Middle East Journal of Family Medicine

Efficacy of Antibiotics in Women with Symptoms of Urinary Tract Infection but Negative Dipstick Urinalysis: Prospective Randomized Controlled Trial
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M Mashaqba MD**
Naser Al-Husban MD, MRCOG**
*Prince Hashem Bin Al-Hussein Hospital, Zarka, Jordan
** Obstetrics & Gynaecology Department

Address correspondence to:
Dr Mahmoud Mashaqba
Jordan - Mafraq
Arab bank
PO Box 296
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ABSTRACT

Background: Infections of the urinary tract are extremely common.
Urine testing with dipsticks that detect the presence of leukocyte and nitrites is commonly used in primary care to predict the subsequent diagnosis of urinary tract infection as determined by standard midstream urine leukocyte and nitrites in turbid urine, had a positive predictive value of finding pure growth on subsequent culture of around 66%2. Conversely, a negative dipstick for both leucocytes and nitrites has a negative predictive value of finding a pure growth on subsequent culture of 80-98.5 %( 1, 2).

Objective: To assess the effectiveness of antibiotic treatment of women with symptoms of urinary tract infection but negative urine dipstick testing.
Design: Prospective, Randomized Controlled trial.
Setting: Obstetrics and Gynaecology clinic at Prince Hashim Bin Al-Hussein hospital, Zarka, Jordan.

Participants: 59 women aged 16-50 years presenting with a history of dysuria and frequency in whom dipstick test of midstream urine was negative (tested for proteinuria, glycosuria, leucocytes, red blood cells, cellular casts and nitrites).

Intervention: Trimethoprim 300 mg daily for three days or placebo. Outcome Measures: self reported diary of symptoms for seven days, recording the presence or absence of individual symptoms each day. The main clinical outcome was resolution of symptoms.
Results: the median time for resolution of dysuria was three days for trimethoprim compared with five days for placebo (p=0.002). At day 3, five (24%) of patients in the treatment group had ongoing dysuria, compared with 20 (74%) in the placebo group (p=0.005). This difference persisted until day 7: two patients (10%) in the treatment group v 11(41%) in the placebo group (p=0.02). The median duration of constitutional symptoms (fever, shivering) was reduced by four days.

Conclusion: although negative dipstick test accurately predicted absence of infection when standard microbiological definition was used (negative predictive value 92%), it did not predict response to antibiotic treatment. Three days' treatment with trimethoprim significantly reduced dysuria in women whose urine dipstick test was negative. These results support the practice of empirical antibiotic use guided by symptoms.

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INTRODUCTION

Infections of the urinary tract are extremely common. Because the symptoms of dysuria and frequency are unpleasant, doctors are under pressure from patients to provide relief (1,2). However, not all such symptoms are associated with growth of bacteria in a standard midstream urine specimen. More detailed microbiological investigation of women with apparently negative urine culture on standard testing indicate that a proportion of them have low count bacteriuria (3). Urine testing with dipsticks that detect the presence of leukocyte and nitrites is commonly used in primary care to predict the subsequent diagnosis of urinary tract infection as determined by standard midstream urine leukocyte and nitrites in turbid urine, had a positive predictive value of finding pure growth on subsequent culture of around 66%2. Conversely, a negative dipstick for both leucocytes and nitrites has a negative predictive value of finding a pure growth on subsequent culture of 80-98.5% (1,2).

The approach to women with symptoms of uncomplicated urinary tract infection and positive urine dipstick results is to give empirical antibiotic treatment4-6. Recommendation for the treatment of women with symptoms and negative dipstick results vary. Some suggest empirical treatment7, but others do not4,5,8. We carried out a pragmatic trial of antibiotic compared with placebo in women with symptoms of uncomplicated urinary tract infection and negative dipstick result.

We designed the study as a prospective randomized placebo controlled trial. The intervention was treatment with trimethoprim 300 mg daily for three days. 59 women aged between 16-50 were randomly chosen from women with symptoms of urinary tract infection and who attended the gynaecology clinic at Prince Hashim Bin Al-Hussein hospital.

All the women who agreed to participate provided a midstream urine specimen tested immediately with a standard urine dipstick and then sent for microbiological examination and culture. We randomly allocated a patient whose dipstick test was negative to receive either three days of trimethoprim 300 mg (standard treatment) for those with even military identification numbers, or placebo for those with odd numbers.

Those women were asked about current symptoms, the presence or absence of dysuria, increased urinary frequency, low back pain, abdominal pain, appearance of blood in the urine, itching, and feeling hot or shivery. Women were also asked about potential risk factors for infection, including use and type of contraceptives, recent sexual activity, past history of infection, and use of other preparations to alleviate symptoms. Participants received a seven-day diary to record their symptoms. They recorded the presence or absence of individual symptoms each day. Where a symptom was absent and had been recorded as present on the day 1 of the questionnaire, we asked the woman to recall the day on which the symptom resolved. Adverse effects potentially related to medication and any other treatments taken were recorded. We asked participants to provide a second midstream urine specimen for microbiological examination and culture.

The main outcome was resolution of dysuria in the intervention and control groups at three and seven days and median time to resolution. Secondary outcomes were resolution of other symptoms. We investigated predictors of response to treatment.

The study was powered to detect clinically important differences between the two groups. With 30 participants in each arm, using a2=0.05 the study has 78% power to show a difference between groups if the true rates are such that symptoms will not resolve in only 10% of women taking antibiotics compared with 40% of women taking placebo. This sample size has 99% power to detect a difference between groups if the true state is such that symptoms will not resolve in only 25%of women taking antibiotics compared with 75% of women taking placebo.

Among all women who reported dysuria on day 1, the median time for resolution of dysuria was three days in the trimethoprim group and five days in the placebo group (p=0.002). At day three, 24.5% of patients in the treatment group who had dysuria on day one still had dysuria compared with 74% of the placebo group (p=0.005); this difference was still present at day 7, when only 10% of the treatment group who reported dysuria on day 1 were experiencing dysuria compared with 41% of the placebo group (p=0.02). Less than a third of the patients in each group experienced constitutional symptoms of feverishness or shivers. However, among those who had symptoms, the median time from clinical presentation and treatment initiation to resolution of feverishness or shivers was two days in the trimethoprim arm, compared with six days in the placebo arm (p=0.02). At day three, 46.5% of patients in the placebo group were still feeling hot and shivery compared with none of the treatment group (p=0.04).

Compared with placebo, administration of trimethoprim notably shortened the median duration of dysuria in women with symptoms of uncomplicated urinary tract infection in whom dipstick results were negative. For those women who reported dysuria at baseline, the duration of dysuria from the time of clinical presentation was shortened by a median of two days. Four women needed to be treated with trimethoprim to shorten the duration of symptoms, for one woman, (number needed to treat=4). Similarly, the median duration of constitutional symptoms indicating infection (feverishness, shivers) was reduced by four days. The duration of any other symptoms did not differ. These results indicate a bacterial or other infectious cause for the symptoms, that was missed by dipstick testing and standard testing in a diagnostic laboratory. The resolution of symptoms that generally accompany infection (feeling feverish or shivery) would provide some support for an atypical or occult infective cause, implying that these women do not have urethral syndrome, a diagnosis of exclusion.

It is known that a past history of urinary tract infection also increases the risk of subsequent infection, and 90% of the women in the sample reported a past history of similar symptoms.

Although negative dipstick results are useful in predicting which women aged 16-50 presenting with symptoms of urinary tract infection will have a negative urine culture, these results show that it does not follow that this will predict response to antibiotic treatment. Further clinical and microbiological study of the group of women who seem not to have infection yet whose symptoms are relieved more quickly with a short course of trimethoprim is needed to understand the aetiology of symptoms in this group. At a population level, a need also exists to find a more discriminating way to avoid unnecessary antibiotic exposure in all women presenting with symptoms of urinary tract infections(9).

Although negative dipstick test accurately predicted absence of infection when standard microbiological definition was used (negative predictive value 92%), it did not predict response to antibiotic treatment. Three days' treatment with trimethoprim significantly reduced dysuria in women whose urine dipstick test was negative. These results support the practice of empirical antibiotic use guided by symptoms.