pipeline

NXL104

NXL103

preclinical

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NXL104/ceftazidime combination  

NXL104 is a novel injectable wide-spectrum beta-lactamase inhibitor from a completely new non-beta-lactam structural class, which in combination with the cephalosporin antibiotic ceftazidime, has demonstrated activity against a broad-range of Gram-negative bacterial pathogens, including Enterobacteriaceae and Pseudomonas.

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The addition of NXL104 to ceftazidime restores the susceptibility of Gram-negative pathogens which are resistant to ceftazidime owing to the production of the two most common classes of beta-lactamase enzymes found in pathogenic bacteria, Class A or Class C beta-lactamases. If developed successfully, NXL104/ceftazidime may be a useful alternative to carbapenems for the first line treatment of serious Gram-negative infections, including those due to resistant pathogens.

Preclinical data indicate that the spectrum of activity of NXL104 is broader than the currently approved beta-lactamase inhibitors (tazobactam, clavulanate, and sulbactam) which inhibit class A (excluding carbapenemases) but not class C beta-lactamases. NXL104 inhibits both class A (including carbapenemases) and class C beta-lactamases. Certain marketed β-lactamase inhibitors, such as clavulanate can induce increased expression of beta-lactamases, thereby making bacteria even more resistant to beta-lactam antibiotics. This is not the case with NXL104.

NXL104 has been shown to have good pharmacological properties, a good pre-clinical safety profile, and when combined with ceftazidime and excellent activity in animal models of infection. NXL104 is primarily renally cleared and thus has a potential to be associated with few drug: drug interactions. NXL104 has been studied in single and multiple dose studies in healthy young men at doses up to 2000mg intravenously, both alone as a single dose and in combination with ceftazidime (500mg NXL104/2000mg ceftazidime) IV for 10 days. In these studies in healthy volunteers, NXL104 demonstrated dose dependent kinetics and was well tolerated.

The first Phase II clinical trial with the NXL104/ceftazidime combination is a multi-center, randomized, investigator blinded trial conducted in ~150 adult patients with complicated urinary tract infections (cUTIs) in the United States. Patients will be treated with either 500mg ceftazidime/125mg NXL104 intravenously every 8 hours or 500mg imipenem/cilastatin intravenously every 6 hours for 4 to 14 days, depending on the time needed for clinical improvement. Patients may be switched to oral ciprofloxacin after 4 days if they have improved clinically and their infection is caused by a susceptible pathogen. In accordance with regulatory guidelines, patients are to receive a total of 7 to 14 days of total antibiotic therapy. The primary endpoint is the microbiological outcome in the microbiologically evaluable population at the follow up visit 5 to 9 days post-therapy.


 

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> Stachyra, T., Levasseur, P., PĂ©chereau, M-C., Girard, A-M., Claudon, M., Miossec C., Black M.T. In vitro activity of the beta-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases, Journal of Antimicrobial Chemotherapy (2009) 64 (2), 326-329.


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