Antibiotic Therapy Kara Birrer, PharmD

Antibiotic Therapy – Kara Birrer, PharmD Objectives • Introduction to basic antimicrobial principals – Pharmacokinetics – Pharmacodynamics Practical...
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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

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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

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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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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