Module 6 Section 2 (Antibiotics) Flashcards
How can a bacterial infection be stopped?
A bacterial infection can be stopped by inhibiting the growth and reproduction of bacteria (bacteriostatic effects) or by directly killing the bacteria (bactericidal effects).
What occurs as a result of inappropriate and over use of antibiotics?
Inappropriate and over use has resulted in a new problem, resistant strains of organisms.
Discuss the structure of bacterial cells.
Bacterial cells have a rigid cell wall, which surrounds the cytoplasmic membrane.
The cell wall contains a peptidoglycan layer, which is a complex, cross-linked polymer of polysaccharides and polypeptides.
- These cross-links give the cell wall its structural rigidity, and are responsible for maintaining the cell’s shape and integrity, preventing cell lysis from high osmotic pressure.
Bacteria are classified as either gram-positive or gram-negative. What does that entail?
Gram-positive bacteria have a thick peptidoglycan layer in their cell wall.
- These bacteria are able to retain the colour of the crystal violet dye in the Gram stain, hence the name.
Gram-negative bacteria have a much thinner peptidoglycan layer in their cell wall and an outer membrane.
- These bacteria do not retain the crystal violet dye in the Gram stain.
Most antibiotics will target one of three key bacterial processes. What are those processes?
1) Cell wall and cell membrane synthesis.
2) Protein synthesis.
3) Nucleic acid metabolism.
Antibiotics target the function of the bacterial cell wall and cell membrane in order to disrupt the structural integrity of the cell. How is this done?
- Breaking down the already formed cell wall
- Inhibiting the production of components necessary to build the cell wall
What is penicillin?
Penicillin was the first antibiotic introduced into use. Since then, many other antibiotics have been derived from this original structure. This group of antibiotics are called the Penicillins.
What are cephalosporins?
Cephalosporins are a group of antibiotics closely related to the Penicillin.
What are the mechanisms of action for penicillin?
Penicillin is closely related to (D)-alanyl-(D)-alanine, a chemical component necessary for the formation of new bacterial cell walls.
Under normal conditions, (D)-alanyl-(D)-alanine binds to the enzyme, transpeptidase, to form cross-links between peptidoglycan chains.
- In the presence of Penicillin, transpeptidase will bind to Penicillin instead, inhibiting the formation of the cross-links and thus, the formation of the cell wall.
- The resulting cells are formed without cell walls - these cells are known as protoplasts and are fragile and can readily burst.
Discuss the therapeutic uses for penicillin.
Penicillins are currently the drugs of choice for a large number of infectious diseases.
- Upper respiratory tract infections
- Urinary tract infections
- Pneumococcal infections and pneumonia
- Streptococcal pharyngitis (Strep throat)
- Syphilis
Discuss the adverse effects for penicillin.
The most common adverse effect to penicillin is an allergic reaction.
- If an individual is allergic to one penicillin preparation, they will be allergic to all penicillin preparations.
- A variety of studies suggest that 1 to 10% of the population is allergic to penicillin.
- The most common manifestations of penicillin allergy include rash, diarrhea, fever, face and tongue swelling, and an eruption of itchy hives (urticaria).
- In rare cases, individuals may experience anaphylactic shock.
Resistance to penicillins is becoming a problem, with certain bacteria being able to produce penicillinase, which is an enzyme capable of inactivating penicillin.
What are the mechanisms of action for cephalosporins?
Cephalosporins are closely related to the penicillins, and they have a similar mechanism of action.
Cephalosporins are selective inhibitors of transpeptidase, so they also cause the formation of cell walls without crosslinks.
Cephalosporins are relatively resistant to penicillinase.
What are the therapeutic uses for cephalosporins?
Third generation cephalosporins are used for:
- serious infections caused by E. coli, among others.
- all forms of gonorrhea and for severe forms of lyme disease.
- treatment of meningitis. Not all antibiotics distribute to the CNS, but some third-generation cephalosporins do, making them useful for treating meningitis.
What are the adverse effects for cephalosporins?
The most common adverse effects include fever and skin rashes.
Renal toxicity may occur in rare cases.
If a patient is allergic to penicillin, they are also allergic to the cephalosporins.
What is the general mechanism of action of cell wall synthesis inhibitors? Why don’t these antibiotics target human cells?
Antibiotics that target the cell wall do so by antagonizing the enzyme transpeptidase.
- This enzyme is responsible for creating the cross-links between peptidoglycan layers in the cell wall.
- In the absence of these cross-links, the cell wall is unstable and the cell can easily burst.
Human cells do not have cell walls and are therefore unaffected by these antibiotics. Thus, penicillins and cephalosporins are selectively toxic to bacteri
The second antibiotic target is protein synthesis. Antibiotics in this class prevent the functioning and growth of bacterial cells by inhibiting translation, and therefore, protein synthesis. How is this done?
Protein synthesis occurs in the ribosome (a complex molecule made of ribosomal DNA).
The bacterial ribosome consists of two subunits - a large subunit (50S) and a small subunit (30S).
Amino acids are brought to the ribosome by transfer RNA (tRNA) and added to the growing polypeptide chain via a peptide bond.
Protein synthesis inhibitors disrupt this process through a variety of mechanisms.
What are the two protein synthesis inhibitors?
- Macrolides
- Antifolate drugs
What are the mechanisms of action for macrolides?
The macrolides are a group of antibiotics that bind to the 50S subunit of the bacterial ribosome.
- Upon binding, macrolides bind to and antagonize the enzyme responsible for forming peptide bonds between adjacent amino acids in the polypeptide chain.
- Thus, amino acids can’t be added to the growing polypeptide chain and protein synthesis is inhibited.
This antibiotic is active against several bacterial infections caused by Gram-positive microorganisms.
What are the therapeutic uses for macrolides?
Macrolides are the drug of choice for treating pertussis and first-line therapy for mycobacterial infections.
When an individual is allergic to penicillin, erythromycin is an effective alternative in treating streptococcal and staphylococcal infections.
What are the adverse effects for macrolides?
Common adverse effects include anorexia, nausea, vomiting, and diarrhea.
- Diarrhea is the most common cause of discontinuing treatment with erythromycin.
It is important to note that some macrolides (e.g. erythromycin, clarithromycin) strongly inhibit CPY3A4 and cause significant drug interactions.
What are the mechanisms of action for antifolate drugs? IMPORTANT
The second class of protein synthesis inhibitors are antifolate drugs, or folate inhibitors.
These drugs inhibit the formation of tetrahydrofolic acid (THF), which is essential for the bacteria to synthesize DNA and protein.
Pteridine + para-aminobenzoic acid (PABA) —dihydropteroate synthetase—> dihydropteroic acid ——> dihydrofolic acid —dihydrofolate reductase—> tetrahydrofolic acid
What are the 2 antibiotics in the antifolate drug class?
1) Sulfamethoxazole: member of the sulfonamide group, competitively inhibits para-aminobenzoic acid (PABA) incorporation into dihydropteroic acid.
- Susceptible microorganisms must synthesize tetrahydrofolic acid from PABA, however, mammalian cells use preformed tetrahydrofolic acid from their surroundings.
- Thus, sulfonamides are selectively toxic to microorganisms.
2) Trimethoprim: it inhibits dihydrofolic acid reductase, thus inhibiting tetrahydrofolic acid formation.
- While humans do possess this enzyme, trimethoprim is selectively toxic to bacteria because it has greater inhibitory actions on the bacterial enzyme than on the human enzyme.
- By inhibiting sequential steps in the metabolic pathway of folate, a synergistic antibacterial effect is produced.
- As such, the drug cotrimoxazole was developed, which consists of sulfamethoxazole and trimethoprim.
What are the therapeutic uses for antifolate drugs?
Cotrimoxazole is very useful in the treatment of recurrent bacterial infections of the urinary tract, and in the treatment of mild acute exacerbations of chronic bronchitis.
- It is also an important antimicrobial agent used in the treatment of Pneumocystis carinii infection in HIV-positive individuals.
What are the adverse effects for antifolate drugs?
Cotrimoxazole causes up to three times as many dermatological reactions (e.g. urticaria) as sulfonamides alone.
Mild and transient jaundice has also been reported.
Individuals that are folate deficient may be more likely to experience adverse effects, as the margin between toxicity for bacteria and that for humans may be relatively narrow.
