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Antimicrobial Resistance

Antimicrobial Resistance. Timothy H. Dellit, MD thdellit@u.washington.edu Infection Control and Antimicrobial Management Harborview Medical Center. Gram Positive Resistance ICU 1995-2004. Methicillin-Resistant Staphylococcus aureus. Vancomycin-Resistant Enterococcus.

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Antimicrobial Resistance

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

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

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

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

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

  6. Resistant StrainsRare Antimicrobial Exposure Resistant Strains Dominant x x 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. Site of β-lactamase Activity O R1 C NH HC H2C C C N C COOH S CH3 CH3 O β-lactamase

  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 (MLSB phenotype) • ermB gene

  11. Clinical Impact of Resistance Increasing resistance • Inpatient (MRSA, VRE, Pseudomonas, Acinetobacter) • Outpatient (E. coli, CA-MRSA, S. pneumoniae) Clinical Condition Mortality Risk MRSA vs. MSSA bacteremia1 1.93 MRSA vs. MSSA SSI2 3.4 VRE vs. VSE bacteremia3 2.52 Emergence of resistant Pseudomonas4 3.0 Enterobacter resistant to 3rd gen ceph5 5.02 MDR-Acinetobacter vs. non-MDR Acin bacteremia6 4.1 1Clin Infect Dis 2003;36:53-9 4Arch Intern Med 1999;159:1127-32 2Clin Infect Dis 2003;36:592-8 5Arch Intern Med 2002;162:185-90 3Clin Infect Dis 2005;41:327-33 6Infect Control Hosp Epidemiol 2007;28:713-9

  12. Economic Impact of Antimicrobial Resistance • Antimicrobials account for upwards of 30% of formulary budgets • 50% of antimicrobial usage is inappropriate Clinical Condition LOS Attributable Cost MRSA in ICU1 $9,275 MRSA vs. MSSA bacteremia2 9 vs. 7 d $7,212 MRSA vs. MSSA SSI3 $13,901 Emergence of resistant Pseudomonas4 OR 1.7 Enterobacter resistant to 3rd gen ceph5 OR 1.47 $29,379 MDR-Acinetobacter vs. 13.4 more days $3,758 non-MDR Acinetobacter bacteremia6 MDR-Acinetobacter in burn unit7 $98,575 Annual cost of infections due to antimicrobial resistant bacteria estimated to be $4 to $5 billion (IOM 1998) 1JAMA 1999;282:1745-1751 5Arch Intern Med 2002;162:185-90 2ICHE 2005;26:166-174 6ICHE 2007;28:713-9 3Clin Infect Dis 2003;36:592-8 7Am J Infect Control 2004;32:342-4 4Arch Intern Med 1999;159:1127-32

  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 regardingS. pneumoniae? • The MIC susceptibility breakpoint for penicillin has recently been lowered due to increased clinical failure with penicillin treatment. • Levofloxacin is the most active fluoroquinolone against S. pneumoniae • The addition of a beta-lactamase inhibitor (ampicillin-sulbactam) can overcome the penicillin resistance. • 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 N Engl J Med 2006;354:1455-63 Meningitis per 100,000 1994-1999 2001-2004 Children < 2 years of age 7.7 2.6 Persons > 65 years of age 1.2 0.8 Clin Infect Dis 2008;46:1664-72

  16. S. pneumoniaeβ-Lactam Resistance SENTRY surveillance: susceptibility increase from 68% to 93% of isolates Clin Infect Dis 2009;48:1596-1600

  17. S. pneumoniae Resistance AntimicrobialNationalLocal 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 Peak • Concentration-dependent killing (AUC:MIC) • Fluoroquinolone targets • DNA gyrase • Topoisomerase IV Drug Concentration Area Under the Curve (AUC) MIC Time

  20. S. pneumoniae and Fluoroquinolones Drug MIC90 AUCFree AUC:MICFree 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 Drug Dose Cmax MIC AUCfree:MIC Ciprofloxacin 400 q12 4.1 0.125 144 400 q8 4.1 0.125 184 Levofloxacin 750 q24 12.1 0.5 152 Gatifloxacin 400 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? • Daptomycin is active against VISA, but not VRSA • VRSA isolates to date have contained vanB • Breakpoint for vancomycin susceptibility is 4.0 mcg/ml • MecA gene encodes PBP2a • Isolates susceptible to erythromycin should undergo “D-test” for inducible clindamycin resistance • 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 TrendAntibiotic Resistance Sentinel Network All isolates Outpatient isolates

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

  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” • 20-40% of people colonized with S. aureus • 20% persistent, 30% intermittent, 50% never Clin Microbiol Rev 1997;10:505-520

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

  32. Test for inducible resistance to clindamycin using D test in erythromycin resistant isolates Methylation of an adenine residue of bacterial 23S rRNA (MLSB phenotype, ermB) Effective in treatment of CA-MRSA in the absence of inducible resistance Staphylococcus aureus and Inducible Resistance to Clindamycin 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 p < 0.02 p = 0.06 Clinical Cure Rate* *All patients with MRSA were cured Ann Intern Med 1992;117:390-398 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 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 Vancomycin Daptomycin Daptomycin MIC, mcg/ml MIC < 1 mcg/ml MIC > 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? Ceftriaxone Ceftazidime Cefepime Imipenem

  44. Problematic β-lactamases *Monotherapy with penicillin or 3rd generation cephalosporin may be associated with inducible resistance

  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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