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Antimicrobial Resistance Timothy H. Dellit, MD Infection Control and Antimicrobial Management Harborview Medical Center.

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Presentation on theme: "Antimicrobial Resistance Timothy H. Dellit, MD Infection Control and Antimicrobial Management Harborview Medical Center."— Presentation transcript:

1 Antimicrobial Resistance Timothy H. Dellit, MD thdellit@u.washington.edu Infection Control and Antimicrobial Management Harborview Medical Center

2 Gram Positive Resistance ICU 1995-2004 National Nosocomial Infections Surveillance (NNIS) System Methicillin-Resistant Staphylococcus aureus Vancomycin-Resistant Enterococcus

3 Gram Negative Resistance ICU 1995-2004 National Nosocomial Infections Surveillance (NNIS) System 3rd Generation Cephalosporin- Resistant Klebsiella pneumoniae Fluoroquinolone-Resistant Pseudomonas aeruginosa

4 Tip of the Iceberg? Percent of Cases Identified 760 Cases of VRE identified between Jan 1997 – Oct 1999 Clin Infect Dis 2003;37:326-32 86% undetected by clinical specimen alone

5 New Resistant Bacteria Mutations XX Susceptible Bacteria Resistant Bacteria Resistance Gene Transfer Emergence of Antimicrobial Resistance

6 Resistant Strains Rare x x Resistant Strains Dominant Antimicrobial Exposure x x x x x x x x x x Selection for Antimicrobial- Resistant Strains

7 Mechanisms of Resistance Inactivation of drug –Beta-lactamases Alteration of the target –Penicillin binding proteins –Ribosomes Decreased permeability Drug efflux

8 R 1 C NH HC H 2 C C C N C COOH S CH 3 O O β-lactamase Site of β-lactamase Activity

9 Increased Macrolide Consumption and the Emergence of Resistance N Engl J Med 1997;337:441-6

10 Macrolide Resistance Efflux of drug in S. pyogenes, S. pneumoniae –M phenotype encoded by mef gene Alteration of 23S rRNA of 50S ribosomal subunit by methylation of adenine –Associated with resistance to macrolides, lincosamides (clindamycin), and streptogramin type B (MLS B phenotype) –ermB gene

11 Clinical Impact of Resistance Increasing resistance –Inpatient (MRSA, VRE, Pseudomonas, Acinetobacter) –Outpatient (E. coli, CA-MRSA, S. pneumoniae) Clinical ConditionMortality Risk MRSA vs. MSSA bacteremia 1 1.93 MRSA vs. MSSA SSI 2 3.4 VRE vs. VSE bacteremia 3 2.52 Emergence of resistant Pseudomonas 4 3.0 Enterobacter resistant to 3 rd gen ceph 5 5.02 MDR-Acinetobacter vs. non-MDR Acin bacteremia 6 4.1 1 Clin Infect Dis 2003;36:53-9 4 Arch Intern Med 1999;159:1127-32 2 Clin Infect Dis 2003;36:592-8 5 Arch Intern Med 2002;162:185-90 3 Clin Infect Dis 2005;41:327-33 6 Infect Control Hosp Epidemiol 2007;28:713-9

12 Economic Impact of Antimicrobial Resistance Clinical ConditionLOS Attributable Cost MRSA in ICU 1 $9,275 MRSA vs. MSSA bacteremia 2 9 vs. 7 d$7,212 MRSA vs. MSSA SSI 3 $13,901 Emergence of resistant Pseudomonas 4 OR 1.7 Enterobacter resistant to 3rd gen ceph 5 OR 1.47$29,379 MDR-Acinetobacter vs. 13.4 more days$3,758 non-MDR Acinetobacter bacteremia 6 MDR-Acinetobacter in burn unit 7 $98,575 1 JAMA 1999;282:1745-1751 5 Arch Intern Med 2002;162:185-90 2 ICHE 2005;26:166-174 6 ICHE 2007;28:713-9 3 Clin Infect Dis 2003;36:592-8 7 Am J Infect Control 2004;32:342-4 4 Arch Intern Med 1999;159:1127-32 Antimicrobials account for upwards of 30% of formulary budgets 50% of antimicrobial usage is inappropriate Annual cost of infections due to antimicrobial resistant bacteria estimated to be $4 to $5 billion (IOM 1998)

13 Antimicrobials and Animals 50% of antimicrobials in tonnage used in food- producing animals and poultry –Disease control and growth promotion Paralleled increase in resistance –Salmonella –Campylobacter MRSA and pigs Community-associated VRE and avoparcin Lancet Infectious Diseases 2001;1:314-25 Clin Infect Dis 2007;45:1353-61 Emerg Infect Dis 2007;13:1834-9 Clin Infect Dis 2008;46:261-3

14 Which of the following is CORRECT regarding S. pneumoniae? A.The MIC susceptibility breakpoint for penicillin has recently been lowered due to increased clinical failure with penicillin treatment. B.Levofloxacin is the most active fluoroquinolone against S. pneumoniae C.The addition of a beta-lactamase inhibitor (ampicillin- sulbactam) can overcome the penicillin resistance. D.Introduction of the pneumococcal conjugate vaccine has been associated with a reduction in non-penicillin susceptible invasive pneumococcal infections.

15 Pneumococcal Conjugate Vaccine Rate of penicillin-nonsusceptible invasive disease per 100,000 19992004 All ages 6.3 2.7 Children < 2 years of age 70.3 13.1 Persons > 65 years of age 16.4 8.4 Serotype 19A 0.3 1.2 Children < 2 years of age 0.8 8.3 Meningitis per 100,000 1994-1999 2001-2004 Children < 2 years of age7.72.6 Persons > 65 years of age1.20.8 N Engl J Med 2006;354:1455-63 Clin Infect Dis 2008;46:1664-72

16 S. pneumoniae β-Lactam Resistance Clin Infect Dis 2009;48:1596-1600 SENTRY surveillance: susceptibility increase from 68% to 93% of isolates CeftriaxoneSusceptibleIntermediateResistant Previous< 0.51.0> 2.0 Non-meningitis<1.02.0> 4.0

17 S. pneumoniae Resistance AntimicrobialNational Local Macrolide 29%25-32% TMP/SMX 32% 30% Tetracyclines 16%17-23% Fluoroquinolones* 2.3% 0-5% *21.9% of S. pneumoniae isolates in 2002-2003 had fluoroquinolone mutations in parC and/or gyrA compared to 4.7% in 1997-1998. Clin Infect Dis 2005;41:139-48 Local Fluoroquinolone Susceptibility Moxifloxacin: 99-100% Levofloxacin: 95%

18 Tetracyclines tet efflux genes Tigecycline is a new glycylcycline derivative of minocycline –Designed to overcome drug-resistance due to efflux and ribosomal protection –In vitro activity against PRSP, MRSA, VRE, and some Acinetobacter, but not Pseudomonas –Emergence of resistance on therapy, particularly with Acinetobacter

19 Fluoroquinolones and AUC:MIC Drug Concentration Time MIC Peak Area Under the Curve (AUC) Concentration-dependent killing (AUC:MIC) Fluoroquinolone targets DNA gyrase Topoisomerase IV

20 S. pneumoniae and Fluoroquinolones Drug MIC 90 AUC Free AUC:MIC Free Ciprofloxacin (750 bid) 1.0 28 28 Levofloxacin (500 qd) 1.0 34 34 Levofloxacin (750 qd) 1.0 70 70 Gatifloxacin (400 qd) 0.25 26 106 Gemifloxacin (320 qd) 0.03 140-280 Moxifloxacin (400 qd) 0.12 24 200 Cutoff criterion of AUC:MIC >33.7 for gram-positives? Clin Infect Dis 2005;41:S127-35

21 Pseudomonas and Fluoroquinolones DrugDose C max MIC AUC free :MIC Ciprofloxacin400 q12 4.1 0.125 144 400 q8 4.1 0.125 184 Levofloxacin750 q24 12.1 0.5 152 Gatifloxacin400 q12 4.6 1.0 28 Moxifloxacin 400 q24 4.2 2.0 10 IDSA and ATS Guidelines recommend Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd Am J Respir Crit Care med 2005;171:388-416

22 35 y o man with a history of HIV and methamphetamine use presents to clinic with a right biceps abscess.

23 49 y o man with a 1 week h/o viral syndrome with progressive dyspnea, hypoxia, and hypotension. Sputum, pleural fluid, and blood cultures with GPC in clusters. Clin Infect Dis 2005;40:100-7 Chest 2005;128:2732-8

24 40 y o man with h/o IDU with heroine presents with fever, chills, cough, and pleuritic chest pain. Doppler demonstrates L common femoral DVT and blood cultures grow GPC with vancomycin MIC 2.0 and remain persistently positive at day 7.

25 Which of the following is correct regarding S. aureus resistance? A.Daptomycin is active against VISA, but not VRSA B.VRSA isolates to date have contained vanB C.Breakpoint for vancomycin susceptibility is 4.0 mcg/ml D.MecA gene encodes PBP2a E.Isolates susceptible to erythromycin should undergo “D-test” for inducible clindamycin resistance F.Linezolid resistance is due to drug efflux

26 Community-Associated MRSA Four pediatric deaths 1997-1999 in Minnesota and North Dakota (MMWR 1999;48:707) Clinical manifestations –Predominantly skin and soft tissue 59% of purulent SSTI in 11 ED, 78% of S. aureus –Necrotizing fasciitis –Necrotizing pneumonia Different from HA-MRSA –SCCmec type IV –Panton-Valentine Leukocidin exotoxin associated with tissue necrosis and leukocyte destruction (or other toxin?) JAMA 2003;290:2976-2984

27 Washington State MRSA Trend Antibiotic Resistance Sentinel Network All isolates Outpatient isolates

28 MRSA Resistance to Beta-Lactams Beta-Lactam Modified from David Spach, MD Cell Wall Cell Membrane Alternative Penicillin Binding Protein PBP2a DNA

29 Nasal Carriage of S. aureus Increased rates –IDDM –HD/CAPD –IDU –HIV MRSA –Healthcare contact Surgery Dialysis Indwelling devices –Long-term care facilities –IDU (Clin Infect Dis 2002;34:425-33) –Correction facilities (Clin Infect Dis 2003;37:1384-8) –MSM (Clin Infect Dis 2005;40:1529-34) –Tattoo (MMWR 2006;55(24):677-9) –Native Americans, Pacific Islanders –Other close contact Athletic (N Engl J Med 2005;352:468-75) –“Spider bite” Clin Microbiol Rev 1997;10:505-520 20-40% of people colonized with S. aureus –20% persistent, 30% intermittent, 50% never

30 Prevalence of MRSA Colonization 2003-2004 National Health and Nutrition Examination Survey (NHANES) 9004 persons (J Infect Dis 2008;197:1226-34) –1.5% vs. 0.8% MRSA colonization in 2001-2002 >10 fold increase in healthy children from 2001 to 2004, with MRSA colonization rate of 9.2% (Pediatr Infect Dis J 2005;24:617-21)

31 2008 MRSA Susceptibilities Clindamycin* Levofloxacin Tetracycline TMP/SMX Vancomycin Harborview UW 71% 60% 21% 27% 95% 94% 91% 95% 100% 100% *D-zone test should be done to look for inducible resistance to clindamycin 9% at HMC and 13% at UWMC

32 Staphylococcus aureus and Inducible Resistance to Clindamycin Test for inducible resistance to clindamycin using D test in erythromycin resistant isolates Methylation of an adenine residue of bacterial 23S rRNA (MLS B phenotype, ermB) Effective in treatment of CA-MRSA in the absence of inducible resistance Clin Infect Dis 2003;37:1257-60 Pediatr Infect Dis J 2003;22:593-8 Pediatr Infect Dis J 2002;21:530-4

33 Treatment Options for MRSA Infections Vancomycin* Linezolid* Daptomycin* Tigecycline* Quinupristin/dalfopristin* TMP-SMX Minocycline/Doxy Clindamycin** Fluoroquinolone Linezolid* IntravenousOral *FDA approved for MRSA **test for inducible resistance if erythromycin–R and clindamycin-S Rifampin should not be routinely used in combination for SSTI and NEVER alone due to rapid emergence of resistance.

34 Trimethoprim-Sulfamethoxazole and Staphylococcus aureus Randomized study comparing TMP-SMX and vancomycin in 101 IDU’s with S. aureus infections Clinical characteristics –47% of isolates were MRSA –65% of patients were bacteremic –32% with skin and soft tissue infections Ann Intern Med 1992;117:390-398 Clinical Cure Rate* p < 0.02p = 0.06 *All patients with MRSA were cured May not be effective against  -hemolytic streptococci (ie Group A strep)

35 IDSW, WA DOH, King and Pierce County Health Departments Incorporation of MRSA risk factor assessment Importance of Incision & Drainage Emphasize culture and susceptibility testing Empiric outpatient or discharge regimens to include trimethoprim-sulfamethoxazole, minocycline or doxycycline, or clindamycin Judicial use of linezolid and daptomycin Outpatient Management of SSTI http://www.doh.wa.gov/Topics/Antibiotics/MRSA.htm

36 Vancomycin MIC Creep Association between increasing MIC and clinical failure, particularly prolonged bacteremia –Breakpoint lowered to < 2 mcg/ml Trough of 15-20 mcg/ml recommended in endocarditis, osteomyelitis, and ventilator-associated pneumonia Clin Infect Dis 2006;42:S51-7

37 Vancomycin MIC and Clinical Outcome Prospective study of 95 patients with MRSA infections Elderly population, 64% in SNF, 77% with PNA or bacteremia 51/95 (54%) with strains having MIC > 1.5 mcg/ml Percentage Arch Intern Med 2006;166:2138-2144

38 Impact of Vancomycin MIC 1.01.52.0Total MRSA21 (39%)19 (35%)14 (26%)54 MSSA19 (41%)10 (22%)17 (37%)46 Vancomycin MICMortality ORP 1.01 1.52.860.08 2.06.39<0.001 414 Episodes of MRSA Bacteremia Clin Infect Dis 2008;46:193-200 Harborview Sample MICs for first blood isolate

39 Vancomycin Resistance Binds to cell wall precursors ending in D- Ala-D-Ala and prevents their incorporation into cell wall synthesis Vancomycin-intermediate resistant S. aureus (VISA) –First documented in Japan 1996, US in 1997 –Increased cell wall thickness limiting glycopeptide access to site of cell wall synthesis Vancomycin-resistant S. aureus (VRSA) –Isolated in June 2002 –Contained vanA resistance gene identical to vanA gene in patient’s vancomycin-resistant Enterococcus faecalis –van genes encode for precursors with alternative termini that have low affinity for vancomycin (eg. vanA encodes D-Ala-D-Lac) VISA

40 Reduced Susceptibility to Vancomycin Associated with Reduced Susceptibility to Daptomycin in S. aureus No. (%) of Isolates VancomycinDaptomycinDaptomycin MIC, mcg/mlMIC 2 mcg/ml < 2 812 (97) 30 (3) 4 11 (20) 43 (80) 8-16 1 (7) 15 (93) > 32* 5 (100) 0 (0) * vanA mediated resistance Clin Infect Dis 2006;42:1652-3

41 So what are non-vanco options? Linezolid Pros –100% oral bioavailability –Benefit in MRSA PNA? –Protein synthesis inhibitor Cons –Static drug –Limited data in bacteremia and endocarditis –Adverse events Marrow suppression Serotonin syndrome Lactic acidosis Optic neuritis, peripheral neuropathy, Bell’s palsy –Cost Daptomycin Pros –Cidal drug –Approved for bacteremia and right sided endocarditis Cons –Not active in the lung –Parenteral only –Decreased susceptibility to vancomycin associated with decreased susceptibility to daptomycin –Emergence of resistance on therapy –Cost

42 35 y o woman develops a catheter-related bloodstream infection with Enterobacter. Monotherapy with which of the following antibiotics would be LEAST preferred even though the organism is susceptible to all three? A. Ceftazidime B. Cefepime C. Imipenem

43 25 y o man with a h/o MVA develops ventilator- associated pneumonia with quantitative BAL culture growing 50,000 cfu Klebsiella pneumonia reported as producing an extended-spectrum beta-lactamase (ESBL). Which of the following antibiotics is the best choice? A.Ceftriaxone B.Ceftazidime C.Cefepime D.Imipenem

44 ESBLAmpC BugsE. coli, KlebsiellaSPICEM organisms (Serratia, Pseudomonas, Providencia, Indole-pos Proteus, Citrobacter, Enterobacter, Morganella GeneticsPlasmidChromosome or plasmid Inducible ResistanceNoYes* Most stable β-lactamsCarbapenemCarbapenem or cefepime *Monotherapy with penicillin or 3 rd generation cephalosporin may be associated with inducible resistance Problematic β-lactamases

45 New Antibacterial Drugs Approved By FDA Linezolid 2000

46 Bad Bugs, No Drugs Gram-positive bacteria –MRSA and VRE –Emergence of vancomycin-resistant S. aureus and linezolid-resistant Enterococcus –Decreased S. aureus susceptibility to vancomycin associated with decreased susceptibility to daptomycin Gram-negative bacteria –Pan-resistant Acinetobacter and Pseudomonas Colistin/Polymixin E –nephrotoxicity 20-30% –neurotoxicity 7% –Extended-spectrum β-lactamase organisms Clin Infect Dis 2006;42:657-68

47 Summary Development of antimicrobial resistance is directly related to antimicrobial usage, especially inappropriate usage Understanding antimicrobial pharmocokinetics/dynamics and resistance mechanisms can help guide appropriate usage Knowledge of local susceptibility patterns is essential Paucity of new antimicrobial agents in pipeline


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