Fosfomycin Therapy for Non-Complicated Lower Urinary Tract Infections during Pregnancy : Tanta University Experience

Objectives: To evaluate the efficacy, compliance, safety and economic cost for Fosfomycin trometamol and Nitofurantoin in uncomplicated lower urinary tract infections during pregnancy. Background: Nitofurantoin and Fosfomycin trometamol are recommended as the first-line agents for treatment of urinary tract infections (UTIs) in the latest guidelines endorsed by the Infectious Diseases Society of America (IDSA) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis and reduces bacterial adherence to uroepithelial cells. Fosfomycin has broad antibacterial activity against both Grampositive and Gram-negative pathogens, as Escherichia coli, Escherichia faecalis, and various Gram-negatives like Citrobacter and Proteus. Both Nitofurantoin and Fosfomycin are category B in pregnancy. Patients and Methods: This study was conducted at Tanta University Hospitals in the period from June, 1, 2015 to January, 1, 2017. Patients were recruited from outpatient clinics of Obstetrics and Gynecology and Urology Departments presenting with asymptomatic bacteruria or cystitis. Patients were allocated randomly into 2 groups: group I (n = 50 cases) received Fosfomycin therapy and group II (n = 50 cases) received Nitofurantoin therapy (n = 50 cases). After treatment, evaluation of patient symptoms, organism count, patient compliance and cost of treatment were done. Results: The enrolled patients were suffering from lower urinary tract infections; asymptomatic bacteruria (17 cases) or cystitis (83 cases). Ten patients were excluded. The demographic data of included patients were not significant for both groups. Complete relief (100%) of symptoms 5 days after start of treatment was noticed in Fosfomycin group while improvement of symptoms after 5 day-treatment was noticed in 86.49% in Nitofurantoin group (p-value = 0.030). The side effects were recorded in 7 cases (18.42%) in Fosfomycin group compared to (35.14%) with significant How to cite this paper: Dawood, A.S., Dawood, A.S., Nagla, S.A. and El-Bakary, M.A. (2017) Fosfomycin Therapy for NonComplicated Lower Urinary Tract Infections during Pregnancy: Tanta University Experience. Open Journal of Obstetrics and Gynecology, 7, 532-544. https://doi.org/10.4236/ojog.2017.75056 Received: April 28, 2017 Accepted: May 22, 2017 Published: May 25, 2017 Copyright © 2017 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
Urinary tract infection (UTI) is considered the most commonly occurring bacterial infection in women [1].Urinary tract infections (UTIs) complicate 3% to 10% of pregnancies and are among the commonest reasons for antibiotic use in obstetrics.Uncomplicated lower UTI is usually defined as acute cystitis occurring with no known abnormalities of the urological tract, and is characterized by symptoms such as dysuria, urgency, frequency, suprapubic pain and/or haematuria [1] [2].
Enterobacteriaceae has been the production of enzymes, known as betalactamases, capable of inactivating some members of the penicillin and cephalosporin class antibiotics, which share a similar beta-lactam chemical ring structure.Most recently extended-spectrum beta-lactamase (ESBL) enzymes have arisen, which cause resistance not only to penicillins and cephalosporins, but also additional resistance to fluoroquinolones, aminoglycosides, and sulfamethoxasoletrimethoprim, and are known as multidrug-resistant organisms (MDROs) [5] [6].
Antibiotic resistance has affected disease management in our specialty.Increased resistance of Neisseria gonorrhea to penicillins and quinolones, emergence of methicillin-resistant staphylococcus aureus (MRSA) and resistance of Group B Streptococcus to erythromycin and clindamycin have led us to modify our antibiotic treatment regimens [5] [6] [7].
Fosfomycin trometamol given in a single oral dose of 3 g achieves high concentrations in urine and is generally well tolerated.The most reported side ef-fects were gastrointestinal (e.g.diarrhoea, nausea) and vaginitis [8] [9] [10].
In this study, we compared the efficacy of single dose 3 g orally versus the conventional oral Nitrofurantoin in non-complicated lower urinary tract infections during pregnancy at Tanta University Hospitals.

Study Design
A prospective, non-blinded, randomized controlled clinical trial.

Study Settings
This study was conducted at Tanta University in both departments of Obstetrics and Gynecology and department of Urology in the period from June, 1, 2015 to January, 1, 2017.

Recruitment
Hundred patients between 12 -36 weeks of gestation were enrolled in this study according to the following inclusion criteria: a) Uncomplicated lower UTIs (asymptomatic bacteruria or cyctitis); b) Patient in whom culture revealed an antibiotic contraindicated with pregnancy.The exclusion criteria were for patients with a) History of congenital urogenital anomalies; b) Cases associated with hydronephrosis due to any cause; c) Urinary stones; d) Diabetic and immune-compromised patients; e) Patients with high grade fever associated with flank pain and/or signs of pyelonephritis; f) Patients with severe nausea and/or vomiting and are unable to receive oral medication.

Sample Calculation
The sample was calculated by Epi info 0.7 programs with 2 sided confidence level 95% at power of 85%.H 0 postulated to denote that Fosfomycin is superior to Nitofurantoin.The estimated sample was 100 patients.

Randomization and Allocation
Patients were allocated randomly into 2 groups.Randomization was done by specific computerized program and alternate allocation for both groups.Group I (n = 50 cases): patients received oral Fosfomycin single dose therapy.Group II (n = 50 cases) received oral Nitrofurantoin.

Dosage and Administration
Fosfomycin trometamin sachet was dissolved into half a cup of water and taken before bed time.Patients should empty their bladder, and then took the dissolved Fosfomycin before bedtime.
Nitrofurantoin 100 mg was given in capsule form three times daily for 7 days.

Methods
All patients age, parity, gestational age, and symptoms plus abdomen /pelvis ultrasonography and urine analysis, were taken at the beginning of the study.After 7 days, questionnaire for symptoms relief, compliance, and complications plus a second urine analysis for counts of organisms.Results were recorded for both groups.
Questionnaire was simply designed and specified by authors' collaboration.It was made of 3 sections: The first section, considered demographic data of participants, the second sections, considered patients' presentation, symptom relief, residual symptoms, compliance and costs of treatment.The third section evaluated the efficacy of treatment by second urine analysis findings and occurrence of side effects and specifying these side effects (Appendix I).

Ethical Approval
This study was obtained before the start of treatment under the code 31242/ 12/16 by Tanta University Ethical committee.

Statistical Analysis
It was done using SPSS version 18, USA.The statistical tests used were mean, standard deviation, Chi square (x 2 ) and p-value.Significance is positive if p ≤ 0.05.

Results
One hundred patients were enrolled in this study from Urology and Obstetrics and Gynecology Departments, Tanta University, Egypt.All patients were suffering either asymptomatic bacteruria (17 cases) or cystitis (83 cases).Ten patients were excluded because they were either not meeting inclusion criteria (7 cases) or declined to participate (3 cases).The flow chart of enrolled patients is demonstrated in Figure 1.
The mean patient's age was 28.5 ± 3.4 years in group I and 27.9 ± 4.02 years in group II.The mean gravidity was (1.2 ± 0.3 and 1.3 ± 0.4) for group I and II respectively.The mean parity was (1.7 ± 0.4 and 1.9 ± 0.9) for group I and II respectively.The mean BMI was (23.7 ± 3.2 and 22.8 ± 2.4) for group I and II respectively.The mean gestational age at presentation was (33.4 ± 1.7 and 34.01 ± 1.23) for group I and II respectively.The demographic data of included patients were not significant for both groups Table 1.A second urine sample was done 7 days after start of treatment where pus cells (0-10/HPF) was found in Fosfomycin group compared to (15 -20 pus cells/HPF) in Nitofurantoin group, (p-value = 0.002).Compliance was 38/38 (100%) in Fosfomycin group compared to 34/37 (91.89%) in Nitrofuantoin group, (p-value = 0.001).The common causes of incomplete compliance were multi-dosing and occurrence of side effects.The cost of therapy was slightly higher in fosfomycin group (45 LE) compared to (35 LE) in Nitofurantoin group.This difference was not significant (p-value = 0.342) (Table 2).

Discussion
Urinary tract infections (UTIs) are common among females; especially pregnant ones due to associated physiological changes that favor the occurrence of UTI.
Although pregnancy is a major risk factor for UTI, there are many other contributing factors like, socioeconomic state, diabetes mellitus, recurrent UTI, and other immunologic and blood diseases [14] [15].
UTIs may be presented as asymptomatic bacteruria, cystitis or pyelonephritis with systemic manifestations [16] [17].Asymptomatic bacteruria should be treated to prevent the occurrence of symptomatic bacteruria as cystitis and pyelonephritis and to prevent its hazards on pregnancy outcomes.At the same time it should be known that asymptomatic bacteruria carries a great risk for development of pre-eclampsia, chorio-amnionitis and preterm delivery [18] [19] [20].
Moreover, repeated urinary tract infection with repeated courses of antibiotic treatment resulted in highly antibiotic resistant bacteria and multi-drug resistant organisms.In addition, the compliance of the patient to take a drug may add a hazard to drug resistant and recurrent infection.So, physicians should shift towards early efficient treatment of UTI in the pregnant females, not only for the health hazards, but also, to decrease progressive UTI during pregnancy which are the most common cause of hospital admissions during pregnancy [21] [22].
It is well known that urine cultures are time and money consuming, contaminated and sometimes antibiotic sensitivity results may be inconvenient with pregnancy; these factors motivate both urologists and obstetricians to begin empirical antibiotic therapy especially in symptomatic patients [17]    treatment in non-complicated UTI [26].Nitrofurantoin is a category B drug during pregnancy and commonly prescribed drug for non-complicated UTI during pregnancy [27] [28].However, there are a lot of concerns about Nitrofurantoin resistance, safety, and patient compliance [29].Also Nitofurantoin not used during delivery or in near term (i.e.>36 weeks) because of the assumed possibility of haemolytic anaemia in the newborn [30].Fosfomycin trometamol is another category B drug used in single dose and shown stability with decreased appearance of mutant urinary strains overtime in many studies.It has higher efficacy and better compliance over Nitofurantoin and other drugs making it a first choice drug for uncomplicated UTIs In pregnancy [10] [31] [32] [33].
Many studies compared the efficacy and safety of both drugs in uncomplicated UTIs in females but not during pregnancy.Both drugs proved to be safe.Side effects were comparable in both groups, but drug compliance was better with Fosfomycin trometamol.Also, subjective and the resolution of infection were better and significantly different in the group of Fosfomycin trometamol [34] [35] [36].
During pregnancy Usta TA, et al. (2011) selected 324 pregnant women with lower urinary tract infection and allocated them randomly into 3 groups, Fosfomycin trometamol, Amoxicilin-calvulinc, and cefuroxime axetil.The treatment groups did not differ significantly in terms of demographics, clinical success rate, microbiological cure rate, or adverse effects.Significantly higher drug compliance was observed in the Fosfomycin trometamol group than in the other 2 groups (p < 0.05).Consequently, they suggested that treatment with a single dose of Fosfomycin trometamol is as effective as the standard course of treatment with Amoxicilin-calvulinc, or cefuroxime axetil, and Fosfomycin trometamol is preferable owing to its simpler use [37].[47] and Mody et al. (2014).[48] The minor side effects of Fosfomycin were confirmed by Bayrak et al. (2007), who revealed associated minor side effects with Fosfomycin [45].
At last, the compliance of both drugs was better in Fosfomycin group 100% versus 91.8% in Nitrofurantoin group.This high compliance with Fosfomycin is greatly attributed to the single administered dose in opposite to the need of 7 days of Nitrofurantoin.

Limitations of the Study
The small sample size and the financial costs of drugs-being self-funded-were the main limitations of the study.

Conclusion
Owing to the higher safety, efficacy, low resistance for Fosfomycin trometamine in management of uncomplicated UTIs during pregnancy, we recommend its wide use at Tanta University Hospitals and to replace other antibiotic regimens as it is cost-effective than other drugs.Moreover, very high patient compliance, fewer side effects were observed with Fosfomycin than other drugs making it a first choice at our hospitals.

Figure 1 .
Figure 1.Flow chart of included patients and their management options.

Figure 2 .
Figure 2. Side effects of drugs tested in the study.

Table 1 .
Demographic data and presentation of enrolled patients.

Table 2 .
Efficacy, safety, compliance and cost of treatment options for both groups.
* means significant p-value.