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Background/Objectives: We aimed to assess the prevalence and risk factors for acquisition of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) in children admitted with urinary tract infection (UTI) at a tertiary university hospital in Saudi Arabia, as well as to investigate antibiotic resistance patterns. Methods: This retrospective cross-sectional study involved hospitalized children aged 0–14 years from January 2018 to December 2022 with urine cultures that grew E. coli or ESBL-producing E. coli. Data of the antimicrobial susceptibility for isolated bacteria were collected. Results: This study analyzed 242 urine samples obtained from 119 children with E. coli UTIs. Of these, 20.7% (n = 50) were ESBL producers. Previous antibiotic use (last 3 months), prophylactic antibiotic use, prior UTI (last 3 months), recurrent UTIs, and underlying co-morbidities (p = 0.011, <0.001, 0.025, <0.001, and 0.013, respectively) had a significant relationship with increased risk of ESBL E. coli UTIs. Generally, the highest resistance rates in the ESBL-producing isolates were for ampicillin and third-generation cephalosporin. Conversely, all ESBL-positive isolates were sensitive to meropenem, with variable resistance rates to other antibiotics as amikacin, nitrofurantoin, quinolones and trimethoprim/sulfamethoxazole (2%, 8%, 56% and 64%, respectively). Conclusions: There is a high prevalence of ESBL production among children hospitalized with E. coli UTIs. Addressing ESBL UTI risk factors helps to recognize high-risk cases and enhance proper antibiotic use. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) constitute one of the main complications in kidney recipients, increasing both morbidity and mortality. Due to the resurgence of antimicrobial resistance, new prophylactic approaches are being investigated. Nitrofurantoin is an antibiotic from the nitrofuran group that is effective against several Gram-negative and Gram-positive organisms; hence, there has been a resurgence in its prescription for treating MDR pathogens. Objectives: This study aims to assess the effectiveness of nitrofurantoin as an add-on to conventional therapy (amikacin + ceftriaxone or cefotaxime) for the treatment of urinary tract infections in kidney recipients. Methods: In a prospective cohort study, we included patients who received a kidney in a tertiary-care hospital. According to the intensive care specialist, group 1 patients were treated with the conventional prophylactic treatment plus nitrofurantoin as an add-on. Group 2 patients were treated only with the conventional prophylactic treatment. They were followed-up for 3 months, and the incidence of urinary tract infections was reported. Results: The UTI incidence for group 1 at 3 months was 20.6%, and for group 2, it was 20.0%; no statistical difference between treatments was observed (p = 0.9). The most commonly isolated pathogens were E. coli (28.5) and K. pneumonie (28.5%). The factor most associated with developing a UTI was female gender (aHR: 7.0; 95% IC 2.3–20.9, p < 0.001). Conclusions: In our cohort study, nitrofurantoin as an add-on in conventional therapy did not prove to be effective in preventing UTI development; therefore, other treatment options should be considered as a part of prophylactic treatment. [ABSTRACT FROM AUTHOR]

The aim of this study is to assess and analyze the intratubular penetration of the intracanal medications nitrofurantoin (Nit), triple antibiotic paste (TAP), and calcium hydroxide (CH). Sixty freshly extracted single-rooted teeth were acquired and decoronated to a standard length of 15 mm. To prepare specimens up to size F3, rotary ProTaper instrumentation was employed. The prepared teeth were divided into three groups, each of which received one of the tested intracanal medicaments: Group I (calcium hydroxide), Group II (triple antibiotic paste), and Group III (nitrofurantoin). Using a size #30 Lentulo spiral, a freshly prepared therapeutic paste was placed into the canals, and the intracanal medicaments were allowed to set in the incubator at 100% humidity. The samples were subsequently sliced perpendicularly to their long axis using a precision saw and assessed under a scanning electron microscope to assess the depth of penetration of intracanal medicaments at the coronal, middle, and apical portions of the root canal dentin. The data were analyzed using one-way ANOVA and Tukey's post hoc test. The statistical analysis revealed a significant difference between the experimental groups in the quantity and depth of sealer penetration (p < 0.05). In particular, as compared to the Nit group, both the CH and TAP groups had significantly smaller penetration areas (p < 0.05). In conclusion, this ongoing investigation indicates that nitrofurantoin penetrated dentinal tubules better than calcium hydroxide or triple antibiotic paste. [ABSTRACT FROM AUTHOR]

Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR. [ABSTRACT FROM AUTHOR]

The treatment of urinary tract infections is usually empirical. For example, nitrofuran derivatives, mainly nitrofurantoin (but also furazidin), are used in Eastern Europe. A significant problem is the assessment of the usefulness of furazidin, as there are no standards for susceptibility testing. Additionally, a high percentage of strains resistant to nitrofurantoin should prompt caution when choosing furazidin in therapy. This study aimed to answer the question of whether it is possible to use nitrofurantoin susceptibility for furazidin drug susceptibility analyses and if there is any cross-resistance in the nitrofuran derivatives group. One hundred E. coli clinical isolates, obtained from the Central Teaching Hospital of the Medical University of Lodz, were cultured from positive urine samples. For susceptibility testing, microdilution and disk diffusion methods, following EUCAST guidelines, were used. The results showed that the MICs of furazidin were equal to or lower than those of nitrofurantoin in 89% of the tested strains. The MIC50/90 values for furazidin were two times lower than those for nitrofurantoin. Positive correlations were found between MICs and growth inhibition zones for both antibiotics. Based on the obtained data and previous studies, it was assumed that the transfer of susceptibility testing results from nitrofurantoin to furazidin is acceptable due to cross-resistance in nitrofuran derivatives. [ABSTRACT FROM AUTHOR]

Thirty-four binary systems of nitrofurantoin with pyridine derivatives were analyzed by combining virtual (molecular complementarity prediction and hydrogen bond propensity calculations) and experimental (liquid-assisted grinding) screening methods. A new modification of the hydrogen bond propensity calculation method (the integrated hydrogen bond propensity calculation method) with significantly improved virtual screening efficiency was proposed. Novel cocrystals of nitrofurantoin with 3-aminopyridine and 2-(1H-Imidazol-2-yl)pyridine were discovered. The crystal structures of the new cocrystals were determined from single-crystal X-ray diffraction data, and the hydrogen bond patterns were studied in conjunction with the Molecular Electrostatic Potential maps of the components. The nitrofurantoin cocrystal with 3-aminopyridine was found to exist in two polymorphic modifications. The origins of the different stability of the polymorphic forms were rationalized both in terms of total lattice enthalpy and free energy derived from periodic DFT-D3 calculations and in terms of the non-covalent interaction energy distribution in crystal. [ABSTRACT FROM AUTHOR]

A new Ni coordination polymer [Ni(MIP)(BMIOPE)]n (1) was constructed (BMIOPE = 4,4′-bis(2-methylimidazol-1-yl)diphenyl ether, and H2MIP = 5-methylisophthalic acid), possessing two-dimensional (2D) twofold parallel interwoven net structure with a 44∙62 point symbol. Complex 1 has been successfully obtained based on mixed-ligand strategy. The fluorescence titration experiments revealed that complex 1 could act as multifunctional luminescent sensor to simultaneously detect UO22+, Cr2O72− and CrO42−, and NFT (nitrofurantoin). The limit of detection (LOD) values for complex 1 are 2.86 × 10−5, 4.09 × 10−5, 3.79 × 10−5 and 9.32 × 10−5 M for UO22+, Cr2O72−, CrO42− and NFT. The Ksv values are 6.18 × 103, 1.44 × 104, 1.27 × 104 and 1.51 × 104 M−1 for NFT, CrO42−, Cr2O72− and UO22+. Finally, the mechanism of its luminescence sensing is studied in detail. These results manifest that complex 1 is a multifunctional sensor for sensitive fluorescent UO22+, Cr2O72−, CrO42− and NFT detection. [ABSTRACT FROM AUTHOR]

There are conflicting reports on the antibacterial activity of ascorbate; all at concentrations much higher than the typical in human plasma, but that can be reached in urine. The effect of 10 mM ascorbate (in itself not inhibitory) along with antibiotics, was tested both in Mueller-Hinton broth (MHb) and in synthetic human urine (SHU), against resistant isolates of Escherichia coli from lower urinary infections. The activity of nitrofurantoin and sulfamethoxazole was higher in SHU than in MHb; minimal inhibitory concentrations (MICs) in SHU with ascorbate were below typical urinary concentrations. For other antibiotics, MICs were the same in MHb vs. SHU, with no effect of ascorbate in MHb; but in SHU with ascorbate, MICs of ciprofloxacin and gentamicin also went below reported urinary concentrations, with a lesser effect with norfloxacin and trimethoprim, and none with ampicillin. The effect of ascorbate was independent of oxygen and not related to the susceptibility of each strain to oxidative stress. Ascorbate oxidizes during incubation in SHU, and bacterial growth partially prevented oxidation. These results suggest that 10 mM ascorbate can enhance the inhibitory activity of antibiotics upon resistant strains in urine. Clinical experimentation with ascorbate–antibiotic combinations against urinary infections caused by resistant bacteria is warranted. [ABSTRACT FROM AUTHOR]

In clinical practice in dogs and cats, antimicrobials are frequently used, sometimes overused or misused, increasing antimicrobial resistance (AMR). In order to limit the phenomenon, laws have been enacted and guidelines for prudent and rational use of antibiotics have been developed. Interestingly, old molecules such as nitrofurantoin could be used to achieve therapeutic success and overcome AMR. To better understand the suitability of this molecule in veterinary medicine, the authors performed a revision of the literature, searching on PubMed and entering the following keywords: nitrofurantoin, veterinary medicine, dog, and cat connected by the Boolean operator "and", without restrictions on the date of publication. Thirty papers were finally selected. It is possible to appreciate that papers dealing with nitrofurantoin have been written from the early 1960s to the middle of the 1970s, and then a long period passed without publications. Only at the beginning of the new century, nitrofurantoin was included or was sometimes the focus of papers dealing with its efficacy in veterinary medicine, mainly in the treatment of urinary tract infections. One recent paper dealt with pharmacokinetic features, and none was dedicated to pharmacokinetic/pharmacodynamic integration or modeling. Nitrofurantoin appears to be still effective against several pathogens that rarely develop resistance to this molecule. [ABSTRACT FROM AUTHOR]

Concern about zoonoses and wildlife has increased. Few studies described the role of wild mammals and environments in the epidemiology of Salmonella. Antimicrobial resistance is a growing problem associated with Salmonella that threatens global health, food security, the economy, and development in the 21st century. The aim of this study is to estimate the prevalence and identify antibiotic susceptibility profiles and serotypes of non-typhoidal Salmonella enterica recovered from non-human primate feces, feed offered, and surfaces in wildlife centers in Costa Rica. A total of 180 fecal samples, 133 environmental, and 43 feed samples from 10 wildlife centers were evaluated. We recovered Salmonella from 13.9% of feces samples, 11.3% of environmental, and 2.3% of feed samples. Non-susceptibility profiles included six isolates from feces (14.6%): four non-susceptible isolates (9.8%) to ciprofloxacin, one (2.4%) to nitrofurantoin, and one to both ciprofloxacin and nitrofurantoin (2.4%). Regarding the environmental samples, one profile was non-susceptible to ciprofloxacin (2.4%) and two to nitrofurantoin (4.8%). The serotypes identified included Typhimurium/I4,[5],12:i:-, S. Braenderup/Ohio, S. Newport, S. Anatum/Saintpaul, and S. Westhampton. The epidemiological surveillance of Salmonella and antimicrobial resistance can serve in the creation of strategies for the prevention of the disease and its dissemination throughout the One Health approach. [ABSTRACT FROM AUTHOR]

In this study, we compared the failure rates of fosfomycin and nitrofurantoin for uncomplicated urinary tract infections. We used Meuhedet Health Services' large database to collect data on all female patients, older than 18 years, who were prescribed either antibiotic during 2013–2018. Treatment failure was a composite endpoint of hospitalization, emergency-room visit, IV antibiotic treatment, or prescription of a different antibiotic, within seven days of the initial prescription. Reinfection was considered when one of these endpoints appeared 8–30 days following the initial prescription. We found 33,759 eligible patients. Treatment failure was more common in the fosfomycin group than the nitrofurantoin group (8.16% vs. 6.87%, p-value < 0.0001). However, reinfection rates were higher among patients who received nitrofurantoin (9.21% vs. 7.76%, p-value < 0.001). Among patients younger than 40 years, patients treated with nitrofurantoin had more reinfections (8.68% vs. 7.47%, p value = 0.024). Treatment failure rates were mildly higher in patients treated with fosfomycin, despite having less reinfections. We suggest that this effect is related to a shorter duration of treatment (one vs. five days) and encourage clinicians to be more patient before declaring fosfomycin failure and prescribing another antibiotic. [ABSTRACT FROM AUTHOR]

Chemotherapy still plays a central role in the treatment of cancer. However, it is often accompanied by off-target effects that result in severe side-effects and development of drug resistance. The aim of this work was to study the efficacy of different repurposed drugs on the viability of MCF-7 and SH-SY5Y breast cancer and neuroblastoma cells, respectively. In addition, combinations of these repurposed drugs with a classical chemotherapeutic drug (doxorubicin) were also carried out. The cytotoxic effects of the repurposed drugs were evaluated individually and in combination in both cancer cell lines, assessed by MTT assays and morphological evaluation of the cells. The results demonstrated that atorvastatin reduced the viability of both cell lines. However, nitrofurantoin was able to induce cytotoxic effects in MCF-7 cells, but not in SH-SY5Y cells. The combinations of the repurposed drugs with doxorubicin induced a higher inhibition on cell viability than the repurposed drugs individually. The combination of the two repurposed drugs demonstrated that they potentiate each other. Synergism studies revealed that the combination of doxorubicin with the two repurposed drugs was more effective in SH-SY5Y cells, compared to MCF-7 cells. Taken together, our preliminary study highlights the potential use of atorvastatin and nitrofurantoin in the context of breast cancer and neuroblastoma. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the effect of sublethal concentrations of nitrofurantoin, ciprofloxacin, and trimethoprim on biofilm formation in 57 uropathogenic Escherichia coli strains (UPEC). The minimum inhibitory concentration of nitrofurantoin, ciprofloxacin, and trimethoprim was determined and the biofilm formation for each isolate with and without sub-lethal concentrations of each antibiotic was then quantified. The statistical significance of changes in biofilm formation was ascertained by way of a Dunnett's test. A total of 22.8% of strains were induced to form stronger biofilms by nitrofurantoin, 12% by ciprofloxacin, and 19% by trimethoprim; conversely 36.8% of strains had inhibited biofilm formation with nitrofurantoin, 52.6% with ciprofloxacin, and 38.5% with trimethoprim. A key finding was that even in cases where the isolate was resistant to an antibiotic as defined by EUCAST, many were induced to form a stronger biofilm when grown with sub-MIC concentrations of antibiotics, especially trimethoprim, where six of the 22 trimethoprim resistant strains were induced to form stronger biofilms. These findings suggest that the use of empirical treatment with trimethoprim without first establishing susceptibility may in fact potentiate infection in cases where a patient who is suffering from a urinary tract infection (UTI) caused by trimethoprim resistant UPEC is administered trimethoprim. This emphasizes the need for laboratory-guided treatment of UTI. [ABSTRACT FROM AUTHOR]

A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm; FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production. [ABSTRACT FROM AUTHOR]

The crystallization of the poorly soluble drug nitrofurantoin (NFT) with 4-aminopyridine (4AmPy) resulted in three multicomponent solid forms with different hydration levels: anhydrous salt [NFT+4AmPy] (1:1), salt monohydrate [NFT+4AmPy+H2O] (1:1:1), and salt tetrahydrate [NFT+4AmPy+H2O] (1:1:4). Each salt was selectively prepared by liquid-assisted grinding in the presence of acetonitrile or ethanol/water mixture at a specific composition. The NFT hydrated salts were characterized using single crystal X-ray diffraction. The [NFT+4AmPy+H2O] salt (1:1:1) crystallized as an isolated site hydrate, while the [NFT+4AmPy+H2O] salt (1:1:4) crystallized as a channel hydrate. The dehydration processes of the NFT salt hydrates were investigated using differential scanning calorimetry and thermogravimetric analysis. A powder dissolution experiment was carried out for all NFT multicomponent solid forms in pH 7.4 phosphate buffer solution at 37 °C. [ABSTRACT FROM AUTHOR]

Herein, we present an electrocatalyst constructed by zinc oxide hexagonal prisms/phosphorus-doped carbon nitride wrinkles (ZnO HPs/P-CN) prepared via a facile sonochemical method towards the detection of nitrofurantoin (NF). The ZnO HPs/P-CN-sensing platform showed amplified response and low-peak potential compared with other electrodes. The exceptional electrochemical performance could be credited to ideal architecture, rapid electron/charge transfer, good conductivity, and abundant active sites in the ZnO HPs/P-CN composite. Resulting from these merits, the ZnO HPs/P-CN-modified electrode delivered rapid response (2 s), a low detection limit (2 nM), good linear range (0.01–111 µM), high sensitivity (4.62 µA µM−1 cm2), better selectivity, decent stability (±97.6%), and reproducibility towards electrochemical detection of NF. We further demonstrated the feasibility of the proposed ZnO HPs/P-CN sensor for detecting NF in samples of water and human urine. All the above features make our proposed ZnO HPs/P-CN sensor a most promising probe for detecting NF in natural samples. [ABSTRACT FROM AUTHOR]

A new series of pyrazolo-benzimidazole hybrid Mannich bases were synthesized, characterized by 1H-NMR, 13C-NMR, IR, UV-Vis, MS, and elemental analysis. In vitro cytotoxicity of the new compounds studied on fibroblast cells showed that the newly synthesized pyrazolo-benzimidazole hybrid derivatives were noncytotoxic until the concentration of 1 μM and two compounds presented a high degree of biocompatibility. The antibacterial and antibiofilm activity of the newly synthesized compounds was assayed on Gram-positive Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, and Gram-negative Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922 strains. All synthesized compounds 5a–g are more active against all three tested bacterial strains Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, and Escherichia coli ATCC25922 than reference drugs (Metronidazole, Nitrofurantoin), with the exception of compounds 5d and 5g, which are less active compared to Nitrofurantoin, and all synthesized compounds 5a–g are more active against Pseudomonas aeruginosa ATCC27853 compared to reference drugs (Metronidazole, Nitrofurantoin). Compound 5f showed the best activity against Staphylococcus aureus ATCC 25923, with a MIC of 150 μg/mL and has also inhibited the biofilm formed by all the bacterial strains, having an MBIC of 310 µg/mL compared to the reference drugs (Metronidazole, Nitrofurantoin). [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Escherichia coli is by far the leading cause of community-acquired UTIs. Pivmecillinam, the oral prodrug of the penicillin derivative mecillinam (amdinocillin), was re-introduced in Germany in March 2016 for first-line treatment of acute uncomplicated cystitis. This study aimed to evaluate the prevalence of resistance to mecillinam in comparison to nine other antibiotics used for oral treatment in E. coli urine isolates after the re-introduction of pivmecillinam. A total of 460 isolates were collected at 23 laboratories of clinical microbiology between October 2019 and March 2020. Forty-six isolates (10.0%) produced an extended-spectrum β-lactamase (ESBL) of the CTX-M family. Resistance to amoxicillin (43.3%) was most widespread, followed by resistance to trimethoprim-sulfamethoxazole (27.0%), amoxicillin-clavulanic acid (18.0%), cefuroxime (11.3%), and ciprofloxacin (11.1%). Twenty-four E. coli isolates (5.2%) were resistant to mecillinam. The concentrations of mecillinam needed to inhibit 50/90% of the ESBL-producing isolates and the remaining isolates were 1/4 mg/L and 0.5/4 mg/L, respectively. The findings support the recommendation to regard pivmecillinam as a first-line option for the treatment of uncomplicated lower UTIs. [ABSTRACT FROM AUTHOR]

In the context of increasing antimicrobial resistance in Enterobacterales, the management of these UTIs has become challenging. We retrospectively assess the prevalence of antimicrobial resistance in Enterobacterales isolates recovered from urinary tract samples in France, between 1 September 2017, to 31 August 2018. Twenty-six French clinical laboratories provided the susceptibility of 134,162 Enterobacterales isolates to 17 antimicrobials. The most frequent species were E. coli (72.0%), Klebsiella pneumoniae (9.7%), Proteus mirabilis (5.8%), and Enterobacter cloacae complex (2.9%). The overall rate of ESBL-producing Enterobacterales was 6.7%, and ranged from 1.0% in P. mirabilis to 19.5% in K. pneumoniae, and from 3.1% in outpatients to 13.6% in long-term care facilities. Overall, 4.1%, 9.3% and 10.5% of the isolates were resistant to cefoxitin, temocillin and pivmecillinam. Cotrimoxazole was the less active compound with 23.4% resistance. Conversely, 4.4%, 12.9%, and 14.3% of the strains were resistant to fosfomycin, nitrofurantoin, and ciprofloxacin. However, less than 1% of E. coli was resistant to fosfomycin and nitrofurantoin. We identified several trends in antibiotics resistances among Enterobacterales isolates recovered from the urinary tract samples in France. Carbapenem-sparing drugs, such as temocillin, mecillinam, fosfomycin, cefoxitin, and nitrofurantoin, remained highly active, including towards ESBL-E. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (1)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (1) were estimated for their antibacterial activity against representative Gram-negative Escherichia coli (ATCC 25922) and Salmonella enterica (SL 5676), as well as Gram-positive Staphylococcus aureus (ATCC 25923) bacterial strains. Their activities in terms of minimum inhibitory concentrations (MICs) varied in the range of 1.1 µM (0.25 µg/mL)–413 µM (128 µg/mL). Amongst the most potent derivatives (1–6), acetyl- and methoxycarbonyl-substituted TPZs (2 and 4) were the strongest agents, which exhibited approximately 4–30 fold greater activities compared to those of TPZ (1) along with the reference drugs chloramphenicol (CAM) and nitrofurantoin (NFT). The inhibitory activities of the compounds were highly impacted by their structural features. No reliable relationships were established between activities and the electron-accepting potencies of the whole set of studied compounds, while the activities of TPZ drug (1) and the structurally uniform set of molecules (2–6) were found to increase with an increase in their electron-accepting potencies obtained by means of density functional theory (DFT) computation. A greater steric, lipophilic and polar nature of the substituents led to a lower activity of the compounds. The combined antibacterial in vitro trial gave clear evidence that TPZs coupled with the commonly utilized antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT) could generate enhanced (suggestive of partial and virtually complete synergistic) and additive effects. The strongest effects were defined for TPZs–NFT combinations, which resulted in a notable reduction in the MICs of di-N-oxides. These preliminary findings suggest that the synthesized novel di-N-oxides might be used as sole agents or applied as antibiotic complements. [ABSTRACT FROM AUTHOR]

A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPPs) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of the ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c] pyridine ( 13g ), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure-activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico.

Cocrystallization could improve most physicochemical properties of specific active pharmaceutical ingredients, which has great potential in pharmaceutical development. In this study, the cocrystal of nitrofurantoin and 4-aminobenzoic acid was prepared with solid-state (solvent-free or green-chemistry) grinding approach, and the above cocrystal has been characterized by Raman and terahertz vibrational spectroscopic techniques. Spectral results show that the vibrational modes of the cocrystal within the whole spectral region are different from those of the corresponding parent materials. The dynamic process of such pharmaceutical cocrystal formation has also been monitored directly with Raman spectra. These results offer us unique means for characterizing the cocrystal conformation from the molecule-level, and provides us with rich information about the reaction dynamic of cocrystal formation within pharmaceutical fields. [ABSTRACT FROM AUTHOR]

Nitrofurantoin is an antimicrobial agent obtained through the addition of a nitro group and a side chain containing hydantoin to a furan ring. The interactions of the antibiotic with human serum albumin (HSA) have been investigated by fluorescence, UV-VIS, Fourier transform infrared spectroscopy (FTIR) spectroscopy, and protein-ligand docking studies. The fluorescence studies indicate that the binding site of the additive involves modifications of the environment around Trp214 at the level of subdomain IIA. Fluorescence and UV-VIS spectroscopy, displacement studies, and FTIR experiments show the association mode of nitrofurantoin to HSA, suggesting that the primary binding site of the antibiotic is located in Sudlow's site I. Molecular modeling suggests that nitrofurantoin is involved in the formation of hydrogen bonds with Trp214, Arg218, and Ser454, and is located in the hydrophobic cavity of subdomain IIA. Moreover, the curve-fitting results of the infrared Amide I' band indicate that the binding of nitrofurantoin induces little change in the protein secondary structure. Overall, these data clarify the blood transportation process of nitrofurantoin and its rapid transfer to the kidney for its elimination, hence leading to a better understanding of its biological effects and being able to design other molecules, based on nitrofurantoin, with a higher biological potential. [ABSTRACT FROM AUTHOR]

Metal-organic frameworks (MOFs) have been rapidly developed for their broad applications in many different chemistry and materials fields. In this work, a multi-dentate building block 5-(4-(tetrazol-5-yl)phenyl)-isophthalic acid (H3L) containing tetrazole and carbolxylate moieties was employed for the synthesis of a two-dimensional (2D) lanthanide MOF [La(HL)(DMF)2(NO3)] (DMF = N,N-dimethylformamide) (1) under solvothermal condition. The fluorescent sensing application of 1 was investigated. 1 exhibits high sensitivity recognition for antibiotic nitrofurantoin (Ksv: 3.0 × 103 M−1 and detection limit: 17.0 μM) and amino acid l-tyrosine (Ksv: 1.4 × 104 M−1 and detection limit: 3.6 μM). This work provides a feasible detection platform of 2D MOFs for highly sensitive discrimination of antibiotics and amino acids. [ABSTRACT FROM AUTHOR]

Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics. [ABSTRACT FROM AUTHOR]

African trypanosomes cause diseases in humans and livestock. Human African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. b. gambiense. Animal trypanosomoses have major effects on livestock production and the economy in developing countries, with disease management depending mainly on chemotherapy. Moreover, only few drugs are available and these have adverse effects on patients, are costly, show poor accessibility, and parasites develop drug resistance to them. Therefore, novel trypanocidal drugs are urgently needed. Here, the effects of synthesized nitrofurantoin analogs were evaluated against six species/strains of animal and human trypanosomes, and the treatment efficacy of the selected compounds was assessed in vivo. Analogs 11 and 12, containing 11- and 12-carbon aliphatic chains, respectively, showed the highest trypanocidal activity (IC50 < 0.34 µM) and the lowest cytotoxicity (IC50 > 246.02 µM) in vitro. Structure-activity relationship analysis suggested that the trypanocidal activity and cytotoxicity were related to the number of carbons in the aliphatic chain and electronegativity. In vivo experiments, involving oral treatment with nitrofurantoin, showed partial efficacy, whereas the selected analogs showed no treatment efficacy. These results indicate that nitrofurantoin analogs with high hydrophilicity are required for in vivo assessment to determine if they are promising leads for developing trypanocidal drugs. [ABSTRACT FROM AUTHOR]

The antibiotic nitrofurantoin is a furan flanked by a nitro group and a hydantoin ring. It is used to treat lower urinary tract infections (UTIs) that have a lifetime incidence of 50−60% in adult women. UTIs are typically caused by uropathogenic Escherichia coli (UPEC), which are increasingly expressing extended-spectrum beta-lactamases (ESBL), rendering them multi-drug resistant. Nitrofurantoin is a first-line treatment for gram-negative ESBL-positive UTI patients, given that resistance to it is still rare (0% to 4.4%). Multiplex PCR of β-lactamase genes of the blaCTX-M groups 1, 2, 9 and 8/25 from ESBL-positive UTI patients treated at three referral hospitals in North Wales (UK) revealed the presence of a novel CTX-M-14-like gene harbouring the missense mutations T55A, A273P and R277C. While R277 is close to the active site, T55 and A273 are both located in external loops. Recombinant expression of CTX-M-14 and the mutated CTX-M-14 in the periplasm of E. coli revealed a significant increase in the Minimum Inhibitory Concentration (MIC) for nitrofurantoin from ≥6 μg/mL (CTX-M-14) to ≥512 μg/mL (mutated CTX-M-14). Consistent with this finding, the mutated CTX-M protein hydrolysed nitrofurantoin in a cell-free assay. Detection of a novel nitrofurantoin resistance gene indicates an emerging clinical problem in the treatment of gram-negative ESBL-positive UTI patients. [ABSTRACT FROM AUTHOR]

Fosfomycin and nitrofurantoin are antibiotics of choice to orally treat non-complicated urinary tract infections (UTIs) of community origin because they remain active against bacteria resistant to other antibiotics. However, epidemiologic surveillance studies have detected a reduced susceptibility to these drugs. The objective of this study was to determine possible mechanisms of resistance to these antibiotics in clinical isolates of fosfomycin- and/or nitrofurantoin-resistant UTI-producing Escherichia coli. We amplified and sequenced murA, glpT, uhpT, uhpA, ptsI, cyaA, nfsA, nfsB, and ribE genes, and screened plasmid-borne fosfomycin-resistance genes fosA3, fosA4, fosA5, fosA6, and fosC2 and nitrofurantoin-resistance genes oqxA and oqxB by polymerase chain reaction. Among 29 isolates studied, 22 were resistant to fosfomycin due to deletion of uhpT and/or uhpA genes, and 2 also possessed the fosA3 gene. Some modifications detected in sequences of NfsA (His11Tyr, Ser33Arg, Gln67Leu, Cys80Arg, Gly126Arg, Gly154Glu, Arg203Cys), NfsB (Gln44His, Phe84Ser, Arg107Cys, Gly192Ser, Arg207His), and RibE (Pro55His), and the production of truncated NfsA (Gln67 and Gln147) and NfsB (Glu54), were associated with nitrofurantoin resistance in 15/29 isolates; however, the presence of oqxAB plasmid genes was not detected in any isolate. Resistance to fosfomycin was associated with the absence of transporter UhpT expression and/or the presence of antibiotic-modifying enzymes encoded by fosA3 plasmid-mediated gene. Resistance to nitrofurantoin was associated with modifications of NfsA, NfsB, and RibE proteins. The emergence and spread of these resistance mechanisms, including transferable resistance, could compromise the future usefulness of fosfomycin and nitrofurantoin against UTIs. Furthermore, knowledge of the genetic mechanisms underlying resistance may lead to rapid DNA-based testing for resistance. [ABSTRACT FROM AUTHOR]

Due to the increasing use of antibiotics, measures are being taken to improve their removal from the natural environment. The support of biodegradation with natural surfactants that increase the bioavailability of impurities for microorganisms that degrade them, raises questions about their effect on bacterial cells. In this paper we present analysis of the interaction of nitrofurantoin (NFT) and saponins from the Saponaria officinalis on the environmental bacteria membrane and the model phospholipid membrane mimicking it. A wide perspective of the process is provided with the Langmuir monolayer technique and membrane permeability test with bacteria. The obtained results showed that above critical micelle concentration (CMC), saponin molecules are incorporated into the POPE monolayer, but the NFT impact was ambiguous. What is more, differences in membrane permeability between the cells exposed to NFT in comparison to that of the non-exposed cells were observed above 1.0 CMC for Achromobacter sp. KW1 or above 0.5 CMC for Pseudomonas sp. MChB. In both cases, NFT presence lowered the membrane permeability. Moreover, the Congo red adhesion to the cell membrane also decreased in the presence of a high concentration of surfactants and NFT. The results suggest that saponins are incorporated into the bacteria membrane, but their sugar hydrophilic part remains outside, which modifies the adsorption properties of the cell surface as well as the membrane permeability. [ABSTRACT FROM AUTHOR]

Urinary tract infections in the elderly are common. Treatment with nitrofurantoin in men may not be sufficient if concomitant tissue involvement is present, resulting in treatment failure. The aim of this study is to determine the prevalence of nitrofurantoin failure in the elderly, and to assess the effect of gender and age. A retrospective observational study was conducted using a Dutch general practice medical record database of 21,789 men and 26,622 women aged 65 years or older in 2015. First, nitrofurantoin prescriptions in 2015 were analyzed. Nitrofurantoin failure (subsequent prescription of antibiotic within 30 days) for men, women, and different age categories were compared. The effect of age and gender was assessed using multivariate logistic regression. A total of 3537 patients had a first nitrofurantoin prescription in 2015; 506 men and 3031 women. Overall, 584 patients (17%) experienced nitrofurantoin failure; 135 (27%) men and 449 (15%) women. Male gender (odds ratio (OR) = 2.09, 95% confidence interval (CI) 1.68–2.61) and age (OR = 1.02, 95% CI 1.01–1.03) was associated with higher treatment failure. Our findings indicate that in a substantial number of elderly men, nitrofurantoin might not be the appropriate treatment. Nitrofurantoin, as a first choice in elderly men with urinary tract infections, should be reconsidered. [ABSTRACT FROM AUTHOR]

The co-crystallization of active pharmaceutical ingredients (APIs) has received increasing attention due to the modulation of the relative physicochemical properties of APIs such as low solubility, weak permeability and relatively inferior oral bioavailability. Crystal engineering plays a decisive role in the systematic design and synthesis of co-crystals by means of exerting control on the inter-molecular interactions. The characterization and detection of such co-crystal formations plays an essential role in the field of pharmaceutical research and development. In this work, nitrofurantoin (NF), melamine (MELA) and their hydrated co-crystal form were characterized and analyzed by using terahertz time-domain spectroscopy (THz-TDS) and Raman vibrational spectroscopy. According to the experimental THz spectra, the hydrated co-crystal form has characteristic absorption peaks at 0.67, 1.05, 1.50 and 1.73 THz, while the THz spectra for the two raw parent materials (NF and MELA) are quite different within this spectral region. Similar observations were made from the experimental Raman vibrational spectra results. Density functional theory (DFT) calculation was performed to help determine the major vibrational modes of the hydrated co-crystal between nitrofurantoin and melamine, as well as identify the structural changes due to inter- and/or intra-molecular hydrogen bonding motifs between NF and MELA. The results of the theoretical frequency calculations corroborate the THz and Raman experimental spectra. The characteristic bands of the NF–MELA-hydrated co-crystal between nitrofurantoin and melamine were also determined based on the DFT simulated calculation. The reported results in this work provide us with a wealth of structural information and a unique vibrational spectroscopic method for characterizing the composition of specific co-crystals and inter-molecular hydrogen bonding interactions upon pharmaceutical co-crystallization. [ABSTRACT FROM AUTHOR]

The continuous exposure of living organisms and microorganisms to antibiotics that have increasingly been found in various environmental compartments may be perilous. One group of antibacterial agents that have an environmental impact that has been very scarcely studied is nitrofuran derivatives. Their representative is nitrofurantoin (NFT)-a synthetic, broad-spectrum antibiotic that is often overdosed. The main aims of the study were to: (a) isolate and characterize new microbial strains that are able to grow in the presence of NFT, (b) investigate the ability of isolates to decompose NFT, and (c) study the impact of NFT on microbial cell properties. As a result, five microbial species were isolated. A 24-h contact of bacteria with NFT provoked modifications in microbial cell properties. The greatest differences were observed in Sphingobacterium thalpophilum P3d, in which a decrease in both total and inner membrane permeability (from 86.7% to 48.3% and from 0.49 to 0.42 µM min -1 ) as well as an increase in cell surface hydrophobicity (from 28.3% to 39.7%) were observed. Nitrofurantoin removal by selected microbial cultures ranged from 50% to 90% in 28 days, depending on the bacterial strain. Although the isolates were able to decompose the pharmaceutical, its presence significantly affected the bacterial cells. Hence, the environmental impact of NFT should be investigated to a greater extent.

Nitrofurantoin is one of the most common drugs implicated in drug-induced pulmonary toxicities, the manifestations of which range from dose-independent acute self-limiting reactions to chronic dose-dependent pathologies. The severity of these pulmonary adverse effects may range from trivial hypersensitivity reactions to extensive and irreversible lung fibrosis leading to respiratory failure and death. Symptomatic and supportive treatment in addition to discontinuation of the drug usually suffices for the management of mild reactions. Corticosteroids have been traditionally used to relieve the symptoms and hasten the resolution of pulmonary lesions in case of severe toxicities. However conclusive evidence in the form of controlled studies in favor of this routine use is lacking. We report a case of an elderly lady who presented to us in respiratory failure due to nitrofurantoin induced chronic lung disease. The patient's symptoms and blood gas abnormalities resolved spontaneously over the course of 6 months after stopping the drug. Radiological lesions including those suggestive of apparently permanent fibrosis also resolved during this time. Corticosteroids, inhalational or systemic, were not used. Spontaneous normalization of clinico-radiological features in nitrofurantoin induced chronic lung disease presenting with respiratory failure has rarely been reported previously. The related literature is also reviewed.

Nitrofurantoin has been in use since 1953 as an effective agent for the prevention of recurrent urinary tract infection. It is associated with a wide range of adverse drug reactions. Chronic active hepatitis has increasingly been observed and many cases have been reported with case fatalities. We present a case of nitrofurantoin induced chronic active hepatitis and briefly review the serology and clinico pathological features of 57 similar cases reported in English literature. The consistent presence of antinuclear antibody, anti smooth muscle antibody, elevated immunoglobulin and pathological feature suggests an immunologic mechanism. Complete recovery is possible in most cases if medication is discontinued in time. Steroids may play a role in management if no improvement occurs despite discontinuation of medication. We suggest all patients who are on prolonged nitrofurantoin therapy be followed up with anti nuclear antibody, anti smooth muscle antibody, serum immunoglobulin and hepatic panel every three months.