L2 - Part 2 Treatment of Bacterial Infection Flashcards
What is peptidoglycan composed of?
N-Acetyl-β-D-Glucosamine (NAG)
N-Acetyl-β-D-Muramic acid (NAM)
What is the role of the peptide stem in peptidoglycan structure?
The peptide stem connects to form interpeptide bridges that strengthen the peptidoglycan layer
How do penicillins affect peptidoglycan structure?
Penicillins target the enzymes responsible for forming the interpeptide bridges, weakening the bacterial cell wall
What are β-lactam antibiotics, and how do they work?
β-lactam antibiotics (e.g., Penicillins, Cephalosporins, Carbapenems, Monobactams) inhibit penicillin-binding proteins (PBPs), preventing cell wall synthesis.
They are only effective on actively dividing bacteria.
What are the risks of β-lactam antibiotics?
Common: Rash or gut issues in 1/10 patients.
Rare: Anaphylactic shock (1 in 100,000 patients).
Avoid Cephalosporins if allergic to Penicillins (15% cross-reactivity).
Why is the brain a difficult target for drug distribution?
The blood-brain barrier (BBB) has tightly joined endothelial cells with gap junctions, preventing diffusion of many substances into the brain.
How does meningitis affect drug distribution to the brain?
Meningitis increases the permeability of the meninges, allowing drugs like penicillin to reach therapeutic levels in the brain.
What is the mechanism of action of vancomycin?
Vancomycin binds to the D-Ala-D-Ala terminus of murein monomer units, preventing peptidoglycan polymerization.
What is the mechanism of action and clinical use of vancomycin?
Binds to D-Ala-D-Ala terminus of murein monomer units, preventing peptidoglycan polymerization.
Used for treating Methicillin-resistant Staphylococcus aureus (MRSA).
What are the limitations of vancomycin?
Ineffective against Gram-negative bacteria due to inability to penetrate the outer membrane.
Does vancomycin show synergy with other antibiotics?
Yes, it shows synergy with aminoglycosides.
How do aminoglycosides inhibit protein synthesis
Bind to the 30S ribosomal subunit and cause misreading of mRNA, leading to incorrect protein synthesis.
What is the mechanism of macrolides and clindamycin?
Bind to the 50S ribosomal subunit and prevent translocation along mRNA, halting protein elongation
How do tetracyclines affect protein synthesis?
Interfere with the attachment of tRNA to the ribosome, blocking protein synthesis
What is the action of chloramphenicol on ribosomes?
Binds to the 50S ribosomal subunit and inhibits peptide bond formation, preventing protein elongation.
What is the mechanism of action of tetracyclines?
Interfere with the attachment of tRNA to the ribosome, preventing protein synthesis.
Where are tetracyclines produced?
Produced by Streptomyces bacteria, which are found in soil
What is the effect of tetracyclines on bacterial growth?
They are bacteriostatic, meaning they inhibit bacterial growth but do not kill the bacteria, which can interfere with the action of penicillins.
Why is tetracycline resistance widespread?
Due to extensive use and misuse, leading to bacterial resistance.
Why are tetracyclines contraindicated during pregnancy, breastfeeding, and in young children?
Tetracyclines bind to Ca²⁺ in bones and teeth, interfering with bone development and potentially causing permanent tooth discoloration.
How does food affect the absorption of tetracyclines?
Uptake is inhibited by certain foods, particularly those containing calcium, iron, or magnesium.
What is a potential side effect of tetracyclines due to their broad-spectrum nature?
They can lead to superinfections, such as Candida overgrowth, due to disruption of normal flora.
How do aminoglycosides affect protein synthesis?
Aminoglycosides, like streptomycin and gentamicin, change the shape of the 30S ribosomal subunit, causing misreading of mRNA and premature termination of protein synthesis.
What is the synergy between aminoglycosides and penicillins/vancomycin?
Penicillins/vancomycin destabilize the bacterial cell wall, increasing aminoglycoside access to the cell, enhancing their effectiveness.
How do aminoglycosides bind to the ribosome?
Aminoglycosides bind to the 30S ribosomal subunit, introducing a slight ‘bump’ that forces misreading of mRNA
What are the potential side effects of aminoglycosides?
Aminoglycosides can cause ototoxicity, leading to ear complications and hearing loss.
How do macrolides and clindamycin affect protein synthesis?
They bind to the 50S ribosomal subunit and prevent translocation along mRNA.
What are the uses of macrolides like erythromycin, clarithromycin, and azithromycin?
They target intracellular bacteria (e.g., Legionella, Chlamydia, Mycobacteria) due to their ability to penetrate membranes.
They are good alternatives for patients with a penicillin allergy, as they have a similar spectrum.
How does chloramphenicol affect protein synthesis?
It binds to the 50S ribosomal subunit and inhibits peptide bond formation.
What are the characteristics and uses of chloramphenicol?
It has a broad spectrum and is highly lipophilic, allowing good tissue penetration.
What are the side effects of chloramphenicol?
It can inhibit liver enzyme p450 synthesis.
In neonates, underdeveloped hepatic function leads to high drug concentration, interfering with mitochondrial ribosomes, causing Grey Baby Syndrome (40% mortality).
How does the lipophilic nature of chloramphenicol contribute to Grey Baby Syndrome?
Chloramphenicol’s lipophilicity allows it to cross plasma membranes and enter mitochondria, where it disrupts mitochondrial ribosomes, impairing aerobic respiration and leading to tissue hypoxia.
How do different antibiotics target protein synthesis?
Aminoglycosides: Bind to the 30S ribosome, causing misreading of mRNA.
Macrolides and Clindamycin: Bind to the 50S ribosome and prevent translocation along mRNA.
Tetracycline: Interferes with the attachment of tRNA to the ribosome.
Chloramphenicol: Binds to the 50S ribosome and inhibits peptide bond formation.
What do Fluoroquinolones inhibit?
Inhibit: Gyrase and topoisomerase.
Effect: Disrupts DNA supercoiling and replication.
How do Fluoroquinolones work synergistically with β-lactams?
Synergy: Fluoroquinolones enter bacterial cells through pores.
Enhances effect: Works alongside β-lactams for better bacterial targeting.
How do Fluoroquinolones affect intracellular bacteria?
Intracellular action: Accumulates in macrophages and neutrophils.
Effective against: Intracellular bacteria, e.g., Legionella.
What are the side effects of Fluoroquinolones?
Cartilage erosion: Avoid in pregnancy and children under 18.
Liver enzyme inhibition: Can increase the availability of drugs like Warfarin.
What is a side effect of Rifampicin?
Resistance: Develops rapidly; used in combination with other antimicrobials.
How does Rifampicin affect contraceptive pills?
Induces p450 enzyme: Increased metabolism of the pill, reducing its efficacy.
What is the mechanism of action of Rifampicin?
Blocks RNA polymerase: Prevents transcription and RNA synthesis.
What is the bactericidal activity of Rifampicin?
Bactericidal: Effective against mycobacteria, Gram-positive (G+), and Gram-negative (G-) bacteria.
How does Rifampicin act on intracellular bacteria?
Intracellular action: Accumulates inside cells and acts on intracellular bacteria, e.g., Tuberculosis and Leprosy.
How does Rifampicin affect RNA synthesis?
RNA polymerase inhibition: Blocks RNA polymerase, preventing RNA from being made.
What is the mechanism of action of Metronidazole?
Binds and disrupts DNA: Causes DNA damage in bacteria.
Is Metronidazole bactericidal?
Bactericidal: Effective against both bacteria and amoebae
What types of bacteria does Metronidazole act on?
Anaerobic bacteria: Specifically targets anaerobic bacteria.
What is the Disulfiram effect of Metronidazole?
Disulfiram effect: When combined with alcohol, it causes nausea, vomiting, cramps, and vertigo.
How does Metronidazole work at the molecular level?
Reactive nitric oxide group: Metronidazole has a highly reactive group that attacks DNA.
What is the role of folate in bacteria?
Folate: Required for DNA synthesis and amino acid synthesis in bacteria.
Where do we get folate, and how do bacteria obtain it?
Humans: Obtain folate from the diet.
Bacteria: Have a separate “Folate synthesis pathway.”
What is the mechanism of action of Sulfonamides?
Sulfonamides: Structural analogues of PABA (a key substrate in folate synthesis) that bind and block DHPS (Dihydropteroate Synthase).
What is the mechanism of action of Trimethoprim?
Trimethoprim: Inhibits DHFR (Dihydrofolate reductase) in the same folate synthesis pathway.
How do Sulfonamides and Trimethoprim work together?
Synergy: Both target different steps in the folate synthesis pathway, resulting in a combined inhibition of DNA and amino acid synthesis.
Why is folate important for bacteria?
Folate: Essential for DNA synthesis and amino acid synthesis in bacteria.
How do humans obtain folate?
Humans: Obtain folate from the diet.
What is the role of PABA in bacteria?
PABA (P-aminobenzoic acid): Used by bacteria in their folate synthesis pathway.
What are Sulfonamides and how do they work?
Sulfonamides: Structural analogs of PABA, blocking the bacterial folate synthesis pathway.
How do Trimethoprim and Sulfonamides work together?
Synergy: Sulfonamides block DHPS, and Trimethoprim inhibits DHFR, both acting in the folate synthesis pathway.
When should Sulfonamides and Trimethoprim not be used?
Cannot be used with pus: Dead cells create an environment rich in amino acids and nucleotides, reducing efficacy.
What is Kernicterus, and how is it related to Sulfonamides?
Kernicterus: Caused by Sulfonamides displacing bilirubin from albumin, leading to toxic bilirubin accumulation in the brain, especially in newborns.
What type of antibiotic is Polymyxin (Colistin)?
Polymyxin: Cationic peptide antibiotic with both hydrophilic and lipophilic groups.
How does Polymyxin target Gram-negative bacteria?
Polymyxin: Attracted to negatively charged lipopolysaccharides (LPS) on the outer membrane of Gram-negative bacteria.
How does Polymyxin affect the bacterial membrane?
Action: Acts as a detergent, disrupting and permeabilizing the bacterial membrane.
Why is Polymyxin not widely used?
Side effects: Serious neurotoxicity and ototoxicity.
Low volume of distribution: Not well absorbed from the GI tract.
When is Polymyxin used therapeutically?
Topical use: For treating ear and skin infections.
Gut sterilization: Due to poor absorption, effective for sterilizing the gut.
What makes Polymyxin effective against bacterial membranes?
Mechanism: The detergent-like structure disrupts membranes, forming aggregates that destabilize the membrane.
What is the target of Isoniazid?
Target: Enzyme responsible for the assembly of mycolic acids in the outer membrane of mycobacteria.
What is the distribution of Isoniazid?
Distribution: Penetrates host cells.
What infection is Isoniazid used to treat?
Treatment: Primarily used for treating Tuberculosis.
