Aminoglycosides and vancomycin Lecture 15

Question 1

Intro: Aminoglycosides

Answer 1

mainstay of therapy for serious gram negative infections (usually in combination with another agent)

Question 2

MoA: Aminoglycosides

Answer 2

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

Question 3

Pharacokinetic: Aminoglycosides

Answer 3

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.

Question 4

AE: aminoglycosides

Answer 4

local reactions: thrombophlebitis

nephrotoxicity 0-50%

ototoxicity (impariment of 8th cranial nerve function): Cochlear 0-62%, Vestibular 0-19%

neuromuscular blockade: rare prolonged paralysis

Question 5

SoA: Aminoglycosides

Answer 5

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

Question 6

Indications: aminoglycosides

Answer 6

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

Question 7

Dosing aminoglycosides

Answer 7

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

Question 8

Dosing aminoglycosides 2

Answer 8

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.

Question 9

Intro: vancomycin

Answer 9

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

Question 10

MoA: vancomycin

Answer 10

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

Question 11

pharmacokinetic properties: vancomycin

Answer 11

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.

Question 12

AE: Vancomycin

Answer 12

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

Question 13

SoA: vancomycin

Answer 13

resistance varies among organism list

G+: stap a (MRSA), S. Epidermidis, strep, entero, clostridium, bacillus, corynebacteria

G-: none

Question 14

Indications: Vancomycin

Answer 14

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

Question 15

INdications: vancomycin 2

Answer 15

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)

Question 16

Dosing: vancomycin

Answer 16

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.

Question 17

Quinupristine/Dalfoprstin Intro

Answer 17

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

Question 18

Linezolid

Answer 18

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

Question 19

Colisitin

Answer 19

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)

Question 20

Mupirocin (bactroban)

Answer 20

topical treatment

MRSA colonization eradication from nares

controversial regarding long term efficacy of eradication

other uses: impetigo or infected wounds

Question 21

Fosfomycin (Monrol)

Answer 21

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

Question 22

tigecycline

Answer 22

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

Question 23

Daptomycin

Answer 23

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)

Question 24

Televancin

Answer 24

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