Explore the vast range of titles available.

In patients with complicated urinary tract infection, clinical and microbiologic treatment success was significantly better with cefepime–taniborbactam (β-lactam and β-lactamase inhibitor) than with meropenem.

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.

Background. The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis. Methods. Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia). Results. Of 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidimeavibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, −2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone. Conclusions. Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting. Clinical Trials Registration. NCT01595438; NCT01599806.

Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5–9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3–14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. Cubist Pharmaceuticals.

Oral antibacterial agents that are active against antimicrobial-resistant bacteria are needed. In this double-dummy, randomized, controlled trial, tebipenem pivoxil hydrobromide (an orally bioavailable carbapenem) was noninferior to intravenous ertapenem for the treatment of complicated urinary tract infection.

Background Urinary tract infection (UTI) is one of the most common bacterial infections in childhood and is associated with long-term complications. We aimed to assess the effect of adjuvant dexamethasone treatment on reducing kidney scarring after acute pyelonephritis (APN) in children. Methods Multicenter, prospective, double-blind, placebo-controlled, randomized clinical trial (RCT) where children from 1 month to 14 years of age with proven APN were randomly assigned to receive a 3-day course of either an intravenous corticosteroid (dexamethasone 0.30 mg per kg/day) twice daily or placebo. The late technetium 99 m-dimercaptosuric acid scintigraphy (> 6 months after acute episode) was performed to assess kidney scar persistence. Kidney scarring risk factors (vesicoureteral reflux, kidney congenital anomalies, or urinary tract dilatation) were also assessed. Results Ninety-one participants completed the follow-up and were finally included (dexamethasone n  = 49 and placebo n  = 42). Both groups had similar baseline characteristics. Twenty participants showed persistent kidney scarring after > 6 months of follow-up without differences in incidence between groups (22% and 21% in the dexamethasone and placebo groups, p  = 0.907). Renal damage severity in the early DMSA (β = 0.648, p  = 0.023) and procalcitonin values (β = 0.065 p  = 0.027) significantly modulated scar development. Vesicoureteral reflux grade showed a trend towards significance (β = 0.545, p  = 0.054), but dexamethasone treatment showed no effect. Conclusion Dexamethasone showed no effect on reducing the risk of scar formation in children with APN. Hence, there is no evidence for an adjuvant corticosteroid treatment recommendation in children with APN. However, the study was limited by not achieving the predicted sample size and the expected scar formation. Trial registration Clinicaltrials.gov, NCT02034851. Registered in January 14, 2014. Graphical abstract “A higher resolution version of the Graphical abstract is available as Supplementary information.”

Acute pyelonephritis is a common infection in adult women, but there is a paucity of controlled trials of its treatment and the optimum duration of antibiotic treatment has not been properly defined. We compared the efficacy of ciprofloxacin for 7 days and 14 days in women with community-acquired acute pyelonephritis. In a prospective, non-inferiority trial undertaken at 21 centres of infectious diseases in Sweden, women (aged ≥18 years) who were not pregnant and had a presumptive diagnosis of acute pyelonephritis were randomly assigned to oral treatment with ciprofloxacin 500 mg twice daily for 7 days or 14 days. The first week was open label. A computer-generated randomisation list in block sizes of two was used for treatment allocation in a 1:1 ratio. The study was double-blind and placebo-controlled during the second week of treatment, which was either continuation of ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment. The primary endpoint was the clinical and bacteriological outcome 10–14 days after completion of treatment with active drug. Analysis was by per protocol. This trial is registered with EudraCT, number 2005-004992-39, and ClinicalTrials.gov, number ISRCTN73338924. 126 of 248 patients were randomly assigned to 7 days and 122 to 14 days of ciprofloxacin. 73 and 83 patients, respectively, were analysed. Short-term clinical cure occurred in 71 (97%) patients treated with ciprofloxacin for 7 days and 80 (96%) treated for 14 days (difference −0·9%; 90% CI −6·5 to 4·8; p=0·004; non-inferiority test). Cumulative efficacy at long-term follow-up was 93% in each group (68 of 73 vs 78 of 84; −0·3%; −7·4 to 7·2; p=0·015). Both regimens were well tolerated. Two patients discontinued ciprofloxacin because of myalgia with 7 days of treatment and itching exanthema with 14 days. Four (5%) of 86 patients assigned to 7 days of treatment who complied with study criteria and six (6%) of 93 assigned to 14 days reported an adverse event after the first week of treatment that was possibly or probably related to the study drug. In those assigned to 7 days, no patient had mucosal candida infection after the first week versus five treated for 14 days (p=0·036). Our results show that acute pyelonephritis in women, including older women and those with a more severe infection, can be treated successfully and safely with oral ciprofloxacin for 7 days. Short courses of antibiotics should be favoured in an era of increasing resistance. Swedish Strategic Programme against Antibiotic Resistance (Strama).

To evaluate whether stopping the effective antibiotic treatment following clinical improvement at Day 7 (Truncated treatment) would be non-inferior to continued treatment until Day 14 (Continued treatment) in patients with acute pyelonephritis (APN) requiring hospitalization treated with non-fluoroquinolone (non-FQ) antibiotics. Hospitalized adult men and non-pregnant women with culture-confirmed APN were eligible for participation after they had clinically improved following empirical or culture-guided treatment with intravenous non-FQ antibiotic(s). We excluded patients with severe sepsis, abscesses, prostatitis, recurrent or catheter-associated urinary tract infection, or urinary tract obstruction. We randomized eligible patients on Day 7 of effective treatment and assessed them at Weeks 1 and 6 after treatment completion. The primary outcome was retreatment for recurrent urinary tract infection. The prespecified non-inferiority margin was 15%. Between March 17, 2015 and August 22, 2016, we randomly allocated 54 patients-27 patients in each arm. Twenty-four (44%) patients were male, and 26 (48%) had diabetes mellitus. Escherichia coli was the most common urinary isolate (47 [87%] patients); 36 (78%) were resistant to ciprofloxacin. In all, 41 (76%) patients received amikacin-based treatment. At the end of 6 weeks, no patient in the truncated treatment arm required retreatment, whereas 1 patient in the continued treatment arm was retreated. Difference (90% CI) in retreatment was -3.7% (-15.01% to 6.15%). Upper bound of the difference (6.15%) was below the prespecified limit, establishing non-inferiority of truncated treatment. Asymptomatic bacteriuria at Week 6 was similar between the two arms (3/24 vs. 3/26; P = 1.0). Patients in the truncated treatment arm had significantly shorter hospital stay (8 [7-10] vs. 14 [14-15] days; P < 0.001) and less antibiotic consumption per patient (8.4 ± 2.8 vs. 17.4 ± 8.3 DDDs; P < 0.001). Stopping the effective non-FQ antibiotics following clinical improvement at Day 7 is non-inferior to continued treatment until Day 14 in selected patients with APN requiring hospitalization. Clinical Trials Registry-India; CTRI/2016/04/006810.

The efficacy of converting to oral fluoroquinolones after initial intravenous antibiotics for the treatment of acute pyelonephritis (APN) caused by the third‐generation cephalosporin resistant Enterobacteriaceae (3‐GCrEC) needs to be investigated. The objective was to compare the clinical and bacteriological outcome of oral prulifloxacin with intravenous ertapenem for the treatment of APN caused by 3‐GCrEC. A pilot, randomized controlled trial of patients with APN caused by 3‐GCrEC was conducted at two hospitals from August 2015 to December 2020. Any intravenous antimicrobial drug was initially permitted for empirical therapy. On day 4, adult patients (aged >18 years) with either non‐bacteremic or bacteremic APN were eligible for the study if their infection was caused by 3‐GCrEC susceptible to the study drugs. The patients were randomly assigned to receive either oral prulifloxacin or intravenous ertapenem. The total duration of antimicrobial therapy was 14 days. Of the 21 enrolled patients, 11 were treated with prulifloxacin, and 10 were treated with ertapenem. At the test of cure visit, there was no statistically significant difference between the patients with overall clinical success who were treated with prulifloxacin (90.9%) and those treated with ertapenem (100%, p = 0.999). In addition, there was no statistically significant difference in microbiological eradication between the prulifloxacin and ertapenem groups (100% vs. 100%, p = 0.999). The converting to oral prulifloxacin after intravenous antibiotics therapy appears to be an alternative option for treatment of APN caused by 3‐GCrEC. A further large randomized controlled trial should be investigated.

The treatment duration of acute uncomplicated pyelonephritis (AUP) is still under debate. As shortening treatment duration could be a means to reduce antimicrobial resistance, we aimed to establish whether 5 days of antibiotic treatment is non-inferior to 10 days in patients with AUP. We performed an open-label prospective randomized trial comparing 5 days to 10 days of fluoroquinolone treatment for AUP. The inclusion criteria were: female patients aged ≥18 years with clinical signs of urinary tract infection, fever >38 °C, and positive urinalysis. Patients were randomized to either 5 or 10 days of fluoroquinolone treatment. Outcome was cure at day 10 and day 30 after the end of treatment. One hundred patients were randomized and 12 were excluded after randomization. The mean ± standard deviation (SD) age was 31.8 ± 11 years old and the mean ± SD temperature was 38.6 ± 0.7 °C. The main bacterium involved was Escherichia coli ( n  = 86; 97.7%) and 3 (3.4%) patients had a positive blood culture. In the post-hoc analysis, clinical cure 10 days after the end of the treatment was 28/30 (93.3%) in the 5-day arm and 36/38 (94.7%) in the 10-day arm ( p  = 1.00). At day 30, the clinical cure rate was 23/23 (100%) in the 5-day arm and 20/20 (100%) in the 10-day arm ( p  = 1.00). The microbiological cure rate was 20/23 (87.0%) in the 5-day arm and 16/20 (80.0%) in the 10-day arm ( p  = 1.00). The efficacy of 5 days of fluoroquinolone treatment does not seem different from 10 days of treatment for AUP.