Chapter 35  ·  Module 1  ·  Antibacterial Agents
Penicillins
Chemistry, mechanism, spectrum, and resistance at a glance
Abbreviations: PBP = penicillin-binding protein  ·  IV = intravenous  ·  IM = intramuscular  ·  BA = bioavailability  ·  TEM/SHV = common penicillinase names  ·  CTX-M = cefotaxime-Munich extended-spectrum beta-lactamase  ·  GFR = glomerular filtration rate
Mechanism of Action
How Beta-Lactams Kill Bacteria
Step 1
Drug Enters
Crosses outer membrane via porins (gram-negative) or directly (gram-positive)
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Step 2
Binds Penicillin-Binding Protein (PBP)
Covalently acylates active-site serine of penicillin-binding protein transpeptidase
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Step 3
Cross-Linking Blocked
Peptidoglycan synthesis halted; autolysins continue degrading existing wall
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Result
Cell Lysis
Bactericidal; time-dependent killing (fT > minimum inhibitory concentration)
Penicillin Subclasses and Key Features
Natural
Penicillin G & V
  • Streptococci, T. pallidum
  • Oral anaerobes, Listeria
  • Penicillin G: intravenous / intramuscular only
  • Penicillin V: oral
  • Syphilis: drug of choice
Aminopenicillins
Ampicillin / Amoxicillin
  • + H. influenzae, E. coli
  • + Enterococcus faecalis
  • Amoxicillin: better oral bioavailability
  • Ampicillin: preferred IV
  • Beta-lactamase susceptible
Antistaphylococcal
Nafcillin / Oxacillin
  • Methicillin-susceptible Staphylococcus aureus only
  • Preferred over vancomycin for methicillin-susceptible Staphylococcus aureus
  • Nafcillin: hepatic elimination
  • No renal adjustment (nafcillin)
  • Dicloxacillin: oral; take fasted
Extended-Spectrum
Piperacillin-Tazobactam
  • Pseudomonas aeruginosa coverage
  • Broad gram-negative spectrum
  • Tazobactam: beta-lactamase inhibitor
  • Avoid for extended-spectrum beta-lactamase bacteremia
  • Renal dose adjustment required
Resistance Mechanisms
Mechanism Example Organisms Overcome by
Beta-lactamase (Class A) TEM, SHV penicillinases Staphylococci, gram-negative enteric bacteria Beta-lactamase inhibitor combinations
Extended-spectrum beta-lactamase (Class A) CTX-M-15 E. coli, Klebsiella pneumoniae Carbapenems (not piperacillin-tazobactam)
Carbapenemase (Class A/B/D) Klebsiella pneumoniae carbapenemase, New Delhi metallo-beta-lactamase Klebsiella, Acinetobacter, Pseudomonas Ceftazidime-avibactam (not metallo-beta-lactamase)
Altered penicillin-binding protein mecA / penicillin-binding protein 2a Methicillin-resistant Staphylococcus aureus Vancomycin; ceftaroline (fifth-generation)
Porin loss + efflux OprD loss, MexAB-OprM Pseudomonas aeruginosa Higher doses; combination therapy
Clinical Rule: Extended-Spectrum Beta-Lactamase Bacteremia

Piperacillin-tazobactam is unreliable for bloodstream infections caused by extended-spectrum beta-lactamase-producing organisms even when the isolate tests susceptible in vitro. Use a carbapenem as definitive therapy for serious extended-spectrum beta-lactamase infections.

Methicillin-resistant Staphylococcus aureus requires vancomycin, daptomycin, or linezolid—no conventional penicillin or cephalosporin is effective.