Murine Neutropenic Thigh Research Articles

Naturally Derived Malabaricone B as a Promising Bactericidal Candidate Targeting Multidrug-Resistant Staphylococcus aureus also Possess Synergistic Interactions with Clinical Antibiotics.

The emergence of multidrug-resistant (MDR) superbugs underlines the urgent need for innovative treatment options to tackle resistant bacterial infections. The clinical efficacy of natural products directed our efforts towards developing new antibacterial leads from naturally abundant known chemical structures. The present study aimed to explore an unusual class of phenylacylphenols (malabaricones) from Myristicamalabarica as antibacterial agents. In vitro antibacterial activity was determined via broth microdilution, cell viability, time-kill kinetics, biofilm eradication, intracellular killing, and checkerboard assays. The efficacy was evaluated in vivo in murine neutropenic thigh and skin infection models. Confocal and SEM analyses were used for mechanistic studies. Among the tested isolates, malabaricone B (NS-7) demonstrated the best activity against S. aureus with a favorable selectivity index and concentration-dependent, rapid bactericidal killing kinetics. It displayed equal efficacy against MDR clinical isolates of S. aureus and Enterococci, efficiently clearing S. aureus in intracellular and biofilm tests, with no detectable resistance. In addition, NS-7 synergized with daptomycin and gentamicin. In vivo, NS-7 exhibited significant efficacy against S. aureus infection. Mechanistically, NS-7 damaged S. aureus membrane integrity, resulting in the release of extracellular ATP. The results indicated that NS-7 can act as a naturally derived bactericidal drug lead for anti-staphylococcal therapy.

Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection.

Avibactam is a new non-β-lactam β-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum β-lactamases (ESBLs) and carbapenemases such as KPCs, class C β-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant Pseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%fT>C(T) 1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %fT>C(T) 1 mg/liter. This parameter of avibactam was further explored for four P. aeruginosa strains in the lung model and six in the thigh model. Parameter estimates of %fT>C(T) 1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %fT>C(T) 1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5% fT>C(T) 1 mg/liter, required for a static effect.