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Antibiotic stewardship

Sarah Doernberg, MD, MASAssociate Professor, Division of Infectious DiseasesMedical Director of Adult Antimicrobial Stewardship

Disclosures

§ Consultant: Genentech

Outline

• Introduction to stewardship• Quick takes:

• How long should I treat…?• Can I switch to oral therapy for…?

• Wrap-up

A story…

§ Find someone sitting next to you§ 2 minutes: Think about a time where you think antibiotic

management could have gone better. Please share with the person sitting next to you and share what factors contributed

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Antibiotic use in the hospital is extensive

https://www.cdc.gov/antibiotic-use/stewardship-report/pdf/stewardship-report.pdfBaggs J et al. JAMA Intern Med. 2016 Nov 1;176(11):1639-1648. doi: 10.1001/jamainternmed.2016.5651.

Average DOT/1000 pt-days: 754.8

Hecker MT et al. Arch Intern Med. 2003;163:972-978.

30% of inpatient antibiotic use is unnecessary§ 58% received ≥ 1 day of unnecessary antibiotics

Noninfectious or

nonbacterial 33%

Colonization or

contamination16%

Duration too long34%

Adjustment not made

3%

Redundant coverage

10%

Spectrum not indicated

4%

Antibiotic use selects for antibiotic resistance

https://www.cdc.gov/antibiotic-use/stewardship-report/pdf/stewardship-report.pdf http://chicago-mosaic.medill.northwestern.edu/antibiotic-resistance-superbugs/

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Antimicrobial resistance threatens human health

23,000 annual deaths > 2 million illnesses

https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf

Attributable mortality of MDROs

0%

5%

10%

15%

20%

25%

30%

CTX-R E coli CTX-R K.pneumoniae

CRE-K MRSA

resistant not resistant

http://www.who.int/drugresistance/documents/AMR_report_Web_slide_set.pdf

What is antibiotic stewardship?

Improve patient outcomes

Decrease antibiotic resistance, AE,

costs

Interventions designed to optimize the appropriate use of antimicrobials

MacDougall C and Polk RE. Clin Microbiol Rev. 2005;18:638-56.

But what exactly does that mean?

AccountabilityResources Expertise

https://www.cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html

Action Tracking/reporting Education

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Does it work?

MDRO incidence rate w/ ASP:0.49 (0.35-0.68)

CDI incidence rate w/ ASP:0.68 (0.53-0.88)

Baur D et al. Lancet Infect Dis. 2017 Sep;17(9):990-1001. doi: 10.1016/S1473-3099(17)30325-0.

Antibiotic checklist

q Does the patient have a bacterial infection requiring antibiotics?

q Have I ordered appropriate cultures before starting abx?

q What is the appropriate antibiotic, accounting for host and syndrome?

q After ~48 hours, can I stop, narrow, or switch to PO?

q What is the appropriate duration?

Tamma PD et al. JAMA. 2018 Dec 27. doi: 10.1001/jama.2018.19509

Outline

ü Introduction to stewardship• Quick takes:

• How long should I treat…?• Can I switch to oral therapy for…?

• Wrap-up

How long would you treat? 76 y/o M with cholangitis and E. coli bacteremia now afebrile and stable on day 2 of ceftriaxoneA. 14 daysB. 10 daysC. 7 daysD. 5 daysE. 3 days

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How long would you treat? 46 year-old M with DM and obesity admitted with LLE cellulitis, improving on day 3 of cefazolinA. 14 daysB. 10 daysC. 7 daysD. 5 daysE. 3 days

How long would you treat? 83 year-old F with dementia and urinary retention requiring CIC admitted with pyelonephritis d/t K. pneumoniae, now stableA. 14 daysB. 10 daysC. 7 daysD. 5 daysE. 3 days

We are all bacteremic at times

Lockhart PB et al. Circulation. 2008 Jun 17;117(24):3118-25. doi: 10.1161/CIRCULATIONAHA.107.758524Lockhart PB. Arch Intern Med. 1996 Mar 11;156(5):513-20.Everett ED and Hirschmann JV. Medicine (Baltimore). 1977 Jan;56(1):61-77.

Parahitiyawa NB et al. Clin Microbiol Rev. 2009 Jan;22(1):46-64, Table of Contents. doi: 10.1128/CMR.00028-08

General principles of shorter-course antibiotics

Sho

rt co

urse • Stabilized

• Source control• Predictable

response

Long

er c

ours

e • Slow response• Inadequate

source control• Very resistant

organism• +/- compromised

host

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How long should I treat?

Yadav K et al. Open Forum Infect Dis. 2018 Dec 3;6(1):ofy319. doi: 10.1093/ofid/ofy319. eCollection 2019 Jan. Supplementary materialAguilar-Guisado et al. Lancet Haematol. 2017 Dec;4(12):e573-e583 Yahav D et al. Clin Infect Dis. 2018 Dec 11. doi: 10.1093/cid/ciy1054.Havey TC et al. Crit Care. 2011;15(6):R267. doi: 10.1186/cc10545. Epub 2011 Nov 15Sutton JD et al. Open Forum Infect Dis. 2018 Apr 21;5(5):ofy087. doi: 10.1093/ofid/ofy087Wald-Dickler N and Spellberg B. Clinical Infectious Diseases, ciy1134, https://doi.org/10.1093/cid/ciy1134

Syndrome Duration (days) CommentsCAP 5 Not studied in ICU/intubated ptsHAP/VAP 7 Includes intubated ptsIntra-abdominal infection 4 Assuming source controlCellulitis 5 If responds to initial treatmentComplicated UTI 5-7 Remove foleyFebrile neutropenia 48-72h post-fever Even if neutropenia persistsEnteric GNR BSI 7 Stable after 48hPneumococcal BSI in CAP 5-7 Extrapolation from RCT subgroups

Areas of uncertainty for short duration

Havey TC et al. Crit Care. 2011;15(6):R267. doi: 10.1186/cc10545. Epub 2011 Nov 15Sutton JD et al. Open Forum Infect Dis. 2018 Apr 21;5(5):ofy087. doi: 10.1093/ofid/ofy087

Maybe

• Other strep BSIs

• Non-enteric GNR BSIs

No-go

• Endocarditis• Staphylococcus

aureus

Is there an oral option?

§ 71 year-old F with recurrent UTIs admitted with cystitis due to ceftriaxone-resistant E. coli

§ 34 year-old M with primary biliary cirrhosis admitted with Klebsiella bacteremia from cholangitis

§ 59 year-old F with Group A Strep cellulitis with positive blood cultures

§ 69 year-old M with complex urological history and chronic foleyadmitted with VRE bacteremia in the setting of a suspected UTI

Bioavailability

Cyriac JM and James E. J Pharmacol Pharmacother. 2014 Apr-Jun; 5(2): 83–87.doi: 10.4103/0976-500X.130042Gilbert DN et al. The Sanford Guide to Antimicrobial Therapy. 45th Ed.

Drug % absorptionAmoxicillin 80Amoxicillin-clavulanic acid 80/30Cephalexin 90Ciprofloxacin 70Clindamycin 90Levofloxacin 99Linezolid 100Metronidazole 100Moxifloxacin 89PCN VK 60-73TMP/SMX 85

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General rules for switching

Clinical stabilityAfebrileWorking GI tractGood bioavailability

Meningitis, other deep-seated infectionsGI dysfunctionCannot take POPoor PO optionsCritically ill

Favo

rs s

witc

h

Do not switch

Most syndromes can be treated with POs

§ Pneumonia§ Cellulitis§ Abscess§ UTI

Oral options for ESBL infections

Drug Urine Non-urine CommentsFluoroquinolone X X ↓SusceptbilityTMP/SMX X X ↓SusceptbilityNitrofurantoin Cystitis No CrCl≥60 onlyFosfomycin Cystitis (coming in IV form) Send-out sensis

Klebsiella ↓susc

Amox-clav Cystitis No Esp if MIC ≤ 8Cefpodoxime+amox-clav X Unknown Hard to schedule

Sorlozano Puerto A. Diagn Microbiol Infect Dis 2006; 54: 135-139.Livermore DM, et al. Clin Microbiol Infect 2008; 14 S1: 189-193; Rodriguez-Bano J, et al. Arch Intern Med 2008; 168: 1897-1902

Falagas ME, et al. Lancet ID 2010; 10: 43-50Pullucku H, et al. Int J Antimicrob Agents 2007; 29: 62-65

• Most serious infections will require IV carbapenems

Can PO antibiotics be used for enteric GNR BSI?

Pts with GNR BSI &• Source control• Pitt score ≤ 1 by d5• Taking POs• PO option(70% FQ, 13% tmp/smx, 16% β-lactam)

PO switch ≤ day 5 (med 3d)(N = 739)

IV rx > 5 days (med 14d)(N = 739)

Propensity score matched

30d mortality

13.1%

13.4%

↓hospital LOSNo diff in recurrent BSI

7-14 days of antibiotics allowed

Tamma TD et al. JAMA Intern Med. 2019 Jan 22. doi: 10.1001/jamainternmed.2018.6226

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Can PO antibiotics be used for streptococcal bacteremias?

Disease PO antibiotic switch? CommentsCAP w/ pneumococcal bacteremia

Yes Small studies

VRE bacteremias Yes (LZD)Group A Strep bacteremia

Likely Lack of data

Amp-susceptible enterococcus

Likely (amox or LZD) Lack of data

Ramirez JA and Bordon J. Arch Intern Med. 2001 Mar 26;161(6):848-50Zhao M,, et al. Int J Antimicrob Agents 2016; 48:231–8

• Open-label RCT• Noninferiority (10%)• All Danish ♥ centers• L-sided NVE or PVE• Gram-positive only• Stable

Continue IV

Switch to PO

≥ 10 dd IV abx

≥ 10 dd abx left(mean 17)

(mean 19 days)

(mean 17 days)

Iverson K et al. New Engl J Med 2018; DOI: 10.1056/NEJMoa1808312Iverson K et al. Am Heart J. 2013 Feb;165(2):116-22. doi: 10.1016/j.ahj.2012.11.006

12.1%

9.0%

Diff: -3.1% (-3.4 to 9.6%)

Failure

No ▲ mortality16d ↓LOS

• Open-label RCT• Native osteomyelitis• Native joint infection• PJI• Fixation device ifxn• Vertebral osteo

Continue IV

Switch to PO

< 7d IV abx >70 days abxPOàmore rif

OK step-down to PO

Li H-K et al. N Engl J Med 2019; 380:425-436. DOI: 10.1056/NEJMoa1710926

14.6%

13.2%

Diff: -1.4% (−5.6 to 2.9)

1y failure

↓LOSMD discretion

Areas of uncertainty for PO antibiotics

Sutton JD et al. Open Forum Infect Dis. 2018 Apr 21;5(5):ofy087. doi: 10.1093/ofid/ofy087Willekens R, et al. Clin Infect Dis. 2018 Oct 23. DOI: 10.1093/cid/ciy916. [Epub ahead of print]

Staph aureus

bacteremias

Non-enteric GNR

bacteremias

Strep bacteremias

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How can you use this in your practice?

§ You can steward use of antibiotics with a checklist§ Shorter courses of antibiotics are safe and effective for most

indications§ Oral antibiotics can be used for most infections, as initial

therapy or step-down

THANK YOU!