Activity of the Novel Aminomethylcycline KBP-7072 and Comparators against 1,057 Geographically Diverse Recent Clinical Isolates from the SENTRY Surveillance Program, 2019

ABSTRACT KBP-7072 is a novel broad-spectrum tetracycline (aminomethylcycline) antibacterial in clinical development (oral and intravenous formulations) for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and complicated intra-abdominal infections. KBP-7072 is active against many of the World Health Organization priority pathogens. In this study, KBP-7072 and tetracycline class comparators were susceptibility tested against 1,057 geographically diverse surveillance isolates from 2019 according to Clinical and Laboratory Standards Institute (CLSI) guidelines. KBP-7072 demonstrated potent in vitro activity against Gram-positive and Gram-negative bacterial pathogens. KBP-7072 was active against Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/liter), methicillin-resistant S. aureus (MIC50/90, 0.06/0.12 mg/liter), S. lugdunensis (MIC50/90, 0.03/0.03 mg/liter), and other coagulase-negative staphylococci (MIC50/90, 0.06/0.25 mg/liter). KBP-7072 was active against Enterococcus faecalis (MIC50/90, 0.03/0.06 mg/liter) and vancomycin-susceptible and -nonsusceptible E. faecium (MIC50/90, 0.03/0.03 mg/liter); Streptococcus pneumoniae (MIC50/90, ≤0.015/0.03 mg/liter), including penicillin- and tetracycline-resistant strains; S. agalactiae (MIC50/90, 0.03/0.06 mg/liter), including macrolide-resistant strains; S. pyogenes (MIC50/90, 0.03/0.03 mg/liter); and viridans group streptococci, including S. anginosus group (MIC50/90, ≤0.015/0.03 mg/liter) isolates. KBP-7072 inhibited 90.2% (MIC50/90, 0.25/2 mg/liter) of all Enterobacterales isolates, including expanded-spectrum β-lactamase-phenotype strains at ≤2 mg/liter. KBP-7072 demonstrated potent activity against Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates (MIC50/90 values, 0.5/1 mg/liter), Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/liter; 100.0% inhibited at ≤0.25 mg/liter), and Moraxella catarrhalis (MIC50/90, 0.06/0.06 mg/liter). Based on MIC90 values, KBP-7072 in vitro activity was generally superior to that the other tetracycline class comparators tested. The potent activity of KBP-7072, including resistant organism groups, merits further clinical investigation in infections where these organisms are likely to occur.

KBP-7072 exhibits potent in vitro antibacterial activity against many of the organisms listed on the World Health Organization (WHO) priority pathogen list, including methicillin-resistant Staphylococcus aureus, penicillin-nonsusceptible Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecium, ampicillin-resistant Haemophilus influenzae, and carbapenem-resistant Acinetobacter baumannii (6,7,14). In the present study, we evaluated the in vitro antimicrobial activity of KBP-7072 and comparator agents against 1,057 isolates of Gram-positive cocci and Gram-negative bacilli collected in 2019 from 117 medical centers located in 35 countries as a part of the SENTRY Antimicrobial Surveillance Program. When available, evaluations of resistant organism subsets were also included for specific pathogen groups.

RESULTS
Overall activity of KBP-7072. Cumulative percent inhibition and MIC 50 /MIC 90 data for KBP-7072 against 1,057 recent geographically diverse organisms and organism groups are detailed in Table 1. KBP-7072 and comparator agent susceptibility data, including MIC range, MIC 50/90 , percent susceptible (S), percent intermediate (I), and percent resistant (R) according to CLSI or FDA breakpoint interpretive criteria, are presented in Tables 2 and 3 Table 2).

DISCUSSION
The WHO has defined which resistant organism groups should be prioritized to help guide the discovery and development of new antibacterial agents (14). Of these, carbapenem-resistant A. baumannii and Enterobacteriaceae were identified as priority 1 (critical) pathogens, vancomycin-resistant E. faecium and MRSA were identified as priority 2 (high) pathogens, and ampicillin-resistant H. influenzae and penicillin-nonsusceptible S. pneumoniae were identified as priority 3 (medium) pathogens (14). The WHO also stressed the importance of orally active agents for the treatment of ESBLproducing Enterobacteriaceae (14). Few therapeutic options are available for some infections, such as those caused by carbapenem-resistant A. baumannii and multidrugresistant organisms (15)(16)(17).
The in vitro activity of KBP-7072 was unaffected by isolates displaying resistance to tetracycline. KBP-7072 remained active against isolates displaying resistance to other antibacterial agents, including ampicillin, ceftazidime, erythromycin, penicillin, and vancomycin.
The potent in vitro activity of KBP-7072 against A. baumannii is also supported by a prior study using 531 isolates that included carbapenem-resistant, colistin-resistant, ESBL-positive, metallo-b-lactamase-producing, and tetracycline-resistant strains (6).
In summary, KBP-7072 demonstrated potent in vitro activity against a collection of 1,057 recent geographically diverse clinical isolates, including staphylococci, streptococci, enterococci, Enterobacteriaceae, H. influenzae, A. baumannii, S. maltophilia, and drug-resistant organisms and organism groups. This study supports the continued clinical development of KBP-7072 in serious infections, including those caused by drug-resistant organisms.