The treatment of community-acquired urinary tract infections with cefazolin vs. fluoroquinolones Amulya Uppala, PharmD PGY-1 Pharmacy Resident Atlantic Health System

BACKGROUND Category A-I: Nitrofurantoin Trimethoprim- sulfamethoxazole Fosfomycin Category A- I/III: FQ “Collateral damage” Category B- I/III: Beta-lactams Gupta K, et al. Clin Infect Dis 2011;52(5):e Paterson DL. Clin Infect Dis 2004; 38 (Suppl. 4):S  Infectious Diseases Society of America (IDSA) guidelines: Asymptomatic bacteriuria Catheter-associated UTI Uncomplicated cystitis and pyelonephritis in premenopausal women

BACKGROUND Clinical studies on fluoroquinolones vs. oral beta-lactam agents for uncomplicated UTI treatment: Studies do not support use of oral beta-lactam agents Hooton TM, et al. JAMA 2005: 293: Hooton TM, et al. JAMA 2012: 307 (6): StudyHooton TM, et al. (2005)Hooton TM, et al. (2012) Treatment armsAmoxicillin-clavulanate vs. Ciprofloxacin Cefpodoxime vs. Ciprofloxacin Duration of treatment3 days Primary objectiveClinical cure OutcomesCiprofloxacin: 77% Amoxicillin/clavulanate: 58% Ciprofloxacin: 93% Cefpodoxime: 82% ConclusionCiprofloxacin more efficacious

BACKGROUND Clinical studies on FQ vs. intravenous beta-lactam agents for complicated UTI and pyelonephritis treatment This study provides promising evidence in favor of intravenous beta-lactams antimicrobials Wagenlehner FM, et al. Lancet 2015; 385(9981): StudyWagenlehner FM, et al. (2015) Treatment armsCeftolozane/tazobactam vs. levofloxacin Duration of treatment7 days Primary objectiveComposite (clinical cure and microbiological cure) OutcomesCeftolozane/tazobactam: 76.9% Levofloxacin: 68.4% ConclusionCeftolozane/tazobactam more efficacious

STUDY RATIONALE Asymptomatic bacteriuria Uncomplicated cystitis and pyelonephritis in premenopausal women Catheter associated UTI 5 Hospitalized patients with community-acquired UTI are not addressed in the guidelines

INSTITUTIONAL UTI GUIDELINES In 2012, Overlook Medical Center (OMC) made cefazolin first line empiric agent for community-acquired UTI treatment 2011 Escherichia coli susceptibilities: Cefazolin: 91% Ciprofloxacin: 82% 6 EmpiricAlternative (severe penicillin allergy) CefazolinCiprofloxacin

STUDY OBJECTIVE To evaluate the effectiveness of cefazolin versus fluoroquinolones for the treatment of community-acquired UTI in an inpatient setting 7

METHODS Study design: Retrospective chart review Institutional review board approval obtained Setting: OMC, a 504-bed community teaching hospital Duration: April January 2016 Study arms: Cefazolin arm: Treated only with cefazolin Fluoroquinolones arm: Treated only with ciprofloxacin or levofloxacin 8

METHODS Patient selection: Generated report of all patients who were prescribed cefazolin or a fluoroquinolone for a UTI indication from pharmacy database Patients were screened according to the established inclusion and exclusion criteria 9

METHODS Inclusion CriteriaExclusion Criteria Age ≥ 18 years Empiric treatment with ≥24 hours of IV cefazolin or an IV/PO fluoroquinolone UTI diagnosis present on admission criteria (community-acquired): Pyuria (≥10 WBC/mm 3 ) AND Bacteriuria (Colony Forming Units ≥ 10 4 bacteria/ml) AND Symptoms: Fever, dysuria, frequency, urgency, hematuria, suprapubic/flank pain, nausea/vomiting, malaise/fatigue, or altered mental status > 1 dose of non-studied antibiotics Pregnancy Anatomical abnormalities of urinary tract Instrumentation of urinary tract Pyelonephritis Health-care associated infections defined as: Skilled nursing facility resident Previous hospitalization within the last 90 days Antibiotic exposure within the last 90 days History of recurrent UTI Concomitant infections (besides bacteremia associated with the current UTI) Neutropenia 10

ENDPOINTS Primary: Clinical failure defined as ≥ 1 of the following: Persistence of one or more signs or symptoms of a UTI that required change of antibiotics Re-initiation of antibiotic during hospital stay for UTI treatment Re-hospitalization within 30 days after discharge with UTI diagnosis 11

ENDPOINTS Secondary: Hospital length of stay Inpatient antibiotic length of treatment Clostridium difficile (C. difficile) infection within 30 days of the end of antibiotics Microbiologic cure (if available) Emergence of resistance to cefazolin or fluoroquinolones during inpatient antibiotic treatment (if available) 12

STATISTICAL ANALYSES Categorical data: Fisher’s Exact Ordinal data: Mann-Whitney U test Continuous data: Independent two-sample t-test 13

PATIENT ENROLLMENT * >1 dose of other antibiotics administered during the same hospitalization prior to cefazolin or fluoroquinolone use ** Pregnant, pyelonephritis, instrumentation/anatomical abnormalities, concomitant infections, sepsis, sensitivity discrepancies, antibiotics ≤ 24 hours patients identified with cefazolin or fluoroquinolones for UTI indication Cefazolin n = 321 Included n = 43 Fluoroquinolones n = 375 Included n = 30 Excluded: 278 Other antibiotics*: 86 Healthcare associated infection: 98 No bacteriuria/ pyuria: 66 Asymptomatic: 11 Other**: 35 Excluded: 345 Other antibiotics*: 113 Healthcare associated infection: 80 No bacteriuria/ pyuria: 93 Asymptomatic: 34 Other**: 61

Characteristic Cefazolin (n = 43) Fluoroquinolones (n = 30) p-value Age, years, median (IQR)* 88 (80-92)79 (64-87)0.01 Gender, Female 34 (79)24 (80)1 Penicillin allergy 1 (2)15 (50)< Symptoms of UTI Urinary symptoms** 15 (35)17 (57)0.09 Fever 8 (17)10 (33)0.18 Nausea/vomiting 7 (16)12 (40)0.03 Malaise/fatigue 26 (61)21 (70)0.46 Altered mental status 29 (67)13 (43) Data presented as n (%) unless otherwise specified *IQR: Interquartile range **Urinary symptoms: Dysuria, frequency, urgency, hematuria, suprapubic pain, flank pain PATIENT CHARACTERISTICS

Characteristic Cefazolin (n = 43) Fluoroquinolones (n = 30) p-value Emergency department antibiotics 35 (81)17 (57) Cefazolin 21 (60)3 (18)0.003 Ceftriaxone 8 (23)3 (18)1 Fluoroquinolones 2 (6)10 (59)< Other* 5 (14)1 (6)0.65 Antibiotic resistance on first culture Cefazolin3 (7)6 (20) 0.15 Fluoroquinolones8 (19)7 (23) 0.77 Antibiotic switched due to sensitivities 2/3 (67)5/7 (71) 1 16 Data presented as n (%) unless otherwise specified *Others: Azithromycin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, tobramycin PATIENT CHARACTERISTICS

17 No statistical difference between treatment arms PATIENT CHARACTERISTICS

PRIMARY ENDPOINT 18 Cefazolin (n = 43) Fluoroquinolones (n = 30) p-value Clinical failure1 (2)2 (7) 0.56 Signs of UTI that require additional antibiotics 1 (2)0 1 Re-initiation of antibiotics during hospital stay for UTI day re-hospitalization for UTI 02 (7) 0.17 Data presented as n (%) unless otherwise specified

SECONDARY ENDPOINTS 19 Characteristic Cefazolin (n = 43) Fluoroquinolones (n = 30) p-value Hospital length of stay, days, median (IQR) 3 (2-5)3 (2-6) 0.88 Inpatient antibiotic length of treatment, days, median (IQR) 3 (2-5)2 (2-4) 0.39 C. difficile within 30 days*0 (0) 1 Microbiological cure (if available)6/6 (100)10/11 (90)1 Emergence of resistance (if available)1 Cefazolin0/0 (0)0/1 (0) Fluoroquinolones0/0 (0)0/1 (0) Data presented as n (%) unless otherwise specified *30 days from the end of antibiotic treatment

DISCUSSION First study on intravenous narrow spectrum beta-lactam agent vs. fluoroquinolones in hospitalized patients for community- acquired UTI Study population Gender: 21% male Median age: 86 years Clinical failure rates were similar between cefazolin and fluoroquinolones (2% vs 7%, respectively, p = 0.56) Validates institutional guidelines No differences in secondary endpoints 20

LIMITATIONS Retrospective analysis Limited to documentation Small sample size Not adequately powered No measurement of clinical success Not able to assess symptom resolution at test of cure visit Symptoms of UTI are mostly non-specific Unable to completely evaluate microbiological cure 21

CONCLUSION No difference in primary endpoint of clinical failure between cefazolin and fluoroquinolones May potentially lead to a reduction in fluoroquinolones utilization Future direction: Larger prospective studies needed to validate the results Report study results and educate physicians Opportunity to improve antibiotic selection in non- penicillin allergic patients 22

QUESTION 1. Based on this study, there is no difference between cefazolin and FQ in rates of clinical failure in community acquired UTI. What are the possible benefits with reduced FQ use? a.Reduce rates of C. difficile b.Reduce collateral damage c.Increase collateral damage d.A and B 23

ACKNOWLEDGEMENTS Esther King, PharmD Dimple Patel, PharmD, BCPS-AQ ID Stephanie Chiu, MPH 24

The treatment of community-acquired urinary tract infections with cefazolin vs. fluoroquinolones Amulya Uppala, PharmD PGY-1 Pharmacy Resident Atlantic Health System