Nabriva Therapeutics AG, a biotechnology company focused on developing pleuromutilins, a new class of antibiotics for treatment of serious infections caused by resistant pathogens, announces that three posters will be presented on the Extended Spectrum Pleuromutilins (ESP) Program and one poster on lefamulin, its lead pleuromutilin antibiotic product candidate, at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2015) in Copenhagen on 25th April 2015 at 3.30pm CET.
Nabriva’s lead product candidate, lefamulin (BC‑3781), is the first systemically available pleuromutilin for human use and is expected to enter Phase 3 clinical studies for the treatment of community acquired bacterial pneumonia (CABP) in the second half of 2015. Lefamulin possesses potent in vitro activity against the most common pathogens associated with CABP, specifically S. pneumoniae, H. influenzae, S. aureus, M. pneumoniae, L. pneumophila, and C. pneumoniae, including multi-drug resistant strains.
The Extended Spectrum Pleuromutilins (ESPs) are a new generation of antibacterials possessing in vitro activity against urgent and serious bacterial threats identified by the Centers for Disease Control and Prevention (CDC) including carbapenem-resistant E. coli and K. pneumonia (CRE), while maintaining the antimicrobial spectrum of lefamulin. As such, the ESPs represent much needed development of a novel class of antimicrobials, with a novel mechanism of action, directed at addressing this significant unmet medical need.
Dr Colin Broom, Chief Executive Officer of Nabriva, commented: “The rapid spread of multi-drug resistance is a growing global public health threat and the development of new antibiotics with a novel mechanism of action against these pathogens is critically important. Lefamulin is currently in late-stage development for intravenous and oral administration and its profile is well suited for the treatment of community-acquired bacterial pneumonia. We look forward to initiating our Phase 3 development program later this year."
Dr Werner Heilmayer, Vice President Research at Nabriva, noted: “Our new generation of pleuromutilin antibiotics – the Extended Spectrum Pleuromutilins (ESPs) – have shown potent activity against Gram-negative and Gram-positive bacterial pathogens including multi-drug resistant E. coli, S. aureus, K. pneumoniae, and S. pneumoniae. These ESPs offer potential as new, and much needed effective treatment options for serious and life threatening infections.”
The four posters are as follows:
Antimicrobial potency of lefamulin (BC-3781) tested against Streptococcus pneumoniae with defined serotypes, including multidrug-resistant isolates causing lower respiratory tract infections in the United States
R.E. Mendes, R.K. Flamm, R.N. Jones, H.S. Sader, G.H. Talbot, S. Paukner, Z. Ivezic-Schoenfeld, D.J. Farrell
This study evaluated the in vitro activity of the investigational systemic pleuromutilin, lefamulin (BC-3781), tested against specific serotypes of S. pneumoniae clinical isolates responsible for lower respiratory tract infections in the USA. These data support the development of lefamulin, currently in late-stage development, for intravenous and oral administration for the treatment of community-acquired bacterial pneumonia (CABP).
Efficacy of Novel Extended Spectrum Pleuromutilins against E. coli In Vitro and In Vivo
Wicha W.W., Paukner S., Strickmann D.B., Thirring K., Kollmann H., Heilmayer W., Ivezic-Schoenfeld Z.
Among the resistant bacterial pathogens causing serious infections, E. coli is one of the most worrisome since multi-drug resistant strains continue to emerge leaving no viable treatment options. The Extended Spectrum Pleuromutilins (ESP) were evaluated for their in vitro activity against E. coli (n = 32) including 78.1 % ESBL (TEM, CTX-M) producing strains by broth microdilution according to CLSI (M7/A9). For evaluation of the metabolic stability and cytotoxicity, primary human hepatocytes were used. The therapeutic potency of the ESP in vivo was evaluated in a lethal murine sepsis model.
The potent in vitro activity of four new ESP derivatives (BC-7634, BC-9074, BC-9529 and BC-9563) demonstrated in this study, which is unaffected by the production of ß-lactames, could be translated into good in vivo efficacy. The potent efficacy, high metabolic stability and low potential for cytotoxicity warrant the further development of ESP for the treatment of serious infections caused by E. coli.
In Vitro and In Vivo Efficacy of Novel Extended Spectrum Pleuromutilins against S. aureus and S. pneumoniae
Paukner S., Wicha W.W., Thirring K., Kollmann H., Ivezic-Schoenfeld Z.
Resistance development to antibiotics is a growing public health threat worldwide. In Europe particularly, the resistance of E. coli and K. pneumoniae against cephalosporins, fluoroquinolones and aminoglycosides has increased significantly while the percentage of MRSA has been decreasing during the last few years. Nevertheless, MRSA remains one of the most frequent causes of antibiotic-resistant healthcare-associated infections worldwide (ECDC, 2013). The recently discovered extended spectrum pleuromutilins (ESPs) address this problem by being active against Gram-negative and -positive bacteria.
This study confirmed the potent in vitro activity of four novel ESP derivatives (BC-7634, BC-9074, BC-9529, and BC-9563) against S. aureus (MSSA, CA-MRSA) and S. pneumoniae including multi-resistant isolates. Furthermore in the S. aureus bacteremia model all selected ESPs showed good in vivo efficacy when compared to the standard antibiotics linezolid and tigecycline. These proof-of-concept studies warrant the further development of ESP since the antibacterial spectrum does not only cover resistant Enterobacteriaceae but ESPs additionally demonstrate potent activity against Gram-positive pathogens.
Kill Curves of the Novel Extended Spectrum Pleuromutilin Antibiotic BC-9529
Paukner S., Kollmann H., Riedl R., Ivezic-Schoenfeld Z.
This study investigated the antibacterial activity and bactericidal properties of the novel investigative ESP derivative BC‑9529 against E. coli, K. pneumoniae and S. aureus. The novel ESP BC-9529 demonstrated good antibacterial activity against highly resistant bacterial pathogens including ESBL and carbapenemase-producing Enterobacteriaceae and CA-MRSA. Furthermore, BC-9529 demonstrated rapid bactericidal activity against E. coli and K. pneumoniae whereas it appeared to be bacteriostatic against S. aureus. The bactericidal effect of BC‑9529 on E. coli was comparable to that of moxifloxacin. The potent antibacterial and bactericidal activity against both, E. coli and K. pneumoniae are attractive qualities in the overall potent antibacterial profile, which might lead to potential future treatment options against serious infections caused by these pathogens.