Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial.

BACKGROUND: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. METHODS: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated. FINDINGS: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. INTERPRETATION: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. FUNDING: Sanofi Pasteur.

Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial.

BACKGROUND: Clostridium difficile, a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B. METHODS: Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40-75 years. Stage I: low (50 µg antigen) or high (100 µg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0-7-30. Stage II: Days 0-7-30, 0-7-180, and 0-30-180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards. RESULTS: In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose+adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0-7-30 ranked above the other two administration schedules. There were no safety issues. CONCLUSIONS: The high dose+adjuvant (100 µg antigen+AlOH) formulation administered at 0-7-30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials.

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges.

BACKGROUND: The licensed four-valent prophylactic human papillomavirus vaccine is highly efficacious in preventing cervical, vulvar, vaginal, and anal cancers and related precancers caused by human papillomavirus types 6, 11, 16, and 18. These four types account for approximately 70% of cervical cancers. A nine-valent human papillomavirus vaccine, including the four original types (6, 11, 16, and 18) plus the next five most prevalent types in cervical cancer (31, 33, 45, 52, and 58) could provide approximately 90% overall cervical cancer coverage. To expedite the nine-valent human papillomavirus vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ∼ 15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. PURPOSE: We discuss the design rationale and implementation challenges of the outcome trial, focusing on the adaptive feature of the seamless Phase IIB/III design. METHODS: Subjects were enrolled in two parts (Part A and Part B). Approximately 1240 women, 16-26 years of age, were enrolled in Part A for Phase IIB evaluation and equally randomized to one of three dose formulations of the nine-valent human papillomavirus vaccine or the four-valent human papillomavirus vaccine (active control). Based on an interim analysis of immunogenicity and safety, one dose formulation of the nine-valent human papillomavirus vaccine was selected for evaluation in the Phase III part of the study. Subjects enrolled in Part A who received the selected dose formulation of the nine-valent human papillomavirus vaccine or four-valent human papillomavirus vaccine continued to be followed up and contributed to the final efficacy and safety analyses. In addition, ∼ 13,400 women 16-26 years of age were enrolled in Part B, randomized to nine-valent human papillomavirus vaccine at the selected dose formulation or four-valent human papillomavirus vaccine, and followed for immunogenicity, efficacy, and safety. RESULTS: A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed four-valent human papillomavirus vaccine and the development objectives for the nine-valent human papillomavirus vaccine. Subjects enrolled in Part A who received either the selected nine-valent human papillomavirus formulation or four-valent human papillomavirus vaccine contributed ∼ 10% of person-years of follow-up due to its earlier start-thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authorities and managing changes in the assay for immunological endpoints. LIMITATIONS: Application of the experience and lesson learned from this seamless adaptive design to other clinical programs may depend on case-by-case consideration. CONCLUSION: A seamless Phase IIB/III adaptive design was successfully implemented in this large outcome study. The development time of the second-generation nine-valent human papillomavirus vaccine was shortened due to improved statistical efficiency.

Multiplexed serologic assay for nine anogenital human papillomavirus types.

A multiplexed human papillomavirus (HPV) immunoassay has been developed for the detection of human IgG antibodies to HPV type 6, 11, 16, 18, 31, 33, 45, 52, and 58 virus-like particle (VLP) types in serum following natural infection or immunization with VLP-based vaccines. The VLP antigens were covalently conjugated to carboxyl Luminex microspheres (MS) using a carbodiimide chemistry. Antibody (Ab) titers were determined in a direct binding format, in which an IgG1- to -4-specific, phycoerythrin (PE)-labeled monoclonal antibody (MAb) (HP6043) binds to human serum IgG antibodies. Pooled serum samples from rhesus macaques immunized with a 9-valent VLP-based vaccine served as the reference standard. The overall specificity of the assay was >99%, and the linearity (parallelism) of the assay was <7% per 10-fold dilution. Total assay precision was <19% across 3 different VLP-microsphere lots, 2 secondary antibody lots, and 2 different operators over a period of 3 weeks. Three different methods were used to evaluate serostatus cutoffs (SCO): (i) a clinical sensitivity/specificity analysis based on "likely negative" and "likely positive" samples from nonvaccinees, (ii) stringent upper tolerance limits on samples from "likely negatives," and (iii) stringent upper tolerance limits from the same "likely negative" sample set after VLP adsorption. Depending on the method to set the serostatus cutoff, the percentage of seropositive samples at the month 48 time point following vaccination with the HPV 6/11/16/18 quadrivalent vaccine ranged from 70% to 100%. This assay has proven useful for measuring the levels of serum antibody to the nine HPV VLPs following natural infection or administration of VLP-based vaccines.

Safety and tolerability of ertapenem versus ceftriaxone in a double-blind study performed in children with complicated urinary tract infection, community-acquired pneumonia or skin and soft-tissue infection.

The carbapenem antibiotic ertapenem has been shown to be safe, well tolerated and effective in treating adults with complicated urinary tract infection, skin and soft-tissue infection and community-acquired pneumonia. In this study, we evaluated ertapenem for treating these infections in children in a randomised, double-blind, active-controlled clinical trial. The primary outcome was the incidence of clinical and laboratory drug-related serious adverse events (AEs). Children were randomised in a 3:1 ratio (ertapenem:ceftriaxone) stratified by index infection and age to receive ertapenem or ceftriaxone; 303 children received ertapenem and 100 children received ceftriaxone. The median duration of parenteral therapy was 4 days for both treatments. The most commonly reported drug-related clinical AEs during parenteral therapy were diarrhoea (5.9% ertapenem, 10% ceftriaxone), infusion site erythema (3% ertapenem, 2% ceftriaxone) and infusion site pain (5% ertapenem, 1% ceftriaxone). One child in each group reported a serious drug-related clinical AE. No serious drug-related laboratory AEs were reported. In children aged 3 months to 17 years, ertapenem was well tolerated and had a comparable safety profile to that of ceftriaxone.

Ertapenem or ticarcillin/clavulanate for the treatment of intra-abdominal infections or acute pelvic infections in pediatric patients.

BACKGROUND: Ertapenem, a group I carbapenem antibiotic, has been shown to be safe and effective in treating adults with complicated intra-abdominal (cIAI) or acute pelvic infection (API). This study evaluated ertapenem for treating these infections in children. METHODS: In an open-label study, children aged 2 to 17 years with cIAI or API were randomized 3:1 to receive ertapenem or ticarcillin/clavulanate. Children 13 to 17 years of age received 1 g parenterally daily, and those 2 to 12 years of age received 15 mg/kg twice daily. Patients < 60 kg received ticarcillin/clavulanate 50 mg/kg 4 to 6 times daily and 3.1 g 4 to 6 times daily for those > or = 60 kg. Patients were assessed for safety and tolerability throughout the study and for efficacy after the completion of therapy. RESULTS: One hundred five patients, 72 (69%) with cIAI, received > or = 1 dose of study drug and were included in the safety analysis. Eighty-one patients were treated with ertapenem. Infusion site pain was the most common drug-related adverse event in both groups. In the modified intent-to-treat analysis, the age-adjusted posttreatment clinical response rates were 87% (43/50 patients) and 100% (25/25 patients) in the cIAI and API patients, respectively, for ertapenem and 73% (11/15 evaluable patients) and 100% (8/8 evaluable patients), respectively, for ticarcillin/clavulanate. Overall age-adjusted response rates were 91% (68/75 evaluable patients) for ertapenem and 83% (19/23 evaluable patients) for the comparator. CONCLUSIONS: This study suggests that ertapenem is generally safe and efficacious for treating cIAI or API in pediatric patients.

Treatment of polymicrobial infections: post hoc analysis of three trials comparing ertapenem and piperacillin-tazobactam.

The efficacy of ertapenem 1 g once a day for the treatment of polymicrobial complicated intra-abdominal, complicated skin/skin-structure and acute pelvic infections was compared with piperacillin-tazobactam 3.375 g every 6 h in a post hoc analysis of data from three large randomized double-blind trials. Of the 1,558 treated patients in the three trials, no pathogen was identified in 345 (22.1%), 423 (27.2%) had a monomicrobial infection and 790 (50.7%) had a polymicrobial infection. At the test-of-cure assessment, there were no significant differences in outcome between the two treatment groups for any of the three infections. Cure rates (clinical and microbiological for intra-abdominal infection, clinical for skin/skin-structure and pelvic infections) in microbiologically evaluable patients for ertapenem and piperacillin-tazobactam, respectively, were 85.6% (154/180 evaluable patients) and 82.5% (127/154) for polymicrobial intra-abdominal infection, 80.3% (53/66) and 78.7% (48/61) for polymicrobial skin/skin-structure infection, and 95.7% (88/92) and 92.6% (88/95) for polymicrobial pelvic infection. Respective cure rates for all evaluable patients in the original trials were: 83.6% and 80.4% for intra-abdominal, 83.9% and 85.3% for skin/skin-structure, and 93.9% and 91.5% for pelvic infections. These data show that in the three trials, ertapenem 1 g once a day was highly effective for the treatment of polymicrobial infections and as effective as piperacillin-tazobactam 3.375 g every 6 h.

Treatment of complicated urinary tract infection in adults: combined analysis of two randomized, double-blind, multicentre trials comparing ertapenem and ceftriaxone followed by appropriate oral therapy.

The efficacy and safety of parenteral ertapenem, a Group 1 carbapenem, 1 g once a day, for the treatment of complicated urinary tract infections (UTIs; i.e. acute pyelonephritis, UTI in men, or UTI associated with obstruction, foreign body or a urological abnormality interfering with normal voiding) in adults, were compared with those of parenteral ceftriaxone, 1 g once a day, in two similarly designed prospective, double-blind, randomized studies. In both studies, patients could be switched to an oral agent after > or = 3 days of parenteral study therapy. At entry, 850 patients were stratified according to whether they had acute pyelonephritis or other complicated UTI without acute pyelonephritis. Two hundred and fifty-six patients in the ertapenem group and 224 in the ceftriaxone group were microbiologically evaluable. Ninety-six per cent of these patients were switched to oral therapy, usually ciprofloxacin; the median (range) duration of parenteral and total therapy, respectively, was 4 (2-14) days and 13 (14-18) days for ertapenem and 4 (2-14) days and 13 (3-17) days for ceftriaxone. The most common pathogens were Escherichia coli and Klebsiella pneumoniae, which accounted for 64.7% and 9.8% of isolates, respectively. At the primary efficacy endpoint 5-9 days after treatment, 229 (89.5%) patients who received ertapenem and 204 (91.1%) patients who received ceftriaxone had a favourable microbiological response (95% confidence interval, -7.4 to 4.0), indicating that outcomes in the two treatment groups were equivalent. Success rates in both treatment groups were similar when compared by stratum and severity of infection. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. In this combined analysis, ertapenem was highly effective therapy for the treatment of complicated UTIs in adults with moderate-to-severe disease.

Safety and tolerability of ertapenem.

Ertapenem is a Group 1 carbapenem that was licensed in the USA in November 2001 and in Europe in April 2002. Its safety profile has been assessed in 240 healthy volunteers participating in 12 clinical pharmacology studies and in 2046 patients enrolled in five Phase IIa and eight Phase IIb/III clinical trials. The most common drug-related adverse events (AEs) reported in trials comparing ertapenem and piperacillin-tazobactam and in trials comparing ertapenem and ceftriaxone were: diarrhoea (ertapenem versus piperacillin-tazobactam 5.0% versus 7.0%; ertapenem versus ceftriaxone 5.6% versus 5.9%); infused vein complications (ertapenem versus piperacillin-tazobactam 4.5% versus 7.9%; ertapenem versus ceftriaxone 3.2% versus 4.6%); nausea (ertapenem versus piperacillin-tazobactam 2.5% versus 3.4%; ertapenem versus ceftriaxone 3.4% versus 3.3%); and elevations in alanine aminotransferase levels (ertapenem versus piperacillin-tazobactam 8.8% versus 7.3%; ertapenem versus ceftriaxone 8.3% versus 6.9%). Most ertapenem-related AEs were reported as mild-to-moderate in intensity. Ertapenem was not associated with prolongation of the QTc interval. Local reactions of moderate-to-severe intensity at the infusion site were infrequent and occurred with similar frequency in the ertapenem and comparator treatment groups. No overall differences in safety were observed between elderly (aged > or = 65 years and > or = 75 years) and younger patients. Ertapenem, 1 g once a day given by intravenous infusion or intramuscular injection, was generally well tolerated and had overall safety and tolerability profiles similar to those of piperacillin-tazobactam and ceftriaxone.

Efficacy of ertapenem against methicillin-susceptible Staphylococcus aureus in complicated skin/skin structure infections: results of a double-blind clinical trial versus piperacillin-tazobactam.

Staphylococcus aureus is the predominant pathogen in complicated skin/skin structure infections. In this analysis of a subgroup of data from a randomised, double-blind trial, the efficacy of ertapenem 1 g daily was compared with piperacillin-tazobactam 3.375 g Q6H for treatment of complicated skin/skin structure infections caused by methicillin-susceptible S. aureus (MSSA). Of the 529 treated patients in this trial, 185 (35.0%) had MSSA as a baseline pathogen. At the test of cure assessment 10-21 days post-therapy, 54 of 67 (80.6%) protocol evaluable patients in the ertapenem group and 55 of 68 (80.9%) in the piperacillin-tazobactam group were cured (odds ratio: 1.0 (95% confidence interval (CI): 0.4-2.4), P = 0.99). In both treatment groups, cure rates were higher in patients with monomicrobial than polymicrobial infections, but the difference was not significant. In this subgroup analysis of patients with MSSA complicated skin/skin structure infections, therapy with ertapenem 1 g daily was as effective as piperacillin-tazobactam 13.5 g divided in four daily doses.

Evaluation of outpatient treatment with ertapenem in a double blind controlled clinical trial of complicated skin/skin structure infections.

OBJECTIVES: The patient characteristics and the efficacy and safety of ertapenem 1 g once daily vs. piperacillin-tazobactam 13.5 g divided Q6H were examined in patients who received outpatient parenteral antimicrobial therapy (OPAT) during a clinical trial of complicated skin/skin structure infections. METHODS: The population analyzed included 363 patients treated at US sites in a large randomized double-blind study. RESULTS: In this analysis, 146 (40%) patients at 19 (66%) sites were managed by OPAT. A lower proportion of treated patients who received OPAT had severe infection (12% vs. 20%, P=0.03). In evaluable patients managed by OPAT, 45 (83.3%) of 54 treated with ertapenem and 41 (82.0%) of 50 treated with piperacillin-tazobactam were cured at the test of cure assessment 10-21 days post-therapy (OR 1.2 (95% CI, 0.4-3.2), P=0.78). The safety profile of both drugs was generally similar; diarrhoea was the most common adverse event in both groups. CONCLUSIONS: In this trial of complicated skin/skin structure infection, OPAT was commonly used by US investigators. Among patients who received OPAT, ertapenem 1 g daily was as effective as piperacillin-tazobactam 3.375 g Q6H.

Efficacy of ertapenem in the treatment of serious infections caused by Enterobacteriaceae: analysis of pooled clinical trial data.

OBJECTIVE: The efficacy of ertapenem, 1 g once a day, for treatment of adults with serious infections caused by Enterobacteriaceae was compared with ceftriaxone 1 g once a day [complicated urinary tract infection (CUTI) and community-acquired pneumonia (CAP)] or piperacillin-tazobactam, 3.375 g every 6 h (complicated intra-abdominal, complicated skin/skin structure and acute pelvic infections). PATIENTS AND METHODS: This combined analysis included the subgroup of all 1167 treated patients infected with Enterobacteriaceae from seven randomized double-blind studies. RESULTS: Escherichia coli was the most common pathogen, accounting for 65.3% of all Enterobacteriaceae. Among evaluable patients with deep tissue (intra-abdominal, skin and pelvic) infections, the combined clinical cure rates were 84.8% (223 of 263) for ertapenem and 82.9% (194 of 234) for piperacillin-tazobactam [95% confidence interval (CI) for the difference, adjusting for infection, -4.9% to 8.9%]. Cure rates by infection for ertapenem and piperacillin-tazobactam, respectively, were: intra-abdominal, 85.1% (143 of 168) and 79.9% (119 of 149); pelvic, 86.8% (46 of 53) and 94% (47 of 50); skin/skin structure, 81% (34 of 42) and 80% (28 of 35). Among patients with CUTI, microbiological cure rates were 90.5% (220 of 243) for ertapenem and 92% (196 of 213) for ceftriaxone (95% CI for the difference, -7.1% to 4.1%). In patients with CAP, clinical cure rates were 95% (19 of 20) for ertapenem and 88.9% (16 of 18) for ceftriaxone. CONCLUSION: Ertapenem therapy was as effective as either piperacillin-tazobactam or ceftriaxone for serious infections caused by Enterobacteriaceae.

Ertapenem versus ceftriaxone followed by appropriate oral therapy for treatment of complicated urinary tract infections in adults: results of a prospective, randomized, double-blind multicenter study.

The efficacy and safety of intravenous (i.v.) ertapenem (1 g once a day) with the option to switch to an oral agent for treatment of adults with complicated urinary tract infections (UTIs) were compared with that of i.v. ceftriaxone (1 g daily) with the same oral switch option in a multicenter, double-blind, prospective, randomized study. At entry, 592 patients were assigned to one of two strata: acute pyelonephritis or other complicated UTI without acute pyelonephritis. After a minimum of 3 days, patients could be switched to an oral antimicrobial agent. A total of 159 patients in the ertapenem group and 171 patients in the ceftriaxone group were microbiologically evaluable. Approximately 95% of patients in each treatment group were switched to oral therapy. The most common pathogens were Escherichia coli and Klebsiella pneumoniae. At the primary efficacy endpoint 5 to 9 days after treatment, 91.8% of patients who received ertapenem and 93.0% of those who received ceftriaxone had a favorable microbiological response (95% confidence interval for the difference, adjusting for strata, -7.6 to 5.1%), indicating that outcomes in the two treatment groups were equivalent. Microbiological success rates for the two treatment groups were similar when compared by stratum and also by severity of infection. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. In this study, ertapenem was as effective as ceftriaxone for the initial treatment of complicated UTIs in adults, was generally well tolerated, and had a similar overall safety profile.

General microbiology and in vitro susceptibility of anaerobes isolated from complicated skin and skin-structure infections in patients enrolled in a comparative trial of ertapenem versus piperacillin-tazobactam.

In a recently completed study of once-a-day ertapenem versus piperacillin-tazobactam every 6 h in the treatment of complicated skin and skin-structure infections, 540 patients were randomized in a 1rcolon;1 ratio and assigned to 1 of 2 strata: those with a complicating underlying disease or all others. The most common infections in the study were deep soft-tissue abscess (18.9%), followed by diabetic lower extremity infection (18.1%); 7.0% of these were perineal cellulitis/abscess. With the exception of methicillin-resistant Staphylococcus aureus, almost all of the predominant aerobic pathogens were susceptible to both study drugs. Eighty-seven patients (16%) had >/=1 anaerobe identified in their baseline wound cultures, with a total of 232 anaerobic isolates. Of the 141 anaerobes tested for susceptibility, 97.2% were susceptible to ertapenem and 97.9% to piperacillin-tazobactam. Ertapenem had excellent in vitro activity against the most common aerobic pathogens and almost all anaerobes recovered from patients with infections of the skin and skin structures.

A prospective, multicenter, randomized, double-blind study comparing ertapenem and ceftriaxone followed by appropriate oral therapy for complicated urinary tract infections in adults.

OBJECTIVES: To compare the efficacy and safety of ertapenem, a new once-daily parenteral beta-lactam, with that of ceftriaxone for the initial empiric treatment of adults with complicated urinary tract infections (cUTIs). METHODS: In a multicenter, prospective, double-blind study, patients with cUTIs were stratified as to whether they had acute pyelonephritis or other cUTIs (without pyelonephritis) and randomized to receive ertapenem, 1 g once a day, or ceftriaxone, 1 g once a day. After 3 days, patients with a satisfactory clinical response could be switched to an oral antimicrobial agent. RESULTS: Of 258 randomized patients, 97 (55.4%) in the ertapenem group and 53 (63.9%) in the ceftriaxone group were evaluated microbiologically. Almost all patients in each treatment group were switched to oral therapy. The mean duration of therapy was similar in both treatment groups: parenteral, approximately 4 days; total, approximately 13 days. The most common pathogen was Escherichia coli. At the primary efficacy endpoint, 5 to 9 days after treatment, 85.6% of patients who received ertapenem and 84.9% who received ceftriaxone had a favorable microbiologic response, indicating that the two treatment groups were equivalent. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. CONCLUSIONS: In this study, ertapenem was as effective as ceftriaxone for the initial treatment of cUTI in adults, was generally well tolerated, and had a similar safety profile.

Comparative in vitro activities of ertapenem against aerobic and facultative bacterial pathogens from patients with complicated skin and skin structure infections.

This study compared the in vitro activities of ertapenem (Merck & Co., Inc.), ceftriaxone, amoxicillin-clavulanate, and piperacillin-tazobactam against 518 aerobic and facultative bacterial pathogens isolated from 340 patients with complicated skin and skin structure infections. Ciprofloxacin was also tested against Gram-negative isolates. Gram-positive cocci accounted for 68.1% of the aerobic bacteria; Staphylococcus aureus was the most common isolate (45.6%). The ertapenem MIC was < or = 2 microg/ml for 80.9% of isolates and > or = 8 microg/ml for 16.2% (including isolates of enterococci, methicillin-resistant S. aureus, Pseudomonas aeruginosa, and other nonfermentative Gram-negative bacteria). Against methicillin-susceptible S. aureus, ertapenem had the most potent activity. Ertapenem was the most active drug against Enterobacteriaceae (100% susceptible), whereas amoxicillin-clavulanate was least active (66% susceptible). Piperacillin-tazobactam was the most active drug against P. aeruginosa (100% susceptible), followed by ciprofloxacin (87% susceptible). In summary, ertapenem was highly active in vitro against many aerobic and facultative bacterial pathogens commonly recovered from patients with complicated skin and skin structure infections.

Ertapenem once daily versus piperacillin-tazobactam 4 times per day for treatment of complicated skin and skin-structure infections in adults: results of a prospective, randomized, double-blind multicenter study.

We conducted a prospective, randomized, double-blind trial comparing ertapenem (1 g once daily) with piperacillin-tazobactam (3.375 g every 6 h) as parenteral treatment for 540 adults with complicated skin and skin-structure infections. The most common diagnoses were skin or soft-tissue abscesses and lower-extremity infections associated with diabetes. The mean duration (+/- standard deviation) of therapy was 9.1+/-3.1 days for ertapenem and 9.8+/-3.3 days for piperacillin-tazobactam. At the assessment of primary efficacy end point, 10-21 days after treatment, 82.4% of those who received ertapenem and 84.4% of those who received piperacillin-tazobactam were cured. The difference in response rates, adjusting for the patients' assigned strata, was -2.0% (95% confidence interval, -10.2% to 6.2%), indicating that the response rates in the 2 treatment groups were equivalent. Cure rates for the 2 treatment groups were similar when compared by stratum, diagnosis, and severity of infection. The frequency and severity of drug-related adverse events were similar in the treatment groups.

Ertapenem versus piperacillin-tazobactam for treatment of mixed anaerobic complicated intra-abdominal, complicated skin and skin structure, and acute pelvic infections.

BACKGROUND: Anaerobes are an important component of many serious, deep tissue infections, especially complicated intra-abdominal (IAI), complicated skin and skin structure (SSSI), and acute pelvic (PI) infections. This study compares the efficacy of ertapenem, 1 g once a day, in the treatment of adults with anaerobic IAI, SSSI, and PI to piperacillin-tazobactam, 3.375 g every 6 hours. METHODS: Three randomized, double-blind trials comparing ertapenem to piperacillin-tazobactam for treatment of IAI, SSSI, and PI were conducted. This subgroup analysis included 623 patients, whose baseline culture grew one or more anaerobic pathogens, from these three studies. RESULTS: Anaerobes most commonly isolated were Bacteroides fragilis group (IAI) and peptostreptococci (SSSI and PI). The median duration of ertapenem and piperacillin-tazobactam therapy, respectively, in these subgroups was 6 and 7 days for IAI, 7 and 8 days for SSSI, and 4 and 5 days for PI. Cure rates for all evaluable patients with anaerobic infection were 89.3% (242/271) for ertapenem and 85.9% (220/256) for piperacillin-tazobactam (95% CI for the difference, adjusting for infection, -2.6% to 9.3%), indicating that the two treatments were equivalent. Cure rates by infection, for ertapenem and piperacillin-tazobactam, respectively, were as follows: IAI, 86.4% (133/154) and 82.4% (117/142); SSSI, 84.4% (27/32) and 82.4% (28/34); PI, 96.5% (82/85) and 93.8% (75/80). The frequency and severity of drug-related adverse experiences were comparable in both treatment groups. CONCLUSION: In this subgroup analysis, ertapenem was as effective as piperacillin-tazobactam for treatment of adults with moderate to severe anaerobic IAI, SSSI, and PI, was generally well tolerated, and had a similar safety profile.

Surgical infections with enterococcus: outcome in patients treated with ertapenem versus piperacillin-tazobactam.

BACKGROUND: The pathogenicity of Enterococcus in polymicrobial surgical infections is controversial. The objective of this analysis was two-fold. The impact of Enterococcus on clinical outcome was assessed in adults with complicated intra-abdominal (IAI), complicated skin and skin structure (CSSSI), or acute pelvic (PI) infection treated with ertapenem or piperacillin-tazobactam, which is more active in vitro against enterococci than ertapenem. Baseline characteristics were identified that were associated with Enterococcus infection and with treatment failure. METHODS: This analysis included 1,558 patients treated in three randomized, triple-blind studies. Of these patients, 223 had Enterococcus in initial cultures: 125 of 623 (20%) with IAI, 28 of 529 (5%) with CSSSI, and 70 of 406 (17%) with PI. Logistic regression models were fit to assess each objective. RESULTS: The cure rates for the two treatment groups were similar in each of the three studies, regardless of the presence or absence of Enterococcus. Cure rates for both treatment groups combined were significantly lower in patients with Enterococcus than without Enterococcus for IAI (76% [69/91] versus 87% [264/305], OR 2.3 [95% CI, 1.2-4.1], P = 0.009) and CSSSI (58% [11/19] versus 84% [241/287], OR 3.8 [95% CI, 1.5-10.0], P = 0.010); but for PI, rates were similar (96% [50/52] versus 92% [188/205], OR 0.4 [95% CI, 0.1-1.9], P = 0.220). Characteristics predictive of the presence of Enterococcus were Pseudomonas aeruginosa as a baseline pathogen for IAI, older age, and the presence of a complicating underlying disease for CSSSI, and infection severity rated moderate rather than severe for PI. The strongest predictors of treatment failure were >2 days postoperative infection at study entry for patients with IAI and older age for patients with CSSSI. CONCLUSION: Choice of antimicrobial therapy did not affect cure rates in patients with or without Enterococcus. The strongest predictors of failure were postoperative infection at study entry in patients with IAI and older age in patients with CSSSI.