Pharmacodynamics and differential activity of nitrofurantoin against ESBL-positive pathogens involved in urinary tract infections.
Although nitrofurantoin has been used for >60 years for the treatment of uncomplicated urinary tract infections, its pharmacodynamic properties are not fully explored. Use is increasing because of increasing resistance to other antimicrobials due to ESBLs.



We tested nine ESBL+ and two ESBL- strains in time-kill assays. Bactericidal activity and regrowth were assessed for all species and concentrations. Early-phase pharmacodynamics was analysed with a sigmoidal Emax model and the maximal killing rate, slope and EC50/MIC ratio were determined for each species.



A bactericidal effect was found at ≥2× MIC for Enterobacter cloacae after 4-8 h, for Klebsiella pneumoniae after 8-10 h and for Escherichia coli after 12-16 h. Overall, no killing was observed at low sub-MIC concentrations, whereas regrowth was found at 0.5-1× MIC after a short decline in cfu. The lowest maximal killing rates were observed for E. coli (0.21 ± 0.05 h(-1)), followed by K. pneumoniae (0.37 ± 0.09 h(-1)) and E. cloacae (0.87 ± 0.01 h(-1)). Surprisingly, the Hill slopes for these three species were significantly different (10.45 ± 9.37, 2.68 ± 0.64 and 1.01 ± 0.06, respectively), indicating a strong concentration-dependent early-phase antibacterial activity against E. cloacae. EC50/MIC ratios were significantly lower for E. coli (0.24 ± 0.08 mg/L) and K. pneumoniae (0.27 ± 0.03 mg/L) as compared with E. cloacae (0.77 ± 0.18 mg/L).



Nitrofurantoin was bactericidal against all species, demonstrating an unusual differential pattern of activity with concentration-dependent-type killing behaviour against E. cloacae and time-dependent killing behaviour against E. coli, which may have significant consequences on species-dependent dosing regimens. The results also demonstrate that the pharmacodynamic properties of some drugs cannot be generalized within a family, here the Enterobacteriaceae.
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands fionafransen@gmail.com.
Fiona
F
Fransen
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Maria J B
MJ
Melchers
Clinical Microbiology Laboratory, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Joseph
J
Meletiadis
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Johan W
JW
Mouton
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000892:Anti-Infective Agents, Urinary / Q000494:pharmacology*; D016972:Enterobacter cloacae / Q000187:drug effects; D004755:Enterobacteriaceae / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009582:Nitrofurantoin / Q000493:pharmacokinetics / Q000494:pharmacology*; D014552:Urinary Tract Infections / Q000382:microbiology*; D001618:beta-Lactamases / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000892:Anti-Infective Agents, Urinary; D009582:Nitrofurantoin; D001618:beta-Lactamases