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Published on: June 24, 2025
Pharmacodynamics of nitrofurantoin at different pH levels against pathogens involved in urinary tract infections
Fiona Fransen1,2, Maria J B Melchers1,2, Claudia M C Lagarde1,2
1Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Background:
Urinary tract infections are among the most common human infections. Due to the progressive increase in ESBL-producing bacteria and the unavailability of new antibiotics, re-evaluation of 'old' antibiotics is needed. However, the pharmacodynamics of nitrofurantoin under variable pH conditions are poorly understood. We determined the pharmacodynamic properties of nitrofurantoin at different pH levels using time-kill assays.
Methods:
Time-kill assays were performed at four pH levels (5.5, 6.5, 7.5 and 8.5), exposing the bacteria to 2-fold increasing concentrations from 0.125 to 32 times the MIC. Seven ESBL-positive and two ESBL-negative strains (MICs 8-32 mg/L) were used. The Δlog10 cfu/mL values at 6 and 24 h were plotted against each log10-transformed concentration and analysed with non-linear regression analysis using the sigmoid maximum effect model with variable slope. Geometric means normalized by the MIC of the EC50, stasis and 1 and 3 log10 cfu/mL kill were calculated.
Results:
Minimum bactericidal effects differed significantly by species and pH level. At pH 5.5-6.5 bactericidal effects were observed at ≥ 0.5 × MIC for Escherichia coli and Enterobacter cloacae. At pH 8.5 only the two highest concentrations were considered bactericidal. Strong pH-dependent pharmacodynamic output parameters were observed in 6 h and especially 24 h modelling. At 24 h, pH 5.5-6.5 for E. coli and Klebsiella pneumoniae required significantly lower nitrofurantoin concentrations compared with pH 7.5 or 8.5. Although for E. cloacae similar strong decreasing trends were visible with decreasing pH, none of the tested pharmacodynamic parameters was significant.
Conclusions:
Nitrofurantoin bactericidal activity against Enterobacteriaceae significantly increases at lower pH levels. Bactericidal activity of nitrofurantoin may be overestimated or underestimated, which may have implications for therapy and the interpretation of clinical breakpoints.
Insights
Nitrofurantoin exhibits increased bactericidal activity against Enterobacteriaceae at lower pH levels. This pH-dependent activity may impact how nitrofurantoin therapy and clinical breakpoints are interpreted.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Urinary tract infections (UTIs) are common, with rising ESBL-producing bacteria necessitating re-evaluation of older antibiotics like nitrofurantoin.
- The pharmacodynamics of nitrofurantoin, particularly its efficacy under varying urinary pH conditions, remain poorly understood.
- Understanding nitrofurantoin's pH-dependent activity is crucial for optimizing UTI treatment strategies.
Purpose of the Study:
- To determine the pharmacodynamic properties of nitrofurantoin at different pH levels.
- To investigate the impact of pH on nitrofurantoin's bactericidal activity against ESBL-producing bacteria.
- To provide data for improved interpretation of nitrofurantoin's clinical efficacy and breakpoints.
Main Methods:
- Time-kill assays were conducted across four pH levels (5.5, 6.5, 7.5, 8.5) using ESBL-positive and ESBL-negative bacterial strains.
- Bacteria were exposed to a range of nitrofurantoin concentrations (0.125x to 32x MIC).
- Non-linear regression analysis using the sigmoid maximum effect model was employed to analyze bacterial killing at 6 and 24 hours.
Main Results:
- Nitrofurantoin's minimum bactericidal effects varied significantly by bacterial species and pH.
- At lower pH (5.5-6.5), bactericidal effects were observed at lower concentrations (≥0.5x MIC) for E. coli and E. cloacae.
- Significantly lower nitrofurantoin concentrations were required for bacterial killing at pH 5.5-6.5 compared to pH 7.5-8.5, especially for E. coli and K. pneumoniae at 24 hours.
Conclusions:
- Nitrofurantoin demonstrates significantly enhanced bactericidal activity against Enterobacteriaceae as urinary pH decreases.
- The pH-dependent activity of nitrofurantoin suggests that its efficacy may be overestimated or underestimated in clinical settings.
- These findings have implications for optimizing nitrofurantoin therapy and refining the interpretation of clinical breakpoints for UTIs.
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