Cell Wall Inhibitors

Penicillins

• Susceptible to penicillinases, often used in combination with penicillinase inhibitors (e.g., tazobactam, clavulanic acid) to enhance activity
• Classification: derivatives of 6-aminopenicillanic acid, contain a beta-lactam ring structure essential for antibacterial activity
• Mechanism of Action:
  • Binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) in bacterial cytoplasmic membrane
  • Inhibition of transpeptidation reaction that cross-links linear peptidoglycan chain constituents of the cell wall
  • Activation of autolytic enzymes that cause lesions in the bacterial cell wall

Narrow-Spectrum Penicillinase-Susceptible Agents

• Penicillin G: prototype, used for infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes
• Penicillin V: oral drug used mainly for oropharyngeal infections
• Activity against enterococci is enhanced by coadministration of aminoglycosides

Very-Narrow-Spectrum Penicillinase-Resistant Drugs

• Methicillin, nafcillin, and oxacillin: used for treatment of known or suspected staphylococcal infections
• Methicillin-resistant staphylococcus aureus (MRSA) and S. epidermidis (MRSE) are resistant to all penicillins and often resistant to multiple antimicrobial drugs

Wider-Spectrum Penicillinase-Susceptible Drugs

• Ampicillin and amoxicillin: have a wider spectrum of antibacterial activity than penicillin G
  • Clinical uses include indications similar to penicillin G, as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis
  • Synergistic with aminoglycosides in enterococcal and listerial infections
• Piperacillin and ticarcillin: have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species
  • Susceptible to penicillinases, often used in combination with penicillinase inhibitors (e.g., tazobactam, clavulanic acid) to enhance activity

Routes of Administration

• Combination of ampicillin with sulbactam, piperacillin with tazobactam, and anti-staphylococcal penicillins nafcillin and oxacillin: administered intravenously (IV) or intramuscularly (IM)
• Penicillin V, amoxicillin, and dicloxacillin: available only as oral preparations
• Depot forms: procaine penicillin G and benzathine penicillin G administered IM, slowly absorbed into circulation and persist at low levels over a long time period

Absorption

• Most penicillins are incompletely absorbed after oral administration, affecting the composition of the intestinal flora
• Food decreases absorption of penicillinase-resistant penicillins due to stomach acid, so they should be taken on an empty stomach

Other Antibiotics

Fosfomycin

• Excreted by the kidney, with urinary levels exceeding minimal inhibitory concentrations (MICs)
• Indicated for urinary tract infections caused by E. coli or E. faecalis
• Adverse effects include diarrhea, vaginitis, nausea, and headache

Daptomycin

• Bactericidal, novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci
• Indicated for treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus
• Inactivated by pulmonary surfactants, so it should never be used in the treatment of pneumonia
• Creatine phosphokinase should be monitored since daptomycin may cause myopathy

Polymyxins

• Cationic polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria
• Have a detergent-like effect that disrupts cell membrane integrity, leading to leakage of cellular components and cell death
• Concentration-dependent bactericidal agents with activity against most clinically important gram-negative bacteria, including P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter spp., and Enterobacter spp.
• However, alterations in the cell membrane, lipid polysaccharides allow many species of Proteus and Serratia to be intrinsically resistant