Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials.     

β-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli, except for one E. cloacae isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.     

Intravenous Doripenem at 500 Milligrams versus Levofloxacin at 250 Milligrams,with an Option To Switch to Oral Therapy,for Treatment of Complicated Lower Urinary Tract Infection and Pyelonephritis

The prospective, multicenter, double-blind study presented in this report evaluated whether or not intravenous (IV) administration of doripenem, a carbapenem with bactericidal activity against gram-negative and gram-positive uropathogens, is inferior to IV administration of levofloxacin in the treatment of complicated urinary tract infection (cUTI). Patients (n = 753) with complicated lower UTI or pyelonephritis were randomly assigned to receive IV doripenem at 500 mg every 8 h (q8h) or IV levofloxacin at 250 mg q24h. Patients in both treatment arms were eligible to switch to oral levofloxacin after 3 days of IV therapy to complete a 10-day treatment course if they demonstrated significant clinical and microbiological improvements. The microbiological cure rate (primary end point) was determined at the test-of-cure (TOC) visit occurring 5 to 11 days after the last dose of antibiotic. For the microbiologically evaluable patients (n = 545), the microbiological cure rates were 82.1% and 83.4% for doripenem and levofloxacin, respectively (95% confidence interval [CI] for the difference, −8.0 to 5.5%); in the microbiological modified intent-to-treat cohort (n = 648), the cure rates were 79.2% and 78.2%, respectively. Clinical cure rates at the TOC visit were 95.1% in the doripenem arm and 90.2% in the levofloxacin arm (95% CI around the difference in cure rates [doripenem cure rate minus levofloxacin cure rate], 0.2% to 9.6%). Both treatment regimens were generally well tolerated. Doripenem was found not to be inferior to levofloxacin in terms of therapeutics and is now approved for use in the United States and Europe for the treatment of adults with cUTI, including pyelonephritis. As fluoroquinolone resistance increases, doripenem may become a more important option for successful treatment of cUTIs, including treatment of pyelonephritis.Urinary tract infections (UTIs) are the leading cause of gram-negative bacteremia for patients of all ages and can be associated with a high risk of morbidity and mortality, especially in the elderly, for whom they can account for nearly 25% of all infections (2). UTIs are responsible for nearly 7 million office visits and 1 million emergency department visits, which result in 100,000 hospitalizations each year, in the United States alone (2, 22) and account for at least 40% of all nosocomial infections (22, 23). Complicated lower UTIs (cLUTIs) and complicated pyelonephritis occur in patients who have a functionally, metabolically, or anatomically abnormal urinary tract. Unlike the narrow and predictable spectrum of pathogens associated with uncomplicated UTIs, a broad range of bacteria can cause complicated infections, and many are resistant to multiple antimicrobial agents (22). For patients with complicated UTIs (cUTIs) requiring intravenous (IV) antibiotic therapy, empirical treatment with a broad-spectrum antibiotic can help avoid the unnecessary risk and cost of disease progression associated with treatment failure.Fluoroquinolones are indicated for the management of acute uncomplicated UTIs as well as cUTIs and pyelonephritis for adults, but uropathogen resistance to them is increasing (20). The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance program demonstrated increasing rates of fluoroquinolone resistance in bacterial isolates from U.S. medical centers, especially among Escherichia coli, Enterobacter, Proteus mirabilis, and indole-positive Proteae spp. (17). Resistance to ciprofloxacin and levofloxacin in E. coli reached 21.6% and 20.4%, respectively, of isolates tested in 2005 (16). In the North American Urinary Tract Infection Collaboration Alliance surveillance study, 5.5% and 5.1% of urinary E. coli isolates from outpatients in the United States and Canada were resistant to ciprofloxacin and levofloxacin, respectively (24). Similar results were reported for a cohort in Israel (12). Pseudomonas aeruginosa fluoroquinolone resistance is also problematic, with rates now exceeding 35% (7). As fluoroquinolone resistance increases, alternative therapies will become more important for successful treatment of cUTIs, particularly for patients at risk for infection with fluoroquinolone-resistant pathogens.Doripenem is a broad-spectrum carbapenem that has been approved for use in the United States and Europe for the treatment of adults with cUTIs, including pyelonephritis, and for the treatment of complicated intra-abdominal infections. It has also been approved in Europe for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Doripenem is primarily eliminated by the kidneys and is concentrated in the urine (Doripenem package insert; Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ). It has potent in vitro activity against the gram-negative aerobic bacteria commonly encountered in cUTIs, including E. coli, other members of the Enterobacteriaceae, and P. aeruginosa (3, 22). Like other carbapenems, doripenem is resistant to hydrolysis by a variety of β-lactamases, including extended-spectrum β-lactamases (ESBLs). Several in vitro studies have shown that doripenem has greater activity than other carbapenems against recent isolates of key gram-negative pathogens, including ESBL-producing strains of E. coli and P. aeruginosa (8, 10, 11). Moreover, under experimental conditions, doripenem was less likely than other carbapenems to select for carbapenem-resistant mutants of P. aeruginosa (14, 19). This profile makes doripenem an attractive agent for the treatment of cLUTIs and pyelonephritis. Doripenem has moderate activity against Enterococcus faecalis (4, 9), with MIC₉₀ values of 4 to 16 μg/ml, i.e., one dilution lower than ertapenem and meropenem. Most current clinical isolates of Enterococcus faecium are resistant to doripenem.This trial was designed in compliance with Food and Drug Administration guidelines for registration studies to compare the microbiological and clinical cure rates of patients with cUTIs who received at least 3 days of IV doripenem or IV levofloxacin therapy, with an option for patients in both treatment arms to switch from IV therapy to oral levofloxacin if specified favorable clinical and microbiological criteria were satisfied.     

Identification and pretherapy susceptibility of pathogens in patients with complicated urinary tract infection or acute pyelonephritis enrolled in a clinical study in the United States from November 2004 through April 2006

OBJECTIVE: The purpose of this study was to assess the pretherapy microbiology and fluoroquinolone susceptibility of pathogens from 650 patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) as part of a multicenter, randomized, controlled clinical trial. METHODS: In this post hoc analysis of a multicenter, randomized, double-blind study, adults with a clinical diagnosis of cUTI or AP were recruited from 130 community-based and institution-based study centers in the United States from November 2004 through April 2006. Urine and blood culture specimens were identified and tested for susceptibility according to Clinical and Laboratory Standards Institute methods. Presence of a pathogen in the urine culture was confirmed by a colony count of =105 colony-forming units per milliliter. Susceptibility to nonstudy drugs (trimethoprim/sulfamethoxazole [TMP/SMX] and ampicillin) and to study drugs (levofloxacin and ciprofloxacin) was categorized as susceptible, intermediate, or resistant. RESULTS: Six hundred fifty patients (417 women, 233 men; age range, 18-94 years) with a diagnosis of cUTI or AP were recruited. A total of 68.2% patients (224 men, 219 women) were diagnosed with cUTI, and 31.8% (198 women, 9 men), with AP. Most (646/650 [99.4%]) infections were community acquired. The most common pathogen was Escherichia coli (65.6%), although 12.2% of patients had gram-positive pathogens. Testing for susceptibility to ampicillin and TMP/SMX found that 50.1% and 22.1% of gramnegative pathogens were fully resistant to ampicillin and TMP/SMX, respectively. However, 91.9% of isolates were susceptible to levofloxacin and ciprofloxacin, with 6.5% of isolates resistant or intermediately resistant to levofloxacin, and 9.7% of isolates resistant or intermediately resistant to ciprofloxacin at study entry (P < 0.001 [Stuart-Maxwell test]). All isolates resistant to levofloxacin were also resistant to ciprofloxacin, whereas 6 isolates that were fully susceptible to levofloxacin were fully resistant to ciprofloxacin. CONCLUSION: In this study, the level of fluoroquinolone susceptibility of urinary pathogens was high (90.6% in cUTI; 98.1% in AP).     

A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia

Introduction

The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.

Methods

This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).

Results

The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).

Conclusions

Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.

Trial Registration

ClinicalTrials.gov: NCT00589693     

Novel β-lactam/β-lactamase inhibitors versus alternative antibiotics for the treatment of complicated intra-abdominal infection and complicated urinary tract infection: a meta-analysis of randomized controlled trials

Introduction: The aim of this study is to compare the efficacy and safety of novelBL/BLIs with alternative antibiotics for the treatment of cIAI and cUTI.

Area covered: We performed a systematic review and meta-analysis of all randomized controlled trials comparing novel BL/BLIs with other antibiotics for the treatment of cIAI and cUTI. The primary outcome included clinical and microbiological treatment success.

Expert commentary: We found that novel BL/BLIs obtained a similar clinical outcome with other antibiotics in CE population (OR = 1.07, 95%CI = (0.80, 1.44), P = 0.64). However, novel BL/BLIs had better clinical treatment success in the cUTI subgroup (OR = 2.14, 95%CI = (1.06, 4.31), P = 0.03). Furthermore, novel BL/BLIs achieved significant microbiological treatment success in patie nts with cUTI (OR = 1.70, 95%CI = (1.29, 2.25), P = 0.0002) and had higher eradication rates for Gram-negative pathogens (OR = 1.82, 95%CI = (1.26, 2.64), P = 0.001) including E.coli and K.pneumoniae. No difference was observed concerning the incidence of mortality and adverse events between the two groups. Therefore, we concluded that novel BL/BLIs are not inferior to other available antibiotics for the treatment of cIAI, and they have advantages in patients with cUTI. Simultaneously, they are sensitive to Gram-negative pathogens, especially for E.coli and K.pneumoniae.     

Prulifloxacin versus Levofloxacin in the Treatment of Respiratory and Urinary Tract Infections: A Multicentre, Double-Blind, Randomized Controlled Clinical Trial

Background: Prulifloxacin is a promising fluoroquinolone antibiotic. A multicentre, double-blind, randomized clinical study was designed to evaluate its efficacy and safety compared to that of levofloxacin for the treatment of respiratory and urinary infections of Chinese patients. Methods: A total of 267 patients were enrolled and each was randomly assigned to either the treatment or the control group. Prulifloxacin 264.2 mg (equivalent to ulifloxacin 200 mg) b.i.d. or levofloxacin hydrochloride 200 mg b.i.d. was administered orally for 5-14 days according to a patient's condition. The clinical response, bacterial eradication and incidence of adverse events were evaluated. Results: Two hundred and forty-three patients completed the study. For the modified intention-to-treat population, the cure and effective rates were 45.53 and 82.93% in the prulifloxacin group and 49.18 and 83.61% in the levofloxacin group. For the per-protocol analysis population, the cure and effective rates were 45.90 and 83.61% in the prulifloxacin group and 49.59 and 83.47% in the levofloxacin group. The bacterial eradication rates were 96.59 and 95.35%, and the drug-related adverse event rates were 7.87 and 5.51% in the prulifloxacin and levofloxacin group, respectively. The cure rate and efficacy rate of respiratory and urinary tract infections of the levofloxacin group were better than those of the prulifloxacin group. However, the difference between the 2 groups was not statistically significant (p > 0.05). Conclusion: Prulifloxacin is as effective and well tolerated as levofloxacin in the treatment of respiratory and urinary tract infections.     

Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study

In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (-16 to 8%) failed to exclude the predefined lower limit for noninferiority of -15%. In addition, therapy of pneumonia caused by an organism producing an extended-spectrum beta-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, -9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P = 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, -23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P = 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P = 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.     

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.     

加替沙星与左氧氟沙星序贯治疗细菌性感染的多中心单盲随机对照研究

目的：评价加替沙星注射液的疗效与安全性。方法：本研究为多中心、单盲、随机、对照试验，下呼吸道及尿路感染患被随机分配接受加替沙星或左氧氟沙星静脉给药继以口服序贯治疗。结果：(1)试验组和对照组临床有效率分别为92．4％(110／119)和91．2％(114／125)，其中下呼吸道感染两组有效率为94．2％(65／69)和90．2％(65／72)，尿路感染两组有效率为90．0％(45／50)和92．5％(42／72)，经统计学分析2组间差异无显性；(2)两组总的细菌清除率分别为94．O％(78／83)和88．0％(8l／92)，其中尿路感染细菌清除率为89．2％(33／37)和92．9％(39／42)，两组间差异无显性；但试验组下呼吸道感染细菌清除率为97．8％(45／46)，高于对照组的84．3％(43／51)，差异有显性；(3)试验组不良反应发生率为29．9％(38／127)，显高于对照组的10．1％(13／129)；两组不良反应均系轻度，患可耐受，无中途停药。两组实验室检查异常分别占24．8％(30／121)和22．1％(27／122)，均系轻度并呈一过性，经统计学分析差异无显性。结论：加替沙星注射荆静脉给药用于全身症状明显感染的初期治疗可使病情早期缓解，继以口服完成疗程，可获良好疗效；加替沙星组临床疗效与对照组相仿，虽不良反应多于对照组，但均属轻度并可为患耐受。     

口服加替沙星与左氧氟沙星治疗下呼吸道和尿路感染的前瞻性多中心随机对照研究

目的：评价加替沙星片治疗下呼吸道感染及尿路感染的疗效与安全性。方法：以左氧氟沙星片为对照药，在248例下呼吸道和尿路感染中进行疗效和安全性的多中心随机对照观察。加替沙星组125例，其中下呼吸道感染50例，尿路感染75例；左氧氟沙星组123例，其中下呼吸道感染54例，尿路感染69例。给药方案分别为治疗下呼吸道感染加替沙星片400mg1次／d口服，左氧氟沙星片200mg2次／d口服，疗程均为7—14d；肾盂肾炎、复杂性尿路感染及反复发作性尿路感染加替沙星片400mg1次／d口服，左氧氟沙星200mg2次／d口服，疗程均为7—14dl急性单纯性下尿路感染加替沙星片200mg1次／d口服，左氧氟沙星片100mg2次／d口服，疗程均为5d。结果：加替沙星组125例和左氧氟沙星组123例的临床有效率分别为95．2％(119／125)和91．9％(113／123)，临床痊愈率分别为68．8％(86／125)和63．4％(78／123)；细菌清除率分别为89．3％(100／112)和89．5％(94／105)；不良反应发生率分别为25．3％(40／158)和18．6％(30／161)，实验室检查异常发生率为14．7％(22／150)和15．8％(24／152)。上述结果经统计学处理，差异均无显性。结论：本研究结果显示加替沙星片治疗下呼吸道及尿路感染的疗效和安全性与左氧氟沙星片相仿。     

Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women.

A randomized study was conducted to assess the clinical and microbiological efficacies of a single 3-g dose of fosfomycin trometamol for the treatment of uncomplicated lower urinary tract infections in women compared with a 5-day regimen of cephalexin at 0.5 g four times daily. One hundred twelve women, all of whom had documented infections with bacteria sensitive to both antibiotics, were included. Fifty-eight women received fosfomycin trometamol, and 54 women received cephalexin. The two groups did not differ in age, severity, or duration of current urinary tract infection, menstrual status, sexual activity, or use of contraceptives. Ninety percent of pathogens in the fosfomycin trometamol group and 81% in the cephalexin group were Escherichia coli (the difference is not significant [NS]). A clinical evaluation at the 5-day follow-up showed that 91% of the women in each group were free of symptoms, while five women in each group were considered therapy failures and were treated by another antibiotic course. A microbiological evaluation at the 5-day follow-up showed a 91% eradication rate in the fosfomycin trometamol group and an 83% eradication rate in the cephalexin group (NS). At the 1-month follow-up, a clinical evaluation demonstrated prolonged resolution in 86 and 78%, respectively, of the participating women (NS). A microbiological evaluation at 1 month demonstrated prolonged eradication in 47 (81%) women treated with fosfomycin trometamol and in 37 (68%) women treated with cephalexin (NS). Three and six women, respectively, had relapsed. No adverse reactions were reported by the fosfomycin trometamol-treated women, while three women treated with cephalexin reported mild adverse reactions but completed the study period. Fosfomycin trometamol in a single 3-g dose is as effective as a 5-day regimen of cephalexin for the treatment of uncomplicated lower urinary tract infection in women.     

左氧氟沙星序贯疗法治疗细菌性感染214例的临床评价

目的：评价左氧氟沙星序贯疗法治疗细菌性下呼吸道感染和尿路感染的有效性及安全性。方法：以左氧氟沙星静脉滴注继以口服为治疗组用药，以头孢曲松静脉滴注继以头孢克肟口服为对照组用药，对两者治疗下呼吸道和尿路感染病例的疗效和安全性进行随机对照观察。两种药物的给药方案分别为左氧氟沙星注射液300mg静脉滴注2次／d，用药3～5d后，改片剂300mg口服，2次／d，总疗程10～14d；头孢曲松2g静脉滴注，1次／d，3～5d后．改头孢克肟200mg，2次/d总疗程10～14d。结果：本研究共入选214例患者，可评价患者192例，治疗组92例．对照组100例。治疗组和对照组的临床总有效率分别为93．5％(86／92)和95．0％(95／100)。痊愈率分别为77．2％(71／92)和82.0％(82／100)；细菌清除率分别为93．0％(53／57)和97．1％(66／68)。上述结果经统计学处理差异无显著性。不良反应发生率治疗组和对照组分别为16．0％(17/106)和4．6％(5／108)，治疗组高于对照组(P=0．012)；前者的不良反应主要为失眠等中枢神经系统反应以及恶心等消化道反应，后者主要为消化道反应；两组的不良反应均轻微，呈一过性。实验室检查异常发生率治疗组为12．3％(13／106)，对照组为13．0％(14／108)，主要为血清氨基转移酶升高，两组相仿。结论：本研究结果显示左氧氟沙星静脉滴注序贯继以口服治疗下呼吸道和尿路感染的疗效良好，与头孢曲松静脉滴注序贯继以头孢克肟口服相仿，不良反应发生率治疗组虽高于对照组,但程度轻微，呈一过性，患者可耐受。     

Doripenem monohydrate,a broad-spectrum carbapenem antibiotic

Background: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic, has been approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs).Objective: This article reviews available information on doripenem in the management of patients with complicated bacterial infections, including its chemistry, spectrum of activity, resistance mechanisms, pharmacokinetics, pharmacodynamics, drug interactions, therapeutic efficacy, tolerability, and dosing and administration. Also discussed are pharmacoeconomic considerations associated with doripenem.Methods: Pertinent English-language literature was identified from searches of MEDLINE (1996–October 2008) and BIOSIS (1993–October 2008). Search terms included, but were not limited to, doripenem, S-4661, spectrum of activity, resistance, pharmacology, pharmacokinetics, pharmacodynamics, adverse events, and therapeutic use. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (2003–2007).Results: Doripenem is a parenteral carbapenem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms. It is stable against a wide variety of β-lactamases, including extended-spectrum and AmpC β-lactamases; it is, however, inactivated by organisms that produce class A enzymes, KPC enzymes, class B metallo-β-lactamases, and class D enzymes. Doripenem is eliminated primarily in the urine (68%–80% unchanged). It should be used cautiously in patients receiving valproic acid, as combined use may lead to a precipitous decline in serum concentrations of valproic acid. A large Phase III study in the treatment of cIAIs found doripenem noninferior to meropenem (clinical cure rates, 83.9% and 85.9%, respectively; difference, ?2.1; 95% CI, ?9.8 to 5.6). A Phase III study in the treatment of cIAIs, including pyelonephritis, found doripenem non-inferior to levofloxacin (clinical cure rates, 95.1% and 90.2%, respectively; 95% CI, 0.2 to 9.6). With respect to the treatment of nosocomial pneumonia, one Phase III study found doripenem noninferior to imipenem (clinical cure rates, 68.3% and 64.8%, respectively; difference, 3.5%; 95% CI, ?9.1 to 16.1), and another found it noninferior to piperacillin/tazobactam (clinical cure rates, 81.3% and 79.8%, respectively; difference, 1.5%; 95% CI, ?9.1 to 12.1). Adverse events with doripenem were similar to those of other antibiotics with which it has been compared. Adverse events in clinical trials of doripenem have included anaphylaxis and rash (l%-5%), gastrointestinal effects (25%–32%, including nausea [1.1%–12.0%], diarrhea [1.9%–11.0%], and vomiting [1.5%-6.6%]), and central nervous system effects (headache [2.1%–16.0%], insomnia [3.7%], anxiety [2.9%], and, rarely, seizures).Conclusions: In Phase III studies, doripenem was noninferior to meropenem in the treatment of cIAIs; noninferior to levofloxacin in the treatment of cUTIs; and noninferior to imipenem and piperacillin/tazobactam in the treatment of nosocomial pneumonia. As with all new antibiotics, because of the risk of selecting for resistant organisms, use of doripenem should be reserved for infections in which a multidrug-resistant gram-negative organism, polymicrobial infection, or Pseudomonas aeruginosa is suspected.     

加替沙星和左氧氟沙星治疗呼吸道感染的临床研究

目的　评价加替沙星治疗呼吸道细菌感染的临床疗效与安全性。方法　以左氧氟沙星为对照药进行随机双盲对照临床试验 ,共治疗呼吸道细菌感染患者 5 3例 ,其中加替沙星组 2 6例 ,左氧氟沙星组 2 7例。结果　加替沙星组临床痊愈率为 5 3 85 % ,有效率为 88 4 6 % ,细菌清除率为 90 91% ;而对照组分别为4 0 74 % ,6 2 96 %和 83 33%。加替沙星组临床有效率高于左氧氟沙星组 ,两组差异有显著性意义 (P <0 0 5 )。两组不良反应发生率分别为 11 5 4 %与 14 81% ,差异无显著性意义 (P >0 0 5 )。结论　加替沙星治疗呼吸道感染的有效性与安全性与左氧氟沙星相似 ,是一种高效、广谱、安全的抗生素     

Efficacy and safety of a novel once-daily extended-release ciprofloxacin tablet formulation for treatment of uncomplicated urinary tract infection in women

The efficacy and safety of a novel once-daily extended-release ciprofloxacin (ciprofloxacin ER) 500-mg dose were compared with those of an immediate-release ciprofloxacin (ciprofloxacin IR) 250-mg twice-daily dose, each administered orally for 3 days in the treatment of acute uncomplicated urinary tract infection (uUTI) in women. Adult female outpatients (mean age, 39 years) with clinical signs and symptoms of acute uUTI and a positive pretreatment urine culture (> or =10(5) CFU/ml) were enrolled in a multicenter, randomized, double-blind, noninferiority trial. Patients were assessed at a test-of-cure visit (4 to 11 days posttreatment) and a late-posttreatment visit (4 to 6 weeks posttreatment) for microbiological and clinical outcomes and safety. The primary efficacy endpoint and microbiological eradication rate at the test-of-cure visit in the ciprofloxacin ER group (254/272; 93.4%) were noninferior to those in the ciprofloxacin IR group (225/251; 89.6%) (95% confidence interval [CI] of difference, -0.99%, 8.59%). Clinical-cure rates at the test-of-cure visit were 85.7% (233/272) for ciprofloxacin ER and 86.1% (216/251) for ciprofloxacin IR (95% CI of difference, -6.37%, 5.57%). At the late-posttreatment visit, microbiological and clinical outcomes were similar for the two treatments and consistent with test-of-cure results. Both treatments were well tolerated, but the frequencies of nausea and diarrhea were lower in the ciprofloxacin ER group than in the ciprofloxacin IR group (nausea, ER, 0.6%; IR, 2.2%; P = 0.033; diarrhea, ER, 0.2%; IR, 1.4%; P = 0.037). Once-daily ciprofloxacin ER was safe, effective, and noninferior to twice-daily ciprofloxacin IR in the treatment of acute uUTI. Additionally, ciprofloxacin ER was associated with significantly reduced frequencies of nausea and diarrhea.     

Prevalence,predictors, and consequences of inappropriate empiric antimicrobial therapy for complicated urinary tract and intra-abdominal infections in Winnipeg hospitals

Information on inappropriate empiric antimicrobial therapy (ET) in Canadian hospitals is scarce. All Manitobans 18 years of age and over who were admitted to a hospital in Winnipeg with a complicated urinary tract infection (cUTI) or complicated intra-abdominal infection (cIAI) from January 2006 to December 2014 were eligible for inclusion in this cohort study. The prevalence of inappropriate ET was 11% for cUTI patients and 9% for cIAI patients. The risk of receiving inappropriate ET was higher for older patients (cUTI patients 65 or older had 2-fold increased risk compared to younger patients; odds ratio 2.1, 95% confidence interval 1.3–3.6; this was 1.6 [0.7–3.5] for cIAI patients) and those hospitalized in the previous year: 1.5 (1.0–2.4) in cUTIs and 1.5 (0.6–3.4) in cIAIs. The risk for a hospital stay over 3 weeks was increased for inappropriate ET in cUTI patients, 2.3 (1.4–3.7), but not in cIAI patients, 0.9 (0.4–2.1).     

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 (>or=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 >or=-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 >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=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 novel approach to noninferiority testing: documented proof rather than arbitrary margins

Noninferiority trials have been criticized for their wide margins of noninferiority, making it virtually impossible to reject noninferiority. Recommendations have been given to replace the practice of arbitrarily set margins. The objective of this study was to review various alternative methods of assessment based on statistical reasoning. Four examples are given. (1) In a 300-patient parallel group study of 2 inhalers for asthma, noninferiority was demonstrated at P = 0.0001. This result was supported by both the lack of a significant difference between the standard and new inhalers and the presence of a significant difference between the new inhaler and a placebo at P = 0.0001. (2) In a 236-patient parallel group sleeping pill study, noninferiority was demonstrated at P = 0.04. The presence of noninferiority was supported by a significant superiority of the new compound against a placebo at P = 0.021. However, the significantly worse performance against the standard treatment undermined these findings. (3) In a 200-patient hypertension study of 2 treatment groups, noninferiority was demonstrated at P = 0.028. The presence of noninferiority was supported by the lack of a significant difference between the new and the standard treatment. However, these findings were undermined by the lacking superiority of the new compound against a placebo. (4) In a 160-patients parallel group cholesterol study, noninferiority was demonstrated at P = 0.01. The presence of noninferiority was undermined by both the significant difference between the new and the standard treatment and the lack of efficacy of the new treatment against a placebo. We conclude that expert investigators traditionally set an arbitrary margin of noninferiority based on clinical arguments and that they benefit from wide margins. As an alternative and more meaningful approach to noninferiority testing, we propose to use (1) margins based on counted rather than on arbitrary criteria, (2) null hypothesis tests between the new and standard treatments, (3) null hypothesis tests between the new treatment and a placebo.     

根除幽门螺杆菌治疗功能性消化不良的临床证据

目的为临床实践提供有关功能性消化不良(FD)根除幽门螺杆菌(HP)治疗的循证医学证据。方法根据HP感染与FD的关系和HP根除治疗在治疗FD中的作用两个临床问题,检索VIP(1989～2005)、CBMdisc(1978～2005)、MEDLINE (1978～2006)以及Cochrane图书馆(2005年第4期)的系统评价,Meta分析,随机对照试验和临床指南,评价HP感染与FD的关系和HP根除治疗在治疗FD中的作用,为临床实践提供最佳的循证医学证据。结果共纳入2篇系统评价、1篇Meta分析和11篇随机对照试验。现有证据显示:FD患者HP感染率高于无症状者,但HP感染在FD发生中的作用还有待流行病学研究及病理生理研究的证据证实。HP根除治疗HP阳性FD,可以减缓部分消化不良患者的症状,但对改善患者生活质量无明显意义。HP根除治疗的成本-效益价值主要取决于患者希望明确诊断的愿望,还没有很好地证据显示需要对HP阳性FD都行HP根除治疗。结论基于目前的临床证据,我们认为对FD是否行HP根除治疗应根据患者的情况,做到个体化,对一些常规治疗差的患者可考虑采用HP根除治疗。