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

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mdros a k a bad bugs current concepts in treatment

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

mdros a k a bad bugs current concepts in treatment2

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

objectives
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
outline
Outline
  • Fundamental principles of ID treatment
  • Current antibiotic therapy for MDROs
    • MDR-GPO
      • MRSA
      • VRE
    • MDR-GNO
      • ESBL-Enterobacteraceae
      • CRE
id fundamental principles
ID Fundamental Principles

Infectious Disease

id fundamental principles8
ID Fundamental Principles

⬇Infectious Disease

id fundamental principles cont d
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
id fundamental principles cont d10
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
id fundamental principles cont d13
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
id fundamental principles cont d14
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
id fundamental principles cont d15
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
id fundamental principles cont d16
ID Fundamental Principles cont’d
  • Pharmacokinetics
    • “What the host does to the drug”
    • Describes the absorption, distribution, metabolism, and elimination of a drug
id fundamental principles cont d19
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
molecular mechanism of methicillin r mrsa
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)
clinical considerations evaluation
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”
slide28
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

clinical considerations evaluation29
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
management of skin infections in the era of ca mrsa
Management of Skin Infections in the Era of CA-MRSA
  • I&D should be routine for purulent skin lesions
management of skin infections in the era of ca mrsa31
Management of Skin Infections in the Era of CA-MRSA
  • I&D should be routine for purulent skin lesions
  • Obtain material for culture
management of skin infections in the era of ca mrsa32
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
management of skin infections in the era of ca mrsa33
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
vancomycin
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
vancomycin moa
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
alternative abx for invasive mrsa
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
alternative abx for invasive mrsa38
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
telavancin vibativ
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
telavancin vibativ moa
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
ceftaroline teflaro
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
ceftaroline teflaro moa
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
slide43

Structure–activity Relationships for Ceftaroline

Laudano J B J. Antimicrob. Chemother. 2011;66:iii11-iii18

management of skin infections in the era of ca mrsa44
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
clinical considerations management
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!

d zone test for inducible clindamycin resistance
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
clinical considerations management48
Clinical Considerations - Management

Antimicrobial Selection (SSTIs)

  • Not optimal for MRSA (High prevalence of resistance or potential for rapid development of resistance):
    • Macrolides
    • Fluoroquinolones
management of severe invasive infections
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

management of skin infections in the era of ca mrsa50
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
case presentation
Case Presentation
  • A physician from an Iowa community medical center calls regarding a 73-year-old female with dysuria, urinalysis with pyuria, positive leukocyte esterase and nitrite, and urine culture with > 100,000 col/ml of “VRE”
  • What is the optimal ABX?
slide55

Mechanism of action of vancomycin and mechanisms of vancomycin resistance in enterococci with vanA-associated vancomycin resistance.

Zirakzadeh A , Patel R Mayo Clin Proc. 2006;81:529-536

© 2006 Mayo Foundation for Medical Education and Research

vre rx linezolid zyvox
VRE Rx—Linezolid (Zyvox®)
  • Bacteriostatic, synthetic oxazolidinone
  • Binds to the 50s ribosome and prevents peptide bond formation
  • Cure in 81% of 500 patients with VRE infection*
  • Dose: 600mg q 12h PO or IV
  • Adverse effects (prolonged use):
    • Thrombocytopenia, anemia
    • Lactic acidosis
    • Peripheral neuropathy
    • Ocular toxicity

*Birmingham MC et al. Clin Infect Dis 2003; 36: 159.

linezolid serotonin syndrome
Linezolid—Serotonin Syndrome
  • When given with other serotonergic agents
    • Selective serotonin reuptake inhibitors
  • Inhibition of monoamine oxidase
  • Hunter Criteria (one of following):
    • Spontaneous clonus
    • Inducible clonus and agitation or diaphoresis
    • Ocular clonus and agitation or diaphoresis
    • Tremor and hypereflexia
    • Hypertonia
    • Temperature >38ºC (>100.4ºF) and ocular or inducible clonus
linezolid serotonin syndrome61
Linezolid—Serotonin Syndrome
  • Clinical diagnosis
  • No laboratory test can confirm the diagnosis
  • Manifest a wide range of clinical symptoms from mild tremor to life-threatening hyperthermia and shock
vre rx daptomycin cubicin
VRE Rx—Daptomycin (Cubicin®)
  • Bactericidal cyclic lipopeptide
  • Depolarization of bacterial cell membrane
  • FDA approved for VS E. faecalis skin/skin structure infections
  • Dose: 4mg/kg IV q day for S/SS infections and 6mg/kg IV q day for bacteremia
  • Adverse effects:
    • Myopathy—monitor serum creatine kinase (CK) and D/C if symptomatic with CK ≥5x ULN or asymptomatic with CK ≥10x ULN
    • Eosinophilic pneumonia
daptomycin moa
Daptomycin—MOA
  • Step 1: Calcium-dependent binding and insertion of the lipophilic tail into gram-positive cytoplasmic membrane
  • Step 2: Oligomerization and channel formation occurs
  • Step 3: Ion leakage and collapse of organism lead to cell death
vre rx tigecycline tygacil
VRE Rx—Tigecycline (Tygacil®)
  • Glycylcycline—binds to the ribosome and inhibits protein synthesis
  • Broad-spectrum (notPseudomonas, Proteus, Providencia, or Morganella)
  • FDA approved for cSSSI and intraabdominal infect.
  • Dose: 100mg IV once followed by 50mg IV q 12h
  • Major adverse effects:
    • Nausea and vomiting
    • Increased risk of mortality when used to Rx serious infections
tigecycline moa
Tigecycline—MOA
  • Bind to the ribosome with five times higher affinity than tetracycline
  • Binds to additional sites of the ribosome in a manner not seen before, interfering with the mechanism of ribosomal protection proteins
  • Not expelled by macrolide or tetracycline efflux pumps
case presentation66
Case Presentation
  • 50-year-old female presents with dysuria, urgency, frequency and left flank pain
  • Urinalysis shows pyuria, positive leukocyte esterase and positive nitrite
  • Urine culture grows >100,000 colonies per ml of Escherichia (E.) coli
esbl producing enterobacteriaceae
ESBL Producing Enterobacteriaceae
  • Antibiotic options—first-line agents
    • Carbapenems
      • Imipenem/Cilastatin (Primaxin®)
      • Meropenem (Merrem®)
      • Ertepenem (Invanz®)
      • Doripenem (Doribax®)
carbapenems
Carbapenems
  • MOA:
    • Inhibits bacterial cell wall synthesis by binding to several of the PBPs
    • Inhibits final transpeptidation step of peptidoglycan synthesis in bacterial cell walls
    • Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes
  • Adverse effects:
    • Rash (2-3%)
    • Diarrhea (4-7%)
    • Anaphylaxis
    • CNS effects—confusional states, seizures
esbl producing enterobacteriaceae70
ESBL Producing Enterobacteriaceae
  • Antibiotic options—alternatives
    • Tigecycline—not in UTIs
    • β-Lactam/β-Lactamase inhibitor combinations (low inoculum)
      • Amoxicillin-clavulanate (Augmentin®)
      • Piperacillin-tazobactam (Zosyn®)
    • Cephalosporins—not recommended
    • Fluoroquinolones, aminoglycosides, & TMP-SMX—use with caution for serious infections
    • Colistin
    • Fosfomycin—for simple UTI
    • Nitrofurantoin—avoid if eGFR <50 ml/minute
carbapenem resistant enterobacteriaceae
Carbapenem-Resistant Enterobacteriaceae
  • Antibiotic options
    • Tigecycline—limited experience
    • Colistin—emerging resistance
    • Rifampin—synergism
    • Fosfomycin (83-93% “S”)
    • Investigational:
      • New β-lactamase inhibitors
        • MK-7655
        • NXL104
        • 6-alkylidenepenam sulfones
      • Bis-indole compounds
colistin coly mycin m
Colistin (Coly-Mycin®M)
  • Dose: 2.5-5mg/kg/day IV or IM in 2-4 divided doses
    • In obese patients dose based on ideal weight
    • Adjust dose for serum creatinine ≤1.3
  • Adverse effects:
    • Renal toxicity (dose dependent)
    • CNS toxicity
    • Respiratory arrest—neuromuscular blockade and apnea
colistin coly mycin m moa
Colistin (Coly-Mycin®M)--MOA
  • A cationic detergent which damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death
cre emerging infectious diseases 5 3 2011
CRE—Emerging Infectious Diseases5/3/2011
  • Proposed consensus (“expert opinion”):
    • Doripenem extended-infusion therapy

+

    • Colistin (limited by major RI)

+/-

    • Rifampin (major CYP450 enzyme inducer)
    • Consider the addition of tigecycline or use it in place of the colistin if RI
    • Fosfomycin (parenteral formulation)
barriers to antimicrobial development
Barriers to Antimicrobial Development
  • Bringing a new drug to market requires more than 10 years and costs from $800 million to $1.7 billion
  • Reduced market potential
    • Infections are acute conditions
    • Development of antimicrobial-resistant bacteria
    • New agents are often reserved for niche indications
  • Regulatory uncertainty
  • Failure of research to discover new molecules
idsa the 10 x 20 initiative
IDSA—The 10 x 20 Initiative
  • The IDSA proposes the developmentof 10 new systemic antibacterial drugs by 2020
    • Discovery of new drug classes
    • New drugs from existing classes
  • The development of improved diagnostic tests specific to multi-drug-resistant infections is key to advancing antibacterial drug development
  • Motivate global political, scientific, industry, economic, intellectual property, policy, medical, and philanthropic leaders to develop creative incentives that stimulate R & D
summary
Summary
  • Antimicrobial resistance has been shaping the field of infectious since the discovery of penicillin
  • Therapeutic approaches for the MDR-GPO and MDR-GNO should be based on the fundamental principles of treating all IDs
  • There have been recent new antimicrobials to help combat MDR-GPO (MRSA, VRE)
  • The antibiotic pipeline has been dry for MDR-GNO
summary cont d
Summary cont’d
  • The 10 x 20 IDSA Initiative proposes the development of 10 new systemic antibacterial drugs by 2020
references
References
  • Liu C, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureusInfections in Adults and Children: Executive Summary. Clin Infect Dis 2011; 52: 285-292.
  • Kanj SS, Kanafani ZA. Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae, Carbapenem-Resistant Enterbacteriaceae, and Multidrug-Resistant Pseudomonas aeruginosa. Mayo ClinProc 2011; 86: 250-259.
  • UpToDate 2011.
  • Lexi-Comp Pediatric Dosage Handbook 2011.
  • The Red Book® Online 2011.
  • The Clinical and Laboratory Standards Institute 2011.
mdros a k a bad bugs current concepts of treatment
MDROs (a.k.a. Bad Bugs)—Current Concepts of Treatment

Thank you for your attention.

Questions or comments?