A 48-year-old man comes to your office with a 6-day history of worsening cough productive of green sputum. He has had fever and chills. He complains of pain in the right midback with deep breathing or coughing. Further history reveals that he has smoked one pack of cigarettes a day for 30 years. He has no other significant medical history. On examination, his temperature is 38.1°C (100.5°F); his respiratory rate is 24 breaths per minute; pulse, 98 beats per minute; blood pressure, 120/75 mm Hg; and saturation of oxygen, 96 percent on room air by pulse oximetry. Auscultation of his lungs reveals rales in the right lower-posterior lung field. The remainder of his examination is within normal limits. A posterior-to-anterior (PA) and lateral chest x-ray show a right lower-lobe infiltrate. A sputum Gram-stain reveals gram-positive cocci, and subsequent sputum and blood culture results confirm the diagnosis of pneumonia caused by Streptococcus pneumoniae (pneumococcus). You treat him with a combination of amoxicillin and clavulanic acid.
What is the mechanism of action of amoxicillin?
What is the mechanism of action of clavulanic acid?
Answers to case: Antibacterial agents
Summary: A 48-year-old man with pneumococcal pneumonia is being treated with amoxicillin and clavulanic acid.
Mechanism of action of amoxicillin: Inactivation of bacterial transpeptidases and prevention of cross-linking of peptidoglycan polymers necessary for cell-wall integrity, resulting in loss of cell-wall rigidity and cell rupture; also inhibition of cell-wall synthesis.
Mechanism of action of clavulanic acid: Irreversible inhibition of β-lactamase.
Clinical correlation
Penicillin is the prototype antibiotic in the β-lactam class. β-Lactam antibiotics interfere with bacterial transpeptidases and thereby prevent the cross-linking of peptidoglycan polymers essential for cell-wall integrity. They do this by binding to the active site of the penicillin-binding protein (an enzyme) that is involved in maintaining cell-wall stability.
β-Lactam antibiotics are bactericidal in growing cells, with gram-positive bacteria being particularly susceptible. Penicillin has activity against many gram-positive aerobic organisms, some gram-negative aerobes and anaerobic organisms. It does not have significant activity against gram-negative rods. Amoxicillin is an extended-spectrum penicillin with better activity against gram-negative rods and similar activity against other organisms. Both penicillin and amoxicillin are susceptible to β-lactamases, which cleave the β-lactam ring required for antibacterial action.
Clavulanic acid (and sulbactam and tazobactam) is structurally similar to penicillin. It has no antimicrobial activity of its own but it irreversibly inhibits certain β-lactamases. It frequently is given in fixed combination with amoxicillin, thus allowing it to be used to treat β-lactamase-producing organisms. Penicillins can cause hypersensitivity reactions in susceptible persons. Approximately 5-10 percent of penicillin-allergic persons will have a cross-sensitivity to cephalosporin drugs as well. Penicillins also have gastrointestinal (GI) side effects, and the addition of clavulanic acid significantly increases the incidence of diarrhea.
Approach to pharmacology of antibacterial agents
Objectives
- Describe the factors in choosing appropriate antibiotic agents.
- List the classes of antibiotics, and describe their mechanisms of action, therapeutic uses, and adverse effects.
- Outline mechanism of development of bacterial drug resistance.
Definitions
Chemotherapy: Therapeutic use of chemical agents that selectively act on microbes and cancer.
Plasmids: Extrachromosomal genetic elements that may be transferred between bacteria.
Continuation: Case: Antibacterial agents. Class