Tetra and Chloro and Aminoglyco Flashcards
what is the mechanism of tetracylines and what is it derived from
- Tetracycline binds to a site on the 30S subunit and therefore interferes with the access of the aminoacyl tRNA. The antibiotic is derived from the bacteria Streptomyces aureofaciens.
what is the structure of the tetracycline
composed of 4 fused six-membered unsaturated rings
what is unique in the mechanism of action for tetracyclines
Organisms that are susceptible to tetracycline actually have an active uptake mechanism and that’s partly the explanation for tetracycline’s selective toxicity
also has greater affinity to the non-host ribosomes which adds to its selective toxicity and this is demonstrated by the fact that intracellular rickettsiae and chlamydiae can be treated
what are the different infections that tetracylcine can cover
- Chlamydial infections
- Mycoplasma pneumonia
- Lyme Disease
- Rocky mountain spotted fever
- Cholera
Tetracycline is also
bacteriostatic
- How do bacteria become resistant to tetracycline?
because it exists in multi-drug resistance gene cassettes. Bacteria that have these multi-drug resistance gene cassettes are resistant to tetracyclines as well as other antibiotics
PUMP most important mechanism of resistance against tetracycline is the development of pumps that allow bacteria to increase efflux of the antibiotic.
bugs can inactivate tetracycline enzymatically
bacteria alter the target of tetracycline so that the drug won’t bind well due to decreased affinity
for treatment of acne vulgaris and rosacea we use
tetracycline
name two pharmacokinetics about tetracycline
it is orally active and it forms chelates with dairy products Mg, Ca, and Al to produce a non-absorbable complex
the most orally active tetracylcine is
doxycycline
tetracyclines bind to
tissues undergoing calcification (teeth and bone)
tetracylines penetrates well in
tissues such as liver and kidneys
tetracylclines is able to cross the
placenta
what is used to treat someone in a meningococcal carrier state and why
Minocycline has high concentrations in the tears and saliva and therefore has been used on occasion to treat someone who is in the meningococcal carrier state. This is when the person doesn’t have an active infection but the meningococci are present and can be shed in nasal secretions, saliva, and tears
a graph explaining the effect of milk on tetracylcine absorption
how is tetracylcine eliminated
all undergo enterohepatic circulation except for doxycycline glucuronide
renal excretion is important for all except doxycycline which is excreted in feces
tetracylcine is metabolized to varying extents by
glucuronide formation
What types of ADRs are associated with the tetracyclines
GI distress
Deposition in bone an dprimary dentition during calcification (contraindicated in children less than 8 years)
discoloration of teeth
Hepatotoxicity in pregnant women
phototoxicity
vestibular disturbance with minocycline
Azotemia, Fanconi-like syndrome with outdated preparations
drug interactions occur with tetracycline and what
Antacids
Warfarin-due in part to decreased intestinal flora which produce vitamin K
Digoxin
- So if you give people on digoxin tetracycline because of an infection, the normal flora will be lowered in number.
- Therefore now there’s less of the oral dose of digoxin being metabolized by normal flora.
- This will increase the amount of digoxin that’s absorbed and thus increase blood levels of digoxin.
Chloramphenical mechanism is similar to
macrolides and clindamycin
how does resistance play a role against chloramphenicol
- Enzymatic conversion to an inactive product by bacteria (acetyl coA transferase)
- Decreased affinity
what is the spectrum and structure
Spectrum:
H. influenzae
Acute typhoid fever
Ricketsial infections
Anaerobic infections
how is chloramphenicol taken
can be orally active and parenteral preparations also
what are the pharmacokinetics of chloramphenicol
well distributed; even enters CNS in absence of inflammation
Crosses placenta
extensive metabolism by host.
what is the excretion and metabolism of chloramphenicol
extensive metabolism by host. Ultimate product is a glucuronide and it is excretd in urine
what are the adverse effects of chloramphenicol
Hematological
- Hemolytic anemia in G6PDH deficiency
- Reversible anemia, lekopenia and thrombocytopenia- dose related; occurs during therapy
- idiosyncratic aplastic anemia-probably allergic in origin
Gray baby syndrome
Drug interactions because of CYP 450 inhibtion: caution in patients on warfarin, phenytoin
Chloramphenicol and aplastic anemia
The only thing that has correlation with the idiosyncratic aplastic anemia is the number of times you’ve taken chloramphenicol. So if you’ve had chloramphenicol two times for two different diseases, or three times for three different diseases, as you increase the exposure to the drug, you increase the risk of the aplastic anemia
the idiosyncratic aplastic anemia is not dose dependent. It doesn’t matter how much chloramphenicol you give the patient because the aplastic anemia can occur at any dose
what is gray baby syndrome
In the neonate, bilirubin(in excess in babys) and chloramphenicol will compete with eachother for the glucuronic acid. So if the neonate is put on chloramphenicol, its capacity to glucuronidate is so impaired that you wind up with elevated levels of chloramphenicol. Therefore unlike sulfonamide-induced kernicterus, the damage isn’t coming from excess bilirubin in gray baby syndrome but it’s due to the direct toxic effects of chloramphenicol. So you can look at a graph to demonstrate gray baby syndrome where the concentration of chloramphenicol and its metabolites in whole blood is on the y-axis while time after dose is on the x-axis
explain this graph
- In neonates 8 days or younger, the rate at which chloramphenicol levels decline in blood is slow. So neonates cannot get rid of the chloramphenicol fast enough which causes it to accumulate and cause toxic effects. The toxic effects of chloramphenicol are on the mitochondria and unfortunately some neonates can succumb to this condition.
- So one toxic effect of chloramphenicol is failure of the baby to thrive.
- The neonate will also have respiratory distress due to chloramphenicol toxicity because the mitochondria cannot utilize oxygen.
- Chloramphenicol toxicity will also cause bluish-gray skin in the baby.
- In contrast, in children 2 years or older, chloramphenicol levels in the blood decline relatively faster after the drug is given.
what are the therapeutic uses
anaerobic infections due to Bacteroides fragilis
Typhoid fever and H. influenzae meningitis when first line therapy fails or cannot be employed
Pneumococcal or meningococcal meningitis in penicillin-allergic patients
Rickettsial diseases as a substitute for tetracycline in those that are sensitive, ESRD, pregnancy,
what is the mechanism of Aminoglycosides
4 things
they are bacteriocidal
- Aminoglycosides binds to the 30S subunit at a site completely different from the site used by the tetracyclines. The binding of the aminoglycoside to the 30S subunit inhibits formation of the initiation complex. If you can’t initiate translation, protein will not be made
- block further translation so that amino acids cannot be added to growing peptide chain and the antibiotic also causes premature termination of the growing chain
3. have an unusual property in that they actually cause misreading of the mRNA codon. This occurs because aminoglycosides sit on a site on the 30S subunit where the 3 nucleotides of the mRNA codon come together to be read
- Entry across the bacterial cell membrane by aminoglycosides requires an active transport mechanism that needs oxygen. This limits the spectrum of organisms that are sensitive to aminoglycosides. So anaerobes won’t be affected by the aminoglycosides
what is the mechanism of resistance of aminoglycosides?
Absence of the oxygen-dependent transport system
Decreased affinity at the 30s subunit binding site
plasmid associated inactivating enzymes that can acetylate, adenylate or phosphorylate the aminoglyoside
what are the five aminoglycosides that were discussed
kanamycin, amikacin, streptomycin, gentamycin, and tobracin
aminoglycosides have a unique way of averting the resistant bacteria can you explain it
Some bacteria have more than one of these inactivating enzymes while others only have one of the inactivating enzymes.
- Kanamycin can be acted upon by 3 different types of acetylation enzymes which will acetylate an amine on the drug to inactivate it. Kanamycin can also be inactivated by enzymes that will phosphorylate or adenylate various sites on the molecule. One of the acetylation enzymes, ACI, doesn’t work very well but all of the other inactivating enzymes are very good at inactivating kanamycin.
- In the case of amikacin, none of the acetylation enzymes, phosphorylation enzymes, or adenylation enzymes are very good at inactivating the antibiotic. So bacteria are less likely to become resistant to amikacin. Amikacin can thus attack organisms that are resistant to kanamycin because the inactivation enzymes are good at inactivating kanamycin but not amikacin. So this is one of the few situations where you can use another aminoglycoside to treat a patient who seems to have developed bacteria that are resistant to the first aminoglycoside you gave.
gentamycin, tobramycin and amikacin are effective against but not effective against
Gentamycin and amikacin and tobramycin are another set of aminoglycosides and they are both effective against Gram negative aerobic bacteria like Pseudomonas aeruginosa. They are not effective against Gram positive organisms
streptomycin is used to treat
mycobacterium tuberculosis
aminoglycosides are also effective agains
tularemia and enterococci
list some combinations between Aminoglycosides and other drugs
Aminoglycoside are often used in combination either with a β-lactam or vancomycin as a means to get maximum killing. Aminoglycosides, β-lactams, and vancomycin are all bactericidal. So this is a place where it’s appropriate to give these drugs together. If you’re giving an aminoglycoside and a β-lactam (or vancomycin) to a patient, you’re probably going to give them intravenously since this combinatorial therapy is usually used to treat serious infections and you don’t want to rely on oral absorption. You don’t want to give an aminoglycoside in the same area and at the same time that you’re giving the β-lactam (or vancomycin) because they actually precipitate eachother by forming a salt. So you might have to have two IV lines in the patient and separate them far apart from eachother. But once the β-lactam (or vancomycin) and the aminoglycoside get into the blood, there’s enough buffering and dilution effects that precipitation won’t occur. You only worry about precipitation when the two sets of drugs are outside of the patient’s body and therefore you don’t want them mixing with eachother at that point
what are the pharmacokinetics of Aminoglycosides
Parenterally
once a day dosing because it exhibits dose dependent killing
Distribution-extracellular fluid, it does not enter CSF
Cross the placenta
Concentrated in renal cortex and endolymph
excretion of aminoglycosides are dependent on
glomerular filtration and must be therapeutically monitored
explain this graph
- So if you’re giving gentamycin 3 times a day, each dose is going to cause the blood concentration of the drug to go up to 10 μg/mL which is above the minimum threshold concentration. The blood concentration of the dug will then slowly go down as time passes on and will go below the minimum threshold concentration at about 6 hours after the dose was given. Therefore if you’re giving a dose of gentamycin every 8 hours, you still have 2 more hours to go until you give the next dose of gentamycin and thus 2 out of 8 hours after each dose is given will be spent below the threshold. This effect is seen each of the 3 times you give the dose of gentamycin throughout the 24 hours in a day. So if you’re giving gentamycin 3 times a day, how much of that time is spent above the threshold? You spend 18 hours of the day (i.e. 75% of the day) above the threshold concentration if you’re giving gentamycin 3 times a day.
You can instead give gentamycin in a single dose which is 3 times the single dose that would be given 3 times a day. So now the blood concentrations of gentamycin start off at 30 μg/mL at the beginning of the day. The blood levels of gentamycin will still lower over the course of the day and they will cross the threshold at the 12 hour mark. So if you give one dose, you’re spending 50% of the time in a day above the threshold. So even though you give a higher dose of gentamycin initially in comparison to giving the drug 3 times a day, you only spend 50% of the day (as opposed to 75%) above the threshold which means that you’ve lowered the risk of the adverse events associated with aminoglycosides. So these days you are likely to only give aminoglycosides once a day since the clinical outcomes in terms of getting rid of the infection are the same and the adverse effects in many cases are actually lessened
aminoglycosides have what special effect
Aminoglycosides have a post-antibiotic effect where they can still exhibit bactericidal effects even after the antibiotic has been stopped
what are some toxicity associated with aminoglycosides
- Aminoglycosides cause vestibulocochlear nerve (CN VIII) damage which means they’re ototoxic.
- You don’t want to give aminoglycosides during pregnancy because auditory toxicity can occur in the fetus as well
- Like vancomycin, aminoglycosides can cause nephrotoxicity although the risk for nephrotoxicity with vancomycin use is less. So not only are aminoglycosides dependent on renal function, but they can impair it as well
- Like clindamycin, aminoglycosides also cause some interference with neuromuscular function
- You don’t give aminoglycosides to people with impaired muscle function.
what are the patient factors affecting dosing of aminoglycosides
age
obesity
renal function
pregnancy
DONT LOOK:hepatic function(THERE ARE NONE)
