3 - Antibiotics 1 Flashcards
A burn patient in the ICU i found to be suffering from a serious bloodstream infection caused by a gram-negative aeorbe identified as pseudomonas aeruginosa. Susceptibility tests on the isolate reveal resistance to amoxicillin. The therapy that would like likely be effective in treating that infection is…?
Amoxicillin and Clavulanic acid
It’s a gram negative bacteria so it has a B-lactam ring. Clavulanic acid is a B lactamase inhibitor so administering it with amoxicillin allows it to be effective again.
What are antibiotics? What is their clinical use?
Molecules that kill bacteria or inhibit their growth. -Can be of biological origin or of (semi) synthetic origin. Clinical use: inhibit specific cellular processes in bacterial cells. Exhibit toxic effects on bacteria by not on humans (selective toxicity).
What is selective toxicity?
Antibiotics exert their activity by inhibiting gene products found in bacterial cells, but not in humans. Ideally such targets are completely absent from humans such as enzymes that make PG or if present in human cells, possess unique properties in bacteria that can be exploited to confer specificity (ribosomes)
What are disinfectants toxic to? What are they used for?
Toxic to humans and bacteria (ie bleach) Nonspecific effects Used to eliminate organisms on inanimate objects and surfaces.
What are antiseptics toxic to? What are they used for?
Generally toxic for bacteria. Non-specific effects (protein denaturation). Too toxic for systemic effects in humans (peroxides, alcohols) but OK for topical use.
Antibiotics can be classified as _______ or ________. Define each term.
Bacteriostatic: inhibit growth of bacteria but do not kill them - rely on immune system to eradicate Bactericidal: kill bacteria directly - important for immunocompromised pts.
What is the pharmacology/bioavailability of antibiotics? What is spectrum activity?
Not all antibiotics penetrate all tissues equally. To be effective, an antibiotic need to get to the site of infection at therapeutic levels. Spectrum activity: collection of bacterial species that is susceptible to a given antibiotic.
Describe the different spectrums of activity of antibiotics?
Narrow spectrum: effective against a relatively small group of bacteria (ie gram + bacteria) Broad spectrum: effective against a wide range of bacteria (ie gram + and gram -)
What is advantage and disadvantage to using broad spectrum antibiotics?
Advantage: can be used when infectious agent is unknown or in an emergency Disadvantage: affects many members of natural microbiota, leading to undesirable secondary effects such as diarrhea and antibiotic resistance.
What does susceptibility mean? How do we determine susceptibility?
Bacteria are susceptible if their growth can be inhibited by concentrations of the antibiotic that can be readily achieved at the site of infection. Determinations of susceptibility made from pure cultures from patients.
Why do we need to measure susceptibility?
Infectious bacteria must be susceptible for an antibiotic to be clinically effective. Not all isolates of a given bacteria are susceptible to an antibiotic so you need to identify the antibiotic susceptibility profile for that specific isolate to determine treatment.
How do we measure susceptibility of bacteria?
We grow the bacteria in a liquid medium to determine: minimum inhibitory concentration (MIC): the lowest concentration of antibiotic that inhibits growth minimum bactericidal concentration (MBC): lowest concentration of antibiotic that kills a defined proportion of bacterial population after specified time. (to be effective an antibiotic must achieve or exceed these at the site of infection in the host).
What are toxic side effects associated with: -Tetracycline -Streptomycin -Chloramphenicol -Penecillin
Tetracyclin: discoloration of teeth Streptomycin: auditory damage Chloramphenicol: anemia Penecillin: anaphylactic shock
What are two adverse effects that have the potential to occur with all antibiotics?
Alteration of normal flora causing antibiotic associated diarrhea/enterocolitis. (C diff a common cause of this). Selection for antibiotic resistance from heritable changes in bacterial genotype that confers enhanced growth in the presence of an antibiotic.
Why is C. difficile an antibiotic associated disease?
Some people may have C diff but at only a small levels, so when they are on antibiotics that kill their normal gut flora, the C diff has a chance to grow and produce toxins A and B that can cause diarrhea.
What are the two ways by which antibiotics usually become resistant?
- Horizontal gene transfer: acquisition of foreign DNA encoding resistance genes; can enable rapid emergence of multi-drug resistant strains 2. Spontaneous mutations: strong selection for growth superimposed on large populations of bacteria can lead to emergence of rare resistant mutations.
What are the three basic mechanisms by which bacteria overcome inhibition by antibiotics?
- Modification (inactivation) of antibiotic molecule itself: cleavage of B-lactams by B-lactamase.
- Modification (reprogramming) of antibiotic target: point mutations in ribosomes or PBPs.
- Reduction of antibiotic concentration/prevent access to target: efflux pumps eject abx frmo cell and can have broad specificity.
What are the main cellular processes that are targeted by antibiotics?
Peptidoglycan Synthesis RNAP and RNA synthesis Key metabolic reactions Ribosomes and protein synthesis DNA replication RNA replication and repair
What is the structure of PG? How does the structure of the cell wall of gram - bacteria impact the effectiveness of antibiotics?
Polymer of alternating sugars (GlcNAc-MurNAc) crosslinked via peptide side chains.
In gram negative bacteria antibiotics need to get through the porins in the outer membrane to get to the PG and have it’s effects. OM is a permeability barrier that restricts the access of antimicrobials into the cell.
Why is PG synthesis a good target for antibiotics?
It must be synthesized during cell growth, and it provides critical structural integrity to bacterial cells that protects them for lysis–therefore growing cells will lyse if PG synthesis is inhibited. PG and the enzymes that synthesize it are unique to bacteria. High specificity and low toxicity for host.
What are the three stages of PG biosynthesis? What is the structure of peptide side chains in PG?
- Synthesis of MurNAc-pentapeptide precursors in the cytoplasm.
- Lipid linkage and transport of disaccharide precursors across the membrane
- Polymerization and cross-linking of precursors into PG occurs extracellularly.
Peptide side chains end in D-ala D-ala
What are the key enzymes in peptidoglycan synthesis called?
Penicillin binding proteins (PBPs): catalyze the polymerization and cross linking of peptidoglycan
How does the B-lactam family of antibiotics work?
B-lactams bind penicillin binding proteins (PBPs) and inactivate them to prevent peptidoglycan crosslinking of the peptide side chains (bactericidal). This inhibits bacterial growth. (all four types of B-lactams do this)
What are the four basic types of B-lactams?
Penicillin
Cephalosporin
Carbapenem
Monobactam
