mMITT Population Research Articles

Efficacy and safety of ceftazidime/avibactam in patients with infections caused by β-lactamase-producing Gram-negative pathogens: a pooled analysis from the Phase 3 clinical trial programme.

This post hoc pooled analysis evaluated clinical and microbiological outcomes and safety in patients with infections caused by β-lactamase-producing Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials of ceftazidime/avibactam in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP). In each trial, RECLAIM/RECLAIM 3 (cIAI), REPRISE (cIAI/cUTI), RECAPTURE (cUTI) and REPROVE (NP, including VAP) patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days. Clinical and microbiological responses at the test-of-cure visit were assessed for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population. In total, 813 patients (ceftazidime/avibactam, n = 389; comparator, n = 424) had ≥1 β-lactamase-producing baseline pathogen identified, amongst whom 792 patients (ceftazidime/avibactam, n = 379; comparator, n = 413) had no MBLs. The most frequent β-lactamase-producing pathogens across treatment groups were Escherichia coli (n = 381), Klebsiella pneumoniae (n = 261) and Pseudomonas aeruginosa (n = 53). Clinical cure rates in the pooled non-MBL β-lactamase-producing mMITT population were 88.1% (334/379) for ceftazidime/avibactam and 88.1% (364/413) for comparators; favourable microbiological response rates were 76.5% (290/379) and 68.8% (284/413), respectively. The safety profile of ceftazidime/avibactam was consistent with previous observations. This analysis provides supportive evidence of the efficacy and safety of ceftazidime/avibactam in patients with infections caused by ESBLs, AmpC and serine carbapenemase-producing Gram-negative pathogens. NCT01499290; NCT01726023; NCT01644643; NCT01595438/NCT01599806; NCT01808092.

Subgroup analysis of phase 2 study of ceftolozane/tazobactam in neonates and young infants with pyelonephritis.

Ceftolozane/tazobactam is approved for the treatment of patients from birth to <18 y old with complicated urinary tract infections (cUTI). This post hoc analysis evaluated the safety, efficacy, and pharmacokinetics (PK) of ceftolozane/tazobactam compared with meropenem in neonates and young infants. NCT03230838 was a phase 2, randomized, active comparator-controlled, double-blind study of patients from birth to <18 y of age with cUTI, including pyelonephritis, given ceftolozane/tazobactam or meropenem in a 3:1 ratio. This subset analysis included only neonates and young infants < 3 mo of age. The microbiologic modified intent-to-treat population (mMITT) included 20 patients (ceftolozane/tazobactam, n = 14; meropenem, n = 6). All patients had pyelonephritis at baseline; two patients in each treatment group had bacteremia (overall 4/20, 20%). Escherichia coli was the most common baseline pathogen (overall 16/20, 80%). Safety and efficacy results were similar between treatment groups and consistent with the overall pediatric population. There were no serious drug-related adverse events (AEs), no discontinuations due to AEs, and no AEs leading to death in either treatment group. For the ceftolozane/tazobactam and meropenem treatment groups, clinical cure rates in the mMITT population were 92.9% and 100%, respectively. The population PK analysis of neonates and young infants demonstrated similar ceftolozane and tazobactam exposures to those of adults, achieving pharmacodynamic targets associated with clinical and microbiologic cure. Ceftolozane/tazobactam has a favorable safety profile and achieves high clinical cure and microbiologic eradication rates in neonates and young infants < 3 mo of age with cUTI and pyelonephritis. IMPORTANCE Extrapolation of antibacterial agent pharmacokinetics from adults to newborns and young infants may not be appropriate; similarly, the clinical manifestations of infectious diseases and outcomes following antibacterial treatment may not be similar. Ceftolozane/tazobactam is an antibacterial drug combination active against Pseudomonas aeruginosa and other multidrug-resistant gram-negative bacteria. A clinical study led to the approval for ceftolozane/tazobactam in patients from birth to 18 y of age who have complicated urinary tract infections, including those with serious kidney infections. Based on data collected during that clinical study, we compared newborns and young infants who were treated with ceftolozane/tazobactam (14 patients) and those who were treated with meropenem (6 patients). We found that ceftolozane/tazobactam treatment of newborns and young infants up to 3 mo of age who have complicated urinary tract infections demonstrated a favorable safety profile and high clinical cure and microbiologic eradication rates, similar to meropenem.

2235. Discordance of Clinical and Microbiological Endpoints in Clinical Trials for Complicated Urinary Tract Infection (cUTI)

Abstract Background Complicated urinary tract infections (cUTI) are a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine or blood culture, accompanied by local and systemic signs and symptoms, in the presence of urinary tract abnormalities or acute pyelonephritis. Current FDA guidance recommends that the primary endpoint for cUTI clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed time after therapy. In recent trials, it has been noted that while some patients have clinical resolution of symptoms, they are considered failures due to positive urine cultures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. Methods We analyzed patient data from 13 phase 3 clinical trials submitted to the FDA. We focused on the microbiological modified intent-to-treat (m-MITT) population, including patients who have at least 1 bacterial pathogen known to cause cUTI and received at least one dose of study drug (N=4842). Outcomes were determined at the Test of Cure (TOC) visit 7-10 days after therapy, and the Late Follow Up (LFU) visit 3-4 weeks after therapy. Clinical and microbiological success were defined as the resolution of cUTI symptoms present at entry, with no new symptoms (clinical cure), and reduction of the pathogen at entry to ≤ 103 CFU/mL on urine culture (microbiological eradication). Results Among all included patients, 70.7% were overall successes at the TOC, exhibiting clinical and microbiological success. 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). In a multivariate logistic regression model, discordance was associated with obesity, lithiasis, use of analgesics, and receipt of carbapenem antibiotics. Discordant patients were at an increased risk for clinical failure at the LFU visit, and the risk of late clinical failure increased with longer time between the TOC and LFU visits. Conclusion Microbiological persistence at the TOC visit despite resolution of symptoms was associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component in the composite endpoint. Disclosures All Authors: No reported disclosures.

Efficacy and Safety of Plazomicin in the Treatment of Enterobacterales Infections: A Meta-analysis of Randomized Controlled Trials

BackgroundIn the present study, we aimed to compare the efficacy and safety of plazomicin with comparators for the treatment of Enterobacterales infections.MethodsRandomized controlled trials (RCTs) assessing plazomicin for Enterobacterales infections were searched on the PubMed, Embase, and Cochrane Library databases. Meta-analyses were used to evaluate the efficacy and safety in RCTs.ResultsA total of 3 RCTs consisting of 761 patients were included in the present analysis. The study population included complex urinary tract infections (cUTIs), bloodstream infections (BSIs), and hospital-acquired pneumonia (HAP). Plazomicin had a clinical remission rate in the modified intention-to-treat (MITT) population that was similar to that of comparators (odds ratio [OR], 1.02; 95% CI, 0.60–1.73; I2 = 45%) in the pooled analysis of the 3 studies. The overall microbiologic eradication rate in the microbiological MITT (mMITT) population was similar to that of the comparators group (OR, 1.46; 95% CI, 0.72–2.95; I2 = 0%). However, the microbiologic recurrence rate of plazomicin for Enterobacterales was lower than that in the comparators group (OR, 0.38; 95% CI, 0.17–0.86; P = .02; I2 = 0%). No significant differences were found between plazomicin and comparators for the risk of any adverse events (OR, 0.78; 95% CI, 0.55–1.11; I2 = 0%).ConclusionsPlazomicin is as good as comparators in terms of efficacy and tolerance in the treatment of Enterobacterales infections. Therefore, plazomicin is a suitable choice for antibiotic treatment in adult patients with cUTIs, BSIs, or HAP.

Treatment outcomes of secondary bacteraemia in patients treated with ceftaroline fosamil: pooled results from six phase III clinical trials

This exploratory pooled analysis assessed the efficacy and safety of ceftaroline fosamil and comparators across six phase III clinical trials in adults with community-acquired pneumonia (CAP) or complicated skin and soft-tissue infection (cSSTI) and secondary bacteraemia. In each trial, FOCUS 1 and 2 (CAP), Asia CAP trial, CANVAS 1 and 2 (cSSTI) and COVERS (cSSTI), patients were randomised to ceftaroline fosamil [600 mg q12h by 1-h i.v. infusion, except in COVERS (600 mg q8h by 2-h i.v. infusion), adjusted for renal function] or comparator. Efficacy assessments included clinical and microbiological responses at test-of-cure visit [microbiological modified intent-to-treat (mMITT) population]. Safety outcomes were assessed. The pooled mMITT population comprised 1976 patients, of whom 138 had baseline bacteraemia (ceftaroline fosamil, n=72; comparator, n=66). Predominant baseline blood pathogens were Staphylococcus aureus (n=29), Streptococcus pneumoniae (n=19) and other streptococci (n=12). Clinical cure rates in bacteraemic patients were 55/72 (76.4%) and 51/66 (77.3%) for ceftaroline fosamil and comparators, respectively, and in non-bacteraemic patients were 822/966 (85.1%) and 717/872 (82.2%). Favourable microbiological response rates in bacteraemic patients were 56/72 (77.8%) for ceftaroline fosamil and 54/66 (81.8%) for comparators, and in non-bacteraemic patients were 825/966 (85.4%) and 719/872 (82.5%). Adverse events in bacteraemic patients were consistent with the known ceftaroline fosamil safety profile or the underlying indications. These pooled clinical and microbiological efficacy data demonstrate generally favourable outcomes for ceftaroline fosamil in patients with CAP or cSSTI and secondary bacteraemia. [Trial Registration: NCT00621504, NCT00509106; NCT01371838; NCT00424190, NCT00423657; NCT01499277].

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial

BackgroundColistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined.MethodsA multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved.ResultsA total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015).ConclusionsThis study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.Trial registrationClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

720. Efficacy of Fosfomycin for Injection (FOS) vs. Piperacillin–Tazobactam (PIP-TAZ) in Adults with Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP): ZEUS Study Outcomes in Patients With Reduced Study Drug Susceptibility

BackgroundFOS is being pursued for US registration in cUTI/AP. Safety and efficacy of FOS vs. PIP-TAZ were demonstrated in the noninferiority ZEUS trial in hospitalized patients with cUTI/AP. Although FOS resistance has been observed in several in vitro studies, resistance rates in clinical settings have remained relatively stable despite >40 years of clinical use of FOS outside of the United States. Here we report outcomes in patients who developed reduced susceptibility to study drug (FOS or PIP-TAZ) after enrollment in ZEUS.MethodsPatients received IV FOS 6g q8h or PIP-TAZ 4.5g q8h for 7 days (no oral switch allowed). The primary endpoint was overall success (clinical cure + microbiologic eradication) in microbiologic modified intent-to-treat (m-MITT) population at test-of-cure (TOC; Day 19–21). Reduced susceptibility to FOS or PIP-TAZ was defined as a ≥4-fold increase from baseline in minimum inhibitory concentration (MIC) at Day 5, end of treatment (EOT; Day 7–8), TOC, or late follow-up (LFU; Day 26 ± 2). Microbiologic eradication/persistence of baseline and postbaseline pathogens was confirmed post hoc by pulsed-field gel electrophoresis (PFGE).ResultsIn all m-MITT patients, overall success/clinical cure/microbiologic eradication rates (with PFGE) at TOC were 69.0/90.8/70.7% (FOS) and 57.3/91.6/60.1% (PIP-TAZ). Reduced study drug susceptibility was identified in 7/184 (3.8%) FOS and 8/178 (4.5%) PIP-TAZ patients; all had monomicrobial infections (Table 1). Of these patients, almost all were aged ≥50 years (93%), male (73%), white (100%), and had a screening diagnosis of cUTI (93%). At TOC, 7/7 FOS patients and 7/8 PIP-TAZ patients had microbiologic persistence but all patients were clinical cures; these responses were all sustained through LFU (Table 1).ConclusionIn the ZEUS study, few patients had urine isolates with reduced postbaseline susceptibility to either FOS or PIP-TAZ. No trend was observed in isolate species associated with decreased susceptibility to FOS or PIP-TAZ, including various Enterobacteriaceae species and Pseudomonas aeruginosa. Despite microbiologic persistence at TOC in a small number of patients, all of these patients were clinical cures at TOC and sustained cures at LFU. Disclosures All authors: No reported disclosures.

1974. Ceftriaxone-Sulbactam-EDTA vs. Meropenem in PLEA (a Phase 3, Randomized, Double-Blind Trial): Outcomes by Baseline MIC in Adults With Complicated Urinary Tract Infections or Acute Pyelonephritis

BackgroundCeftriaxone–sulbactam–disodium EDTA (CSE) is being developed for Gram-negative infections caused by multidrug-resistant (MDR) bacteria. PLEA was a Phase 3, double-blind, multicenter, randomized study of CSE vs. meropenem (MR) for treatment of adults with complicated urinary tract infections (cUTI) or acute pyelonephritis (AP). Non-inferiority of CSE over MR at the EMA/FDA primary endpoints has been reported. The effect of baseline MIC on clinical and microbiological outcome at the test of cure (TOC) visit was investigated.MethodsAdult patients were randomized 1:1 to receive either CSE (1 g ceftriaxone/500 mg Sulbactam/37 mg EDTA) every 12 h or MR 1g every 8 hours as 30 minutes IV infusion for 5–14 days. Oral step-down therapy was not allowed. Prior to dosing, urine specimens were collected, and MICs were conducted using CLSI methods for both study drugs. Patients that were nonsusceptible to MR were not included in the mMITT population.ResultsOf 230 subjects randomized, 143 (62.2%) were included in the mMITT population. Baseline Enterobacteriaceae was found in 131 (91.6%) patients, 67/74 (90.5%) in CSE and 64/69 (92.8%) in MR arm. Mean duration of IV therapy was 7 days. Favorable clinical and microbiological outcomes were observed in ≥90% patients for all MICs across the two study groups, with the exception of MIC 1 μg/mL in MR (associated with >20% failures). Overall, both clinical cure and microbiological eradication rates were higher in CSE as compared with MR (95.9% Vs. 89.9% and 94.6% vs. 88.4% respectively) (Table 1).CSEMRMIC(μg/mL)Clinical Cure n/N (%)Microbiological Eradication n/N (%)MIC(μg/mL)Clinical Cure n/N (%)Microbiological Eradicationn/N (%)<0.2516/16 (100)16/16 (100)<0.2520/22 (90.9)21/22 (95.4)0.254/4 (100)4/4 (100)0.2512/12 (100)11/12 (91.7)0.53/3 (100)2/3 (66.7)0.514/14 (100)13/14 (92.7)19/10 (90)9/10 (90)116/21 (76.2)16/21 (76.2)223/23 (100)23/23 (100)416/17 (94.1)16/17 (94.1)80/1 (0)0/1 (0)Overall71/74 (95.9)70/74 (94.6)Overall62/69 (89.9)61/69 (88.4)ConclusionCSE showed a high in vitro–in vivo correlation of >97% for MICs up to 4 μg/mL and is a potential new treatment option in patients with cUTI or AP.Disclosures P. Mandale, Venus Medicine Research Centre: Employee, Salary. M. A. Mir, Venus Medicine Research Centre: Employee, Salary. S. Chaudhary, Venus Medicine Research Centre: Employee and Shareholder, Salary. M. Chaudhary, Venus Medicine Research Centre: Board Member and Shareholder, Salary. A. Pyasi, Venus Medicine Research Centre: Employee, Salary.

1964. Microbiological Outcomes With Plazomicin (PLZ) vs. Colistin (CST) in Patients With Bloodstream Infections (BSI) Caused by Carbapenem-Resistant Enterobacteriaceae (CRE) in the CARE Study

BackgroundPLZ is a next-generation aminoglycoside with structural modifications that protect it from aminoglycoside-modifying enzymes (AMEs) and in vitro activity against multidrug-resistant (MDR) Enterobacteriaceae, including aminoglycoside- and carbapenem-resistant strains. In the CARE study, PLZ was associated with improvement in 28-day all-cause mortality vs. CST in patients with CRE BSI. We report the microbiological outcomes in the CARE study by pathogen and key resistance mechanism.MethodsCARE was a multinational, open-label trial that enrolled BSI patients with documented or presumed CRE into two cohorts. Patients in the randomized cohort received PLZ (15 mg/kg q24h IV) or CST (300-mg load [CST base activity] then 5 mg/kg/day IV) plus adjunctive tigecycline or meropenem. Patients in the observational cohort received PLZ plus investigator’s choice of adjunctive agent. Treatment duration was 7–14 days. Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and carbapenemase genes. Microbiological outcomes were assessed in patients with confirmed CRE who received ≥1 dose of study drug (mMITT population).ResultsOf 45 BSI patients enrolled, 43 had confirmed CRE (mMITT), including Klebsiella pneumoniae (n = 42) and Enterobacter aerogenes (n = 1). Against CRE, PLZ MICs ranged from 0.12 to >128 µg/mL; 25/28 (89.3%) isolates from PLZ-treated patients had a PLZ MIC ≤4 µg/mL, while 3 had a PLZ MIC ≥128 µg/mL and a confirmed 16S ribosomal methyltransferase gene. CST MICs ranged from 0.25 to >128 µg/mL; 6/16 (37.5%) isolates from CST-treated patients had an MIC >2 µg/mL. There were 47 distinct Enterobacteriaceae pathogens isolated from 43 patients, and of these, AME genes were detected in 43/47 (91.5%), most commonly aac(6’)-Ib (n = 29). Carbapenemase genes were detected in 45/47 (95.7%) isolates, most commonly blaKPC (n = 33). PLZ demonstrated higher microbiological eradication rates than CST against CRE, including AME- and carbapenemase-producing isolates (table).ConclusionThe results provide evidence of the efficacy of PLZ-based therapy for patients with BSI due to MDR Enterobacteriaceae, including AME- and carbapenemase-producing organisms. Disclosures A. W. Serio, Achaogen, Inc.: Employee and Shareholder, Salary. A. Smith, Achaogen, Inc.: Employee and Shareholder, Salary. K. M. Krause, Achaogen, Inc.: Employee, Salary. I. Galani, Achaogen, Inc.: Scientific Advisor, Research funding and honoraria. MSD: Scientific Advisor, Honoraria. A. C. Gales, MSD: Consultant and Speaker, Consulting fee. Pfizer: Consultant and Speaker, Consulting fee. BD: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. A. Jubb, Achaogen, Inc.: Employee and Shareholder, Salary. L. E. Connolly, Achaogen, Inc.: Consultant, Consulting fee.

124. Microbiological Outcomes With Plazomicin (PLZ) Versus Meropenem (MEM) in Patients With Complicated Urinary Tract Infections (cUTI), Including Acute Pyelonephritis (AP) in the EPIC Study

BackgroundPLZ is a next-generation aminoglycoside (AG) that is structurally protected from common AG-modifying enzymes (AMEs) in Enterobacteriaceae and with in vitro activity against multidrug-resistant Enterobacteriaceae, including ESBL-producing, AG-resistant, and carbapenem-resistant isolates. We report microbiological outcomes in the EPIC study, including outcomes for resistant pathogens and by the PLZ MIC.MethodsEPIC was a multinational, randomized, double-blind study in hospitalized patients with cUTI or AP. Patients received IV PLZ (15 mg/kg q24h) or IV MEM (1 g q8h) for 4–7 days, followed by optional oral therapy, for a total of 7–10 days of therapy. The extended mMITT population included patients with ≥1 qualifying baseline pathogen (≥105 CFU/mL urine) who received study drug. Microbiological outcomes were assessed at TOC (day 15–19). Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and β-lactamase genes.ResultsOf 609 patients enrolled, 407 (66.8%) were included in the extended mMITT population. The most common uropathogen was Escherichia coli (63.4%) followed by Klebsiella pneumoniae (19.7%). PLZ and MEM MIC50/90 for Enterobacteriaceae were 0.5/2 μg/mL (range: ≤0.06–>128 mg/mL) and 0.015/0.06 mg/mL (range: ≤0.004–128 mg/mL), respectively. ESBL and AG-NS phenotypes were found in 29% and 27% of isolates, respectively. Genotyping detected β-lactamase and AME genes in 32.5% and 36.8% of isolates, respectively, most commonly blaCTX-M-15 (n = 98), blaOXA-1/OXA-30 (n = 82), aac(6′)Ib-cr (n = 79), and aac(3)-IIa (n = 56). Rates of microbiological eradication are shown in Table 1. All Enterobacteriaceae in the PLZ group with a PLZ MIC of 4 µg/mL (6/6) were eradicated at TOC (Table 2). Across 49 patients with concurrent bacteremia, 100% (27/27) and 96% (24/25) of Enterobacteriaceae were cleared from the blood at TOC in the PLZ and MEM groups, respectively.ConclusionPLZ demonstrated comparable or higher microbiological eradication rates compared with MEM for common Gram-negative uropathogens, including resistant pathogens. The results support PLZ as a potential treatment option for cUTI, including AP, caused by Enterobacteriaceae with PLZ MICs of ≤4 mg/mL. Disclosures T. R. Keepers, Achaogen, Inc.: Employee, Salary. D. S. Cebrik, Achaogen, Inc.: Employee, Salary. D. J. Cloutier, Achaogen, Inc.: Employee and Shareholder, Salary. A. Komirenko, Achaogen, Inc.: Employee and Shareholder, Salary. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. Krause, Achaogen, Inc.: Employee, Salary.

Efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs): A meta-analysis of randomized controlled trials

The aim of this study was to assess the efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs) with meta-analysis method. We included six randomized clinical trials identified from Medline, Embase, Cochrane Library, "ISRCTN Register" and "ClinicalTrials.gov" which compared ceftazidime-avibactam with comparison group. The meta-analysis was performed using Review Manager software version 5.3. Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on microbiological evaluable populations at the test-of-cure visit (95CI 1.10-2.38, p=0.02) and late-follow-up visit (95CI 1.09-2.23, p=0.02) for the treatment of CUTIs. Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on EME populations at the test-of-cure visit (95CI 1.08-4.27, p=0.03) and late-follow-up visit (OR=1.75, 95CI 1.33-2.29, p<0.0001) for the treatment of CUTIs. Similar results were obtained at the late-follow-up visit (OR = 1.58, 95CI 1.26-1.97, p<0.0001) on microbiologically modified intent-to-treat (mMITT) populations for the treatment of CUTIs. We can find better eradication rates for E. coli and Klebsiella pneumoniae based on mMITT populations. In terms of AEs, SAEs and mortality, ceftazidime-avibactam had a safety and tolerability profile broadly similar to the comparison group. This meta-analysis provides evidence of the efficacy of ceftazidime-avibactam as a potential alternative for the treatment of patients with CUTIs, and CIAIs.

CSE-1034 versus Ceftriaxone: Efficacy and Safety Analysis from a Randomized, Open-labeled Phase III Study in Complicated Urinary Tract Infections.

Objective:The aim of this study was to determine the clinical outcome, microbiological outcome and safety profile of CSE-1034, a novel combination of Ceftriaxone, Sulbactam and EDTA in patients with complicated urinary tract infections (cUTI).Materials and Methods:This was a randomized, controlled, open-labeled Phase-3 trial with the primary objective of assessing the efficacy and safety of CSE-1034 versus Ceftriaxone for the empirical treatment of cUTI. Adult cUTI patients were randomized to receive either intravenous dose of CSE-1034 or Ceftriaxone. The primary end point was composite cure rate (clinical response and bacterial eradication) in mMITT population at test of cure (TOC) visit. Secondary measures included verification of primary endpoint across other visits in different population sets, safety of patients and treatment duration.Results:Overall, 204 patients were enrolled in the study and received one of the two treatments. At primary endpoint (TOC visit), the composite cure rate was much higher in CSE-1034 treatment arm compared to Ceftriaxone arm i.e. 97% (68/70) vs 83% (58/71) (treatment difference 12.6%; 95% CI: 5.9% to 26.4%). The adverse events (AEs) rates reported in two treatment arms were 21% in CSE-1034 and 36% in Ceftriaxone groups. Additionally, the treatment duration in CSE-1034 arm was significantly less (P < 0.05).Conclusions:CSE-1034 3 g every 24 h showed a high favorable clinical and bacteriological response, and 95% CI around the treatment difference prove the superiority of CSE-1034 vs. Ceftriaxone for the treatment of cUTI. Therefore, CSE-1034 provides an effective alternative in the treatment of patients with cUTI.

Intravenous Fosfomycin (ZTI-01) for the Treatment of Complicated Urinary Tract Infections (cUTI) Including Acute Pyelonephritis (AP): Results from a Multi-center, Randomized, Double-Blind Phase 2/3 Study in Hospitalized Adults (ZEUS)

ZTI-01 (fosfomycin for injection) is a novel injectable epoxide antibiotic with a unique mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has a broad in vitro spectrum of activity, including multidrug-resistant (MDR) Gram-negative pathogens, and is being developed for the treatment of complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) in the USA. The ZEUS study was a multicenter, randomized, double-blind Phase 2/3 trial designed to evaluate safety and efficacy of ZTI-01 in the treatment of hospitalized adults with cUTI or AP vs. piperacillin/tazobactam (P-T). The primary endpoint of overall success was defined as clinical cure plus microbiologic eradication in the microbiologic modified intent-to-treat (m-MITT) population at the test-of-cure (TOC) visit (Day 19). Patients enrolled (n = 465) were randomized to receive 6 g ZTI-01 as a one-hour IV infusion q8h (18 g total daily dose) or 4.5 g IV P-T as a one-hour infusion q8h (13.5 g total daily dose) for a fixed 7 days, except patients with concurrent bacteremia received up to 14 days. Oral step-down therapy was prohibited. In the m-MITT population, ZTI-01 met the primary objective of non-inferiority compared with P-T with an overall success rate of 64.7% (119/184 patients) vs. 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% CI: −0.4, 20.8). Clinical cure rates at TOC were high and similar between treatment groups (90.8% vs. 91.6%, respectively). ZTI-01 was generally well tolerated. In the safety population (n = 464), treatment-emergent adverse events (TEAEs) were observed in 42.1% and 32.0% of patients in the ZTI-01 and P-T groups, respectively. Most TEAEs were mild and transient; premature discontinuation of study drug was uncommon. The most frequent clinical TEAEs were gastrointestinal in nature. Serious adverse events were uncommon (5 ZTI-01, 6 P-T), with no deaths reported during the study. These results demonstrate efficacy and tolerability of ZTI-01 in patients with cUTI and AP. If approved in the US, ZTI-01 would provide a new IV therapeutic option with a unique MOA for patients with difficult to treat Gram-negative infections. K. S. Kaye, Zavante Therapeutics, Inc.: Scientific Advisor, Consulting fee; L. B. Rice, Zavante Therapeutics, Inc.: Scientific Advisor, Consulting fee; A. Dane, Zavante Therapeutics, Inc.: Consultant, Consulting fee; V. Stus, Zavante Therapeutics, Inc.: Investigator, Research support; O. Sagan, Zavante Therapeutics, Inc.: Investigator, Research support; E. Fedosiuk, Zavante Therapeutics, Inc.: Investigator, Research support; A. Das, Zavante Therapeutics, Inc.: Consultant, Consulting fee; D. Skarinsky, Zavante Therapeutics, Inc.: Employee and Shareholder, Salary; P. B. Eckburg, Zavante Therapeutics, Inc.: Consultant and Shareholder, Consulting fee; E. J. Ellis-Grosse, Zavante Therapeutics: Employee and Shareholder, Salary

A network meta-analysis of antibiotics for treatment of hospitalised patients with suspected or proven meticillin-resistant Staphylococcus aureus infection

Infections due to meticillin-resistant Staphylococcus aureus (MRSA) pose a serious health risk. Novel methods for assessing comparative effectiveness and safety may provide valuable insights into therapeutic choices. We did a systematic review searching electronic databases including the archives of FDA/CDER and performed a Bayesian network meta-analysis to compare parenteral antibiotics used for treating hospitalised adults with complicated skin and soft-tissue infections (cSSTIs) or hospital-acquired or ventilator-associated pneumonia (HAP/VAP). Models were adjusted for clinical heterogeneity due to between-arm differences in the proportion of patients with diabetes (for cSSTI) and in those requiring mechanical ventilation (for pneumonia). Treatments were ranked on efficacy, defined as clinical success in the modified intention-to-treat population (MITT) and in the MITT population with MRSA at baseline (MRSA m-MITT), on all-cause mortality (in pneumonia only), and on serious adverse events and withdrawals due to adverse events. We identified 24 randomised controlled trials (17 for cSSTI and 10 for HAP/VAP) comparing one of six antibiotics with vancomycin. The network meta-analysis indicated that vancomycin ranked third (of six antibiotics) in cSSTI and second (of four) in pneumonia on both efficacy and safety. However, direct pairwise meta-analyses remained inconclusive as evidenced by the adjusted median odds ratios (ORs) and their 95% credible intervals. In cSSTI, linezolid and ceftaroline were non-significantly more effective than vancomycin. Linezolid ORs were 1.15 (0.74–1.71) and 1.01 (0.42–2.14) and ceftaroline ORs were 1.12 (0.78–1.64) and 1.59 (0.68–3.74) in the MITT and MRSA m-MITT populations, respectively. For HAP/VAP, linezolid was non-significantly better than vancomycin, with ORs of 1.05 (0.72–1.57) and 1.32 (0.71–2.48) in the MITT and MRSA m-MITT populations, respectively. We suspect performance and detection bias in cSSTI trials involving linezolid, but regression methods could not adjust for this potential bias. In these clinical trials, the preferred agents for treating serious MRSA infections were ceftaroline (for cSSTI, not studied in HAP/VAP) and linezolid. However, translation of these findings into practice should consider the small size of the evidence networks and the consequent uncertainty associated with the parameter estimates, the lack of evidence for ceftaroline in patients with severe renal impairment, and the lower internal validity of some of the linezolid trials.

Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are causing serious nosocomial infections. Tigecycline was evaluated in hospitalized patients with MRSA or VRE infection. A randomized (3:1), double-blind, multicentre, Phase 3 study compared the safety and efficacy of tigecycline with vancomycin or linezolid in hospitalized patients with MRSA or VRE infection, respectively. Patients were treated for 7-28 days and the test-of-cure (TOC) assessment was made 12-37 days after the last dose. The primary efficacy endpoint was the clinical response (cure, failure and indeterminate) in the co-primary, microbiologically evaluable (ME) and microbiologically modified intent-to-treat (m-mITT) populations at the TOC assessment. For MRSA infection, clinical cure rates in the ME population (n = 117) were 81.4% (70 of 86 patients) with tigecycline and 83.9% (26 of 31 patients) with vancomycin. In the m-mITT population (n = 133), clinical cure occurred in 75 of 100 tigecycline-treated patients (75.0%) and in 27 of 33 vancomycin-treated patients (81.8%). In patients with complicated skin and skin structure infections caused by MRSA, cure rates were similar with tigecycline or vancomycin (86.4% versus 86.9% in ME population; and 78.6% versus 87.0% in m-mITT population). In patients with MRSA infection, nausea or vomiting occurred more frequently with tigecycline than with vancomycin (41.0% versus 17.9%); most cases were mild, with only three patients discontinuing treatment. In patients with VRE (total enrollment, 15), 3 of 3 and 3 of 8 patients in the ME and m-mITT populations, respectively, were cured by tigecycline, compared with 2 of 3 patients in the ME and m-mITT populations treated with linezolid. Tigecycline is safe and effective in hospitalized patients with serious infection caused by MRSA. There were too few cases of VRE to draw any conclusions.

The Efficacy and Safety of Tigecycline for the Treatment of Complicated Intra-Adominal Infections - The European Experience

The polymicrobial nature of complicated intra-abdominal infections makes these infections particularly challenging to treat. The initial selection of antimicrobial therapy is therefore extremely important. Inappropriate empiric antimicrobial therapy has been shown to delay clinical resolution, increase length of hospital stay, and increase the risk of mortality. In addition, the increasing frequency with which resistant isolates (e.g., extended spectrum beta-lactamases [ESBLs]) are recovered from patients mandates that empiric antimicrobial therapy covers these difficult-to-treat organisms.Here, we assessed the efficacy of a new antimicrobial agent, tigecycline. This is a combined analysis of data from the European sites that participated in two Phase III, double-blind trials to evaluate the efficacy and safety of tigecycline, versus that of imipenem/cilastatin, in adults with complicated intra-abdominal infections. Patients received either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 hours) or imipenem/cilastatin (500/500 mg intravenously every 6 hours) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-44 days after therapy) in the co-primary microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations. For the ME group, clinical cure rates at the test-of-cure visit were 92.4% (219/237) for tigecycline versus 88.8% (198/223) for imipenem/cilastatin (95% CI = −2.2, 9.4). Clinical cure rates for the m-mITT populations were 87.3% (247/283) for tigecycline versus 83.5% (228/273) for imipenem/cilastatin (95% CI = −2.5, 10.0) at the test-of-cure visit. Pretherapy in vitro activity against baseline isolates for tigecycline and imipenem/cilastatin were also determined. The mean MIC90 for tigecycline against the most commonly isolated aerobes and anaerobes was >2.0 μg/mL. No pretherapy isolates displayed resistance to tigecycline based on the breakpoints used. Bacterial susceptibilities to tigecycline appeared to be consistent with clinical responses. Most commonly reported treatment emergent adverse events for tigecycline and imipenem/cilastatin were nausea (14.7% and 11.8%, respectively, p = 0.267) and vomiting (10.7% and 7.3%, respectively p = 0.146). This combined analysis demonstrates that tigecycline is safe and effective for the treatment of complicated intra-abdominal infections, and reflects the findings of the global population.

Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study

Background: Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. Doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. Objective: This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. Methods: In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (≥1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95% CI for the difference (doripenem minus meropenem) in the proportion of patients classified as clinical cures was ≥-15%. Results: A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. Doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced ≥1 adverse event (AE) and 13.2% and 14.0% experienced ≥1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. Conclusions: The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.

A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744

BackgroundComplicated intra-abdominal infections (cIAI) remain challenging to treat because of their polymicrobial etiology including multi-drug resistant bacteria. The efficacy and safety of tigecycline, an expanded broad-spectrum glycylcycline antibiotic, was compared with imipenem/cilastatin (IMI/CIS) in patients with cIAI.MethodsA prospective, double-blind, multinational trial was conducted in which patients with cIAI randomly received intravenous (IV) tigecycline (100 mg initial dose, then 50 mg every 12 hours [q12h]) or IV IMI/CIS (500/500 mg q6h or adjusted for renal dysfunction) for 5 to14 days. Clinical response at the test-of-cure (TOC) visit (14–35 days after therapy) for microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations were the co-primary efficacy endpoint populations.ResultsA total of 825 patients received ≥ 1 dose of study drug. The primary diagnoses for the ME group were complicated appendicitis (59%), and intestinal (8.8%) and gastric/duodenal perforations (4.6%). For the ME group, clinical cure rates at TOC were 80.6% (199/247) for tigecycline versus 82.4% (210/255) for IMI/CIS (95% CI -8.4, 5.1 for non-inferiority tigecycline versus IMI/CIS). Corresponding clinical cure rates within the m-mITT population were 73.5% (227/309) for tigecycline versus 78.2% (244/312) for IMI/CIS (95% CI -11.0, 2.5). Nausea (31.0% tigecycline, 24.8% IMI/CIS [P = 0.052]), vomiting (25.7% tigecycline, 19.4% IMI/CIS [P = 0.037]), and diarrhea (21.3% tigecycline, 18.9% IMI/CIS [P = 0.435]) were the most frequently reported adverse events.ConclusionThis study demonstrates that tigecycline is as efficacious as imipenem/cilastatin in the treatment of patients with cIAI.

Tigecycline is efficacious in the treatment of complicated intra-abdominal infections

BackgroundEmpiric treatment of complicated intra-abdominal infections (cIAI) represents a clinical challenge because of the diverse bacteriology and the emergence of bacterial resistance. The efficacy and safety of tigecycline (TGC), a first-in-class, expanded broad-spectrum glycylcycline antibiotic, were compared with imipenem/cilastatin (IMI/CIS) in patients with cIAI. MethodsIn this prospective, double-blind, phase 3, multinational trial, patients were randomly assigned to intravenous (IV) TGC (100mg initial dose, then 50mg every 12h) or IV IMI/CIS (500/500mg every 6h) for 5–14 days. Clinical response was assessed at the test-of-cure (TOC) visit (14–35 days after therapy) for microbiologically evaluable (ME) and microbiologically modified intent-to-treat (m-mITT) populations (co-primary efficacy endpoint populations in which cure/failure response rates were determined). ResultsOf 817 mITT patients (i.e., received≥1 dose of study drug), 641 (78%) comprised the m-mITT cohort (322 TGC, 319 IMI/CIS) and 523 (64%) were ME (266 TGC, 256 IMI/CIS). Patients were predominantly white (88%) and male (59%) with a mean age of 49 years. The primary diagnoses for the mITT group were complicated appendicitis (41%), cholecystitis (22%), and intra-abdominal abscess (11%). For the ME population, clinical cure rates at TOC were 91.3% (242/265) for TGC versus 89.9% (232/258) for IMI/CIS (95% CI −4.0, 6.8; P<0.001). Corresponding clinical cure rates within the m-mITT population were 86.6% (279/322) for TGC versus 84.6% (270/319) for IMI/CIS (95% CI −3.7, 7.5; P<0.001 for noninferiority TGC versus IMI/CIS). The most commonly reported adverse events for TGC and IMI/CIS were nausea (17.6% TGC versus 13.3% IMI/CIS; P=0.100) and vomiting (12.6% TGC versus 9.2% IMI/CIS; P=0.144). ConclusionsTGC is efficacious in the treatment of patients with cIAIs and TGC met per the protocol-specified statistical criteria for noninferiority to the comparator, IMI/CIS.