• 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

1. The Coming Storm:
Antimicrobial Resistance and Selection

2. 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

3. 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

4. 3.5
3
2.5
2
1.5
1
0.5
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
New Systemic Antibacterial Agents
Approved

5. 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• FDA regulatory system is outdated

6. 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 viridans
streptococcal endocarditis=$1600

7. Clinical Impact of Antimicrobial
Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces
resistance

8. Clinical Impact of Antimicrobial
Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces
resistance

9. Klebsiella pneumoniae resistant to carbapenems
NHSN Data
14
12
10
8
6
4
2
0
2000 2007 2010

10. Colistin Use JHU
1800
1600
1400
1200
1000
800
600
400
200
0
Colistin Courses
2009
2014
96
1600
JG Bartlett, Clin Infect Dis. (2011) 53 (suppl 1): S4-S7

11. Clinical Impact of Antimicrobial
Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces
resistance

12. 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).

13. Mortality associated with carbapenem resistant
(CR) vs susceptible (CS) Klebsiella
pneumoniae (KP)
60
50
40
30
20
10
0
p<0.001
Overall Mortality Attributable
Mortality
Percent of subjects
CRKP
CSKP
OR 3.71 (1.97-7.01) OR 4.5 (2.16-9.35)
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106
p<0.001

14. 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, 2012
Munoz-Price LS ICHE 31:1074-7, 2010

15. Gram Negative Resistance Mechanisms
• Beta-lactamases-ESBL
• Multi-drug efflux pumps
• Porin changes-reduce permeability of outer
membrane (imipenem)

16. 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

17. 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.

18. 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

19. Clinical Impact of Antimicrobial
Resistance
• Resistance is rising
• Resistance increases mortality
• Decreasing antimicrobial use reduces
resistance

20. Annual prevalence of imipenem
resistance in P. aeruginosa vs.
carbapenem use rate
80
70
60
50
40
30
20
10
0
r = 0.41, p = .004
(Pearson correlation coefficient)
0 20 40 60 80 100
% Imipenem-resistant
P. aeruginosa
Carbapenem Use Rate
45 LTACHs, 2002-03 (59 LTACH years) Gould et al. ICHE 2006;27:923-5

21. P. aeruginosa susceptibilities before and after
implementation of antibiotic restrictions
(CID 1997;25:230)
100
80
60
40
20
0
Ticar/clav Imipenem Aztreonam Ceftaz Cipro
Percent susceptible
Before After
P<0.01 for all increases

22. Impact of Improving Antibiotic Use on
Rates of Resistant Enterobacteriaceae
Carling P et al. Infect Control Hosp Epidemiol. 2003;24(9):699-706.

23. Impact of fluoroquinolone restriction
on rates of C. difficle infection
2.5
2
1.5
1
0.5
0
2005 2006
Month and Year
HO-CDAD cases/1,000 pd
2007
Infect Control Hosp Epidemiol. 2009 Mar;30(3):264-72.

24. Targeted antibiotic consumption and
nosocomial C. difficile disease
Tertiary care hospital; Quebec, 2003-2006
Valiquette, et al. Clin Infect Dis 2007;45:S112.

25. What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control nosocomial transmission of resistant
pathogens
• Reduce overall use of antimicrobial agents

26. 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

27. 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

28. Resistance-A Simplified Approach
Old Breakpoints
CLSA M100 S19
Revised Breakpoints
January 2012
CLSI M-100 S22
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

29. 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

31. KPC Klebsiella pneumoniae
colonization
35
30
25
20
15
10
5
0
KPC Prevalence
ICUs LTACHs
KPC Prevalence
Lin M Y et al. Clin Infect Dis. 2013;57:1246-1252

32. What Can I Do?
• Ensure antimicrobial resistance is recognized
• Control transmission of resistant pathogens
• Reduce overall use of antimicrobial agents

33. 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

34. 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

35. 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

36. 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

37. 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

38. Risk Factors for Mortality from CRE
• Age
• Mechanical ventilation
• Malignancy
• Heart disease
• ICU stay

39. But-removal of the primary focus of
infection (incision and drainage or
device removal) is independently
associated with survival

40. 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

41. 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

42. 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

43. 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.

44. 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

45. 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

46. 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

47. 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.

48. Pneumonia Scoring Systems
PSI Score-outpatients
http://pda.ahrq.gov/clinic/psi/psicalc.asp
CPIS Score-VAP
http://www.surgicalcriticalcare.net/Resources/CPIS.php
Curb 65 Score: One point per factor, score > 2 warrants hospitalization
Parameter Criteria
Confusion 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

49. Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-
Associated Pneumonia in Adults
JAMA. 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.
Date of download: 9/23/2014
Copyright © 2014 American Medical
Association. All rights reserved.
Figure Legend:

50. Pulmonary Infection Recurrence
50
45
40
35
30
25
20
15
10
5
0
Non-fermenters MRSA Other bacteria
8 day
15 day
* NS NS

51. 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

52. 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.

53. 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

54. 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

55. 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

56. 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

57. Case 2
• Lab WBC 14,000 12% bands 75% segs
• UA
– Positive Leukocyte esterase
– > 50 WBCs/hpf, 3+ bacteria

58. What empiric therapy would you
select?
A. Vancomycin + pipracillin-tazobactam
B. Vancomycin + cefepime
C. Meropenem
D. Ciprofloxacin

59. 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

60. 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

61. 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

62. Case 2
• What is the recommended duration of
therapy?
A. 3 days
B. 7 days
C. 10 days
D. 14 days