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

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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

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

• [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