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
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Patient Case: JR
>50 >50--60% of the dosing interval
• ≥ 125:1
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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
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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
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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
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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
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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
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Cephalosporins
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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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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
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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
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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) 23
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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
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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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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
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Linezolid (Zyvox®)
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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)
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Synercid®
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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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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
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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
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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
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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.
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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
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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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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
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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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