, 95% CrI 0.0 ~ 0.7; OR = 0.0, 95% CrI 0.0 ~ 0.64, respectively). Compared with tigecycline, eravacycline was associated with fewer discontinuations because of AEs (OR = 0.17, 95% CrI 0.03 ~ 0.81). Compared with meropenem, ceftazidime/avibactam plus metronidazole had a higher rate of discontinuation due to AEs (OR = 2.09, 95% CrI 1.0 ~ 4.41). In pairwise meta-analyses, compared with ceftriaxone plus metronidazole, ertapenem and moxifloxacin (one trial, OR = 1.93, 95% CI 1.06 ~ 3.50; one trial, OR = 4.24, 95% CI 1.18 ~ 15.28, respectively) were associated with significantly increased risks of serious AEs. Compared with imipenem/cilastatin, tigecycline (four trials, OR = 1.57, 95%CI 1.07 ~ 2.32) was associated with a significantly increased risk of serious AEs. According to the surface under the cumulative ranking curve, Cefepime plus metronidazole was more likely to be optimal among all treatments in terms of efficacy and safety, tigecycline was more likely to be worst regimen in terms of tolerability, and eravacycline was more likely to be best tolerated. CONCLUSION: This study suggests that cefepime plus metronidazole is optimal for empirical treatment of patients with cIAIs and that tigecycline should be prescribed cautiously considering the safety and tolerability concerns. However, it should be noted that data currently available on the effectiveness, safety, and tolerability of antimicrobial agents pertain mostly to lower-risk patients with cIAIs.
Subject(s)
Anti-Infective Agents , Intraabdominal Infections , Adult , Humans , Metronidazole/adverse effects , Meropenem/therapeutic use , Network Meta-Analysis , Tigecycline/therapeutic use , Cefepime/therapeutic use , Anti-Bacterial Agents/adverse effects , Intraabdominal Infections/drug therapy , Intraabdominal Infections/microbiology , Tazobactam/therapeutic use , Anti-Infective Agents/adverse effectsABSTRACT
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.