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 11 12 2 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 17 01/14/2009 18 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) 23 01/14/2009 24 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 29 01/14/2009 30 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) 35 01/14/2009 36 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) – – – – 41 01/14/2009 Gram (+) including MRSA Gram ((-) Atypicals (Mycoplasma, (Mycoplasma, Chlamydia, Rickettsia) Alternative for H. pylori 42 7 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 47 01/14/2009 48 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 01/14/2009 9
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