General Principles of Antimicrobial Therapy

1. When Is Antimicrobial Therapy Indicated?

1. Is an antimicrobial agent indicated based on clinical findings, or is it prudent to wait?
2. Have appropriate specimens been collected for microbiologic diagnosis?
3. What are the most likely etiologic agents?
4. Are there public health measures needed to prevent secondary cases?
5. Is there clinical evidence that antimicrobial therapy will confer benefit?

• Can a narrower-spectrum agent replace the empiric drug?
• Is monotherapy or combination therapy required?
• What is the optimal dose, route, and duration?

2. Establishing a Microbiologic Diagnosis

• Gram stain - rapid bedside identification of organism morphology and Gram-type
• Culture and sensitivity - definitive identification + MIC determination
• Molecular/PCR tests - rapid identification for select pathogens
• Serologic tests - useful for organisms that don't culture easily (e.g., Mycoplasma, Legionella)

3. Empiric vs. Definitive Therapy

4. Choice of Antimicrobial Agent

Host Factors

1. Immune status - HIV, neutropenia, transplant, cytotoxic chemotherapy, immunosuppressants all alter response and risk of opportunistic organisms
2. Prior adverse drug reactions - allergies (especially penicillin allergy) guide choice
3. Organ function - renal or hepatic impairment affects drug elimination and dosing
4. Age - neonates (immature enzymes), elderly (reduced renal function)
5. Pregnancy - many drugs are teratogenic (fluoroquinolones, tetracyclines, aminoglycosides) or unsafe (metronidazole in first trimester)
6. Epidemiologic exposure - recent hospitalization, travel to endemic areas, occupational exposure, new sexual partners

Pharmacologic Factors

1. PK/PD - absorption, distribution, metabolism, and elimination kinetics
2. Penetration to site of infection - CNS (blood-brain barrier), prostate, bone, abscess cavity
3. Toxicity profile
4. Drug-drug interactions
5. Route of administration - oral vs. IV; IV-to-oral switch is cost-effective for prolonged courses
6. Cost - when multiple agents have comparable efficacy and toxicity

5. Pharmacokinetic/Pharmacodynamic (PK/PD) Principles

6. Bacteriostatic vs. Bactericidal Drugs

7. Monitoring Therapeutic Response & Duration of Therapy

• Clinical improvement should be evident within 48-72 hours for most bacterial infections
• If no improvement, consider: wrong diagnosis, resistant organism, undrained abscess, drug not reaching site, or drug-drug interaction
• Duration depends on:
  • The pathogen (e.g., TB requires months)
  • The site of infection (endocarditis: 4-6 weeks; uncomplicated cystitis: 3-5 days)
  • Host factors - immunocompromised patients generally require longer courses

8. Combination Antimicrobial Therapy

1. Empiric broad coverage is needed in severely ill patients before organism identification
2. Polymicrobial infections (e.g., intra-abdominal abscess with aerobic + anaerobic organisms)
3. Prevent emergence of resistance - most clearly shown in tuberculosis
4. Reduce dose-related toxicity (e.g., combining flucytosine with amphotericin B for cryptococcal meningitis allows lower amphotericin B doses)
5. Achieve synergism - enhanced killing greater than either drug alone

Synergism vs. Antagonism

• Synergism: Combined effect is ≥4-fold reduction in MIC/MBC vs. individual drugs. Classic example: penicillin + gentamicin for enterococcal endocarditis (penicillin alone is only bacteriostatic against enterococci; adding an aminoglycoside achieves bactericidal activity)
• Antagonism: Combined effect is less than either drug alone. Classic example: penicillin + tetracycline for pneumococcal meningitis (bacteriostatic tetracycline interferes with the bactericidal action of penicillin)

1. Sequential blockade of a metabolic pathway (e.g., trimethoprim + sulfamethoxazole)
2. Inhibition of enzymatic inactivation (e.g., beta-lactamase inhibitors restore penicillin activity)
3. Enhanced cell wall penetration allowing a second drug to enter (e.g., penicillin + aminoglycoside in enterococcal endocarditis)

9. Antimicrobial Stewardship

Enterococcus faecium, Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.

• Use antibiotics only when clearly indicated
• Use the narrowest spectrum effective agent
• Optimize dose, route, and duration
• De-escalate once culture data are available
• Avoid treating asymptomatic bacteriuria in most patients
• Monitor and act on local antibiograms (susceptibility patterns)

10. Special Considerations

Renal Insufficiency

• Drugs cleared primarily renally require dose adjustment (e.g., aminoglycosides, beta-lactams, vancomycin)
• Renal failure may impair urinary drug concentration, making urinary tract infections harder to eradicate

Obstruction/Abscess

• Abscesses and obstructed spaces must be drained surgically - antibiotics alone are often insufficient because:
  • Drug penetration is poor in necrotic/avascular tissue
  • Bacteria in biofilm or stationary phase are less susceptible

Prophylaxis

• Pre-procedure/surgical prophylaxis is given to prevent, not treat, infection
• Should cover the most likely organisms for that surgical site
• Should be given within 60 minutes before incision and stopped within 24 hours post-op

• S - Specimen collection before therapy
• M - Microbiologic diagnosis (Gram stain, culture)
• A - Appropriate drug (host factors + pharmacologic factors)
• R - Review and de-escalate once results return
• T - Target duration based on infection type and host