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Treatment of uncomplicated symptomatic urinary tract infections: Resistance patterns and misuse of antibiotics

Introduction: Uncomplicated but symptomatic urinary tract infections (UTIs) are a common problem seen in practice. The study was undertaken to assess the most common pathogens responsible for uncomplicated symptomatic UTIs and the antimicrobial resistance pattern in a hospital in Bangalore. The study also explores the issue of antibiotic usage for these patients. Materials and Methods: The study was conducted in the Medicine department of a tertiary hospital in Bangalore. In all, 196 patients presented with symptoms of UTI. Bacterial growth was determined by standard microbiology techniques on freshly voided mid-steam urine samples collected from recruited patients. Patients’ demographic data, urine culture results, resistance rates to antimicrobial agents and prescribed empiric antimicrobial therapy were analyzed. Results: The prevalence of UTI was 32.1%; majority (67.9%) of the symptomatic did not have UTI based on culture report. Gram-negative bacteria constituted the largest group with a prevalence of 84.1% (53/63), with Escherichia coli being the most common (70%) uropathogen. Gram-negative isolates showed high level of sensitivity to amikacin (90.6%) and nitrofurantoin (77.4%). Most of the gram-positive organisms were susceptible to nitrofurantoin (70%) and gentamicin (50%). Uropathogens isolated demonstrated high resistance to cotrimoxazole, fluoroquinolones, and beta-lactam antibiotics. It was found out that 30.1% of the patients were wrongly managed of which 14.7% were over treated. Conclusion: UTI can be over diagnosed and over treated on the basis of clinical signs, symptoms and urine microscopy. In the era of emerging anti-microbial resistance, effective counseling and delay in antibiotic initiation or empirical therapy with a short course of nitrofurantoin is highly recommended. Empirical therapy guidelines should be updated periodically to reflect changes in antimicrobial resistance of uropathogens.


Introduction
Urinary tract infections (UTIs) are one of the most common types of bacterial infections occurring both in the community and hospital settings. [1][2][3][4] Today it represents one of the most common diseases encountered in medical practices [5] with the prevalence of UTI varying from 21.8% to 31.3% in various parts of India. [6][7][8] The current study was undertaken to assess the most common pathogens responsible for uncomplicated UTIs and the antimicrobial resistance pattern in a tertiary hospital in Bangalore. Additionally, the study throws light into the issues of overtreatment, under treatment and wrong treatment of UTI.

Materials and Methods
The study was conducted in Bangalore Baptist Hospital, Bangalore. Assuming a prevalence of 24% [7] of UTI in symptomatic patients at 6% precision and 95% confidence level, the sample size calculated was 196.
Patients who came to the medicine OPD with symptoms (dysuria, frequency, urgency and suprapubic tenderness with or without fever) of UTI or any patients in whom the physician suspected uncomplicated UTI were recruited into the study. Patients with signs of pyelonephritis (a body temperature >38°C orally and flank pain or costovertebral angle tenderness), three or more episodes of UTI in the past year, symptoms of UTI in the last 3months, previous upper UTI, other functional and structural urinary tract abnormalities, indwelling or recent use of a catheter, previous history of genitourinary system operation including urinary stones, current pregnancy, antibiotic use during the previous 2 weeks and patients who were hospitalized for any reason during past 3months were excluded from the study.
The patients were interviewed using a semi-structured questionnaire which contained demographic information and symptomatology.
A freshly voided, midstream urine sample was collected in a sterile container from each patient enrolled for the study. All of them were given clear instructions on how to collect a midstream urine specimen.
The sample was inoculated for semi-quantitative culture on Cystine-Lactose-Electrolyte-Deficient (CLED) media using a calibrated loop. The culture plate was incubated at 37°C for 18-24 hours under aerobic conditions. Identification of bacterial growth was determined by Gram's staining and standard microbiology techniques.

Definition of terms
Urinary tract infection: A quantitative count of more than 10 [5] Colony Forming Units of one bacterial species per ml from a properly collected midstream "clean catch" urine sample is considered as UTI. [10] Uncomplicated UTI: Uncomplicated UTI is defined as UTI in a person with a normal urinary tract and function.
Correct management: • A person presented with symptoms of UTI, had a positive urine culture and treated with an antibiotic which was effective against the uropathogen isolated or • A person presented with symptoms of UTI, had a negative urine culture and not treated with an antibiotic or • A person who was started on empirical therapy with a resistant antibiotic, but was subsequently changed to an uropathogen sensitive antibiotic after culture report.
Wrong management: • A person presented with symptoms of UTI, and a positive urine culture but treated with antibiotic which was not effective against the uropathogen isolated or • A person presented with symptoms of UTI, had a negative urine culture but treated with an antibiotic or • A person presented with symptoms of UTI, had a positive urine culture but not treated with an antibiotic or • A person who was started on empirical therapy with an antibiotic, but was not changed to an uropathogen sensitive antibiotic after culture report.

Ethics
The study was conducted in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 1983. The study was approved by the Institution Review Board of Bangalore Baptist Hospital. Written informed consent was obtained from every recruited patients and confidentiality was maintained at every stage of the research.

Statistics
The data collected was first coded and then transferred to a master chart on Microsoft Excel which was programmed to minimize the error. The range of the continuous values was specified and codes were picked from drop down menu as a measure to reduce the error. Data was validated by double-checking by randomly picking different segments to look for incorrectly entered data. Descriptive analysis was done in SPSS to look for numbers that are out of range or errors in data entry.
Distribution as well as co-relation tables were prepared, analyzed and statistically evaluated by SPSS version 16.0. UTI prevalence was expressed in percentage. The Chi-square test was done to identify the variables associated with UTI (age, gender, presence of co morbidities). Frequencies and percentages were calculated for distribution of uropathogens in different age groups, gender and among diabetics.

Results
Among the 204 eligible patients approached, 196 people agreed to participate in the study, yielding a response rate of 96.1%. The mean age of the study population was 43.84 years. Majority (60.7%) were females. 17.8% of the patients had diabetes and 13.7% had hypertension. 71.4% had no co-morbid conditions.
Almost half (42.3%) of the studied population presented with dysuria alone and another 33.2% had a combination of fever and dysuria. The prevalence of UTI was 32.1%. The prevalence of UTI was higher in females (39.5%) than males (20.8%) and this was statistically significant. The prevalence of UTI was more in diabetics (44.4%) than non-diabetics (29.4%); however this was not statistically significant (P = 0.13). Even though the prevalence of UTI is more in people above 80 years and those with co morbidities. the association was not statistically significant [  Table 2].
The antibiotic sensitivity pattern is shown in Table 3. Amikacin (90.6%), nitrofurantoin (77.4%) and cotrimoxazole (49.1%) were the most effective antibiotics against gram-negative organisms. Most of the gram-positive organisms were susceptible to nitrofurantoin (70%) followed by gentamicin (50%) and ampicillin (30%). Ciprofloxacin was effective against 20% of gram-positive and 37.7% gram-negative organisms. It was found out that 30.1% of the patients were wrongly managed in spite of urine culture [ Table 4]. Wrong management included not treating culture-positive patients, treating with the incorrect (resistant) antibiotics and prescribing an antibiotic when the culture is negative. 14.3% of the patients were overtreated (treatment not needed but treated) and under treatment (treatment needed but not treated) was in 7.1%. Among the people who needed treatment, only (32/63) 50.7% were treated with correct antibiotics. Almost one fifth of patients (28/133) who did not require treatment were treated with antibiotics. Overtreatment was not associated with age, gender and the presence of co-morbidities. The presence of 6-15 pus cells was associated with overtreatment [ Table 5].

Discussion
The prevalence of UTI in our study was 32.1% and it was significantly higher in females (39.5%) compared to males (20.8%). Similar observations were also recorded by Astal et al., [11] Khalifa et al., [9] and Ahmed et al. [12] Several reports have also indicated that females are more prone to having UTIs than males, [13] as the urethra is shorter in females than males thus being more readily and easily prone to micro-organisms. [14] The bacteria isolated were E. coli with a frequency rate of 69.8% followed by K. pneumoniae (7.9%), CoNS (4.8%), Pseudomonas sp. (4.8%), S.viridans (4.8%), Enterococcus (4.8%), MRSA (1.6%) and non-fermenting gram-negative bacilli (1.6%). All the micro-organisms isolated in this study were of clinical significance and were similar to the data recorded by Manikandan et al. [15] and Al-Sweih et al. [16] The isolation frequency of the bacterial species reported in this study falls within the range of frequencies reported from other parts of India [17] too.
The microbiological and antibiotic sensitivity pattern observed in our study is similar to findings of Banerjee et al., [18] and Sharma et al. [19] The alarming finding was AMP, AMC and most of the Cephalosporins were resistant to most of the strains. The possible explanation may be because these antibiotics have been in use for a long period and more often due to the misuse of antimicrobial drugs, which has today led to a general rise in the emergence of resistant bacteria. [20,21]  The present study reports that 14.3% of the studied population was over treated. Overtreatment in elderly patients presenting with symptoms of UTI has been reported in other studies. [22,23] Literature also rates UTI as the second most common reason for empirical antibiotic therapy in secondary care. [22] However, in this study old age and gender was not associated with overtreatment. Urine routine report of 6-15 pus cells in a symptomatic patient was associated with overtreatment. Predictive value of 6-15 pus cells is low and therefore treating with antibiotic without consulting the culture report might have resulted in overtreatment.
8.7% were treated with resistant drugs which could have been avoided if the physician waited for the culture report. The patient could have been managed by other symptom relieving drugs or by empirical therapy with nitrofurantoin. Among these 17 patients who were treated with a resistant drug, 11 (64.7%) were sensitive to nitrofurantoin. The chance of treating with resistant antibiotic was higher when the physician started on cephalosporins (cefixime, ceftriaxone and cefoperazone sulbactam). This was because most of the organisms were resistant to cephalosporins. This implies the importance of checking the culture report before starting on antibiotics.
There are no country specific guidelines for treating UTI; the Indian Society of Nephrology states that knowledge of local resistance pattern is needed to guide empirical therapy in the light of rising resistance to amoxicillin, sulfa drugs, cotrimoxazole and fluoroquinolones. [24] According to an update by the Infectious Diseases Society of America (IDSA) guidelines, a short-course therapy (3 day) with either nitrofurantoin or trimethoprim-sulfamethoxazole (if the local resistance prevalence less than 20%) is recommended. [25] However, trimethoprim-sulfamethoxazole is not a good option for empirical therapy as there are many studies including the present study which reports a resistance of more than 20%.
Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommends a 7 day course of fluoroquinolones for cystitis in men, however a more detailed evaluation is recommended in men. [26] Fluoroquinolones may not be appropriate for empirical drug therapy as 85.7% of men with E. coli demonstrated resistance to fluoroquinolones in the present study. Though    Consequently, evolving practice seeks to achieve good symptom control for uncomplicated acute cystitis while reducing antibiotic use. For example, European practice increasingly includes the option of offering a 48-hour delayed antibiotic prescription to be used at the patient's discretion. [27] Conclusion Almost one third of the patients were managed inappropriately in spite of the availability of a culture report. Ciprofloxacin and Cotrimoxazole were preferred by most of the physicians, with one fifth of patients being started on parenteral antibiotics with no apparent rationale.
Periodic surveillance of antimicrobial resistance of uropathogens, re-evaluation of empirical therapy, pre-therapy counseling for delayed antibiotic initiation and short-course antibiotic therapy with sensitive antibiotics are vital in an era of emerging antimicrobial resistance.