Principal of antimicrobial therapy pharmacology

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Principles of Antimicrobial Therapy - Pharmacology

Antimicrobial therapy is guided by six interlocking principles: identifying the pathogen, determining susceptibility, choosing the right drug for the right site, applying pharmacokinetic/pharmacodynamic (PK/PD) optimization, understanding resistance, and practicing stewardship.

I. Selection of Antimicrobial Agents

Selection of the most appropriate agent requires knowledge of:

The identity of the microorganism
The susceptibility of the organism to the agent
The site of infection
Patient factors (age, immune status, renal/hepatic function, allergy)
The safety and efficacy of the antimicrobial
The cost of therapy

Most patients require empiric therapy - immediate drug administration prior to bacterial identification and susceptibility testing. Therapy is subsequently adjusted once culture results return.

Lippincott Illustrated Reviews: Pharmacology, p. 907

II. Identifying the Infecting Organism

Characterization of the pathogen is central to appropriate therapy. Methods include:

Laboratory techniques for diagnosing microbial diseases

Direct microscopic visualization (Gram stain) - rapid assessment for normally sterile body fluids (blood, CSF, pleural, synovial, urine)
Culture and identification - definitive diagnosis; must be obtained before antibiotics are started
Antigen detection
Nucleic acid detection (PCR, MALDI-TOF MS) - highly accurate, rapid; allows detection of resistant genes (e.g., mecA gene for MRSA)
Host immune response (serology)

Key clinical note: Culture specimens must be collected before initiating antibiotic therapy. A negative culture on an already-treated patient cannot differentiate absence of organism from antibiotic effect.

III. Empiric Antimicrobial Therapy

When culture results are unavailable, empiric therapy selection is guided by:

Timing: Sepsis with hypotension requires antibiotics within 1 hour of diagnosis; neutropenic patients and meningitis require immediate treatment
Site of infection: Identifies the most probable pathogen (e.g., urinary vs. pulmonary vs. CNS)
Patient history: Age, prior infections, recent antibiotics, immune status, travel history, hospital vs. community acquisition
Local antibiogram: Summary of local susceptibility patterns; used to guide empiric drug choices

Broad-spectrum therapy is appropriate initially when the organism is unknown or polymicrobial infection is likely. De-escalation to targeted therapy follows culture results.

IV. Antimicrobial Susceptibility Testing

Disk Diffusion (Kirby-Bauer)

Paper disks containing antibiotics are placed on agar. The drug diffuses outward, creating a zone of inhibition. Zone diameter is measured and compared to CLSI standards to classify the organism as susceptible (S), intermediate (I), or resistant (R).

Minimum Inhibitory Concentration (MIC)

The MIC is the lowest antimicrobial concentration that prevents visible bacterial growth after 24 hours. It provides a quantitative measure of in vitro susceptibility. Serial broth dilutions are inoculated with a standardized inoculum, and the lowest clear tube = MIC.

Minimum Bactericidal Concentration (MBC)

The MBC is the lowest concentration that kills ≥99.9% (3-log reduction) of the original inoculum. MBC is rarely determined in routine clinical practice due to labor intensity.

Jawetz Melnick & Adelberg's Medical Microbiology 28E, p. 775

V. Bacteriostatic vs. Bactericidal Drugs

Property	Bacteriostatic	Bactericidal
Definition	Arrests growth/replication at achievable levels	Kills ≥99.9% of organisms within 18-24 hours
MBC:MIC ratio	>4	≤4
Examples	Tetracyclines, macrolides, sulfonamides, linezolid, clindamycin	Penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin
When bactericidal preferred	Endocarditis, meningitis, immunocompromised hosts	-

Bactericidal vs bacteriostatic drug kinetics

Note: This classification is context-dependent. Linezolid is bacteriostatic against S. aureus and enterococci but bactericidal against most S. pneumoniae. Recent evidence shows bacteriostatic and bactericidal agents have similar efficacy for many common infections.

Lippincott Illustrated Reviews: Pharmacology, p. 914

VI. Pharmacokinetics and Pharmacodynamics (PK/PD)

Rational dosing is based on three key PK/PD parameters:

A. Concentration-Dependent Killing

Killing rate increases as drug concentration rises above the MIC
The higher the peak:MIC ratio, the greater the killing
Best parameter: Peak:MIC ratio (Cmax/MIC)
Examples: Aminoglycosides, fluoroquinolones, daptomycin, metronidazole
Dosing strategy: Once-daily (high-dose) bolus to achieve high peak levels

B. Time-Dependent (Concentration-Independent) Killing

Efficacy is determined by how long drug levels remain above the MIC
Increasing concentration beyond the MIC does not increase killing
Best parameter: %T>MIC (time drug concentration exceeds MIC)
- Penicillins: need T>MIC for ~50% of dosing interval
- Cephalosporins: ~60% T>MIC
Examples: Beta-lactams (penicillins, cephalosporins), macrolides, clindamycin, linezolid
Dosing strategy: Extended infusions (3-4 hours) or continuous infusions rather than bolus

C. AUC/MIC-Dependent Killing

Efficacy best predicted by total drug exposure relative to MIC
Best parameter: AUC24/MIC ratio
Examples: Fluoroquinolones, vancomycin

D. Postantibiotic Effect (PAE)

Persistent suppression of bacterial growth after drug levels fall below the MIC
Long PAE drugs (aminoglycosides, fluoroquinolones) can be dosed once daily
Short/no PAE: beta-lactams (against gram-negative rods) - require more frequent dosing or continuous infusion
Lippincott Illustrated Reviews: Pharmacology, p. 921

VII. Effect of Site of Infection

Adequate drug levels must reach the site of infection. Key considerations:

Site	Special Requirements
CNS (meningitis)	Drug must penetrate blood-brain barrier (BBB); bactericidal agents required; e.g., penicillin G, ceftriaxone, vancomycin. Lipophilic drugs cross BBB better
Endocarditis	Bactericidal drugs mandatory; prolonged IV therapy required
Abscesses	Poor drug penetration; surgical drainage often necessary
Bone	Good penetration by fluoroquinolones, clindamycin, rifampin
Urine (uncomplicated UTI)	Blood levels less important; urinary concentration critical
Prostate/kidney (febrile UTI)	Blood levels matter; need agents with tissue penetration

Drug concentration in urine may be reduced by renal insufficiency or urinary obstruction, making eradication more difficult.

Campbell-Walsh-Wein Urology, p. relevant section

VIII. Patient Factors

Renal insufficiency: Dose adjustments needed for renally cleared drugs (aminoglycosides, vancomycin, carbapenems, beta-lactams). Impaired kidneys may also fail to concentrate drugs in the urine.
Hepatic insufficiency: Adjust drugs metabolized hepatically (metronidazole, clindamycin, chloramphenicol)
Pregnancy: Many antibiotics are contraindicated (tetracyclines, fluoroquinolones, aminoglycosides)
Immune status: Immunocompromised patients often require bactericidal agents and broader empiric coverage
Age: Neonates lack certain drug-metabolizing enzymes; elderly have reduced renal clearance
Drug allergies: Cross-reactivity between penicillins and cephalosporins (~1-2% true cross-reactivity)

IX. Routes of Administration

Oral: For uncomplicated infections and stable patients; bioavailability varies widely by drug
IV: Required for severe infections, poor oral absorption, or specific tissue penetration needs
IV to oral (step-down): Once clinical improvement occurs, switch to oral agents with good bioavailability (fluoroquinolones, linezolid, metronidazole have near 100% oral bioavailability)
Topical: Mupirocin (skin infections), ophthalmic drops, inhaled (tobramycin for CF)

X. Mechanisms of Antimicrobial Resistance

Resistance is a major threat to modern antimicrobial therapy. Mechanisms include:

Mechanism	Examples
Enzymatic inactivation	Beta-lactamases destroy penicillins/cephalosporins; aminoglycoside-modifying enzymes
Altered target site	PBP-2a (MRSA mecA gene) prevents beta-lactam binding; altered 30S ribosome (aminoglycoside resistance)
Decreased permeability	Loss of porin channels reduces drug entry (carbapenem resistance in gram-negatives)
Efflux pumps	Active drug expulsion; common in fluoroquinolone and tetracycline resistance
Bypass pathway	MRSA uses alternative PBP-2a; VRE uses alternative cell wall precursors (D-Ala-D-Lac)
Biofilm formation	Polymicrobial biofilms reduce drug access and host immunity

Resistance spreads via:

Chromosomal mutation (spontaneous)
Horizontal gene transfer: conjugation (plasmids), transformation, transduction

Antibiotic use exerts selection pressure, enriching resistant populations. Broad-spectrum agents (especially cephalosporins and fluoroquinolones) carry the highest risk of collateral damage to normal flora, promoting selection of resistant organisms and C. difficile.

Medical Microbiology 9e; Goldman-Cecil Medicine; Jawetz Microbiology

XI. Combination Antimicrobial Therapy

Indications for combination therapy:

Synergy - two drugs together kill more than either alone (e.g., beta-lactam + aminoglycoside for serious gram-negative infection)
Broad-spectrum empiric coverage when pathogen is unknown
Prevention of resistance emergence (e.g., tuberculosis treatment: INH + RIF + PZA + EMB)
Polymicrobial infections requiring coverage of multiple organisms

Risks of combination therapy:

Increased toxicity
Antagonism (possible with bacteriostatic + bactericidal combinations in some settings)
Cost
Disruption of normal flora

XII. Antibiotic Stewardship

Antimicrobial stewardship is the systematic effort to optimize antibiotic prescribing:

Treat based on clinical indication, not just a positive culture (e.g., asymptomatic bacteriuria generally should not be treated)
De-escalate from broad- to narrow-spectrum therapy once the pathogen is identified
Use shortest effective duration
Avoid antibiotics for viral infections
Monitor local resistance patterns (antibiogram)

As stated in Campbell-Walsh-Wein: "The decision to initiate antibiotic therapy should not be based on treating a positive urine culture alone; rather clinical presentation in conjunction with urine testing should be considered, and we must assess the likelihood that the patient will benefit from or be harmed by antibiosis."

Inappropriate antibiotic use drives collateral damage - selection of multidrug-resistant organisms, C. difficile infection, disruption of microbiome, and adverse drug effects.

Summary Table: Key PK/PD Concepts

Parameter	Drug Class	Strategy
Peak:MIC (Cmax/MIC)	Aminoglycosides, daptomycin	Once-daily high-dose bolus
%T>MIC	Beta-lactams, macrolides, clindamycin, linezolid	Frequent dosing or extended infusion
AUC24/MIC	Fluoroquinolones, vancomycin	Balanced dosing; TDM
Postantibiotic effect	Aminoglycosides, fluoroquinolones	Once-daily dosing feasible

Sources: Lippincott Illustrated Reviews: Pharmacology, Chapter 28 (pp. 907-922); Jawetz, Melnick & Adelberg's Medical Microbiology 28E (pp. 774-776); Campbell-Walsh-Wein Urology; Medical Microbiology 9e

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