8.1 Antibiotics
Antibiotics are antimicrobial agents that target bacterial structures and processes, inhibiting bacterial growth (bacteriostatic) or killing bacteria (bactericidal). Understanding their mechanisms, spectrum, and resistance patterns is crucial for effective therapy.
Principles of Antibiotic Therapy
Bactericidal vs Bacteriostatic
Bactericidal: Kill bacteria (β-lactams, aminoglycosides, fluoroquinolones)
Bacteriostatic: Inhibit growth (tetracyclines, macrolides, sulfonamides)
Spectrum of Activity
Narrow spectrum: Specific organisms (penicillin G)
Broad spectrum: Gram+ and Gram- (amoxicillin-clavulanate)
Beta-Lactam Antibiotics
Mechanism of Action
β-lactams contain a four-membered β-lactam ring that binds to penicillin-binding proteins (PBPs), inhibiting bacterial cell wall synthesis by blocking transpeptidase cross-linking of peptidoglycan.
Penicillins
- Natural: Penicillin G/V (Strep, Staph, syphilis)
- Anti-staphylococcal: Methicillin, nafcillin (MSSA)
- Aminopenicillins: Ampicillin, amoxicillin (broader: H. influenzae, E. coli)
- Anti-pseudomonal: Piperacillin (+ tazobactam for β-lactamase)
Cephalosporins
- 1st Gen: Cefazolin (Gram+ surgical prophylaxis)
- 2nd Gen: Cefuroxime (H. influenzae, Neisseria)
- 3rd Gen: Ceftriaxone, cefotaxime (serious Gram- infections, meningitis)
- 4th Gen: Cefepime (Pseudomonas, Gram+/-)
- 5th Gen: Ceftaroline (MRSA)
Carbapenems
- Imipenem: Broadest spectrum, with cilastatin to prevent renal metabolism
- Meropenem: Less seizure risk, used for severe sepsis
- Ertapenem: Once-daily dosing, outpatient therapy
- ⚠️ Reserve for multidrug-resistant organisms
Monobactams
- Aztreonam: Gram- only (Pseudomonas, Enterobacteriaceae)
- Safe in penicillin allergy (no cross-reactivity)
β-Lactamase Inhibitors
These compounds irreversibly bind β-lactamases, protecting β-lactams from degradation:
- • Clavulanate: Amoxicillin-clavulanate (Augmentin)
- • Sulbactam: Ampicillin-sulbactam (Unasyn)
- • Tazobactam: Piperacillin-tazobactam (Zosyn)
- • Avibactam: Ceftazidime-avibactam (for carbapenem-resistant organisms)
Aminoglycosides
Mechanism & Clinical Use
Bind 30S ribosomal subunit, causing misreading of mRNA and inhibiting protein synthesis. Concentration-dependent killing; require oxygen for uptake (ineffective in anaerobes).
Common Agents:
- • Gentamicin: Gram- sepsis, endocarditis (with β-lactam)
- • Tobramycin: Pseudomonas (CF patients)
- • Amikacin: Resistant organisms
- • Streptomycin: Tuberculosis, plague
⚠️ Major Toxicities:
- • Nephrotoxicity: Reversible acute tubular necrosis (monitor CrCl)
- • Ototoxicity: Irreversible vestibular/cochlear damage (vertigo, hearing loss)
- • Neuromuscular blockade: Risk in myasthenia gravis
- Monitor peak/trough levels; once-daily dosing reduces toxicity
Fluoroquinolones
Mechanism of Action
Inhibit bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, preventing DNA supercoiling and replication. Bactericidal, concentration-dependent killing.
Generations:
- 1st (Nalidixic acid): Obsolete, UTI only
- 2nd (Ciprofloxacin): Gram- (UTI, GI, anthrax, Pseudomonas)
- 3rd (Levofloxacin): Improved Gram+ (pneumonia)
- 4th (Moxifloxacin): Anaerobes + respiratory
Adverse Effects:
- • GI upset, QT prolongation
- • Tendonitis/rupture (Achilles tendon)
- • Cartilage damage (avoid in pregnancy/children)
- • CNS effects (seizures, confusion)
- • Photosensitivity
- ⚠️ FDA black box warning for tendon/nerve/CNS effects
Macrolides
Mechanism & Clinical Applications
Bind 50S ribosomal subunit, blocking translocation and protein synthesis. Generally bacteriostatic.
Common Agents:
- • Erythromycin: Gram+ (Strep, Staph), atypicals, GI motility
- • Azithromycin: Community-acquired pneumonia, STIs (Chlamydia)
- • Clarithromycin: H. pylori, MAC in HIV
Clinical Features:
- • Excellent tissue penetration
- • Alternative for penicillin allergy
- • Cover atypicals (Mycoplasma, Legionella, Chlamydia)
- • Adverse: GI upset, QT prolongation, CYP3A4 inhibition
- ⚠️ Drug interactions via CYP inhibition
Antibiotic Resistance Mechanisms
β-Lactamase Production
- • Extended-spectrum β-lactamases (ESBLs): Destroy 3rd gen cephalosporins
- • Carbapenemases (KPC, NDM-1): Destroy carbapenems
- • Treatment: β-lactamase inhibitors, carbapenems for ESBL
Altered Target
- • MRSA: mecA gene → altered PBP2a (resistant to β-lactams)
- • VRE: vanA/B genes → altered peptidoglycan precursors
- • Penicillin-resistant Strep pneumoniae: Altered PBPs
Efflux Pumps
- • Active transport pumps expel antibiotics
- • Common in Pseudomonas (fluoroquinolones, β-lactams)
Reduced Permeability
- • Loss of porin channels (Gram- bacteria)
- • Decreased uptake of aminoglycosides (anaerobes)
Key Clinical Syndromes & Empiric Therapy
| Syndrome | Common Pathogens | First-Line Therapy |
|---|---|---|
| Community-acquired pneumonia | S. pneumoniae, H. influenzae, atypicals | Amoxicillin-clavulanate + macrolide OR levofloxacin |
| Urinary tract infection | E. coli, Klebsiella, Proteus | Nitrofurantoin, trimethoprim-sulfamethoxazole |
| Bacterial meningitis | S. pneumoniae, N. meningitidis, H. influenzae | Ceftriaxone + vancomycin (± ampicillin for Listeria) |
| Cellulitis/skin infection | S. aureus, Streptococcus | Cephalexin (PO) or cefazolin (IV); add MRSA coverage if suspected |