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TRANSCRIPT
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!