Protein Synthesis Inhibitors MOA
tRNA 8 binds to acceptor site; tRNA 7 binds 7 AA to 8AA (transpeptidation); uncharged tRNA 7 released, and tRNA 8 transfers to peptidyl site (translocation);
Chloramphenicol and macrolides block transpeptidation and T blocks binding to the acceptor site on 30S ribosome
Protein Synthesis Inhibitors
Erythromycin Modified Macrolides/Azolides Telithromycin Cethromycin Tetracyclines Clindamycin Linezolid Nitrofurantoin others
Erythromycin MOA
Reversibily binds to 50S resulting in inhibition of translocation of tRNA, thus blockage of transpepidation reactions
Bacteriostatic
Gram + > gram -
Erythromycin SOA Atypical pathogens
mycoplasma pneumoniae chlamydia pneumoniae chlamydia trachomatis ureaplasma urealyticum Does NOT cover MRSA
Erythromycin clinical use
Chlamydial infections
URI/LRIs caused by strep pneumonia, mycoplasma and legionella in PCN allergy pts
strep pharyngitis in PCN allergy
Diptheria, Pertussis, cat-scratch fever (Bartonella)
Acne-topical
Oral prep for bowel surg
Erythromycin
Bioavilability 35 +/- 25%
Best taken on empty stomach, take with food if n/v
Does NOT cross BBB, crosses placenta (cat B)
Primarily hepatic and biliary elimination
Erythromycin ADEs
GI hepatotoxicity: cholestatic jaundice EES hepatotoxicity--hypersensitivty to ester hypersensativity Cardiotoxicity--prolonged QT Ototoxicity
Erythromycin drug interactions
Inhibition of CyP450 metabolism of other drugs Theophylline Carbamazepine Warfarin Cyclosporin
Erythromycin Dosing
Erythromycin base, estolate or stearate 250 mg - 500 mg qid
EES: 400-800mg q6-12 hrs
IV: 500mg qid, up to 4gm for severe infections
Modified Macrolides/Azolides
Developed to overcome limitations of erythromycin
Modified macrolides/Azolides drugs
Clarithromycin (Biaxin) (PO)
Azithromycin (Zithromax) (PO and IV) (Improved resistance to acid degradation, improved tissue penetration) - azolide
Troleandomycin (TAO) – orphan drug
Azithromycin SOA
Gram +, slighly less than erythro for staph
Gram -, slighly better for h. flu than erythro
Highly active against chlamydia
All macrolides/azolides: **Active against mycobacterium avium intracellulare complex
Clarithromycin clinical use
treat h. pylori (with amox + omperazole)
Azithromycin clinical use
STD (chlamydia, chancroid, NGU, PID)
Both clarithromyicn and azithromycin use
Upper and lower respiratory tract infections, community acquired pneumonia, alternative to cephalosporin or Augmentin for sinusitis, otitis media; skin and skin structure infections;
Treatment of Mycobacterium Avium Complex
Azithromycin Pharmacokinetics
best taken 1 hr before/2 hrs after meals, but with meals okay High tissue level distribution large Vd Preg Cat B Hepatic metabolism, biliary elimination t1/2=68hrs
Clarithromycin Pharmacokinetics
55-68% absorption, no effect or slightly increased with food
high tissue level distribution
Preg Cat C
hepatic metabolism with active metabolite (some renal clearance 18%)
t1/2=3.5-5 hours
Adjust dose in renal insufficiency (CrCl <30ml/min)
Modified macrolides/azolides ADEs
GI (less than erythro) metallic taste ototoxicity in high dose, long term use hypersensativity (<1%) hepatotoxicity (rare)
Macrolides/azolides drug interactions
similar to erythro.
azithromycin has MANY fewer; case reports with HMG-CoA RI and warfarin
Digoxin–clarith and erythro
Azithromycin dose
(Zithromax) generic (Susp, tablets, IV):
500mg x1, then 250mg qd x4days (Z-pak)
1gm PO x1 for Chlamydia cervicitis, urethritis
MAC: 600mg daily
Clarithromycin dose
(Biaxin) tablets, susp: 250 – 500mg bid (renal insufficiency: 500mg x1, then 250mg bid); ER tablets: 2 x 500mg qd; suspension tastes nasty
Telithromycin
Active against strep pneumonia, including multi drug resistant h. flu moracella catarhalis chlamydia pneumonia mycloplasma pneumonia USE: mild to moderate CAP
Cethromycin
new ketolide with activity against CA-MRSA; studied for CAP–possible approval
FDA found safe but not effective
Tetracyclines drugs available
Short acting: tetracycline
intermediate: demeclocycline (used to treat SIADH)
long-acting: doxycyclcine, minocycline, tigecycline–used most often
Tetracyclines MOA
enter cell via passive diffusion or active transport, reversibly bind to 30S, prevent binding of tRNA and protein synthesis
bacteriostatic
Tetracycline resistance
widely used in animal feeds
decreased intracellular concentration d/t decrease in influx or increased efflux by active transport.
Tetracyclines SOA
gram + aerobes–bacillus anthracus, listeria monocytogenes, s. aures
gram - aerobes- h flu, m. catarrhalis, pasturella mluocida, bartonella, vibrio
gram + anaerobes- strep
gram 0 anaerobes: fuscobacterium
others: chlmydia, mycoplasma pneu., borrelia, ricettsial, h. pylori, treponema pallidum
tetracyclines clinical use
CAP: s. pneumonia, chlamydia, mycoplasma--doxycycline Rickettsia Alt for syphillis, lyme disease h. pylori uncomme gram neg ace--propionibacterium acnes demecloclycline: SIADH
Tigecycline
glycylcycline–tetracycline-like antibiotic
indications: skin infect00e.coli, e. faecalis, s. aurus (MRSA), strep, bacteroides frgailis
complicated abdominal infections
tetracyclines pharmacokinetics
tetra- 60-80% absorbed, impaired by good
doxy, minocyc- 90-100%
Tigecycline–NO PO absorption, IM poor, erratic absorption
Distribution: Wide, including CNS
Crosses placena: Preg Cat C
Elimination: primarily hepatic, some renal, doxy and tige don’t need to adjust dose for renal
Tetracyclines ADRs
GI
Esophagitis (don’t take right before lying down)
Photosensitivity
Teeth/bone–tetra deposited in calicfying areas
Vestibular
Renal effects
Tigecycline
bacteriostatic ADRs: n/v/d, photosensitivity Drug interactions: inhibits warfarin Dose: 100mg IV follow by 50mg IV q12h used for resistant organisms
Tetracycline drug interactions
Divalent/trivalent cations (esp tetra!)
doxycycline: carbamazepine, phenytoin, barbiturates, chronic alcohol shorten half life
wafarin: alteration of gut flora
digoxin
anti-infective agents: TCN and PCN (static vs cidal)
Tetracycline dose
250-500mg q6h PO
Doxycycline Dose
100mg qd or bid
Minocycline Dose
PO, IV 100 mg bid
Clindamycin SOA
Gram + aerobes, anaerobes NOT C. diff
Gram - anaerobes bacteroids, fusobacterium
Pneumocystis carinii
toxoplasma gondii
Clindamycin clinical uses
Bacteroides infections
Penetrating abdominal wounds
BV
Skin infections
dental/oral infections
endocarditis prophylaxis in pts allergic to PCN
AIDS: PCP (with primaquine) toxoplasmosis
Clindamycin pkin
absorption: well absorbed from GI, 70% bioavailabily
distribution: widely, 90% protein bound
Minimal BBB crossing
Preg cat B
Elimination: metabolized in liver, excreted in bile
1/2 life 2-4 hours, need to dose 3-4 x / day
Clindamycin ADRs
Diarrhea, mild, self-limited (make sure not c. diff overgrowth diarrhea!)
esophageal irritation–don’t lie down for 1 hr
local
hepatotoxicity
hypersensitivity–rashes, fever
Clindamycin dosing
150-450 mg q6h PO
Chloramphenicol
gram + aerobes strep and staph
gram - aerobes h. flu, neisseria, bordetella, salmonella, shigella
gram + anaerobes-c. perfringes, corynebacterium diptheriaea, peptococcus
gram - anaerobes: bacteroides, fusobacteria
rickettsial spp
Chloramphenicol clinical uses
serious infections unresponseive to other antibiotics
rickettsia infections
alt for salmonella
severe infections–high pcn resistant strep pneu, meningococcus with PCN allergy–crossess BBB even w/o inflammaed meninges
topical: eye
Chloramphenicol ADRs
(important)
Hematologic–dose-related, reversible bone marrow suppresion
Aplastic anemia
Gray baby syndrome: circulatory collapse
Optic neuritis –> blindness
GI, hepatitis, n/v/d unpleasant taste, glossitis
drug interactions: inhibits hepatic enzymes, warprin, phenytoin
Quinupristin/Dalfopristin SOA
Resistance with VRE
SOA: bacterostatic againsts E. faecium and cidal against staph (MRSA, MSSA) and PCN-resistant
s. pneu. legionella pneu, listeria mono.
Quinupristin/Dalfopristin clinical use
tx of life-threatening infections associates with VRE bacteremia
complicated skin infect by s. aureus and strep pyogenes
Quinupristin/Dalfopristin pkin
administered IV only q8-12 hrs
mainly fecal elimination, some urinary
Quinupristin/Dalfopristin ADRs
Venous irritation
Skin rash
myalgias, arthralgias significant
VERYY EXPENSIVE
Linezolid
oxazolidinone; new class of abx
primarily bacterostatic–inhibits protein synthesis
binds with 23 S ribosome (no cross resistance)
Unique MOA
Totally synthetic drug, resistance reported within months of marketing
Linezolid clinical use
tx of serious infections caused by VRE
effective for MRSA and infections caused by high-level PCN reistant s. pneu
less effective than vancomycin for MRSA endocarditis
Linezolid ADRs
Myelosuppresion, reversible thrombocytopenia with prolonged therapy
GI
headache
$$$$$$$
Many drug interactions (I-MAOs, foods with tyramine (severe HTN), SSRI)
Nitrofurantoin
Macrodantin or Macrobid
MOA: urinary antiseptic
SOA: many gram + and -, NOT p. aeruginosa and proteus
Nitrofurantoin clinical Use
UTI (acute cystitis, not pyelo)
Nitrofurantoin dose
absorption better with meals. 50-100mg PO 4x/d for 7 days Macrobid: 100 mg BID UTI prophylaxis: 50-100mg PO at bedtime do not use if CrCl is less than 60mL/min
Nitrofurantoin ADRs
GI
Hematologic: hemolytic anemia. avoid in G-6-PD definiciency and infants <1mo
Hepatic: cholestatic jaundice syndrome, hepatic necrosis, hepatitis
immunologic: hypersensitivity, pulmonary fibrosis
peripheral neuropathy