AMC - Overview of currently used Abx - exam 1

all done slides and notes from class

how to treat a dental abscess

extraction of molar and initial treatment - 5 days augmentin (amoxicillin/clavulanic acid)
follow up treatment - 5 days amoxicillin, 5 days metronidazol

abx def

an agent that specifically kills or inhibitors the growth of a bacterium

abx types

natural, semi-synthetic (modified natural compound), synthetic

cell wall importance for abx

important permeability barrier and often determines activity of antibiotics - gram +vs has 1 membrane and a thick peptidoglycan layer; gram -ve has 2 cell membranes and thin peptidoglycan

common gram+ pathogens (3)

staphylococcus aureus, streptococcus (S. pneumoniae, S. pyrogenes), listeria monocytogenes

5 important gram -ve pathogens

pseudomonas aeruginosa, escherichia coli, salmonella (S. typhi, S. enterica), neisseria (N. meningitidis, n. gonorrhoae), klebsiella pneumoniae

5 classes of bacteria

mycobacteria, gram negative, gram +ve, chlamydias, rickettsias

what classes of bacteria are 98% of infections in NL

gram -ve and gram +ve

broad vs narrow spectrum abx + egs

broad - work for many diff types of bacteria, eg tetracyclines which work for gram -ve, gram +ve, chlamydias and rickettsias; streptomycin which works for mycobacteria and gram -ve bacteria; penicillins which work for gram -ve, gram +ve and some chamydias
narrow - only work for some, eg isoniazid - only some mycobacterium, polymyxins - only some gram -ve

when should you use broad vs narrow spectrum

broad if you dont know the cause, if you do know the cause then narrow is often better

egs of obligate intracellular pathogens

rickettsia, chlamydia - difficult for abx to target cause they need to go inside the cell

bactericidal vs bacteriostatic abx (when are they useful also) `egs

bactericidal - kills the bacteria - very helpful,
bacteriostatic - inhibits the growth of bacteria - can be used and then immune system handles the rest,

egs of bacteriostatic and bactericidal abx (3;2)

bacteriostatic: tetracyclines, aminoglycosides, sulfonamides
bactericidal: beta lactam, quinolone

what do tests (like Kirby Bauer disk diffusion) test?

Minimal inhibitory concentration - to test minimal bactericidal concentration would have to take the bacteria out and see if you can culture them again

how do diff gen abx work

many abx discovered as natural compounds and then improved over time

1st gen abx descr

can work sufficiently but the compounds were never intended as medicine (ie to work in a vertebrate) - have suboptimal ADMET

2nd gen abx - using example of tetracyclines

chemical modifications to increase absorption and stability, lower toxicity, preserve effectivity; also for broadening the working spectrum of the antibiotic; 2nd gen of tetracycline is doxycyline which is semi-synthetic

what is this - label top and bottom - what can you change

doxycycline - top is upper peripheral modification region (can change side groups and keep activity while improving ADME); bottom is lower peripheral non modifiable region (need to keep it the same)

3rd gen abx

when bacteria develop resistance, new abx needed - eg tigecycline cannot be pumped out by efflux pumo

what does this show

1st gen, 2nd gen and 3rd gen tetracyclines

most important group of antibiotics

beta lactams

penicillin functional groups - (left to right)

N-acyl group, beta lactam ring, thiazodiline ring ; 6-aminopenicillanic acid

penicillin G features (2)

gram +ve activity, beta lactamase sensitive

what is the target of beta lactams

peptidoglycan biosynthesis, normally peptidoglycan cross linking by transpeptidase gives rigidity to bacteria - very tight layer, penicillin binds to transpeptidase which prevents it from cross linking and greatly weakens the peptidoglycan layer, killing the bacterium; beta lactam ring resembles D-Ala-D-Ala

what is this a mechanism of

penicillin

diff between left and right (what are the arrows pointing at?)

left: penicillin - bond that is cleaved by PBPs but resulting enzyme-antibiotic bond cannot be resolved
right: D-Ala-D-Ala, bond that is cleaved by PBPs

penicillin G descr

benzylpenicillin, only parenteral (ie not oral) administration; spectrum: excellent gram + and anaerobe activity; used for serious infections causes by streptococci; active against some gram -ve (eg N. meningitidis)

what do diff penicillins change

N-acyl group

label top to bottom

penicillin G, amoxicillin, flucloxacillin

3 types of penicillins descr

amoxicillin - spectrum: excellent gram+ (inc eterococci) and anaerobic activity, broader gram- activity than penicillin G, good bioavailability → oral administration
flucloxacillin - semisynthetic penicillin resistant to the action of penicillinases, infections by S aureus (not MRSA tho)
piperacillin - broad gram- activity, inc. P. aeruginosa (but usually w/ beta-lactamase inhibitor tazobactam)

eg of 2nd class of beta lactam abx

cephalosporins - also from natural compounds, have the same mode of action as penicillins

label 1 and 2

1 - penicillins
2 - cephalosporins

cephalosporins what do they have in common in name

all start w/ “cef”

cephalosporins descr - also gen 1 descr

mostly iv administration
1st gen - eg cefazolin, excellent gram+ activity (inc S. aureus), good gram-activity; used in surgical prophylaxis in dutch hospitals

gen 2 cephalosporins

eg cefuroxim, broader gram-ve activity, gram+ activity maintained, emipirical therapy for infections of unknown origin

3rd gen cephalosporins (3 egs + 3 points)

eg ceftriaxon, cefotaxum, ceftazidime (activity against psuedomonas), even broader gram- activity, gram+ activity partly lost (S. aureus), empirical therapy for infections of unknown origin; specific use: meningitis, gonorrhea

3rd group of beta lactam abx

carbapanems - natural compound is thienamycin which is highly instable, 2nd/3rd gen are meropenem, imipenem, ertapenem; very broad gram+, gram- and anaerobic activity; “agents of last resort”

carbapenems - how to recognize

end in “penem”, S is missing in chemical structure

label left to right

penicillin, cephalosporin, carbapanem

resistance against beta lactam abx and what we can do about it

resistance often from beta lactamases - enzymes that hydrolyze beta lactams; class A beta-lactamases (serine beta-lactamases) can be inhibited by clavulanic acid or the derivative tazobactam

other antibiotics that work at the cell envelope- 1, egs, what is it a product of

glycopeptides, eg vancomycin, teicoplanin, product of soil bacterium amycolatopsis orientalis - huge compounds - natural

features + administration and usage of glycopeptides

active against most Gram+ bacteria, also anaerobe, no gram- activity;
administration and usage - iv - serious infections w/ gram+ bacteria resistant to beta lactams (MRSA) and for patients allergic to beta lactams
oral - intestinal infection w/ c. diff

descr

glycopeptide antibiotic mechanism - glycopeptide binds on peptidoglycan and prevents transpeptidases from cross linking

another abx working at the cell envelope - 2

colistin (polymyxin E), cyclic polypeptide w/ molecular weight of 1155 (HUGE); product of paenibacillus polymyxa, acts as as a detergent to permeabilize bacteria cell membrane (excellent gram- activity, esp pseudomonas)

what is use of colistin limited by

nephrotoxicity

current uses for colistin

reserve abx to treat infections w/ gram- bacteria resistant against other abx, topical use (ear drops), aerosol to treat lung infections of patients w/ cystic fibrosis

how can antibiotics work at the ribosome?

bacteria have a diff ribosome from us, prevents it from attacking our ribosomes

4 types of abx working at the ribosome

chloramphenicol (binds to 50S - inhibits formation of peptide bond)
macrolides (binds to 50S - prevents translocation - movement of ribosome along mRNA)
tetracyclines (interfere w/ attachment of tRNA to mRNA-ribosome complex
aminoglycosides (changes shape of 30S portion, causes code on mRNA to be read incorrectly)

aminoglycosides - 3 egs and more info

gentamicin, tobramycin, streptomycin (TB DRUGS CAUSING HEARING LOSS)
found in 1940s as a product of streptomyces spp; active against most gram- bacteria & staphylococci, no anaerobic activity (uptake O2 dependent); topical or iv administration, rapid resistance and toxic (ototoxic & nephrotoxic) - limited use

tetracyclines descr

identified in 1940s as a product of soil bacteria (streptomyces); very broad spectrum - active against many gram+ and gram- & some anaerobic bacteria, ALSO mycoplasma, chlamydia, rickettsie, borrelia; oral administration - well tolerated - widespread use in outpatient settings (skin & soft tissue infections, respiratory tract infections)

macrolides egs (3)

erythromycin (product of streptomyces erythreus), clarithromycin, azithromycin (semi-synthetic derivatives)

what are macrolides active against

most gram+ and some gram- bacteria (haemophilus, influenzae, campylobacter, legionella), some mycobacteria, mycoplasma, chlamydia

is clindamycin a macrolide abx?

NO but has the same mode of action (blocking ribosome 50S)

what is clindamycin active against

most gram+ bacteria, excellent anaerobic activity, also some antiparasitic activity (malaria, toxoplasma)

clindamycin features

excellent bioavailability/tissue penetration/intracellular accumulation - widely used in outpatient settings (eg skin and soft tissue infections, respiratory tract infection, intestinal infections), BUT be careful of C. diff risk

fluoroquinolones mode of action

bind to DNA gyrase and topoisomerase IV → inhibition of DNA unwinding which causes double stranded DNA breaks

how to tell if something is a fluoroquinolone

ending of “floxacin”

fluoroquinolines 3 egs

ciprofloxacin, levoflocaxin, moxifloxacin

fluoroquinolones descr + 1st gen and how you get to fluoroquinolones

synthetic group of abx, discovered as a side product of chloroquine synthesis, 1st gen - nalidixic acid, addition of fluorine - fluoroquinolones

ciprofloxacin descr features

excellent gram- activity (inc pseudomonas aeruginosa), some gram+ activity (staphylococci); newer agents have improved gram+ activity (levofloxacin) and anaerobic activity (moxifloxacin)

which abx does blocking of DNA integrity/synthesis + descr

metronidazole - member of nitroimidazole class, prodrug that is reduced under anaerobic conditions - active compound causes DNA damage; active against anaerobic bacteria and some protozoa

metronidazole - administration, resistance

administration - iv or oral, various infections involving anaerobic bacteria, advised to avoid alc consumption (important!!), works in abscess where most other abx done work
resistance - rare in more anaerobes (but species dependent)

co trimoxazole what is it

combination of trimethoprim and sulfamethoxazole - inhibition of folic acid biosynthesis

co trimoxazole descr features

excellent gram- activity, some gram+ activity (staphylococci) - unreliable for enterococci and many streptococci bc of capacity to take up folic acid;
good bioavailability - commonly used in out-patient settings (eg UTIs)

label top 1

beta lactams; peptidoglycan biosynthesis (PBP inhibition); penicillins (strep, staph), cephalosporins (surgical prophylaxis, meningitis), carbapanems (last resort)

label 2

glycopeptides; peptidoglycan biosynthesis (binds D-Ala-D-Ala); vancomycin (MRSA), oral for C. diff

label 3

aminoglycosides, tetracyclines, macrolides; protein synthesis (ribosome); gentamicin (gram-, toxic), doxycycline (broad spectrum), azithromycin (respiratory infections)

label 4

fluoroquinolones; DNA gyrase/topoisomerase IV; ciprofloxacin (gram- inc. pseudomonas), levofloxacin (respiratory)

label 4

metronidazole; DNA damage (anaerobic conditions); anaerobic infections, protozoa, avoid alcohol

label last

co-trimoxazole (trimethoprim & sulfonamide); folic acid synthesis inhibition; UTIs (e coli, depending on resistance)