Explore the vast range of titles available.

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.

Intravenous cefiderocol (Fetroja ® ; Fetcroja ® ) is the first siderophore cephalosporin approved for the treatment of adults with serious Gram-negative bacterial infections. Cefiderocol is stable against all four Ambler classes of β-lactamases (including metallo-β-lactamases) and exhibits excellent in vitro activity against many clinically relevant Gram-negative pathogens, including multidrug resistant strains. In randomized, double-blind clinical trials, cefiderocol was noninferior to imipenem/cilastatin for the treatment of complicated urinary tract infections (cUTI) and to meropenem for nosocomial pneumonia. Furthermore, in a pathogen-focused clinical trial in patients with carbapenem-resistant (CR) infections, cefiderocol showed comparable efficacy to best available therapy (BAT), albeit all-cause mortality rate was higher in the cefiderocol arm, the cause of which has not been established. Cefiderocol had a good tolerability and safety profile in clinical trials. Thus cefiderocol is a novel, emerging, useful addition to the current treatment options for adults with susceptible Gram-negative bacterial infections (including cUTI and nosocomial pneumonia) for whom there are limited treatment options. Plain Language Summary Infections caused by carbapenem-resistant (CR) Enterobacterales and nonfermenters (such as Pseudomonas , Acinetobacter , Stenotrophomonas , Burkholderia ) are a major global health threat. Cefiderocol, a cephalosporin with activity against CR Enterobacterales and nonfermenters, uses the bacteria’s own iron uptake system to gain cell entry, like a Trojan horse. Once inside, the drug disrupts the formation of the bacterial cell wall, killing the bacteria. Cefiderocol is approved for the treatment of serious Gram-negative bacterial infections. In clinical trials, cefiderocol was effective versus carbapenems or best available therapy for complicated urinary tract infections, nosocomial pneumonia and bloodstream infections/sepsis, including those caused by CR bacteria. The drug had a good tolerability and safety profile. Thus, cefiderocol is a useful addition to the current treatment options for adults with cefiderocol-susceptible Gram-negative bacterial infections for whom there are limited treatment options.

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. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. Methods. Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5–14 days. Results. Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. Conclusions. Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. Trial registration. ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Background Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result. Methods The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy. Results In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n  = 53; meropenem, n  = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [− 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem. Conclusions This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates. ClinicalTrials.gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 .

Background Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). Methods This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. Results There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively ( P  = 0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively ( P  = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) ( P  = 0.616)); hospital mortality (25.2% versus 35.4% ( P  = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) ( P  = 0.918). Conclusions The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. Trial registration ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.

Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to \"ecological fallacy\". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients. This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems. For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions. There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU. This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.

Ceftaroline is a broad-spectrum cephalosporin currently under clinical investigation for the treatment of complicated skin and skin-structure infections (cSSSI), including those caused by meticillin-resistant Staphylococcus aureus (MRSA), and community-acquired pneumonia (CAP). Ceftaroline has the ability to bind to penicillin-binding protein (PBP)2a, an MRSA-specific PBP that has low affinity for most other β-lactam antibacterials. The high binding affinity of ceftaroline to PBP2a (median inhibitory concentration 0.90 μg/mL) correlates well with its low minimum inhibitory concentration for MRSA. Ceftaroline is active in vitro against Gram-positive cocci, including MRSA, meticillin-resistant Staphylococcus epidermidis , penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis (not E. faecium). The broad-spectrum activity of ceftaroline includes many Gram-negative pathogens but does not extend to extended-spectrum β-lactamase-producing or AmpC-derepressed Enterobacteriaceae or most nonfermentative Gram-negative bacilli. Ceftaroline demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. Limited data show that ceftaroline has a low propensity to select for resistant subpopulations. Ceftaroline fosamil (prodrug) is rapidly converted by plasma phosphatases to active ceftaroline. For multiple intravenous doses of 600 mg given over 1 h every 12 hours for 14 days, the maximum plasma concentration was 19.0 μg/mL and 21.0 μg/mL for first and last dose, respectively. Ceftaroline has a volume of distribution of 0.37 L/kg (28.3 L), low protein binding (<20%) and a serum half-life of 2.6 hours. No drug accumulation occurs with multiple doses and elimination occurs primarily through renal excretion (49.6%). Based on Monte Carlo simulations, dosage adjustment is recommended for patients with moderate renal impairment (creatinine clearance 30–50 mL/min); no adjustment is needed for mild renal impairment. Currently, limited clinical trial data are available for ceftaroline. A phase II study randomized 100 patients with cSSSI to intravenous ceftaroline 600 mg every 12 hours or intravenous vancomycin 1 g every 12 hours with or without intravenous aztreonam 1 g every 8 hours (standard therapy) for 7–14 days. Clinical cure rates were 96.7% for ceftaroline compared with 88.9% for standard therapy. Adverse events were similar between groups and generally mild in nature. In a phase III trial, 702 patients with cSSSI were randomized to ceftaroline 600 mg or vancomycin 1 g plus aztreonam 1 g, each administered intravenously every 12 hours for 5–14 days. Ceftaroline was noninferior to vancomycin plus aztreonam in treating cSSSI caused by both Gram-positive and -negative pathogens. Adverse event rates were similar between groups. Ceftaroline is well tolerated, which is consistent with the good safety and tolerability profile of the cephalosporin class. In summary, ceftaroline is a promising treatment for cSSSI and CAP, and has potential to be used as monotherapy for polymicrobial infections because of its broad-spectrum activity. Further clinical studies are needed to determine the efficacy and safety of ceftaroline, and to define its role in patient care.

Background Foot infections are a major cause of morbidity in people with diabetes and the most common cause of diabetes-related hospitalization and lower extremity amputation. Staphylococcus aureus is by far the most frequent species isolated from these infections. In particular, methicillin-resistant S. aureus (MRSA) has emerged as a major clinical and epidemiological problem in hospitals. MRSA strains have the ability to be resistant to most β-lactam antibiotics, but also to a wide range of other antimicrobials, making infections difficult to manage and very costly to treat. To date, there are two fifth-generation cephalosporins generally efficacious against MRSA, ceftaroline and ceftobripole, sharing a similar spectrum. Biofilm formation is one of the most important virulence traits of S. aureus. Biofilm growth plays an important role during infection by providing defence against several antagonistic mechanisms. In this study, we analysed the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains isolated from diabetic foot infections. The antibiotic minimum inhibitory concentration (MIC) was determined for ten antimicrobial compounds, along with the minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC), followed by PCR identification of genetic determinants of biofilm production and antimicrobial resistance. Results Results demonstrate that very high concentrations of the most used antibiotics in treating diabetic foot infections (DFI) are required to inhibit S. aureus biofilms in vitro, which may explain why monotherapy with these agents frequently fails to eradicate biofilm infections. In fact, biofilms were resistant to antibiotics at concentrations 10–1000 times greater than the ones required to kill free-living or planktonic cells. The only antibiotics able to inhibit biofilm eradication on 50 % of isolates were ceftaroline and gentamicin. Conclusions The results suggest that the antibiotic susceptibility patterns cannot be applied to biofilm established infections. Selection of antimicrobial therapy is a critical step in DFI and should aim at overcoming biofilm disease in order to optimize the outcomes of this complex pathology.