Antibiotics I Flashcards
What are Abx and where do they come from?
molecules produced by one organism which inhibit the growth of another organism.
most are originally produced by fungi or bacteria, a few are purely synthetic
5 major classes of Abx
- Antimetabolites (inhibit synthesis of nucleotides)
- Inhibitors of Peptidoglycan Synthesis
- Inhibitors of Protein Synthesis
- Inhibitors of DNA-stability
Inhibitors of RNA synthesis
what is meant by selective toxicity, in terms of Abx
Abx need to be toxic to something in the bacteria, that is not toxic to the host
What are the two things Abx target in order to be selectively toxic (toxic to bacteria but not to the host)
- something in the bacteria, but not in the host (ie enzymes to make peptidoglycan)
- something that differs from the corresponding molecule in the host (i.e. ribosome)
Therapeutic index
The Toxic Dose for 50% of people/the Effective dose for 50% of the people (TD50/ED50)
define the “spectrum” of Abx
the species against which an Abx is typically effective
- it can be associated with characteristics of a bact (gram pos. v gram neg., aerobic vs anaerobic, specific species)
3 determinants of Abx efficacy
- ability of abx to reach target
- ability to bind target and inhibit function
- ability of abx to resist inactivation
when is Abx susceptibility testing performed (2 times)?
- when the abx has therapeutic potential for that organism at that infected body site
- if the susceptibility can’t be predicted from the species of organism
Minimum Inhibitory Concentration (MIC) for Abx
the concentration of Abx which inhibits the visible growth of the bacteria (found by putting the bacteria in vials with increasing levels of Abx). this is the common method for determining abx susceptibility
Minimum Bactericidal Concentration (MBC)
the concentration of Abx which kills 99.9% of the bacteria (found by growing the subculture on an agar). this is rarely used to determine abx susceptibility
Disk Diffusion Abx Susceptibility Testing/Aka a Kirby Bauer Test
put many Abx onto a plate and try to culture bacteria. Abx that are effective agst the bacteria will form clear circles around them. The bigger the clear circle, the more effective the Abx and so the lower the Minimum Inhibitory Concentration (MIC)
Baceriostatic Abx
block the growth of bacteria (so that the immune system can kill them)
Bactericidal Abx
kill the bact
Bacteriostatic Abx are effective agst most infections, but bactericidal Abx are better for the treatment of what two diseases and in what type of person?
bactericidal Abx = better for:
- endocaritis
- meningitis
- immunocompromised pts (ie on steroids or HIV +)
Indifference vs antagonistic vs synergistic combos of Abx
indifference: when the combination of both is no different than the effectiveness of 1
2. antagonistic: when using both gives worst results than using one (ie you give a bactericidal Abx which can only be effective during replication, but you also give a bacteriostatic which halts replication)
3. synergistic: the combo of drugs is more effective than either alone
5 classes that are usually bactericidal
- aminoglycosides
- Rifamycins
- cell-wall synthesis inhibitors
- daptmycin
- flouroquinolones
3 classes of usually bacteriostatic Abx
- protein-synthesis inhibitors other than aminoglycosides
- trimethoprim (antimetabolites)
- sulfonamides (antimetabolites)
4 mechanisms of synergy
- one abx allows second abx to reach a greater concentration at site of activity
- one abx enhances binding of the second
- one abx blocks destruction of the second
- two abx partially inhibit separate steps of a synthetic pathway
Pharmacokinetics
the absorption, districution, metabolism and excretion of drugs
4 means of administering Abx
- topical
- oral
- IV
- intramuscular
what are topical abx used for?
topical infections only!
advantages, disadvantages and uses of oral abx
advantages: convenient, some drugs aren’t absorbed, so you can treat bacteria in the gut
disadvantages:
- systemic levels are variable (depends on absorption, breakdown and exretion)
- some might not get absorbed
uses:
-most outpt care
advantages, disadvantages and uses of IV abx
advantages: - bypass absorption disadvantage: - inconvenient (has to be administered at medical facility, or have a nurse sent to a home) uses: -serious infections - organisms resistant to oral meds
advantages, disadvantages and uses of intramuscular abx
advantage: - bypass absorption disadvantage: - inconvenient - painful uses: -occasional outpt txt
what effect does the anatomic separation between circulation and the CNS or prostatic tissues have on Abx concentrations
it reduces diffusion of most abx into these tissues
what sorts of drugs will reach high concentrations in prostatic tisues? why?
basic drugs like trimethoprim and fluoroquinolones because they’re attracted to the acidic prostatic secretions
how is abx concentration regulated in the CNS when there’s no infection? when there is infection?
when there is no inflammation in the CNS, penicillin will diffuse in low concentrations across the blood brain barrier (BBB), pass through the choroid plexus and is sent back out into systemic circulation, keeping penicillin concentrations very low.
If there is inflammation in the choroid plexus, however, the penicillin stays inside the CSF and so concentrations of peicillin quickly increase
which 3 abx reach adequate levels in the CNS in the presence of inflammation?
- penicillin
- ampicillin
- 3rd and 4th generation cephalosporins
2 antimetabolite abx
- trimethoprim
2. sulfonamides
the importance of folic acid, and where does it come from in bacteria?
folic acid is needed for the synthesis of DNA because it allows the transfer of 1 Carbon to form thymidine, purines and some aa
bacteria are capable of making folic acid themselves (mammals bring it into the cell from EC sources)
tetrahydrofolate
a folic acid derivative necessary to make thymidine, purines and aa
what enzyme that is only present in bacteria do sulfamides work on?
dihydropteroate synthase (which converts pteridine and PABA into Dihyropteroic acid (on the pathway to make a folic acid derivative)
what enzyme that is present in hmans and bacteria does trimethoprim work on?
dihydrofolate reductase which converts dihydrofolate into tetrahydrofolate (which can add single carbons to make thymidine, purines and aa)
sulfonides and trimethoprim are synergistic because they
are a sequential blockade of the pathway to synthesizing tetrahydrofolate, which inhibits thymidine, purine and aa synthesis
Sulfonides are analogues of what and work on what enzyme?
PABA analogues that inhibit dihydroperoate synthase from making dihydropteroate out of pteridine and PABA
trimethoprim are analogues of what, and they work on which enzyme to inhibit production of tetrahydrofolate?
Pteridine analogues that work o dihydrofolate reductase
what class of drugs are dihydropteroate synthase (DS) inhibitors?
sulfonamides
what class of drugs are dihydrofolate reductase inhibitors (DHFR)
trimethoprim
sulfonomides are monotherapeautic for…
UTIs
bacterial spectrum for sulfonamide (Dihydropteroate Synthase (DS) inhibitors) and trimethoprim (Dihydrofolate reductase (DHFR) inhibitors)
most bacteria
TMP (trimethoprim)/SXT (sulfonomides) are used together for many infections, especially (2)
- GI infections (enterobacteriaceae are often susceptible)
2. S aureus (including MRSA)
adverse effects of sulfonamides
adverse effects involve the skin:
- hypersensitivity is common (immune mediated itchy skin– usually not severe)
- rare severe adverse effects (stevens-Johnson syndrome (loss of superficial layers of skin and mucus), anemia due to hemolysis with G6PD)
adverse effects of trimethoprim
- rarely causes bone marrow suppression by inhibiting human DHFR (people with low folate = more susceptible) leading to anemia, granulocytopenia, throbocytopenia
* all = reversible by stopping the drug
what is the folate pathway required for?
biosynthetic stepsperformed by all organisms
Class of drugs that are Inhibitors of DNA-Stability
Flouroquinolones and Quinolones
adverse effects of quinolones
- tendinitis and rupture occors rarely in adults
- may predispose to cardiac arrhythmias (avoid using with antiarrhythmics)
*cartilage erosion occurs in juvenile animals, but doesn’t seem to happen in children
2 classes of inhibitors of RNA synth
- Rifamycins
2. Fidaxomicin
mechanism of Fidaxomicin (and RNA synth inhibitor)
It binds the RNA-polymerase-DNA complex and blocks the separation of DNA strands
Mechanism of Rifamycis (a DNA synth inhibitor)
It binds the Beta subunit of RNA polymerase in the RNA-Polymerase-DNA complex and blocks progression of nuc. acids through the DNA/RNA channel, inhibiting new bonds on the RNA chain (so RNA chain can’t be constructed)
Rifamycin spectrum, and how it’s used
broad spectrum of activity and it’s highly lipid soluble leading to excellent tissue penetration, but resistance rapidly develops with monotherapy
- used in combination for txt serious infections like: myobacterial infections (tb) and staph endocarditis/joint infections
adverse effects of rifamycin (3)
- tears, urine and saliva turn orange
- hepatic failure in pt with another source of injury (ie another drug)– this is rare
- increased expression of metabolic enzymes leading to increased metabolism of many drugs
spectrum/use of fidaxomicin
- Poor lipid solubility, so poor PO adsorption, so it stays in the GI tract
- variable activity against Gram +, but as good as vancomycin to fight C diff
even though fidaxomicin is as effective as vancomycin for curing C diff and relapse with fidaxomicin is less common, why is it not currently used for C diff generally?
too expensive and too new
when is fidaxomicin used instead of vancomycin to treat c diff?
with people who either didn’t recover on vancomycin, or who relapsed after taking vancomycin
two topoligical challenges faced by mammals and bacteria during transcription and DNA replication?
- separation of the two strands of DNA leads to supercoiling
- after DNA replication the parent and daughter strands are “catenated” (linked together)
what are gyrase and topoisomerase IV?
two enzymes that work together to cut the double stranded parent DNA to release the daughter DNA, and then reform the bond in the parent DNA
mechanism of Quinlones (DNA stability inhibitor)
block the activity of the Gyrase and topoisomerase activity IV after they have cut the parent DNA, so there is no repair of the parent DNA. The presence of the double stranded DNA leads to bacterial death
spectrum of flouroquinolones
there are several available, each with a different spectrum: some gram pos, some gram neg, some for anaerobic bact and some for mycobact
naladixic acid, a quinolone is used for txtmt of…
UTIs
difference btwn quinolone and flouroquinolone
flouroquinolone has an added fluorine which increases the blood levels, penetration and half life of the quinolones
