cilastatin--imipenem-drug-combination and Pneumonia--Ventilator-Associated

An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC.. The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046.. Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group.. Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains.. Entasis Therapeutics and Zai Lab.

Topics: Acinetobacter baumannii; Adult; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Cilastatin, Imipenem Drug Combination; Colistin; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Sepsis

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Topics: Anti-Bacterial Agents; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Cross Infection; Double-Blind Method; Drug Combinations; Hospital Mortality; Humans; Imipenem; Microbial Sensitivity Tests; Minocycline; Pneumonia; Pneumonia, Ventilator-Associated; Tigecycline; Treatment Outcome

In order to investigate the effect of carbapenems on systemic endotoxemia, 20 patients with severe sepsis due to ventilator-associated pneumonia and Gram-negative bacteremia were enrolled; 10 (group A) were administered 1 g t.i.d. of imipenem/cilastatin and 10 (group B) 2 g t.i.d. of meropenem. Blood was sampled at 0 time and after 1, 2, 4, 6, 12, 24, 36, 48, 60, 72, 84 and 96 hours for detection of endotoxins (LPS), interleukin-6 (IL-6), C-reactive protein (CRP) and drug levels. LPS were determined by the QCL-1000 LAL assay, IL-6 by an enzymeimmunoassay, CRP by nephelometry and carbapenem levels by a microbiological assay. We did not find that carbapenems had any effect on the kinetics of LPS and CRP; IL-6 of group A was lower than group B at 72 and 84 hours. No correlation was observed between drug levels of any carbapenem and LPS, IL-6 or CRP. It is concluded that in septic patients with Gram-negative bacteremia administration of either imipenem or meropenem did not affect systemic endotoxemia. The above data support the safe administration of both carbapenems in patients with severe sepsis.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; C-Reactive Protein; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Endotoxemia; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Interleukin-6; Lipopolysaccharides; Male; Middle Aged; Pneumonia, Ventilator-Associated; Sepsis

The article describes the use of the last-resort carbapenem antibiotic imipenem in combination with relebactam, a novel b-lactamase inhibitor, in the treatment of ventilator-associated pneumonia developing after SARS-CoV-2 infection in a young pregnant patient. The introduction briefly describes the mechanism and spectrum of activity of the antibiotic, including its dosage.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin, Imipenem Drug Combination; COVID-19; Humans; Imipenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; SARS-CoV-2

To compare the clinical efficacy between salvage antimicrobial regimen consisting of tigecycline plus extended-infusion imipenem/cilastatin (TIC) and regimen of sulbactam plus imipenem/cilastatin (SIC) for patients with ventilator-associated pneumonia and pneumonic bacteremia due to extensively drug-resistant (XDR) Acinetobacter baumannii (Ab) isolates, and determine the correlation of results of in vitro tigecycline-imipenem synergy test with clinical efficacy.. The comparative survey was conducted at a medical center in Taiwan in 2013. Patients comprising the TIC group (n = 28) received tigecycline plus extended-infusion imipenem/cilastatin following unresponsiveness to 3-day sulbactam-imipenem/cilastatin therapy, and those in the SIC group (n = 56) received sulbactam-imipenem/cilastatin throughout the course. Univariate and multivariate analyses were applied to explore 30-day case-fatality independent predictors. Additionally, the checkerboard test and time-kill analysis were performed for the bloodstream XDR-Ab isolates from patients in the TIC group, and molecular characterization was done for the bloodstream XDR-Ab strains of all patients.. We found that the TIC scheme has a significant benefit on improving patients' survival status (the mortality rate of TIC and SIC group patients was 14.3% and 64.3%, respectively), corresponding well with in vitro synergy or additivity results by the checkerboard test. Twenty TIC group cases had monomicrobial XDR-Ab cultured from tracheal aspirates after 10 days of tigecycline-imipenem/cilastatin therapy, but none developed subsequent pneumonia. However, breakthrough primary Burkholderia cepacia (n = 3) and Pseudomonas aeruginosa (n = 1) bacteremias were attributed to four TIC case fatalities. Shock, SIC regimen usage, and development of breakthrough bacteremia were independent predictors of 30-day in-hospital mortality.. Although the TIC regimen showed good efficacy, its value regarding managing XDR-Ab ventilator-associated pneumonia bacteremia needs further evaluation.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Imipenem; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Pneumonia, Ventilator-Associated; Salvage Therapy; Sulbactam; Taiwan; Tigecycline; Treatment Outcome

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Minocycline; Pneumonia, Ventilator-Associated; Prognosis; Retrospective Studies; Salvage Therapy; Survival Analysis; Tigecycline; Tunisia

Topics: Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Doripenem; Drug Combinations; Early Termination of Clinical Trials; Evidence-Based Medicine; Humans; Imipenem; Pneumonia, Ventilator-Associated; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome

Ventilator-associated pneumonia (VAP) is a common complication of critical illness among surgical and trauma patients. Inappropriate empiric treatment of VAP increases the mortality rate. The rates of Pseudomonas aeruginosa (PA) VAP susceptibility to doripenem (DOR) are higher than those to imipenem-cilastatin (IMI). We developed a model to quantify outcome differences between strategies of empiric treatment of VAP with DOR vs. IMI.. We designed a cost-effectiveness model comparing empiric treatment of VAP with DOR vs. IMI from both the hospital and societal perspectives. We examined the differences in the number of deaths, hospital length of stay (LOS), total costs, and quality-adjusted life years (QALY) under each scenario and conducted Monte Carlo simulations and sensitivity analyses to determine the stability of our estimates. Drug costs were taken as 80% of wholesale acquisition costs, with other inputs derived from the literature.. In the base case analysis, assuming a PA-VAP attributable mortality rate of 38.4% and a 49% relative risk reduction in deaths in PA-sensitive (PA-S) infections to empiric drug compared with a resistant PA (PA-R) organism, DOR use resulted in three additional deaths avoided, 117.4 days of hospitalization averted, and hospital savings of $422,524 per 1,000 patients treated at a cost of $5,748/QALY. All estimates were most sensitive to the costs of treating PA-S and PA-R infections. In a multivariable analysis, hospital cost savings persisted across >80% of the simulations (95% confidence interval $432,615-$2,148,540).. Given the current microbiologic sensitivity profile of PA to DOR and IMI, and depending on the local susceptibility patterns and in institutions where DOR in vitro susceptibilities are superior to those of other carbapenems for PA clinical isolates, empiric treatment of VAP with DOR may dominate that with IMI by being both life- and cost-saving.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Cost-Benefit Analysis; Doripenem; Drug Combinations; Humans; Imipenem; Length of Stay; Middle Aged; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Quality-Adjusted Life Years; Young Adult

Early, empiric, broad-spectrum antibiotics followed by de-escalation to pathogen-specific therapy is the standard of care for ventilator-associated pneumonia (VAP). In our surgical intensive care unit (SICU), imipenem-cilastatin (I-C) in combination with tobramycin (TOB) or levofloxacin (LEV) has been used until quantitative bronchoalveolar lavage results are finalized, at which time de-escalation occurs to pathogen-specific agents. With this practice, however, alterations in antimicrobial resistance remain a concern. Our hypothesis was that this strict regimen does not alter antimicrobial susceptibility of common gram-negative VAP pathogens in our SICU.. After Institutional Review Board approval, a retrospective review of SICU-specific antibiograms was performed for the sensitivities of common gram-negative VAP pathogens. Time periods were defined as early (January-June 2005) and late (July-December 2006). Chart review of empiric and de-escalation antibiotic usage was obtained. Data were collated, and statistical significance was assessed with the chi-square test using the on-line Simple Interactive Statistical Analysis tool.. Imipenem-cilastatin was used 198 times for empiric VAP coverage (811 patient-days), whereas TOB and LEV were given a total of 149 (564 patient-days) and 61 (320 patient-days) times, respectively. Collectively, the susceptibility of gram-negative organisms to I-C did not change (early 91.4%; late 97%; p = 0.33). Individually, non-significant trends to greater sensitivity to I-C were noted for both Pseudomonas aeruginosa (early 85.7%; late 90.9%; p = 0.73) and Acinetobacter baumannii (early 80%; late 100%; p = 0.13). Further, both TOB (early 77.1%; late 70.0%; p = 0.49) and LEV (early 74.3%; late 70.0%; p = 0.67) were found to maintain their susceptibility profiles. The frequency of resistant gram-positive VAPs was unchanged during the study period. Our de-escalation compliance (by 96 h) was 78% for I-C, 77.2% for TOB, and 59% for LEV. When infections requiring I-C were removed from the analysis, de-escalation compliance was improved to 92%.. In our SICU, early, empiric broad-spectrum VAP therapy followed by de-escalation to pathogen-specific agents did not alter antimicrobial resistance and is a valid practice. Further, our compliance with de-escalation practices was higher than published rates.

Topics: Anti-Bacterial Agents; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Bacterial; Gram-Negative Bacteria; Humans; Imipenem; Levofloxacin; Microbial Sensitivity Tests; Ofloxacin; Pneumonia, Ventilator-Associated; Retrospective Studies; Tobramycin