Abstract
Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (Cmax) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67–26.10 mg·h/L, and elimination half-life (T1/2) 0.8–1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25–80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25–160 mg/kg, every 24 h) were conducted. The sigmoid Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.
Highlights
Nemonoxacin is a novel nonfluorinated quinolone with potent antibacterial effect against Gram-positive cocci and Gram-negative bacilli, including atypical pathogens penicillin-resistant Streptococcus pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus (MRSA) (Adam et al, 2009; Chen et al, 2009; Lauderdale et al, 2010; Li et al, 2010)
The minimum inhibitory concentration (MIC) values of nemonoxacin against six S. pneumoniae isolates used in this study are shown in Table 1, ranging from 0.125 to 0.25 mg/L
Using a neutropenic murine lung infection model, our study determined the magnitudes of fAUC0-24/MIC of nemonoxacin associated with various levels of bacterial reduction for S. pneumoniae strains
Summary
Nemonoxacin is a novel nonfluorinated quinolone with potent antibacterial effect against Gram-positive cocci and Gram-negative bacilli, including atypical pathogens penicillin-resistant Streptococcus pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus (MRSA) (Adam et al, 2009; Chen et al, 2009; Lauderdale et al, 2010; Li et al, 2010). Nemonoxacin is indicated for community-acquired pneumonia (CAP), and clinical trials demonstrated its good clinical and microbiological efficacy by oral administration of 500 mg once daily for 7 to 10 consecutive days (Guo et al, 2012; Liu et al, 2017; Yuan et al, 2019). This new antibiotic was approved in China in 2016, its approved label gived an initial breakpoint S ≤ 1 mg/L for the definition of susceptible S. pneumoniae strains. In vivo PK/PD study in an animal infection model has become an important basis for the establishment of PK/ PD breakpoints due to its flexible experimental design and similar target results to that in humans (Mouton et al, 2012; Nielsen and Friberg, 2013; Vinks et al, 2014)
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