Antimicrobial Therapy

Structure of Gram-Positive Bacteria

Penicillin Binding
Proteins

DNA

Cell Cell Wall

Membrane
 Structure of Gram-negative Bacteria

Outer
Membrane
Cell
Wall
Periplasmic
Space
Cell Membrane
DNA

Porin Channel
Antimicrobials: Site of Action
Cell Wall
- Beta-Lactams
- Glycopeptides
Cytoplasm
23 S Ribosome
- Linezolid
Cell
30S Ribosome
Membrane - Aminoglycosides
- Daptomycin - Tetracyclines
DNA 50S Ribosome
Inhibitor - Macrolides/Ketolides
- Clindamycin
- Fluoroquinolone
- Chloramphenicol
- TMP-SMX
- Quinupristin-Dalfopristin
- Metronidazole
 Antimicrobial Spectrum

Resistant Gram- Resistant Gram-

Gram-Positives Gram-Negatives Negatives
Positives

Anaerobes
 Antimicrobial Spectrum

Gram-Positives Gram-Negatives

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

Anaerobes

Highly Resistant
Anaerobes
DHS/PP
 Classification of Antibiotics

 Bacteriostatic  Bactericidal
Bacteriostatic vs Bactericidal
 Bacteriostatic allows for natural immunity to deal
with the microbe
• Antibodies, Phagocytosis etc

 Bactericidial may lead to release of toxins and

microbial contents leading to subsequent illness and
inflammatory responses.
Classification of Antibiotics

 Chemical Structure
 Spectrum of Activity
 Mechanism of Action
Mechanism of Action
Inhibitors of Cell Wall Synthesis
 Time-Dependent,
Time-Dependent (with minimal Concentration-Dependent Concentration-Enhanced (with
or no PAE) (with PAE) PAE)
Beta-lactams Aminoglycosides Clarithromycin

Vancomycin Daptomycin Clindamycin

Fluoroquinolones Erythromycin

Metronidazole Linezolid

Azithromycin Streptogramins

Ketolides Tetracyclines

Tigecycline
Beta-Lactam Antibiotics
 Penicillins
 Cephalosporins
 Monobactam
 Carbapenems
Antimicrobials: Question

• What is the mechanism of action for beta-lactam

antimicrobials?
Beta-Lactams: Mechanism of Action
Penicillin Binding
Proteins Beta-Lactam

DN
A

Cell Cell Wall

Membrane
Beta-Lactams: Mechanism of Action
Cell Wall Synthesis Beta-Lactam

DN
Cell A
Membrane
Penicillin Binding Cell Wall
Proteins
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/P
Piperacillin-Tazobactam

Highly Resistant Highly Resistant

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

Anaerobes
Antimicrobials: Question

• Which of the cephalosporins typically

have anti-pseudomonal activity?
Antimicrobials: Question

• Which of the 3rd Generation Cephalosporins would

be appropriate for treatment of Pseudomonas
meningitis:

a. Ceftriaxone
b. Ceftazidime
c. Cefoperazone
d. Cefotaxime
Ceftriaxone - 3rd-Generation Cephalosporin

Highly Resistant Highly Resistant

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

Enterococcus sp.

Anaerobes
Ceftazidime-3rd-Generation Cephalosporin

Highly Resistant Highly Resistant

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

Anaerobes
Cefepime -4th-Generation Cephalosporin

Highly Resistant Highly Resistant

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

Enterococcus sp.

Anaerobes
Antimicrobials: Question

• Which of the following organisms do you think

cefixime would NOT routinely have good activity
against?

a. Staphyloccus aureus (MSSA or MRSA)

b. Streptococcus pneumoniae
c. Haemophilus influenzae
d. Moraxella (Branhamella) catarrhalis
Cefixime -2nd/3rd Generation ORAL Cephalosporin

Highly Resistant Highly Resistant

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

Staphylococcus
aureus
Enterococcus sp.

Anaerobes
Monobactams:-Aztreonam

Highly Resistant Highly Resistant

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

Anaerobes
Carbapenems

 Imipenem + Cilastatin
 Meropenem
 Ertapenem
 Doripenem

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.
Imipenem, Meropenem & Doripenem

Highly Resistant Highly Resistant

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

Anaerobes
Ertapenem

Highly Resistant Highly Resistant

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

Anaerobes
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
Vancomycin
Antimicrobials: Question

• What is vancomycin’s mechanism of action?

Vancomycin: Mechanism of Action
Vancomycin
Cell Wall Synthesis

DN
A
Vancomycin: Mechanism of Action
Ligase

D-Ala D-Ala

Tripeptide Intermediate

D-Ala D-Ala

Cell Wall Pentapeptide

Precursor
D-Ala D-Ala Vancomycin
Vancomycin: Mechanism of Action
Vancomycin

Highly Resistant Highly Resistant

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

VIS
A
VR
E

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

1
Ca2+ K+

K+

DN
Altered A
Penicillin
Binding Protein
Cell Membrane
Daptomycin

Highly Resistant Highly Resistant

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

Anaerobes
Daptomycin (Cubicin)
 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
Daptomycin (Cubicin) vs Comparator for MSSA
&
MRSA Bacteremia & Endocarditis

Study Success 42 Days Post

 Methods Design Treatment
- Adults with known/suspected Daptomycin

bacteremia Standard Therapy

or endocarditis (n = 236) 60
- Randomized, open-label 50 45
49
44 42 44

Success Rate (%)

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

Regimens: MRSA 10
- Daptomycin: 6 mg/kg IV qd 0
- Vancomycin + Gentamicin (first 4 Total MSSA MRSA

days or until blood cultures negative x

48h)
Source: Fowler VG et al. N Engl J Med 2006;355:653-65.
Linezolid
Antimicrobials: Question
 Which of the following is TRUE regarding the antimicrobial
Linezolid ?

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

30
S

70 S Initiation
Complex

DN
A
Linezolid

Highly Resistant Highly Resistant

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

Anaerobes
Tigecycline
Antimicrobials: Question

• Which organism is Tigecycline typically NOT effective

against?

1. Pseudomonas aeruginosa
2. Acinetobacter sp.
3. Methicillin-resistant Staphylococcus aureus
4. E. coli
Tigecycline: Mechanism of Action
Tigecycline

DN
A
30S Ribosomal Subunit Binding
Sites
Tigecycline

Highly Resistant Highly Resistant

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

Anaerobes
 Tigecycline

 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
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
Fluoroquinolone: Mechanism of Action

Fluoroquinolone

DNA Topoisomerase
DNA Gyrase IV

DNA

Cell Cell Wall

Membrane
Fluoroquinolones

 Levofloxacin
 Moxifloxacin
 Gemifloxacin

 Ciprofloxacin
 Norfloxacin
 Ofloxacin
Questions ?