ANTIBACTERIAL STEWARDSHIP IN FEBRILE (FN)

LOW-RESISTANCE VS HIGH-RESISTANCE SETTINGS

MONICA SLAVIN DEPARTMENT OF INFECTIOUS DISEASES PETER MACCALLUM CANCER CENTRE AND ROYAL MELBOURNE HOSPITAL, MELBOURNE, AUSTRALIA

ESCMID eLibrary © by author DISCLOSURE

. Research grants: Gilead, Merck, Pfizer

. Consultant: Gilead, Merck, Pfizer

. Invited speaker: Gilead, Merck, Pfizer ESCMID eLibrary © by author SCOPE . Most studies relate to haematological malignancy (HM) . choice and approach according to resistance setting- focus on gram negatives . Processes and pathways for management of febrile neutropenia (FN) . New approaches to management and neutropenia: • sparing • New • Infusional Beta-lactams • Earlier diagnosis and new tests . Controversies in management: ESCMID• Antibiotic prophylaxis eLibrary © by author STEWARDSHIP PROGRAM IN CANCER 2017 It’s not just about the FN antibiotic protocol..….. ESCMID eLibrary © by author Surveillance • Screening • Antibiogram • Outcome

Audit and feedback Processes/Pathways • Membership of team Stewardship • High/low risk scores • Consultant involvement in cancer • Sepsis management 2017 • Allergy de-labeling • prevention • Diagnostics

Antibiotic choice & approach FN • Escalation/de-escalation • Prophylaxis or not ESCMID• Clinical algorithmseLibrary © by author ESBL PRODUCING ENTEROBACTERIACEAE (ESBL-PE) . Prevalence in cancer patients: • 20% colonised with ESBL-PE • 33% in Asia . 13 x higher risk ESBL-PE blood stream infection (BSI) compared to non-colonised . Significantly higher 30 day mortality than non-ESBL-PE Alevizakos ESCMIDM et al, Int J Antimicrob agents 2016; 48:647 Baker eLibrary TM and Satlin MJ Leuk lymphoma 2016:57:2245 © by author CARBAPENEMASE PRODUCING ENTEROBACTERIACEAE (CPE)

Ref Country Group Years Organism % resist Mortality

Trecarichi Italy HM 2009-2012 K. pneumoniae 35% 46 vs15% 2015 p=0.04 Cattaneo Italy HM, AL 2012-2014 CPE 9% 30 vs7% 2016 P=0.0001

. Incidence in K. pneumoniae infection in allogeneic and autologous HSCT Italy 2010-13: 2% and 0.4% . Colonisation pre-HSCT: infection post-HSCT in 39% allogeneic, 26% autologous . Inappropriate initial antibiotic therapy associated 23% mortality cf 10% (p<0.001)

Trecarichi EM et al Clin Microbiol Infect 2015; Cattaneo C et al Ann Haematol 2016, Girmenia C et al, Transpl 2015ESCMID. eLibrary © by author ESCMID eLibraryAverbuch D et al, Haematologica 2013 © by author EUROPEAN CONFERENCE ON IN LEUKEMIA (ECIL)

ESCMID eLibrary © by author EUROPEAN CONFERENCE ON INFECTIONS IN LEUKEMIA (ECIL)

ESCMID eLibrary © by author . Modify empiric therapy for unstable patient or positive results suspicious for resistant bacteria (B-III) . Risk factors: previous infection or colonization and high rates of endemicity in hospital.

ESBLs: Consider early use of a carbapenem (B-III). KPCs: Consider early use of polymyxin-colistin or tigecycline(C-III) ESCMID eLibraryFreifeld A et al, Clin Infect Dis 2011 © by author ESBL-PE: CAN ß-LACTAM-ß-LACTAMASE INHIBITORS (ßL-ßLIS) REPLACE ?

. Conflicting outcomes in blood stream infection (BSI): • 1.92 higher risk death with -tazobactam (PTZ) cf carbapenem (n=231) • No difference in mortality ßL-ßLIs cf carbapenem in empiric or definitive treatment (n=966) • Metanalysis no difference all cause mortality ßL-ßLIs cf carbapenem (n=258)

Bassetti M et al, Curr Opin Infect Dis 2016, Vardakas KZ et al JAC 2012, Tamma PD et al. Clin Infect Dis 2015, Tamma PD et al Clin ESCMIDInfect Dis 2017, Guiterrez-Guiterrez B et al AAC 2016 , eLibrary © by author ESBL-PE: CONFLICTING RESULTS . Source infection: Biliary/renal…low inoculum? . Organism: Klebsiella vs E. coli? . MIC for piperacillin-tazobactam varied . Piperacillin-tazobactam: 6 hourly dosing or extended 8 hourly infusion not always used . Severity of illness, proportion in ICU

Randomised trial PTZ vs : MERINO

Carbapenem: critically ill, higher inoculum infection, high piperacillin MIC PTZ: 4.5g 6 hourly or 4.5 g 8 hourly extended infusion ± aminoglycoside Tamma ESCMIDPD et al Clin Infect Dis 2017, Bassetti M et al, eLibraryCurr Opin Infect Dis 2016, Harris PN Trials 2015. © by author ESBL-PE IN FN: PTZ

Low resistance: Empiric carbapenem reserved for known colonised patients with severe sepsis. High resistance: carbapenem or prolonged infusion PTZ ± amikacin replaced carbapenems as empiric therapy Exceptions: • High-risk patients previously colonized or infected with ESBL-PE who presented with severe sepsis, septic shock or nosocomial pneumonia, • Recently transferred from the with a high endemicity of multidrug-resistant Gram-negative bacilli. No change mortality, reduced carbapenem consumption ESCMIDTam CS eLibraryet al et al Int Med J 2011, Metan G et al Infez Med 2017 © by author NEW ßL-ßLI AGENTS . Ceftolozane–tazobactam

. Ceftazidime-avibactam

. Cost .ESCMIDData lacking in FN eLibrary © by author TARGET ATTAINMENT: PTZ IN FN SINGLE DOSE 4.5G OVER 30 MIN IN 12 HM PATIENTS

fT>MIC: Proportion of time free-drug concentration remains above MIC ESCMID eLibrarySime FB et al J Antimicrob Chemother 2014 © by author THERAPEUTIC DRUG MONITORING (TDM) PIPERACILLIN IN FN

n=32

. PTZ 4.5 g 8 hourly over 30 mins plus gentamicin in haematology patients . PK/PD target: free trough concentration 100% fT>MIC at MIC 16 if no organism . First TDM performed after 3rd or 4th dose . Dose adjustment: ↑frequency administration by 25-50% and/or extended infusion ESCMID eLibrarySime FB et al J Antimicrob Chemother 2015 © by author DISCONTINUATION FQ PROPHYLAXIS . Benefits FQ prophylaxis debated, association resistance . Ceased prophylaxis: HM neutropenia mean 12 days, n=153 Re-•assessRapid decrease role of in resistance:fluoroquinolone 73% → 8% prophylaxis in view• Rapidof: decrease in ESBL: 42% → 10% Better• Reduction sepsis carbapenem managementuse (NS) Concerns• No difference re: selection length antibiotic of resistant treatment, LOS, gram no mortalitynegatives Prevalence• Rapid return of FQ to pre resistant-discontinuation organisms rates resistance after re- Changesinstitution in cancer FQ prophylaxis treatment and transplant . 47 allogeneic HSCT: no change BSI/IFD/mortality cf historical protocolscontrols Gafter-Gvili A et al Cochrane Reviews 2014;Kimura S et al. J Infect 2014; Imran H et al, Eur J Clin Microbiol Infect Dis 2008 ESCMIDVerlinden A et al Eur J Haematol 2014,eLibrary Heidenreich D et al Ann Haematol 2016 © by author Process mapping VISEO

ESCMID eLibrary © by author ESCMID eLibrary © by author CANCER HOSPITAL-WIDE SEPSIS PATHWAY 2013

Outcome Historical On pathway Not on pathway Number P value (n=111) Time to antibiotics all FN 110 min 45 min 235 min 114/22 0.002

Time to antibiotics HM FN 240 min 60 min 220 min 135/33 0.002

1st Antibiotic appropriate 76% 95% 76% 402/47 <0.001

ICU 35% 18% 29% 322/127 0.012

Mortality Day 30 All-cause 21% 10% 20% 322/127 0.002

ESCMID eLibraryTeh B et al, ECCMID 2015:abstract EP198 © by author INCREMENTAL COST: EFFECTIVENESS

RATIO Incremental lives saved per treated patient

Cost $$$

~$8000 and 0.1 life saved for each haem/onc patient placed on the sepsis pathway ESCMID eLibraryPoster #66 Thursky,Teh, ASID 2017 © by author Oral Risk Ambulatory Antibiotic Stratification Care Switch 1. MASCC score within first 24 hours for eligible patients 2. If low risk AND meets all criteria: oral antibiotic switch 3. If meets all early discharge criteria  Referral to Neutropenic Fever (NF) nurse and ambulatory program MASCC: ESCMID multinational association for supportiveeLibrary care in cancer © by author AMBULATORY PROGRAM Historical low-risk NF group from 2011 cf program cohort 2014-2015 Nurse led, 0.1 EFT ID physician

Historical NF group Prospective NF group n=27 n=25 Male, n (%) 18 (67%) 13 (52%) Age, n (range) 51 (20-83) 53 (27-75) Solid tumour, n (%) 21 (78%) 20 (80%) Hospital LOS – median (range) 4 days (1-10) 1.1 days (0.2-5.9) Duration of IV antibiotics - median 3 days <1 day Cost of hospital admission, (range)* $8,800 ($7,220-$10,540) $2,640 ($1,985-$2,898) *Based on $2,000/day

Lingaratnam S, et al Internal Medicine Journal 2011 Jan;41(1b):110-120, Lingaratnam S, et al Internal Medicine Journal 2011 Jan;41(1b):121-9, Lingaratnam S, et al Australian Health Review. Aust Health Rev. 2011 Nov;35(4):491-500, Lingaratnam ESCMIDS, Mellerick A, et al Intern Med J. 2013 Sep;43(9):979-86. eLibrary © by author ANTIBIOTIC ALLERGY LABELS Peter MacCallum Cancer Centre (2010-2012) . 23% of cancer in-patients had an antibiotic allergy label: • Increased antibiotic use per admission (3 vs. 2, p=0.01) • Increased percentage fluroquinolone use (14.6% vs. 5.6%, p<0.001) • Increased antibiotic course duration (15 vs. 13 days, p=0.09) • Higher readmission rates (53% vs. 28%, p<0.001) • Less concordance with therapeutic guidelines (47% vs. 91%, p<0.001)

ESCMIDTrubiano J et al Antimicrob eLibraryResist Infect Control. 2015 © by author ANTIBIOTIC ALLERGY DELABELLING . Prospective study antibiotic allergy testing (AAT) in 66 immunocompromised patients: • 91% had >1 label removed • 60% had all labels removed

. Compare pre and post AAT: • Increased narrow spectrum antibiotic use and appropriateness, decreased restricted antibiotic use ESCMIDTrubiano J et al,eLibrary Poster EPO992 Monday 24th April ECCMID 2017 © by author STEWARDSHIP DELIVERY Consultants cannot be replaced by rotating registrars Constant/dedicated team: training and succession planning Adherence to protocol associated with decreased mortality day 28

ESCMIDYeo CL et al ARIC 2012:1:36 eLibrary Rosa RG et al BMC infect Dis 2014:14:286 © by author EARLY DIAGNOSIS Enhanced laboratory diagnosis • Carba-NP-II:Sens 79; Spec 100; PPV 100; NPV 98.7% • CRE agar: detected 97% KPC CRE within 18 hours • PCR: Multiplex- KPC, NDM, VIM, OXA-48: false positives • Malditof Differentiating bacterial infection • Presepsin (soluble CD14), Procalcitonin, IL-6, Lipopolysaccaride-binding protein

ESCMIDMetan G and Akova M Curr Opin Infect Dis 2016 ; StomaeLibrary et al Haematol Oncol Stem Cell Ther 2017 © by author CONCLUSIONS . In management of febrile neutropenic patients focus has been on antibiotic selection . Pathways e.g. sepsis, outpatient management low risk febrile neutropenia, allergy delabelling are important stewardship tools . Pathways can improve outcomes . Re-evaluate utility of fluoroquinolone prophylaxis, consider the role of ßL-ßLI as carbapenem sparing • Optimisation of ßL-ßLI dosing, such with as extended infusion ESCMIDpiperacillin tazobactam eLibraryshould be evaluated © by author THANKYOU ESCMID eLibrary © by author