Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial.

OBJECTIVES: Avibactam, a novel non-ß-lactam ß-lactamase inhibitor, restores the in vitro activity of ceftazidime against class A, C and some class D ß-lactamase-producing pathogens, including those commonly associated with complicated intra-abdominal infections (cIAIs). This randomized, active-controlled, double-blind, Phase II trial (NCT00752219) aimed to evaluate the safety and efficacy of ceftazidime/avibactam plus metronidazole compared with meropenem in hospitalized patients with cIAI. METHODS: Adults with confirmed cIAI requiring surgical intervention and antibiotics were randomized 1 : 1 to receive intravenously either (i) 2000 mg of ceftazidime plus 500 mg of avibactam plus a separate infusion of 500 mg of metronidazole or (ii) 1000 mg of meropenem plus placebo every 8 h for a minimum of 5 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 2 weeks after the last dose of study therapy. RESULTS: Overall, 101 patients received ceftazidime/avibactam plus metronidazole; 102 received meropenem. The median duration of treatment was 6.0 and 6.5 days, respectively. Favourable clinical response at the TOC visit in the ME population was observed in 91.2% (62/68) and 93.4% (71/76) of patients in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively (observed difference: -2.2%; 95% CI: -20.4%, 12.2%). The incidence of treatment-emergent adverse events was similar for ceftazidime/avibactam plus metronidazole (64.4%) and meropenem (57.8%). CONCLUSIONS: Ceftazidime/avibactam plus metronidazole was effective and generally well tolerated in patients with cIAI, with a favourable clinical response rate in the ME population of >90%, similar to that of meropenem.

Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study.

OBJECTIVES: The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime-avibactam and imipenem-cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens. PATIENTS AND METHODS: Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam 125 mg every 8 hours or imipenem-cilastatin 500 mg every 6 hours. Patients meeting pre-specified improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a total of 7-14 days. The primary efficacy objective was a favorable microbiological response at the test-of-cure (TOC) visit 5-9 days post-therapy in microbiologically evaluable (ME) patients. RESULTS: Overall, 135 patients received study therapy (safety population); 62 were included in the ME population (ceftazidime-avibactam, n = 27; imipenem-cilastatin, n = 35). The predominant uropathogen was Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving ceftazidime-avibactam and 71.4% receiving imipenem-cilastatin at the TOC visit (observed difference -1.1% [95% CI: -27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens, response was observed in 6/7 (85.7%) receiving ceftazidime-avibactam. Adverse events were observed in 67.6% and 76.1% of patients receiving ceftazidime-avibactam and imipenem-cilastatin, respectively. Limitations of the study include the small number of patients in the ME population. CONCLUSION: The results suggest that the efficacy and safety of ceftazidime-avibactam may be similar to that of imipenem-cilastatin.

The immunogenicity and safety of different formulations of a novel Staphylococcus aureus vaccine (V710): results of two Phase I studies.

Merck V710 is a novel vaccine that contains the highly conserved Staphylococcus aureus iron surface determinant B (IsdB) protein. V710 has induced positive immune responses in healthy subjects. The purpose of the two studies described herein was to evaluate the immunogenicity and safety of two different formulations of V710. Both studies were randomized, controlled, double-blind, parallel-group trials. Study 1 compared liquid, aluminum-adjuvanted V710 (30 µg) with liquid, non-adjuvanted V710 (30 µg) in a 1:1 ratio in 64 healthy adults (18-70 years). Study 2 compared non-adjuvanted lyophilized V710 (60 µg) with saline placebo in a 4:1 ratio in 51 healthy adults (18-80 years). Blood was collected at screening and up to Day 360 postvaccination in Study 1, and at screening and up to Day 84 postvaccination in Study 2. Sera were analyzed for IsdB-specific antibodies using a total IgG assay. The primary endpoints in Study 1 were the proportion of patients with a positive immune response (≥2-fold rise in IsdB-specific IgG antibody level) the geometric mean concentration (GMC), and the geometric mean-fold rise (GMFR), all from baseline at Day 14. The primary endpoint in Study 2 was the GMFR in IsdB-specific IgG antibody concentration from baseline at Day 14. In Study 1, 84.4% responded in the adjuvanted V710 group, and 71.9% in the non-adjuvanted V710 group. The GMC was 115.4 µg/mL in the adjuvanted group and 99.1 µg/mL in the nonadjuvanted group. The GMFR in antibody concentration in the group receiving aluminum-adjuvanted V710 was 4.5 and the GMFR in the group receiving non-adjuvanted V710 was 4.0. In Study 2, the GMFR in antibody concentration in the V710 group was 5.3, and 80.5% had a positive immune response. None responded in the placebo group. Positive immune response was seen in the active treatment groups over the full duration of each study. There were no serious adverse experiences (AE) in either study, and no patients discontinued due to an AE. There were no clinically meaningful differences in AEs between groups in either study. In conclusion, V710, both with and without aluminum adjuvant, and in both liquid and lyophilized formulations, was immunogenic within 14 days of vaccination. All treatments showed similar safety profiles.

Safety and immunogenicity of a novel Staphylococcus aureus vaccine: results from the first study of the vaccine dose range in humans.

Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 µg, 30 µg, or 90 µg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 µg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-µg (86%; geometric mean concentration of 116 µg/ml) and 90-µg (87%; geometric mean concentration of 131 µg/ml) dose groups than in the V710 5-µg (29%; geometric mean concentration of 51 µg/ml) or placebo (4%; geometric mean concentration of 23 µg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-µg or 90-µg dose was more immunogenic than the 5-µg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

Caspofungin for the treatment of less common forms of invasive candidiasis.

OBJECTIVES: Caspofungin has demonstrated efficacy in invasive candidiasis. However, in a comparative study, most patients (>83%) had candidaemia. Therefore, we performed a study in patients with non-fungaemic invasive candidiasis. PATIENTS AND METHODS: Adults with proven non-fungaemic invasive candidiasis or probable chronic disseminated candidiasis (CDC) received caspofungin primary or salvage monotherapy. Most patients received 50 mg daily following a 70 mg loading dose. Patients with endocarditis, osteomyelitis or septic arthritis received caspofungin at 100 mg daily and were allowed dose escalation up to 150 mg. Primary efficacy endpoint was the overall response at end of caspofungin therapy. A favourable overall response required complete resolution of symptoms and either eradication of Candida or radiographic resolution. RESULTS: All 48 patients enrolled had confirmed infection and received>or=1 dose of caspofungin. At study entry, 8% were neutropenic. The mean APACHE II score was 14.3. Most infections were due to Candida albicans (60%) or Candida glabrata (14%). The overall success at end of caspofungin therapy was 81%. Success by site of infection was as follows: peritonitis 77% (10/13), abdominal abscess 89% (8/9), CDC 88% (7/8), osteomyelitis/septic arthritis 100% (4/4), endocarditis 33% (1/3) and multiple sites 75% (6/8). Outcomes were similar across Candida spp. None of the patients had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Overall mortality until 12 week follow-up was 23%. CONCLUSIONS: In deep-seated invasive candidiasis, including peritonitis, abdominal abscesses, CDC and arthritis, caspofungin was effective and safe at regular doses and up to 100 mg daily.