Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial
BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h6544 (Published 23 December 2015) Cite this as: BMJ 2015;351:h6544
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1. Why did you choose a 10^2 cfu/mL cutoff to determine status of microbiological culture? Generally speaking, the norm in practice is to use 10^5 cfu/mL, as does the IDSA in defining significant bacteriuria. If you had done so, I suspect that status of microbiological culture would have consisted in an even more accurate predictor of women who can benefit from antibiotic treatment.
2. I also question your decision to transpose bioequivalence accepted margins to your definition of non-inferiority. Bioequivalence margins define a range of pharmacokinetic parameters within which the clinical effect of a single drug is deemed to be equivalent. However, in the case of non-inferiority, we seek to define the range of a clinical parameter (outcome) within which two drugs would be considered equivalent. In this case, the range of non-inferiority is very difficult to estimate, considering the lack of evidence.
Competing interests: No competing interests
Author´s reply: Thank you for this comment. We agree that the potential antimicrobial properties of ibuprofen are an important factor which is, however, still under discussion. Obad et al. showed that for E. coli, the main causative agent for urinary tract infection (UTI), no inhibition zones were obtained in a disk diffusion assay with ibuprofen. Thus, for UTI the antimicrobial effect of ibuprofen remains unclear. Further research is needed, as planned in a Scandinavian UTI trial by Vik et al.
Vik I, Bollestad M, Grude Net al. Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol. BMC Infect Dis 2014;14: 693
Obad J, Šušković J, Kos B. Antimicrobial activity of ibuprofen: new perspectives on an "Old" non-antibiotic drug. Eur J Pharm Sci. 2015 Apr 25;71:93-8
Competing interests: No competing interests
I read with interest the article by Gágyor I, Bleidorn J, Kochen MM et al. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial (BMJ 2015;351:h6544), but I am wondering why the authors haven’t taken into consideration that Ibuprofen is a non-antibioticum (1, 2) and that it has antimicrobial activity like many other non-antibiotics. If note of the non-antibiotic activity was made in the protocol and results sections, then this would have led to a clearer understanding of the observed beneficial effects of ibuprofen described in the conclusions. The use of ibuprofen for ‘symptomatic treatment’ implies that one is relying on its ‘painkiller’ activity whereas in practice it may well be that it is the broad spectrum antimicrobial activity of ibuprofen that is the most significant. In particular the possibility for microbial resistance development again ibuprofen should also be discussed, even it is “only” used as painkiller in UVI investigation.
The antimicrobial activity of the large and diverse groups of non-antibiotics is unfortunately often overlooked when treating patients suffering fromnon-infectious diseases. Regrettably, it is not mandatory to mention these antimicrobial “side effects” in the information materials supplied, even though they might be positive.
1. Kristiansen JE. 1991. Antimicrobial activity of nonantibiotics. ASM News 57:135–139.
2. Jelena Obada, Jagoda Šuškovićb, Blaženka Kosb. Antimicrobial activity of ibuprofen: New perspectives on an “Old” non-antibiotic drug. European Journal of Pharmaceutical Sciences Volume 71, 25 April 2015, Pages 93–98
Competing interests: No competing interests
Authors' reply
We agree with Al-Wali that (if an antibiotic treatment approach was chosen) women should be treated with firt line antibiotics to reduce the emergence of resistance.
In the ICUTI trial we choose fosfomycin as comparator because
- German guidelines on UTI recommend Trimethoprim, Nitrofurantoin and Fosfomycin as first line choices (1).
- In Germany the use of nitrofurantoin is restricted. According to the summary of product characteristics provided by the manufacturer nitrofurantoin is allowed only, “when more effective and less risky antibiotics can not be used”. The consequence is, that nitrofurantoin as first line therapy represents an off-label use.
- ecological risks of an increased use of fosfomycin ("emergence of resistance") were discussed and taken into account during the development of the german guideline. Based on the current evidence in 2011 the experts rated the risk as low.
We further agree with Al Wali that data on local antimicrobial resistance are needed. During the conceptualization of the study the information on resistant rates of causative agents in the german primary care setting were scarce. In the meantime a cross sectional study (2) showed low resistance rates for fosfomycin and nitrofurantoin (4.5%, 2.2%) and intermediate rates for trimethoprim (17.5%).
(1) Wagenlehner, FME., Hoyme U, Kaase M, Fünfstück R, Naber KG, Schmiemann G. „Uncomplicated Urinary Tract Infections“. Deutsches Ärzteblatt International 108, Nr. 24 (Juni 2011): 415–23. doi:10.3238/arztebl.2011.0415.
(2) Schmiemann, G, Gágyor I, Hummers-Pradier E, Bleidorn J. „Resistance Profiles of Urinary Tract Infections in General Practice - an Observational Study“. BMC Urology 12, Nr. 1 (21. November 2012): 33. doi:10.1186/1471-2490-12-33.
Competing interests: No competing interests
We have read the research findings of Gagyor et al. with interest. However, we wish to point out that the choice of using fosfomycin in the treatment arm wouldn't be advisable as first line treatment for uncomplicated urinary tract infections. Other antimicrobials such as nitrofurantoin would be preferrable.The reason being that this antimicrobial is reserved for highly resistant organisms and in particular extended spectrum beta-lactamase (ESBL) producing Gram-negative bacteria. Furthermore, fosfomycin in its intravenous form is now licensed for the treatment of a range of highly resistant Gram-negative organisms; therefore the frequent use of oral fosfomycin to treat a very common infection i.e. UTI would invalidate its use because of the inevitable emergence of resistance.
It is always best practice to test the urine for culture and sensitivity to establish not only the nature of the infecting organism and its sensitivity pattern but also the prevalence of antimicrobial resistance in a particular demographic region.
Competing interests: No competing interests
Author's reply
Uncomplicated urinary tract infections (UTI) in general practice are known as often self-limiting conditions as shown in placebo controlled trials (1, 2) and reported by women (3). In this pragmatic trial we did not compare two drugs but rather two different treatment strategies: symptomatic treatment first and antibiotics only if symptoms persist or worsen versus antibiotic treatment first. Relief of symptoms and cure of infection are different aspects of treatment indeed but the main aspect for women is symptom relief (4). For this purpose, symptomatic treatment may be effective in many cases, in particular since increasing resistance rates request prescribing antibiotics only to those who really need them. With this rationale, the Ethic Committees did not see ethical problems with the trial.
Furthermore, it is known that many otherwise healthy women have bacteria in their urine. To focus on bacterial cure as a treatment target is not recommended any more (5, 6), nor to treat otherwise healthy non-pregnant women with asymptomatic bacteriuria.
Use of ibuprofen when there is evidence of UTI: In the pilot trial HWI-01 urine cultures were tested initially and again at day 7 (7). Negative cultures were seen more often in the ciprofloxacin group (23/33, 71.9%) than in the ibuprofen group (16/36, 48.5%) while the symptom relief was achieved in almost all participants. Women who received antibiotic treatment during the follow-up period consulted their GPs up to day 9. Within the follow-up period of four weeks none of the women with asymptomatic bacteriuria consulted their GP again. In the study reported in the BMJ (ICUTI) second urine cultures were not done but the re-consultations were distributed similarly during the follow-up period. We assume that women with bacteriuria did not differ from those with a negative urine culture.
Pyelonephritis is a rare but potentially severe acute condition which can also occur as complication of uncomplicated UTI (8, 9). We agree that the risk of pyelonephritis after non- antibiotic UTI treatment should be monitored carefully, but pyelonephritis is too rare an occurrence to act as primary outcome. The ICUTI trial was not powered to compare the numbers but meta-analyses of current and future European UTI trials are planned.
Symptomatic treatment might be recommended to women who want to avoid antibiotics when this treatment is as safe as antibiotic treatment. Another approach could be to identify women with a high risk to develop pyelonephritis when they initially present. Therefore, we are now conducting a systematic review of UTI- trials to identify factors associated with worsening UTI outcomes including pyelonephritis.
1) Christiaens, TCM, de Meyere M, Verschraegen G, et al. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract 2002;52:729–734.
2) Ferry SA, Holm SE, Stenlund H, et al. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis 2004; 36: 296–301.
3) Butler CC, Hawking MK, Quigley A, McNulty CA. Incidence, severity, help seeking, and management of uncomplicated urinary tract infection: a population-based survey. Br J Gen Pract. 2015;65:e702-7.
4) Willems CS, van den Broek D'Obrenan J, Numans ME, et al. Cystitis: antibiotic prescribing, consultation, attitudes and opinions. Fam Pract 2014; 31: 149–55.
5) Epidemiology, diagnostics, therapy and management of uncomplicated bacterial community acquired urinary tract infection in adults, German S3-Guideline, 2010. (http://www.awmf.org/leitlinien/detail/ll/043-044.html; last accessed on Jan 7, 2016)
6) Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40:643–654
7) Bleidorn J, Gágyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--results of a randomized controlled pilot trial. BMC Med. 2010;8:30.
8) Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. 2014 Mar;28:1-13.
9) Czaja CA, Scholes D, Hooton TM, Stamm WE.Population-based epidemiologic analysis of acute pyelonephritis. Clin Infect Dis. 2007;45:273-80.
Competing interests: No competing interests
Since uncomplicated UTI is a self -limiting disease like most of diarrheal or upper respiratory infection, it is okay to give symptomatic treatment with ibuprofen in order to stop irrational use of antibiotics and hence avoid antibiotic resistance from developing. So we disagree with Dr. Rajiv Kumar from Chandigarh, India who asks:
"Is it rational to compare analgesic anti-inflammatory drugs like ibuprofen with antibiotics like fosfomycin, because relief of symptoms and cure of infection are different aspects of treatment".
Competing interests: No competing interests
Ethical approval for this trial was obtained by the Independent Ethics Committees of the Hannover Medical School (No. 5986 M). I would be interested in any comments on whether this design generated some kind of debate inside the Committee. A previous reply stated that it is rational to compare analgesic anti-inflammatory drugs with antibiotics in uncomplicated urinary tract infection in women. The argument is that relief of symptoms and cure of infection are different aspects. The problem is that the two aspects are put on the same level; but is it ethical? A mere palliative attitude for infection is assumed when potentially curative means are too aggressive, of dubious effectiveness and the prognosis of the patient is too poor. What would have done if I had participated in this Ethics Committee discussing the approval for a trial that supports treating infections with antibiotics? I do not know...
Competing interests: No competing interests
Uncomplicated urinary tract infections are common in women and are usually treated with antibiotics (1). Evidence from the study shows that trimethoprim-sulfamethoxazole and nitrofurantoin remain first-choice empirical therapy for uncomplicated UTIs and fluoroquinolones should remain a second-line choice for treatment; also guidelines have been developed but their usefulness is little because of conflicting recommendations (1).
In this research, the trial authors concluded that initial treatment with ibuprofen was less effective for symptom relief in women aged 18-65 with mild to moderate symptoms of uncomplicated urinary tract infection, substantially reduced antibiotic use and there were more cases of pyelonephritis as compared with fosfomycin (2).
Fosfomycin is a broad-spectrum antibiotic which acts by inhibiting bacterial cell wall synthesis with useful activity against uropathogen E. coli (3). Hence the superiority of fosfomycin and other antibacterial drugs in the treatment of uncomplicated urinary tract infection in women is difficult to ignore.
Which treatment strategy for women with symptoms of urinary tract infection? (4) The report from a prospective cohort study is that women with symptoms of uncomplicated urinary tract infection are often willing to delay antibiotic treatment (5). However, empirical delayed prescription can help to reduce antibiotic use (6).
An open question with regards to Pharmacology Principle:
Is it rational to compare analgesic anti-inflammatory drugs like ibuprofen with antibiotics like fosfomycin, because relief of symptoms and cure of infection are different aspects of treatment.
With regards
References:
1. Lindsay Nicolle, Peter A.M. Anderson, John Conly, Thomas C. Mainprize, Jamie Meuser, J. Curtis Nickel, Vyta M. Senikas, George G. Zhanel. Uncomplicated urinary tract infection in women: Current practice and the effect of antibiotic resistance on empiric treatment.Can Fam Physician. 2006 May 10; 52(5): 612–618.
2. BMJ 2015;351:h6544
3. Maraki S, Samonis G, Rafailidis PI, Vouloumanou EK, Mavromanolakis E, Falagas ME. Susceptibility of urinary tract bacteria to fosfomycin. Antimicrob. Agents Chemother. 2009:53(10);4508-4510.
4. BMJ 2015;351:h6888
5. BMC Fam Pract 2013;14: 71.doi:10.1186/1471-2296-14-71
6. BMJ 2010;340: c199. doi:10.1136/bmj.c199
Competing interests: No competing interests
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