Robert A. Weinstein, MD April 9, 2016

The C. Anderson Hedberg, MD Professor of Medicine Rush Medical College

Chairman Emeritus Department of Medicine, Cook County Hospital

Disclosures: Sage Inc (Remote) & CDC (Current) Funding

1. The Problem

2. Treatment Options

3. Combating Resistance A. Follow the Causal Pathway

B. Antimicrobial Stewardship

4. National Action Plan

Cook P, Current Issues in and Approaches to Antimicrobial Resistance, October 2015

http://www.cdc.gov/drugresistance/threat-report-2013/

1. THE PROBLEM

Molton et al, Clin Infect Dis 2013; 56:1310-8

Abbreviations: AmpC, AmpC–producing Enterobacteriaceae; ESBL, extended-spectrum β-lactamase– producing Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase–producing Enterobacteriaceae; MRSA, methicillin-resistant Staphylococcus aureus; NDM-1, New Delhi metallo-β-lactamase-1–producing Enterobacteriaceae; PRSA, penicillin-resistant S aureus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant S aureus.

Enterobacteriaceae Pseudomonas

aeruginosa

Acinetobacter Staphylococcus

aureus

AmpC -lactamases

ESBL

Carbapanemases

DNA gyrase/

topoisomerase

mutations

Aminoglycoside-

modifying enzymes

Multidrug efflux pumps

Porin mutations

Altered penicillin-

binding protein

Penicillinase

Cook P, Current Issues in and Approaches to Antimicrobial Resistance, October 2015

Last accessed on 14 October 2015 at www.idse.net

Guh et al, JAMA 2015; 314(14):1479-87

• 7 U.S. Metropolitan areas population- and laboratory-based active

surveillance in 2012-2013

• CRE defined as carbapenem-nonsusceptible (excluding ertapenem) and

extended-spectrum cephalosporin-resistant E coli, Enterobacter or

Klebsiella from sterile-site or urine cultures

• 599 CRE cases in 481 individuals, 86.8% from urine and 11.4% from blood

• CRE rates significantly higher in Georgia, Maryland and New York and

lower in Colorado, New Mexico and Oregon: East to West spread?

• Associations: Prior hospitalization, indwelling devices, discharge to LTC,

out-patient cultures

• CRE death rate 9% overall and 28% if CRE from normally sterile site

• Relative population prevalence: CDI 6x > MRSA 9x > CRE

Outcome measures

Relative risk of worse outcome for

infections with resistant compared

to susceptible bacteria*

Hospital length of stay 1 - 1.7

Hospital charges 1 - 1.7

Mortality 1.3 - 5

Adapted from Cosgrove, Clin Infect Dis 2006; 42:S82–9.

* Gram-negative bacilli, Staphylococcus aureus, Enterococci.

CRE, Carbapenem-resistant enterobacteriaceae

Tzouvelekis et al, Clin Microbiol Infect 2014; 20(9): 862-72

2. Treatment Options

Regimen B vs. regimen A: p, not significant. Regimens C, C1 and C2 vs. regimen B: p 0.001, p 0.034, and p <0.0001, respectively. Numbers above columns indicate the number of patients.

All R 1S ≥2S w/o carb

with carb

Activity of therapy

Tzouvelekis et al, Clin Microbiol Infect 2014; 20(9): 862-72

Methicillin Resistant Staphylococcus aureus Skin & Soft Tissue Infections & Beyond – Antibiotic

Treatment for Cellulitis with Abscess

Drug Potential Limitations

I & D alone Inferior to I&D plus TMP-SMZ? (NEJM 3/3/2016)

Dicloxacillin MRSA gap

Vancomycin MIC Creep; inadequate dosing

Trimethoprim-sulfamethoxazole (TMP-

SMZ)

Group A strep gap?; pus factor?

Clindamycin “D-test” positive MRSA gap

Doxycycline or minocycline Group A strep gap

Daptomycin Cost; rhabdomyolysis; dosing questions

Linezolid, Tedizolid Cost, side-effect profile

Oritavancin, Dalbavancin Less experience (though single or weekly dose!)

Ceftaroline Less experience, cost

Fluoroquinolone & rifampin Less experience, drug interactions, resistance

development

TMP-SMZ & Clindamycin Less experience

TMP-SMZ & Rifampin Less experience, drug interactions

• Enrolled cellulitis, abscesses larger than 5 cm in diameter, or both

• Clindamycin or trimethoprim–sulfamethoxazole (TMP-SMX) for 10 days

• The primary outcome was clinical cure 7 to 10 days after the end of treatment

• 524 patients: 30.5% had an abscess, 53.4% had cellulitis, 15.6% had mixed infection; S. aureus was isolated in 41.4% and 77.0% of these infections were MRSA

• No significant difference between clindamycin and TMP-SMX in efficacy or side-effect profile

Miller et al, N Engl J Med 2015; 372:1093-103.

Robinson et al, Eur J Clin Microbiol Infect Dis 2012; 31:2421-8.

Flowchart of S aureus bacteraemia

episodes analysed in the study Survival curve of S aureus bacteraemia episodes.

What Did Fictional

Scientist Martin

Arrowsmith, MD

Discover?

SHORT-TERM

New Antibiotics

LONG-TERM

New Approaches?

August 2015 March 28, 1994

2015 1994

“When the situation was manageable it was neglected, and

now that it is thoroughly out of hand we apply too late the

remedies which then might have effected a cure. There is

nothing new in the story… it falls into… the confirmed

unteachability of mankind. Want of foresight, unwillingness

to act when action would be simple and effective, lack of

clear thinking, confusion of counsel until the emergency

comes… these are the features which constitute the

endless repetition of history.”

Winston Churchill Speech -- Air Parity Lost May 2, 1935 British House of Commons

Adapted from Weinstein & Kabins, Am J Med 1981; 70:449-54

RESISTANCE “ICEBERG”

Regional Spread Intra-facility Spread

Skin Colonization (Fecal Patina)

Environmental Contamination

If MDRO GI Colonization

~100% ~15-20%

40%

MDRO, Multi-drug resistant organism; GI, Gastrointestinal

Healthcare Worker Hand Contamination

15-20%

Patient Cross-Colonization

Vernon et al, Arch Intern Med 2006; 166:306-12

MDRO, Multi-drug resistant organism

Karki and Cheng, J Hosp Infect 2012; 82:71-84; J Hosp Infect 2013; 84:266-7

IRR, incidence rate ratio; CI, confidence interval

Lin et al, Clin Infect Dis 2013; 57(9):1246-52

KPC colonization

prevalence 9-fold

higher in LTACHs

than in short-stay

acute care hospital

adult ICUs

LTACH, Long-term acute care hospital; ICU, intensive care unit

• 22/24 (92%) patients ≥1 skin site KPC-positive

• 49/96 (51%) skin cultures KPC-positive

• 2/371 (0.5%) environmental sites in patient rooms or common areas grew KPC

• Environmental site of concern: SINKS?

Thurlow et al, Infect Control Hosp Epidemiol 2013; 34(1):56-61

KPC, Klebsiella pneumoniae carbapenemase; LTACH, long-term acute care hospital

Before After LTACH, Long-term acute care hospital;

CRE, Carbapenem-resistant Enterobacteriaceae

See Hayden MK et al, Clin Infect Dis 2015; 60(8):1153-61

LTACH, long-term acute care hospital; KPC, Klebsiella pneumoniae carbapenemase producers

Hayden et al, CID 2015; 60:1153-61

Pre-Intervention Intervention

No. of

events

Events/

1000 pt-days

No. of

events

Events/

1000 pt-days P-value

KPC in any clinical

culture 656 3.7 285 2.5 .001

KPC bloodstream

infection 165 0.9 48 0.4 .008

Bloodstream

infection due to any

pathogen

2004 11.2 870 7.6 .006

Skin Colonization (Fecal Patina)

Environmental Contamination

If MDRO GI Colonization

~100% ~15-20%

40%

MDRO, Multi-drug resistant organism; GI, Gastrointestinal

Healthcare Worker Hand Contamination

15-20%

Patient Cross-Colonization

Light et al, Am J Dis Child 1967; 113:291

Sprunt et al, Pediatr Res 1980; 14:308

Spor, Koren, Ley, Nature Rev Microbiol 2011; 9:279

WE ARE WHAT WE EAT?

• Gut Microbiomes of Malawian Twins Discordant for Kwashiorkor, Science 2013; 339:548-54

• Antibiotics Treat Malnutrition? N Engl J Med 2013; 368:425-35

• Intestinal Metabolism and Cardiac Risk, N Engl J Med 2013; 368:1575-84

• Gut Microbiota in Diabetes, Nature 2012; 490:55-60

• Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile, N Engl J Med 2013; 368:407-15

Fridkin et al, MMWR March 7, 2014; 63(9):194

• Antimicrobial Stewardship takes too much time, which affects our productivity

• Antimicrobial Stewardship risks unhappy patients, which affects our income

• Lessening antibiotic use in animal husbandry is still largely voluntary, which annoys many doctors who say, “Don’t bother us until that bigger problem is solved”

Arakaki et al, JAMA Dermatol 2014; 150(10):1056-61.

Evans et al, N Engl J Med 1998; 338(4):232-8

When Doctors Followed Computer-driven

Recommendations for Antibiotic Therapy --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Shorter Hospital Stays: 10 days vs 17 days (p<0.001)

Lower Costs per stay: $26,000 vs $45,000 (p<0.001)

Agarwal and Schwartz, Clin Infect Dis 2011; 53(4):379-87.

Procalcitonin guidance of antimicrobial duration appears to decrease antimicrobial use in the ICU safely and significantly and may also decrease the length of stay in the ICU.

UK’s Longitude Prize in Antibiotic Resistance

• Longitude Prize is a £10 million challenge

• Public decided the focus of the new prize to be antibiotic resistance

• The 5-year race has begun to develop a point-of-care test that will identify when antibiotics are needed and - if they are - which ones to use

• Prize is the largest UK challenge and the first prize of its kind to be determined through a public vote

• As of Aug 5, 2015 - 92 teams from 15 countries have registered

Submission Period begins June 2, 2015, 9:00 a.m. EST. Submission Period ends

5 p.m. EST July 17, 2015.

http://www.cdc.gov/drugresistance/solutions-initiative/

March 2015

4. NATIONAL ACTION PLAN

• Higher-level Political Will

• Continuing Infection Control Refinements

• Renewed Focus on Antimicrobial Stewardship

• Dramatic Informatics Abilities

• Striking Advanced Molecular Diagnostics

• Major Microbiome Insights

Thank You!