Antimicrobial Susceptibility StudyIn vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent and molecularly characterized Pseudomonas aeruginosa isolates from a global surveillance program (2017–2018)
Introduction
Carbapenem-resistant and multidrug-resistant (Magiorakos et al., 2012) P. aeruginosa are recognized by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) as critical priority 1 and serious threat pathogens, respectively (WHO, 2017; CDC, 2019). Resistance to even the most recently approved antibacterials including ceftazidime-avibactam and ceftolozane-tazobactam has been observed in carbapenem-resistant and MDR P. aeruginosa (Sader et al., 2017; Shortridge et al., 2018). Therefore, new therapeutic treatment options developed from novel antibacterial targets are needed to overcome these preexisting resistance mechanisms. The bacterial LpxC enzyme and inhibition of Lipid A synthesis represents an attractive antibacterial target (Mdluli et al., 2006). KHP-3757 is the most recent LpxC inhibitor of the hydroxamate class currently being evaluated in preclinical development studies that demonstrates potent in vitro activity based on MIC values against Gram-negative bacterial species including Pseudomonas aeruginosa (Huband et al., 2019).
In this study, the in vitro antibacterial activity of KHP-3757 was examined against a collection of 116 P. aeruginosa isolates that included 93 contemporary (2017–2018), geographically diverse clinical isolates, 10 colistin-resistant isolates, 7 metallo-β-lactamase-positive (MBL; IMP, VIM, and NDM), and 6 extended-spectrum β-lactamase-positive (ESBL; GES, PER, PME, SHV, and VEB) isolates.
Section snippets
Bacterial strains tested
Pseudomonas aeruginosa (n = 116) were selected primarily from the United States and Europe from a collection of 7274 SENTRY Surveillance Program isolates obtained from patients in 85 medical centers located in 20 countries including the United States (52 isolates chosen; 47 medical centers located in all 9 Census Divisions; 44.8% of overall selected isolates), Europe (63 isolates; 37 medical centers; 54.3% overall), and the Asia-Pacific region (1 isolate; 1 medical center; 0.9% overall).
Activity of KHP-3757 against Pseudomonas aeruginosa
KHP-3757 (MIC50/90, 0.25/0.5 mg/L; 97.4% inhibited at ≤0.5 mg/L) was the most potent agent tested based on MIC90 values against 116 P. aeruginosa isolates, including colistin-resistant, ESBL-positive, and MBL-positive strains (Table 1, Table 2). Except for colistin (MIC50/90, 0.5/2 mg/L; −%/91.4% susceptible [S] [CLSI/EUCAST]), P. aeruginosa susceptibility rates (CLSI/EUCAST) for the comparator agents were all less than 90%. Susceptibility for amikacin, ceftazidime, ciprofloxacin, meropenem,
Discussion
LpxC inhibitors with potent in vitro activity against susceptible and MDR P. aeruginosa isolates including ACHN-495, CHIR-090, and PF-05081090 have been described previously (Andresen, 2003; Badal et al., 2013; Castanheira et al., 2013; Tomaras et al., 2014; Erwin, 2016; Krause et al., 2019). In those previous studies the in vitro activity of PF-05081090 against P. aeruginosa isolates was shown to result in a MIC90 of 1 mg/L (Tomaras et al., 2014) and for ACHN-975 to be 0.25 mg/L (Krause et
Conclusions
KHP-3757 represents a novel LpxC inhibitor with potent in vitro antibacterial activity (based on MIC values) against recent, geographically diverse, and molecularly characterized P. aeruginosa isolates, including ESBL-positive, MBL-positive, and colistin-R strains that have recently begun to emerge (Delaware Health and Social Services, Division of Public Health, 2014; Shortridge et al., 2019). Additional preclinical development studies with KHP-3757 including in vitro time-kill, resistance
Author disclosure statement
This study was performed by JMI Laboratories and supported by KBP Biosciences Co., Ltd. which included funding for services related to preparing this manuscript.
JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea Pharmaceutica Ltd.,
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