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Basics of Antimicrobial Therapy
Treatment of infection requires consideration of many factorsPharmacokinetics (PK)
The process by which a drug is absorbed, distributed, metabolized, and eliminated from the bodyPharmacokinetics (PK): Absorption
Intravenous = 100% alwaysOther routes are HIGHLY variable
- Gl Tract: Oral, Rectal, Gi Tube, NG tube, etc
- Intramuscular: not commonly used in ID
Bioavailability (F, BA)= %Absorbed / Total Dose Administered
Bypass systemic circulation by direct instillation into various sites of infection
- Inhaled, intraperitoneal, intrathecal
Pharmacokinetics (PK): Distribution
Volume of Distribution (Vd)
- Drug must reach sites of infection at adequate concentrations!
- Factors: lipid solubility, tissue penetration, blood flow to tissues, pH, plasma protein binding
Pharmacokinetics (PK): Metabolism
Hepatic: the liver is the primary site
- Phase 1: primarily CYP450 enzymes: Macrolides, sulfonamides, rifamycins, chemotherapeutic antiinfectives, azole antifungals, antiretrovirals
- Phase 2: glucuronidation, sulfation, acetylation: Isoniazid
Other organs and tissues also have metabolic capability
Pharmacokinetics (PK): Elimination
Renal
- Passive: glomerular filtration
- Active: tubular secretion = saturable, dose-dependent
- Dialysis: Hemo-, peritoneal, CVVH
Non-renal
- Biliary: Ceftriaxone, Zosyn - Intestinal: Azithromycin
- Respiratory (surfactant): Aminoglycosides
Antibacterial Mechanisms of Action
Cell Wall-Active agents
- Daptomycin, Azoles, B-Lactams, Vancomycin, Telavancin
Protein Synthesis Inhibitors
- 305 = Tetracyclines
- 505 = macrolides, clindamycin, chloramphenicol, Synercid
- DNA Gyrase, Topoisomerase (fluoroquinolones)
- RNA polymerase (rifamycins)
- Other ribosomal agents (linezolid)
Cationic Detergents that dissolve the cell wall
- Polymyxins
Free Radical Formation
- Metronidazole
Resistance Mechanisms
Drug Enzymatic Inactivation
- Most common
- Example: B-lactamases and aminoglycoside-modifying enzymes
Altered Target Site
- Changes to ribosomes, penicillin-binding proteins (PBPS), DNA gyrase, Topoisomerase
Decreased Permeability
- Porin Channels
- Efflux pumps: can increase quickly, "up-regulation"
Pharmacodynamics (PD)
Describes how the drug performs in the body
- Pharmacological and toxic effects
Relationship between drug concentration and antimicrobial effect
- Bactericidal vs Bacteriostatic
- Concentration vs Time-Dependent Killing
- Antimicrobial Synergy
- Post-Antibiotic Effect
BACTERIOSTATIC
Inhibit growth and replication
- Inhibit folic acid synthesis: sulfonamides
- May also inhibit protein synthesis: linezolid
BACTERICIDAL
Cause bacterial cell death
- Disrupt cell wall or cell membrane --> cell lysis --> death: B-Lactams
- Inhibit nucleic acid synthesis: fluoroquinolones
- Inhibit protein synthesis: aminoglycosides
The MIC
MIC: Minimum Inhibitory Concentration
MBC: Minimum Bactericidal Concentration
Dose-related Killing Capacity
Concentration-dependent
Time-dependent
AUC: MIC
- [Peak]: MIC
Time-dependent
- Time > MIC
AUC: MIC
- Area Under Curve: MIC
Concentration-Dependent Killing
Examples: Aminoglycosides, Daptomycin, Fluoroquinolones
Post-antibiotic Effect (PAE)
- Persistent, sustained "injury" post-dose
Aminoglycosides
- Dosing regimens
- PAE
Time-Dependent Killing
Time > MIC
- Linezolid
- B-Lactams
Opportunity for creative dosing strategies
ULH Dosing Strategies: B-Lactams
Continuous infusions over 24 hours
- Penicillin, Cefazolin, Nafcillin
Prolonged infusions
- Zosyn infused over 4h q8h
Smaller doses at more frequent dosing intervals
- Meropenem 500mg IV q6h
- Less total daily drug exposure
- Cost savings, decreased toxicity
AUC: MIC Killing
A "Mash-up" between concentration and time
Vancomycin, azoles, tetracyclines, macrolides
Concept of Antimicrobial "Synergy"
Specific for a particular bug/drug combination
Well-recognized examples
- B-Lactams + AG (Pseudomonas, Enterococcus)
- Sulfamethoxazole + Trimethoprim (many organisms)
- Vancomycin + Gentamicin (S. aureus)
Real-life Considerations on Rounds
Host characteristics
Pathogen
- Normal flora vs pathogen
- Multidrug-resistant, Gram (+) versus Gram (-)
MIC or resistance patterns at my institution
- Local antibiogram
Site of infection and drug penetration
Dosing Regimen
- ABX Standardized Dosing Policy
- ABX Formulary
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