Pharmacokinetic and pharmacodynamic evaluation of nitrofurantoin against Escherichia coli in a murine urinary tract infection model.

The antimicrobial agent nitrofurantoin is becoming increasingly important for treatment of urinary tract infections (UTIs) due to widespread occurrence of multidrug-resistant Escherichia coli. Despite many years of use, little data on nitrofurantoin pharmacokinetics (PK) or -dynamics (PD) exist. The objective of this study was to (i) evaluate the pharmacokinetics of nitrofurantoin in a mouse model and (ii) use that data to design an in vivo dose fractionation study in an experimental model of UTI with E. coli for determination of the most predictive PK/PD index. Nitrofurantoin concentrations in urine were approximately 100-fold larger than concentrations in plasma after oral administration of 5, 10, and 20 mg/kg nitrofurantoin. The area under the curve over the minimum inhibitory concentration (AUC/MIC) was weakly correlated to bacterial reduction in urine (r2 = 0.24), while no such correlation was found for the time that nitrofurantoin stayed above the MIC (T > MIC). Increasing size of single-dose treatment was significantly correlated to eradication of bacteria in the urine, while this was not apparent when the same doses were divided in 2 or 3 doses 8 or 12 h apart. In conclusion, the results indicate that nitrofurantoin activity against E. coli in urine is driven by AUC/MIC.

Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison).

Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E. coli and S. delphini infections in mink.

Urinary antibacterial activity of fosfomycin and nitrofurantoin at registered dosages in healthy volunteers.

Given emerging uropathogen resistance to more recent antibiotics, old antibiotics used for uncomplicated urinary tract infection (UTI) warrant re-examination. In this study, the urinary antibacterial activities of fosfomycin and nitrofurantoin were investigated by determining the urinary inhibitory titre and urinary bactericidal titre against uropathogens in urine samples from female volunteers following administration of single-dose fosfomycin (3 g) or nitrofurantoin (50 mg q6h or 100 mg q8h). Urine samples were collected over 48 h (fosfomycin) or 6 or 8 h (nitrofurantoin), with drug levels quantified with every void. Fosfomycin concentrations ranged from <0.75 mg/L [lower limit of quantification (LLOQ)] to 5729.9 mg/L and nitrofurantoin concentrations ranged from <4 mg/L (LLOQ) to 176.3 mg/L (50 mg q6h) or 209.4 mg/L (100 mg q8h). There was discrepancy in the response to fosfomycin between Escherichia coli and Klebsiella pneumoniae, with fosfomycin displaying strong bactericidal activity for 48 h against E. coli but moderate bactericidal activity for 18 h against K. pneumoniae. This effect was not related to the strain's baseline minimum inhibitory concentration but rather to the presence of a resistant subpopulation. Maximum titres of nitrofurantoin were obtained during the first 2 h, but no antibacterial effect was found in most samples regardless of the dose. In the rare samples in which antibacterial activity was detectable, titres were comparable for both species tested. These findings confirm doubts regarding fosfomycin administration in UTIs caused by K. pneumoniae and reveal a discrepancy between nitrofurantoin's measurable ex vivo activity and its clinical effect over multiple dosing intervals.

Differences in the pharmacokinetics of flumequine after single and continuous oral administration in non-fasted broiler chickens.

The aim of this study was to determine the influence of feed on the pharmacokinetics of flumequine (FLU) administered to broiler chickens as follows: directly into the crop (10 mg/kg of BW) of fasted (group I/control) and non-fasted chickens (group II), or administered continu- ously with drinking water (1 g/L for 72 h) and with unlimited access to feed (group III). Plasma concentration of FLU was determined by high-performance liquid chromatography with fluo- rescence detection. In group II, a significant decrease in the maximum concentration (Cmax = 2.13±0.7 µg/mL) and the area under the concentration curve from zero to infinity (AUC0→∞ = 7.47±2.41 µg·h/mL) was noted as compared to the control group (Cmax = 4.11±1.68 µg/mL and AUC0→∞ = 18.17±6.85 µg·h/mL, respectively). In group III, the decrease in AUC was signifi- cant only in the first 3 hours (AUC0→3 = 5.02±1.34 µg·h/mL) as compared to the control group (AUC0→3 = 7.79±3.29 µg·h/mL). The results indicate that feed reduced the bioavailability of FLU from the gastrointestinal tract by at least 50% after the administration of a single oral dose. However, continuous administration of FLU with drinking water could compensate for the feed-induced decrease in absorption after single oral dose.

Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings.

A number of antibacterial agents have emerged into the U.S. market in the last 2 decades to address growing concerns of antimicrobial resistance. These agents have demonstrated noninferiority to comparators for treatment of a range of complicated infections in their respective clinical trials. However, with select agents, a trend of reduced therapeutic efficacy was observed among study patients with baseline renal impairment. This phenomenon was seen in phase III studies involving ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin. Although these were largely post hoc findings among small subpopulations, this observation is still concerning, given that renal impairment is a common occurrence among patients in real-world care settings. Cautions for use in this population are featured in the prescribing information of all four agents. Although well-defined reasons for these findings across trials are diverse or unknown, several potential pharmacokinetic and pharmacodynamic explanations for these discordant response rates exist. In this review, we summarize the phase III studies that observed lower response rates with ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin relative to their comparators among patients with moderate renal impairment, discuss potential explanations for the observed findings, provide considerations for future antibiotic development, and offer strategies for optimizing antibiotic dosage selection among patients with moderate renal impairment in clinical settings. Although all of these agents are discussed, ceftazidime-avibactam is used as a motivating example to demonstrate the implications of inappropriate dosage selection.

Effect of administration route and dose alteration on sulfadiazine-trimethoprim plasma and intestinal concentrations in pigs.

Potentiated sulfonamides, such as sulfadiazine-trimethoprim (SDZ-TRIM), are frequently used antimicrobials in both human and veterinary medicine. To optimise their use in relation to the emerging problem of resistance selection, this paper studied the impact of dose and administration route of SDZ-TRIM on the exposure of the gut microbiota to these antimicrobials. An animal experiment was conducted with 36 pigs, divided into six different treatment groups (n = 6). Three different administration routes were outlined: oral (PO) gavage, intramuscular (IM) injection and medicated feed, with 5-day therapy duration. Conventional dosing (30 mg SDZ-TRIM/kg bodyweight [BW]) and half dosing (15 mg SDZ-TRIM/kg BW) was performed for the oral routes in two applications per day. For the IM route, a conventional dose of 15 mg SDZ-TRIM/kg BW or a double dose of 30 mg SDZ-TRIM/kg BW was administered once daily. After daily collection of blood and faeces, the intestinal content of all animals was sampled in different gastrointestinal tract (GIT) segments, and SDZ and TRIM were quantified. Remarkably, SDZ accumulated in distal GIT segments, independently of the administration route. High concentrations (mean ± standard deviation) up to 26.93 ± 8.36 µg/g, 11.15 ± 3.78 µg/g and 19.36 ± 1.86 µg/g after PO gavage, IM administration and medicated feed, respectively, were measured for SDZ. In contrast, TRIM concentrations decreased from proximal to distal segments and were mostly below the limit of quantification (0.025 µg/g). The high oral bioavailability of SDZ indicates gastrointestinal secretion is a substantial elimination route for SDZ.

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against ß-lactamase-producing Escherichia coli in a hollow-fibre infection model.

The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens. The four investigational E. coli strains included #2805 (no ß-lactamase), #2890 (AmpC ß-lactamase), #2842 (CMY-10 ß-lactamase) and #2807 (CTX-M-15 ß-lactamase). Each strain was exposed to regimens simulating 1 g ceftolozane, 2 g ceftolozane, 1 g ceftolozane/0.5 g tazobactam, and 2 g ceftolozane/1 g tazobactam utilising a starting inoculum of ca. 106 CFU/mL. Whereas 1 g of ceftolozane eradicated strains #2805 and #2842 without subsequent regrowth, 1 g ceftolozane/0.5 g tazobactam was required to eradicate strain #2890. For strain #2890, ceftolozane monotherapy led to bacterial growth on plates impregnated with 20 mg/L ceftolozane by 24 h, whilst combination treatment with tazobactam completely suppressed the development of ceftolozane resistance. In contrast, none of the regimens, including 2 g ceftolozane/1 g tazobactam, were able to entirely suppress bacterial growth in strain #2807, with bacterial counts exceeding 108 CFU/mL by 48 h and ceftolozane-resistant populations being amplified after 24 h. Thus, the combination of ceftolozane and tazobactam achieved bactericidal activity followed by sustained killing over 10 days for three of four isogenic E. coli strains. Ceftolozane/tazobactam is a promising new agent to counter multidrug-resistant Gram-negative bacteria.

Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes.

The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [(14)C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding-induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs.

Pharmacokinetics and bioavailability of flumequine in blunt snout bream (Megalobrama amblycephala) after intravascular and oral administrations.

In this study, the pharmacokinetic profile of flumequine (FMQ) was investigated in blunt snout bream (Megalobrama amblycephala) after intravascular (3 mg/kg body weight (b.w.)) and oral (50 mg/kg b.w.) administrations. The plasma samples were determinedby ultra-performance liquid chromatography (UPLC) with fluorescence detection. After intravascular administration, plasma concentration-time curves were best described by a two-compartment open model. The distribution half-life (t1/2α ), elimination half-life (t1/2ß ), and area under the concentration-time curve (AUC) of blunt snout bream were 0.6 h, 25.0 h, and 10612.7 h·µg/L, respectively. After oral administration, a two-compartment open model with first-order absorption was also best fit the data of plasma. The t1/2α , t1/2ß , peak concentration (Cmax ), time-to-peak concentration (Tmax ), and AUC of blunt snout bream were estimated to be 2.5 h, 19.7 h, 3946.5 µg/L, 1.4 h, and 56618.1 h. µg/L, respectively. The oral bioavailability (F) was 32.0%. The pharmacokinetics of FMQ in blunt snout bream displayed low bioavailability, rapid absorption, and rapid elimination.

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim.

Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3'- and 4'-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4'-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4'-demethylation. TMP 3'-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.

Finafloxacin for the treatment of urinary tract infections.

INTRODUCTION: In the past decade, the indiscriminate use of fluoroquinolones in the prophylaxis and treatment of urinary tract infections (UTIs) has led to an increase of antibiotic resistance patterns. Finafloxacin is a new generation fluoroquinolone with interesting preclinical characteristics and pH-related efficacy. AREAS COVERED: This review summarizes finafloxacin's safety profile and prospectively evaluates its specific use in the treatment of UTIs. This article was based on a Medline English literature search. EXPERT OPINION: In vitro and in vivo studies have shown that finafloxacin expresses its full antibacterial activity in acidic environments and is able to exert significant bactericidal effects in difficult-to-treat infections. Finafloxacin has a broad antibacterial spectrum and efficient pharmacokinetic absorption. Moreover, it undergoes extensive tissue distribution, resulting in good antibacterial activity for daily dosages from 400 to 800 mg. This novel compound has also been successfully tested on biofilm-related Escherichia coli. Finafloxacin has demonstrated a good safety and tolerability profile in humans when administered orally or intravenously and is thus an interesting compound for the treatment of UTIs. However, further prospective randomized clinical trials will be necessary to confirm these preliminary results before definitive conclusions can be made.

Nitrofurantoin enteric pellets with high bioavailability based on aciform crystalline formation by wet milling.

The aim of the present study was to grind nitrofurantoin (NF) with HPMC solution and to determine the dissolution and bioavailability of the enteric pellets prepared with the NF cogrounds and other excipients. During milling, crystalline transformation occurred--the aciform microcrystalline monohydrate II replaced the coarse crystal anhydrate ß and the particle size markedly reduced. In vitro test demonstrated that the enteric pellets prepared with NF cogrounds (4 h) revealed a faster dissolution than the commercial tablet and 50% was released within 30 min in the basic medium. Finally, an in vivo test was conducted in beagle dogs. The Cmax and AUC(0 → 24) of the pellets were 2.19 ± 0.74 µg/ml and 6.73 ± 4.71 µg/ml h, respectively, while the corresponding values were 0.49 ± 0.42 µg/ml and 1.38 ± 1.17 µg/ml h for the tablet. Thus, the bioavailability of the pellets was increased significantly. In conclusion, the wet grinding that reduced the particle size and created the microcrystalline played a major role in the acceleration of the dissolution of NF and, consequently, enhanced the bioavailability, and the wet grinding process offers an alternative approach to improve the dissolution and bioavailability of drugs with poor aqueous solubility.

Using nitrofurantoin while breastfeeding a newborn.

QUESTION: My patient has a urinary tract infection and is currently breastfeeding. Her son is only 3 weeks old. Is nitrofurantoin a safe antibiotic for treatment? ANSWER: The use of nitrofurantoin in breastfeeding mothers is generally safe, as only small amounts transfer into the breast milk. Despite the lack of documented reports, there is a risk of hemolytic anemia in all newborns exposed to nitrofurantoin owing to their glutathione instability, especially in infants with glucose-6-phosphate dehydrogenase deficiency. Although some suggest that nitrofurantoin be avoided in infants younger than 1 month, studies have noted that glutathione stability might be established by the eighth day of life. In infants younger than 1 month, an alternative antibiotic might be preferred; however, if an alternative were not available, the use of nitrofurantoin would not be a reason to avoid breastfeeding. In any such case the suckling infant should be monitored by his or her physician.

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era.

In the era of multidrug resistance, it is critical to utilize antibiotics in an appropriate manner and to identify new treatments or revisit the use of 'forgotten' drugs. Because urinary tract infections (UTIs) are common, particularly in an increasing elderly population, the 'forgotten' drug, methenamine, may become important as a preventive therapy for recurrent UTIs. Methenamine, a urinary antibacterial agent, can be used as methenamine hippurate or methenamine mandelate preparations and is United States Food and Drug Administration-approved. This article discusses the place of preventive therapy for recurrent UTIs, chemistry, mechanism of action, pharmacology, clinical uses, dosage, adverse reactions and safety, and drug interactions of methenamine. Because of its unique antiseptic property, the authors suggest that methenamine should be considered when more commonly used antibiotics fail to suppress recurrent UTIs.

Quantitation of nitrofurantoin in human plasma by liquid chromatography tandem mass spectrometry.

A reliable, selective and sensitive LC-MS/MS assay has been proposed for the determination of nitrofurantoin in human plasma. The analyte and nitrofurazone were extracted from 100 µL of human plasma via SPE on Strata-X 33 µm extraction cartridges. Chromatography was done on a BDS Hypersil C18 (100 mm × 4.6 mm, 5 µm) column under isocratic conditions. Quantitation was done using the multiple reaction monitoring (MRM) mode for deprotonated precursor to product ion transitions of nitrofurantoin (m/z 237.0 → 151.8) and nitrofurazone (m/z 197.0 → 123.9). The limit of detection and the lowest limit of quantitation of the method were 0.25 ng mL-1 and 5.00 ng mL-1, respectively, with a linear dynamic range of 5.00-1500 ng mL-1 for nitrofurantoin. The intra- -batch and inter-batch precision (RSD, %) was ≤ 5.8 %, while the mean extraction recovery was > 92 %. The method was successfully applied to a bioequivalence study of a 100 mg nitrofurantoin capsule formulation in 36 healthy subjects.

Antiadhesion therapy for urinary tract infections--a balanced PK/PD profile proved to be key for success.

The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose-binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed, avoiding selection pressure and thereby implying a reduced risk of resistance. Here, we present a new class of highly active antimicrobials, targeting the virulence factor FimH. When the most potent representative, an indolinylphenyl mannoside, was administered in a mouse model at the low dosage of 1 mg/kg (corresponding to approximately 25 µg/mouse), the minimal therapeutic concentration to prevent UTI was maintained for more than 8 h. In a treatment study, the colony-forming units in the bladder could be reduced by almost 4 orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg, sc).

[Physico-chemical characteristic of medicinal preparations for intrabladder electrophoresis in patients presenting with bladder diseases (an experimental study)].

The physico-chemical characteristic of medicinal preparations used for the treatment of various bladder diseases is provided including their electrophoretic activity and the ability to penetrate into bladder tissues, e.g. during electrophoresis. The optimal parameters of intracavitary electrophoresis are considered.

Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg) in healthy volunteers receiving a single oral dose.

BACKGROUND: Finafloxacin is a novel 8-cyano-fluoroquinolone under investigation for treatment of urinary tract infection. METHODS: Urinary concentrations and urinary bactericidal titers (UBT) of finafloxacin 200- and 800-mg single doses in 6 healthy volunteers were measured up to 48 h. UBT were determined for a reference strain and 9 selected clinical uropathogens at the pH of native, acidified (pH 5.5) and alkalinized (pH 8.0) urine. RESULTS: The mean maximum urine concentrations for 200 and 800 mg finafloxacin were 69.3 mg/l (0-2 h) and 150 mg/l (4-8 h). Median UBT were between 0 and 1:>2,048 and were in general agreement with minimal inhibitory concentrations of strains and urinary pH values. UBT in alkaline urine were significantly lower than those in native or acidic urine, except for Enterococcus faecalis. CONCLUSIONS: Finafloxacin exhibited significant bactericidal activity against susceptible uropathogens. The urinary bactericidal activity of finafloxacin was enhanced in acidic urine and significantly lower in alkaline urine.

[Antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in adults]. / Antimikrobielle und klinische Wirksamkeit von Nitrofurantoin in der Behandlung akuter Infekte der unteren ableitenden Harnwege bei Erwachsenen.

BACKGROUND AND PURPOSE: In the light of increasing resistance to antibiotics used for the treatment of acute urinary tract infections, nitrofurantoin currently experiences a renaissance. Nitrofurantoin shows good efficacy against most bacteria expected in urinary tract infection, and the development of resistance is low. A study on the antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections was conducted in Mexico City, an area where resistance rates of uropathogens to trimethoprim/sulfamethoxazole (cotrimoxazole) are high. PATIENTS AND METHODS: In this open-label, single-arm study 20 adult patients (18 females, 2 males) with positive urine culture were treated orally with nitrofurantoin sustained release 100 mg twice daily for 7 days. Urinary nitrofurantoin concentrations were determined at baseline and day 4 of the study. Primary endpoint was the antimicrobial efficacy of nitrofurantoin at 12 to 16 days after baseline, assessed by changes in urine culture results. RESULTS: In the patient population treated per protocol, primary endpoint analysis revealed a microbial eradication rate of 92.3%. At 35 to 42 days, the eradication rate was 83.3%. At these times, all patients in the per protocol population were free of symptoms. In patients with complicating factors, e.g. diabetic polyneuropathy, both antimicrobial and clinical efficacy appeared to be reduced. Urinary nitrofurantoin concentrations were mostly above minimum inhibitory concentrations of the isolated uropathogens. The study drug was generally well tolerated. Most frequent drug-related adverse event was mild headache, occurring in 10.8% of patients. Two patients discontinued the study due to rash. CONCLUSION: The results of the present study indicate good antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute uncomplicated urinary tract infections as well as acceptable tolerability in adults.