AUTHOR=Wei Yanzhe , Ji Xuan , Zhang Fuhui , Zhang Suiling , Deng Qin , Ding Huanzhong 

TITLE=PK-PD integration of enrofloxacin and cefquinome alone and in combination against Klebsiella pneumoniae using an in vitro dynamic model

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1226936

DOI=10.3389/fphar.2023.1226936

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold><italic>Klebsiella pneumoniae</italic> is classified as a critical pathogen in both animals and humans and infections can be fatal in chickens resulting in substantial economic losses. However, the misuse of antibiotics can also lead to drug resistance and a potential transmission chain between animals and humans. Three <italic>K. pneumoniae</italic> strains with different susceptibility phenotypes were chosen to study the pharmacokinetic/pharmacodynamic (PK/PD) integration of enrofloxacin (ENR) and cefquinome (CEQ) alone and in combination.</p><p><bold>Results:</bold> Checkerboard assay results indicated that the combination treatment for type strain ATCC 700603 was synergistic effect with a fractional inhibitory concentration index (FICI) of ≤0.5. The other two clinical strains demonstrated an additive effect (FICI &gt;0.5 to ≤1). Furthermore, static time-kill curves indicated that enrofloxacin and cefquinome added singly were effective in killing <italic>K. pneumoniae</italic> at concentrations of &gt;2 MIC and ≥1 MIC, respectively. Additionally, the combination of enrofloxacin and cefquinome led to an enhanced antibacterial activity of cefquinome. The dynamic time-kill curves indicated that enrofloxacin and cefquinome had bactericidal and bacteriostatic activities, respectively at ≥1.5 mg/L (single-dose) and 4 mg/L (8 h split-dose) causing a decrease in bacterial counts of ≥4.45 and &gt;2 log<sub>10</sub> CFU/mL. Enrofloxacin possessed no bacteriostatic effects against <italic>K. pneumoniae</italic> at a constant concentration of 1× MIC. Cefquinome used in combination with 1× MIC enrofloxacin exhibited bactericidal activity at ≥4 mg/L (12 h split-dose) with reductions of ≥3.65 log<sub>10</sub> CFU/mL. The PK/PD parameters were also analyzed to determine the concentration and duration of the drugs needed to reduce bacteria by 3 log<sub>10</sub> CFU/mL. For enrofloxacin alone, the AUC<sub>24</sub>h/MIC was 23.29 h and the C<sub>max</sub>/MIC was 3.18. For cefquinome alone, the %T &gt; MIC was 48.66 and when used in combination with enrofloxacin was 18.04. The combined use of cefquinome and enrofloxacin can increase the antibacterial activity of cefquinome against <italic>K. pneumoniae</italic> under a 12-h split-dose regimen regardless of individual drug susceptibility.</p><p><bold>Discussion:</bold> The static and dynamic time-kill curves indicated that enrofloxacin exhibited concentration-dependent activity, while cefquinome exhibited time-dependent activity. In the <italic>in vitro</italic> dynamic model, enrofloxacin alone exhibited better antimicrobial effects against <italic>K. pneumoniae</italic> compared to cefquinome alone. However, the antibacterial effect of cefquinome can be enhanced by combining it with enrofloxacin. These findings suggest a potentially effective approach for combating <italic>K. pneumoniae</italic> infections.</p>