multidrug resistant organisms: detection, epidemiology...
TRANSCRIPT
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
1
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.
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
2
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
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
3
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
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
4
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.
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
5
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
http://www.cdc.gov/drugresistance/threat-report-2013/
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
6
http://www.cdc.gov/drugresistance/threat-report-2013/
http://www.cdc.gov/drugresistance/threat-report-2013/
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
7
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
http://www.cdc.gov/drugresistance/threat-report-2013/
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
8
http://www.cdc.gov/drugresistance/threat-report-2013/
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.
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
9
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
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
10
S. aureus Skin and Soft Tissue Infections by Age
Suaya JA, et al. BMC Infect Dis 2014;14:296
Medical Cost Associated with S. aureus Hospitalization
Suaya JA, et al. BMC Infect Dis 2014;14:296
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
11
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!
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
12
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
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
13
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.
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
14
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.
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
15
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
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
16
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
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
17
Wong PHP et al. BMC Infect Dis 2014;14:393
Al-Hasan MN, et al. Clin Microbiol Infect 2013;19:948-54
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
18
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
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
19
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
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
20
http://www.cdc.gov/drugresistance/threat-report-2013/
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
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
21
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
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
22
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
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
23
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
http://www.cdc.gov/drugresistance/threat-report-2013/
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
24
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 0.4%
KPC K. pneumoniae 0%
KPC K. pneumoniae 0%
KPC K. pneumoniae 2.4%
KPC K. pneumoniae 28.6%
KPC K. pneumoniae 0.6%
KPC K. pneumoniae 18%
KPC K. pneumoniae 0%KPC K. pneumoniae 1%
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
25
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
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
26
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
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
27
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%
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
28
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
Antibiotic Old BP New BP
Aztreonam ≤8 ≤4
Ertapenem ≤2 ≤0.5
Imipenem ≤4 ≤1
Meropenem ≤4 ≤1
Doripenem ≤1
*S-DD (Susceptible Dose-dependent) – 4-8 mg/L
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
29
http://www.cdc.gov/drugresistance/threat-report-2013/
Ceftolozane/Tazobactam(Zerbaxa™)
• Ceftolozane – new antipseudomonal cephalosporin but limited anaerobic activity
• Approved for cUTI and cIAI– Ceftolozane/Tazobactam 1.5 g q8h
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
30
Microbiological Activity of Ceftolozane/Tazobactam
P. aeruginosa Revised CLSI Breakpoints
Kohner PC, et al. J Clin Microbiol. 2009;47:2419-2425
Antibiotic Old BP New BP
Piperacillin ≤64 ≤16
Piperacillin/Tazobactam
≤64/4 ≤16/4
Imipenem ≤4 ≤2
Meropenem ≤4 ≤2
Doripenem ≤2
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
31
http://www.cdc.gov/drugresistance/threat-report-2013/
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
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
32
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
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
33
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
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
34
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.
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
35
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.