‘Old’ is not always bad
Authors: T.J. Verheij, S.E. Geerlings
Journal: Clinical Microbiology and Infection (2016)

Increasing antimicrobial resistance rate is currently one of the most important healthcare problems. The total consumption of antibiotics is the main driving force [1Goossens H. Ferech M. Vander Stichele R. Elseviers M. ESAC Project GroupOutpatient antibiotic use in Europe and association with resistance: a cross-national database study.Lancet. 2005; 365: 579-587Abstract Full Text Full Text PDF PubMed Scopus (1539) Google Scholar, 2Tacconelli E. Antimicrobial use: risk driver of multidrug resistant microorganisms in healthcare settings.Curr Opin Infect Dis. 2009; 22: 352-358Crossref PubMed Scopus (123) Google Scholar]. Major problems are anticipated for an increasing number of antimicrobial agents and pathogens. The WHO signalled the emergence of antimicrobial resistance, along with the steady decline in the discovery of new antimicrobials, as a major health threat for the coming decade. To help control antimicrobial resistance, better use of the current agents is necessary [[3]World Health Organisation Global action plan on antimicrobial resistance. WHO, Geneva2015www.who.int/drugresistance/enGoogle Scholar]. Therefore, re-assessing the effects and side effects of off-patent anti-microbiological agents such as nitrofurantoin should be applauded. ‘Old’ antibiotics are generally under-used both in primary and in secondary care leading to unnecessary costs and a reduced repertoire of last-resort antibiotics. Several recent trials showed that we can safely use the traditional antibiotics when treating common acute infections like urinary tract infections (UTIs) and pneumonia [4Little P. Moore M.V. Turner S. Rumsby K. Warner G. Lowes J.A. et al.Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial.BMJ. 2010; 340: c199Crossref PubMed Scopus (150) Google Scholar, 5Postma D.F. van Werkhoven C.H. van Elden L.J. Thijsen S.F. Hoepelman A.I. Kluytmans J.A. et al.CAP-START Study GroupAntibiotic treatment strategies for community-acquired pneumonia in adults.N Engl J Med. 2015; 372: 1312-1323Crossref PubMed Scopus (259) Google Scholar]. Next to respiratory infections, UTIs are the most common bacterial infection and approximately 20%–30% of the women with a UTI will have a recurrence. Recurrent UTIs are defined as at least three episodes of a UTI in 12 months or at least two episodes in 6 months. Antibiotics are effective for low-dose antibiotic prophylaxis in the prevention of UTIs [[6]Albert X. Huertas I. Pereiro I.I. Sanfelix J. Gosalbes V. Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women.Cochrane Database Syst Rev. 2004; : CD001209PubMed Google Scholar], but lead to an increase in antibiotic resistance [[7]Sanchez G.V. Baird A.M. Karlowsky J.A. Master R.N. Bordon J.M. Nitrofurantoin retains antimicrobial activity against multidrug-resistant urinary Escherichia coli from US outpatients.J Antimicrob Chemother. 2014; 69: 3259-3262Crossref PubMed Scopus (55) Google Scholar]. For that reason, it is highly relevant to see whether we can still use off-patent antibiotics without putting patients at risk for inferior efficacy or unwanted rates of side effects. Muller et al. conclude from the results of their review that nitrofurantoin is a valid option for prophylaxis for UTIs, in both the short and long term [[8]Muller A.E. Verhaegh E.M. Harbarth S. Mouton J.W. Huttner A. Nitrofurantoin's efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials.Clin Microbiol Infect. 2016; https://doi.org/10.1016/j.cmi.2016.08.003Abstract Full Text Full Text PDF Scopus (38) Google Scholar]. This review confirms the conclusions of the review of Price et al., published earlier this year [[9]Price J.R. Guran L.A. Gregory W.T. McDonagh M.S. Nitrofurantoin vs other prophylactic agents in reducing recurrent urinary tract infections in adult women: a systematic review and meta-analysis.Am J Obstet Gynecol. 2016; ([Epub ahead of print])Google Scholar]. This conclusion seems logical as nitrofurantoin is very effective in acute infections, is mainly present in the urinary tracts with low tissue levels and does not cause bacterial resistance as quickly as many other antibiotics. However, in practice, nitrofurantoin has an image problem. Many physicians think that nitrofurantoin can be dangerous, because most of them have seen at least one incident of severe pulmonary reaction or hepatic toxicity, simply because a large number of patients receive this agent, which leads to the fact that even very rare severe adverse events occur. In addition, some physicians might feel that it is better to prescribe newer medicine instead of this ‘old’ agent, which has been available for the treatment of lower UTIs since 1953. The authors assessed the quality of the studies using the Cochrane Collaborations tool and found that only five of the 26 included trials were of good or fair methodological quality. We can therefore conclude that the evidence is not convincing, as the vast majority of trials suffer from methodological flaws making it difficult to interpret their results. Many trials date from several decades ago. But ‘old’ is not always bad and we must try to use this information. For example, the authors found that nitrofurantoin has similar efficacy compared with other antibiotics in the prevention of UTIs, and only four patients would require prophylaxis to prevent one UTI. In the trials, after 3 years of prophylaxis only one of 511 patients experienced a severe side effect, namely an interstitial pneumonia. In the cohort studies serious adverse effects such as pulmonary fibrosis or liver-related events were only described in prolonged users. It might be possible that under-reporting of adverse events took place, but the findings confirm the recommendations of most guidelines to prescribe prophylaxis for no longer than 6–12 months. When prophylaxis for a longer period is needed, studies on the efficacy and adverse events with different forms of non-antimicrobial prophylaxis are urgently warranted. For example, results of trials with intravaginal suppositories containing Lactobacillus crispatus or oral capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 are promising [[10]Beerepoot M. Geerlings S. Non-antibiotic prophylaxis for urinary tract infections.Pathogens. 2016; 5 (pii: E36)Crossref PubMed Scopus (69) Google Scholar]. In conclusion, the evidence available seems to support current prophylactic use of nitrofurantoin for a period of 6–12 months. However, for many patients their problem does not stop after that period and therefore more evidence to determine the precise indications of non-antibiotic prophylactic treatment is needed. The authors declare no conflicts of interest. No funding was received. Nitrofurantoin's efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trialsClinical Microbiology and InfectionVol. 23Issue 6PreviewNitrofurantoin has been used for the prevention of urinary tract infection (UTI) for over 60 years. We conducted a systematic review and meta-analysis to assess its efficacy and safety in the prophylaxis of UTI. Full-Text PDF Open Archive