6. Antimicrobial Therapy Flashcards
Define the following:
a) antibiotic
b) broad spectrum
c) bacteriostatic
When should you use a bacteriostatic vs a bactericide?
a) naturally occuring product active against bacteria
b) kills most germs
c) prevents bacteria multiplying e.g. erythromycin (bactericidal = actively kills bacteria e.g. beta-lactams like penicillin)
Depends on microorganism and antibiotic concentration. Important if immune system is compromised (e.g. neutropaenia). Inadequate penetration to infection site (e.g. osteomyelitis, endocarditis).
Distinguish between synergistic and antagonistic antimicrobial combinations.
Give an examples of antimicrobial agents with a high theraputic index and a low theraputic index.
List some classes of bactericidal and bacteriostatic antibiotic.
Synergistic: if their combined activity is greater than the sum of the individual activities e.g. B-lactam (e.g. penicillin) and aminoglycoside (e.g streptomycin).
Antagonistic: if the activity of one drug is compromised by the other e.g. tetracycline associated with B-lactam, or 2 B-lactams together
High TI: B-lactam Low TI: aminoglycosides
Bactericidal: B-lactams, aminoglycosides, glycopeptides (e.g. vancomycin), quinolones (e.g. levofloxacin)
Bacteriostatic: sulfonamides (e.g. sulfanilamide), tetracyclines, macrolides (e.g. erythromycin), chloramphenicol
Which antimicrobials work on the following sites of action:
Distinguish between gram +ve and -ve cell walls
a) cell wall synthesis: B-lactams, glycopeptides
b) DNA-directed RNA pol: rifampicin
c) Protein synthesis (50S inhibitors): macrolides
d) Protein synthesis (30S inhibitors): aminoglycosides, tetracyclines
+ve: lipotechoic acid (functions as antigen) and thick peptidoglycan CW
-ve: thinner peptidoglycan CW, phospholipid bilayer, porin proteins allowing small molecules to pass through, polysaccharide (anitgen)
List some mostly gram +ve antimicrobials.
List some mostly gram -ve antimicrobials.
LIst some broad spectrum antimicrobials.
Penicillins, macrolides, clindamycin, glycopeptides, daptomycin, oxacolidinones. All work on streptococci and some on staphylococci and enterococci. Fusidic acid.
Polymyxin (colistin), trimethoprim, aminoglycosides (also active against strepto/staphylo/enterococci), monobactams (aztreonam), temocillin
B-lactams: carbapenems, amoxicillin, piperacillin, cephalosporins. Chloramphenicol. Tetracycline.
Where do B-lactam agents (penicillins, cephalosporins (4 generations), carbapenems, aztreonam) and glycopeptides (vancomycin and teicoplanin) act?
How can penicillin be delivered?
What is it used for?
What are some known issues?
The bacterial cell wall composed of peptidoglycan. Bind to penicillin binding protein and prevent CW synthesis. Glycopeptides insert into CW. Monobactams disrupt CW
Oral or IV. Inhibits transpeptidation of cell wall (bactericidal).
Used for meningitis, pneumonia, respiratory tract infections, and syphillis.
Issues: resistance, allergies, cross-hypersensitivity
Answer the following regarding glycopeptides (vancomycin/teicoplanin):
a) mechanism of action and spectrum
b) side effects and resistance
c) administration route and penetration
d) dosing regimin
e) clinical use
f) mechanism of microbial resistance
a) acts on cell wall. Gram +ve only (incl. anaerobe C.diff)
b) nephrotoxic. VRE
c) IV. Large molecule, poor penetration - none into CSF
d) 1-2 times/day
e) problem gram +ve infections
f) alteration of binding site
Which antimicrobial agents inhibit protein synthesis?
How can aminoglycosides (e.g. streptomycin, amikacin) be delivered?
What is it used for?
What are some known issues?
Aminoglycosides, tetracyclines, chloramphenicol, macrolides (e.g. erythromycin), clindamycin, fusidic acid. NB only aminoglycosides are bactericidal.
IM or IV, topical, nebulised. Irreversibly inhibit protein synthesis. Bactericidal
Almost always used along with a cell-wall synthesis inhibitor. Used for pneumonia, MRSA, G- and some G+ bacteria, endocarditis, bacteremia, sepsis, UTIs, GI/GU procedures.
Ototoxicity (rev vestibular and irrev auditory), nephrotoxicity (rev), NMJ blockade (high dose), pregnacy cat c drug
How can macrolides (e.g. erythromycin) be delivered?
What is it used for?
What are some known issues?
Oral, IV. Binds to 50S and blocks transcription in protein synthesis. Bacteriostatic
Upper respiratory tract infections (pharyngitis, tonsillitis, sore throat), ottis media, lower respiratry tract infections (pneumonia, MAC, Legionnaire’s), Ulcers (H. pylori) - drug combo incl. clarithromycin, uncomplicated skin infections (staph), STDs
Nausea, vomiting, diarrhea, abdo pain, liver toxicity, drug interactions
List 3 agents affecting nucleic acid metabolism.
How can fluoroquinolone be delivered?
What is it used for?
What are some known issues?
Quinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin - these are the only oral anti-pseudomonal agents), Rifampicin, Metroidiazole (active against most anaerobes)
Oral, IV. Inhibits DNA gyrase and topoisomerase IV. Bactericidal
Opthalmic infections, bone/joint/soft tissue infections, respiratory infections e.g. TB, inhaled anthrax, GI and abdo infections, prostatitis, UTIs, STDs
Tendon rupture, children <18 (cartilage), pregnancy cat C, seizures, prolong QT, dizziness, confusion, photosensitivity.
How does folic acid synthesis differ in prokaryotes and eukaryotes?
Give 2 antifolate examples.
Human cells don’t synthesise folic acid and lack dihydropteroate synthase. Instead they contain dihydrofolate reductase.
Sulphonamides (inhibits dihydropteroate synthase), Trimethoprim (inhibits dihydrofolate reductase 50,000x more active on bacterial enzyme)
Describe the toxicity of membrane disorganising agents, and give 3 examples.
Give examples of antifungals which act on different sites.
In what 2 places are antibiotics used the most?
Generally show fairly poor toxicity b/c similarity of bacterial and mammalian membranes. Amphotericin (antifungal), colistin (polymixin), daptomycin.
Azoles inhibit ergosterol synthesis. Polyenes bind to the fungal call membrane and cause it to leak. Echinocandins inhibit glucan synthesis.
Farming. Healthcare.
What are the issues surrounding farming beind the biggest consumer of antimicrobials?
How can resistance alleles arise in bacteria?
Farm animals = greatest source of bacterial resistance? Raising bigger chickens - broiler chicken size increase. Antibiotics have growth-promoting effect in humans.
A few bacteria in populations that have never been exposed to artificial antibiotics probably carry alleles that give resistance. Can also arise by mutation.
Overuse of antibiotics and no new discoveries for a while = problem!
Approach to antibiotic therapy: what do you need to consider:
a) host factors
b) microorganism/infection factors
c) drug factors
a) immunocompetent vs immunosuppressed, broad vs narrow spectrum, age, pregnancy, allergy
b) empiric (based on experience) vs definitive diagnosis, site of infection (chest usually G+ve, urinary usually G-ve), susceptibility pattern (antibiotic discs)
c) administration route, bacteriocidal vs bacteriostatic, synergy, pharmacodynamics and pharmacokinetics (ADME), excretion, relevant efficacy
44 year old lady with HIV related lymphoma and renal failure, currently having chemotherapy, comes to A and E confused with a fever, and in septic shock. You think she might have meningitis. Do you:
a) Await microbiological results before starting antibiotics?
b) Give empiric therapy with narrow spectrum antibiotics?
c) Give empiric therapy with broad spectrum antibiotics?
d) Give no antibiotics and hope for the best?
What 2 things are important to consider here when picking an antibiotic?
c)
Meningitis: some drugs won’t pass BBB so need one that does. Renal failure so reduce dose of antibiotics.
What are the 2 main resistance mechanisms of bacteria when treated with penicillin?
B-lactamases: hydrolyses B-lactam wall, stops killing activity of B lactams
PBP: some bacteria mutate their penicillin binding proteins so beta lactam ring can’t show any affinity because bacteria changed structure (MRSA)
