Fosfomycin and nitrofurantoin in the treatment of recurrent urinary tract infections in type 2 diabetic women: a preliminary report

Background. The aim of this study was to compare the efficacy and safety of long-term use of fosfomycin and nitrofurantoin in the treatment of recurrent uncomplicated lower urinary tract infections (uUTIs) in type 2 diabetic women. Materials and methods. The study included type 2 diabetic women, aged 50–70 years old, suffering from uUTIs and presenting with dysuric symptoms and positive urine culture for a pathogen sensitive to nitrofurantoin and fosfomycin. Fifty women were qualified for the study and divided into two groups depending on the treatment used. Group 1 comprised patients treated with fosfomycin, group 2 with nitrofurantoin. The follow-up period was 6 months. Patients diagAddress for correspondence: dr med. Jan Ruxer Klinika Kardiologii Interwencyjnej, Kardiodiabetologii i Rehabilitacji Kardiologicznej UM ul. Żeromskiego 113a, 91–473 Łódź e-mail: [email protected] Diabetologia Doświadczalna i Kliniczna 2006, 6, 5, 277–282 Copyright © 2006 Via Medica, ISSN 1643–3165 Introduction Management of patients with type 2 diabetes suffering from recurrent episodes of uncomplicated urinary tract infections (uUTIs) continues to be an unsettled issue. Current opinions on the selection of an antibiotic and the duration of treatment in diabetic patients vary. Chronic urinary tract infections are believed to be associated with numerous problems, such as non-compliance, adverse drug reactions and the emergence of resistance among the causative uropathogens of uUTIs [1–4]. The agents most commonly used in the treatment of urinary tract infections include: co-trimoxazole, nitrofurantoin (NF) and other nitrofuran derivatives, ciprofloxacin, norfloxacin, ofloxacin, ampicillin and fosfomycin trometamol (FT) [5–9]. nosed with urinary tract infections during the follow-up visits were excluded from the remainder of the study. The antibacterial treatment was considered effective when complete resolution of dysuric symptoms and eradication of the uropathogens in follow-up urine bacteriology were achieved. Results. There were no significant differences between the study groups in the percentage of patients in whom no uUTIs were seen at 3 and 6 months of long-term treatment. Conclusion. Nitrofurantoin and fosfomycin are effective chemotherapeutic agents both in the treatment and prevention of recurrent uUTIs in type 2 diabetic women. key words: fosfomycin, nitrofurantoin, type 2 diabetes The chemotherapeutic agent nitrofurantoin is a nitrofuran derivative with a bacteriostatic and bacteriocidal activity against gram-positive and gram-negative bacteria (such as Escherichia coli, Klebsiella spp., Staphylococcus aureus). Resistance to NF is rare and develops very slowly. No cross-resistance with other urinary antiseptics has been reported. Nitrofurantoin rarely leads to adverse effects, such as: nausea, vomiting, diarrhoea, skin allergy, anaphylactic reactions in the elderly, asthma-like bronchial hyperreactivity, pulmonary oedema, drug-induced fever, headache, vertigo, depression, increased activity of serum aminotransferases, haematologic abnormalities and symptoms of peripheral polyneuropathy. Contraindications to NF include: hypersensitivity to the drug, acute renal failure, the postpartum period, lactation and a diagnosis of peripheral polyneuropathy. The safety of NF in patients below 12 years of age has not been unequivocally determined. Nitrofurantoin should be used with caution in patients suffering from allergies, pulmonary or hepatic disorders and in patients with neurological abnormalities [10, 11]. Fosfomycin trometamol may be an interesting alternative to the currently used long-term treatment of Diabetologia Doświadczalna i Kliniczna 2006, Vol. 6, No. 5 www.ddk.viamedica.pl 278 uUTIs. FT is an inhibitor of enolpyruvate transferase which exerts a bactericidal action by inhibiting the pathogen’s cell wall synthesis. Fosfomycin trometamol demonstrates anti-adhesive effects preventing the bacteria from adhering to the walls of the urinary tract. The drug does not lead to the emergence of cross-resistance to other antibiotics. It has a broad spectrum of activity that includes: Escherichia coli, Citrobacter spp., Klebsiella spp., Proteus spp., Staphylococcus spp., Salmonella spp., Streptococcus faecalis, Pseudomonas aeruginosa and Serratia spp. Adverse reactions to FT are rare and develop in 1–8% of all the patients, with the most common ones being: diarrhoea, nausea, vomiting, skin rash, heartburn, vaginitis, headache, chills and asthaenia. Contraindications to FT include: hypersensitivity to the drug and renal disease with creatinine clearance below 10 ml/min. An exceptionally convenient dosage schedule is a significant advantage of FT–– in acute urinary tract infections, the drug is given as a single dose of 3.0 g [12–15]. The study was aimed to compare the efficacy and safety of long-term use of fosfomycin and nitrofurantoin in the treatment of recurrent uncomplicated lower urinary tract infections in type 2 diabetic women. Materials and methods The study included type 2 diabetic women presenting with dysuric symptoms (frequency, painful passing of small volumes of urine, urgency or suprapubic pain) who had not taken any antibacterials within one month prior to inclusion, aged 50–70 years old, suffering from uUTIs (at least three recurrent episodes of urinary tract infection in the past year) managed by the Diabetology Outpatient Clinic. In all the women, before the study, a medical examination, a urinalysis and a complete blood cell count were performed and the following parameters in the serum were measured: urea, creatinine, alanine aminotransferase, aspartate aminotransferase, bilirubin, fasting glucose, glycated haemoglobin (HbA1c). A urine bacteriology and an abdominal ultrasound were performed in women with leukocyturia. Only those women were eventually qualified for the study who were diagnosed with significant bacteriuria (bacterial counts of more than 10 CFU/ml in the urine cultures) and whose pathogen cultured from the urine (a single strain) was sensitive to both NF and FT. The exclusion criteria were: serum creatinine above 1.5 mg/dl, alanine aminotransferase and aspartate aminotransferase levels of more than twice the upper limit of normal, bilirubin exceeding 1.3 mg/dl, sonographic changes in the hepatic and renal parenchyma and nephrolithiasis. Women with a history of renal or hepatic disorders, late diabetic complications, haemopoietic system disorders and alcoholism were excluded from the study. Fifty women were included in the study. The patients were randomly assigned to two groups according to the antibacterial treatment. Group 1 consisted of patients receiving FT [Monural 3.0 g (Zambon) in the form of sachets]. The granules were dissolved in a glass of boiled water and given two hours after dinner, after voiding, every 30 days. Group 2 consisted of patients managed with NF [Nifuratio retard 100 mg (Ratiopharm) in the form of capsules]. The drug was given at 100 mg every 12 hours (at breakfast and dinner time) for 7 days followed by 100 mg once daily at dinner time. The study group characteristics is shown in Table 1. Urine bacteriology in Group 1 revealed the presence of Escherichia coli in 16 patients, Enterobacter spp. in 4, Enterococcus spp. in 3 and Staphylococcus spp. in 2 patients. In the NF group, Escherichia coli was revealed in 18 patients while Enterobacter spp. and Enterococcus spp. in 4 and 3 patients, respectively. The study was carried out in the outpatient setting. The duration of follow-up was 6 months, during which time the women were receiving long-term treatment with either FT or NF. During the 3-month and 6-month follow-up visits at the Diabetology Outpatient Clinic, urine bacteriology and complete blood cell count were performed, aminotransferase levels were measured and renal function parameters were assessed. Patients with manifestations of urinary tract infection at 3 months (dysuric Table 1. Characteristics of the study groups Group 1 Group 2 P value Size of the group (n) 25 25 NS Age (years) ± SD 57.8 ± 7.6 60.0 ± 7.9 NS HBA1c (%) ± SD 7.0 ± 1.7 7.3 ± 1.4 NS Fasting glycaemia [mg/dl] ± SD 140 ± 38 136 ± 41 NS Duration of type 2 diabetes (years) ± SD 6.2 ± 3.4 6.0 ± 4.2 NS Mean number of uUTI episodes in the past year (n) ± SD 4.3 ± 1.1 4.1 ± 0.9 NS NS — non significant Jan Ruxer et al. Fosfomycin and nitrofurantoin in the treatment of UTI in DM www.ddk.viamedica.pl 279 symptoms and presence of a pathogen in the urine culture) were excluded from the remainder of the study. The antibacterial treatment was considered effective if complete resolution of dysuric symptoms and eradication of the uropathogen in the follow-up urine bacteriology were achieved. All the patients were informed of the aim and methodology of the study and gave voluntary written consent. The study protocol was approved by the Ethics Committee of the Medical University of Łódź. The study parameters between the groups were compared by t-Student test. The percentage of patients without the signs of urinary tract infection in both groups was compared by Pearson’s χ test. A significance level (P value) of 0.05 was assumed. The statistical analysis was performed using the STATISTICA software.