The pharmacokinetics, tolerability, and serum inhibitory and bactericidal titers of telavancin, a new rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens, were assessed in a two-part, randomized, double-blind, placebo-controlled, ascending-dose study with 54 healthy men. In part 1, single ascending intravenous doses of 0.25 to 15 mg/kg of body weight were studied. In part 2, multiple ascending doses (30-min infusions of 7.5 to 15 mg/kg/day) were studied over 7 days. Following the administration of multiple doses, steady state was achieved by days 3 to 4. At day 7 after the administration of telavancin at 7.5, 12.5, and 15 mg/kg/day, peak concentrations in plasma were 96.7, 151.3, and 202.5 g/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 g ⅐ h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses >5 mg/kg. Most adverse events were mild in severity. At 24 h postinfusion, serum from subjects given telavancin demonstrated potent bactericidal activity against methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae strains. The results suggest that telavancin may be an effective once-daily therapy for serious bacterial infections caused by these pathogens. , abstr. F-2108, 2003). Data from in vitro and animal studies indicate that telavancin has superior activity to ␤-lactams, older glycopeptides (e.g., vancomycin), and the oxazolidinone linezolid (6). This antimicrobial agent is rapidly bactericidal against staphylococci, with Ͼ99.9% killing achieved within 4 h of exposure at concentrations achievable in vivo (8).Unlike most glycopeptides, telavancin has multiple mechanisms of action. In addition to inhibiting peptidoglycan synthesis by blocking the transglycosylation step, telavancin also interacts with the bacterial membrane, dissipating the membrane potential and effecting changes in cell permeability. The multiple mechanisms of action may lead to a lower frequency of resistance (Debavov et al., 43rd ICAAC; K. Krause, D. Debabov, J. Pace, and K. Kaniga, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1810, 2003). The rapid bactericidal activity of this agent may result in a reduction in the duration of therapy and improved clinical outcomes. This paper reports the results of a two-part, randomized, double-blind, placebo-controlled study of sequentially ascending doses of telavancin with healthy adult male subjects. The study objectives were to assess the safety, pharmacokinetics, and pharmacodynamics (serum inhibitory and bactericidal titers) of intravenous (i.v.) telavancin. Study subjects. Eligible male subjects (age, 18 to 50 years; weight, 50 to 100 kg) with no clinically relevant abnormal physical or laboratory findings and normal electrocardiograms (ECGs), blood pressure, and heart rate were included in the study. Subjects had to be able to comply with the study requirements and to provide written inf...

UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 (N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

The pharmacokinetic disposition of telavancin administered 7.5 mg/kg of body weight every 24 h was determined in plasma and skin blister fluid. The mean penetration of telavancin into blister fluid was 40%. This study reveals that adequate concentrations are achieved in both plasma and blister fluid for pathogens frequently implicated in skin and soft tissue infections.

Plazomicin is an aminoglycoside with activity against multidrug-resistantEnterobacteriaceae. Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the α-, β-, and γ-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08 liters/h, respectively. Starting dose adjustments for CLCRare sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCRand BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.

Plazomicin is an aminoglycoside with in vitro activity against multidrug‐resistant Enterobacteriaceae. A phase 1, randomized, double‐blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty‐six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30‐minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30‐minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline‐adjusted, placebo‐corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1‐sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was <5 milliseconds, and the upper limit of a 2‐sided 90%CI for plazomicin ΔΔQTcF was <10 milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15‐ and 20‐mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration‐time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model‐derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.