Abstract
<p class="ADMETkeywordsheading">The notorious Staphylococcus aureus resistant strains with ever changing resistance patterns have limited treatment options and have led to substantial number of deaths. Almost dried antibiotic pipeline has led us to look into combinations of already approved antibiotics for tackling rising incidence of antibacterial resistance. Recommended use of vancomycin and ceftriaxone together for treating severe infections involving resistant S. aureus is limited by dose adjustments and different dose frequencies. We have developed a pharmacodynamically synergistic fixed dose combination (FDC) of ceftriaxone and vancomycin (2:1), for eliminating individual component dose adjustments and frequencies. For identification of optimum exposure-response of FDC, one compartment in vitro system was used for dose escalation, fractionation and dose-response studies. The in-silico pharmacokinetic/pharmacodynamic (PK/PD) modeling, simulations and validations were done. The results suggested % T&gt;MIC<sub>comb</sub> (percentage of time fractional inhibitory concentrations of the drugs combined remained above the MIC<sub>comb</sub> [minimum inhibitory concentration for FDC]) followed by AUC<sub>comb</sub>/MIC<sub>comb</sub> (ratio of area under fractional inhibitory curves to MICc<sub>omb</sub>) can predict the exposure (dose of FDC)-response (reduction in bacterial load) relationships effectively (r2 &gt;0.9). Total exposure of 6 g in two divided doses (3 g each) was identified to be optimum. Monte Carlo simulations were performed to evaluate the effect of increasing doses against different MICs. Clinical breakpoint of the FDC was identified to be 4 µg/mL, which was 2 fold higher than that of vancomycin suggesting better antibacterial coverage.</p>
Highlights
The bacteria methicillin-resistant Staphylococcus aureus (MRSA) is one of most common pathogen responsible for nosocomial infections
The current formulation is a fixed dose combination (FDC) of ceftriaxone and vancomycin in 2:1 (w/w), results in reduction of combined MIC from 16 to 4 μg/mL against a MRSA bacterial strain used for this study
The present study was focused on dose optimization of the FDC using in vitro studies, PK/PD modeling and Monte Carlo simulations
Summary
The bacteria methicillin-resistant Staphylococcus aureus (MRSA) is one of most common pathogen responsible for nosocomial infections. It is associated with an increased risk of mortality and morbidity, requiring prolonged duration of treatment and increased cost [1]. It is reported that out of 10,800 deaths per year by infections in United States, 5,500 deaths are linked to MRSA. The prevalence of MRSA is extrapolated to 1 billion people by year 2022 [1]. Vancomycin is the empirical choice for treating these infections. Extensive vancomycin use has led to emergence of MRSA with reduced vancomycin susceptibility.
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