Broad-spectrum, orally bioavailable -lactam antibiotics play a critical role in the management of human infectious diseases, both in the hospital and community settings, facilitating exit from the ICU and treatment in the general ward, early discharge and/or prevention of hospitalization. The rapid spread of -lactamase-driven resistance in Enterobacteriaceae in both the hospital and community settings is regarded as an emerging healthcare crisis. The only orally bioavailable protected -lactam, amoxicillin-clavulanic acid (Augmentin), discovered over 3 decades ago, is ineffective against these new resistance enzymes (for example, Class A carbapenemases (KPC-type), Class C cephalosporinases). Under the auspices of a separate SBIR award, we have identified a broad-spectrum series of parenteral (i.v.) -lactamase inhibitors (BLIs) with activity that extends to Ambler Class A carbapenemases and Class C cephalosporinases. Prodrugs of an early prototype in the series demonstrated high oral bioavailability in mice and in vivo efficacy in combination with an oral cephalosporin in a lethal murine septicemia model of bacterial infection. This Phase I application endeavors to now marry the Proof of Concept of the earlier prototype work to the more recently optimized parenteral compounds in order to further extend the utility of these BLIs to the oral settings (hospital step-down and community use). Successful realization of this goal would be expected to have a significant medical (treatment success) and health-economic impact (avoidance of hospitalization cost and risk of hospital-acquired infection).
Ambler Class A carbapenemases and Class C cephalosporinases are spreading throughout Enterobacteriaceae and pose a serious threat to -lactam efficacy in both the hospital and community settings. The only orally bioavailable -lactam/-lactamase inhibitor combination on the market, Amoxicillin/Clavulanate, is ineffective against these new resistant strains. The combination therapies proposed in this Application, including a novel, broad-spectrum, orally bioavailable -lactamase inhibitor, will directly address this emerging healthcare crisis.