What Are Last Resort Antibiotics?

Antimicrobial stewardship for last resort antibiotics old and new

Inge C Gyssens 23 October 2014 ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ICG 2014 ESCMID Online Lecture Library © by author

Munoz-Price et al. Lancet Infect Dis 2014 ICG 2014 Last resort Antibiotics DEFINITION ESCMID Online Lecture Library © by author ICG 2014 Pubmed search “last resort antibiotics”

• "last resort antibiotics"[All Fields] OR "last resort"[All Fields] AND ("antibacterial agents"[Pharmacological Action] OR "anti-bacterial agents"[MeSH]

• 183 hits

• Old drugs but “toxic”: colistin/polymyxin, nitrofurantoin, chloramphenicol, isepamicin • Old drugs, high resistance potential: fosfomycin, aztreonam

• Newer drugs, very broad spectrum : carbapenems , tigecycline

• Newer drugs, VRSA .. : dalbavancin, oritavancin …. ESCMID Online Lecture Library © by author ICG 2014 B Huttner et al. PlosOne 2012

ESCMID Online Lecture Library © by author ICG 2014 Huttner et al. PlosOne 2012

ESCMID Online Lecture Library Pathogens© by isolated author when polymyxin was used ICG 2014

ESCMID Online Lecture Library © by author ICG 2014 ESCMID Online Lecture Library © by author Science 2014 ;345:1299 ICG 2014 Vancomycin and daptomycin resistant S. aureus

ESCMID Online Lecture Library © by author ICG 2014 What are last resort antibiotics?

Antibiotics that your patient needs when most available antibiotics are not working

Last resort antibiotics can be totally different depending on the geographic area and over time. It mainly depends on the selection pressure by antibiotic consumption in that area

ESCMID Online Lecture Library © by author ICG 2014 What are last resort antibiotics in different countries?

US, most EU countries colistin tigecycline …

Geneva: faropenem (oral carbapenem) from Japan

Croatia: ampicillin sulbactam ?

France: colistin, chloramphenicol (but never used it) Austria: mecillinam and temocillin now imported Greece : isepamicin .. I ESCMID Online Lecture Library © by author ICG 2014 ESCMID Online Lecture Library © by author ICG 2014 ANTIMICROBIAL STEWARDSHIP ESCMID Online Lecture Library © by author ICG 2014 Antimicrobial Stewardship

Definition

“Antimicrobial stewardship programs focus on ensuring the proper use of antimicrobials to provide the best patient outcomes, lessen the risk of adverse effects, promote cost- effectiveness, and reduce or stabilize levels of resistance” MacDougall C. and Polk RE. Clin Microbiol Rev 2005;18:638-56

Other terms:

“Responsible use, appropriate use, sustainable use, optimal use..ESCMID” Online Lecture Library © by author ICG 2014 ESCMID Online Lecture Library © by author AS Recommendation FORMULARY RESTRICTION FORESCMID LAST RESORTOnline LectureANTIBIOTICS? Library © by author ICG 2014 ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author Kolkata 2012 Health center outpatient pharmacy: restriction: no fluoroquinolones

ESCMID Online Lecture Library © by author ICG 2014 Kolkata 2012 • Veterinary sector: promotion campaign

ESCMID Online Lecture Library ENDO FLOX VET oral suspension © by author enrofloxacin ICG 2014 Netherlands: antibiotic use in the veterinary sector

Oral antibiotics for prostatitis

Last resort

ESCMID Online Lecture Library © by author ICG 2014 Netherlands: antimicrobial stewardship in the veterinary sector

Last resort

ESCMID Online Lecture Library © by author ICG 2014 AS Recommendation AUDIT AND FEEDBACK FORESCMID LAST RESORTOnline LectureANTIBIOTICS Library © by author ICG 2014 ESCMID Online Lecture Library © by author ICG 2014 Criteria for review of individual Antibiotic Prescriptions

• Indication

• Choice of antibiotic Start

Sufficient no VI Stop antimicrobial activity data yes toxicity AB indicated no V Stop yes

More effective yes IVa width of spectrum alternative no

Alternative yes IVb less toxic cost no

Alternative yes IVc less costly • The antibiotic regimen no

yes Alternative IVd narrower • The dose no

Duration no Duration no Correct Dose no IIa too long too short • The interval yes yes yes IIIa IIIb no Correct Interval IIb • The way of administration yes

Correct Route no IIc • The duration yes Correct Timing no I

yes The timing • Not in categories I - IV ESCMID Online Lecture Library0 © by author Gyssens. Int J Antimicrob Agents 2001;17:9-19 Van der Meer & Gyssens Clin Microbiol Infect Dis 2001;7suppl 6:12-15 AS Recommendation EDUCATION ESCMID Online Lecture Library © by author ICG 2014 Education on good antimicrobial use

ESCMID Online Lecture Library © by author

Pulcini&Gyssens, How to educate prescribers Virulence 2013 AS Recommendation DEVELOPMENT OF NATIONAL GUIDELINESESCMID Online Lecture Library © by author ICG 2014 Dutch Working Party on Antibiotic Policy www.swab.nl/guidelines

National guidelines for hospitals ee Community acquired pneumonia Meningitis Sepsis Surgical prophylaxis Urinary tract infections Acute diarrhea MRSA carriage FungalESCMID infections Online Lecture Library … © by author ICG 2014 Increasing prevalence of ESBL positive E. coli and K. pneumoniae in

urine isolates - K. pneumoniae inpatient isolates

Percentage derde generatie cephalosporine resistentie: urine isolaten Trend 2008-2011 14 Inpatients Outpatients General 12 P=0.023 practice 10

8 P<.0001 P<.0001 P<.0001 % % I/R 6 P<.0001

P<.0001 4

0 ESCMIDECO (gem. KPN Online (gem. ECO (gem. LectureKPN (gem. ECO Library(gem. KPN (gem. ©n=10.862) by authorn=1.786) n=14.811) n=2.256) n=44.099) n=4.445) Netherlands -Muilwijk J and Leverstein –van Hall unpublished data 2012 ICG 2014 ESCMID Online Lecture Library

Nordberg P, Monnet DL, Cars O. Antibacterial drug resistance [Background document for the WHO project: Priority Medicines for Europe© andby the World. author ‘A Public Health Approach to Innovation’]. 2004. Available from: http://soapimg.icecube.snowfall.se/stopresistance/Priority_Medicine_Antibacterial_background_docs_final.pdf Netherlands

Because of these ESBL scares, several microbiologists tried to challenge the 2011 sepsis guidelines by recommending more frequent empirical use of carbapenems

In 2013 an outcome analysis was published:

Use and resistance in Nethmap MARAN and ECDC 2014 coming

ESCMID Online Lecture Library © by author ICG 2014 AS Recommendation in hospitals ESTABLISH AN ANTIBIOTIC COMMITTEEESCMID Online AND LectureAN ANTIBIOTIC Library STEWARDSHIP TEAM © by author ICG 2014 Recommendation SOLVE THE DRUG SHORTAGES PROBLEMESCMID Online Lecture Library © by author ICG 2014 Survey on antibiotic shortages in the EU

• Shortages affect the care of critically ill patients

• Shortages lead to the use of more expensive and broad-spectrum or less efficacious substitute agents. These substitutes may further accelerate the emergence and selection of antibiotic resistance

• For instance, replacing piperacillin by piperacillin/tazobactam for susceptible Pseudomonas spp, minocycline by tigecycline for methicillin-resistant Staphylococcus aureus or penicillin byESCMID ceftriaxone for Onlinestreptococcal Lecture infections broadens Library the spectrum of therapy unnecessarily and increases healthcare costs © by author ICG 2014 33% of hospitals had trouble finding equivalent drugs or substitutes

Shortage duration ranged from 1 week ESCMIDto 18Online months Lecture Library © by author Recommendation SOLVE THE FORGOTTEN ANTIBIOTICS PROBLEM:ESCMID Online IMPROVE Lecture ACCESS Library © by author ICG 2014

SWAB guidelines for

Antibacterial therapy of adult patients with Sepsis

Dutch Working Party on Antibiotic Policy (SWAB)

Preparatory Committee SWAB board, Chair Prof. dr I.C. Gyssens Coordinator H.I. Bax DutcAztreonamh Society fo couldr Infec tinotous Diseabe includedses (VIZ) in the recommendationsDr E.F. Schippers, S. van for Asse sepsisn in beta- Dutch Society for Internal Medicine (NIV) Dr E.F. Schippers, S. van Assen Dutch Society for Microbiology (NVMM) Dr C.W. Ang, Dr P. Sturm DutclactamESCMIDh Assoc allergiciation of patients Hospit alOnline P withharma cneutropeniaists (NVZA) Lecture Dr Y.G. van der Me Libraryer Dutch Society for Surgery (NVH) Dr M.A. Boermeester Dutcbecauseh Societ ity hadfor Intensi beenve Cremovedare (NVIC) from the marketDr J.A. Schoute in then, Netherlands Dr P. Pickkers Dutch Soc©iety forby Hae maauthortology (NVvH) Drs J.J.W.M. Janssen ICG 2014 Dr. N. Blijlevens

SWAB conceptrichtlijn Sepsis Juni 2010 ESCMID Online Lecture Library © by author ICG 2014 ICG 2012 Nafcillin Mecillinam temocillin 2 countries Temocillin

Pristinamycin

Thiamphenicol Fosfomycin ; iv fosfomycin iv 5 countries Cefoperazone-sulbactam

Spectinomycin

Methenamine Hippurate

Methenamine Mandelate

Quinupristin-dalfopristin

Dicloxacillin

Cefpodoxime

Pivmecillinam

Oxacillin

Cefoxitin

Procaine benzylpenicillin

Ceftibuten

Cloxacillin Flucloxacillin aztreonam Fosfomycin ; oral

Aztreonam

Chloramphenicol

Trimethoprim

Fusidic acid

Colistin colistin

Tobramycin

Benzathine benzylpenicillin

Teicoplanin

Cefepime

Nitrofurantoin

Ertapenem Any antistaphylococcalESCMID penicillin Online Lecture Library Phenoxymethylpenicillin (Penicillin V)

Benzylpenicillin (Penicillin G) © 0by author5 10 15 20 25 30 35 Number of countries where the antibiotic is available (over a total of 38) Slovenia Croatia Rep. of Macedonia Kosovo Albania Latvia Switzerland Serbia Lithuania Hungary Iceland Estonia Malta Romania Ireland Czech Rep. Norway The Netherlands Luxembourg United Kingdom Canada Belgium Austria Turkey Slovakia Poland Denmark Italy Germany Bulgaria Sweden Portugal Greece Australia ESCMIDSpain Online Lecture Library Finland France US © by author 0 5 10 15 20 25 Number of antibiotics available (over a total of 33) Conclusions on stewardship aspects

• Gaps identified

1. There are no special guidelines for “last resort” antibiotics. • But are these needed? • Geographical differences • Evolution over time More important: 2. Re-development of useful forgotten antibiotics 3. Update of regulations 4. Improving access 5. Re-thinking of veterinary formularies