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Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial

BMJ 2015; 351 doi: (Published 23 December 2015) Cite this as: BMJ 2015;351:h6544

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Re: Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial

Re: Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial

Using a low numerical cut-off point, the authors are unlikely to have missed any infections with recognised urinary pathogens. This still leaves a large number of women with unexplained symptoms. Although the numbers are not directly comparable with the many studies which followed Kass’s (1) work in the middle of the last century, the conclusion is the same: infection is not detected in the urine of as many as one half the number of women who present with symptoms suggestive of urinary tract infection (UTI). Many courses of antibiotics are prescribed for these women and there is an urgent need to reduce them. Although Dr. Gágyor and his colleagues are cautious in the conclusions they draw from this study, there is little doubt that ibuprofen will now be prescribed for urinary symptoms in women.

Our work over the course of some years suggests there is an alternative. If urine specimens from women with urinary symptoms which yield a negative culture on a primary isolation medium after overnight incubation in air are re-incubated for a further 24h in a CO2 incubator (7 % CO2) many yield high bacterial counts in pure culture. The majority of the isolates were Lactobacillus spp. If cultures are incubated initially for 48h in a CO2 incubator they may yield other bacterial species in high counts and pure growth, Gardnerella vaginalis and some species of streptococci being the commonest. Once alerted to the possibility that these bacteria might be significant pathogens in some circumstances,(2,3 ) we undertook a 2y prospective study (4) of 51 women who had persistent urinary symptoms in spite of repeated courses of antibiotics, and whose urine – sent to the laboratory by GPs at a time when they had symptoms – had yielded a ‘fastidious’ organism in pure culture and high count. All specimens – suprapubic aspirates of urine (SPA), urethral swabs, and mid-stream specimens of urine (MSU) were cultured using the ‘fastidious organism’ protocol. Effercitrate (a palatable preparation of potassium citrate mixture, which was the standard medication for cystitis in the pre-antibiotic era) was given to all patients for relief of symptoms. Any patient who developed severe symptoms came to the hospital for MSU collection and culture. If this yielded a pure culture of a recognised urinary pathogen they were given a 3day course of an appropriate antibacterial agent, and reminded to keep up a good fluid intake and to empty the bladder as completely as possible every 2 hours.

From the findings of this study we postulated that repeated courses of antibiotics may distort the balance of the commensal flora of the urethra, killing the sensitive species such as staphylococci and some streptococci. facilitating multiplication of resistant species such as lactobacilli ,which might then cause symptoms due to inflammation of the urethra and possibly the periurethral glandular tissue. This suggestion was supported by the clinical finding of paraurethral tenderness on vaginal examination. Characteristically, the symptoms of which the patients complained were related to this area – dysuria with urge incontinence, and often dyspareunia. A careful clinical history can point towards this diagnosis. We concluded that antibiotics were implicated in the causation of symptoms, providing an additional reason for withholding them. Explanation both to patients and their doctors, ,and close liaison with the laboratory were fundamental to the success of this study.

We also studied (5 ) 20 patients (19 women, 1 man) who had a long history of antibacterial treatment and were said to have ‘interstitial cystitis’ and persistent ‘sterile pyuria’. Bacteria were isolated from CSUs and bladder biopsies of 12 patients . These included Gardnerella vaginalis 6 and Lactobacillus spp 2 , suggesting that this might be an advanced stage of the natural history of UTI.(6)

In this response I have used the terms that were in use at the time of the studies. However, since that time important advances in the field of the microbiome/ microbiota of urine and the urinary tract have been made by the multidisciplinary team working in Chicago under the leadership of Professors Linda Brubaker and Alan Wolfe, using DNA sequencing.(7,8) This is leading to wide acceptance that urine has an extensive microbiome ,and that microbiology laboratories must take account of this so that their protocols can be tailored to the clinical needs of patients and their doctors.

1) Kass, E.H. Bacteriuria and the diagnosis of infections of the urinary tract. Arch Intern Med 1957; 100: 709-13.
2) Abercrombie G F., Allen J, Maskell R. Corynebacterium vaginale urinary infection in a young man. Lancet 1978; 1: 766.
3) Maskell R. Pead L. Allen J. The puzzle of 'urethral syndrome': a possible answer? Lancet 1979; 1: 1058-59.
4) Maskell R, Pead L, Sanderson RA. Fastidious bacteria and the urethral syndrome: a clinical and bacteriological study of 51 women. Lancet 1983; 2: 1277-1280.
5) Wilkins EGL, Payne SR, Pead PJ, Moss S, Maskell R. Interstitial cystitis and the urethral syndrome: a possible answer. Br J Urol 1989; 64: 39-44.
6) Maskell R M. Medical Hypotheses 2010; 74: 802-806 The natural history of urinary tract infection in women. Medical Hypotheses 2010; 74: 802-806.
7) Hilt E E, McKinley K, Pearce MM et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Miicrobiol 2014; 52: 871-876.
8) Brubaker L, Wolfe AJ. The new world of the urinary microbiome in women. Am J Obset Gynecol 2015; [Epub. ahead of print.]

Competing interests: No competing interests

14 April 2016
Rosalind M Maskell
Retired Clinical Microbiologist
Retired 1993
Formerly St Mary's Hospital Portsmouth UK