1. What is Lurking Beneath the Surface? The War Against Superbugs
Monique Dodd, PharmD, PhC, MLS(AMCP)CM
Clinical Solutions Specialist
TriCore Reference Laboratories
July 27, 2018

2. Employee of TriCore Reference Laboratories
Disclosures
Employee of TriCore Reference Laboratories

3. Objectives
At the end of this presentation, the attendee will be able to:
Summarize the clinical and economic impact of the most concerning superbugs encountered in clinical practice.
Discuss regulatory initiatives to combat antimicrobial resistance.
Discuss lab initiatives and other statewide efforts targeting antimicrobial resistance in the state of New Mexico.

4. The War Against Superbugs

5. As long as antibiotics are used against them, bacteria will continue to develop and use resistance mechanisms.

6. Mechanisms of Resistance

7. Mechanisms of Resistance

8. Mechanisms of Resistance

9. Mechanisms of Resistance

10. Mechanisms of Resistance

11. Mechanisms of Resistance

12. Other Factors of Antibiotic Resistance
Infection control
Bacterial population density
High risk patient populations
Global travel
Limited rapid diagnostics
Lack of vaccines
(See pg 316 of Antibiotic Resistance: Challenges and Opportuniteis)
Two factors that have really been highlighted in the media are:
Antibiotic overuse in agriculture
Improper antibiotic prescribing
Adapted from National Institute of Allergy and Infectious Diseases. NIAID’s antibacterial resistance program: current status and future directions Available at: Accessed June 28, 2016.

14. ~2 million infections from antibiotic resistant bacteria
$20 billion per year
Cost
Patient Outcomes
~2 million infections from antibiotic resistant bacteria
23,000 deaths per year
Roberts RR, et al. Clin Infect Dis. 2009;49:
Center for Disease Control and Prevention. CDC. “Antibiotic Resistance Threats in the United States,” 2013

16. 2014 2015 2017 Post-antibiotic Era? Dalvance (dalbavancin)
Orbactive (oritavancin)
Sivextro (tedizolid)
Zerbaxa (ceftolozane/tazobactam)
2015
Avycaz (ceftazidime/avibactam)
2017
Baxdela (delafloxacin)
Vabomere (meropenem/vaborbactam)
Post-antibiotic Era?
FDA.gov [internet]. Available at: Accessed June 28, 2018.

17. Antibiotic-resistant Organisms of Most Concern

18. Urgent: Clostridium difficile Carbapenem-resistant Enterobacteriaceae
Drug-resistant Neisseria gonorrhoeae
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

19. Clostridium difficile
250,000 infections
14,000 deaths
$1M in excess medical costs
Though C. diff is not itself significantly resistant to the drugs used to treat it, it is directly related to antibiotic use and resistance.
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

20. Key Recommendations
Unexplained and new-onset ≥3 unformed stools in 24 hours
Oral vancomycin or fidaxomicin is recommended over metronidazole
Repeat testing (within 7 days) during same episode of diarrhea
McDonald LC, et al. Clin Infect Dis DOI: /cid/cix1085

21. Carbapenem-resistant Enterobacteriaceae
140,000 infections
Mortality of 26-44%
$147M-$553M in excess medical costs
CRE infections account for an estimated 140,000 cases of healthcare-associated infections annually.
Associated with mortality rates of 26-44%.
Bartsch SM, et al. Clin Microbiol Infect DOI: /j.cmi
Falagas ME, et al. Emerg Infect Dis. 2014;20:1170-5
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

22. Carbapenamase-producing CRE And one of the following:
Case Definitions
Carbapenem-resistant enterobacteriaceae (CRE)
Enterobacteriaceae that have resistance to antibiotics in the class of carbapenems
Carbapenamase-producing CRE
Resistant to at least one carbapenem
And one of the following:
Positive for carbapenemase production by a phenotypic test (e.g. Modified Hodge, Carba NP positive) OR
Positive for known carbapenemase resistance mechanism (e.g., Carba-R positive)
CDC.Gov [internet]. CP-CRE 2018 Case Definition. Available at: Accessed on June 28, 2018.

23. Carbapenemase genes are commonly transmitted on plasmids
KPC
Klebsiella pneumoniae carbapenemase
NDM
New Delhi metallo-beta-lactamase
IMP
Imipenemase metallo-beta-lactamase
VIM
Verona integron-encoded metallo-beta-lactamase
OXA-48
Oxacillinase-48
Non-carbapenemase carbapenem resistance in these bacteria is mediated by a combination of mechanisms, typically via production of an extended-spectrum β- lactamase or extended-spectrum cephalosporinase (also called ESBL or AmpC) plus decreased permeability of the bacterial cell wall (e.g., porin mutations) to influx of carbapenem antibiotics
KPC is the most widespread in the US

24. Discuss with your antimicrobial stewardship team
How to Treat?
Discuss with your antimicrobial stewardship team
Infection Source
Core Drugs
Possible Adjunct Drugs
Blood
High dose meropenem + polymyxin B
aminoglycoside, tigecycline, fosfomycin, rifampin
Lung
tigecycline, aminoglycoside, fosfomycin, rifampin GI
High dose meropenem + polymixin B + tigecycline
fosfomycin, rifampin
Urine
High dose meropenem + fosfomycin or aminoglycoside
colistin
Case studies are what we have!
Potential treatment options for CRE KPC-Producing Klebsiella pneumoniae
Morrill HJ, et al. Open Forum Infect Dis DOI: /ofid/ofv050.

25. Drug-resistant Neisseria gonorrhoeae
246,000 infections
$235M in excess medical costs
Some 820,000 cases of gonorrhea are reported in the U.S. every year, making it the second most reported communicable disease behind chlamydia. According to the CDC, an estimated 246,000 of those gonorrhea cases are of the drug-resistant strain.
The CDC estimates that direct medical costs if the strain spreads will be $235 million over the 10 years, but that costs would likely be even higher due to case management and patient follow-ups with doctors.
"The strain is tricky," said Smith. "And it's asymptomatic, meaning people might not know they have it because they are not showing symptoms for it
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

26. Treatment Options Theory of Dual Therapy
Ceftriaxone (or cefixime) + azithromycin or doxycycline
On the basis of experience with other microbes that have developed antimicrobial resistance rapidly, a theoretical basis exists for combination therapy using two antimicrobials with different mechanisms of action (e.g., a cephalosporin plus azithromycin) to improve treatment efficacy and potentially slow the emergence and spread of resistance to cephalosporins. Use of azithromycin as the second antimicrobial is preferred to doxycycline because of the convenience and compliance advantages of single-dose therapy and the substantially higher prevalence of gonococcal resistance to tetracycline than to azithromycin among GISP isolates, particularly in strains with elevated cefixime MICs (118,540). In addition, clinical trials have demonstrated the efficacy of azithromycin 1 g for the treatment of uncomplicated urogenital GC (561,562).
Limited data suggest that dual treatment with azithromycin might enhance treatment efficacy for pharyngeal infection when using oral cephalosporins (563,564). In addition, persons infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the longstanding recommendation that persons treated for gonococcal infection also be treated with a regimen that is effective against uncomplicated genital C. trachomatis infection, further supporting the use of dual therapy that includes azithromycin (565).
Workowski KA, et al. MMWR Recomm Rep. 2015;64:60-63.
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

27. Serious:
Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs)
Vancomycin-resistant Enterococcus (VRE)
Methicillin-resistant Staphylococcus aureus (MRSA)
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

28. ESBL Producing Enterobacteriaceae
Confers resistance to:
Most β-lactams, including 3rd and 4th generation cephalosporins and monobactams
Hydrolyze penicillins and cephalosporins
Susceptible to carbapenems
26,000 infections
1,700 deaths
$40K in excess medical costs
ESBLs are correlated with shifts in medical care.
Nearly 26,000 (or 19%) healthcare-associated enterobacteriaceae infections are caoused by ESBLs.
Patients with bloodstream infections caused by ESBL-producing Enterobacteriaceae are about 57% more likely to die.
$40,000 in excess medical costs per year for each infection
Bartsch SM, et al. Clin Microbiol Infect DOI: /j.cmi
Falagas ME, et al. Emerg Infect Dis. 2014;20:1170-5
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

29. 20,000 infections 1,300 deaths VRE E. faecalis E. faecium Daptomycin+
β-lactam
Others?
ampicillin + ceftriaxone Or
ampicillin + aminoglycoside
Bartsch SM, et al. Clin Microbiol Infect DOI: /j.cmi
Falagas ME, et al. Emerg Infect Dis. 2014;20:1170-5
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

30. vancomycin resistance
MRSA
80,461 infections
11,285 deaths
$322M in excess medical costs
vancomycin resistance
CRE infections account for an estimated 140,000 cases of healthcare-associated infections annually.
Associated with mortality rates of 26-44%.
daptomycin
cefteroline
dalbovancin
Ortivancin
telavancin
Stone PS. Expert Rev Pharmacoecon Outcomes Res. 2009;9:
Adapted from Centers for Disease control and Prevention. Antibiotic resistance threats in the United States Available at: Accessed June 28, 2018.

31. Regulatory Initiatives

33. 1. Improving surveillance
2. Developing better diagnostic tools
3. Accelerating drug development
4. Combatting global antibiotic resistance

34. Hospitals & Nursing Care Centers Antimicrobial Stewardship Programs
January 1, 2017
Hospitals & Nursing Care Centers
Antimicrobial Stewardship Programs
Leadership commitment
Accountability
Drug expertise
Action
Tracking
Reporting
Education
Organization priority
Provider education
Patient education
Multidisciplinary team
Core Elements
Protocols and procedures
Collect, analyze and report data
Improve program
Centers for Disease Control and Prevention. CDC. “Core Elements of Hospitals Antibiotic Stewardship Programs.”

35. TriCore Initiatives

36. Strength of a Clinical Laboratory
Clinical labs guides 70% of medical decisions and provides significant value in patient evaluation1,2
Patients may have multiple providers
Clinical laboratories provide the longitudinal history
Can Identify high risk patients using clinical labs near real-time3
State with longitudinal data
Effective care coordination relies on real-time standardization of health data4
Forsman, R. W. Clin Chem. 1996;42:
Laposata ME et al. Arch Pathol Lab Med. 2004;128:
Ho Ahn C et al. PLoS One. 2016;11:e
Burton LC. et al. Milbank Q. 2004;82:

37. Summary

38. Identify hot spots

39. A Peak into Antibiotic Susceptibility (2017)
Antibiotic – n(%S)
Ceftaroline – 133 (96%)
# of Isolates
Ceftazidime-avibactam (Avycaz)
Ceftolozane-tazobactam (Zerbaxa)
Pseudomonas aeruginosa 14
79%
63.6%
Escherichia coli 1
100.0%
0.0% (Intermediate)
Klebsiella pneumoniae 2
50.0%
(1 resistant)
Klebsiella oxytoca
Enterobacter cloacae

40. Discussion
Antimicrobial resistance is both clinically and economically taxing
There are national initiatives to combat antimicrobial resistance
Automated antibiograms initiative in hopes we can help AS Project ECHO and NM DOH identify resistance patterns in the state of NM (ask Mark if we can use a few snap shots)
The laboratory can play a collaborative role in antimicrobial resistance surveillance

41. Monique Dodd, PharmD, PhC, MLS(AMCP)CM
Clinical Solutions Specialist
TriCore Reference Laboratories