34. Protein Synthesis Inhibiting Abx Flashcards
bacterial ribosome vs human ribosome?
bacterial: 30S + 50S = 70 S
human: 40S + 60S = 80S
aminoglycosides mechanism of action and resistance?
gentamicin or amikacin
binds 30S ribosomal subunit, causes misreading or termination of genetic code, inhibits protein synthesis
unable to penetrate GP cell wall (but use for SYNERGY w/B-lactams which interfere w/cell wall synthesis and allow these to enter)
aminoglycosides general properties/PK/PD?
bactericidal or bacteriostatic (depends on [ ] )
IV only, high [ ] in ear and kidneys, inactivated by acidic env’ts (low [ ] in lungs/inhibited by pH so avoid in pneumonia and not good for abscesses)
CAN’t treat adverse events! So monitor closely, qd dosing, and avoid nephrotoxins
adverse events of aminoglycosides?
gentamicin, maikacin
OTOTOXICITY (peak levels, irreversible, cochlear damage: hearing loss; vestibular damage: vertigo)
NEPHROTOXICITY/tubular necrosis (variable damage, irreversible, increased risk w/radiocontrast, cyclosporine, amphotericin B, or vancomycin)
respiratory distress in pts w/myesthenia gravis
aminoglycosides spectrum of activity and uses?
broad spectrum vs. GN (incl pseudomonas), innefective vs GP when used alone (synergy w/B-lactams vs S.aureus and enterococci)
NO anaerobic coverage
use for mycobacteria, YERSENIA PESTIS (plague) or FRANCISELLA TULARENSIS (tularemia)
use for enterococci (endocarditis) w/b-lactams, use for UTIs (alone), or for serious GN infections (double coverage)
A 35 year old man is admitted with a kidney stone obstructing his right kidney. He is started on ampicillin and gentamicin. Three days into therapy, he starts complaining of difficulty hearing.
What is going on?
Ototoxicity; irreversible and dose-related side effect of gentamicin
tetracyclines mechanism of action/resistance
action:
Binds 30S ribosomal subunit (reversible), blocks access of tRNA to mRNA, inhibits bacterial protein synthesis, lipophilic, allows entry into GN/GP
resistance:
Common; plasmid-mediated; active efflux from bacterial cell (GN/GP) or ribosomal protection proteins (GN/GP/anaerobes)
tetracyclines general properties/PK/PD
doxycline, tetracycline, minocycline
Bacteriostatic (reversibly binds)
Dairy, ca++ decrease absorption; binds to tissues undergoing calcification (concentrated in teeth/bones)
tetracyclines adverse effects, spectrum of activity and clinical indications?
doxycline, tetracycline, minocycline
Do not give to young kids/pregnant women; deposition into bone and primary dentition during calcification (staining of teeth, hypoplasia of teeth, stunted growth); photosensitivity
GP: Staphylococci (and some CA-MRSA) and some streptococci
GN:Broad spectrum (not pseudomonas), limited by resistance
other: Some anaerobic; use for chlamydia and mycoplasma
use: Bronchitis, CA-PNA, stis: chlamydia
A 2nd year medical student after a grueling year of school goes to Thailand for 1 month. She is prescribed doxycline for malaria prophylaxis. 1 week into her trip he notices that his skin is burning despite using sunscreen.
What is going on?
Photosensitivity rash related to doxycycline
glycylcyclines?
tigercycline
Semi-synthetic derivative of tetracyclines – w/structural modifications for broader coverage and overcomes resistance to tetracyclines
resistance: Rapidly may develop in GN orgs, limiting clinical use
IV only
Do not give to young kids/pregnant women; deposition into bone and primary dentition during calcification (staining of teeth, hypoplasia of teeth, stunted growth); photosensitivity; INCREASED MORTALITY RISK WHEN USE FOR USE VS PNEUMONIA
GP: Staphylococci (incl MRSA), streptococci, enterococci (incl VRE)
GN:Except pseudomonas, proteus, morgnaella
other:most anaerobes
use:
Complicated skin/soft tissue, complicated intra-abd infection, CA-PNA
You are treating a 65 year-old women for an infected, complicated diabetic foot ulcer. Despite treatment with tigecycline and adequate surgical debridement the ulcer is not improving and in fact appears to be getting worse. She now has a fever.
What may be going on?
Tigecycline has a broad spectrum of activity and is approved for complicated skin and soft tissue infections; however, it has no coverage against Pseudomas/Proteus – either of which may be leading to progression of infection in this patient.
macrolides mechanism of action and resistance?
(azithromycin, clarithromycin, erythromycin)
Binds to 50S ribosomal subunit, blocks translocation, inhibits bacterial protein synthesis
resistance: Decreased microbial entry, permeability, efflux pumps, target site alterations (erm gene), enzymatic drug inactivation
macrolides general properties/PK/PD
Bacteriostatic
Widely dist in tissues, azithromycin has long ½ life (give qd X 5 d and covered for 1-2 weeks), erythromycin (metab by p450 system, many rx-rx interactions)
macrolides adverse effects, spectrum of activity, and use?
azithromycin, clarithromycin, erythromycin)
Epigastric distress (esp erythromycin – now used mostly for motility); QT prolongation
activity:
GP:Staphylococci, streptococci (incl susceptible pneumococcus)
GN:Many, not pseudomonas
Other: Some GN anaerobes, atypicals (mycoplasma, legionella, chlamydia)
use:
azithromycin: CA-pneumonia/bronchitis, atypical pneumonia, STIs (chlamydia), traverler’s diarrhea, MAC prophylaxis in HIV/AIDs
Erythromycin: gut motility, prokinetic
Clarythromycin: (combo w/other rx) mycobacterium avium complex disease, H.pylori
An 18-year-old college student was seen at the student infirmary for community-acquired pneumonia and given a course of antibiotics. She returns 2 days later with profuse nausea and vomiting.
What is the most likely antibiotic she was given?
She was most likely given a macrolide antibiotic with excellent coverage against organisms responsible for CAP and atypical pneumonia and which has the common side effect of significant GI distress.
licosamides mechanism of action/resistance?
clindamycin
action:
Binds to 50S ribosomal subunit, blocks translocation, inhibits bacterial protein synthesis
resistance:
Single gene mutation (erm gene) causing MLS resistance (esp S.aureus) – suspect this on S. aureus orgs that demonstrate clindamycin susceptibilty and erythromycin resistance on antibiograms – TEST W/D TEST
licosamides general properties/PK/PD?
clindamycin
Bactericidal at high doses
Good penetration of most tissues (NOT CNS)
licosamides adverse effects, spectrum, and use?
clindamycin
adverse:
C. diff
Hepatotoxicity, agranulocytosis
spectrum:
GP:Staphylococci (including some CA-MRSA) and streptococci
GN:none
other:Oral anaerobes, “above the diaphragm”, Bacteroides fragilis, malaria, toxoplasmosis, Babesia
use:
CA-aspiration pna (oral anaerobes), oral/ENT infections, abscesses “above the diaphragm”, human bite wounds, s/st infections re: CA-MRSA, toxic shock syndrome due to group A strep
80-year-old woman admitted from home following episode of syncope leading to aspiration pneumonia with cultures growing anaerobes. She is put on clindamycin and 5 days later develops severe watery, non-bloody diarrhea
What is going on?
C. difficile infection is the most significant adverse effect of clindamycin use
oxasolidinones mechanism of action/resistance?
lenizolid and tedizolid
action:
Binds to 50S subunit, prevents 70S formation, inhibits translocation process, inhibits bacterial protein synthesis
Additional target site interactions w/peptidyl transferase binding region of rRNA (increased potency)
resistance:
Uncommon, spontaneous point mutations at drug target site, acquisition of plasmid-mediated resistance gene, cfr; tedizolid overcomes this!
oxasolidinones general properties/PK/PD?
lenizolid and tedizolid
Bacteriostatic
100% bioavailability, PO or IV
oxasolidinones adverse effects, spectrum and use?
adverse:
Bone marrow suppression (thrombocytopenia w/prolonged use – monitor CBC), inhibits monoamine oxidase activity (lead to serotonin syndrome when given in conjunction w/SSRIs – can be fatal), lactic acidosis (serotonin syndrome NOT SEEN with tedizolid)
spectrum:
GP:Staph (incl MRSA), strep, enterococci (incl VRE)
GN:none
other:No anaerobic, mycobacteria some activity
use:
VRE infections, nosocomial pneumonia due to MRSA, complicated skin/ST infections
A 45-year-old man who receives hemodialysis through a permanent intravenous catheter is admitted with recurrent low grade fevers. Blood cultures grow vancomycin-resistant Enterococcus faecalis. The catheter was removed and he received several days of an IV antibiotic. He is now being discharged and you want to send him home on an oral agent?
What are your choices?
Linezolid has activity against VRE and is 100% bio-available in the oral formulation.
mupirocin mechanism of action/resistance?
action:
Binds tRNA synthetase (reversible), inhibits protein and RNA synthesis
resistance:
Presence of second, plasmid-encoded tRNA synthetase that retains activity in presence of Rx
mupirocin general properties, PK, PD?
Weaker activity vs normal skin flora contributes to clinical use as these are important natural defense vs infection
Topical only – formulated in polyethylene glycol water-miscible ointment base, not appreciably absorbed via skin
muripocin adverse effects? spectrum? use?
adverse: Not significant (very low affinity for human tRNA synthetase); propylene glycol base may irritate mucous membranes or broken skin (contact dermatitis)
spectrum: GP:S. aureus, other strep and staph None vs enterococci GN:none other: No anaerobic coverage
use:
skin infections, MRSA decolonization of nares, prophylaxis vs catheter-related infection (Abx-coated catheters)
imidazoles mechanism of action?
metronidazole, tinidazole
Enters bacteria by diffusion, production of free radicals leads to cytotoxic effects
imidazoles adverse effects?
metronidazole, tinidazole
Metallic tasete; CNS: vertigo, HA, confusion, psychosis; disulfram-like effect w/alcohol (vomiting, flushing)
imidazoles spectrum and use?
metronidazoles, tinidazole
spectrum:
Anaerobes: below the diaphragm (classic, not absolute), including Bacteroides fragilis, protozoa (trich, amoeba, giardia)
(NO GP OR GN)
use: Anaerobic infections (C.diff, intra-abdominal infections/abscesses), protozoa (trich/BV, amoebiasis, giardiasis), crohns, bacterial overgrowth
A 24-year-old college student is taking metronidazole for bacterial vaginosis. Last night she attended a party to celebrate end of year exams. This morning she has profuse vomiting and facial flushing.
What is going on?
She is most likely having a Disulfram reaction caused by the combination of metronidazole and ETOH
what is the most commonly used Abx in general practice?
azithromycin
adverse effects: eminoglycosides? tetracyclines? ery/azithromycin? clindamycin? linezolid?
Aminoglycosides: Oto/Nephrotoxicity
Tetracylcines: Bone/teeth and photosensitivity
Ery/Azithromycin: GI, QT prolongation
Clindamycin: C. difficile Infection
Linezolid: BM suppression, Serotonin Syndrome
which RNA/DNA inhibitors cover anaerobes?
clindamycin, metronidazole, tigecycline, tetracyclines, macrolides
which RNA inhibitors are GP only?
linezolid, mupriocin
