Docstoc

Case History Question

Document Sample
Case History Question Powered By Docstoc
					 Antimicrobial Therapy

      David H. Spach, MD
      Professor of Medicine
 Division of Infectious Diseases
University of Washington, Seattle



                                    DHS/PP
        Structure of Gram-Positive Bacteria

Penicillin Binding Proteins




                              DNA

Cell Membrane                           Cell Wall

                                                    DHS/PP
              Structure of Gram-Negative Bacteria



Outer Membrane

Cell Wall

Periplasmic Space


 Cell Membrane
                                  DNA



   Porin Channel



                                                    DHS/PP
               Antimicrobials: Site of Action

 Cell Wall
  - Beta-Lactams
  - Glycopeptides                     Cytoplasm
                                      23 S Ribosome
                                      - Linezolid
Cell Membrane
- Daptomycin                          30S Ribosome
                                      - Aminoglycosides
                                      - Tetracyclines
DNA Inhibitor                         50S Ribosome
- Fluoroquinolone                     - Macrolides/Ketolides
- TMP-SMX                             - Clindamycin
- Metronidazole                       - Chloramphenicol
                                      - Quinupristin-Dalfopristin




                                                             DHS/PP
                     Antimicrobial Spectrum

Resistant Gram-Positives                                       Resistant Gram-Negatives
                           Gram-Positives     Gram-Negatives




                                       Anaerobes




                                                                       DHS/PP
                   Antimicrobial Spectrum

                    Gram-Positives        Gram-Negatives



Highly-Resistant                                           Highly-Resistant
 Gram-Positives                                              Gram-Negatives




                                 Anaerobes




                           Highly Resistant Anaerobes

                                                                        DHS/PP
Beta-Lactams




               DHS/PP
Beta-Lactam Antibiotics

     Penicillins
     Cephalosporins
     Monobactam
     Carbapenems

                          DHS/PP
           Antimicrobials: Question


•   What is the mechanism of action for beta-lactam
    antimicrobials?




                                                 DHS/PP
         Beta-Lactams: Mechanism of Action
   Penicillin Binding Proteins
                                       Beta-Lactam




                                 DNA



Cell Membrane                                Cell Wall

                                                    DHS/PP
           Beta-Lactam: Mechanism of Action

Cell Wall Synthesis                      Beta-Lactam




                                DNA


Cell Membrane
                                              Cell Wall
  Penicillin Binding Proteins
                                                     DHS/PP
              Antimicrobials: Question
•   Which of the following beta-lactam animicrobial is
    typically active against Enterococcus faecalis (assume
    this is not a resistant enterococcus):

    a.   Cefotetan
    b.   Aztreonam
    c.   Piperacillin
    e.   Nafcillin



                                                        DHS/PP
             Piperacillin-Tazobactam (Zosyn)


Highly Resistant                                      Highly Resistant
Gram-Positives     Gram-Positives    Gram-Negatives   Gram-Negatives




                              Anaerobes




                                                            DHS/PP
      Antimicrobials: Question


•   Which of the cephalosporins typically have
    anti-pseudomonal activity?




                                                 DHS/PP
             Antimicrobials: Question
•   Which of the 3rd Generation Cephalosporins would be
    appropriate for treatment of Pseudomonas meningitis:

    a.   Ceftriaxone
    b.   Ceftazidime
    c.   Cefoperazone
    d.   Cefotaxime



                                                     DHS/PP
                      Ceftriaxone (Rocephin)
                   3rd-Generation Cephalosporin


Highly Resistant                                          Highly Resistant
Gram-Positives       Gram-Positives      Gram-Negatives   Gram-Negatives




  Enterococcus sp.




                                  Anaerobes




                                                                        DHS/PP
     Ceftazidime (Fortaz, Tazicef, Tazidime)
          3rd-Generation Cephalosporin

Highly Resistant                                        Highly Resistant
Gram-Positives     Gram-Positives      Gram-Negatives   Gram-Negatives




                                Anaerobes




                                                              DHS/PP
                      Cefepime (Maxepime)
                   4th-Generation Cephalosporin


Highly Resistant                                          Highly Resistant
Gram-Positives       Gram-Positives      Gram-Negatives   Gram-Negatives




Enterococcus sp.




                                  Anaerobes




                                                                DHS/PP
            Antimicrobials: Question
•   Which of the following organisms do you think cefixime
    (Suprax) would NOT routinely have good activity
    against?

    a. Staphyloccus aureus (MSSA or MRSA)
    b. Streptococcus pneumoniae
    c. Haemophilus influenzae
    d. Moraxella (Branhamella) catarrhalis



                                                        DHS/PP
                   Cefixime (Suprax)
         2nd/3rd Generation ORAL Cephalosporin


    Highly Resistant                                         Highly Resistant
    Gram-Positives                          Gram-Negatives   Gram-Negatives
                        Gram-Positives




Staphylococcus aureus

        Enterococcus sp.

                                     Anaerobes




                                                                           DHS/PP
   Monobactams

 Aztreonam (Azactam)



                        DHS/PP
                          Aztreonam

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives




                               Anaerobes




                                                             DHS/PP
           Carbapenems

 Imipenem + Cilastatin (Primaxin)
 Meropenem (Merrem)
 Ertapenem (Invanz)
 Doripenem (Doribax)


                                     DHS/PP
                 Antimicrobials: Question

•   What is the major difference between Imipenem and
    Ertapenem?

    1.   Imipenem has significantly better gram-negative activity
    2.   Imipenem has much greater anaerobic activity
    3.   Ertapenem has much better gram-positive activity
    4.   Ertapenem has better activity against Acinetobacter sp.



                                                            DHS/PP
Imipenem (Primaxin) & Meropenem (Merrem) &
            Doripenem (Doribax)

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives




                               Anaerobes




                                                              DHS/PP
                   Ertapenem (Invanz)

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives




                               Anaerobes




                                                             DHS/PP
              Antimicrobials: Question
•   A 63-year-old woman with CLL is admitted to the
    hospital with fever. She is started on Ceftriaxone, but
    2 days later has no improvement. LP now shows
    2,600 WBCs (65% polys) and gram-positive rods.
    You recommend:

    1.   Add Ampicillin
    2.   Change to Imipenem
    3.   Add Clindamycin
    4.   Change to Cefazolin

                                                        DHS/PP
Vancomycin




             DHS/PP
          Antimicrobials: Question


•   What is vancomycin’s mechanism of action?




                                                DHS/PP
          Vancomycin: Mechanism of Action

                                        Vancomycin
Cell Wall Synthesis




                        DNA




                                              DHS/PP
      Vancomycin: Mechanism of Action
                                                  Ligase


                                          D-Ala            D-Ala


Tripeptide Intermediate

                                      D-Ala        D-Ala




       Cell Wall Pentapeptide Precursor

                            D-Ala     D-Ala                Vancomycin



                                                                        DHS/PP
                         Vancomycin

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives

VISA

VRE




                               Anaerobes




                                                             DHS/PP
                      Antimicrobial: Question

   For ICU patients with nosocomial pneumonia, what Vancomycin trough level
    should you aim for (based on IDSA/ATS Guidelines)?

    1. Trough < 5
    2. Trough 5-10
    3. Trough 10-15
    4. Trough 15-20




                                                                       DHS/PP
Daptomycin (Cubicin)




                       DHS/PP
                   Antimicrobial: Question

   Which of the following is TRUE regarding the antimicrobial Daptomcyin
    (Cubicin)?

    1. Daptomycin is a bacterial cell wall inhibitor
    2. Based on recent data, daptomycin is the drug of choice for MRSA pneumonia
    3. Daptomycin’s mechanism of action takes place at the bacterial cell membrane
    4. Daptomycin causes renal failure in 10-20% of patients




                                                                            DHS/PP
        Daptomycin (Cubicin): Mechanism of Action
   1. Ca2+-Dependent Binding to Cell Membrane              Daptomycin
   2. Membrane Depolarization and K+ Efflux

                                                       1
                                                Ca2+              K+

                                                              2

                                                  K+



                                       DNA
Altered Penicillin
Binding Protein

    Cell Membrane
                                                                        DHS/PP
                         Daptomycin

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives




                               Anaerobes




                                                             DHS/PP
                                 Daptomycin
   Class: Lipopeptide
   Mechanism: Disrupts plasma membrane function (depolarization of membrane)
   Dose: 4 or 6 mg/kg IV q24 hours
   Activity: MSSA, MRSA, VRSA, coag -Staph, S. pyogenes, S. pneumoniae, E. faecium
    and E. faecalis (including VRE)
 Clinical: VRE, Complicated skin and soft tissue infections; MSSA & MRSA bacteremia
    and right-sided endocarditis; not for use for pneumonia
 Adverse Effects: well tolerated
 Renal Insufficiency: Reduce dose to 4 mg/kg q48 hours if Cr clearance <30 mL/min


                                                                             DHS/PP
           Daptomycin (Cubicin) vs Comparator for
          MSSA & MRSA Bacteremia & Endocarditis

             Study Design                        Success 42 Days Post Treatment
 Methods                                                                                          Daptomycin
- Adults with known/suspected bacteremia                                60
                                                                                                   Standard Therapy
  or endocarditis (n = 236)
                                                                        50                         49
- Randomized, open-label                                                     44 42            45           44
 Regimens: MSSA




                                                     Success Rate (%)
                                                                        40
- Daptomycin: 6 mg/kg IV qd                                                                                     32
- Nafcillin + Gentamicin (first 4 days or                               30
  until blood cultures negative x 48h)
                                                                        20
Regimens: MRSA
- Daptomycin: 6 mg/kg IV qd                                             10
- Vancomycin + Gentamicin (first 4 days
                                                                        0
  or until blood cultures negative x 48h)                                    Total            MSSA         MRSA

                                                                                     DHS/PP
Source: Fowler VG et al. N Engl J Med 2006;355:653-65.
Linezolid (Zyvox)




                    DHS/RTI/PP
                  Antimicrobial: Question

   Which of the following is TRUE regarding the antimicrobial Linezolid
    (Zyvox)?

    1. The oral bioavailability of linezolid is excellent
    2. About 30% of MRSA now resistant to linezolid
    3. Neutropenia is the most common lab abnormality
    4. It works by disrupting bacterial cell wall synthesis




                                                                 DHS/PP
                  Linezolid: Mechanism of Action
                50 S Ribosome
                                                   Linezolid
30 S Ribosome
                                      50
                       fMet-tRNA      S


                        30
                        S



                 70 S Initiation Complex


                                           DNA




                                                          DHS/PP
                     Linezolid (Zyvox)

Highly Resistant                                       Highly Resistant
Gram-Positives     Gram-Positives     Gram-Negatives   Gram-Negatives




                               Anaerobes




                                                             DHS/PP
  Nosocomial Pneumonia: Vancomycin vs. Linezolid

            Study Design                                                     Clinical Cure
                                                                                                 Vancomycin
 Methods                                                              100                       Linezolid
- Retrospective analysis of 2 prospective,
  randomized, case-control studies                                      80
- N =1019 Adults




                                                     Clinical Cure %
                                                                               P = 0.182       P = 0.009
- Nosocomial pneumonia                                                                                59
                                                                        60                52
- Suspected gram-positive pneumonia
                                                                               43
- 339 with documented S. aureus                                         40                     36
- 160 with documented MRSA
 Regimens                                                              20
- Vancomycin + Aztreonam
- Linezolid + Aztreonam                                                  0
                                                                              S. aureus        MRSA


From: Wunderink RG, et al. Chest 2003;124:1789-97.                                                    DHS/PP
                 Antimicrobial: Question

   A 62-year-old woman is started on linezolid for MRSA vertebral
    osteomyelitis. Her medications include coumadin, atorvastatin, and
    citalopram.
   Two days later the patient presents with confusion and fever.
    Exam shows a diaphoretic and confused patient with
    T = 38.8°C, P = 126, BP 160/110, dilated pupils, hyperactive
    bowel tones, and hyperreflexia in the lower extremities.
   What is the likely cause of this patient’s symptoms?




                                                               DHS/PP
        Linezolid (Zyvox) & Serotonin Syndrome

     29 cases in postmarketing data
     Age Range: 17-83
     Most common class of drug was SSRI
     3/29 resulted in death; 7/29 resulted in hospitalization
     No clear recommendations for prevention



                                                                 DHS/PP
From: Lawrence KR, et al. Clin Infect Dis 2006;42:1578-83.
Tigecycline (Tygacil)
                  Antimicrobials: Question
•   Which organism is Tigecycline typically NOT effective against?

    1.   Pseudomonas aeruginosa
    2.   Acinetobacter sp.
    3.   Methicillin-resistant Staphylococcus aureus
    4.   E. coli




                                                                     DHS/PP
Tigecycline: Mechanism of Action

                                          Tigecycline




                                DNA


    30S Ribosomal Subunit Binding Sites



                                                   DHS/PP
                   Tigecycline (Tygacil)


Highly Resistant                                         Highly Resistant
Gram-Positives      Gram-Positives      Gram-Negatives   Gram-Negatives




                                 Anaerobes




                                                            DHS/PP
                           Tigecycline (Tygacil)

   Class: Glycylcycline
   Mechanism: Inhibits protein synthesis (binds to 30S ribosome)
   Dose: 100 mg IV x 1, then 50 mg IV q12 hours
   Activity:
    - Broad gram-positive: MSSA, MRSA, VRE, DRSP
    - Gram-negative: Enterobacteriaceae, Acinetobacter sp.
    - Not ideal for Pseudomonas sp. or Proteus sp.
   Clinical:
    - Complicated skin and soft tissue infections
    - Complicated intra-abdominal infections
   Adverse Effects: significant nausea and vomiting


                                                                    DHS/PP
            Complicated Intra-Abdominal Infections
                          Tigecycline versus Imipenem

             Study Design                                               Clinical Cure
                                                                                             Tigecycline
 Methods                                                         100                        Imipenem
- Pooled analysis of 2 phase 3 trials                                   86   86
                                                                                            80    82
- Double-blind trial                                               80
- N = 1642 Adults




                                                     Patients %
- Complicated intra-Abdominal Infections                           60

 Regimens                                                         40
- Tigecycline 100 mg x1, then 50 mg q12h
- Imipenem: 500 mg q6h
                                                                   20

                                                                    0
                                                                        CE                  ITT
                                                                             Test of Cure

From: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7.                                              DHS/PP
Fluoroquinolones




                   DHS/PP
         Antimicrobials: Question

•   The new fluoroquinolone Moxifloxacin typically
    has activity against all of the following except:

    1. Haemophilus influenzae
    2. Methicillin-resistant Staphylococcus aureus
    3. Legionella pneumoniae
    4. Streptococcus pneumoniae


                                                    DHS/PP
        Fluoroquinolone: Mechanism of Action

                                          Fluoroquinolone



                   DNA Topoisomerase IV
                DNA Gyrase




                    DNA


Cell Membrane                                  Cell Wall

                                                           DHS/PP
  Fluoroquinolones

 Levofloxacin (Levaquin)
 Moxifloxacin (Avelox)
 Gemifloxacin (Factive)

 Ciprofloxacin (Cipro)
 Norfloxacin (Noroxin)
 Ofloxacin (Floxin)
                            DHS/PP
Questions?




             DHS/PP

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:2
posted:9/22/2012
language:English
pages:57