Urine should not be seen as a useless excretion product. Doping experts know, as do clinical microbiologists. In two recently published studies zillions of urine cultures were drained from computer systems and linked to primary care data, yielding very interesting findings. One study from Israel quantified the effects of direct and indirect fluoroquinolone use on antibiotic resistance in E. coli, see also our comments to that study. The second comes from the UK, the country that has an ambition to reduce Gram-negative bacterial bloodstream infection rates by 50%, because of increasing BSI rates. This study may provide both the reason for the problem and the direction to meet that ambition.
The study in short: they analysed 312.896 UTI episodes, that were categorized upon the timing of antibiotic prescription by the GP: Immediate (n=271.070), deferred (n=19.292) or none (n=22.534). Then they quantified the proportion of patients developing BSI (<60 days of UTI) which was 0,2% (n=479) among those with immediate antibiotics and 2.2% (n=413) and 2.9% (n=647) for those with deferred and no antibiotics, respectively. Control of confounders yielded odds ratio for BSI of 7.12 (6.22-8.14) and 8.08 (7.12-9.16) for deferred and no antibiotics, compared to immediate antibiotics. Actually, adjusted hazard ratios for mortality at day 60 after UTI were 1.16 (1.06-1.27) and 2.18 (2.04-2.33) for deferred and no antibiotics, compared to immediate antibiotics.
The signal is clear: early antibiotics for UTI prevent subsequent BSI and even death. And if immediate antibiotics would have reduced the incidence of BSI to 0.2% it would have prevented – in this cohort – 976 episodes of BSI, being 63% of all BSI. Yet, that would also extend lives and thus increase likelihood of other UTIs (that should then be treated immediately). These benefits would come at a price: around 8% more antibiotic prescriptions among subjects with UTI.
So why were elderly (average age of the cohort was 76.9 years) not treated with antibiotics for UTI? The authors state: ”It could be patient or doctor choice, but it is also possible that antimicrobial stewardship programmes and quality premium payments are encouraging a culture of more judicious antibiotic use. Public Health England recently reported a 13.2% reduction in antibiotic prescribing in primary care between 2013 and 2017.”
There are a few caveats: This remains to be a retrospective study, and although considerable adjustment for confounding was performed, you will never be able to fully adjust. And there is confounding, as can be seen by the differences in crude and adjusted odds and hazard ratios.
But even then: this study “puts the finger at the painfull spot” (Dutch expression). Antibiotic stewardship is not by definition safe. It is crucial to determine safety when we admit to our desire to withhold antibiotics as much as possible in order to save them for the future.
Antibiotics do more than causing resistance.
The accompanying editorial said more or less the same, but nicer.
Reflections on Infection Prevention and Control 
We posted a rapid response to the article because we believe that one of the problems of the article is adequately defining UTI in elderly patients:
We have read with great interest the article by Gharbi et al in which the authors evaluate the risk of bloodstream infection, hospital admission and mortality within 60 days after an index case of urinary tract infection (UTI) in elderly patients diagnosed in primary care (1). The results of the study show that elderly patients with a UTI in which antibiotics were not prescribed or were deferred had an increased risk of bloodstream infection, required more oftenly hospital admission and had an increased mortality rate when compared to those in which immediate antimicrobial was started. The authors conclude that early initiation of antibiotics in older adults with a UTI should be recommended to avoid serious complications. We belive that this conclusion without further clarification could lead to an unjustified increase in antimicrobial consumption.
Urinary tract infection is an important clinical problem affecting older populations and the main source of community acquired bacteraemia (2,3). Despite its high frequency, UTI are frequently overdiagnosed in older populations leading to an incorrect diagnostic and antimicrobial treatment in the presence of nonspecific urinary symptoms (2). In a study by Sundvall et al the authors observed that many nonspecific symptoms such as increased falls, fatigue or loss of appetite, which are frequently attributed to UTI and treated with antibiotics, were unlikely to be caused by bacteria in the urine (4). According to the study by Gharby et al only 7.5% of the UTI episodes presented at least one of a range of specific urinary or non specific signs and symptoms. It would have been interesting that the authors had provided information on which urinary non specific signs and symptoms were considered to suspect a UTI. In addition, no information is given regarding the diagnostic criteria for the dignosis of UTI applied for the remaining 92.5% patients included in the study (1). Finally no data on the type of bacteria isolated in the bacteremic episodes and reasons for hospital admission is provided which is of particular interest as the authors considered the later outcome regardless of the reason for hospital admission if it happened 60 days after the index UTI episode.
The authors recognise the uncertainties around the UTI diagnosis in elderly patients included in the study and that they cannot exclude a non-urinary source for the bacteremic episodes. Therefore, at the end it comes down to having clear criteria for the diagnoses of UTI in the older population. Recently a consensus decission tool for empiric antimicrobial treatment of suspected UTI in frail older adults, with and without indwelling urinary catheter, has been developed (5). The applicability and impact of this decision tool in primary care and in the the acute care setting is yet to be established.
Lastly we believe that deferring antimicrobial in the elderly population with a suspected UTI is a reasonable options, as it has been suggested by others, if signs or symptoms are not clearly indicative of an UTI or even in patients with low urinary symptoms awaiting the results of urine cultures although as pointed by the editorial accompanying the article further research is needed to identify those in whom delaying treatment (while awaiting investigation) is safe (2,6).
REFERENCES
1. Gharbi M, Drysdale JH, Lishman H, et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all cause mortality: population based cohort study. BMJ 2019; 364:l525. doi: 10.1136/bmj.l525
2. Nicolle LE. Urinary tract infections in the older adult. Clin Geriatr Med 2016; 32: 523-38.
3. Yahav D, Eliakim-Raz N, Leibovici L, Paul M. Bloodstream infection in older patients. Virulence 2016; 7: 341-52.
4. Sundvall PD, Elm M, Ulleryd P, et al. Interleukin-6 concentrations in the urine and dipstick analyses were related to bacteriuria but not symptoms in the elderly: a cross sectional study of 421 nursing home residents. BMC Geriatr 2014; 14: 88. doi: 10.1186/1471-2318-14-88.
5. van Buul LW, Vreeken HL, Bradley SF, et al. The Development of a Decision Tool for the Empiric Treatment of Suspected Urinary Tract Infection in Frail Older Adults: A Delphi Consensus Procedure. J Am Med Dir Assoc 2018;19 757-764.
6. Hay AD. Antibiotic prescribing in primary care. BMJ 2019. Feb 27;364:l780. doi: 10.1136/bmj.l780.
Competing interests: No competing interests
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