Aminoglycosides and vancomycin Lecture 15 Flashcards
Intro: Aminoglycosides
mainstay of therapy for serious gram negative infections (usually in combination with another agent)
MoA: Aminoglycosides
binds to outer membrane of cell, resulting in a rearrangement of LPS
Uptake is energy dependent (slow phase and rapid phase); the source of energy is an electrochemical gradient (this gradient is decreased in an anaerobic environment)
once across the membrane the drug is irreversibly trapped into bacteria cytoplasm (very high intracellular concentrations).
aminoglycosides then binds to 30S and 50S ribosomal subunit resulting in decresased protein synthesis and increased misreading of mRNA
bactericidal, although mechanism would appear to indicate statc activity. Not fully understood
Postantibiotic effect: after expsoure to inhibitory concentration of AMGs, continuted killing occurs. Concentration dependent killing
Pharacokinetic: Aminoglycosides
absorption: poorly absorbed from GI tract
Distribution: concentrations in the lungs are 20-50% of those achieved in the serum
excretion: excreted almost entirely unchanged via glomerular filtration.
Alterations: Elderly (decreased Vd and Ke), Critically Ill, change in vd, renal disease (decreased ke; change in Vd), cachexia/malnourshied (decreased Vd and creatnine production)
Half life are fiarly short. dose every 8 or 12 hours.
AE: aminoglycosides
local reactions: thrombophlebitis
nephrotoxicity 0-50%
ototoxicity (impariment of 8th cranial nerve function): Cochlear 0-62%, Vestibular 0-19%
neuromuscular blockade: rare prolonged paralysis
SoA: Aminoglycosides
resistance varies among organisms listed below and agent used
G+: staphlyococus
G-: morganella, H. Flu, Providencia, proteus mirabilis, E coli, klebsiella pneumonia, serratia, pseudomonas aeruginosa, acinteobacter, citrobacter, enterobacter, pseudomonas
Indications: aminoglycosides
serious negative infections: bacteremias, intraabdominal infections, skin and soft tissue infections, lower respiratory infections, bone and joint infections, compicated UTIs. Gentamicin, tobramycin, amikacin are the primary agents used.
specific uses of streptomycin/gentamicin: TB (streptomycin), brucellosis (severe; in combination with tetracycline or chloramphenicol) (gentamicin)
oral aminoglycosides: suppression of intestinal bacterial floar for elective colorectal surgical prophylaxis (neomycin. Hepatic coma; decreases the number of ammnia forming bacteria (neomycin). Intestinal ambiasis (tape worm (paromomycin)
Topical aminoglycosides: Eye, ear, and skin infections
Dosing aminoglycosides
Individualization of dosing: pharmocokinetics principles- most accurate method, associated with lowest toxicity and lowest failure rates
trail and error: least accurate method, associated with highest toxicity and highest failure rates
nomograms: substantial variations exist in concentrations achieved compared to predicted values
once daily aminoglycosides dosing: trough concentrations may be allowed to fall below the MIC forthe organism for significant periods of time relying on the post anitbiotic effect. During this period of low serum concentrations, the kidney cells are allowed time to process drug and thereby reduce effects of accumulation and therefore decrease nephortoxicity
Dosing aminoglycosides 2
aminoglycoside monitoring; narrow therapetic index. A peak and trough should be ordered with the third dose (steady state) after initiation of therapy. Further peaks and troughs should be ordered after dosage adjustments or with changes in renal function. Peak concentration correlate with efficacy. A correlation exists with excessive trough concentrations and prolonged exposure to aminoglycoside with toxicity. Standard doses do not corelate well with desired concentrations
topical aminoglycoside preparations: gentamicin, tobramcyin, neomycin opthalmic solution. Gentamicin topical preparations. Gentamicin, tobramycin, kanamycin injection used as wound irrigations.
Intro: vancomycin
glycopeptide antibiotic derived from streptomyces orientalis.
introduced in the late 1950s but was replaced by less toxic antistaph pencillins (methicillin, nafcillin)
resurgence of use due to increase in methicillin resistant staph
MoA: vancomycin
vancomycin inhibits the biosynthesis of peptidoglycan polymers during cell wall formation (complexes with D alanyl- D alanine precursor). The drug also injures protoplasts by altering their cytoplasmic membranes
bactericidal for multiplying organisms
postantibiotic effect: after exposure to inhibitory concentrations of vancomycin continued killing occurs
pharmacokinetic properties: vancomycin
absorption: porrly absorbed from GI tract. must be given IV except for clostridium difficle.
distribution: distribution to CSF only with inflammation
excretion: excreted almost entirely unchanged via glomerular filtration
Alterations in pharmacokinetics
characteristics of vancomycin: 6-8 half life. Elimination: renal.
AE: Vancomycin
purified preparations of vancomycin now available are well tolerated when properly administered. Previous frequent reports of adverse effects with early preparations appear to have been caused by impurities
local reactons: thrombophlebitis. Red-man/Red-neck syndrome (histamine like reaction characterized by erythematous macular rash involving the face, neck, upper trunk, back and arms; fever, chill, flushing, hypotension
nephrotoxcity: more common when used concomitantly with aminoglycosides or other nephrotoxic agents
ototoxciiy: more common with increased peak concentrations
neuromuscular blockade
SoA: vancomycin
resistance varies among organism list
G+: stap a (MRSA), S. Epidermidis, strep, entero, clostridium, bacillus, corynebacteria
G-: none
Indications: Vancomycin
TX: serious infections by beta lactam resistant gram positive organisms. Vancomycin may be less bacteriacidal than beta lactam agents for beta lactam susceptible staph
tx of infections caused by G+ organisms in patients with serious allergies to beta lactams
clostridium dificle colitis that does not respond to metronidazole or is severe and potentially life threatening
prophylaxis for major surgical procedures involving implantation of prostehtic materials (cardiac and valvular procedures and total hip replacement) at institutions that have a high rate of infections caused by MRSA or MRSE.
surgical prohylaxis in a patient with life threatening allergy to beta lactam antibiotics
INdications: vancomycin 2
prophylaxis in a patient with a life threatening allergy to beta lactam antibiotics
prophylaxis as recommended by AHA, for endocarditis in patients at high risk for endocarditis.
vancomycin use should be discouraged in the following: routine surgical prophylaxis. Empiric therapy in febrile neutropenic patients, unless evidence of possible gram _ infection (inflamed catheter site) or MRSA infections are prevalent in the hospital. Coagulase negative staph in one blood culture (contamination). Continued empiric use in patients whose cultures are negative. Eradication of MRSA colonization. Primary tx of C dif colitis. TX of infections caused by beta lactam sensitive gram positive organisms in patients with renal failure (dosing convenience)
Dosing: vancomycin
INdividualization of dosing
vancomycin monitoring: a peak and trough should be ordered with the third dose (steady state) after initiation of therapy. Further peaks and troughs should be ordered after dosage adjustments or with changes in renal function.
throughts vary on monitoring. Will find advocates for no monitoring, trough monitoring only, and peak and trough monitoring.
Quinupristine/Dalfoprstin Intro
streptogramin antibiotics (30-70 mixture)
both components irreversibly bind to different sites on the 50S bacterial ribosomal subunit
quinupristin inhibits peptide chain formation which results in early termination
dalfopristin inhibits peptide chain elongation by interfering with eptidyl transferse
individaully bacteriostatic: combination: bactericidal
gram positive cocci, including vancomycin resistant enterococcus faecium (vre), penicillin resistant streptococcus pneumoniae, MRSA, but VRE is relatively resistant
possibly anaerobes and some gram - pathogens (H. flu)
infusion site reactions occur if given through peripheral line. PICC line or central preferred
Linezolid
oxazolinone class
inhibits protein synthesis; binds to 23 s ribosomal RNA of 50s subunit
oral is 100% bioavailable (oral antibiotic give same levels as IV dosing)
coverage of resistant gram + including: MRSA, PCN resistant strep pneumo, VRE and VISA
AE: Thrombocytopenia, MAO inhibition
Colisitin
Polymyxin class of antibiotics
bacteriocidal
only two commercially avaible polymyxin B and E
polymyxin E
Great g- coverage: SPACE
colistin is administered in prodrug format colistimethate sodium (IV)
various uses are based upon need of last resort antibiotic
use was big in early 1980s however with safer alternative colistin and its side effects too a back seat
lower utilization over the past decades has allwed sensitivities to remain high for MDR pathogens.
Unique uses: nebulization (inhaled) or intrathecal (rare)
AE: nephrotoxicity and neurotoxicity
resereved for last ditch efforts as most labs don’t report sensitivites for colistin. Pseudomonas and Acinetobacter (SPACE). Resistant PE (carbapenem resistance enterobactericae CRE)
Mupirocin (bactroban)
topical treatment
MRSA colonization eradication from nares
controversial regarding long term efficacy of eradication
other uses: impetigo or infected wounds
Fosfomycin (Monrol)
phosphoric acid derivative class
bacteriocidal
mostly used for UTIs in united states due to low serum concentrations
commonly used in resistant UTIs or with organisms that are considered MDR pathogens (MRSA, VRE, ESBL or space bug type infections)
dosed for convenience: 3 grams packet taken orally
usually only need 1 dose; however presistent UTIs may need a repeat course
limited sutdies reviewed repeating this 3 gm packet q 48 hours x3 doses total
fairly well tolerated with the most common side effects being GI upset
tigecycline
glycylcycline class
bacteriostatic
FDA 2005 for complicated skin infections, intra abdominal infection and community acquired pneumonia. Many other options can be used for CAP therefore not a great niche unless several allergies to other antibiotics. Should not be used to treat bacteremias as it does not attain high serum concentration
in large 3 and 4 trails they noticed higher all cause mortality (3 v 4%) which has limited its use some as well
niche coverage allows use in some difficult infections including resistant gram psoitive organisms (MRSA/VRE) as well as resistant gram negative organisms (Carbapenem resitant enterobacteria (CRE), acinetobacter baumanii that is resistant to most other options ( not pseudomonas) and other anaerobes
Daptomycin
lipopeptide antibiotics call
bacterilcidal
excellent gram positive converage including higher resistant MRSA and VRE
FDA approved for complicated skin and soft tissue infections and staph aureus including MRSA bacteremia as well as right sided endocarditis
interestin quir of dapto is it does not cover pneumonia because it is inactiviated by pulmonary surfactant
most common side effect are rhabdomyolysis which requires monitoring of CPK
a rare but complicated side effect is eosinophilic pneumonia (good board question)
Televancin
glycolipopeptide class
semi synthetic derivative of vancomycin
FDA approved in 2009 for skin and soft tissue infections caused by g- organisms
AE: nephortoxicity, red man syndrome with infusion, QT prolongation, pancreatitis
