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Antibiotics Review Part I: Basics of Antimicrobial Therapy, Pharmacokinetics, Antibacterial Mechanisms of Action, Resistance Mechanisms

Source: www.newdelhitimes.com

    Basics of Antimicrobial Therapy

    Treatment of infection requires consideration of many factors


    Pharmacokinetics (PK)

    The process by which a drug is absorbed, distributed, metabolized, and eliminated from the body


    Pharmacokinetics (PK): Absorption

    Intravenous = 100% always
    Other 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

    • Passive: glomerular filtration
    • Active: tubular secretion = saturable, dose-dependent
    • Dialysis: Hemo-, peritoneal, CVVH

    • 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 

    Inhibit growth and replication
    • Inhibit folic acid synthesis: sulfonamides
    • May also inhibit protein synthesis: linezolid

    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

    • [Peak]: MIC

    • Time > MIC

    AUC: MIC
    • Area Under Curve: MIC

    Concentration-Dependent Killing

    Examples: Aminoglycosides, Daptomycin, Fluoroquinolones

    Post-antibiotic Effect (PAE)
    • Persistent, sustained "injury" post-dose

    • 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
    • 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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