hr-810 and ceftobiprole

Ceftobiprole is a promising new broad-spectrum cephalosporin with activity against several multidrug-resistant gram-positive and gram-negative species, including methicillin-resistant Staphylococcus aureus. In order to make efficacy predications against these resistant bacteria in soft-tissue infections, i.e., skin and skin structure infections, ceftobiprole's ability to reach the site of action should be explored. Therefore, a microdialysis study was conducted in 12 healthy volunteers to determine the penetration of ceftobiprole into skeletal muscle and subcutaneous (s.c.) adipose tissue after a single intravenous dose of 500 mg. Plasma and tissue interstitial space fluid (ISF) drug concentrations were measured for 24 h from the start of the 2-h intravenous infusion. Pharmacokinetic parameters were determined using noncompartmental analysis. The penetration of ceftobiprole into the ISF of tissues was assessed by comparing the ratios between tissue and plasma of the free drug area under the concentration-time curve (fAUC). It was found that ceftobiprole distributes into the muscle (fAUC(muscle)/fAUC(plasma) of 0.69 +/- 0.13) and s.c. adipose tissue (fAUC(s.c.adipose)/fAUC(plasma) of 0.49 +/- 0.28). The concentrations in both skeletal muscle and s.c. adipose tissue met the efficacy breakpoint (percentage of the time that free drug concentrations remained above the MIC) for at least 40% of the 8-h dosing interval for organisms with a MIC of 2 mg/liter. Therefore, ceftobiprole qualifies as a potential agent with drug penetration capabilities to treat complicated skin and skin structure infections due to both gram-negative and gram-positive pathogens with MICs equal to or below 2 mg/liter.

Topics: Adipose Tissue; Adult; Anti-Bacterial Agents; Cephalosporins; Humans; Infusions, Intravenous; Male; Microdialysis; Muscle, Skeletal; Young Adult

Bacterial resistance to β-lactams antibiotics is a serious threat to human health. The most common cause of resistance to the β-lactams is the production of β-lactamase that inactivates β-lactams. Specifically, class A extended-spectrum β-lactamase produced by antibiotic resistant bacteria is capable of hydrolyzing extended-spectrum Cephalosporins and Monobactams. Mutations in class A β-lactamases play a crucial role in substrate and inhibitor specificity. In this present study, the E166A point mutant, R274N/R276N double mutant, and E166A/R274N/R276N triple mutant class A β-lactamases are analyzed. Molecular dynamics (MD) simulations are done to understand the consequences of mutations in class A β-lactamases. Root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessibility surface area, hydrogen bond, and essential dynamics analysis results indicate notable loss in stability for mutant class A β-lactamases. MD simulations of native and mutant structures clearly confirm that the substitution of alanine at the position of 166, Asparagine at 274 and 276 causes more flexibility in 3D space. Molecular docking results indicate the mutation in class A β-lactamases which decrease the binding affinity of Cefpirome and Ceftobiprole which are third and fifth generation Cephalosporins, respectively. MD simulation of Ceftobiprole-native and mutant type Class A β-lactamases complexes reveal that E166A/R274N/R276N mutations alter the structure and notable loss in the stability for Ceftobirole-mutant type Class A β-lactamases complexes. Ceftobiprole is currently prescribed for patients with serious bacterial infections; this phenomenon is the probable cause for the effectiveness of Ceftobiprole in controlling bacterial infections.

Topics: Alanine; Anti-Bacterial Agents; Asparagine; beta-Lactamases; Cefpirome; Cephalosporins; Humans; Hydrogen Bonding; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutation