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1 BMJ Open TREATMENT OF FEBRILE GERIATRIC PATIENTS WITH SUSPECTED URINARY TRACT INFECTIONS IN A HOSPITAL WITH HIGH RATES OF ESBL PRODUCING BACTERIA Journal: BMJ Open Manuscript ID bmjopen-0-0 Article Type: Research Date Submitted by the Author: 0-Aug-0 Complete List of Authors: Shimoni, Zvi; Laniado Hospital, Infectious Disease unit and Internal Medicine B Cohen, Regev; Laniado Hospital, Infectious disease Avdiaev, Ruslan; Laniado Hospital, internal medicine B Froom, Paul; School of Public Health, Epidemiology and Preventive Medicine <b>primary Subject Heading</b>: Infectious diseases Secondary Subject Heading: Geriatric medicine Keywords: GERIATRIC MEDICINE, Urinary tract infections < UROLOGY, INFECTIOUS DISEASES BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

2 Page of BMJ Open TREATMENT OF FEBRILE GERIATRIC PATIENTS WITH SUSPECTED URINARY TRACT INFECTIONS IN A HOSPITAL WITH HIGH RATES OF ESBL PRODUCING BACTERIA Zvi Shimoni MD Regev Cohen MD - Internal medicine B, Laniado Hospital, Netanya, Israel & Technion Ruth and Bruce Rappaport School of Medicine, Haifa, Israel - Infectious Disease Department, Laniado Hospital, Netanya, Israel Ruslan Avdiaev MD - Internal Medicine B, Laniado Hospital, Netanya, Israel Paul Froom MD -Department of Clinical Utility, Laniado Hospital, Netanya, Israel & School of Public Health, University of Tel Aviv, Tel Aviv, Israel Fax- 0, Telephone: 0 froomp@gmail.com, Running title: Bacterial resistance in Febrile UTIs Word count Address for correspondence: Prof. Paul Froom, Laniado Hospital, Netanya, Israel, Fax- 0, Telephone: 0 froomp@gmail.com BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

3 BMJ Open Page of ABSTRACT PURPOSE: To determine the consequences of treating febrile geriatric patients with a suspected urinary tract infection with antibiotics that have high resistance rates due primarily to extended-spectrum β-lactamase (ESBL) producing bacteria. METHODS: In this cohort study, we selected consecutive hospitalized patients 0 years old with a chief complaint of fever possibly due to a urinary tract infection and initially treated with antibiotics with rates in our hospital of urinary culture resistance > 0%. Patients with severe sepsis were excluded. Main outcomes measures were in vitro bacterial resistance to initial antibiotic therapy (BRIAT), response to therapy, hospitalization days, and mortality. RESULTS: Urine cultures were positive in.% (/) of the patients and BRIAT occurred in.0% (/). Response rates were 00% (/) in those with bacteria sensitive to initial antibiotic therapy,.% (/) in the culture negative patients, and.% (/) in those with BRIAT (p < 0.00). There were no deaths due to deterioration during the initial treatment period because of BRIAT. In the patients with BRIAT the median length of hospitalization was days longer than in the other patients ( and days respectively, p < 0.00). CONCLUSIONS: We conclude that initial broad spectrum antibiotic treatment could potentially lower the median length of hospitalization by days in many hospitalized geriatric patients without an extra-urinary tract source for their fever. This benefit needs to be balanced against the risk to the individual patient and to the general public of increasing bacterial resistance rates to broader spectrum antibiotics often held in reserve. Key words: ESBL; urinary tract infection; geriatric patients; fever; treatment BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

4 Page of BMJ Open Strengths and limitations of this study. This cohort study included all geriatric febrile patients with a suspected urinary tract infection rather than only those who were diagnosed with a UTI in retrospect.. We focused on the proper treatment of patients with a febrile urinary tract infection, and therefore excluded those with severe urosepsis, who require initial treatment with broad spectrum antibiotics.. It is unclear how referral and admission practices might have influenced the results.. We did not have information on recent antibiotic therapy before hospitalization that might have affected our ability to predict bacterial resistance.. A much larger cohort is needed to rule out an early mortality risk from BRIAT. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

5 BMJ Open Page of INTRODUCTION Urinary tract infections (UTI) are a common reason for hospital admission in febrile geriatric patients, and prompt initiation of empiric antimicrobial therapy can improve clinical outcomes, []. Today however, there are many European countries with extended-spectrum β-lactamase (ESBL) producing bacteria rates of over 0%, []; in such settings, it is unclear whether to accept a significant risk for bacterial resistance to initial antibiotic therapy (BRIAT) or to treat the patient with wider spectrum antibiotics that are generally held in reserve in order to decrease future resistance rates, [,,, ]. Despite high rates of ESBL producing bacteria in our hospital, we reserve initial treatment with amikacin or a carbapenem (antibiotics with very low resistance rates in our hospital) for patients with either severe sepsis, [] or those who have a history of a bacterial resistant infection. Physicians most commonly prescribe either ceftriaxone or cefuroxime. In order to study the consequences of our hospital policy we selected geriatric patients hospitalized with a chief complaint of fever and a suspected urinary tract infection. Excluded were patients with findings on admission consistent with an infection outside the urinary tract, and those with an indication for empiric wide spectrum antibiotics (e.g. severe sepsis). We determined the proportion of patients with BRIAT, the hour response rate to antibiotics, the length of hospitalization, and associated early mortality. METHODS In this historical prospective study, we selected consecutive patients 0 years or older with a chief complaint of fever hospitalized in one of three internal medicine departments from June 0 until the end of August 0. Excluded were patients with severe sepsis, [] or those with a source of fever on admission outside the urinary tract (those with new pulmonary infiltrates or an infiltrate in a patient without a previous chest x-ray (CXR), a BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

6 Page of BMJ Open cough with or without shortness of breath and no definite infiltrate on CXR, purulent bedsores, new areas of cellulitis, and a presentation of vomiting and/or diarrhea consistent with gastrointestinal tract infections or other conditions whose presentation suggested another diagnosis) (Table ). Finally, we excluded those with a past history of a urinary tract infection due to resistant bacteria who received initial treatment with broad spectrum antibiotics with urine culture resistance rates < 0% (rates in our hospital over the last months-.% for piperacillin/tazobactam,.% for amikacin and.% for ertapenem). All other antibiotics had resistance rates > 0%. Also excluded were patients who did not receive antibiotics on admission. Patients were divided into those with and without BRIAT. The diagnosis of a urinary tract infection required a history of fever, and a positive urine or blood culture [] but without a source of fever outside the urinary tract. Significant bacteriuria was defined as the presence of 0 colony forming units per milliliter of urine. External quality control (College of American Pathologists External Quality Assurance Proficiency Testing) did not include ESBL testing but all bacterial resistance (N=) and bacterial sensitivity (N=) to various antibiotics were identified correctly over the last years. Internal quality controls identified correctly (AST-N0, BioMerieux) positive and negative ESBL test results done over the last three years. BRIAT was defined as initiation of treatment with an antimicrobial agent to which the infecting bacteria was ultimately shown not to be susceptible in vitro. The major outcome variable was the response to therapy that was defined by the absence of fever, or a trend for decreasing body temperatures by hours when the results of urine cultures were available and the decision for continuing or changing antibiotic therapy was made. Other outcome variables were total hospitalization days, and in hospital mortality. All deaths were reviewed BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

7 BMJ Open Page of by two of the authors (ZS and PF) independently and it was determined if mortality was related to BRIAT. Statistical analysis. The chi-squared test was used to compare differences between proportions. The Wilcoxon rank test was used for comparing continuous data. A p value of < 0.0 was considered statistically significant. We used logistic regression analysis to predict those with BRIAT. All independent variables were entered into the model and retained only if they added significantly. Then non-significant variables were added back one at a time and again retained only if they added significantly to the model. Finally the area under the curve (AUC) with % confidence intervals (CI) was calculated. Ethical approval: Ethics committee: We received approval from the hospital ethics committee lnd. The Israeli Ministry of Health reviews the decisions of the hospital's ethics committee. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

8 Page of BMJ Open RESULTS There were 0 patients (0.%) who presented to the ED with a chief complaint of fever out of patients age 0 years, hospitalized in the internal medicine departments. The mean age of the patients was ± in those with and without a chief complaint of fever, but there were fewer females in those with fever (0% (/0 compared to % /0, p < 0.00). The study group included patients without a source for their fever outside the urinary tract and who were treated empirically with antibiotics; (.%) were culture positive and (.0%) had BRIAT according to the culture results (.% (/) of those with positive culture results). Since in vitro urinary culture resistance rates to either amikacin or ertapenem in our hospital are around %, the estimated decreased rate of BRIAT is % (% - %) if the patients were treated empirically with one of those antibiotics. Resistance was due to ESBL positivity in and there were another 0 ESBL negative patients with resistance to treatment with ceftriaxone (N=), and amoxicillin/clavulanate (N=). The resistant bacteria included Proteus spp (N=), Klebsiella pneumoniae (N=), Pseudomonas aeruginosa (N=) and Enterococci spp (N=). Those with BRIAT had significantly more patients who were bedridden, demented, and who had a permanent urinary catheter or a history of a urinary tract infection (Table ). A logistic regression model showed that both being bedridden and having a permanent urinary catheter increased the odds of BRIAT (odds ratio (OR).00 (% CI.-.0) and OR. (% CI.-.) respectively. However the logistic regression model was poorly predictive of BRIAT with an AUC of only.% (% CI-.%-.%) Initial therapy was primarily with ceftriaxone (n=0), or cefuroxime (N=) but there were a few patients treated with ciprofloxacin (N=), ofloxacin (N=), gentamicin (N=0), amoxicillin/clavulanate (N=) or ampicillin (N=). BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

9 BMJ Open Page of E coli infections were by far the most common cause of the culture positive patients, and together with klebsiella pneumoniae and proteus spp made up over 0% of the bacterial species (Table ). There were positive blood cultures, with the same species found in the urine in cases. The other patients had negative or mixed urine cultures but positive blood cultures (E coli-, klebsiella pneumoniae - and proteus spp-). ESBL positivity was found in 0.0% (/). Response rates were 00% (/) in those with bacteria sensitive to initial antibiotic therapy,.% (/) in the culture negative patients, and.% (/) in those with BRIAT (Table )(p < 0.00). Those with BRIAT had a median hospitalization time of days ( st - rd quartiles = - days) compared to days for the rest of the cohort ( st - rd quartiles = - days)(p < 0.00), that was the same for culture positive and negative patients. The in-hospital death rate in those with a culture positive UTI was.% (/) but BRIAT might have increased the risk in only one year-old male patient who had a UTI with ESBL producing E. coli, responded to treatment with ceftriaxone, but on day, one day after treatment was changed to ertapenem (according to culture sensitivities), died from septic shock. The other two patients responded to antibiotics; one died of aspiration pneumonia and the other from multiple complications 0 days later unrelated to the UTI. There were no deaths in the culture negative patients. DISCUSSION The main finding of our study is that initial broad spectrum antibiotic treatment could potentially lower the median length of hospitalization by days in % of selected hospitalized geriatric patients without an extra-urinary tract source for their fever. However, most patients with BRIAT responded to therapy, and no patient become septic before the BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

10 Page of BMJ Open availability of urinary culture results. To our knowledge this is the first cohort study of geriatric febrile patients that included all those with a suspected urinary tract infection. Esparcia et al retrospectively studied geriatric patients whose primary diagnosis on discharge was a UTI, []; they reported an in-hospital mortality rate of.% and found that "inadequate empirical antimicrobial therapy" was an independent risk factor for mortality (odds ratio., % CI.-.). They did not however separate out patients presenting with severe urosepsis or control for it in their models. Their findings supports the need for wide spectrum antibiotics in those with severe urosepsis, [] but cannot be extrapolated to patients with uncomplicated febrile urinary tract infections. Our results support a recent meta-analysis estimation of no definite increase in the risk for mortality in patients of all ages treated with BRIAT on internal medicine wards for upper urinary tract infections, [0]. Similarly, Peralta G et al reported that antibiotic resistance for patients with bacteremia due to ESBL producing E. coli or Klebsiella spp. was not associated with mortality in patients without severe sepsis or septic shock, []. We found that two-thirds of the patients responded to treatment despite BRIAT, and those who did not respond were then given antibiotics according to sensitivities after the availability of the culture results. The death rate in those with positive cultures was.% (/) but delayed therapy with broad spectrum antibiotics might have decreased the prognosis in one patient. This is consistent with two studies that reported response rates similar to ours in patients with BRIAT and no increase in short term mortality even though the antibiotics were often not changed after culture results became available, [, ]. Whether or not antibiotics should be changed in responsive patients with BRIAT needs to be studied. This study has a number of limitations. Our ability to predict patients with BRIAT was poor, although the odds were higher in those who were bedridden or had a permanent urinary BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

11 BMJ Open Page 0 of catheter, consistent with previous reports attempting to predict the presence of ESBL, []. We did not however have the history of recent antibiotic usage that has also been consistently shown to increase the risk for ESBL positivity, []. Secondly, extrapolation to other setting should be done with caution because of possible selection bias. The general policy of the emergency department is to consider admitting all patients years old with fever, but it is unclear how actual referral and admission practices might have influenced the results. Our cohort also did not include patients with neutropenic fever or with hematological malignancies who were hospitalized in the Hematology department or patients with known lesions in the urinary tract who were hospitalized in surgery departments. Nevertheless it is likely that our results can be extrapolated to other uncomplicated hospitalized geriatric patients whose chief complaint is fever. Finally, there is no gold standard for the diagnosis of an upper urinary tract infection. We used the chief complaint of fever as a selector for suspected upper urinary tract infections that required intravenous antibiotics, and excluded all those with another possible source of infection. Fever in a patient with a urinary tract infection is commonly considered to differentiate between those with pyelonephritis from a bladder infection, []. Although the patients came to the hospital because of fever, not all our patients had fever on admission; the proportion of culture positive patients was nearly identical to those with an elevated body temperature on admission (results not shown) but the reliability of the history of fever was not studied. In fact we cannot rule out both over and under diagnosis of a upper UTI that is common in geriatric patients, [, ]. Over diagnosis is due to the high prevalence of asymptomatic bacteriuria that affects -0% of men and -0% of women and even higher proportions of institutionalized non-catheterized older people [, ]. Under diagnosis might have resulted from exclusion of culture positive patients with other sources of infection BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

12 Page of BMJ Open but where the source of the fever was actually the urinary tract. The diagnosis of the patients who received treatment despite negative culture results, most without urinary tract symptoms is also unclear. However, because of the very high response rate it is likely that many of these patients did not have a urinary tract infection and might have been treated unnecessarily. It is uncertain however, how to select patients who don't require initial antibiotic therapy. The strength of our historical prospective study is that we had a clearly defined cohort, not selected by outcome variables. We were thus able to define the potential benefits of a policy of using wide spectrum antibiotics on admission in these selected patients and found that treatment of all patients with amikacin or a carbapenem could potentially decrease the number of hospitalization days by a median of days in % of the patients; this is consistent with the estimate by Parienti JJ et al who assumed extra days of hospitalization in internal medical department patients who received BRIAT, [0]. Our bacterial sensitivity profiles have been stable over the last months with very low resistance rates for amikacin and ertapenem (results not shown); but it is unclear if this is due in part to our policy of limiting the use of those antibiotics. It has been shown that a strong risk factor for infection with carbapenem-resistant bacteria is previous use of a carbapenem, [] and even brief exposure to a carbapenem increases the risk of colonization with imipenem-resistant gram negative bacteria in patients under intensive care, []. We conclude that initial treatment with antibiotics that have high in vitro resistance rates is reasonable in selected elderly patients with fever and without an extra-urinary tract source on admission, although there is a risk for longer hospitalization times. This decision however, is dependent on the unknown estimated risk to the patient and to the general population of treating all febrile patients with a suspected UTI on admission with broader spectrum antibiotics. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

13 BMJ Open Page of Contributorship statement: All authors contributed significantly to this manuscript, including contributions in the study design (ZS, RC, RA, PF), chart reviews (ZS, RA, PF), interpretation of the data (ZS,RC, RA, PF), and preparation of the manuscript (ZS, RC, RA, Competing interests: None of the authors have competing interests. Funding: this study was not funded. Data sharing: no additional data available. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

14 Page of BMJ Open REFERENCES. Norman DC. Fever in the elderly Clin Infect Dis 000; :-. Jones RN, Flonta M, Gurler N et al. Resistance surveillance program report for selected European nations (0) Diagn Microbiol Infect Dis 0::-. Chang HJ, Hsu PC, Yang CC et al. Risk factors and outcomes of carbapenemnonsusceptible Escherichia coli bacteremia: a matched case-control study. J Microbiol Immunol Infect 0;: 0.. Armand-Lefevre L, Angebault C, Barbier F Emergence of imipenem-resistant gramnegative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother 0;:.. Harris PN, Tambyah PA, Paterson DL β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis 0;:-. Cantón R, Akóva M, Carmeli Y et al. European Network on Carbapenemases. Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe. Clin Microbiol Infect 0;:-. Angus DC, van der Poll T Severe sepsis and septic shock. N Engl J Med. 0;:0-. Esparcia A, Artero A, Eiros JM et al. Influence of inadequate antimicrobial therapy on prognosis in elderly patients with severe urinary tract infections. Eur J Intern Med 0;:-.. Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 00;:-. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

15 BMJ Open Page of Parienti JJ, Lucet JC, Lefort A et al. Empirical therapies among adults hospitalized for community-acquired upper urinary tract infections: A decision-tree analysis of mortality, costs, and resistance. Am J Infect Control 0; Jul. pii: S0- ()00-. doi: 0.0/j.ajic Peralta G, Lamelo M, Alvarez-García P et al. Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study. BMC Infect Dis 0;:. doi: 0./---.. Asakura T, Ikeda M, Nakamura A et al. Efficacy of empirical therapy with noncarbapenems for urinary tract infections with extended-spectrum beta-lactamaseproducing Enterobacteriaceae. Int J Infect Dis 0;:-.. Wie SH, Kim HW, Chang UI Effects of gentamicin monotherapy for the initial treatment of community-onset complicated non-obstructive acute pyelonephritis due to Enterobacteriaceae in elderly and non-elderly women. Clin Microbiol Infect 0;0:-.. Oteo J, Pérez-Vázquez M, Campos J Extended-spectrum [beta]-lactamase producing Escherichia coli: changing epidemiology and clinical impact. Current Opinion in Infectious Diseases 00; :0-.. McMurdo MET, Gillespie ND Urinary tract infection in old age: Over-diagnosis and over-treated. Age Ageing 000;:-.. Woodford HJ, George J Diagnosis and management of urinary tract infection in hospitalized older people J Am Geriatr Soc 00;:0-. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

16 Page of BMJ Open Table Included and excluded febrile geriatric patients by discharge diagnosis Diagnosis N (%) Urinary tract infection (.0)* Pneumonia (.0)** Lower respiratory tract infection (.)** Culture-negative yet treated 00 (.)*** Sever sepsis (.)** Not treated-viral infection? (.)** Cellulitis (.)** Infected pressure sores (.)** Gastro-intestinal disease (.)** Other**** (.0)** Total 0 * patients were excluded because they received broad spectrum antibiotics on admission **excluded from the study *** patients excluded because they received broad spectrum antibiotics on admission **** Endocarditis (N=), gall bladder infection (N=), collagen vascular disease (N=), cancer (N=), q fever (N=). BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

17 BMJ Open Page of Table Patients with no source for fever outside the urinary tract Variables Others BRIAT* P value N= N (%) N = N (%) Age (years) ± ± < 0.00 Female (0.) (.) 0. Bedridden (.) (0.) < 0.00 Demented 00 (.) (.) 0.0 Permanent urinary catheter 0 (.) (.) < 0.00 Diabetes mellitus (.) (.) 0.0 History of UTI 0 (.) (.) < 0.00 Urinary tract symptoms (.) (.) 0.00 Temperature. o C (.) (.) 0. *BRIAT- bacterial resistance to initial antibiotic therapy BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

18 Page of BMJ Open Table Bacterial cultures in patients with a culture positive urinary tract infection Bacteria N (%) E coli (.) Klebsiella pneumoniae (.) Proteus spp (0.) Pseudomonas aeruginosa (.0) Enterococci spp (.0) Other (.) ESBL positivity* (0.0) *Extended-spectrum β-lactamase (ESBL) producing bacteria BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

19 BMJ Open Page of Table Response rates of selected febrile geriatric patients without a source of fever outside the urinary tract and treated with antibiotics that have high urinary culture resistance rates. Final Diagnosis N Response N (%) Deaths N (%) Culture positive 0 (.) (.) BRIAT* (.) (.) Sensitive Culture negative (00)** (.) (.) 0 (0.0) *BRIAT- bacterial resistance to initial antibiotic therapy ** compared to BRIAT, p < 0.00 BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

20 Page of BMJ Open STROBE Statement checklist of items that should be included in reports of observational studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the Introduction abstract- x IN the abstract, page (b) Provide in the abstract an informative and balanced summary of what was done and what was found-x page Background/rationale Explain the scientific background and rationale for the investigation being reportedx page Objectives State specific objectives, including any prespecified hypotheses- page Methods Study design Present key elements of study design early in the paper- page - Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection- page - Participants (a) Cohort study Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up-page - Case-control study Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study For matched studies, give matching criteria and number of exposed and unexposed No matching Case-control study For matched studies, give matching criteria and the number of controls per case Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable- page - * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group- page -t Bias Describe any efforts to address potential sources of bias- None Study size 0 Explain how the study size was arrived at- Time period, consecutive patients Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why- page - Statistical methods (a) Describe all statistical methods, including those used to control for confoundingpage (b) Describe any methods used to examine subgroups and interactions -none (c) Explain how missing data were addressed- No missing data (d) Cohort study If applicable, explain how loss to follow-up was addressed- no loss to follow-up Case-control study If applicable, explain how matching of cases and controls was addressed Cross-sectional study If applicable, describe analytical methods taking account of sampling strategy (e) Describe any sensitivity analyses-none BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

21 BMJ Open Page 0 of Continued on next page BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

22 Page of BMJ Open Results Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed- Table page (b) Give reasons for non-participation at each stage- only one stage (c) Consider use of a flow diagram- we believe the table is more appropriate. Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders- table page (b) Indicate number of participants with missing data for each variable of interest-none (c) Cohort study Summarise follow-up time (eg, average and total amount)- length of hospitalization, page Outcome data * Cohort study Report numbers of outcome events or summary measures over time- page, table Case-control study Report numbers in each exposure category, or summary measures of exposure Cross-sectional study Report numbers of outcome events or summary measures Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included Not needed. (b) Report category boundaries when continuous variables were categorized-x (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses- logistic regression analysis to predict BRIAT- page results Discussion Key results Summarise key results with reference to study objectives- page Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. - xdiscuss both direction and magnitude of any potential bias- pages,0, Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence- page Generalisability Discuss the generalisability (external validity) of the study results- page 0 Other information Funding Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based - *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

23 BMJ Open TREATMENT OF FEBRILE GERIATRIC PATIENTS WITH SUSPECTED URINARY TRACT INFECTIONS IN A HOSPITAL WITH HIGH RATES OF ESBL PRODUCING BACTERIA: A COHORT STUDY Journal: BMJ Open Manuscript ID bmjopen-0-0.r Article Type: Research Date Submitted by the Author: -Sep-0 Complete List of Authors: Shimoni, Zvi; Laniado Hospital, Infectious Disease unit and Internal Medicine B Cohen, Regev; Laniado Hospital, Infectious disease Avdiaev, Ruslan; Laniado Hospital, internal medicine B Froom, Paul; School of Public Health, Epidemiology and Preventive Medicine <b>primary Subject Heading</b>: Infectious diseases Secondary Subject Heading: Geriatric medicine Keywords: GERIATRIC MEDICINE, Urinary tract infections < UROLOGY, INFECTIOUS DISEASES BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

24 Page of BMJ Open TREATMENT OF FEBRILE GERIATRIC PATIENTS WITH SUSPECTED URINARY TRACT INFECTIONS IN A HOSPITAL WITH HIGH RATES OF ESBL PRODUCING BACTERIA Zvi Shimoni MD Regev Cohen MD - Internal Medicine B, Laniado Hospital, Netanya, Israel & Technion Ruth and Bruce Rappaport School of Medicine, Haifa, Israel - Infectious Disease Department, Laniado Hospital, Netanya, Israel Ruslan Avdiaev MD - Internal Medicine B, Laniado Hospital, Netanya, Israel Paul Froom MD -Department of Clinical Utility, Laniado Hospital, Netanya, Israel & School of Public Health, University of Tel Aviv, Tel Aviv, Israel Fax- 0, Telephone: 0 froomp@gmail.com, Running title: Bacterial resistance in Febrile UTIs Word count Address for correspondence: Prof. Paul Froom, Laniado Hospital, Netanya, Israel, Fax- 0, Telephone: 0 froomp@gmail.com BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

25 BMJ Open Page of ABSTRACT PURPOSE: To determine the consequences of treating febrile geriatric patients with a suspected urinary tract infection with antibiotics that have high resistance rates due primarily to extended-spectrum β-lactamase (ESBL) producing bacteria. METHODS: In this cohort study, we selected consecutive hospitalized patients 0 years old with a chief complaint of fever possibly due to a urinary tract infection and initially treated with antibiotics with rates in our hospital of urinary culture resistance > 0%. Patients with severe sepsis were excluded. Main outcomes measures were in vitro bacterial resistance to initial antibiotic therapy (BRIAT), response to therapy, hospitalization days, and mortality. RESULTS: Urine cultures were positive in.% (/) of the patients and BRIAT occurred in.0% (/). Response rates were 00% (/) in those with bacteria sensitive to initial antibiotic therapy,.% (/) in the culture negative patients, and.% (/) in those with BRIAT (p < 0.00). There were no deaths due to deterioration during the initial treatment period because of BRIAT. In the patients with BRIAT the median length of hospitalization was days longer than in the other patients ( and days respectively, p < 0.00). CONCLUSIONS: We conclude that initial broad spectrum antibiotic treatment could potentially lower the median length of hospitalization by days in many hospitalized geriatric patients without an extra-urinary tract source for their fever. This benefit needs to be balanced against the risk to the individual patient and to the general public of increasing bacterial resistance rates to broader spectrum antibiotics often held in reserve. Key words: ESBL; urinary tract infection; geriatric patients; fever; treatment BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

26 Page of BMJ Open Strengths and limitations of this study. This cohort study included all geriatric febrile patients with a suspected urinary tract infection rather than only those who were diagnosed with a UTI in retrospect.. We focused on the proper treatment of patients with a febrile urinary tract infection, and therefore excluded those with severe urosepsis, who require initial treatment with broad spectrum antibiotics.. It is unclear how referral and admission practices might have influenced the results.. We did not have information on recent antibiotic therapy before hospitalization that might have affected our ability to predict bacterial resistance.. A much larger cohort is needed to rule out an early mortality risk from BRIAT. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

27 BMJ Open Page of INTRODUCTION Urinary tract infections (UTI) are a common reason for hospital admission in febrile geriatric patients, and prompt initiation of empiric antimicrobial therapy can improve clinical outcomes, []. Today however, there are many European countries with extended-spectrum β-lactamase (ESBL) producing bacteria rates of over 0%, []; in such settings, it is unclear whether to accept a significant risk for bacterial resistance to initial antibiotic therapy (BRIAT) or to treat the patient with wider spectrum antibiotics that are generally held in reserve in order to decrease future resistance rates, [,,, ]. Despite high rates of ESBL producing bacteria in our hospital, we reserve initial treatment with amikacin or a carbapenem (antibiotics with very low resistance rates in our hospital) for patients with either severe sepsis, [] or those who have a history of a bacterial resistant infection. Physicians most commonly prescribe either ceftriaxone or cefuroxime. In order to study the consequences of our hospital policy we selected geriatric patients hospitalized with a chief complaint of fever and a suspected urinary tract infection. Excluded were patients with findings on admission consistent with an infection outside the urinary tract, and those with an indication for empiric wide spectrum antibiotics (e.g. severe sepsis). We determined the proportion of patients with BRIAT, the -hour response rate to antibiotics, the length of hospitalization, and associated early mortality. METHODS In this historical prospective study, we selected consecutive patients 0 years or older with a chief complaint of fever hospitalized in one of three internal medicine departments from June 0 until the end of August 0. Excluded were patients with severe sepsis, [] or those with a source of fever on admission outside the urinary tract (those with new BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

28 Page of BMJ Open pulmonary infiltrates or an infiltrate in a patient without a previous chest x-ray (CXR), a cough with or without shortness of breath and no definite infiltrate on CXR, purulent bedsores, new areas of cellulitis, and a presentation of vomiting and/or diarrhea consistent with gastrointestinal tract infections or other conditions whose presentation suggested another diagnosis) (Table ). Finally, we excluded those with a past history of a urinary tract infection due to resistant bacteria who received initial treatment with broad spectrum antibiotics with urine culture resistance rates < 0% (rates in our hospital over the last months-.% for piperacillin/tazobactam,.% for amikacin and.% for ertapenem). All other antibiotics had resistance rates > 0%. Also excluded were patients who did not receive antibiotics on admission. Admission independent variables included age, gender, being chronically bedridden who need help to get out of bed (nearly always nursing home patients), patients being treated for diabetes mellitus, any history of a treated urinary tract infection mentioned in the chart, urinary tract symptoms (dysuria, frequency, or lower abdominal pain), the presence or absence of a permanent urinary catheter on admission, the need for a urinary catheter to obtain a urine specimen, the residual urine volume in those catheterized, chronic dementia (recorded in the chart), active cancer or present treatment with steroids, and admission temperature to the internal medicine department. Patients were divided into those with and without BRIAT. The diagnosis of a urinary tract infection required a history of fever, and a positive urine or blood culture [] but without a source of fever outside the urinary tract. Significant bacteriuria was defined as the presence of 0 colony forming units per milliliter of urine. External quality control (College of American Pathologists External Quality Assurance Proficiency Testing) did not include ESBL testing but all bacterial resistance (N=) and bacterial sensitivity (N=) to various antibiotics were identified BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

29 BMJ Open Page of correctly over the last years. Internal quality controls identified correctly (AST-N0, BioMerieux) positive and negative ESBL test results done over the last three years. BRIAT was defined as initiation of treatment with an antimicrobial agent to which the infecting bacteria was ultimately shown not to be susceptible in vitro. The major outcome variable was the response to therapy that was defined by the absence of fever, or a trend for decreasing body temperatures by hours when the results of urine cultures were available and the decision for continuing or changing antibiotic therapy was made. Other outcome variables were total hospitalization days, prolonged hospitalization (hospital days ), and in hospital mortality. All deaths were reviewed by two of the authors (ZS and PF) independently and it was determined if mortality was related to BRIAT. Statistical analysis. We calculated proportions, medians, quartiles, % confidence intervals (CI), means and standard deviations. The chi-squared test was used to compare differences between proportions. For small numbers Fisher's exact test was substituted. The Kruskal- Wallis test that does not assume a normal distribution was used for comparing continuous data. A p value of < 0.0 was considered statistically significant. We used logistic regression analysis to predict those with BRIAT and those with prolonged hospitalizations. All independent variables were entered into the model and retained only if they added significantly. Then non-significant variables were added back one at a time and again retained only if they added significantly to the model. Finally, the area under the curve was calculated. The model is considered fair if the area under the curve is 0%, good if 0%- %, and excellent if 0% or more. Ethical approval: Ethics committee: We received approval from the hospital ethics committee lnd. The Israeli Ministry of Health reviews the decisions of the hospital's ethics committee. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

30 Page of BMJ Open RESULTS There were 0 patients (0.%) who presented to the ED with a chief complaint of fever out of patients age 0 years, hospitalized in the internal medicine departments. The mean age of the patients was ± in those with and without a chief complaint of fever, but there were fewer females in those with fever (0% (/0 compared to % /0, p < 0.00). The study group included patients without a source for their fever outside the urinary tract and who were treated empirically with antibiotics; (.%) were culture positive and (.0%) had BRIAT according to the culture results (.% (/) of those with positive culture results). Since in vitro urinary culture resistance rates to either amikacin or ertapenem in our hospital are around %, the estimated decreased rate of BRIAT is % (% - %) if the patients were treated empirically with one of those antibiotics. Resistance was due to ESBL positivity in and there were another 0 ESBL negative patients with resistance to treatment with ceftriaxone (N=), and amoxicillin/clavulanate (N=). The resistant bacteria included Proteus spp (N=), Klebsiella pneumoniae (N=), Pseudomonas aeruginosa (N=) and Enterococci spp (N=). Those with BRIAT had significantly more patients who were bedridden, demented, and who had a permanent urinary catheter or a history of a urinary tract infection (Table ). A logistic regression model showed that both being bedridden and having a permanent urinary catheter increased the odds of BRIAT (odds ratio (OR).00 (% CI.-.0) and OR. (% CI.-.) respectively. However, the logistic regression model was poorly predictive of BRIAT with an AUC of only.% (% CI-.%-.%). There were patients who were not bedridden and without a permanent catheter; (.%)(% CI.%-.0%) had BRIAT. BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

31 BMJ Open Page of Initial therapy was primarily with ceftriaxone (n=0), or cefuroxime (N=) but there were a few patients treated with ciprofloxacin (N=), ofloxacin (N=), gentamicin (N=0), amoxicillin/clavulanate (N=) or ampicillin (N=). E coli infections were by far the most common cause of the culture positive patients, and together with klebsiella pneumoniae and proteus spp made up over 0% of the bacterial species (Table ). There were positive blood cultures, with the same species found in the urine in cases. The other patients had negative or mixed urine cultures but positive blood cultures (E coli-, klebsiella pneumoniae - and proteus spp-). ESBL positivity was found in 0.0% (/). Response rates were 00% (/) in those with bacteria sensitive to initial antibiotic therapy,.% (/) in the culture negative patients, and.% (/) in those with BRIAT (Table )(p < 0.00). Those with BRIAT had a median hospitalization time of days ( st - rd quartiles = - days) compared to days for the rest of the cohort ( st - rd quartiles = - days)(p < 0.00), that was the same for culture positive and negative patients. The proportion of prolonged hospitalizations was also nearly identical in culture positive patients without BRIAT and in culture negative patients (Table ). The prolonged median hospitalization time in those with BRIAT might in part have been due to more patients being bedridden and with a permanent catheter in the BRIAT group. However, a logistic regression model showed that BRIAT increased the odds for a hospitalization time of days or more by. fold (% CI.-.) after adjustment for being bedridden and for having a permanent catheter (variables that did not add significantly to the model). The in-hospital death rate in those with a culture positive UTI was.% (/) but BRIAT might have increased the risk in only one -year-old male patient who had a UTI with ESBL producing E. coli, responded to treatment with ceftriaxone, but on day, one day after treatment was changed to ertapenem (according to culture sensitivities), died from septic BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.

32 Page of BMJ Open shock. The other two patients responded to antibiotics; one died of aspiration pneumonia and the other from multiple complications 0 days later unrelated to the UTI. There were no deaths in the culture negative patients. DISCUSSION The main finding of our study is that initial broad spectrum antibiotic treatment could potentially lower the median length of hospitalization by days in % of selected hospitalized geriatric patients without an extra-urinary tract source for their fever. However, most patients with BRIAT responded to therapy, and no patient become septic before the availability of urinary culture results. To our knowledge this is the first cohort study of geriatric febrile patients that included all those with a suspected urinary tract infection. Esparcia et al retrospectively studied geriatric patients whose primary diagnosis on discharge was a UTI, []; they reported an in-hospital mortality rate of.% and found that "inadequate empirical antimicrobial therapy" was an independent risk factor for mortality (odds ratio., % CI.-.). They did not however separate out patients presenting with severe urosepsis or control for it in their models. Their findings supports the need for wide spectrum antibiotics in those with severe urosepsis, [] but cannot be extrapolated to patients with uncomplicated febrile urinary tract infections. Our results support a recent meta-analysis estimation of no definite increase in the risk for mortality in patients of all ages treated with BRIAT on internal medicine wards for upper urinary tract infections, [0]. Similarly, Peralta G et al reported that antibiotic resistance for patients with bacteremia due to ESBL producing E. coli or Klebsiella spp. was not associated with mortality in patients without severe sepsis or septic shock, []. We found that two-thirds of the patients responded to treatment despite BRIAT, and those who did not respond were then given antibiotics according to sensitivities after the BMJ Open: first published as 0./bmjopen-0-0 on December 0. Downloaded from on May 0 by guest. Protected by copyright.