WCK 4282 (high-dose cefepime-tazobactam) extends coverage to carbapenem-resistant Klebsiella harbouring multiple ESBLs, OXA 48/181 in conjunction with impermeability

2016 ◽  
Author(s):  
Mahesh Patel
Keyword(s):  
High Dose ◽  
Carbapenem Resistant

scholarly journals Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections

2019 ◽  
Author(s):  
David W Wareham ◽  
M H F Abdul Momin ◽  
Lynette M Phee ◽  
Michael Hornsey ◽  
Joseph F Standing
Keyword(s):  
Fixed Ratio ◽  
Vitro Activity ◽  
Definitive Treatment ◽  
High Dose ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Pharmacodynamic Modelling ◽  
Carbapenem Resistant ◽  
Combination Regimens

Abstract Background β-Lactam (BL)/β-lactamase inhibitor (BLI) combinations are widely used for the treatment of Gram-negative infections. Cefepime has not been widely studied in combination with BLIs. Sulbactam, with dual BL/BLI activity, has been partnered with very few BLs. We investigated the potential of cefepime/sulbactam as an unorthodox BL/BLI combination against MDR Gram-negative bacteria. Methods In vitro activity of cefepime/sulbactam (1:1, 1:2 and 2:1) was assessed against 157 strains. Monte Carlo simulation was used to predict the PTA with a number of simulated cefepime combination regimens, modelled across putative cefepime/sulbactam breakpoints (≤16/≤0.25 mg/L). Results Cefepime/sulbactam was more active (MIC50/MIC90 8/8–64/128 mg/L) compared with either drug alone (MIC50/MIC90 128 to >256 mg/L). Activity was enhanced when sulbactam was added at 1:1 or 1:2 (P < 0.05). Reduction in MIC was most notable against Acinetobacter baumannii and Enterobacterales (MIC 8/8–32/64 mg/L). Pharmacokinetic/pharmacodynamic modelling highlighted that up to 48% of all isolates and 73% of carbapenem-resistant A. baumannii with a cefepime/sulbactam MIC of ≤16/≤8 mg/L may be treatable with a high-dose, fixed-ratio (1:1 or 1:2) combination of cefepime/sulbactam. Conclusions Cefepime/sulbactam (1:1 or 1:2) displays enhanced in vitro activity versus MDR Gram-negative pathogens. It could be a potential alternative to existing BL/BLI combinations for isolates with a cefepime/sulbactam MIC of 16/8 mg/L either as a definitive treatment or as a carbapenem-sparing option.

scholarly journals 2214. Comparison of Cefepime–Zidebactam (WCK 5222), Ceftazidime–Avibactam, and Ceftolozane–Tazobactam Tested Against Gram-Negative Organisms Causing Pneumonia in United States Hospitals in 2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S755-S755 ◽  
Author(s):  
Helio S Sader ◽  
Cecilia G Carvalhaes ◽  
Rodrigo E Mendes ◽  
Mariana Castanheira ◽  
Robert K Flamm
Keyword(s):  
Therapeutic Option ◽  
High Dose ◽  
Gram Negative ◽  
E Coli ◽  
Highly Active ◽  
Medical Centers ◽  
Carbapenem Resistant ◽  
Gram Negative Organisms ◽  
Dual Mechanism

Abstract Background Zidebactam (ZID) is a bicyclo-acyl hydrazide antibiotic with a dual mechanism of action: selective Gram-negative PBP2 binding and β-lactamase inhibition. We evaluated the frequency and antimicrobial susceptibility (S) of Gram-negative bacilli (GNB) isolated from patients with pneumonia in US hospitals. Methods All 3,086 clinical isolates were consecutively collected from patients hospitalized with pneumonia (1/patient) in 29 US medical centers in 2018, and the GNB (n = 2,171) were S tested against cefepime (FEP)-ZID (1:1 ratio) and comparators by reference broth microdilution methods. The FEP S breakpoint of ≤8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was applied. Enterobacterales (ENT) isolateswere screened for β-lactamase genes by whole-genome sequencing. Results GNB represented 70.3% of the collection, and the most common GNB were P. aeruginosa (PSA; 34.9% of GNB), K. pneumoniae (10.9%), E. coli (9.7%), S. marcescens (7.7%), and S. maltophilia (XM; 6.4%). FEP-ZID was highly active against PSA (MIC50/90, 2/8 mg/L; 98.8% and 99.9% inhibited at ≤8 and ≤16 mg/L, respectively; highest MIC, 32 mg/L), including resistant subsets (table). Among comparators, colistin (99.6%S), ceftazidime–avibactam (CAZ-AVI; 95.2%S), and ceftolozane–tazobactam (C-T; 94.5%S) were the most active compounds against PSA. FEP-ZID inhibited all ENT at ≤4 mg/L, including ESBL-producers (MIC90, 0.25 mg/L) and carbapenem-resistant ENT (MIC90, 4 mg/L). The most active comparators against ENT were CAZ-AVI (99.9%S), amikacin (98.5%S), and meropenem (MEM; 98.3%S). FEP-ZID inhibited 75.0% and 97.9% of XM isolates at ≤8 and ≤16 mg/L, respectively (highest MIC, 64 mg/L). The only other compounds active against XM were co-trimoxazole (MIC50/90, ≤0.12/2 mg/L; 95.7%S) and levofloxacin (MIC50/90, 1/2 mg/L; 70.7%S). FEP-ZID inhibited 71.0% and 98.9% of A. baumannii isolates at ≤8 and ≤64 mg/L,, respectively. Conclusion FEP-ZID showed potent in vitro activity against GNB causing pneumonia in US hospitals and may represent a valuable therapeutic option for these difficult-to-treat infections Disclosures All authors: No reported disclosures.

scholarly journals Tigecycline Therapy for Nosocomial Pneumonia due to Carbapenem-Resistant Gram-Negative Bacteria in Critically Ill Patients Who Received Inappropriate Initial Antibiotic Treatment: A Retrospective Case Study

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaomai Wu ◽  
Yefei Zhu ◽  
Qiuying Chen ◽  
Liuyang Gong ◽  
Jian Lin ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Critically Ill ◽  
Nosocomial Pneumonia ◽  
Critically Ill Patients ◽  
Standard Dose ◽  
High Dose ◽  
Gram Negative Bacteria ◽  
Loading Dose ◽  
Icu Mortality ◽  
Carbapenem Resistant

Background. Nosocomial pneumonia due to carbapenem-resistant Gram-negative bacteria (CRGNB) is a growing concern because treatment options are limited and the mortality rate is high. The effect of tigecycline (TGC) on nosocomial pneumonia due to CRGNB in patients who have received inappropriate initial empiric antibiotic treatment (IIAT) is unclear. Therefore, this study aimed to examine the effect of TGC on nosocomial pneumonia due to CRGNB in critically ill patients who had received IIAT. Methods. A retrospective study was conducted in an adult respiratory intensive care unit. Data were obtained and analyzed for all patients who were treated with TGC ≥ 3 days for microbiologically confirmed nosocomial pneumonia due to CRGNB and had experienced initial antibiotic failure. Clinical and microbiological outcomes were investigated. Results. Thirty-one patients with hospital-acquired pneumonia or ventilator-associated pneumonia were included in the study. The majority of the responsible organisms were carbapenem-resistant Acinetobacter baumannii (67.7%), followed by Klebsiella pneumoniae (16.1%) and Escherichia coli (9.7%). Twenty patients were treated with high-dose TGC therapy (100 mg every 12 h after a 200 mg loading dose), and the others received a standard-dose therapy (50 mg every 12 h after a 100 mg loading dose). The duration of TGC therapy was 14.3±2.8 days. The global clinical cure rate and the microbiological eradication rate were 48.4% and 61.3%, respectively. The overall ICU mortality rate was 45.2%. A higher score on the Acute Physiology and Chronic Health Evaluation II and a longer duration of IIAT were associated with clinical failure. High-dose TGC therapy had a higher clinical success rate [65.0% (13/20) versus 18.2% (2/11), P=0.023] and a lower ICU mortality rate [30.0% (6/20) versus 72.7% (8/11), P=0.031] than the standard-dose therapy. Conclusions. TGC, especially a high-dose regimen, might be a justifiable option for critically ill patients with nosocomial pneumonia due to CRGNB who have received IIAT when the options for these patients are limited.

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

scholarly journals Emergency Combination of Four Drugs for Bloodstream Infection Caused by Carbapenem-Resistant Enterobacteriaceae in Severe Agranulocytosis Patients with Hematologic Malignancies after Hematopoietic Stem Cell Transplantation

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaofan Li ◽  
Yaqun Hong ◽  
Xianling Chen ◽  
Ping Chen ◽  
Nainong Li
Keyword(s):  
Bloodstream Infection ◽  
Combination Treatment ◽  
Drug Combination ◽  
Conventional Treatment ◽  
Hematologic Malignancies ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Carbapenem Resistant

Bloodstream infection (BSI) caused by multidrug-resistant (MDR) bacteria or extensively drug-resistant (XDR) bacteria is a global threat. However, an effective treatment regimen is still controversial and inadequate due to the rapid deterioration caused by the bacteria. In immunocompromised and neutropenic patients, MDR-BSI is an emergency, which causes treatment-related mortality. In this study, four agranulocytosis patients with hematologic malignancies after HSCT receiving treatment for carbapenem-resistant Enterobacteriaceae- (CRE-) BSI were included. Conventional treatment using two to three combined antibiotics was administered in the first and second patients. Combination treatment using four drugs, polymyxin B, high-dose tigecycline, fosfomycin, and double-dose carbapenem, was administered in the third and fourth patients. None of the patients receiving conventional treatment survived. Both patients receiving combination treatment using four drugs survived. Therefore, four-drug combination therapy may be needed in CRE-BSI patients who experienced severe agranulocytosis after HSCT. The efficacy of the four-drug combination treatment for CRE-BSI patients as well as the adverse effects need to be further studied.

scholarly journals Clinical Experience with High-Dose Polymyxin B against Carbapenem-Resistant Gram-Negative Bacterial Infections—A Cohort Study

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 451
Author(s):  
Yiying Cai ◽  
Hui Leck ◽  
Ray W. Tan ◽  
Jocelyn Q. Teo ◽  
Tze-Peng Lim ◽  
...  
Keyword(s):  
Cohort Study ◽  
Bacterial Infections ◽  
Kidney Injury ◽  
Polymyxin B ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Median Daily Dose

Population pharmacokinetic studies have suggested that high polymyxin B (PMB) doses (≥30,000 IU/kg/day) can improve bacterial kill in carbapenem-resistant Gram-negative bacteria (CR-GNB). We aim to describe the efficacy and nephrotoxicity of patients with CR-GNB infections prescribed high-dose PMB. A single-centre cohort study was conducted from 2013 to 2016 on septic patients with CR-GNB infection and prescribed high-dose PMB (~30,000 IU/kg/day) for ≥72 h. Study outcomes included 30-day mortality and acute kidney injury (AKI) development. Factors associated with AKI were identified using multivariable regression. Forty-three patients with 58 CR-GNB received high-dose PMB; 57/58 (98.3%) CR-GNB were susceptible to PMB. The median daily dose and duration of high-dose PMB were 32,051 IU/kg/day (IQR, 29,340–34,884 IU/kg/day) and 14 days (IQR, 7–28 days), respectively. Thirty-day mortality was observed in 7 (16.3%) patients. AKI was observed in 25 (58.1%) patients with a median onset of 8 days (IQR, 6–13 days). Higher daily PMB dose (aOR,1.01; 95% CI, 1.00–1.02) and higher number of concurrent nephrotoxins (aOR, 2.14; 95% CI; 1.03–4.45) were independently associated with AKI. We observed that a sizable proportion developed AKI in CR-GNB patients described high-dose PMB; hence, the potential benefits must be weighed against increased AKI risk. Concurrent nephrotoxins should be avoided to reduce nephrotoxicity.

Ventilator-associated pneumonia due to carbapenem-resistant Providencia rettgeri

2021 ◽  
Vol 14 (7) ◽  
pp. e243908
Author(s):  
Nupur B Patel ◽  
Gaurav Jain ◽  
Saurabh Chandrakar ◽  
Beeraling Ningappa Walikar
Keyword(s):  
Early Identification ◽  
Resistance Pattern ◽  
High Dose ◽  
Ventilator Associated Pneumonia ◽  
Nosocomial Pathogen ◽  
Providencia Rettgeri ◽  
Mortality And Morbidity ◽  
Carbapenem Resistant ◽  
Successful Weaning ◽  
Extended Infusion

Ventilator-associated pneumonia (VAP) is one of the leading cause of mortality and morbidity in critically ill patients on mechanical ventilation. We report a case of VAP caused by Providencia rettgeri in a postoperative 58-year-old man with prepyloric perforation. The patient’s ICU stay was complicated by VAP. As the organism was carbapenem resistant, high-dose extended infusion of meropenem along with cefepime was started. Early identification and treatment helped in successful weaning of the patient from the ventilator. Providencia is an emerging nosocomial pathogen with an increase in resistance pattern. This case highlights the rarity and importance of Providencia as a cause of VAP.

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