Optimizing dosing of nitrofurantoin from a PK/PD point of view: What do we need to know?

Wijma, Rixt A.; Fransen, Fiona; Muller, Anouk E.; Mouton, Johan W.

doi:10.1016/j.drup.2019.03.001

Cited by 19 publications

(17 citation statements)

References 63 publications

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“…Similar to fosfomycin, aminopenicillins achieve high urinary concentrations and have been reported to overcome the resistance mechanisms in enterococci and provide a therapeutic option, despite a laboratory report of nonsusceptibility (36,37). Nitrofurantoin is another active oral antimicrobial option, although activity is largely limited to E. faecalis isolates (38)(39)(40). Other oral options, albeit with limitations, include linezolid (toxicity risk), quinupristin-dalfopristin (E. faecium only), nitroxoline (not widely available), newer fluoroquinolones (moxifloxacin, gatifloxacin, gemifloxacin; toxicity risk) and doxycycline (effective in the setting of high urinary concentrations; synergy reported in combination with fosfomycin) (19,39,(41)(42)(43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model

Abbott

Gorp

Meijden

et al. 2020

Antimicrob Agents Chemother

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There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC50/90 32/64 μg/ml; E. faecium MIC50/90 64/128 μg/ml). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log10 CFU/ml; E. faecalis 8.0 ± 1.0 log10 CFU/ml). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and after two doses given over two days with low urinary concentration exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log10 kill from the starting inoculum compared with E. faecium. The ƒAUC0-72/MIC and ƒ%T > MIC0-72 for E. faecalis were 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC postexposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log10 kill) in the majority of isolates.

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Section: Discussionmentioning

confidence: 99%

Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model

Abbott

Gorp

Meijden

et al. 2020

Antimicrob Agents Chemother

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“…Then, rotenone (5 μM), paraquat (500 μM), or a damaging concentration of NFT (125 μM) were added for 24 h. Viability was assessed by the resazurin reduction assay, cell homogenates were assessed for their glutathione content. Differences were tested for significance by two-way ANOVA (pretreatment vs. w/o pretreatment for individual NFT or paraquat concentrations), followed by a Bonferroni's post hoc test *p < 0.05 were reported to be in the range of 1-15 μM (Novelli and Rosi 2017;Wijma et al 2019). To our knowledge, tissue NFT concentrations have not yet been determined in specific human organs.…”

Section: Activation Of Antioxidant Responses By Nrf2mentioning

confidence: 99%

Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes

et al. 2021

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Toxicity is not only a function of damage mechanisms, but is also determined by cellular resilience factors. Glutathione has been reported as essential element to counteract negative influences. The present work hence pursued the question how intracellular glutathione can be elevated transiently to render cells more resistant toward harmful conditions. The antibiotic nitrofurantoin (NFT) was identified to stimulate de novo synthesis of glutathione in the human hepatoma cell line, HepG2, and in primary human hepatocytes. In intact cells, activation of NFT yielded a radical anion, which subsequently initiated nuclear-factor-erythroid 2-related-factor-2 (Nrf2)-dependent induction of glutamate cysteine ligase (GCL). Application of siRNA-based intervention approaches confirmed the involvement of the Nrf2-GCL axis in the observed elevation of intracellular glutathione levels. Quantitative activation of Nrf2 by NFT, and the subsequent rise in glutathione, were similar as observed with the potent experimental Nrf2 activator diethyl maleate. The elevation of glutathione levels, observed even 48 h after withdrawal of NFT, rendered cells resistant to different stressors such as the mitochondrial inhibitor rotenone, the redox cycler paraquat, the proteasome inhibitors MG-132 or bortezomib, or high concentrations of NFT. Repurpose of the antibiotic NFT as activator of Nrf2 could thus be a promising strategy for a transient and targeted activation of the endogenous antioxidant machinery.

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“…These results indicated that the 30 mg/kg per oral administration in the current study might induce a sufficiently high concentration to kill T. congolense in the bloodstream. The pharmacokinetic parameters of orally administered NF (50–300 mg/head) in humans were as follows: C max , 0.21–3.7 µg/mL; T max , 0.5–5.0 h; and t 1/2 , 0.9–6.3 h [ 37 , 38 ]. Our previous in vitro study showed that the IC 50 s against other trypanosomes (except T. congolense ) were higher than 300 ng/mL (0.3 µg/mL) [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of Orally Administered Nitrofurantoin against Animal African Trypanosomosis Caused by Trypanosoma congolense Infection

et al. 2022

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Animal African trypanosomosis (AAT) leads to emaciation and low productivity in infected animals. Only six drugs are commercially available against AAT; they have severe side effects and face parasite resistance. Thus, the development of novel trypanocidal drugs is urgently needed. Nitrofurantoin, an antimicrobial, is used for treating bacterial urinary tract infections. Recently, we reported the trypanocidal effects of nitrofurantoin and its analogs in vitro. Furthermore, a nitrofurantoin analog, nifurtimox, is currently used to treat Chagas disease and chronic human African trypanosomiasis. Thus, this study was aimed at evaluating the in vivo efficacy of nitrofurantoin in treating AAT caused by Trypanosoma congolense. Nitrofurantoin was orally administered for 7 consecutive days from 4 days post-infection in T. congolense-infected mice, and the animals were observed for 28 days. Compared to the control group, the treatment group showed significantly suppressed parasitemia at 6 days post-infection. Furthermore, survival was significantly prolonged in the group treated with at least 10 mg/kg nitrofurantoin. Moreover, 100% survival and cure was achieved with a dose of nitrofurantoin higher than 30 mg/kg. Thus, oral nitrofurantoin administration has potential trypanocidal efficacy against T. congolense-induced AAT. This preliminary data will serve as a benchmark when comparing future nitrofurantoin-related compounds, which can overcome the significant shortcomings of nitrofurantoin that preclude its viable use in livestock.

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Optimizing dosing of nitrofurantoin from a PK/PD point of view: What do we need to know?

Cited by 19 publications

References 63 publications

Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model

Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model

Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes

Therapeutic Efficacy of Orally Administered Nitrofurantoin against Animal African Trypanosomosis Caused by Trypanosoma congolense Infection

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