Favorable Microbiological Response Research Articles

Outcome of intravenous and inhaled polymyxin B treatment in patients with multidrug-resistant gram-negative bacterial pneumonia

PurposeThe incidence of pneumonia caused by multidrug-resistant gram-negative bacteria (MDR GNB) is increasing, which imposes significant burden on public health. Inhalation combined with intravenous polymyxins has emerged as a viable treatment option. However, pharmacokinetic studies focusing on intravenous and inhaled polymyxin B (PMB) are limited. MethodsThis study included seven patients with MDR GNB-induced pneumonia who were treated with intravenous plus inhaled PMB from March 1 to November 30, 2022, in the intensive care unit of the First Affiliated Hospital of Zhejiang University School of Medicine. Clinical outcomes and therapeutic drug monitoring data of PMB in both plasma and epithelial lining fluid (ELF) were retrospectively reviewed. ResultsMedian PMB concentrations in the ELF were 7.83 (0.72–66.5), 116.72 (17.37–571.26), 41.1 (3.69–133.78) and 33.82 (0.83–126.68) mg/L at 0, 2, 6 and 12 h, respectively, and were much higher than those detected in the serum. ELF concentrations of PMB at 0, 2, 6 and 12 h were higher than the minimum inhibitory concentrations of pathogens isolated from the patients. Steady-state concentrations of PMB in the plasma were >2 mg/L in most patients. Of the patients, 57.14% were cured and 71.43% showed a favourable microbiological response. The incidence of side effects with PMB was low. ConclusionsInhaled plus intravenous PMB can achieve high ELF concentrations and favourable clinical outcomes without an increased adverse effect profile. This treatment approach appears promising for the treatment of patients with pneumonia caused by MDR-GNB.

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.

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis.

In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making. A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment. Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment. This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL. NCT02493764.

2236. Effectiveness of TBP-PI-HBr in Patients with Instrumentation, Anatomic or Functional Abnormalities: Secondary Analysis from ADAPT-PO

Abstract Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem with activity against Enterobacterales uropathogens, including drug resistant strains. The ADAPT-PO trial demonstrated the non-inferiority of oral TBP-PI-HBr vs. intravenous (IV) ertapenem (ERT) in treating patients with cUTI and/or acute pyelonephritis (AP). Patients with certain anatomical disorders, functional (metabolic or neurological) disorders and/or urinary tract instrumentation (i.e., indwelling catheters) are at increased risk for poor outcomes and recurrent bacteriuria. This secondary analysis of ADAPT-PO evaluated outcomes in patients with various cUTI risk factors. Methods ADAPT-PO was a Phase 3 multinational, double-blind, double-dummy trial evaluating oral TBP-PI-HBr vs. IV ERT in 1372 hospitalized adult patients with cUTI/AP. Patients were randomized 1:1 to oral TBP-PI-HBr or IV ERT for 7-10 days. The primary efficacy endpoint was overall response (composite favorable clinical and microbiologic response) in the microbiological intent-to-treat (micro-ITT) population. Overall outcomes were assessed among patients with identified with at least one cUTI risk factor at baseline. Results At baseline, 382/449 (85.1%) and 361/449(86.2%) of patients in the TBP-PI-HBr and ERT arms, respectively had ≥1 risk factor and 289 (64.4%) and 268 (64.2%) had ≥2 risk factors. Anatomical abnormalities and/or urinary track instrumentation were present in 252 (56.1%) TBP-PI-HBr and 242 (57.8%) ERT patients; functional abnormalities were present in 90 (20.0%) and 85(20.3%) respectively). Among patients with ≥1 risk factor, overall response at TOC was 56.3% and 59.6% with TBP-PI-HBr and ERT, respectively, vs. 73.1% and 74.1% among those with no risk factors. Clinical response rates at TOC were high and similar in both arms in patients with (≥92.9%) and without (≥91.4%) risk factors whereas microbiologic responses were more variable between the 2 subsets. Conclusion In cUTI patients with ≥1 risk factor for complicated disease at baseline, outcomes were comparable between oral TBP-PI-HBr and IV ERT. As expected, these patients were at higher risk for recurrent bacteriuria. Overall responses in both groups were higher among patients without these risk factors. Disclosures Angela K. Talley, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Paul B. Eckburg, MD, AN2 Therapeutics: Stocks/Bonds|Spero Therapeutics: Advisor/Consultant Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Gary E. Moore, PhD, Spero Therapeutics: Advisor/Consultant Nivedita Bhatt, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds David Melnick, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds.

Role of tigecycline in the treatment of urinary tract infections: a systematic review of published case reports.

The emergence of multi-drug resistance has forced clinicians to occasionally use drugs that are not approved to treat urinary tract infections (UTIs). This systematic review aimed to evaluate the utility of tigecycline in patients with UTIs. A systematic review of case studies was used to retrieve articles between 1.1.1999 to 1.1.2021 from two databases, PubMed and Embase. The title-abstract screening was done for 198 articles, out of which 69 articles were included for full-text screening. A total of 18 articles with 27 cases were included for final analysis. Of the 27 cases, there were 13 cases with complicated UTI and five had catheter-associated UTI. The most common organisms were Klebsiella pneumoniae (n=11), Acinetobacter baumannii (n=9), and Escherichia coli (n=6). Tigecycline was used as monotherapy in 19 patients and as a combination therapy in 8 patients. The median duration of tigecycline was 13 (10-15) days. A favourable clinical or microbiological response at varying intervals was seen in 24/27 (88.9%). Within three months of a favourable response, recurrence of symptoms was seen in four patients. In a small analysis of published case reports, tigecycline appeared to be a relatively effective treatment in patients with UTIs, caused by multidrug-resistant organisms. Where tigecycline is the only susceptible drug, it can be used for treatment. Further research, such as randomized controlled trials, is needed to fully assess the drug's efficacy in this context.

Effectiveness, nephrotoxicity, and therapeutic drug monitoring of polymyxin B in nosocomial pneumonia among critically ill patients.

ObjectivesWe aimed to assess the effectiveness and nephrotoxicity of polymyxin B in critically ill patients with nosocomial pneumonia and to evaluate the utility of its therapeutic drug monitoring (TDM).MethodsWe retrospectively analyzed patients who received polymyxin B treatment for ≥48 h since the establishment of polymyxin B TDM in a 26‐bed tertiary referral intensive care unit. Univariate and multivariate analyses were conducted to assess the variables associated with polymyxin B effectiveness and nephrotoxicity.ResultsA total of 62 patients were enrolled. Most (56.5%) of the patients performed TDM, 54.3% of them reached the therapeutic target of area under curve across 24 h at steady state (AUCss,24h) of 50–100 mg h L−1, and 10 patients had an AUCss,24h value of <50 mg h L−1. Thirty‐six (58.1) and 31 (50.0%) patients had favorable clinical and microbiological responses, respectively. Reaching the therapeutic target of AUCss,24h (odds ratio [OR] = 13.15, p = 0.015), a favorable microbiological response (OR = 40.80, p = 0.00), and complicated with septic shock (OR = 0.12, p = 0.021) were independently associated with favorable clinical outcomes of polymyxin B treatment. The incidence of acute kidney injury (AKI) was 45.2%. A lower creatinine clearance (OR = 0.96, p = 0.008) and concomitant treatment with loop diuretics (OR = 5.93, p = 0.046) were predictive of nephrotoxicity.ConclusionOur findings show that TDM of polymyxin B is a valuable intervention, and the achievement of its optimal pharmacodynamic target can improve treatment outcome. Renal insufficiency and concomitant treatment with loop diuretics were found to be associated with the risk of nephrotoxicity.

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection

BackgroundThere is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase–producing and fluoroquinolone-resistant strains.MethodsIn this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%.ResultsA total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, −3.3 percentage points; 95% confidence interval [CI], −9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, −0.6 percentage point; 95% CI, −4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache.ConclusionsOral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.)

A Prospective Randomized Study Comparing Ceftolozane/Tazobactam to Standard of Care in the Management of Neutropenia and Fever in Patients With Hematological Malignancies.

BackgroundWith increased use of antibiotics in high-risk patients, the investigation of new antibiotics to cover potentially resistant pathogens is warranted. In this prospective randomized trial, we compared ceftolozane/tazobactam (C/T), a new cephalosporin/β-lactamase inhibitor, to the standard of care (SOC) for the empiric treatment of neutropenia and fever in patients with hematological malignancies.MethodsWe enrolled 100 patients to receive intravenous (IV) C/T or SOC antibiotics (cefepime, piperacillin/tazobactam, or meropenem) in combination with gram-positive antibacterial agents. We evaluated responses at the end of IV therapy (EOIV), test of cure (TOC; days 21–28), and late follow-up (LFU; days 35–42).ResultsWe analyzed 47 C/T patients and 50 SOC patients. C/T patients had a higher rate of favorable clinical response at EOIV (87% vs 72%). A 1-sided noninferiority analysis indicated that C/T was at least not inferior to the SOC for favorable clinical response at EOIV (P = .002), TOC (P = .004), and LFU (P = .002). Superiority tests showed that C/T led to significantly lower rates of clinical failure at TOC (6% vs 30%; P = .003) and LFU (9% vs 30%; P = .008). C/T and SOC patients with documented infections had similar rates of favorable microbiological response. Serious adverse events leading to drug discontinuation (2% vs 0%; P = .48) and overall mortality (6% vs 4%; P = .67) were similar in both groups.ConclusionsThe empiric use of C/T in high-risk patients with hematological malignancies and febrile neutropenia is safe and associated with better clinical outcomes than SOC antimicrobial agents.Clinical Trials RegistrationNCT03485950.

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].

Efficacy and safety of daptomycin in Japanese pediatric participants with complicated skin and soft tissue infections or bacteremia caused by gram-positive cocci

IntroductionComplicated skin and soft tissue infections (cSSTIs) and bacteremia caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are common causes of infection for children worldwide. Here, the safety and efficacy of daptomycin in Japanese pediatric participants are reported. MethodsThis open-label, single-arm phase 2 study (NCT03643952) enrolled Japanese pediatric participants (age 1–17 years) with cSSTI or bacteremia caused by gram-positive cocci. Participants received age-adjusted doses of intravenous daptomycin for 5 to up to 14 days (cSSTI) or 5 to up to 42 days (bacteremia). The primary objective was safety and tolerability; efficacy among participants with infections caused by MRSA was a secondary objective. ResultsA total of 18 participants (cSSTI, n = 14; bacteremia, n = 4) were enrolled across 12 study sites in Japan. The most common pathogen was S. aureus (15/18 [83.3%]), including methicillin-susceptible and -resistant isolates. Adverse events (AE) were reported in 42.9% (6/14) of participants with cSSTI and 100% (4/4) of participants with bacteremia. No deaths, serious AEs, discontinuations of study medication due to an AE, or events of clinical interest occurred in the study. In participants with infections caused by MRSA, 87.5% [7/8] achieved favorable clinical response at test of cure (TOC) visit (cSSTI, 85.7% [6/7]; bacteremia, 100% [1/1]). In this population, favorable microbiological response at TOC was achieved by 71.4% (5/7) of participants with cSSTI and 100% (1/1) of participants with bacteremia. ConclusionsDaptomycin was well tolerated, exhibited a favorable safety profile, and was effective for the treatment of cSSTI or bacteremia in Japanese children.

Clinical and Microbiological Outcomes of Ceftazidime-Avibactam Treatment in Adults with Gram-Negative Bacteremia: A Subset Analysis from the Phase 3 Clinical Trial Program.

IntroductionThis exploratory analysis assessed efficacy and safety outcomes in patients with Gram-negative bacteremia treated with ceftazidime-avibactam or comparator across five phase 3, randomized, controlled, multi-center trials in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP).MethodsIn each trial, RECLAIM and RECLAIM 3 (cIAI; NCT01499290/NCT01726023), REPRISE (cIAI/cUTI; NCT01644643), RECAPTURE (cUTI; NCT01595438/NCT01599806), and REPROVE (HAP/VAP; NCT01808092), patients were randomized 1:1 to intravenous ceftazidime-avibactam (plus metronidazole for those with cIAI) or comparators (carbapenems in > 97% patients) for 5–21 days. Efficacy assessments included clinical and microbiological responses at the test-of-cure visit in the pooled Gram-negative extended microbiologically evaluable (GNeME) population (bacteremia subset). Safety outcomes were summarized for patients with positive bacterial blood culture(s) at baseline who received ≥ 1 dose of study treatment.ResultsThe overall safety population included 4050 patients (ceftazidime-avibactam, n = 2024; comparator, n = 2026). The GNeME population (bacteremia subset) comprised 101 patients (ceftazidime-avibactam, n = 54; comparator, n = 47). Clinical cure rates (all indications combined) were 47/54 (87.0%) for ceftazidime-avibactam and 39/47 (83.0%) for comparators; favorable microbiological response rates were 43/54 (79.6%) and 32/47 (68.1%), respectively. Clinical and microbiological responses in the bacteremia subset were generally similar to those in the overall set. The pattern of adverse events in patients with bacteremia was similar between treatment groups and was consistent with the known safety profile of ceftazidime-avibactam.ConclusionThis analysis provides supportive evidence of the efficacy and safety of ceftazidime-avibactam in patients with Gram-negative bacteremia associated with cIAI, cUTI/pyelonephritis, or HAP/VAP.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00506-7.

Effectiveness and Nephrotoxicity of Intravenous Polymyxin B in Chinese Patients With MDR and XDR Nosocomial Pneumonia.

Background: Nosocomial pneumonia is a major health and economic burden globally. Multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria are the most common causative pathogens in critically-ill patients. Polymyxin B is a salvage therapy for MDR Gram-negative pathogens; however, the current literature on its effectiveness and nephrotoxicity is limited, including in Chinese patients. Methods: We retrospectively analyzed 107 patients with nosocomial pneumonia caused by MDR or XDR Gram-negative bacteria treated with intravenous polymyxin B (2–3 mg/kg/day). Renal function was evaluated on the day before commencement of polymyxin B therapy and on the third and 7 days of treatment. Univariate and multivariate analyses were conducted to determine risk factors for the effectiveness and nephrotoxicity of polymyxin B. Sixty-seven (62.6%) and sixty-five (60.7%) patients had favorable clinical and microbiological responses, respectively. Acute physiology and chronic health evaluation II (APACHE II) scores, cardio-pulmonary resuscitation (CPR) history, numbers of pathogens per patient and a favorable microbiological response were independently associated with favorable clinical outcomes of polymyxin B treatment in Chinese patients with MDR or XDR nosocomial pneumonia. Initial renal dysfunction was not associated with late nephrotoxicity (on day 7), although early nephrotoxicity (on day 3) was independently associated with late nephrotoxicity (OR = 39.43, 95% CI 7.64–203.62, p = 0.00). Conclusion: Our findings support polymyxin B treatment for MDR and XDR pneumonia, with the severity of disease and polymicrobial infection being risk factors for a poor clinical outcome. Nephrotoxicity following 3 days of polymyxin B treatment was found to be a reliable risk factor for later nephrotoxicity.

The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter, open-label, noncomparative phase 3 study

IntroductionRelebactam, a novel class A/C β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens. MethodsThis phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5–14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis. ResultsOf 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT. ConclusionsA favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.

Tedizolid Versus Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis.

This meta-analysis aims to assess the efficacy and safety of tedizolid, compared to linezolid, in the treatment of acute bacterial skin and skin structure infection (ABSSSI). PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid Medline and Embase databases were accessed until 18 July 2019. Only randomized controlled trials (RCTs) comparing the efficacy of tedizolid with linezolid for adult patients with ABSSSIs were included. The outcomes included the clinical response, microbiological response, and risk of adverse events (AEs). A total of four RCTs involving 2056 adult patients with ABSSSI were enrolled. The early clinical response rate was 79.6% and 80.5% for patients receiving tedizolid and linezolid, respectively. The pooled analysis showed that tedizolid had a non-inferior early clinical response rate to linezolid (odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.77–1.19, I2 = 0%). The early response rate was similar between tedizolid and linezolid among patients with cellulitis/erysipelas (75.1% vs. 77.1%; OR = 0.90, 95% CI = 0.64–1.27, I2 = 25%), major cutaneous abscess (85.1% vs. 86.8%; OR = 0.93, 95% CI = 0.42–2.03, I2 = 37%) and wound infection (85.9% vs. 82.6%; OR = 1.29, 95% CI = 0.66–2.51, I2 = 45%). For methicillin-resistant Staphylococcus aureus patients, tedizolid had a favorable microbiological response rate of 95.2% which was comparable to linezolid (94%) (OR = 1.19, 95% CI = 0.49–2.90, I2 = 0%). In addition to the similar risk of treatment-emergent AEs (a serious event, the discontinuation of the study drug due to AEs and mortality between tedizolid and linezolid), tedizolid was associated with a lower risk of nausea, vomiting and abnormal neutrophil count than linezolid. In conclusion, once-daily tedizolid (200 mg for six days) compared to linezolid (600 mg twice-daily for 10 days) was non-inferior in efficacy in the treatment of ABSSSI. Besides, tedizolid was generally as well tolerated as linezolid, and had a lower incidence of gastrointestinal AEs and bone marrow suppression than linezolid.

Safety and Efficacy of Ceftazidime–Avibactam in the Treatment of Children ≥3 Months to &lt;18 Years With Complicated Urinary Tract Infection: Results from a Phase 2 Randomized, Controlled Trial

Ceftazidime-avibactam is effective and well tolerated in adults with complicated urinary tract infection (cUTI), but has not been evaluated in children with cUTI. This single-blind, multicenter, active-controlled, phase 2 study (NCT02497781) randomized children ≥3 months to <18 years with cUTI (3:1) to receive intravenous (IV) ceftazidime-avibactam or cefepime for ≥72 hours, with subsequent optional oral switch. Total treatment duration was 7-14 days. Primary objective was assessment of safety. Secondary objectives included descriptive efficacy and pharmacokinetics. A blinded observer determined adverse event (AE) causality and clinical outcomes up to the late follow-up visit (20-36 days after the last dose of IV/oral therapy). In total, 95 children received ≥1 dose of IV study drug (ceftazidime-avibactam, n = 67; cefepime, n = 28). The predominant baseline Gram-negative uropathogen was Escherichia coli (92.2%). AEs occurred in 53.7% and 53.6% patients in the ceftazidime-avibactam and cefepime groups, respectively. Serious AEs occurred in 11.9% (ceftazidime-avibactam) and 7.1% (cefepime) patients. One serious AE (ceftazidime-avibactam group) was considered drug related. In the microbiologic intent-to-treat analysis set, favorable clinical response rates >95% were observed for both groups at end-of-IV and remained 88.9% (ceftazidime-avibactam) and 82.6% (cefepime) at test-of-cure. Favorable per-patient microbiologic response at test-of-cure was 79.6% (ceftazidime-avibactam) and 60.9% (cefepime). Ceftazidime-avibactam was well tolerated in children with cUTI, with a safety profile consistent with that of adults with cUTI and of ceftazidime alone, and appeared effective in children with cUTI due to Gram-negative pathogens.

Comparison of the microbiological efficacy of tedizolid and linezolid in acute bacterial skin and skin structure infections: pooled data from phase 3 clinical trials

We evaluated the microbiological efficacy of tedizolid compared with that of linezolid against common and emerging pathogens using pooled data from 2 phase 3 trials (NCT01170221 and NCT01421511) in patients with acute bacterial skin and skin structure infections. Patients received tedizolid 200 mg once daily for 6 days (n = 664) or linezolid 600 mg twice daily for 10 days (n = 669). Favorable microbiological outcome in both treatment groups, defined as eradication or presumed eradication at the end of treatment and at the posttherapy evaluation, exceeded 85% for most pathogens, including methicillin-resistant Staphylococcus aureus. Favorable microbiological response was observed for staphylococci and streptococci at tedizolid minimal inhibitory concentration values ≤0.5 mg/L and 0.25 mg/L, respectively. The studies demonstrated positive microbiological outcomes against common pathogens with a 6-day, once-daily regimen of tedizolid phosphate in patients with acute bacterial skin and skin structure infections.

1963. Combined Microbiological Response Rates From Two Phase 3 Trials Demonstrating the Activity of Eravacycline in the Treatment of Complicated Intra-abdominal Infections: A Pooled Analysis of IGNITE1 and IGNITE4

BackgroundIGNITE1 and IGNITE4 were randomized, double-blind, double-dummy, multicenter studies which demonstrated the efficacy and safety of eravacycline (ERV) compared with a carbapenem in subjects with complicated intra-abdominal infections (cIAIs). The primary objective of this analysis was to compare the microbiological response at the test-of-cure (TOC) visit for subjects in the two treatment groups.MethodsAppropriate aerobic and anaerobic specimens for culture at the time of the initial procedure were collected from the site of infection and directly inoculated into transport media. Blood and intra-abdominal specimens were cultured, and species identified according to local laboratory practice. Pure cultures of isolates were sent to a reference laboratory for susceptibility analysis to ERV and comparators. Favorable microbiological response rates at the TOC visit were determined for each baseline pathogen isolated from blood and/or intra- or extra-abdominal specimens in the micro-ITT population.ResultsFor subjects with infections caused by Enterobacteriaceae, the overall favorable microbiological response rates for ERV-treated subjects were 86.3% and 91.8% for IGNITE1 and IGNITE4, respectively. The favorable microbiological response rates among pooled ERV-treated subjects are shown in the Table.Baseline PathogenERV No./Total No. (%)Baseline PathogenERV No/Total No. (%) Enterobacteriaceae 277/314 (88.2) Streptococcus viridans group109/120 (90.8) E. coli 223/253 (88.1) E. faecalis 45/54 (83.3) E. cloacae 18/21 (85.7) E. faecium 39/45 (86.7) K. pneumoniae 38/39 (97.4) S. aureus 24/24 (100) A. baumannii 13/13 (100) B. fragilis 74/84 (88.1)ConclusionIn IGNITE1 and IGNITE4 studies, high favorable microbiological responses were observed for ERV. More than 88% of five Enterobacteriaceae spp. and B. fragilis, the most common bacteria associated with intraabdominal infections, were eradicated by ERV. Comparable eradication rates were observed following ertapenem and meropenem therapy, further establishing that ERV was at least as effective as carbapenem treatments. These data support in vitro observations that ERV has broad-spectrum activity against common isolates found in intra-abdominal infections.Disclosures J. Newman, Tetraphase Pharmaceuticals: Employee, Salary. S. Izmailyan, Tetraphase Pharmaceuticals: Employee, Salary. C. Fyfe, Tetraphase Pharmaceuticals: Employee, Salary. L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary.

2373. Evaluation of Delafloxacin Activity and Treatment Outcome for Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial Anaerobic Isolates

BackgroundDelafloxacin (DLX) is a broad-spectrum fluoroquinolone (FQ) antibacterial; approved in 2017 by the Food and Drug Administration for treatment of acute bacterial skin and skin structure infections (ABSSSIs). DLX is in clinical development for community-acquired bacterial pneumonia (CABP). In this study, in vitro susceptibility (S) for DLX and comparator agents for Gram-negative (GN) and Gram-positive (GP) anaerobic isolates from Phase 3 ABSSSI clinical trials were determined and compared with the microbiologic response for evaluable isolates.MethodsA total of 84 anaerobic isolates were collected during Phase 3 ABSSSI clinical trials and 9 additional Bacteroides fragilis (BF) were collected as part of the 2017 SENTRY surveillance program. The isolates tested included 11 BF, 13 Clostridium perfringens (CP), and other species with <10 isolates (table). Isolate identifications were confirmed by molecular methods. Susceptibility testing was performed according to CLSI agar dilution methodology (M11, 2012). Other antimicrobials tested included clindamycin (CD), metronidazole (MTZ), and moxifloxacin (MXF). In addition, the activity of DLX and MXF were compared at standard pH 7.0 and at pH 6.0.ResultsDLX had the lowest MIC50/90 values against both GP and GN species and was 32-fold more active than MXF for all organisms. For BF, DLX was 4- to 16-fold more active than the other comparators. For CP, DLX was 32- to 64-fold more active than the 3 comparators. When comparing the activity of DLX and MXF at pH 6 vs. pH 7, DLX had the same MIC50/90 values while MXF MIC50/90 values were 2-fold less active at the lower pH (Table 1). Of the 84 clinical trial isolates, 21 were recovered from subjects in the microbiologically evaluable at follow-up (MEFU) population. All of the subjects had a favorable microbiological response (presumed eradication) at FU.ConclusionDLX demonstrated potent in vitro antibacterial activity against anaerobic isolates tested, including BF and CP and was more active than MXF. For all isolates combined, DLX activity was unchanged at lower pH while MXF MIC values increased 2-fold. These data suggest that DLX activity remains potent at a lower pH common at sites of infection. Disclosures D. Shortridge, Melinta Therapeutics: Research Contractor, Research support. S. P. McCurdy, Melinta Therapeutics: Employee, Salary. P. R. Rhomberg, Melinta Therapeutics: Research Contractor, Research support. M. D. Huband, Melinta Therapeutics: Research Contractor, Research support. R. K. Flamm, Melinta Therapeutics: Research Contractor, Research support.

A Multicenter, Randomized, Observer-blinded, Active-controlled Study to Evaluate the Safety and Efficacy of Ceftaroline Versus Comparator in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infection.

Ceftaroline has in vitro activity against bacterial isolates, including methicillin-resistant Staphylococcus aureus. This is the first study to investigate ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs). A multicenter, observer-blinded study (NCT01400867) in pediatric patients (2 months-17 years of age) with ABSSSIs. Patients were randomized 2:1 to receive intravenous (IV) ceftaroline fosamil or IV comparator (vancomycin or cefazolin, plus optional aztreonam) with optional switch to oral antibacterials from Day 4. Safety and clinical outcomes were assessed. Of 163 enrolled patients, 159 received treatment. Treatment groups were comparable for baseline characteristics. Rates of study drug-related treatment-emergent adverse events were similar for ceftaroline fosamil [22% (23/106)] and comparator [23% (12/53)]. One serious adverse event, considered to be related to IV study drug, occurred in the ceftaroline fosamil group (hypersensitivity). In both the treatment groups, 85% (ceftaroline fosamil, 91/107 and comparator, 44/52) of the modified intent-to-treat population achieved early clinical response (≥20% reduction in infection area from baseline). Clinical cure rates at test-of-cure were high [ceftaroline fosamil, 94% (101/107) and comparator, 87% (45/52)]. For patients evaluated 8 to 15 days after the last dose of any antibiotic (IV or oral), from whom methicillin-resistant Staphylococcus aureus was initially isolated, a favorable microbiologic response (reflecting the efficacy of oral/IV therapy and capturing a relapse or reinfection) was achieved with ceftaroline fosamil [89% (16/18)] and comparator [57% (4/7)]. Ceftaroline fosamil, with optional oral switch, was as well-tolerated and effective in pediatric patients with ABSSSIs as comparator therapy.

Zabofloxacin versus moxifloxacin in patients with COPD exacerbation: a multicenter, double-blind, double-dummy, randomized, controlled, Phase III, non-inferiority trial

A new quinolone, zabofloxacin, has now been developed; hence, a non-inferiority trial is needed to compare this new compound with another widely used quinolone to examine its efficacy and safety for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations. This was a prospective, multicenter, double-blind, double-dummy, randomized, controlled, parallel-group, Phase III, non-inferiority clinical trial designed to compare oral zabofloxacin (367 mg once daily for 5 days) with moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation. In all, 345 COPD patients with a moderate COPD exacerbation were enrolled in the study via the outpatient clinics at 31 university hospitals. Clinical per protocol analysis revealed that the clinical cure rate for zabofloxacin was 86.7% and that for moxifloxacin was 86.3% (the rate difference, 0.4%; 95% confidence interval, −7.7%–8.6%). Intention-to-treat analysis revealed clinical cure rates of 77.1% and 77.3% (difference, −0.2%; 95% confidence interval, −9.0%–8.8%), respectively. These results confirm that zabofloxacin is not inferior to moxifloxacin. The favorable microbiological response rate for zabofloxacin was 67.4% and that for moxifloxacin was 79.5% (P=0.22). Patients in the zabofloxacin group showed better patient-oriented outcomes, as measured by EXAcerbations of Chronic Pulmonary Disease Tool-Patient-Reported Outcome and the COPD assessment test scores, than patients in the moxifloxacin group. Adverse drug reactions related to zabofloxacin occurred in 9.7% of cases and those related to moxifloxacin occurred in 9.6% of cases (P=0.97). The dropout rate due to adverse events was 0% (0/175) in the zabofloxacin group and 1.8% (3/167) in the moxifloxacin group (P=0.12). Oral zabofloxacin (367 mg once daily for 5 days) was not inferior to oral moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation.