Explore the vast range of titles available.

Abstract Background ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. Results Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. Conclusions ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. Clinical Trial Registration NCT02753946 ZEUS, a Phase 2/3 trial, studied ZTI-01 (fosfomycin for injection) in the treatment of hospitalized adults with complicated urinary tract infection and acute pyelonephritis versus piperacillin-tazobactam. ZTI-01 was non-inferior to piperacillin-tazobactam and was well tolerated.

Nosocomial pneumonia due to antimicrobial-resistant pathogens is associated with high mortality. We assessed the efficacy and safety of the combination antibacterial drug ceftolozane–tazobactam versus meropenem for treatment of Gram-negative nosocomial pneumonia. We conducted a randomised, controlled, double-blind, non-inferiority trial at 263 hospitals in 34 countries. Eligible patients were aged 18 years or older, were undergoing mechanical ventilation, and had nosocomial pneumonia (either ventilator-associated pneumonia or ventilated hospital-acquired pneumonia). Patients were randomly assigned (1:1) with block randomisation (block size four), stratified by type of nosocomial pneumonia and age (<65 years vs ≥65 years), to receive either 3 g ceftolozane–tazobactam or 1 g meropenem intravenously every 8 h for 8–14 days. The primary endpoint was 28-day all-cause mortality (at a 10% non-inferiority margin). The key secondary endpoint was clinical response at the test-of-cure visit (7–14 days after the end of therapy; 12·5% non-inferiority margin). Both endpoints were assessed in the intention-to-treat population. Investigators, study staff, patients, and patients' representatives were masked to treatment assignment. Safety was assessed in all randomly assigned patients who received study treatment. This trial was registered with ClinicalTrials.gov, NCT02070757. Between Jan 16, 2015, and April 27, 2018, 726 patients were enrolled and randomly assigned, 362 to the ceftolozane–tazobactam group and 364 to the meropenem group. Overall, 519 (71%) patients had ventilator-associated pneumonia, 239 (33%) had Acute Physiology and Chronic Health Evaluation II scores of at least 20, and 668 (92%) were in the intensive care unit. At 28 days, 87 (24·0%) patients in the ceftolozane–tazobactam group and 92 (25·3%) in the meropenem group had died (weighted treatment difference 1·1% [95% CI −5·1 to 7·4]). At the test-of-cure visit 197 (54%) patients in the ceftolozane–tazobactam group and 194 (53%) in the meropenem group were clinically cured (weighted treatment difference 1·1% [95% CI −6·2 to 8·3]). Ceftolozane–tazobactam was thus non-inferior to meropenem in terms of both 28-day all-cause mortality and clinical cure at test of cure. Treatment-related adverse events occurred in 38 (11%) of 361 patients in the ceftolozane–tazobactam group and 27 (8%) of 359 in the meropenem group. Eight (2%) patients in the ceftolozane–tazobactam group and two (1%) in the meropenem group had serious treatment-related adverse events. There were no treatment-related deaths. High-dose ceftolozane–tazobactam is an efficacious and well tolerated treatment for Gram-negative nosocomial pneumonia in mechanically ventilated patients, a high-risk, critically ill population. Merck & Co.

Background Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding. Methods ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors. Results Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI − 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam. Conclusions There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam. Trial registration clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

Background Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a hospital mortality in excess of 40%. Along with insufficient and delayed empirical antimicrobial therapy, inappropriate antimicrobial exposure has been identified to negatively affect patient outcomes. Receipt of prolonged infusion (i.e. extended or continuous infusion) of piperacillin/tazobactam (TZP) improves antimicrobial exposure and is associated with reduced mortality in patients with sepsis. Using therapeutic drug monitoring (TDM) with dosing tailored to the altered pharmacokinetics of the individual patient to avoid under- and overdosing may be a further strategy to improve patient outcomes. This current trial will address the question whether a TDM-guided therapy with TZP administered by continuous infusion will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion of the total daily dose of TZP without TDM. Methods The study is an investigator-initiated, multi-centre, parallel-group, single-blinded, randomised controlled trial. The trial will be conducted in several centres across Germany. Adult patients (aged ≥ 18 years) with severe sepsis or septic shock will be eligible for study participation. Participants will be randomly assigned to receive either TZP by continuous infusion guided by daily TDM of piperacillin (experimental group) or by continuous infusion without TDM guidance (total daily dose in normal renal function 13.5 g TZP) (control group). The pharmacokinetic (PK)/pharmacodynamic (PD) target will be 100% f T >4MIC (percentage of time during a dosing interval that the free [f] drug concentration exceeds 4 times the minimum inhibitory concentration). The primary efficacy endpoint is the change in mean total Sequential Organ Failure Assessment score from day 1 after randomisation until day 10 or discharge from the intensive care unit or death, whichever comes first. Secondary outcomes include mortality, clinical cure, microbiological cure, overall antibiotic use, individual components of the primary outcome, adverse events and analysis of PK and (PD) indices. Discussion This trial will assess for the first time whether continuous infusion of TZP guided by daily TDM in patients with sepsis will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion without TDM. Trial registration German Clinical Trials Register (GermanCTR), DRKS00011159 . Registered on 10 October 2016.

PurposeInsufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.MethodsRandomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.ResultsAmong 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9, p < 0.001).ConclusionTDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

A detailed study of the reaction of CF[sub.3]-ynones with NaN[sub.3] was performed. It was found that the reaction permits the selective synthesis of either 4-trifluoroacetyltriazoles or 5-CF[sub.3]-isoxazoles. The chemoselectivity of the reaction was switchable via acid catalysis. The reaction of CF[sub.3]-ynones with NaN[sub.3] in EtOH produced high yields of 4-trifluoroacetyltriazoles. In contrast, the formation of 5-CF[sub.3]-isoxazoles was observed under catalysis by acids. This acid-switchable procedure can be performed at sub-gram scale. The possible reaction mechanism was supported by DFT calculations. The synthetic utility of the prepared 4-trifluoroacetyltriazoles was demonstrated.

Acute appendicitis is the most common indication for emergency surgery in children. In cases of perforation, patients require post-operative intravenous antibiotics in hospital. However, some children fail to respond adequately, resulting in prolonged hospitalization. The optimal antibiotic regimen for perforated appendicitis remains uncertain. We propose a double-blind, randomized controlled pilot trial comparing two commonly used antibiotic strategies. Eligible participants include children <18 years undergoing laparoscopic appendectomy for perforated appendicitis. Following surgery, participants will be randomized to receive either: (1) piperacillin/tazobactam; or (2) ceftriaxone and metronidazole. The sample size for the pilot study is 16 participants (i.e., 8 per group). Feasibility outcomes include recruitment rate, protocol adherence, loss to follow-up, and cost per participant. This pilot study will assess the feasibility of conducting a blinded randomized controlled trial of postoperative antibiotic therapy in children with perforated appendicitis. To date, only one randomized trial has addressed this question, but it was limited by its single-center design, lack of blinding, and susceptibility to ascertainment bias and other methodological concerns. Findings from this pilot will inform the design of a larger, multicenter study with rigorous blinding and standardized outcome assessment to determine whether piperacillin-tazobactam or ceftriaxone and metronidazole provides superior outcomes. ClinicalTrials.gov: NCT05943223.

[...]it is reasonable to assume that most of these patients were undergoing renal replacement therapy (RRT), most likely continuous RRT (CRRT) though this was not reported [1]. The results suggest that the following ceftolozane/tazobactam doses, administered every 8 h according to renal function, are recommended for adults with HABP/VABP [7,8,9]: CrCl > 50 mL/min (including critically ill patients with ARC): 3 g; CrCl 30 to ≤ 50 mL/min: 1.5 g; CrCl 15 to < 30 mL/min: 750 mg; and end-stage renal disease on hemodialysis: single loading dose of 2.25 g, followed by 450 mg every 8 h. Importantly, among the ventilated HABP (vHABP) subgroup, only 1 of the 108 participants in the meropenem arm underwent RRT, including CRRT, while on study treatment (i.e., a protocol deviation). [...]the influence of RRT on the analysis and interpretation of results reported for participants with vHABP treated with meropenem was exceedingly small. [...]RRT was not permitted during study treatment, and only 1 participant in the vHABP subgroup deviated from the protocol and received CRRT during study treatment. [...]underdosing of meropenem in the setting of RRT did not appreciably affect the findings of our recently published analysis of participants with vHABP [1].