Antibiotics- protein synthesis/nucleic acid synthesis inhibitors & metabolite inhibitors

which drugs affect the 30S ribosomal subunit?

aminoglycosides, tetracyclines

which drugs affect the 50S ribosomal subunit?

macrolides/ketolides, chloramphenicol, clindamycin, quinupristin-dalfopristin

how do prokaryotic ribosomes differ from eukaryotic ribosomes?

ribosomes responsible for translation of mRNA are made of a 30S and 50S comprising of a 70S unit

eukaryotic ribosome:

60S + 40S = 80S

MOA of aminoglycosides:

irreversible binds to 30S ribosomal subunit -> inhibition of translation (bactericidal)

transport of aminoglycosides across the bacterial membrane is oxygen-dependent, therefore these bacteria cannot kill:

anaerobes

Aminoglycosides are often used with what in order to break down the cell wall and facilitate diffusion of aminoglycosides into bacteria?

beta-lactams, especially for treatment of S. Auerus, S. epidermidis

what must we constant check when administering aminoglycosides? why?

plasma concentration of the drug to minimize toxicity, its not metabolized so should be used with caution in patients with renal impairment

Aminoglycosides are typically used to treat infections caused by:

aerobic gram - bacilli, Enterics, Pseudomonas aeuginosa

Streptomycin is an ________ and is administered:

aminoglycoside, IV

which bacteria do streptomycin treat:

Yersinia Pestis (plague), Francisella tularensis (tularemia- other diseases spread by ticks)

which aminoglycoside is the most common? what does it treat and how is it administered?

Gentamicin IV or topical, Infective endocarditis, aerobic gram - bacteria, Pseudomonas aeruginosa

which aminoglycoside is only available topically?

neomycin, nephrotoxin if administered orally

Neomycin (kills both gram + and -) is often available as a triple-antibiotic in combination with what?

Bacitracin (kills gram+), Polymyxin (kills gram -)

list all the aminoglycosides:

tobramycin, amikacin, gentamicin, streptomycin, neomycin

What would lead to resistance of aminoglycosides?

deficiency on ribosomal receptor (part binding to 30S subunit), enzymatic destruction of aminoglycoside, lack of permeability to aminoglycoside

adverse effects of aminoglycosides:

ototoxicity (vertigo/loss of balance), nephrotoxicity, neurotoxicity (neuromuscular blockade resulting in respiratory paralysis - rare)

MOA of tetracyclines

binds reversibly to the 30S ribosomal subunit, preventing attachment of aminoacyl-tRNA-> inhibition translation (bacteriostatic)

examples of tetracyclines:

doxycycline, minocycline, tetracycline, tigecycline

all tetracyclines are administered ____ except for:

oral or IV, Tigecycline is JUST IV

main difference between aminoglyosides and tetracyclines:

aminoglycocides are bacteriocidal while tetracyclines are bacteriostatic

which bugs does doxycycline target?

Rickettsiae infections (rocky mountain fever), Chlamydia, Borrelia burgodoferi (lymes), Mycoplasma pneumoniae, H. pylori, Propionbacterium acnes, Epididymitis, CA-pneumonia, Brucella, Vibrio Cholera, MRSA (staph)

tigecycline in particular is good for:

MRSA soft skin infections,

intra-abdominal infections from B. Fragillis, E. faecalis and E. coli

CA pneumonia from Strep pneumo and mycoplasma pneumonia

tigecycline is also considered to be a:

back pocket drug to limit resistance

tetracyclines bind to ______, hence they should not be taken with:

divalent and trivalent cations, dairy/antacids

Metabolism and excretion of tetracyclines:

undergo little metabolism, excreted in bile

Adverse effects of tetracyclines:

bone/teeth deformities in growing teeth

hepatotoxicity: liver necrosis, esp. in pregnancy

nephrotoxicity: avoid in patients taking aminoglycosides

photosensitivity: drug may accumulate in skin when exposed to sunlight

what photosensitive effects could tetracycline cause in patients?

reaction to suburn

what bone/teeth reactions to tetracyclines cause in GROWING teeth and bones?

bind to Ca+ deposits causing fluorescence, discoloration, and growth inhibition

Macrolides MOA:

Inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes --> block addition of amino acids to a growing peptide chain

macrolides are generally _______ and occasionally _________ for some:

bacteriostatic, bacteriocidal for gram + organisms

examples of macrolides:

Erythromycin, azithromycin, clarithromycin

macrolides are typically administered _______ but can also be available in which forms?

orally, IV and topical (acne)

metabolism and excretion of macrolides:

metabolized well and eliminated in the bile (sometimes the urine) - increased risk of gallstones

which macrolide has the smallest half life?

eryhtromycin (2 hr half life and only 23-35% bioavailability)

which bugs do erythromycin target?

Pneumonia caused by legionella pneumoniae, group A strep, pneumococci, mycoplasma pneumoniae, bordetella pertussis, mapylobacter jejuni

Which macrolide is best for treating peptic ulcers caused by H. Pylori?

clarithromycin

which bugs do azithromycin target?

chlamydia trachomatis, cat-scratch disease from bartonella henselase, URIs sensitive to erythromycin, Hameophilus influenzae, moraxella catarrhalis

which drugs do telithromycin target?

Legionella, Chlamydia, CA-pneumonia

clindamycin can be available topically for :

acne

what are some adverse effects of macrolides?

GI irritation (esp with erythromycin)

Rare cholestatic hepatitis

Ototoxicity: tinnitus/impaired hearing

PROLONGED QT INTERVAL

due to the potential for a prolonged qt interval, macrolides can potentially lead to:

torsades de pointes: fatal arrythmia

Erythromycin and clarithromycin inhibit ___________ which can elevate the plasma concentration of drugs metabolized by it, thus creating DDIs for:

P450 isozyme 34A (CYP34A)

Carbamazepine, Statins, Calcium channel blockers

which macrolide is specifically used for cat scratch disease caused by bartonella henselae

azithromycin

telithromycin is a ________ that is used for the treatment of:

ketolide, CA-pneumonia from S. pneumonia, legionella, chlamydia

contraindications for telithromycin:

myasthenia gravis

adverse effects of telithromycin:

blurred vision, prolonged QT interval (arrythmia), Liver toxicity

MOA of chloramphenicols:

Binds to 50S subunit of ribosomes and inhibits protein synthesis

because chloramphenicols are highly ________, they are effective for:

lipophilic, meningitis caused by pneumococci, meningococci and H. influenzae

List all the bacteria chloramphenicols can fight against:

Salmonella, B. Fragilis, Rickettsial infections, pneumococci, meningococci and H. influenzae

Chlmoramphenicols are only used:

when there is no alternative, not first line

adverse effects of chloramphenicol:

bone marrow toxicity

grey baby syndrome

explain how chloramphenicol causes gray baby syndrome:

neonates are unable to fully conjugate chloramphenicol in the liver or excrete it via kidneys --> high blood levels of chloramphenicols --> toxicity = vasomotor collapse, cyanosis, abdominal distention

if a baby has meningitis and there are no other alternative antibiotics, which one would be appropriate? however what are the downfalls?

chloramphenicol, gray baby syndrome

MOA of clindamycin:

Binds to 50S subunit and inhibits protein synthesis

Which infections are clindamycin typically prescribed for?

Clostridium & Bacteroides fragilis (gram + anaerobes)

- also effective against MRSA and is a topical for ance

common side effects of clindamycin:

NVD, skin rashes, pseudomembranous colitis (wipes out normal flora)

MOA of quinupristin/dalfopristin:

combination of 2 antibiotics that synergistically inhibit the 50S ribosomal subunit

Quinupristin/dalfopristin are effective against:

gram + bacteria, drug resistant staph, penicillin-resistant pneumococci, vancomycin resistant E. faecium

When would we use quinupristin/dalfoprisitn? what are the side effects?

not often, "back pocket drug"

local phlebitis (given IV), painful arthralgia

MOA of oxazolidinones:

prevent the formation of 70S initiation complex required for the beginning of protein synthesis

which drugs are in the oxazolidinone class? how are the administered?

linezolid, tedizolid (IV/oral )

Which bacteria do linezolid and tedizolid target?

gram + organisms (esp gram + resistant bacteria), MRSA, penicillin-resistant strep and enterococci, vancomycin-resistant E. faecium

oxazolidinones (linezolid/tezizolid) are given iv for:

serious infections such as necrotizing fasciitis and pneumonia

oxazolidinones are given orally for:

skin and soft tissue infections

side effects/contraindications for oxazolidinones:

inhibits monoamine oxidase -> seritonin syndrome for patients taking SSRIs/SNRIs

- potential for causing thrombocytopenia with prolonged therapy

MOA of mupirocin:

disrupts formation of isoleucyl tRNA --> fewer tRNAs binding rna --> Inhibits protein synthesis

clinical indications for mupriocin:

impetigo from different strains of streptococci and staphylococci

mupirocin is a _________ to eradicate nasal carriage of S. aureus

nasal ointment, S. aureus

nucleic acid synthesis inhibitors:

fluoroquinolones, metronidazole

MOA of fluoroquinolones and metronidazole:

prevent DNA replication by inhibiting enzymes DNA gyrase and type IV topoisomerase) involved in replication cycle --> no reproduction of bacterial cells

Older fluoroquinolones

Ciprofloxacin

advanced or "respiratory" fluoroquinolones:

Levofloxacin

Moxifloxacin

ciprofloxacin is administered ___

IV/oral/topical

ciprofloxacin is able to treat UTIs caused by:

aerobic gram - bacilli (E. Coli)

cirprofloxacin is able to treat osteomyelitis caused by as well as chronic prostatitis/epididymitis caused by:

P. aeurginosa and several enterics

ciprofloxacin is able to treat infectious diarrhea caused by:

campylobacter, salmonella, shigella

ciprofloxacin is able to treat inhalation of ________ as well as non-gonococcal bacterial conjunctivitis caused by:

bacillus anthracic, H. influenzae, M. catarrhalis, S. pneumoniae

levofloxacin and moxifloxicin are commonly used in _____, how are they administerd?

respiratory infections, IV/oral

list all the bacteria levofloxacin and moxifloxicin can treat:

CA pneumonia (Legionella pneumonia), H. Influenza, M. catarrhalis, S. pneumonia

contraindications for taking fluoroquinolones:

tendonitis, QT interval prolongation, changes in blood glucose, GI distress, wipes out gut flora (C. diff), CNS toxicity

fluroquinolone use is not reccomended for patients under 16 why? what should be recommended for patients with musculoskeletal symptoms?

increases risk of tendon rupture, pts should stop taking corticosteroids or discontinue pt

Similar to tetracyclines, ________ also bind divalent and trivalent cations, hence they should not be taken with:

fluroquinolones, Dairy

what kind of blood glucose changes might patients taking fluroquinolones experience?

hypo and hyperglycemia (could be secondary to CNS toxicity)

which drug is the DOC for parasitic infections? how is it typically administered?

metronidazole, OCP

which protozoans/ameobas does metronidazole target?

entamobea histolytica, giardia lamblia, trichomonas vaginalis

which bacteria does metronidazole target?

clostridium, bacteroides, anaerobic bugs, used in combination with tetracyclines for H. pylori, topical treatment of acne

Metronidazole MOA is similar to FQs, however instead of preventing DNA replication it does what?

attacks DNA to produce a cytotoxic effect and prevent x - linking

adverse effects of metronidazole:

NVD, vertigo/headaches, disulfiram-like reaction when taken with alcohol, decreases metabolism of warfarin (increased bleeding)

which drug is avoided during pregnancy due to potential mutagenic effects? what drug schedule is this?

metronidazole, class X

MOA of metabolite inhbitors:

inhibits folate, a metabolite necessary for DNA synthesis

why dont metabolite inhibitors attack human cells if we also need folate?

bacteria make dihydrofolate, humans don't we ingest it and only run one rxn to form tetrahydrofolate --> Purine bases

why are trimethoprium and sulfamethoxazole administered synergistically?

they both shut down key enzymes in the baterial formation of tetrahydrofolic acid needed to make purine bases for DNA, kill many more aerobic gram +/gram - when together

trimethoprium-sulfamethoxazole (TMP-SMX) targets which bacteria:

aerobic gram + and gram - bacteria

which enzyme does the antibiotic sulfonamide shut down? what about trimethoprium?

dihydropteroate synthetase, dihydrofolate reductase

metabolism and excretion of FQs:

not metabolized extensively by the liver, excreted via urine

Kobe was believed to have ruptured his achilles tendon while taking which drug?

fluroquinolones

Which bugs do TMP-SMX cover?

Enterics causing diarrhea: Shigella, Salmonella, E.Coli

UTIs caused by E. Coli

usually TMP-SMX is well-tolerated, however which side effects may occur?

hypersensitivity rxn: Stevens-Johnson Syndrome --> toxic to epidermis (skin sluffs off)

- NVD, Crystalluria (kidney stones)

- thrombocytopenia, leukopenia

TMP-SMX could also cause ______ in patients with G6DP deficiency, hence they should not take any:

hemolytic anemia, sulfa drugs