Serious infections caused by pathogens resistant to all available antimicrobial agents are becoming more common and represent significant dilemmas of management. Compounding this is awareness of a dry antimicrobial pipeline for the near future. At 2011 ICAAC, a few agents were presented, which are in the clinical development phase and may offer some hope for the future. The following are abstracts of a few of these agents.
A2-023. USE OF A POPULATION PHARMACOKINETIC MODEL FOR DOSE SELECTION IN PHASE 2B STUDIES FOR GSK2251052. TENERO ET AL1
GSK2251052 is a novel boron-containing leucyl-tRNA synthetase inhibitor with in vitro activity against Pseudomonas aeruginosa and multidrug-resistant Enterobacteriaceae, which is being developed for treatment of serious gram-negative infections. A population pharmacokinetic (PK) model was developed and used to support dose selection for phase 2b studies. Healthy volunteers (n = 6/dose group) received single (200–3000 mg as salt) or repeat (433–1733 mg) doses 2 times a day for up to 14 days of 1-hour intravenous infusions. A population PK model was developed to describe the concentration-time data for the novel antibacterial GSK2251052. The model was used for simulation and selection of doses for phase IIb studies, which are expected to provide Enterobacteriaceae and P aeruginosa coverage that is similar or superior to standard of care.
Aminoacyl-transfer RNA (tRNA) synthetase LeuRS, which is essential for protein synthesis, attaches leucine to the 3′ terminal nucleotide of tRNA. Thus, this is a new type of antimicrobial agent, which seems promising for many multidrug-resistant Pseudomonas and Enterobacteriaciae. However, in vitro data suggest that it does not have very good activity for multidrug-resistant Acinetobacter species. According to the authors of this study, phase 2 studies are soon to start.
A2-572. PHARMACOKINETICS AND SAFETY OF THE NOVEL SULFACTAM ANTIBIOTIC BAL30072 AFTER SINGLE ASCENDING DOSE INFUSIONS IN HEALTHY VOLUNTEERS. SCHMITT-HOFFMAN ET AL2
The safety, tolerability, and pharmacokinetics of BAL30072 were investigated in a double-blind, randomized, single ascending dose study in 40 healthy male subjects. Cohorts of 8 subjects/dose were randomized to placebo (n = 2) or BAL30072 (n = 6) given as 500-mL intravenous infusion. Doses investigated were 500, 1000, 2000 (1-hour infusion), 4000 (1.5-hour infusion), and 8000 mg (2.5-hour infusion). The mean Cmax values were 28.5, 76.0, 103, 226, and 286 mg/L, with corresponding area-under-the-curve values of 43.8, 140, 183, 549, and 1040 mg hour/L after infusions of 500, 1000, 2000, 4000, and 8000 mg, respectively. The elimination half-life of sulfactam ranged from 1.6 to 2.3 hours, the volume of distribution at steady state was between 11.1 and 15.3 L, and the total systemic clearance was 7.4 to 12 L/h. Approximately 50% of the dose administered was recovered unchanged in urine. All doses were well tolerated, with no serious or severe adverse events reported. No trends or clinically significant changes in laboratory parameters, vital signs, or electrocardiographic recordings were observed. The results of this first-in-man trial pave the way to further develop this unique compound against difficult-to-treat infections caused by multidrug-resistant gram-negative bacteria.
BAL30072 is a novel monocyclic β-lactam antibiotic belonging to the sulfactams, which has potent activity against Enterobacteriacae and nonfermenters, including Acinetobacter species, and is being developed as a new therapeutic option for the treatment of infections caused by multidrug-resistant gram-negative pathogens including carbapenem-resistant strains. There is limited cross-resistance with aztreonam. In contrast to GSK 2251052 (see above), BAL 30072 seems to be very promising for Acinetobacter but is not as active against multidrug-resistant P aeruginosa. The clinical use for empirical therapy of either GSK 2251052 or BAL 30072 will be enhanced by use of point-of-care molecular testing to provide early identification of such pathogens as Acinetobacter or Pseudomonas species.
L2-909. CEFTAZIDIME AVIBACTAM (NXL 104) VS IMIPENEM FOR COMPLICATED UTI IN HOSPITALIZED PATIENTS. VAZQUEZ ET AL3
This prospective, multinational, randomized, investigator-blinded phase 2 study compared the efficacy and safety of ceftazidime avibactam (CAZ104) and imipenem/cilastatin (IMI) in hospitalized adults with complicated urinary tract infections due to gram-negative pathogens. Patients were stratified by type of infection (acute pyelonephritis or other complicated urinary tract infections) and randomized (1:1) to receive CAZ104 (CAZ, 500 mg/NXL104, 125 mg) intravenous (IV) every 8 hours or IMI, 500 mg, IV every 6 hours. The patients were treated for 7 days or more to 14 days or less; those who met prespecified criteria for clinical improvement after day 4 and had susceptible pathogens could be switched to oral ciprofloxacin, 500 mg, every 12 hours. One hundred thirty-five patients received study treatment, including 62 microbiologically evaluable patients (CAZ104, n = 27; IMI, n = 35). The predominant uropathogen in both groups was Escherichia coli. Favorable microbiological response was achieved in 70.4% on CAZ104 and 71.4% on IMI at the test-of-cure visit (observed difference, 1.1%), and in 57.7% and 60.0% of the patients, respectively, at the late follow-up visit. Response was observed in 6 (85.7%) of 7 and 9 (81.8%) of 11 CAZ-resistant organisms with CAZ104 and IMI, respectively. During IV treatment, drug-related adverse events were reported in 35% of pts on CAZ104 and 48% on IMI. Although adverse event frequencies were similar overall (most commonly, headache and gastrointestinal effects), more infusion site reactions were reported with IMI.
Avibactam (NXL104) is a novel non–β-lactam β-lactamase inhibitor active in vitro against Ambler class A and C enzymes. These data suggest that ceftazidime-avibactam has promising potential to address many of the gram-negative bacterial resistance issues that challenge us today. Avibactam is also being developed by Forest in combination with ceftaroline as well.
L2-966. PHASE 2 STUDY COMPARING THE SAFETY AND EFFICACY OF 2 DOSES OF BC-3781 IV VS VANCOMYCIN IN ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS. PRINCE ET AL4
BC-3781 safety and efficacy was investigated in a 20-center, randomized, double-blind phase 2 study. Patients with ABSSSI caused by gram-positive pathogens were randomized to intravenous BC-3781 (100 or 150 mg every 12 hours) or vancomycin (1 g every 12 hours or adjusted to institutional guidelines) for 5 to 14 days. Response was assessed in the clinically evaluable (CE) population at test of cure 7 to 14 days after end of treatment and on days 1 to 5. Early clinical response was assessed in the intent-to-treat population. Seventy-one patients received 150-mg BC-3781, 70 patients received 100-mg BC-3781, and 66 patients received vancomycin. Distribution of infection types among the 3 treatment groups was similar: cellulitis, 50.7%; abscess with cellulitis, 30.9%; wound infections, 17.9%. Staphylococcus aureus was the most prominent pathogen, isolated in 95.1% of patients with a baseline pathogen, 74.1% of which were methicillin-resistant S aureus. Clinical cure rates in clinically evaluable patients at test of cure were 90.0% and 88.9% for 100- and 150-mg BC-3781, respectively, and 92.2% for vancomycin. The early clinical response was assessed for cessation of spread of erythema plus lack of fever at day 3 with the following success: 85.7% and 83.1% for 100- and 150-mg BC-3781, respectively, and 80.3% of the patients in the vancomycin group. The incidence of drug-related adverse events was higher in the vancomycin-treated patients than in those receiving BC-3781. BC-3781 was well tolerated, with no signs or symptoms of clinical concern.
BC-3781 is the first pleuromutilin for systemic use in clinical development for the treatment of skin and skin structure infections and respiratory tract infections, showing excellent antimicrobial activity against relevant pathogens including methicillin-resistant S aureus and multidrug-resistant Streptococcus pneumoniae. This study demonstrated that the efficacy of BC-3781, dosed at 100 or 150 mg intravenous every 12 hours, is comparable to vancomycin and is a positive proof of concept for BC-3781 for the treatment of patients with acute bacterial skin and skin structure infections and other indications caused by susceptible bacteria.
1. Tenero DM, Zane LT, JF LT, et al. Use of a population pharmacokinetic model for dose selection in phase IIb studies for GSK2251052. ICAAC 2011. Abstract A2-023.
2. Schmitt-Hoffman A, Roos B, Maares JJ, et al. Pharmacokinetics and safety of the novel sulfactam antibiotic BAL30072 after single ascending dose infusions in healthy volunteers. ICAAC 2011
. Abstract A2-572.
3. Vazquez J, González Patzán L, Stricklin D, et al. Ceftazidime avibactam (NXL 104) vs imipenem for complicated UTI in hospitalized patients. ICAAC 2011. Abstract L2-966.
4. Prince WT, Obermayr F, Ivezic-Schoenfeld Z, et al. Phase 2 study comparing the safety and efficacy of two doses of BC-3781 IV vs vancomycin in ABSSSI. ICAAC 2011. Abstract L2-966.