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The Coming Storm:Antimicrobial Resistance and Selection
Objectives
• Describe the role of antibiotic use in the development of resistance
• Review toxicity of commonly used antibiotics
• Understand the prevalence and clinical impact of carbapenem resistant enterobacteriaceae
• State the prognosis antimicrobial resistant Staph aureus infections
Which of the following are indications to treat asymptomatic bacteriuria?Choose all that apply
A. Pyuria
B. Pregnancy
C. Preparation for transurethral resection of the prostate
D. Diabetes
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1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
New Systemic Antibacterial Agents Approved
Why has the antibiotic pipeline failed?
• All the easy ones have been discovered
• Antibiotics are not a good investment for drug companies
• FDA regulatory system is outdated
Society expects antibiotics to be cheap
• Cost of Trastuzumab for breast cancer = $54,000 per year
• Cost of Ipilimumab for melanoma = $240,000 for induction course
• Cost of ceftriaxone x 4 weeks for viridansstreptococcal endocarditis=$1600
Clinical Impact of Antimicrobial Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces resistance
Clinical Impact of Antimicrobial Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces resistance
Klebsiella pneumoniae resistant to carbapenemsNHSN Data
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Colistin Use JHU
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Colistin Courses
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JG Bartlett, Clin Infect Dis. (2011) 53 (suppl 1): S4-S7
Clinical Impact of Antimicrobial Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces resistance
Mortality of resistant (MRSA) vs.
susceptible (MSSA) S. aureus
• Mortality risk associated with MRSA
bacteremia, relative to MSSA bacteremia:
OR: 1.93; p < 0.001.1
• Mortality of MRSA infections was higher than
MSSA: relative risk [RR]: 1.7; 95% confidence
interval: 1.3–2.4).2
1. Clin. Infect. Dis.36(1),53–59 (2003).
2. Infect. Control Hosp. Epidemiol.28(3),273–279 (2007).
Mortality associated with carbapenem resistant
(CR) vs susceptible (CS) Klebsiella
pneumoniae (KP)
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Overall Mortality Attributable Mortality
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Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106
OR 3.71 (1.97-7.01) OR 4.5 (2.16-9.35)
p<0.001
p<0.001
Mortality Associated with CRE
• Crude mortality 48%-61%
• Infection-related mortality = 33%-40%
Patel G, ICHE 29:1099-1106, 2008; Snitkin ES, Science Translational Medicine 4:1-9, 2012Munoz-Price LS ICHE 31:1074-7, 2010
Gram Negative Resistance Mechanisms
• Beta-lactamases-ESBL
• Multi-drug efflux pumps
• Porin changes-reduce permeability of outer membrane (imipenem)
Gram Negative Resistance Mechanisms
• Carbapenemases
– KPC-Klebsiella pneumonia carbapenemase
– NDM-New Dehli Beta-lactamase
– VIM-Verona-integron-encoded metallobetalactamase-found often in P. aeruginosa, occasionally in Enterobacteriaceae
– IMP-imipenemase
What’s the big deal about KPC?
• It confers resistance to all beta-lactams, and is frequently associated with resistance to other drug classes
• Many isolates are sensitive only to aminoglycosides, colistin, and tigecycline.
What’s the big deal about KPC?
• It is coded by blaKPC gene, which is plasmid mediated and can be transferred from one organism to another, facilitating rapid spread of resistance
Clinical Impact of Antimicrobial Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces resistance
Annual prevalence of imipenem
resistance in P. aeruginosa vs.
carbapenem use rate
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% I
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Carbapenem Use Rate
45 LTACHs, 2002-03 (59 LTACH years) Gould et al. ICHE 2006;27:923-5
r = 0.41, p = .004
(Pearson correlation coefficient)
P. aeruginosa susceptibilities before and after
implementation of antibiotic restrictions (CID 1997;25:230)
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Ticar/clav Imipenem Aztreonam Ceftaz Cipro
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Before After
P<0.01 for all increases
Impact of Improving Antibiotic Use on
Rates of Resistant Enterobacteriaceae
Carling P et al. Infect Control Hosp Epidemiol. 2003;24(9):699-706.
Impact of fluoroquinolone restriction
on rates of C. difficle infection
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Infect Control Hosp Epidemiol. 2009 Mar;30(3):264-72.
Targeted antibiotic consumption and
nosocomial C. difficile disease
Valiquette, et al. Clin Infect Dis 2007;45:S112.
Tertiary care hospital; Quebec, 2003-2006
What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control nosocomial transmission of resistant pathogens
• Reduce overall use of antimicrobial agents
What Can I Do?
• Ensure antimicrobial resistance is recognized
– Proper laboratory test protocols
– Identify patients at risk for colonization
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents
– Urinary tract
– Skin and soft tissue
– Respiratory tract
Resistance Definition
• Nonsusceptible to one of the 3 carbapenems-imipenem, meropenem, or doripenem by 2012 CLSI breakpoints
AND
• Resistant to all of the third generation cephalosporins tested-ceftriaxone, cefotaxime, ceftazidime
*Morganella morganii, Proteus spp and Providencia spp. Are intrinsically resistant to imipenem-look for resistance to another carbapenem
Resistance-A Simplified Approach
Agent S I R S I R
Doripenem < 1 2 > 4
Ertapenem < 2 4 > 8 < 0.5 1 > 2
Imipenem < 4 8 > 16 < 1 2 > 4
Meropenem < 4 8 > 16 < 1 2 > 4
Old BreakpointsCLSA M100 S19
Revised BreakpointsJanuary 2012CLSI M-100 S22
What Can I Do?
• Ensure antimicrobial resistance is recognized
– Proper laboratory test protocols
– Identify patients at risk for colonization
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents
– Urinary tract
– Skin and soft tissue
– Respiratory tract
KPC Klebsiella pneumoniaecolonization
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ICUs LTACHs
KPC Prevalence
KPC Prevalence
Lin M Y et al. Clin Infect Dis. 2013;57:1246-1252
What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents
CRE-Florida SICU Outbreak
• Daily CHG baths
• Cohorting during shifts-RTs, nurses, nurse aids
• Monitoring of environmental cleaning-black light and culture
• Active surveillance cultures
Munoz-Price LS ICHE 31:1074-7, 2010
CDC Guidance-Core Measures
1. Hand Hygiene
2. Contact Precautions for all patients who are colonized or infected with CRE
3. HCW Education
4. Minimize use of devices, e.g. CVCs, endotracheal tubes, urinary catheters
CDC Guidance-Core Measures
5. Cohort patients and staff
6. Notification system for lab to promptly inform Infection Control of all CRE
7. Antimicrobial stewardship
8. Screen contacts of patients colonized or infected with CRE
Contact Precautions-Starting and Stopping
• Micro lab should inform Infection Control of all CRE
• Flag chart to identify patient for precautions on re-admission
• Colonization may persist for 6 months or longer
• If screening for persistent colonization is used to DC precautions, must screen > once
• CRE should not preclude transfer to another facility
Contact Precautions for Long Term Care
• Patients who are dependent on caregivers for ADLs should be nursed in precautions
• For long term care residents who are able to perform hand hygiene, are continent of stool, are independent in ADLs and without draining wounds contact precautions might be relaxed
Risk Factors for Mortality from CRE
• Age
• Mechanical ventilation
• Malignancy
• Heart disease
• ICU stay
But-removal of the primary focus of infection (incision and drainage or device removal) is independently
associated with survival
What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents– Is an antibiotic truly needed?
– Discontinue or narrow therapy when data return
– Minimize duration of therapy
Antibiotic Assumptions
• Antibiotics are well tolerated insurance against a bad outcome
• Treating longer is better
• My duty is to the patient in my care-if treating him with an antibiotic increases societal risk, that is secondary
Antibiotic Assumptions
• Antibiotics are well tolerated insurance against a bad outcome
• Treating longer is better
• My duty is to the patient in my care-if treating him with an antibiotic increases societal risk, that is secondary
Case presentation
• 28 year-old male with no past medical history admitted with fever and rash.
• On morning of admission: Red, bumpy, itchy rash on right arm, pt thought possibly due to bed bugs
• Rash progressed over course of the day to involve chest, back, other arm, neck, face.
• Also c/o fever, malaise, sore throat, blurry vision.
Case presentation
• Past medical history: kidney stone
• Past surgical history: none
• Medications: none on admission; recent Cipro use for kidney stone
• Allergies: NKDA
• Family history: DM in mother and father
Clinical course
• Persistent high fever, tachycardia• Rapidly progressive rash (vesicles large bullae) and
generalized facial edema• Transferred to ICU on HD #3 due to concern for airway
compromise, intubated
• Derm evaluation: – Clinical findings c/w toxic epidermal necrolysis– SJS/TEN confirmed by shave biopsy
• Dx: SJS/TEN due to ciprofloxacin
Antibiotic Assumptions
• Antibiotics are well tolerated insurance against a bad outcome
• Treating longer is better
• My duty is to the patient in my care-if treating him with an antibiotic increases societal risk, that is secondary
Stewardship optimizes patient safety:
decreased patient-level resistance
Cipro Standard
Antibiotic
duration
3 days 10 days
LOS ICU 9 days 15 days
Antibiotic
resistance/
superinfection
14% 38%
Study terminated early because attending
physicians began to treat standard care group
with 3 days of therapy
Singh N et al. Am J Respir Crit Care Med. 2000;162:505-11.
CPIS Score-VAPhttp://www.surgicalcriticalcare.net/Resources/CPIS.php
PSI Score-outpatientshttp://pda.ahrq.gov/clinic/psi/psicalc.asp
Parameter CriteriaConfusion Disoriented to time/place/person or by other objective test
Uremia >20 mg/dL. Our normal range is 10-26 mg/dL so I think above normal is an appropriate cutoff. Also, not everyone includes this as it requires having completed labs.
Respiratory rate > 30 breaths/minute
Low Blood pressure < 90 mm Hg systolic or > 60 mm Hg diastolic
Age > 65 years
Curb 65 Score: One point per factor, score > 2 warrants hospitalization
Pneumonia Scoring Systems
Date of download: 9/23/2014Copyright © 2014 American Medical
Association. All rights reserved.
Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-
Associated Pneumonia in AdultsJAMA. 2003;290(19):2588-2598. doi:10.1001/jama.290.19.2588
Probability of survival is for the 60 days after ventilator-associated pneumonia onset as a function of the duration of antibiotic
administration.
Figure Legend:
Pulmonary Infection Recurrence
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Non-fermenters MRSA Other bacteria
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15 day
* NSNS
Antibiotic Assumptions
• Antibiotics are well tolerated insurance against a bad outcome
• Treating longer is better
• My duty is to the patient in my care-if treating him with an antibiotic increases societal risk, that is secondary
– But…treating a patient with an antibiotic increases that patient’s risk of resistance
Effect of antibiotic prescribing in primary care on
antimicrobial resistance in individual patients:
systematic review and meta-analysis
Costelloe C et al. BMJ.
2010;340:c2096.
What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents
– Urinary tract
– Respiratory tract
– Skin and soft tissue
Case 1
• 79 y/o man admitted for left foot gangrene
• Surgeons plan amputation
• PMHx chronic foley for urinary retention
• ROS negative
• Pre-op UA
– Dipstick + leukocyte esterase
– Microscopy > 50 WBC/hpf
How should the team respond to this UA?
A. Order urine culture and treat empirically with ciprofloxacin
B. Order urine culture and await results
C. Change the foley catheter
D. Watchful waiting
Case 2
• 81 y/o man admitted with fever, hypotension, confusion
• PMHx DM, HTN, dementia, prostatism with a chronic foley
• ROS unable to provide due to confusion
• Exam suprapubic tenderness, no flank tenderness
Case 2
• Lab WBC 14,000 12% bands 75% segs
• UA
– Positive Leukocyte esterase
– > 50 WBCs/hpf, 3+ bacteria
What empiric therapy would you select?
A. Vancomycin + pipracillin-tazobactam
B. Vancomycin + cefepime
C. Meropenem
D. Ciprofloxacin
Case 2
• Hospital course: treated with vancomycin + pipracillin-tazobactam, defervesces, appears pleasantly demented on day 2
• Blood and urine growing lactose fermenting gram negative rods
How should therapy be altered?
A. Continue current management-he is responding
B. Discontinue vancomycin-there is no evidence of gram positive infection
C. Discontine vanc + pip-tazo and substitute ceftriaxone
D. Discontinue vanc + pip-tazo and substitute oral ciprofloxacin
Case 2
• C & S shows E. coli, resistant to cipro and sensitive to the following agents. Which one would you choose?
A. Ampicillin
B. Ampicillin-sulbactam
C. Cefazolin
D. TMP-SMX
Case 2
• What is the recommended duration of therapy?
A. 3 days
B. 7 days
C. 10 days
D. 14 days