Antibiotic Therapy – Kara Birrer, PharmD
Objectives
• Introduction to basic antimicrobial principals
– Pharmacokinetics
– Pharmacodynamics
Practical Antimicrobial
Therapy
py
• Provide an overview of some of the most
common antimicrobial drug classes
Kara L. Birrer, PharmD
Clinical Pharmacist
Trauma/General Surgery
–
–
–
–
ß-lactam antibiotics
Aminoglycosides
Fluoroquinolones
A few others…
2
Background
PD Principals
120
– Time
Time--dependant killing
– Concentration
Concentration--dependant killing
• Pharmacokinetics (PK)
Peak & Trough serum concentrations
Half-life (T ½ )
HalfSource of metabolism
Source of excretion (kidney, GI, etc)
80
60
40
20
MIC
Time Above MIC Killing
100
0
80
60
40
20
MIC
0
0
4
8
12
16
20
24
0
1
Time (Hours)
• Pharmcodynamics (PD) – relationship between PK &
minimum inhibitory concentration (MIC)
2
3
4
5
6
T ime (hours)
25
Concentration (mcg/mL)
–
–
–
–
120
AUC: MIC Killing
100
Concentration (mcg/mL)
Area Under the Curve (AUC)
• Basic mechanism of action:
Peak : MIC Killing
20
15
10
MIC
5
0
0
3
PD Goals
Parameter
Time above MIC
Goal
12
16
20
24
Time (hours)
4
• 73yom s/p AAA repair & then LL-carotid
endarterectomy
• Pseuodomonas pneumonia:
Antimicrobial
Drug Classes
• All ßß-lactams
• Macrolides
• Linezolid
Peak Conc : MIC
ratio
≥ 10:1
Aminoglycosides vs.
Gram(--) organisms
Gram(
Area under the
Curve (AUC) : MIC
ratio
• ≥ 3030-50:1
• Fluoroquinolones
vs. Gram(+) orgs
• Fluoroquinolones
vs. Gram(Gram(-) orgs
– S: Zosyn (MIC=64), Tobramycin (MIC≤
(MIC≤1)
– I:
I Cefepime
C f i
(MIC=16)
(MIC 16)
• Current Antibiotics:
– Cefepime 1g IV q6h
– Tobramycin 540mg IV q48 (7mg/kg)
• Is this adequate therapy?
5
01/14/2009
8
Patient Case: JR
>50
>50--60% of the
dosing interval
• ≥ 125:1
4
6
1
Antibiotic Therapy – Kara Birrer, PharmD
JR
Concentrration (mcg/mL)
Pharmacodynamic Modeling
225
200
175
150
125
100
75
50
25
0
The Drugs
0
1
2
3
4
5
6
Time (hours)
Cefepime 1g IV q6
Cefepime 2g IV q6
Zosyn 4.5g IV q6
Zosyn MIC=64
Cefepime MIC=16
PLAN:: Increase Cefepime to 2g IV q6
PLAN
7
Mechanisms of Action
Mechanism of Action
Mechanisms of Action
Antibacterial Family
Inhibition of Cell Wall Synthesis
• ß-lactams
• Vancomyicn
Inhibition of protein synthesis
• Aminoglycosides
• Linezolid
• Tetracyclines
Inhibition of DNA synthesis
• Fluroquinolones
Inhibition of folic acid synthesis
• Trimethoprim/
Sulfamethoxazole (Bactrim)
Inhibition of RNA synthesis
• Rifampin
Disruption of cell membrane
integrity
• Daptomycin
• Polymyxin B, E (Colistin)
Other
• Metronidazole
• Nitrofurantoin
DNA Synthesis Inhibitor:
Fluoroquinolones
Cell Wall Synthesis:
Penicillins
Carbapenems
Cephalosporins
Monobactam
Vancomycin
DNA
RNA Synthesis Inhibitor:
Rifampin
mRNA
50 50 50
30 30 30
Protein Synthesis:
(30S & 50S Inhibitor)
Amikacin
Gentamicin
Tobramycin
Protein Synthesis:
(30S Inhibitor)
Tetracycline
10
Tigecycline
PABA
9
Protein Synthesis:
(50S Inhibitor)
Erythromycin
Clindamycin
Ribosomes
Folic Acid
Metabolism Inhibitor:
Trimethoprim
Sulfonamides
Cell Membrane
Inhibitor:
Polymyxins (Colistin)
Daptomycin
PCN Gram(Gram(-)
Spectrum of Activity
Penicillins
• Bactericidal cellcell-wall synthesis inhibitors
• Gram(+) activity maintained across spectrum
• Gram(
Gram(--) activity dependent on ability to cross
porin channels
• ß-lactamase inhibitor combinations:
Amino
Side Chain
Penicillin
Carboxy
Side Chain
Ampicilin
Ureido
Side Chain
Ticarcillin
Piperacillin
N. meningitidis
E. coli
Proteus spp.
H. influenzae
– MethicillinMethicillin-Sensitive S. aureus (MSSA) coverage
– Enhanced anaerobic activity
Klebsiella spp.
Pseudomonas spp.
http://www.pastorschwarz.cz/www/web/knihovna/internet/Penicillium%20notatum.gif
01/14/2009
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12
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Antibiotic Therapy – Kara Birrer, PharmD
Extended-Spectrum
ExtendedPenicillins
Penicillins
• Major Adverse Events:
• Piperacillin/Tazobactam (Zosyn®)
– Anaphylaxis
– Rash and/or hives
– Seizures
– Sodium content Î 1.85 mEq per gram
– Dosing:
• Serious Infection/Pneumonia: 4.5g IV q6
• Other Infections: 3.375g IV q6
• Anti
Anti--Staphylococcus aureus Penicillins
• Ticarcillin/Clavulanic Acid (Timentin®)
– Resistant to ß-lactamase
– NO Gram(Gram(-) activity
– ORMC Formulary: Nafcillin 2g IV q4 (no renal
adjustment)
– Sodium content Î 5.2 mEq per gram
– 2nd Line agent for Stentrophomonas maltophilia
13
14
Cephalosporin
Spectrum of Activity
Cephalosporins
• Bactericidal cellcell-wall synthesis inhibitors
• DO NOT treat Enterococcus spp.
• Gram(+) activity generally decreases with
each generation
• Gram(
Gram(--) activity increases with generation
• Weak anaerobic activity with 2nd generation
Gram(--) Coverage
Gram(
Gram(+) Coverage
1st
2nd
3rd
4th
15
Cephalosporins
16
Cephalosporins
• 1st Generation (EX: Cefazolin)
• 3rd Generation (EX: Ceftriaxone, Ceftazidime)
– Excellent MSSA activity
– Some Gram(
Gram(--) activity – E. coli, Klebsiella spp.
– Major role in surgical prophylaxis
• 2nd Generation (EX: Cefotetan, Cefoxitin)
– Good Gram(
Gram(--), moderate Gram(+) & anaerobic
coverage
– Primarily used for abdominal surgery prophylaxis
– 1st ß-lactams with Pseudomonas coverage
(Ceftazidime)
– Ceftazidime selects out multimulti-drug resistant
organisms
i
(MDR G
Gram((-),
Gram() VRE
VRE, C.
C diffi
difficile
difficile,
il , MRSA)
– Ceftriaxone –
• Excellent CSF penetration
• Excellent Streptococcus pneumoniae drug
• 4th Generation (EX: Cefepime)
– Excellent MSSA and Pseudomonas spp coverage
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3
Antibiotic Therapy – Kara Birrer, PharmD
Cephalosporins
Carbapenems
• Major Adverse Events
•
•
•
•
– Rash
– Anaphylaxis
– Seizures
• Cross
Cross--Sensitivity with Penicillins
Bactericidal cell
cell--wall synthesis inhibitors
Broadest--spectrum antimicrobials available
Broadest
Stable against most ß-lactamases
Some intrinsic Resistance:
–
–
–
–
–
– 1-10%
– Concern if patient has history of anaphylaxis
Enterococcus faecium
MRSA
Stenotrophomonas maltophilia
Burkholderia spp.
PCN--resistant S. pneumoniae
PCN
19
20
Carbapenems
Monobactam
• A.K.A.: Aztreonam (Azactam®)
• Bactericidal cell wall synthesis inhibitor
• Pure Gram(
Gram(--) coverage –
• 4 Drugs:
–
–
–
–
Imipenem/Cilastatin (Primaxin®)
Meropenem (Merrem®)
Ertapenem (Invanz®)
®)
Doripenem
p
(Doribax
(
– including Pseudomonas
• No crosscross-sensitivity with penicillins /
cephalosporins
• Major Adverse Events:
• Incomplete class crosscross-resistance
• Major Adverse Events:
– Seizures (Imi >> Mero >> Dori)
– Rash
– Anaphylaxis
– Rash
– GI upset
– Injection
Injection--site thrombophlebitis
• Cross
Cross--Sensitivity with Penicillins < 1%
21
22
Fluoroquinolones
Fluoroquinolones
• DNA synthesis inhibitors:
Area U
Under the Curve (AUC)
120
– DNA
DNA--gyrase inhibitor in Gram(
Gram(--) bacteria
– Topoisomerase IV inhibitor in Gram(+) bacteria
• Concentration dependant
p
killers
– Gram(
Gram(--) AUC:MIC Goal ≥ 125:1
– Gram(+) AUC:MIC Goal ≥ 10:1
Cipro 400mg IV – AUC~25
AUC: MIC Killing
100
Pseudomonas MIC ≤0.25
80
60
Urine AUC:MIC = 100:1
40
20
MIC
0
0
4
8
12
16
20
24
Sputum AUC:MIC = 10:1
(only ~10% penetration)
Time (Hours)
• Anti
Anti--Pseudomonal Agents:
– Ciprofloxacin
– Levofloxacin (non(non-formulary)
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4
Antibiotic Therapy – Kara Birrer, PharmD
Fluoroquinolones
Aminoglycosides
• Gram(+) Coverage:
• Inhibit bacterial protein synthesis at 30S &
50S ribosomal subunits
• Concentration
Concentration--dependant killers
– Class has POOR Staphylococcus aureus drugs
– Select out MRSA
– Newer agents excellent Strep. pneumoniae
coverage
– Goal Peak : MIC = 10 : 1
– Post
Post--antibiotic effect
• Major Adverse Events:
– QT Prolongation
Moxifloxacin >>> levofloxacin >>> ciprofloxacin
– C. difficile colitis
Concentration (mcg/mL)
25
• Drug Interactions: phenytoin, warfarin
Peak : MIC Killing
20
15
10
MIC
5
0
0
4
25
Aminoglycosides
8
12
16
20
24
Time (hours)
26
Aminoglycosides
• Place in Therapy:
• Gentamicin/Tobramycin
– Treatment of Gram(
Gram(--) Infections
– Gentamicin for Gram(+) synergy in combination
with a ß-lactam or vancomycin
– Gram(Gram(-) non
non--Burn: 7mg/kg IV q24
– Gram(
Gram(--) Burn: 2.52.5-3mg/kg IV q8q8-12h
– Gentamicin Gram(+) Synergy: 1mg/kg IV q8
• Major Adverse Events:
• Amikacin
– Nephrotoxicity (high trough)
– Ototoxicity (prolonged duration of therapy)
– Gram(Gram(-) non
non--Burn: 1515-20mg IV Q24
– Gram(
Gram(--) Burn: 7.5 mg/kg IV Q8
• Drug Interactions:
– Neuromuscular blockers
Dose Calculator: www.surgicalcriticalcare.net
27
Aminoglycosides
28
Aminoglycosides
• Colistin (Polymyxin E)
Polymyxin B & Colistin
• Major Adverse Events:
– Reserved for multimulti-drug resistant Gram(
Gram(--) orgs
– Nebulized: 150mg inhaled q12h
q8-12
– IV ((VERY
VERY nephrotoxic): 2.5 mg/kg IV q8-
– Nephrotoxicity
– Neurotoxicity
y
• Polymyxin B
• Drug Interactions:
– Also reserved for multimulti-drug resistant orgs
– IV: 15,00015,000-25,000 units/kg/day divided q12
– Neuromuscular blockers
• No way to monitor levels for IV polymyxins
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5
Antibiotic Therapy – Kara Birrer, PharmD
Vancomycin
Vancomycin
• Inhibits bacterial cell wall synthesis
• Time
Time--dependant killer (time above MIC)
• Dosing:
– IV: 20mg/kg IV x1, then 15mg/kg IV q8
q8--12h
– PO: 125125-250mg PO q6h
– Some concentrationconcentration-dependant characteristics
• Major
j Adverse Events:
• Uses:
– Red Man Syndrome – slow down infusion
– Not nephrotoxic – but accumulates
– IV: treatment of Gram(+) infections
– PO: treatment of C. difficile colitis
31
Linezolid (Zyvox®)
32
Linezolid (Zyvox®)
• Oxazolidindione – inhibits bacterial protein
synthesis
• Major Adverse Events
– Thrombocytopenia/Pancytopenia
– Blurred vision
– Serotonin Syndrome
– Bacteriostatic: Enterococcus, Staphylococcus
– Bacteriacidal: Streptococcus
• DOC: VRE
• Large volume of distribution
• Dosing: 600mg IV/PO q12
• Drug Interactions
– Selective Serotonin Reuptake Inhibitors (SSRIs)
33
Synercid®
34
Synercid®
• Quinupristin/Dalfopristin – inhibits bacterial
protein synthesis
• Major organisms:
• Major Adverse Events
– Hyperbilirubinemia
– Infusion site reaction
– Infusion
Infusion--related arthralgias/myalgias
– VRE
– MSSA & MRSA
– Streptococcus pyogenes
• Drug Interactions
– No significant
• Dose:
– 7.5mg/kg IV q8q8-12 (no renal adjustment)
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6
Antibiotic Therapy – Kara Birrer, PharmD
Daptomycin
Daptomycin
• Cell membrane disruption leading to
inhibition of DNA/RNA/protein synthesis
• Bacteremia, Endocarditis, Skin/Soft Tissue
infections
• Does NOT treat pneumonia!
• Spectrum of Activity:
• Dose:
– 4-6mg/kg IV q24
– Adjust for renal dysfunction
• Major
j Adverse Events:
– Anemia
– Constipation/N/V
– Injection
Injection--site reactions
– MRSA
– VRE
37
38
Bactrim®
Bactrim®
• Sulfamethoxazole/Trimethoprim
• Interferes with bacterial folic acid synthesis
• Drug of Choice:
• Dosing:
– Based on Trimethoprim (TMP) component
– UTI: Bactrim® DS (800/160) 1 po bid
– Severe Infections
(MRSA/PCP/Stenotrophomonas
(MRSA/PCP/
Stenotrophomonas):
):
5 mg TMP/kg IV/PO/PT q6q6-8h
– Adjust for renal dysfunction
– Stenotrophomonas maltophilia
– Pneumocystis carinii pneumonia (PCP)
– Alternative for MRSA
39
40
Bactrim®
Tetracyclines
• Major Adverse Events:
–
–
–
–
–
• Inhibit bacterial protein synthesis
• Bacteriostatic
• Spectrum of Activity
Stevens-Johnson Syndrome
StevensRash
Hyponatremia (IV)
Hyperkalemia
GI upset (large PO doses)
–
–
–
–
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Gram (+) including MRSA
Gram ((-)
Atypicals (Mycoplasma,
(Mycoplasma, Chlamydia, Rickettsia)
Alternative for H. pylori
42
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Antibiotic Therapy – Kara Birrer, PharmD
Tetracyclines
Tigecycline
• 3 Agents:
• A glycylcline – protein synthesis inhibitor
• Spectrum of Activity:
– Tetracycline 250250-500mg po q6
– Doxycycline 100mg po/IV q12
– Minocycline
– Gram (+) including MRSA and VRE
– Gram ((--) including
g E. coli & Klebsiella
– Anaerobes
• Major Adverse Events:
– Photosensitivity
– Teeth/enamal discoloration in children
– Hepatotoxicity
• Does not cover:
– Pseudomonas spp.
– Proteus spp.
43
44
Tigecycline
Macrolides
• Inhibit RNARNA-dependant protein synthesis
• Spectrum of Activity
• Dose: 100mg IV x1, 50mg IV q12
• Major Adverse Events:
– Gram (+) – including MSSA
– Gram ((-) (Haemophilus spp)
– Atypicals
At i l (Chlamydia
(Chl
di spp, M
Mycoplasma,
l
Legionella)
– N/V
– Abdominal p
pain
– Super infections (P. aeruginosa, Proteus)
• Several Agents:
– Erythromycin
– Clarithromycin
– Azithromycin
45
46
Macrolides
Clindamycin
• Erythromycin
• Inhibits bacterial protein synthesis
• Spectrum of Activity
– Used for ADE – GI motility
– Used for surgical prophylaxis with neomycin
– Gram (+) – MSSA, Streptococcus, some MRSA
– Anaerobes
• Azithromycin
y
– used for CAP
• Clarithromycin – used for CAP, H. pylori
• Major Adverse Events:
• Excellent alternative for PenicillinPenicillin-allergic
patients
• Major Adverse Events:
– Abdominal pain/cramping (E >> C >> A)
– N/V/Diarrhea
– Headache
– Diarrhea
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8
Antibiotic Therapy – Kara Birrer, PharmD
Metronidazole
Antimicrobial Resistance
• Unsuppressed production of β-lactamase
• Interacts with DNA causing strand breakage
and ultimately inhibits protein synthesis
• Spectrum of Activity: Anaerobes
– AMPC
– ESBL
• Alteration in bacterial cell membrane
– C. difficile diarrhea
– Vancomycin
Vancomycin--resistant Enterococcus
• Major Adverse Events:
– N/V
– Diarrhea
• Pseudomonas spp.
– Aminoglycoside
Aminoglycoside--altering enzymes
– Efflux pump – pump out drug
– Alter porin channel – drug can’t get in
• Dosing:
– C. difficile: 500mg PO/PT q6
49
50
Take Home Points
• Penicillins – increase Gram(Gram(-) and maintain
Gram(+)
• Addition of β-lactamase inhibitor = anaerobic
coverage
g
• Cephalosporins – avoid 3rd generation
• Carbapenems – reserve for last resort
• Vancomycin – aim high trough
• Pharmacodynamic
Pharmacodynamic--based drug dosing
51
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9