factors influencing antibiotic choice

where does tetracycline come from? is it considered broad spectrum?
oxytetracycline—produced by streptomyces rimosus; demelocycline—produced by streptomyces aureofaciens. tetracycline is classifies as a “broad-spectrum” antibiotic
are tetracyclines bacteriostatic or -cidal?
bacteriostatic
what is the M/A of tetracycline?
it (reversibly) binds the Active subunit of the 30s subunit of bacterial ribosomes and blocks the binding of amino-acyl tRNA which inhibits protein synthesis
what does bacterial resistance to tetracycline involve?
the TetA resistance protein involves the Mg dependent drug efflux R factor (drug pump) as well as changes in ribosomal binding and production of inactivating enzymes
how do tetracyclines enter bacterial cells?
passive diffusion through the outer wall, active transport through the cytosolic membrane
is there anything that can reduce the PO availabilty of tetracycline?
antacids such as Al, Mg, Ca, Zn, Fe and dairy products will decrease PO absorption
what is the distrobution of tetracyline in the body? how is it excreted?
tetracyline’s distribution is wide, 25% CNS, 50-60% placenta/nursing. its excretion is primarily unchanged in the urine via glomerular filtration and tetracyline will accumulate in renal failure
does tetracyline have activity against chlamydia trachomatis, anthrax, cholera, and lyme disease?
yes w/doxycyline – the most widely used tetracycline
what is a common combination with tetracyline to fight anaerobic bacteria?
doxycyline and cephalosporin
does doxycyline accumulate in renal insufficiency?
no, it is mainly excreted via bile, feces, or inactive conjugate/chelate – therefore it does not accumulate in renal insufficiency
are there any side effects associated with doxycyline?
doxycyline can cause photosensitivity and it will complex with bone
what is beneficial about minocycline vs doxycyline?
minocycline is more lipid soluble ( 100% PO bioavailability), so it gets into CNS better as well as better for acne b/c of skin penetration, (propionibacterium acnes)
can tetracyclines be used against gram +?
gram + such aas staph/strep are susceptible to tetracyclines, but other drugs are preferred due to bacteriostatic action/increased resistance
can tetracyclines be used against gram -? pseudomonas?
yes, against e. coli, h. influenzae, k. pneumonia (3rd line drugs), however it they are ineffective against pseudomonas
what are the main indications for tetracyclines?
lyme disease- borrelia burgdorferi, GI ulcers- helicobacter pylori, rocky mountain spotted fever- rickettsiae, chlamydia and cholera
what are the ADRs for tetracyclines?
photosensitivity, skeletal defects in developing children/fetuses, neurotoxicity/vertigo, expired drugs can cause nephrotoxicity
what is the chemical structure of the aminoglycosides?
aminoglycosides are polar sugars and differ via various substitutions on the R position
where do aminoglycosides come from?
aminoglycosides were orginally produced by soil bacteria, but synthetic products are used more
how does aminoglycoside M/A compare to tetracylcine?
aminoglycosides are bacteriocidal due to irreversible binding to the 30s bacterial ribosomal subunit @ the AUG site (initiation codon), causing premature termination of protein synthesis. they diffuse through porins in the outer call and are actively transported through the cytosolic membrane in an 02-dependent process, (thus ineffective against anaerobes), and produce an additional destructive membrane effect. tetracyclines only bind it reversibly 30s subunit.
what does bacterial resistance to aminoglycosides look like?
resistance to aminoglycosides includes production of microbial enzymes, acetylases, phosphorylases, adenylases, as well as impaired entry into the cell and an altered binding receptor protein on the ribosomal subunit
which aminogylcoside do bacteria have the least resistance to? the most?
amikacin has the least amount of bacterial resistance, tobramycin has the most, (not very good against resistant bacteria)
are aminogylcosides water soluble? what is their PO ability? do they have any CNS penetration? what is their half life like? protein binding? do they have a post-antibiotic effect? is excretion changed in urine?
aminoglycosides are water soluble, have poor CNS penetration, poor PO and since their excretion is unchanged in urine, dosage must be adusted in renal dysfunction. they have a 2-3 hr half life, low protein binding, (10%), however its residual cical effect lasts longer than MIC in plasma – allowing for once/day dosing, (conc. dependent)
where do aminoglycosides concentrate?
they can concentrate in the lymph/perilymph (ear) – very ototoxic, risk of hearing loss in children
why are aminoglycosides given in once-daily dosings?
the aminoglycoside cidal effect is conc-dependent, with significant a post-antibiotic effect. aminoglycoside toxicity is both time and conc. dependent, and once the toxicity threshold is met – time above this threshold is critical for toxicity. therefore multiple smaller daily doses of the drug increase the time above the toxicity threshold more than one daily single dose
how are aminoglycosides uses for gram +?
aminoglycoside gram + usage is limited to mainly staph and they are not used alone (due to increased resistance), but in combination with PCN/cephs for serious staph, strep, enterococcal infections
how are aminoglycosides uses for gram -?
serious aerobic gram – infections are the primary indication for aminoglycosides, which are adminstered along with 3-4th gen PCNs for pseudomonas, cephs for klebsiella, and other drugs for serious gram – infections
what are clinical indications for streptomycin? how is it in terms of gram -?
generally used in combination with other drugs via deep IM injection. w/PCN for enterococcal endocarditis, for multi-resistant TB in initial therapy, w/PO tetracyclines for tularemia/plague (y. pestis). it has less gram – rod activity than other aminoglycosides
what is the most widely used systemic aminoglycoside?
gentamycin, which is less expensive and active against serratia, better than tobramycin against enterococci when in combination w/PCN – however streptomycin is still preferred w/PCN for enterococci
is tobramycine effective against pseudomonas?
yes, however they are less effective against pseudomonas
what are the clinical indications for netilmicin?
netilmycin is more resistant to microbial enzymes, and is used in gentamycin resistance. it is otherwise comparable to other aminoglycosides
what are the clinical indications for amikacin, an aminoglycoside?
amikacin is more expensive, but is also the least resistant to microbial enzymes due to protective sidec chain substitutions. it is used in gentamycin and tobramycin resistance
what are ADRs for aminoglycosides?
ototoxicity, (esp with amikacin), damage to hair cells, degeneration of the vestibulocochlear nerve (CN VIII). someone with CHF should not be given aminoglycosides (possible permanent hearing loss), they should be given a loop diuretic. they have some nephrotoxicity, increased BUN, increased serum creatinine, proteinuria (monitor creatinine). some neuromuscuar blockade, respiratory difficulties with anesthetics/neuromuscular blockers, (can be attenuated with Ca++ salts). superinfections are a risk. usually low incidence of allergy
what is septinomycin? when is it used?
septinomycin is similar to aminoglycosides, and is only used when pts are allergic to PCN or gonococci are resistant to other drugs such as fluroquinolones. it may also be used during pregnancy, (in contrast to the aminoglycosides)
what are polymyxin B, bacitracin, mupirocin used in?
ointments
what is the M/A for macrolides? are they bacteriostatic/-cidal
these drugs inhibit the growth of the polypeptide chain and do so at the 50s bacterial ribosomal subunit transferase site. they are bacteriostatic.
where do macrolides come from?
developed by a bacteria: streptomyces erythreus
what is macrolides, and specicically azithromycin (Zpack) used for?
azithromycin has a long half life and is good for noncompliant pts to fight community aquired pneumonia/chlamydia. azithromycin and clarithromycin are good for PCN/cephalosporin allergic people
how do bacteria form resistance to macrolides?
they methylate the 50s binding side, esp seen in gram + bacteria
is the macrolide erythromycin bacteriostatic/-cidal? what are common ADRs?
it is primarily bacteriostatic, (binds 50s/inhibits protein synth). ADRs include ototoxicity, tinnitus, hearing loss, (but not as significant as AGs), as well as GI disturbances, rash and cholestatic hepatitis
why is erythromycin particularly used in fighting gram + infections?
they have resistance to beta-lactamases, and can be used by people allergic to PCN/ceph esp w/strep and pneumococal minor throat/ear infections
how good is the macrolide erythromycin in fighting gram + infections?
pretty broad spectrum – it can be used in chlamydia, gonorrhea, and certain types of pneumonia except gram – enteric organisms
why would macrolide azithromycin be used in fighting sinusitus and community aquired pneumonia? how is its action against gram -?
it has a long half life (2-3 days), which is good for pts non-compliant with tetracyclines. azithromycin has increased gram – activity esp w/h. influenzae, n. gonorrhoeae
what is the spectrum of macrolide clarithromycin like?
it is comparable to erythromycin, but has increased gram – activity esp with chlamydia, leg. pneumophila, mycobacterium avium complex (AIDS, helicobacter pylori, borrelia burgdorferi
what are possible ADRs with erythromycin and clarithromycin?
both inhibt cytochrome P-450s/isoenzyme CY34A4, which may inhibit the metabolism of othe drugs and increase their effect. cardiac arrhythmias are possible with higher doses, and this can happen with drugs that inhibit the metabolism of erythromycin and clarithromycin.
is clindamycin considered a macrolide? what are its uses? is it bacteriostatic/-cidal? does it interact with erythromycin? what is its activity against gram +? ADRs?
no, clindamycin is related to, but not a macrolide. it is mainly used for anaerobic infections, DOC for c. dif. it is bacteriostatic, binding to the 50s, (antagonistic for erythromycin binding). it is active againse most gram + and anerobes. ADRs include GI/diarrhea, superinfections, esp. pseudomembranous colitis due to overgrowth of clostridium difficile within GI tract
what is metronidazole effective against? how does it work? what is it the DOC for?
metronidazole causes DNA strand breaks, is antiprotozoal and is active against anaerobic bacteria. is is the DOC for c. dif. it is a misc. drug
what is quinupristine-dalfopristine? what does it inhibit? when is it used?
quinupristine-dalfopristine is classified as a two drug synergistic combination, binding to different areas on the 50s subunit and inhibiting protein synthesis. this is used when gram + are resistant to vancomycin, (MRSA). it is a misc. drug
what is linezolid? where does it bind? when is it used? what is its activity against streptococci?
it is an oxazolidinone, and similar to macrolides in that it binds at the 50 S subunit. it is used in vancomycin and PCN/ceph resistant cases. it is bacteriocidal for streptococci. it is a misc. drug.
what is chloramphenicol? what is its M/A? what can it cause in infants? what else does it inhibit?
it is similar to macrolides, bacteriostatic, binds 50S, inhibits protein synthesis. it has good PO, wide distribution including the CNS, metabolism glucuronidation (usually deficient in infants) “gray baby syndrome”: depressed breathing, CV collapse, cyanosis, abdominal distension, loose green stools, related to inhibition mitochondria (70S). choramphenicol inhibits CYP450 enzymes, leading to possible drug interactions.
what is a toxicity related to chloramphenicol?
it can cause (dose dependent) bone marrow suppression/anemia due to its inhibitory effect on protein synth and Fe incorporation into heme. mortality increases between treatment and onset of aplastic anemia and there is an increased risk of leukemia in those who develop this and recover
what is often used in combination with aminoglycosides for empiric tx of severe bacterial infections to provide coverage against many staphylococci?
nafcillin