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201 Cards in this Set
- Front
- Back
Where do protein synthesis inhibitors start to work?
|
From mRNA on
|
|
Steps in protein synthesis
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Initiation
Elongation Translocation Termination |
|
Parts of the initiation complex
|
30S + IFs + mRNA
AUG (start codon) + N-fMet-tRNA 50S |
|
Direction that AA move in ribosome and description of each site
|
A - new tRNA
P - tRNA with peptide chain E - torqued to pry tRNA from mRNA |
|
Role of EF-Tu
|
delivers aa-tRNA to A site and gives energy for peptide bond formation
|
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Role of EF-G
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gives energy for translocation
|
|
Where do most drugs bind the ribosome?
|
at RNA (not protein)
|
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Mupirocin - target
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isoleucyl-tRNA-synthase
|
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Mupirocin - MOA
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prevents isoleucine-tRNA formation
|
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Mupirocin - static or cidal
|
static
|
|
AG - synthetics
|
Amikacin (S)
Isepamicin (M) Netilimicin (M) |
|
Mupirocin - spectrum
|
Gram positive only (due to LPS on G-, large molecule)
Staph aureus Strep pyogenes |
|
Mupirocin - source
|
Pseudomonas fluorescens
|
|
Mupirocin - use
|
topical only (selective and non-toxic but esther is rapidly hydrolyzed)
nasal Staph carriers (HCW) |
|
Aminoglycosides - drugs
|
Streptomycin
Kanamycin Tobramycin Neomycin Amikacin Gentamicin Sisomicin Isepamicin Netilimicin |
|
AG - Streptomyces sourced
|
Streptomycin
Kanamycin Tobramycin Neomycin |
|
AG - Micromonospora sourced
|
Gentamicin
Sisomicin |
|
How is Streptomycin different from other AGs?
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no deoxystreptamine (2 sugars instead of three)
one-step resistance (change in S12 protein) |
|
Streptomycin - target
|
16S rRNA on 30S (near interface)
S12 protein assisted (proofreading protein) |
|
Streptomycin - static or cidal
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cidal (irreversible binding and frame shift mutations)
|
|
Streptomycin - MOA
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A-site blocked (fMet-tRNA cannot bind)
Blocks IF3 binding (mRNA cannot bind) A-site distortion into error-prone 30S conformation (frame-shift mutations) |
|
AG - general RNA binding mechanism
|
AG+ (NH)
RNA- (PO4) |
|
AG - static or cidal
|
cidal (irreversible and misreading)
|
|
AG - MOA
|
protein synthesis inhibition by 30S binding (O2 and pH dependent)
- inhibit translocation - premature peptide release - misreading, faulty proteins |
|
AG - spectrum
|
Enterobacteriacae
Pseudomonas aeruginosa Acinetobacter spp. Staphylococcus aureus NO ANAEROBES NO LOW pH |
|
AG - mechanisms of resistance
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Alteration in target site
Efflux pump Impermeability (anaerobes) Enzymatic (AGIEs) - major mechanism Methylate 16S-rRNA (what producers do) |
|
AG - spectrum of AGIE resistance (least to most)
|
Gentamicin
Tobramycin Amikacin - resistant (will not report Amikacin sensitivity if bug is Tobramycin S) |
|
AG - AGIE names
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AG acetyltransferases (AAC)
AG adenylytransferases (ANT-nucleotidyl) AG phosphotransferases (APH) numbers denote site of modification |
|
AG - oral
|
yes, but poorly absorbed
GI infections only bowel surgery hepatic coma |
|
Streptomycin - resistance mech
|
one-step chromosomal gene mutation of S12 protein (no cross-resistance with this change)
AGIEs (affect all AGs) |
|
AG - injection
|
IV or IM, especially for systemic infection
Restricted to serious G- - Pseudomonas (often w/ Pens) - Proteus - E. coli - KES |
|
AG - topical
|
large wounds
surgical bowel lavages |
|
AG - volume of distribution
|
equal to ECF (body water)
0.25 L/kg |
|
AG - increase drug dose
|
CHF
Peritonitis Ascites Edema |
|
AG - decrease drug dose
|
Dehydration
|
|
AG - poor penetration
|
ocular fluid
CSF (intrathecal for meningitis) adipose tissue |
|
AG - good penetration
|
synovial fluid
peritoneal fluid URINE (100x serum) |
|
AG - route of elimination
|
excreted unchanged in urine
GFR estimator |
|
AG - renal dysfunction
|
significant accumulation
|
|
AG - hepatic dysfunction
|
no effect
|
|
AG - dialysis
|
removes up to 50% of drug
|
|
AG - SE
|
ototoxicity
nephrotoxicity neuromuscular blockade hypersensitivity rxn injection site rxn |
|
AG - ototoxicity
|
8th cranial nerve damage from hair cell or vestibular apparatus damage
auditory = reversible, tinnitus vestibular = irreversible, NVD, vertigo, nystagmus, difficulty walking |
|
AG - nephrotoxicity
|
more common
usually reversible acute tubular necrosis with accumulation in proximal tubular cells occurs at >5 days of tx gradual rise in BUN and SCr (monitor 2-3x week) |
|
AG - nephrotoxicity risk factors
|
advanced age
renal dysfunction liver dysfunction duration of therapy nephrotoxic drugs (amphotercin B, radiocontrast, furosemide) obesity (tend to overdose) volume depleted (tend to overdose) shock/sepsis (decrease renal perfusion) |
|
AG - neuromuscular blockade
|
rare
reverse w/ Ca gluconate |
|
AG - neuromuscular blockade risk factors
|
anesthesia
myasthenia gravis hypocalcemia hypomagnesemia CCBs |
|
AG - target
|
multiple 30S sites
|
|
AG - Beta-lactams DI
|
synergy vs G+ and G- aerobes
- low dose for G+ (80 mg) - high dose for G- (120 mg) precipitates out in IV bag (ion pair) inactivates Pen in bloodstream (amine attacks B-lactam) pipercillin/tazobactam is Y-site compatible (EDTA) |
|
AG - Vancomycin DI
|
synergy vs Enterococcus, Staphylococcus and Streptococcus
G+ so use low dose (80 mg) |
|
AG - resistant to AGIEs
|
amikacin
netilmicin (not resistant to all AGIEs) |
|
AG - AGIE MOA
|
adenylate
aceylate phosphorylate |
|
AG - mechanism of AGIE resistance
|
block key amino group
- 2-OH-4-NH2-butyrate (amikacin) - ethyl group (netilmicin) |
|
Gentamicin - use
|
synergy for G+ and G-
inhalation for difficult respiratory infections opthalmic ointment and solution |
|
Tobramycin - use
|
synergy for G+ and G-
inhalation for difficult respiratory infections opthalmic ointment and solution |
|
Amikacin - use
|
synergy for G+ and G-
inhalation for difficult respiratory infections opthalmic ointment and solution |
|
Kanamycin - use
|
irrigation
|
|
Neomycin - use
|
oral bowel preparation
topical ointment |
|
AG - traditional vs extended-interval
|
toxicities associated with number of doses per day, not peak level
uptake into hair cells and nephrons is saturable can give much higher amounts (5-6x) with the same risk of toxicity |
|
AG - monitor trough
|
prevent accumulation
prevent toxicity |
|
AG - monitor PK and 12 hr
|
efficacy
ensuring bactericidal |
|
AG - no levels
|
minimal effort
reducing cost fine esp if short-term (3-5 days) |
|
AG - random (8 h)
|
prevent low AUCs and drug accumulation
identifying pts with extreme levels |
|
Tetracyclines - structure
|
napthacene carboxamide
not planar (first 3 rings are, 4th at right angle) bottom part chelates metal, cannot be altered right side also cannot be altered |
|
Tetracyclines - drugs and generation
|
Chlortetracycline (1st)
Demeclocycline (1st) Tetracycline (2nd) Doxycycline (2nd) Minocycline (2nd) |
|
Tetracyclines - sources of instability
|
H+ (prolonged exposure)
OH- (don't expose to base, usually not a problem) salt formation (HCl supersolution forms if stored for too long) chelation (don't take w/ dairy, antacids, etc) |
|
Tetracyclines - patient instructions
|
take 1 hr ac or 2 hr pc
do not take with dairy or antacids take all of the drug do not take out of date take with a full glass of water |
|
Tetracyclines - target/MOA
|
reversibly binds 30S at interface
chelates Mg to block A site stops elongation |
|
Tetracyclines - selectivity
|
binds to 30S (bug) and 40S (us)
TC carrier confers selectivity |
|
Tetracyclines - mechanisms of resistance
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block carrier (plasma-mediated antagonist)
ribosomal alteration to prevent binding - major mechanism efflux pumps |
|
Minocycline - uses
|
serious G+ skin infections
maybe MRSA? |
|
Tetracyclines - efflux pumps
|
Tet(A) and Tet(D) translocases
TC/H+ antiporter from Streptomyces |
|
Tetracyclines - side effects
|
GI upset (N/V, anorexia, epigastric burning, caustic to mucosa)
superinfection hepatotoxicity (esp in pregnancy, rare but fatal, more in tetra) teeth/bone hypoplasia mottling of teeth (mid-preg to 8 yo) photosensitization nephrotoxicity (Fanconi Syndrome, expired drug) hypersensitivity (rare) neurotoxic (not common) |
|
Tetracyclines - Superinfection
|
done by bugs that are generally resistant
Candida Staph (bloody diarrhea) C. difficile (pseudomembranous colitis, watery diarrhea) begins with the first dose but takes time for symptoms to appear |
|
Tetracyclines - static or cidal
|
static
|
|
Tetracyclines - spectrum
|
G+ aerobes (MSSA, not Enterococcus)
G- aerobes (acquired resistance is common) anaerobes (esp G-, Bact) Mycoplasma, Chlamydia, Rickettsiae, B. burgdorferi |
|
Tetracyclines - absorption
|
tetracycline = 60-80% (decreased by 50% with food)
doxy/mino = 90-100% (food does not effect) |
|
Doxicycline - advantages over other tetracyclines
|
much lower dose needed (100 v 250)
longer half-life (QD v QID) not as likely to mottle (weaker chelation) can take with meals very well absorbed (less GI flora disruption) |
|
alpha-1 acid glycoprotein
|
binds drugs like albumin does
- macrolides - clindamycin - tetracyclines fluctuates based on stress, infections, etc. binding fluctuates also probably not an issue except in severe legionella |
|
Tetracyclines - protein binding
|
to alpha-1 acid glycoprotein
doxy 90% mino 76% tetracycline 65% |
|
Tetracyclines - tissue penetration
|
poor CSF penetration
mino > doxy > tetra |
|
Tetracyclines - routes of elimination
|
tetra = renal (6-12 hr)
doxy = feces (15-24 hr) deme = renal/feces mino = metabolism (not P450, 11-22 hr) |
|
Tetracycline - pregnancy category
|
D
crosses placenta and enters breast milk |
|
Tetracycline - drug interaction with cations
|
divalent and trivalent
decrease absorption Ca, Mg, Al, Fe, Na Bicarb, cimetidine, milk |
|
Tetracycline - drug interaction with penicillin/AGs
|
antagonism (cidal + static)
|
|
Tetracycline - drug interaction with oral contraceptives
|
lower effectiveness of OC
impaired bacterial hydrolysis of conjugated esters |
|
Tetracycline - drug interaction with anesthesia
|
Methoxyflurane anesthesia
fatal nephrotoxicity |
|
Doxycycline - drugs that increase metabolism
|
carbamazepine
phenytoin barbiturates |
|
Tetracycline - uses
|
Rickettsia infections
STDs (chlamydia) Anthrax Lyme disease (DOC for B. burgdorferi) URTI and LRTI if pt cannot tolerate macrolides |
|
Glycylcyclines - efflux pumps
|
substrate for uptake but not for efflux pump
|
|
Tetracycline - dosing
|
tetra - 250-500 mg po qid
doxy - 100 mg po/IV q12h mino - 100 mg po/IV q12h (could give 200 mg qd but increases GI upset) |
|
Glycylcyclines - drugs
|
tigecycline (derived from minocycline)
|
|
Glycylcyclines - structural difference
|
glycine residue
|
|
Glycylcyclines - MOA
|
same as tetracycline (chelation of Mg on 30s subunit, blocks A site)
binding is 5x higher |
|
Glycylcyclines - spectrum
|
G+ aerobes including MRSA, VRE
G- aerobes including ESBL and Acinetobacter, NOT P. aeruginosa Anaerobes Atypicals |
|
Glycylcyclines - absorption
|
poor
IV only |
|
Glycylcyclines - volume of distribution
|
large (10 L/kg)
|
|
Glycylcyclines - metabolism/elimination
|
hepatic metabolism (not P450)
billiary/fecal elimination not for UTI's 36 hr |
|
Glycylcyclines - dosing
|
100 mg LD with 50 mg IV q12h
(doesn't match t1/2, but GI AE to >90% at QD dosing) |
|
Glycylcyclines - side effects
|
similar to TC (limited data)
GI (N/V/D, dose-dependent) CNS |
|
Glycylcyclines - uses
|
complicated skin/skin-structure infections
intra-abdominal infections CAP (under study) not for bloodstream or UTI's |
|
Glycylcyclines - penetration
|
extremely good into tissue
very little left in blood MIC = 0.5-2, Cmax = 0.87 (do not use in bloodstream infections) |
|
Macrolides - 14-membered drugs
|
erythromycin
clarithromycin dirithromycin roxithromycin |
|
Macrolides - 15-membered drugs
|
azithromycin
|
|
Macrolides - spectrum
|
G+ aerobes
- S. aureus (MSSA) - S. pyogenes, S. pneumoniae G- aerobes - H. flu (not erythromycin) - M. cat - NOT: E. coli, Kleb, Enterobacter, P. aeruginosa, Acinetobacter Intracellular organisms - Chlamydia - Mycoplasma (DOC) - Legionella (DOC) - Camphylobacter Mycobacterium No enterococcal or MRSA activity |
|
Macrolides - source
|
Streptomyces erythreus (erythromycin)
|
|
Macrolides - instability
|
acid unstable
forms a hemi-ketal which inactivates drug and irritates stomach deal with pain or enteric coat |
|
Macrolides - target/MOA
|
binds 23S of 50S
blocks peptide exit tunnel derails translocation premature peptide release |
|
Macrolides - specificity
|
does not bind mammalian ribosome
|
|
Macrolides - static or cidal
|
static (low conc) - generally static b/c reversible
cidal depends on - high concentration at site - organism - inoculum size |
|
Macrolides - mechanism of resistance
|
methylation of 23S rRNA
mutation of rRNA esterases efflux pumps |
|
Macrolides - bacteriocidal combinations
|
Erythromycin
- S. pneumoniae - S. pyogenes Clarithromycin, Azithromycon - H. influenzae - S. pneumoniae - S. pyogenes |
|
Macrolides - methylation of 23S rRNA
|
by the ermB gene (erythromycin ribosome methylation)
N,N-dimethylation of Ad2058 (domain 5) MLS resistance common in European S. pneumo |
|
Macrolides - efflux pump
|
more common US S. pneumo
mef, msr and vga (mefA primarily) confers low-level resistance that can be overcome |
|
Macrolides - distinguishing modes of resistance
|
clindamycin has the same target site but is not touched by the efflux pump
|
|
Macrolides - oral bioavailability drugs
|
Roxithromycin (72-85%, oral only)
Clarithromycin (55%, w/ or w/o food, oral only) Azithromycin (37%, take w/o food, also IV) Erythromycin (25-60%, also IV) Dirithromycin (6-14%) oral forms are stepdown therapy (do not give oral azithromycin to the elderly or hospitalized) |
|
Macrolides - distribution
|
very lipophilic
large volume of distribution high intracellular concentrations (esp macrophages, pump drug into other cells) tissue and cellular conc > plasma |
|
Macrolides - protein binding
|
alpha-1 acid glycoprotein
|
|
Macrolides - tissue penetration
|
does not penetrate BBB (not for meningitis, also static)
crosses the placenta |
|
Macrolides - metabolism/elimination
|
eryth/clarith = P450 3A4 to active metabolites
azith = metabolized but not by P450 (fewer drug interactions) dirith = metabolized by P450 but too slow to cause interactions |
|
Macrolides - side effects
|
Clarithromycin and azithromycin are better tolerated and have fewer SE than erythromycin.
GI (most common, hemi-ketal, erythromycin) hepatotoxicity (rare but serious, bile excretion, builds up in liver if already damaged) ototoxicity (reversible) thrombophletis (IV, esp erythromycin) allergic rxns (rare) QTc prolongation (clarithromycin and erythromycin) |
|
Macrolide - drug interactions
|
TDP through 3A4 inhibition (CI)
- Astemizole (withdrawn) - Cisapride (withdrawn) - Ergotamine - Terfenadine (withdrawn) P450 inhibitors used in combination for mycobacterium - rifampin - rifabutin inhibit the P-glycoprotein |
|
Macrolides - uses
|
Mediterranean spotted fever (rickettsia)
Lyme disease (B. burgdorferi) MAC PUD (H. pylori) STDs Endocarditis prophylaxis (if pen allergic) Skin and soft tissue (if pen allergic, less now with MRSA) LRTI (CAP, COPD exacerbation) URTI (improper, most are viral) |
|
Clarithromycin - dosing
|
IR: 250-500 mg po bid
XL: 1 g qd (two tablets, must be taken together) |
|
Azithromycin - dosing
|
Z-pak: 500 mg po day 1, 250 mg po qd for days 2-5 (URTI)
1 g x 1 day (?) 2 g x 1 day 500 mg po x 3 days 500 mg po or IV qd (500 mg po is the proper step down therapy, not a Zpak) |
|
Dirithromycin - dosing
|
500 mg po qd
|
|
Clarithromycin - structure
|
-OCH3 prevents hemi-ketal
- more stable - less GI irritation - higher levels allow BID dosing first-pass metabolism to active OH same P450 issues |
|
Clarithromycin - uses (v. Erythromycin)
|
more potent for G+
More potent for URTI (Strep, H. flu, Mycoplasma) More potent for Chlamydia Used for disseminated TB |
|
Dirithromycin - structure
|
like erythromycin with a linker that makes it act like a depot formation
not a prodrug b/c linker decomposes spontaneously major advantage: qd dosing enteric coat Amino erythromycin (NH2 replaces ketone) no P450 issues (like azithromycin) |
|
Azithromycin - structure
|
15-membered azilide
more lipohilic (replace ketone with NCH3) - PML's pump into cells - longer t1/2 (qd dosing) - no P450 issues enhanced G- (?) |
|
Ketolides - structure vs. macrolides
|
also 14-membered
replace two OH's with carbamate - blocks efflux pump - tighter ribosomal binding (2 places) remove one sugar and add a ketone - enhanced with respiratory pathogens - enhanced activity - prevent MLS resistance change OH to OR - enhanced acid stability |
|
Ketolides - target
|
23S rRNA
binds strongly to domain 5 AND domain 2 |
|
Ketolides - resistance v. macrolides
|
not a substrate for efflux pump
not effected by MLS resistance DOES NOT INDUCE MLS RESISTANCE |
|
Ketolides - drugs
|
telithromycin
|
|
Ketolides - spectrum
|
same as macrolides + multi-drug resistant S. pneumoniae
|
|
Ketolides - absorption
|
oral formulation only
57% unaffected by food |
|
Ketolides - distribution
|
large VD
60-70% protein bound |
|
Ketolides - uses/indications
|
had most indications removed when black box was added
CAP macrolide-resistant pneumococci |
|
Ketolides - elimination
|
metabolism
P450 interactions |
|
Ketolides - side effects
|
black box: CI in myasthenia gravis
liver damage (severe: transplants, fatalities) vision problems (accommodation, esp in women <40 yo) fainting |
|
Ketolides - CI
|
hypersensitivity to telithromycin or macrolide
Cisapride (withdrawn) Primozide (antipsychotic) |
|
Ketolide - drug interactions
|
Statins
- atorvastatin - lovastatin - simvustatin Antiarrhythmics IA - quinudine - lidocaine - procainamide III - amiodarone - bretylium - ibutilide - sotalol |
|
Ketolide - dosage
|
CAP: 800 mg qd for 7-10 days
|
|
Telithromycin - structure
|
long arm off of carbamate binds to domain 2
|
|
Lincomycin - source
|
Streptomyces lincolnensis
|
|
Clindamycin - source
|
semi-synthetic lincomycin
|
|
Clindamycin - structure vs. lincomycin
|
replace R with Cl (20x more lipophilic, better bacterial penetration)
|
|
Lincomycin/Clindamycin - target
|
23S rRNA of 50S
overlaps erythromycin site, but distinct (not domain 5) blocks peptidyl transferase (peptide bond fools PTC) |
|
Clindamycin - spectrum
|
G+ aerobes
- not enterococcus or MRSA G+ and G- anaerobes Protozoa G- aerobes are resistant |
|
Clindamycin - absorption
|
oral well absorbed w/ or w/o food
IM well absorbed palmitate ester suspension well absorbed (hydrolyzed to active base) |
|
Clindamycin - distribution
|
binds to alpha-1 acid glycoprotein (concentration dependent)
poor CSF penetration good tissue penetration |
|
Clindamycin - excretion
|
metabolized (85%)
eliminated in bile not removed in HD or PD no adjustment for renal dysfunction |
|
Clindamycin - side effects
|
GI (most common)
- NVD - metallic taste - antibiotic-associated colitis (C. diff, potentially fatal) hypersensitivity transient LFT increase hematologic |
|
Clindamycin - uses
|
B. frag (and other PCN-resistant anaerobes outside CNS)
- abdominal - PID - pulmonary C. diff (alternative to PCN) alternative for Staph and Strep acne vulgaris community-acquired MRSA toxoplasmosis and PCP in AIDS |
|
Clindamycin - dosing
|
Oral
mild: 150-300 mg po qid (or tid for GI) severe: 300-450 mg po qid Parenteral mild: 300-600 mg q8h severe: 600-900 mg q8h |
|
Clindamycin - resistance
|
MLS resistance (b/c target is close to macrolide binding site)
|
|
Chloramphenicol - source
|
Streptomyces venezuelae
|
|
Chloramphenicol - target
|
same as clindamycin
50S rRNA inhibits peptidyl transferase (resembles peptide) stops elongation partial overlap with erythromycin |
|
Chloramphenicol - uses/dosage
|
brain abscess: 100 mg/kg/day
meningitis: 100 mg/kg/day typhoid fever: 50 mg/kg/day rickettsial infection: 50 mg/kg/day (when tetracyclines and macrolides don't work/aren't tolerated) |
|
Chloramphenicol - spectrum
|
G+ and G- aerobes
- Salmonella typhi (DOC) G+ and G- anaerobes - B. frag Spirochetes Rickettsia Chlamydia Mycoplasma meningitis - H. flu (was ampicillin, now vaccinate) - Strep - Neisseria |
|
Chloramphenicol - side effects
|
Penetrates mitochondria, 70S rRNA
- blood dyscrasias - dose-dependent BM suppression - idiosyncratic aplastic anemia (1:25,000-40,000, fatal) - hemolytic anemia (drug deposition?) Gray Baby Syndrome - lack glucuronidation, poor excretion - cyanosis - 40% fatal Hemorrhage - reduce Vit K (gut flora) - inhibit P450 warfarin metabolism CNS (penetrates BBB) - optic/peripheral neuritis - HA - depression - mental confusion |
|
Chloramphenicol - resistance
|
enzymatic (acetylation)
not common |
|
Chloramphenicol - absorption/formulations
|
suspension: palmitate ester
- hydrolyzed by lipases in small intestines Capsule: free base - does not need to be hydrolyzed IV: succinate - undergoes hydrolysis |
|
Chloramphenicol - distribution
|
large Vd (~100 L, wide)
penetrates CSF bound to albumin lipophilic |
|
Chloramphenicol - excretion
|
metabolized by glucuronidation
10-15% in urine (not for UTI) half-life of 4-6h monitor peak and trough |
|
Polymixins - drugs
|
polymixin B
colistatin (polymixin E) |
|
Colistin - formulations
|
sulfate: oral or topical
methane sulfate: IV (hydrolyzed to active) sulfate is 4-8x more active |
|
Polymixins - target
|
bacterial cell wall
|
|
Polymixins - static or cidal
|
static at low concentrations
cidal at high concentrations |
|
Polymixins - spectrum
|
G- aerobes
- P. aeruginosa - Acinetobacter baumannii (respiratory) |
|
Polymixins - distribution
|
poor into the following
- synovial - pleural - CSF - adipose |
|
Polymixins - excretion
|
renal (requires adjustment)
normal half-life: 6 h anuric half-life: 2-3 d not removed by HD (unlike AG) |
|
Polymixins - side effects
|
not seen as often, maybe doing dosing better
nephrotoxicity (higher than AG) - acute tubular necrosis neurotoxicity - in renal impaired - can cause respiratory failure injection site reaction - fever - rash - pain |
|
Polymixins - uses
|
G- negative infections, esp with MDR Pseudomonas and Acinetobacter
- pneumonia - bacteremia - wound infections - UTI |
|
Streptogramins - target
|
23S rRNA of 50S
|
|
Streptogramins - static or cidal
|
cidal (irreversible binding)
|
|
Streptogramins - structure
|
macrocyclic peptide
|
|
Streptogramins - source
|
Streptomyces graminofaciens
|
|
Linezolid - target
|
23S rRNA of 50S
bind initiation complex, cannot translocate allows assembly but not procession |
|
Streptogramins - drugs
|
Synercide (quinupristin/dalfopristin)
- synergistic 30:70 ratio (16x more potent) |
|
Streptogramins - domain targets
|
dalfopristin: domain 5
quinupristin: domain 2 link together |
|
Streptogramins - resistance
|
does not induce MLS resistance
susceptible to MLS resistance blocks dalfopristin binding quinupristin cannot link |
|
Linezolid - static or cidal
|
Burgess: static
Davis: static (Enterococci) or cidal (Strep) |
|
Streptogramins - spectrum
|
G+ only
Entercoccus faecium (vanco-resistant) MRSA, MRSE Streptococcus Not active against E. feacalis! |
|
Streptogramins - side effects
|
infusion site rxn (>30%)
thrombophlebitis GI (NVD) arthralgia and myalgia cause DC |
|
Linezolid - resistance
|
no cross-resistance b/c a novel mechanism
23S rRNA mutation - seen even in trials - hospital-wide outbreaks of resistance |
|
Streptogramins - dosing
|
7.5 mg/kg IV q8-12
central line preferred (thrombophlebitis) infuse over 1 hr D5W only (flush with D5W too) only 5 hrs at room temp (54 in fridge) |
|
Linezolid - spectrum
|
G+ aerobes
- MRSA - VRE. faecium - Entercoccus faecalis |
|
Streptogramins - absorption
|
poor
IV only |
|
Streptogramins - distribution
|
large Vd
|
|
Linezolid - absorption
|
excellent (100%)
IV or oral |
|
Streptogramins - elimination
|
metabolized (not much P450)
fecal excretion less than 1 hr t1/2 |
|
Streptogramins - uses
|
VRE (no longer 1st choice, 3rd or 4th)
Not used for any longer - nosocomial pneumonia - skin and skin structure - CAP |
|
Linezolid - distribution
|
40-50L (large)
31% bound (not much) |
|
oxazolidinones - drugs
|
linezolid (Zyvox)
eperezolid (pending approval) |
|
Linezolid - excretion
|
metabolized by oxidation
no P450 effects half-life: 5-7 hr no dosage adjustment for hepatic or renal dysfunction |
|
Linezolid - side effects
|
overall, well tolerated
GI (NVD) CNS - HA - insomnia - serotonin syndrome (MAOI) - peripheral and optic neuropathy LFT increases Reversible BM suppression (long-term, 10-4 days, monitor CBC) |
|
Linezolid - drug interactions
|
significant pressor response (increase BP)
- tyramine - pseudoephedrine - phenylpropanolamine MAOI interactions |
|
Linezolid - uses
|
HAP and CAP
skin/skin-structure infections (uncomplicated and diabetic foot infections) - better for MRSA than Vancomycin VRE Deep infections (surprising with a static drug) - endocarditis - bone and joint infections NOT FOR CATHETER-RELATED INFECTIONS (use Vanc) |
|
Linezolid - dosage
|
600 mg po or IV q12h
10 mg/kg IV or po q8h (peds) |
|
Streptomycin - uses
|
Plague
TB (combo therapy) Enterococcus shortage issues b/c only one manufacturer |