Ceftolozane/Tazobactam: a new option in the treatment of complicated gram-negative infections.
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ABSTRACT:
SUBMITTER: Sorbera M
PROVIDER: S-EPMC4264669 | biostudies-other | 2014 Dec
REPOSITORIES: biostudies-other
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Ceftolozane/Tazobactam: a new option in the treatment of complicated gram-negative infections.
Sorbera Maria M Chung Elizabeth E Ho Christopher W CW Marzella Nino N
P & T : a peer-reviewed journal for formulary management 20141201 12
Ceftolozane/tazobactam: a new option in the treatment of complicated gram-negative infections. ...[more]
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Project description:Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ?18?years and receipt of C/T (?72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n?=?226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ?1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.
| S-EPMC7179316 | biostudies-literature
Project description:Drug-resistant pathogens have gained a foothold especially in the most vulnerable patient populations, hospitalized and immunocompromised individuals. Furthermore, extended-spectrum β-lactamase and carbapenemase-producing organisms are finding their way even into the community, with patients presenting to the hospital with established colonization and infection with resistant Enterobacteriaceae in particular. Recently, a novel antipseudomonal cephalosporin in combination with an established Class A β-lactamase inhibitor, ceftolozane/tazobactam has been approved by the FDA for use in the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Ceftolozane is a uniquely potent antipseudomonal cephalosporin because of its high affinity for the penicillin-binding proteins of Pseudomonas aeruginosa, its low affinity for the intrinsic Class C β-lactamases of P. aeruginosa, its ability to enter P. aeruginosa through the outer membrane without the utilization of OprD protein, and the fact that it is not a substrate of the often upregulated MexAB/OprM efflux system of P. aeruginosa. The biological chemistry, pharmacokinetics/pharmacodynamics, microbiologic spectrum, and clinical trials that led to the approval of ceftolozane is reviewed. A discussion regarding its potential role in the treatment of complicated intra-abdominal infections and other infectious disease syndromes associated with drug-resistant pathogens follows.
| S-EPMC4461093 | biostudies-literature
Project description:The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel ?-lactam/?-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some ?-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum ?-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.
| S-EPMC4878668 | biostudies-literature
Project description:BackgroundCeftolozane/tazobactam (C/T) is approved in 70 countries, including the United States, for the treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible Gram-negative pathogens. C/T is of particular importance as an agent for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections. The current study summarizes 2018-2019 data from the United States on lower respiratory tract isolates of Gram-negative bacilli from the SMART global surveillance program. The CLSI reference broth microdilution method was used to determine in vitro susceptibility of C/T and comparators against isolates of P. aeruginosa and Enterobacterales.ResultsC/T inhibited 96.0% of P. aeruginosa (n = 1237) at its susceptible MIC breakpoint (≤4 μg/ml), including > 85% of meropenem-nonsusceptible and piperacillin/tazobactam (P/T)-nonsusceptible isolates and 76.2% of MDR isolates. Comparator agents demonstrated lower activity than C/T against P. aeruginosa: meropenem (74.8% susceptible), cefepime (79.2%), ceftazidime (78.5%), P/T (74.4%), and levofloxacin (63.1%). C/T was equally active against ICU (96.0% susceptible) and non-ICU (96.7%) isolates of P. aeruginosa. C/T inhibited 91.8% of Enterobacterales (n = 1938) at its susceptible MIC breakpoint (≤2 μg/ml); 89.5% of isolates were susceptible to cefepime and 88.0% susceptible to P/T. 67.1 and 86.5% of extended-spectrum β-lactamase (ESBL) screen-positive isolates of Klebsiella pneumoniae (n = 85) and Escherichia coli (n = 74) and 49.6% of MDR Enterobacterales were susceptible to C/T. C/T was equally active against ICU (91.3% susceptible) and non-ICU (92.6%) Enterobacterales isolates.ConclusionData from the current study support the use of C/T as an important treatment option for lower respiratory tract infections including those caused by MDR P. aeruginosa.
| S-EPMC7936229 | biostudies-literature
Project description:Ceftolozane/tazobactam (C/T) was tested and compared against 93 nonfermenting, Gram-negative clinical isolates from cystic fibrosis specimens. Based on current breakpoints for intra-abdominal and urinary tract infections (which may not be appropriate for pulmonary infections), C/T was found to be the most active agent against P. aeruginosa (95.7% susceptible), followed by piperacillin/tazobactam (89.4% susceptible). For other Gram-negative pathogens included, C/T had varying activity.
| S-EPMC6055570 | biostudies-other
Project description:Understanding which antimicrobial agents are likely to be active against Gram-negative bacilli can guide selection of antimicrobials for empirical therapy as mechanistic rapid diagnostics are adopted. In this study, we determined the MICs of a novel ?-lactam-?-lactamase inhibitor combination, imipenem-relebactam, along with ceftolozane-tazobactam, imipenem, ertapenem, meropenem, ceftriaxone, and cefepime, against 282 drug-resistant isolates of Gram-negative bacilli. For isolates harboring blaKPC (n = 110), the addition of relebactam to imipenem lowered the MIC50/MIC90 from 16/>128 ?g/ml for imipenem alone to 0.25/1 ?g/ml. For isolates harboring blaCTX-M (n = 48), the MIC50/MIC90 of ceftolozane-tazobactam were 0.5/16 ?g/ml (83% susceptible). For isolates harboring blaCMY-2 (n = 17), the MIC50/MIC90 of ceftolozane-tazobactam were 4/8 ?g/ml (47% susceptible). Imipenem-relebactam was active against most KPC-producing (but not NDM- or IMP-producing) Enterobacteriaceae and is an encouraging addition to the present antibiotic repertoire.
| S-EPMC6105828 | biostudies-literature
Project description:Ceftolozane-tazobactam (C/T) is a combination of an advanced-generation cephalosporin (ceftolozane) with a β-lactamase inhibitor (tazobactam). It is approved for the treatment of complicated urinary-tract/intra-abdominal infections and hospital-acquired/ventilator-associated pneumonia. This systematic review and meta-analysis (registered prospectively on PROSPERO, no. CRD42019134099, on 20 January 2020) aimed to evaluate the effectiveness of C/T combination therapy compared to C/T monotherapy for the treatment of severe infections and to describe the prevalence of microorganisms in the included studies. We retrieved literature from PubMed, EMBASE, and CENTRAL, until 26 November 2020. Eligible studies were both randomised trials and nonrandomised studies with a control group, published in the English language and peer-reviewed journals. The primary outcome was all-cause mortality; secondary outcomes were (i) clinical improvement and (ii) microbiological cure. Eight nonrandomised studies were included in the qualitative synthesis: Seven retrospective cohort studies and one case-control study. The meta-analysis of the four studies evaluating all-cause mortality (in total 148 patients: 87 patients treated with C/T alone and 61 patients treated with C/T combination therapy) showed a significant reduction of mortality in patients receiving C/T combination therapy, OR: 0.31, 95% CI: 0.10-0.97, p = 0.045. Conversely, the meta-analysis of the studies evaluating clinical improvement and microbiological cure showed no differences in C/T combination therapy compared to C/T monotherapy. The most consistent data come from the analysis of the clinical improvement, n = 391 patients, OR: 0.97, 95% CI: 0.54-1.74, p = 0.909. In 238 of the 391 patients included (60.8%), C/T was used for the treatment of infections caused by Pseudomonas aeruginosa.
| S-EPMC7830767 | biostudies-literature
Project description:The effectiveness of ceftolozane/tazobactam for the treatment of infections in neutropenic patients caused by hypervirulent multidrug-resistant (MDR) Pseudomonas aeruginosa has not been previously reported. We identified seven cases of MDR P. aeruginosa infection in neutropenic patients over a four-month period within the same hematology ward. Four cases were associated with rapid progression despite piperacillin-tazobactam or meropenem therapy, and three patients developed sepsis or extensive skin/soft tissue necrosis. In three of the four cases, patients were empirically switched from meropenem to ceftolozane/avibactam before carbapenem susceptibility test results were available, and all four patients underwent extensive surgical debridement or amputation of affected tissues and survived. Further investigation revealed a common bathroom source of MDR P. aeruginosa clonal subtypes ST175 and ST235 that harbored genes for type III secretion system expression and elaboration of ExoU or ExoS exotoxin. We conclude that ceftolozane/tazobactam plus early source control was critical for control of rapidly progressing skin and soft infection in these neutropenic patients caused by highly virulent ST175 and ST235 clones of MDR P. aeruginosa.
| S-EPMC7767535 | biostudies-literature
Project description:Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.
| S-EPMC6535558 | biostudies-literature
Project description:Treatment of Pseudomonas aeruginosa remains challenging, despite the availability ceftolozane-tazobactam. We report a treatment failure with ceftolozane-tazobactam salvage therapy for pneumonia complicated by lung abscess. Drug resistance, dose selection, and source control are possible contributing factors. Ceftolozane-tazobactam susceptibility testing should precede therapy and consideration should be given to dosing selection.
| S-EPMC6028400 | biostudies-literature