EDITORIAL COMMENTARY
Asymptomatic Bacteriuria—Shift of Paradigm Florian M. E. Wagenlehner1 and Kurt G. Naber2 1
Technical University of Munich, and 2Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany
(See the Major Article by Cai et al, on pages 771–7.)
Initial studies on quantitative urine cultures obtained from large numbers of patients have established so-called significant (true) bacteriuria at a threshold of ≥105 colony-forming units per milliliter [1]. Because asymptomatic bacteriuria (ABU) has been found with particular frequency in populations more likely to develop pyelonephritis (ie, individuals with diabetes mellitus, pregnancy, obstructive uropathy, past history of instrumentation of the urinary tract), a strong relationship between bacteriuria and pyelonephritis was assumed. This was consolidated by the observation that in pregnancy elimination of ABU decreases the risk for a symptomatic infection [2]. Although bacteriuria is present in a relatively asymptomatic population, it is virtually always necessary for the development of symptomatic disease. Therefore, it was assumed that the presence of bacteriuria defines a population at risk and the elimination of bacteriuria minimizes the risk for a clinically symptomatic disease [2]. The discrepancy between the frequency of pyelonephritis found in autopsies and that diagnosed during life in only about one-fifth of the
Received 29 May 2012; accepted 31 May 2012; electronically published 7 June 2012. Correspondence: Kurt Naber, Karl-Bickleder-Str. 44c, D-94315 Straubing, Germany (
[email protected]). Clinical Infectious Diseases 2012;55(6):778–80 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.
[email protected]. DOI: 10.1093/cid/cis541
778
•
CID 2012:55 (15 September)
•
cases was explained by a high incidence of clinically atypical or inapparent infections [3]. At that time bacteriuria was considered dangerous in any case, because bacteriuria detected at a significant quantity, even if asymptomatic, was associated with a substantially increased risk of pyelonephritis and premature delivery. Subsequently well-performed, randomized clinical studies in adult women, schoolgirls, long-term care facility residents, spinal cord–injured patients, and diabetic women, however, have consistently documented that the treatment of bacteriuria in asymptomatic patients does not provide any benefit for the patient [4, 5]. Therefore, the term “asymptomatic urinary tract infection” (UTI) was abandoned and redefined as ABU. The diagnosis of ABU is made independent of the presence of pyuria commonly found in patients with ABU [4]. Nowadays ABU is considered a stable bacterial colonization of the urinary tract, similar to commensalism at other mucosal sites [6]. Apart from clinical trials, ABU has been investigated through molecular methods [6]. ABU Escherichia coli isolates from outpatients or hospitalized patients after catheterization or other urological invasive procedures were compared with commensal E. coli isolates from the intestinal flora of healthy individuals [6]. The ABU isolates had a similar overall virulence gene repertoire, which sets them apart from many commensals. Typical uropathogenic E. coli (UPEC) virulence
EDITORIAL COMMENTARY
genes, however, were less frequently observed in hospital ABU strains than in outpatient ABU strains or commensals [6]. The diminished virulence from outpatient ABU isolates compared with that of ABU strains from hospitalized patients shows that loss of expression or decay of virulence genes facilitate longterm carriage and adaptation to host environments [6]. A prototype ABU strain, E. coli 83972, isolated from a schoolgirl with long-lasting ABU with this strain, has been completely sequenced in the meantime [7]. Comparing this ABU strain with UPEC strains, the ABU strain has a smaller genome than the UPEC strains with deletions or point mutations in several virulence genes, suggesting that ABU strains undergo a programmed reductive evolution within human hosts [6, 8]. In asymptomatic patients colonized in the lower urinary tract with this ABU strain, superinfection with other strains seems to be prevented even if left untreated [8–11]. This phenomenon, the socalled bacterial interference, is due to the fact that within our body’s bacterial habitats microbial interaction exists, in competing for nutrients and producing toxic molecules. Thus, a microbial balance is established on colonized surfaces, such as the skin and mucosal orifices. This socalled human microbiome is considered a potent defense mechanism against superinfecting pathogenic bacteria [8]. The idea of bacterial interference was further developed. The ABU E. coli
strain 83972 was deliberately introduced into the lower urinary tract of selected patients with impaired bladder emptying who experienced recurrent symptomatic UTI in order to prevent uropathogenic bacteria from installing an infection. The patients stayed colonized for 3 months to 4 years [8]. The E. coli strains cultured regularly from patients’ urine and investigated further by genome-wide sequencing showed host-specific mutations over time, although the identical clonal strain was installed. Each host developed his own personal microflora [7]. The environment unique in each human host has selected host-specific adaptations. In addition to stochastic events, adaptive bacterial evolution is driven by individual host environments. The loss of gene function also supports the hypothesis that evolution toward commensalism rather than virulence is favored during asymptomatic bladder colonization [7]. Cai et al’s prospective, randomized clinical study on the role of ABU in young women with recurrent UTI includes a high number of sexually active premenopausal women between 18 and 40 years with recurrent UTI [12]. It translates the results of the molecular, pathophysiological, and clinically experimental studies mentioned above to this group of patients. About one-fifth of the patients had 3, and four-fifths had >3, symptomatic episodes per year. The authors selected only patients without known (complicating) risk factors for recurrent UTI and those with ABU after antibiotic therapy. Obviously these patients were screened regularly for ABU for research purposes, as so many patients without symptoms were included. Unfortunately it is not known what proportion of young women with recurrent UTI developed ABU after antibiotic therapy. A rough estimation by the authors might be informative. The authors investigated whether periodical antibiotic treatment of detected ABU in this kind of patient is beneficial, indifferent, or even harmful to reduce
UTI recurrences. The results of their study provide a clear answer: The antibiotic treatment of ABU in young women with recurrent UTI is not only unnecessary but harmful. In the untreated group, 76% of participants remained asymptomatic up to 1 year, compared to only 17% in the treated group. Unfortunately the total number of symptomatic episodes during the study period was not reported for either group. We hope the results of this study will be rapidly spread to all physicians treating such patients, as the management of these patients could be improved; investigations for screening of ABU and antibiotic consumption could be decreased; and not only cost but also antimicrobial selection pressure in the community (and thus emergence of antibiotic resistance) could be reduced. Unfortunately this study does not show whether young women with recurrent UTI developing ABU after antibiotic therapy are better protected from recurrences than those who do not develop ABU. This question should also be given a high research priority. Another interesting aspect in the study should further be pursued. Diverging shifts in the bacterial spectrum causing ABU in the 2 groups were observed. From an almost evenly distributed spectrum between gram-negative and gram-positive organisms in the treated group, there was a clear shift toward gram-negative organisms and in the untreated group toward grampositive organisms, especially Enterococcus faecalis. This may lead to the question whether specific strains of E. faecalis, able to adhere to the bladder mucosa but not virulent enough to produce symptomatic UTI, may be even better suited for study of bacterial interference than E. coli strains. In conclusion, well-performed clinical and basic molecular studies have changed our understanding of ABU completely during the last 50 years. ABU is now considered a generally
benign and sometimes even protective condition. Not to treat ABU in general (except during pregnancy and before invasive intervention of the urinary tract), and especially not in young women with recurrent UTI as shown by Cai et al (this issue), is highly recommended and should become the standard of care. Note Potential conflicts of interest. F. M. E. W. has received research funding from Calixa, MerLion, OM Pharma/Vifor, Rosen Pharma, and Zambon; has been a consultant for Astellas, MerLion, OM Pharma/Vifor, Rosen Pharma, and Serag-Wiessner; has served on the speakers’ bureau for Bayer, Cernelle, Janssen-Cilag, Pierre Fabre, Strathmann, and Zambon; and has received honorarium for publication by Sanofi. K. G. N. has received research funding from Basilea, Bionorica, GlaxoSmithKline, MerLion, OM Pharma/Vifor, and Rosen Pharma; has been a consultant for Basilea, Bionorica, GlaxoSmithKline, MerLion, OM Pharma/Vifor, Pierre Fabre, Rosen Pharma, Galenus, and PolyMedix; has served on the speakers’ bureau for Angelini, Bayer, Bionorica, Daiichi Sankyo, OM Pharma/ Vifor, Pierre Fabre, Rosen Pharma, and Zambon; and has received honorarium for publication from Sanofi. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Kass EH. Bacteriuria and pyelonephritis of pregnancy. Arch Intern Med 1960; 44:194–8. 2. Kass EH, Savage W, Santamarina BAG. The significance of bacteriuria in preventive medicine. In: Kass EH, ed. Progress in pyelonephritis. Philadelphia, PA: Davis, 1965:3–10. 3. Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc Am Phys 1956; 69:56–64. 4. 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; 40:643–54. 5. Nicolle LE. Asymptomatic bacteriuria—to treat or not to treat. In: Naber KG, Schaeffer AJ, Heyns C, Matsumoto T, Shoskes D, Bjerklund-Johansen TE, eds. Urogenital infections. Arnhem, Netherlands: European Association of Urology–International Consultation on Urological Diseases, 2010: 303–13. 6. Salvador E, Wagenlehner F, Kohler CD, et al. Comparison of asymptomatic bacteriuria
EDITORIAL COMMENTARY
•
CID 2012:55 (15 September)
•
779
Escherichia coli isolates from healthy individuals versus those from hospital patients shows that long-term bladder colonization selects for attenuated virulence phenotypes. Infect Immun 2012; 80:668–78. 7. Zdziarski J, Brzuszkiewicz E, Wullt B, et al. Host imprints on bacterial genomes—rapid, divergent evolution in individual patients. PLoS Pathog 2010; 6:e1001078. 8. Wullt B, Sundén F. Asymptomatic bacteriuria with the model strain Escherichia coli 83972 protects against symptomatic urinary
780
•
CID 2012:55 (15 September)
•
tract infections. In: Naber KG, Schaeffer AJ, Heyns C, Matsumoto T, Shoskes D, Bjerklund-Johansen TE, eds. Urogenital infections. Arnhem, Netherlands: European Association of Urology–International Consultation on Urological Diseases, 2010:314–8. 9. Hansson S, Caugant D, Jodal U, SvanborgEden C. Untreated asymptomatic bacteriuria in girls: I—Stability of urinary isolates. BMJ 1989; 298:853–5. 10. Hansson S, Jodal U, Lincoln K, SvanborgEden C. Untreated asymptomatic bacteriuria
EDITORIAL COMMENTARY
in girls: II—Effect of phenoxymethylpenicillin and erythromycin given for intercurrent infections. BMJ 1989; 298:856–9. 11. Hansson S, Jodal U, Noren L, Bjure J. Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 1989; 84: 964–8. 12. Cai T, Mazzoli S, Mondaini N, et al. The Role of Asymptomatic Bacteriuria in Young Women with Recurrent Urinary Tract Infections: To Treat or Not to Treat? Clin Infect Dis 2012; 55:771–7.
