multidrug resistant organisms: detection, epidemiology...

SIDP – Antimicrobial Stewardship Certificate ProgramMultidrug Resistant Organisms: Detection, Epidemiology, and Management

David S. Burgess, Pharm.D., FCCPProfessor & Chair, Dept of Pharmacy Practice and Science, University of Kentucky, College of Pharmacy

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Multidrug Resistant Organisms: Detection, Epidemiology, and

Management

David S. Burgess, Pharm.D., FCCPProfessor and Chair

Department of Pharmacy Practice and Science

Objectives

• Discuss the mechanisms of resistance behind common multidrug resistant (MDR) pathogens.

• Describe the microbiology challenges associated with the identification of multidrug-resistant bacteria.

• Discuss the prevalence and epidemiology of multidrug resistant bacteria.

• Describe the current evidence-based strategies in the management of invasive multidrug resistant bacteria.



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Anderson DJ et al. Infect Control Hosp Epidemiol 2007;28:767-773

Healthcare-Associated Infections (HAIs)

• Approximately 1 in every 20 hospitalized patients experiences a healthcare-associated infection.– 2.1million HAIs annually in the US

Conditions Medicare Does Not Pay for if Acquired During Hospitalization

• Catheter-associated urinary tract infection

• Vascular catheter-associated infections

• Mediastinitis following coronary artery bypass grafting

• Decubitus ulcers (stage III or IV)

• Object left in during surgery

• Air embolism following procedure

• Blood incompatibility

• Hospital-acquired trauma

• Deep venous thrombosis/pulmonary embolism

• Surgical site infection

• Poor glycemic control

http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/HospitalAcqCond/Hospital-Acquired_Conditions.html



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The Joint Commission National Patient Safety Goals

• Goal 7: Reduce the risk of health care-associated infections– Meet hand hygiene guidelines

– Prevent multidrug-resistant organism infections

– Prevent central line-associated bloodstream infections

– Prevent surgical site infections

– Prevent catheter-associated UTI

http://www.jointcommission.org/standards_information/npsgs.aspx



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

Bad Bugs, No Drugs: No ESKAPE!

• E: E. faecium (vancomycin-resistant enterococci)

• S: S. aureus (MRSA)

• K: ESBL-producing E. coli and K. pneumoniae(K: K. pneumoniae carbapenemase-hydrolyzing β-lactamases)

• A: A. baumannii• P: P. aeruginosa• E: Enterobacter species

Boucher HW, et al. Clin Infect Dis. 2009;48:1-12.



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Cost of Antimicrobial-Resistant Infections

Had ARI been reduced by 3.5% to 10%• $910,812 savings for the hospital

• $1.8 million savings for society

Roberts RR, et al. Clin Infect Dis. 2009;49:1175-1184.

Medical cost attributable to antimicrobial resistant infection

$18,588 - $29,069 / patient

Excess length of stay 6.4 – 12.7 days

Attributable mortality 6.5%

Society cost $10.7 - $15.0 million

188/1391 patients (13.5%) with Antimicrobial Resistant Infection

4 Core Actions to Prevent Antibiotic Resistance

• 1. Preventing Infection

Preventing the Spread of Resistance

• 2. Tracking

• 3. Improving Antibiotic Stewardship

• 4. Developing New Drugs and Diagnostic Tests




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Mechanisms of Antibiotic Resistance

• Modification of the Antibiotic Target– Aminoglycosides, ß-lactams, Fluoroquinolones,

Glycopeptides, Macrolides, Tetracyclines

• Limiting Access (permeability)– Aminoglycosides, ß-lactams, Fluoroquinolones

• Active Efflux– Fluroquinolones, Macrolides, ß-lactams, Tetracyclines

• Enzymatic Inactivation– Aminoglycosides, ß-lactams




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HA-MRSA vs CA-MRSACharacteristic CA-MRSA HA-MRSA

Susceptibility,a drug

Chloramphenicol Usually susceptible Frequently resistant

Clindamycin Usually susceptible Frequently resistant

Erythromycin Usually resistant Usually resistant

Fluoroquinolone Geographic variability Usually resistant

TMP-SMZ Usually susceptible Usually susceptible

SCC mec type IV II

Lineage USA 300, USA 400 USA 100, USA 200

Toxin-producing More Fewer

PVL-producing Common Rare

Healthcare exposure Less frequent More frequent

HA, healthcare associated; CA, community associated; SCC, staphylococcal chromosome cassette; TMP-SMZ, trimethoprim-sulfamethoxazole; PVL, Panton-Valentine leukocidin

a Susceptibility based on in vitro testing and CLSI breakpoints.

Weber JT. Clin Infect Dis 2005;41:S269-72.



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USA 300 MRSA vs Non-USA 300 MRSA on Mortality

Nair R, et al. Infect Control Hosp Epid 2014;35:31-41

Incidence of S. aureus Hospitalizations

Suaya JA, et al. BMC Infect Dis 2014;14:296



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S. aureus Skin and Soft Tissue Infections by Age


Medical Cost Associated with S. aureus Hospitalization




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Treatment Options for MRSA Infections

Therapeutic Options for CA-MRSAOral Antimicrobials

• TMP-SMX

• Rifampin

• Minocycline

or Doxycyline

• Clindamycin

• Linezolid

• Tedizolid

Parenteral Antimicrobials

• TMP-SMX?

• Clindamycin?

• Vancomycin

• Linezolid

• Quinupristin/Dalfopristin

• Daptomycin

• Tigecycline

• Ceftaroline

• Televancin

• Dalbavancin

• Oritavancin

No randomized prospective data are available to support one antimicrobial regimen over another!



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Advantages and Disadvantages of TMP-SMX

Advantages

• Oral and IV formulation

• Bactericidal

• Excellent bioavailability

• Resistance rare

• Good safety data

• Inexpensive

• Dosed: 1-2 DS bid (10 mg/kg/day of TMP)

Disadvantages

• Rash or allergic rxn

• Bone marrow suppression

• Poor beta-hemolytic streptococci activity– S. pyogenes (Group A)

– S. agalactiae (Group B)

Advantages and Disadvantages of Clindamycin

Advantages

• Oral and IV formulation

• Good bioavailability

• Streptococci activity

• Good safety data

• Inexpensive

Disadvantages

• Bacteriostatic

• Resistance - inducible

• Pseudomembranous colitis

• Dosed: 300 - 450 mg qid



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Advantages and Disadvantagesof Linezolid

Advantages

• Broad spectrum

• Low propensity for development of resistance

• Excellent bioavailability

• Excellent tissue penetration

• Little or no interaction with cytochrome P450 system

Disadvantages

• Bacteriostatic

• Some emergence of resistance among enterococci

• BID dosing

• Toxicity– bone marrow suppression

– MAO inhibition

– peripheral neuropathy

– lactic acidosis

Tedizolid

• Oxazolidinone antibiotic inhibits protein synthesis by binding to 50S subunit of bacterial ribosome

• 91% oral bioavailability = equivalent PO and IV doses

• 70-90% protein bound

• Metabolized by sulfation, does not undergo CYP450 mediated metabolism

• >80% excreted in feces as inactive sulfate metabolite

• Terminal t1/2=12hrs

• No dosage adjustment for hepatic dysfunction, renal impairment, or dialysis

• Potentially less serotonergic activity than linezolid

Sivextro [package insert]. Lexington, MA: Cubist Pharmaceuticals, 2015.



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Advantages and Disadvantages of Ceftaroline

Advantages

• Broad spectrum

• Bactericidal

• No TDM

Disadvantages

• $$

• IV only

• BID dosing approved but need TID dosing for severe infections

• Must be refrigerated

Dalbavancin: Overview

• Lipoglycopeptide antibiotic, inhibits peptidoglycan cross-linking by binding to D-ala-D-ala

• 93% protein bound

• Does not undergo CYP450 metabolism

• Terminal half-life 2 weeks

• 20% excreted in feces, 33% excreted unchanged in urine, 12% metabolite excreted in urine

• Adjust for severe renal impairment CrCl <30 mL/min, not on HD

• No dose adjustment required for regularly scheduled HD, can give normal dose without regard for timing around HD

Boucher HW. NEJM. 214; 370: 2169-2179.Dalvance [package insert]. Chicago, IL: Durata Therapeutics; 2014.



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Oritavancin: Overview

• Lipoglycopeptide antibiotic with 3 concentration-dependent, bactericidal mechanisms of action

• 85% protein bound

• Drug Interactions Noncompetitive inhibitor of CYP450 enzymes including 1A2, 2D6,

2C9, 2C19, and 3A4

Weak inducer of 3A4 and 2D6

• Slowly excreted unchanged in urine and feces

• Prolonged terminal half life

• No dose adjustment for renal or hepatic impairment required

Orbactiv [package insert]. Parsippany, NJ: The Medicines Company; 2014.

JAMA 2014;312:1552-64



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Vancomycin High vs Low MIC Impact on Outcomes

High MIC Low MIC P value

Overall Mortality 734/2740 1430/5551 0.43

Hospital Mortality 329/913 648/2053 0.27

30-day Mortality 405/1827 782/3498 0.73

MIC 1.5 Cutoff 473/1880 640/2537 0.72

MIC 2.0 Cutoff 223/75. 618/2614 0.34

BMD Assay 134/447 399/1301 0.71

Etest Assay 600/2293 1031/4250 0.55

JAMA 2014;312:1552-64

GRAM-NEGATIVE BACTERIA



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Wong PHP et al. BMC Infect Dis 2014;14:393

Al-Hasan MN, et al. Clin Microbiol Infect 2013;19:948-54



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Probability of 28-Day Mortality with Gram-negative Bloodstream Infection

Al-Hasan MN, et al. Clin Microbiol Infect 2013;19:948-54

Mechanisms of Antibiotic Resistance

• Modification of the Antibiotic Target

• Limiting Access (permeability)

• Active Efflux

• Enzymatic Inactivation



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Evolution of β-Lactamases

Wild-Type

β-lactamase (TEM-1, TEM-2, SHV-1)

AmpC; ESBL (TEM, SHV, CTX-M)

Carbapenemase (KPC, NDM, MBL)

Penicillins

β-lactam/β-lactamase inhibitors; Cephalosporins

Carbapenems

ESBL, extended-spectrum β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β-lactamase; TEM-1,TEM-2, SHV-1, TEM, SHV, CTX-M, types of β-lactamases.

Adapted from Burgess DS, et al. Am J Health Syst Pharm . 2008;65:S4-S15.

What Are The Risk Factors?

• Prior antibiotic therapy In the preceding 90 days

• Current hospitalization ≥ 5 days• High prevalence of resistance in

the facility/community• Immunosuppression• Recent contact with LTCF

Am J Respir CritCare Med 2005; 171:388-416Adapted from Clin Microbiol Infect 2010; 16:902-908



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Extended-Spectrum Beta-Lactamases (ESBL)

• Hydrolyze penicillins, cephalosporins, and aztreonam– Co-resistant to multiple other antibiotic classes (i.e.,

aminoglycosides, fluoroquinolones, TMP/SMX)

• Most frequently encountered are TEM, SHV, and CTX-M

• Primarily found in E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis

• Infections include bacteremia, respiratory, urinary tract, intra-abdominal, skin/soft tissue

• Typically hospital and healthcare-associated infections; however, community-acquired infections are increasing

Thomson KS. J Clin Microbiol 2010;48:1019-25Paterson DL, Bonomo RA. Clin Micro Review 2005;18:657-686



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Increase in Beta-lactamase Families

Annu Rev Microbiol 2011;65:455-78

Incidence of ESBLs in the US

Antimicrobial Agents Chemotherapy 2013;57:3012-20



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In Vitro Activity of Antibiotics against ESBL

Antimicrobial MIC50 MIC90 %S

Meropenem ≤0.5 1 100%

Tigecycline 0.5 1 98%

Pip/Tazobactam 16/4 16/4 93%

Minocycline 4 32 70%

Ciprofloxacin 1 8 65%

Antimicrob Agents Chemother 2006;50:2695-99

Impact of ESBL K. pneumoniae Bloodstream Infections

OR (95% CI)

Previous antibiotic therapy

11.81 (2.72-51.08)

Age 1.14 (1.08-1.21)

Length of hospitalization

1.10 (1.04-1.16)

Risk Factors for ESBL BSI Mortality Rate

Tumbarello M et al. Antimicrob Agents Chemother 2006;50:498-504



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Impact of Antimicrobial Therapy on ESBL Bloodstream Infections

Parameter OR (95% CI)

Septic shock 5.88 (1.26-27.45)

Unidentified source

4.28 (1.71-10.69)

Inadequate initial therapy

6.22 (2.33-16.61)

Predictors of 21 day mortality

Tumbarello M et al. Antimicrob Agents Chemother 2008;52:3244-52

p=0.04

p<0.01




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Carbapenemases• Beta-lactamases that hydrolyze penicillins, cephalosporins,

monobactams, and carbapenems

• Members of the molecular class A, B, and D

– Class A and D enzymes are serine-based (i.e., KPC)• Primarily found in K. pneumoniae and other enterobacteriaceae

– Class B enzymes are metallo-beta-lactamases (i.e., IMP)• Primarily found in P. aeruginosa

– Class D enzymes are OXA-type• Primarily found in A. baumannii

Queenam AM et al. Clin Micro Review 2007;20:440-458Srinivasan A, Patel JB. Infect Control Hosp Epidemiol. 2008;29:1107-1109

Incidence of KPCs in the US

Antimicrobial Agents Chemotherapy 2014;58:833-8

KPC K. pneumoniae 5.5%


KPC K. pneumoniae 0%






KPC K. pneumoniae 0%KPC K. pneumoniae 1%



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Susceptibility of Carbapenem Resistant K. pneumoniae

0102030405060708090

100

Pe

rce

nt

TIG COL DOX CFT GEN CFP

J Antimicrob Chemother 2005;56:128-132

N=90

New Delhi Metallo-Beta-Lactamase (NDM-1)

• First reported in US during Jan – Jun 2010

• 3 Enterobacteriaceae

– E. coli, K. pneumoniae, E. cloacae• Patients received medical care in India

• Confers resistance to all beta-lactams– Except aztreonam

MMWR 2010;59:750



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Impact of Carbapenem-Resistant K. pneumoniae Bacteremia

Study patients (N=32)

Control patients (N=32)

Required intensive care 38% 9%

Required mechanical ventilation

53% 25%

Required central venous catheter

59% 28%

Crude mortality rate 72% 22%

Attributable mortality: 50% (95% CI 15.3 – 98.6)Mortality risk ratio: 3.3 (95% CI 2.9 - 28.5)

Borer A et al. Infect Control Hosp Epidemiol 2009;30:972-976

CRE Treatment Options• Colistin/Polymyxin B containing combination

• Aminoglycoside containing combination

• Tigecycline containing combination

• Dual Carbapenems



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Ceftazidime/Avibactam (Avycaz™)

• Avibactam (formerly NXL104)– Beta-lactamase inhibitor with activity

against ESBL and KPC enzymes

• Approved for cUTI and cIAI– Ceftazidime (2g)/Avibactam (0.5g) q8h

infused over 2hrs

– Ceftazidime (500mg)/Avibactam (125mg) q8h

Microbiological Activity ofCeftazidime/Avibactam

Organism Cefepime Ceftazidime Ceftazidime/ Avibactam

E. cloacae 99% 77% 99%

E. coli 98% 95% 100%

ESBL E. coli 60% 35% 100%

K. pneumoniae 99% 99% 100%

ESBL K. pneumoniae 67% 67% 100%

KPC K. pneumoniae 0% 0% 100%

P. aeruginosa 85% 83% 95%

AmpC P. aeruginosa ND 4% 96%

MDR P. aeruginosa ND 4% 60%



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Microbiological Activity ofCeftazidime/Avibactam

Enterobacteriaceae Revised CLSI Breakpoints

Antibiotic Old BP New BP

Cefazolin ≤8 ≤2

Cefotaxime ≤8 ≤1

Ceftriaxone ≤8 ≤1

Ceftazidime ≤8 ≤4

Cefepime* ≤8 ≤2

Kohner PC, et al. J Clin Microbiol. 2009;47:2419-2425


Aztreonam ≤8 ≤4

Ertapenem ≤2 ≤0.5

Imipenem ≤4 ≤1

Meropenem ≤4 ≤1

Doripenem ≤1

*S-DD (Susceptible Dose-dependent) – 4-8 mg/L



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Ceftolozane/Tazobactam(Zerbaxa™)

• Ceftolozane – new antipseudomonal cephalosporin but limited anaerobic activity

• Approved for cUTI and cIAI– Ceftolozane/Tazobactam 1.5 g q8h



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Microbiological Activity of Ceftolozane/Tazobactam

P. aeruginosa Revised CLSI Breakpoints

Kohner PC, et al. J Clin Microbiol. 2009;47:2419-2425


Piperacillin ≤64 ≤16

Piperacillin/Tazobactam

≤64/4 ≤16/4

Imipenem ≤4 ≤2

Meropenem ≤4 ≤2

Doripenem ≤2



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Acinetobacter baumannii

“A. baumannii is a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline.”

• Nosocomial pathogen that causes a variety of infections (i.e., pneumonia, wound, urinary tract, bloodstream, intra-abdominal)

• Resistant to all antibioticsincluding the carbapenems

Clin Infect Dis 2006;42:657-68



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Castanheira M, et al. Clin Infect Dis 2014;59(suppl 6):S367-73

Castanheira M, et al. Clin Infect Dis 2014;59(suppl 6):S367-73



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Significance of Appropriate Therapy for A. baumannii Bloodstream Infections

Risk Factor HR (95% CI)

Inadequate initial therapy

2.4 (1.3-4.2)

Septic shock 2.6 (1.4-4.8)

Age >65 yrs 2.1 (1.2-3.7)

Mechanical ventilation

3.3 (1.5-7.4)

Erbay A et al. Internat J Antimicrob Agents 2009;34:575-9

Risk Factors for Mortality

p=0.011

Impact of appropriate initial therapy

Mortality and Hospital Cost in VAP Due to Gram-negative Resistance

• VAP due to P. aeruginosa, A. baumannii, and S. maltophilia• Initial inappropriate therapy

– A. baumannii (67%)

– S. maltophilia (33%)

– P. aeruginosa (17%)

• 30 day mortality significantly higher in patients that initially received inappropriate therapy

• Overall hospital cost was not significantly different ($68,597±55,466 vs $86,644±64,433, p=0.390)

Koellef KE et al. Chest 2008;134:281-287



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Streamlining Antibiotic Therapy

Site(s) of InfectionCommunity vs. Hospital

Infected Patient

Laboratory TestsCollection of Infected Materials

Gram Stain

Culture ResultsIdentification of Organism

SensitivityAbx

Antimicrobial Spectrum of Activity Precision and Time

Baseline

1 h

24–48 h

48–72 h

72–96 hStreamline therapy

Discontinue agents

Broad-spectrumempirictherapy

Rapid Diagnostic Tests• MALDI-TOF

– MALDI Biotyper® (Bruker Daltonics)

– Vitek MS® (bioMérieux)

• PCR-based tests – FilmArray System® (BioFire Diagnostics)

– Verigene® (Nanosphere)

– Xpert® (Cepheid)

• PNA QuickFISH– PNA-FISH® (AdvanDx)–

– Bauer KA, et al. Clin Infect Dis 2014;59 (Suppl 3):S134-45.



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Summary

• Infections due to multidrug resistant pathogens are a major worldwide public health problem.

• Treatment options for MDR infections are extremely limited.

• Initial inadequate antimicrobial therapy clearly leads to increase mortality.

• Hence, you must know the local prevalence and susceptibility patterns to adequately select an initial empiric antimicrobial regimen.

multidrug resistant organisms: detection, epidemiology...

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