PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

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Project summary/Abstract Children exposed to tuberculosis (TB) bacterium have a greater risk of progressing to active TB disease. Younger children (<2 years) are especially susceptible to developing disseminated disease due to ineffective immunologic containment. As per World Health Organization 2017 report, ~1 million children become ill with TB each year representing nearly 10% of the total TB cases. In 2016, ~3% of the reported cases in children diagnosed to have multi-drug resistant (MDR) TB (defined as being resistant to the two most potent first-line anti-TB drugs, isoniazid and rifampin). One of the hurdles in pediatric TB management is the availability of a safe and effective treatment regimen for MDR-TB designed specifically for children considering the age specific pharmacokinetic variability. Our broad objective is to use our hollow fiber system model for TB to streamline TB drug development. Given that the pipeline for novel TB drugs is still slim, there is renewed interest in repurposing old drugs for new use. β-lactam antibiotics are the backbone of many antibacterial treatment regimens; however, their efficacy against Mycobacterium tuberculosis (Mtb) have not been fully explored. We screened 13 drugs from the β-lactams class of the antibiotics including the cephalosporins sub-class, against drug resistant clinical strains of Mtb. In this grant application we will advance 6 cephalosporins to the next phase of investigations. Cephalosporins have an advantage because the pharmacokinetic and safety profile in children is well defined. We will combine the leading cephalosporins with two other oral drugs—moxifloxacin, an integral backbone of MDR-TB treatment regimens in people of all ages, and tedizolid, a new oxazolidinone effective against gram-positive pathogens as well as Mtb to create a potent regimen effective against MDR-TB in children. Our drug and combination regimen development approach apply pharmacokinetic/pharmacodynamic science using our validated hollow fiber system model for intracellular Mtb (HFS-TB). We have information on each drug’s optimal exposure target for maximal Mtb kill as monotherapy from the HFS-TB studies performed to collect preliminary data. The workflow of the current application will be - (1) use of checkerboard studies to evaluate additivity, synergy or antagonism of each cephalosporin with moxifloxacin, (2) add tedizolid at concentration to achieve optimal exposure target to the cephalosporins-moxifloxacin drug pair(s) to test in the HFS-TB comparing Mtb kill rates with a second-line MDR-TB regimen of five drugs (amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide) using MDR-TB clinical strains, (3) mathematical modeling of the HFS-TB results to predict Mtb time-to-extinction that will inform optimal duration of therapy with the proposed novel drug combination regimens, (4) in silico clinical trial simulations incorporating pediatric-specific pharmacokinetic variability as well as Mtb-strain minimum inhibitory concentration variability to establish optimal dose of each drug to achieve exposure targets among pediatric populations. The outcome will be novel treatment regimen(s) specially designed for MDR-TB in children in relatively short time span, addressing a major unmet clinical need in the global era of TB elimination.