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closeBut are antibiotics superior to placebo?
Posted by WilliamYang on 19 Jun 2018 at 18:56 GMT
Vik and colleagues’ study on treatment of uncomplicated urinary tract infections concludes that antibiotics are indicated for uncomplicated “UTI” and that ibuprofen alone is not recommended. The results suggest the inferiority of ibuprofen with respect to symptoms. But seven patients in the ibuprofen group developed pyelonephritis, an incidence higher than in any of the placebo-controlled trials, and five of these patients were hospitalized. The authors suggest that this may indicate a harmful effect of ibuprofen when treating “UTIs”. At the same time, symptoms resolved without antibiotics in most of the women in the ibuprofen group.
As Voltaire famously stated, “The art of medicine consists in amusing the patient while nature cures the disease.” Nearly all women with dysuria, bacteriuria or both simultaneously will recover spontaneously. However, the authors considered it unethical to have a placebo arm because of the existing data suggesting antibiotics as superior to placebo. We feel that this represents an unfortunate omission from the study as a placebo arm would have helped to characterize the potential harms of ibuprofen. We also consider it likely that the use of antibiotics to treat “UTIs”, apparently better than ibuprofen, might be considered only less detrimental than ibuprofen, yet not necessarily better than no treatment at all. A prior review of uncomplicated urinary tract infection emphasized that “Acute uncomplicated cystitis rarely progresses to severe disease, even if untreated; thus, the primary goal of treatment is to ameliorate symptoms.” (1) We have used quotes around “UTI” here because of its ambiguous definition. (2) For example, about a third of the patients in this study had negative urine cultures.
1. Hooton T. Uncomplicated Urinary Tract Infection. N Engl J Med 2012; 366:1028-1037 DOI: 10.1056/NEJMcp1104429
2. Finucane TE. "Urinary Tract Infection"-Requiem for a Heavyweight.J Am Geriatr Soc. 2017 Aug;65(8):1650-1655. doi: 10.1111/jgs.14907.
Author's response
ivik replied to WilliamYang on 27 Jun 2018 at 11:19 GMT
Dear Dr. Thomas Finucane and Dr. William Yang,
Thank you both for your relevant comments.
We agree that it would have been interesting to have had placebo as a third treatment arm in our trial, hence making it easier to compare the natural course of an uncomplicated urinary tract infection (UTI) to treatment with ibuprofen or antibiotics. As placebo versus antibiotics for uncomplicated cystitis had already been tested and placebo found to be inferior to antibiotic treatment, we thought it would be difficult to get ethical approval for including a placebo arm.[1]
We know from the placebo trials that the rate of pyelonephritis was similar in the placebo and the antibiotic groups, hence placebo did not seem to cause more severe harm other than a prolonged course of illness.[2] In General Practice antibiotics are mainly used to shorten the course of an illness and prevent complications. In a time where we are trying to reduce unnecessary use of antibiotics, it is more interesting than ever to consider the natural course of self-limiting diseases. In future studies on uncomplicated UTIs, which is considered a self-limiting condition, we believe it would be interesting to include three arms, comparing an analgesic (i.e. paracetamol) to a placebo and an antibiotic, hopefully it will be possible to get ethical approval for such a trial.
Our study was not powered to look at complications, and we agree that the play of chance could be involved in the difference between the two groups. However, with the results of the trial of Gagyor et al. and Kronenberg et al. both showing a higher rate of pyelonephritis in the NSAID groups compared to the antibiotic groups, we are inclined to believe that NSAIDs could play a part in facilitating the bacterial infection becoming more invasive. We know that ibuprofen can inhibit the function of leukocytes at the infection site as well as inhibit antibody production.[3,4] This could be part of the explanation as to why some patients developed a more severe infection, further research is needed to look into this. As mentioned in the article we are planning to perform an individual patient data (IPD) analysis of all the placebo and NSAID trials to try to find predictors that can help us identify which patients are likely to develop complications.
A positive urine culture has been used as a gold standard to “prove” that a patient has a urinary tract infection, but placebo trials have shown that patients with a negative culture can have persistent symptoms if left untreated. We also know that patients with a negative urine culture experience the same symptomatic relief from antibiotic treatment as the patients with positive cultures. A recent study from Belgium showed that conventional culturing only found significant growth of E.coli in 81% of the samples, whereas PCR identified E.coli in almost 96% of the patients, indicating that almost all women with symptoms of an acute UTI actually have a bacterial infection.[5] The definition of a UTI is, as you correctly point out, ambiguous, and we decided to use clinical symptoms, not a positive urine culture. This represents the everyday challenges of the general practitioners where you have to rely on clinical symptoms and point of care (POC) tests to make the correct diagnosis and choose the suitable empirical treatment.
1. Helsinki declaration, point 33, https://www.wma.net/polic...
2. Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. The Journal of infection. 2009;58(2):91-102.
3. Bancos S, Bernard MP, Topham DJ, et al. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol 2009;258(1):18-28. doi: 10.1016/j.cellimm.2009.03.007 [published Online First: 2009/04/07]
4. Suleyman H, Demircan B, Karagoz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep 2007;59(3):247-58. [published Online First: 2007/07/27]
5. Heytens S, De Sutter A, Coorevits L, Cools P, Boelens J, Van Simaey L, et al. Women with symptoms of a urinary tract infection but a negative urine culture: PCR-based quantification of Escherichia coli suggests infection in most cases. Clin Microbiol Infect. 2017;23(9):647-52.