MDROs (a.k.a. Bad Bugs)-- Current Concepts in Treatment

1. MDROs (a.k.a. Bad Bugs)--Current Concepts in Treatment 16th Annual Pharmacological Conference forAdvanced Practice Nurses Robert G. Penn, MD, FACP, FSHEA, FIDSA Infectious Diseases Associates, P.C. Medical Director of Epidemiology, Methodist Hospital RobertPenn@IDmidwest.com July 22, 2011

2. MDROs (a.k.a. Bad Bugs)--Current Concepts in Treatment There are no potential conflicts of interest relevant to this presentation. Robert G. Penn, MD, FACP, FSHEA, FIDSA Infectious Diseases Associates, P.C. Medical Director of Epidemiology, Methodist HospitalRobertPenn@IDmidwest.com July 22, 2011

3. Objectives • Discuss fundamental principles of infectious disease treatment • Review the preferred and the alternative antimicrobial therapy for multi-drug resistant organisms (MDROs) • Identify the mechanism of action (MOA) of select antibiotics

4. Outline • Fundamental principles of ID treatment • Current antibiotic therapy for MDROs • MDR-GPO • MRSA • VRE • MDR-GNO • ESBL-Enterobacteraceae • CRE

5. The Gram Stain

6. Bacterial structure—GPO and GNO

7. ID Fundamental Principles Infectious Disease

8. ID Fundamental Principles ⬇Infectious Disease

9. ID Fundamental Principles cont’d • Does the patient have a Systemic Inflammatory Response Syndrome (“SIRS”)?—two or more: • Body temperature <36ºC (96.8ºF) or >38ºC (100.4ºF) • Heart rate >90 beats per minute • Respiratory rate >20 breaths per minute (or an arterial partial pressure of carbon dioxide < 32 mmHg) • WBC <4000 cells/mm³ or >12,000 cells/mm³ (or >10% Bands) • Does the patient have a sepsis syndrome? • When “SIRS” is due to infection

10. ID Fundamental Principles cont’d • Obtain an accurate infectious disease diagnosis • Determine the site of infection • Define the host • Establish (when possible) a microbiological diagnosis • Study antimicrobial susceptibility test results • Timing of initiation of antimicrobial therapy • Empiric versus definitive antimicrobial therapy

11. ID Fundamental Principles cont’d

12. ID Fundamental Principles cont’d

13. ID Fundamental Principles cont’d • Bactericidal versus bacteriostatic therapy • Use of antimicrobial combinations • Synergism • Empiric therapy for critically ill patients • Polymicrobial infections • To prevent emergence of resistance

14. ID Fundamental Principles cont’d • Host factors to consider in selection of ABX • Renal and hepatic function • Age • Genetic variation • Pregnancy and lactation • History of allergy or intolerance • History of recent antimicrobial use

15. ID Fundamental Principles cont’d • Consider the drug-host-microbe system • In order for “cure” the ABX must: • Have the ability to reach the target site • Achieve adequate concentration at the site, and • Remain there for a sufficient time to accomplish its mission • Two distinct components • Pharmacokinetics • Pharmacodynamics

16. ID Fundamental Principles cont’d • Pharmacokinetics • “What the host does to the drug” • Describes the absorption, distribution, metabolism, and elimination of a drug

17. Pharmacokinetics of Vancomycin

18. Pharmacokinetics of Vancomycin

19. ID Fundamental Principles cont’d • Pharmacodynamics • “What the drug does in the host to the bacteria” • Describes the relationship that exists between the drug concentration to which the bacteria is exposed at various sites of infection and bacterial killing • ABX can be classified: • Time-dependent killing • Concentration-dependent killing

20. Pharmacodynamics

22. Cutaneous Abscess on the Hip

23. Gram stain

25. Molecular Mechanism of Methicillin “R”Background

26. Molecular Mechanism of Methicillin “R”MRSA • Methicillin (1959) resistance requires the presence of mec gene (mecA) • Encodes the PBP2A • Establishes resistance to β-lactams • Low affinity for β-lactam antibiotics • Detected by PCR • MecA is found on Staphylococcal chromosomal cassette (SCCmec—types I, II, III, IV, V)

27. Clinical Considerations - Evaluation • MRSA belongs in the differential diagnosis of skin and soft tissue infections (SSTI’s) compatible with S. aureus infection: • Abscesses, pustular lesions (purulent drainage or exudate), “boils” • Nonpurulent cellulitis? • “Spider bites”

28. MRSA Was the Most Commonly Identified Cause of Purulent SSTIs Among Adult ED Patients (EMERGEncy ID Net), August 2004 59% (97% USA300) 54% 39% 15% 74% 55% 51% 68% 60% 60% 72% 67% Moran et al NEJM 2006;355:666-674

29. Clinical Considerations - Evaluation • MRSA should also be considered in differential diagnosis of severe disease compatible with S. aureus infection: • Osteomyelitis • Empyema • Necrotizing pneumonia • Septic arthritis • Endocarditis • Sepsis syndrome • Necrotizing fasciitis • Purpurafulminans

30. Management of Skin Infections in the Era of CA-MRSA • I&D should be routine for purulent skin lesions

31. Management of Skin Infections in the Era of CA-MRSA • I&D should be routine for purulent skin lesions • Obtain material for culture

32. Management of Skin Infections in the Era of CA-MRSA • I&D should be routine for purulent skin lesions • Obtain material for culture • Empiric antimicrobial therapy may be needed

33. Management of Skin Infections in the Era of CA-MRSA • ABX recommended for abscesses associated with: • Severe or extensive disease (e.g., involving multiple sites of infection) • Rapid progression of associated cellulitis • Signs or symptoms of systemic illness • Associated comorbidities or immunosuppression • Extremes of age • Difficult to drain area (face, hand, genitalia) • Associated septic phlebitis • Lack of response to I & D alone

35. Vancomycin • Glycopeptide • Loading dose of 15mg/kg up to 2000mg IV • Continue dosing based on renal function • T1/2 for normal renal function = 4 to 6 hours • T1/2 for ESRD = 200 to 250 hours • Adverse effects • Red-man syndrome (~20%) • Nephrotoxity • Thrombocytopenia

36. Vancomycin--MOA • Vancomycin binds to the pentapeptides of the peptidoglycan monomers • Prevents the transglycosylation step in peptidoglycan polymerization • This weakens the cell wall and damages the underlying cell membrane

37. Alternative ABX for Invasive MRSA • Daptomycin (Cubicin®) • Cyclic lipopeptide (Inhibited by pulmonary surfactant….) • 4 to 6 mg/kg daily IV • Linezolid (Zyvox™) • Synthetic oxazolidinone (Thrombocytopenia….) • 600 mg bid IV or PO • Tigecycline (Tygacil®) • Glycylcycline (Nausea and vomiting….) • 100 mg then 50 mg q 12h IV

38. Alternative ABX for Invasive MRSA • Quinupristin-dalfopristin (Synercid®) • Streptogramin (Requires a central line….) • 7.5 mg/kg q 12h IV • Telavancin (Vibativ™) • Semisynthetic lipoglycopeptide (Screen for pregnancy….) • 10 mg/kg daily IV • Ceftaroline (Teflaro™) • 5th generation cephalosporin (Adjust dosage for RI….) • 600 mg q 12h IV

39. Telavancin (Vibativ™) • Glycopeptide • Dosing for complicated SSSI: • 10mg/kg q 24 hours IV over 60 minutes • Adjust dose for eGFR ≤50 mL/minute • Adverse effects: • Red-man syndrome • Serum creatinine increased (8%) • May prolong QTc interval • May interfere with tests to monitor coagulation • Foamy urine (13%) • Solubilizercyclodextrin

40. Telavancin (Vibativ™) MOA • Inhibits bacterial cell wall synthesis by blocking polymerization and cross-linking of peptidoglycan by binding to a portion of the cell wall Plus • Disruption of membrane potential and changes cell permeability

41. Ceftaroline (Teflaro™) • FDA approved for: • Community-acquired pneumonia • Complicated skin and skin structure infections • Dose: 600mg q 12 hours IV • Adjust dose if eGFR is ≤50 mL/minute • Adverse effects • Rash (3%) • Use with caution in penicillin allergic patient

42. Ceftaroline (Teflaro™) MOA • Inhibits bacterial cell wall synthesis • Binds to penicillin binding proteins (PBPs) 1 through 3 • Blocks the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls • Strong affinity for PBP2a, a modified PBP in MRSA

43. Structure–activity Relationships for Ceftaroline Laudano J B J. Antimicrob. Chemother. 2011;66:iii11-iii18

44. Management of Skin Infections in the Era of CA-MRSA • I&D should be routine for purulent skin lesions • Obtain material for culture • Empiric antimicrobial therapy may be needed • Alternative agents have +’s and –’s: More data needed to identify optimal strategies

45. Clinical Considerations - Management Oral Antimicrobial Selection (SSTIs)* • Clindamycin – Potential for inducible resistance, Relatively higher risk of C. difficile associated disease? • TMP/SMX – Group A Strep isolates commonly resistant • Doxycycline or Minocycline – Not recommended for <8yo • Rifampin – Not as a single agent • Linezolid – Expensive, Potential for resistance *More data needed to establish effectiveness!

47. D-zone test for Inducible Clindamycin Resistance E CC • Perform on erythromycin-resistant, clindamycin-susceptible S. aureus isolates • Clinical implications unclear, but treatment failures have occurred • Does not require pre-treatment or co-treatment with erythromycin in vivo

48. Clinical Considerations - Management Antimicrobial Selection (SSTIs) • Not optimal for MRSA (High prevalence of resistance or potential for rapid development of resistance): • Macrolides • Fluoroquinolones

49. Management of Severe / Invasive Infections • Vancomycin remains a 1st-line therapy for severe infections possibly caused by MRSA • Other IV agents may be appropriate--Consult an infectious disease specialist. • Final therapy decisions should be based on results of culture and susceptibility testing • Severe community-acquired pneumonia: Vancomycin or linezolid if MRSA is a consideration* *IDSA/ATS Guidelines for treatment of CAP in adults: Mandell et al. CID 2007;44:S27-72

50. Management of Skin Infections in the Era of CA-MRSA • I&D should be routine for purulent skin lesions • Obtain material for culture • Empiric antimicrobial therapy may be needed • Alternative agents have +’s and –’s: More data needed to identify optimal strategies • Use local susceptibility data for treatment