Transcript Aminoglycoside

Aminoglycoside
Ahmad Noor, PharmD
Aminoglycosides are a group of antibiotics that are
effective against:
Aminoglycoside
(AGL)
Aerobic gram( - )bacteria
e.g.: pseudomonas,
Acinetobacter,
enterobacter
Some mycobacteria
e.g.:
bacteria that cause
tuberculosis
Some gram ( + ) bacteria
Mechanism of action & pharmacokinetic:

MOA : They bind to ribosomal units ( 30S-50S ) in bacteria
& inhibits protein synthesis

Pharmacokinetic :
• PO poor absorption; IM or IV best
• Distribution: hydrophillic, poor CSF, cross placenta
• Metabolism :
Excreted unchanged, special dosing for renal failure
Aminoglycoside
(AGL)
Stretomyces
Suffix -mycin
Micromonospora
Suffix -micin
Streptomycin
Paromomycin
Gentamicin
Neomycin
Tobramycin
Netilmicin
Amikacin
Drug
Use
Streptomycin

(Streptomycin Sulfate ® )
Second-choice medications: for
tuberculosis (TB)
 streptococcal endocarditis (with B- lactam)
 enterococcal endocarditis ( with penicillins )
Paromomycin

( Humatin ®)
Neomycin
( mycifrdish ®)
Tobramycin
( Nebcin ®) , (Tobi®)
Gentamicin
( garamycin ®)
Intestinal infections
Ttt of hepatic encephalopathy
 Ttt of amebiasis
prophylaxis GI surgery
 prevention of hepatic encephalopathy &
hypercholesterolemia

Ttt of systemic infection
 respiratory tract infection

Ttt
of systemic infection
 life threatening infection
 eye infection
( Amikin ® )
Respiratory tract infection
 Skin infection
 Urinary tract infection
 Blood, abdomen or bones infection
Netilmicin

Amikacin
( NETROMYCIN ®)

septicemia
 Lower respiratory tract infection
 Urinary tract infection
 peritonitis and endometritis
Drug
Streptomycin
Dose regimen
Available dosage form
(if creatinine clerance > 90ml/min)
( all aminglycosides have very
poor absorption from G.I.T )
I.V
25-30 mg/weak ( tuberculosis )
I.V , I.M
(Streptomycin Sulfate ® )
Paromomycin
Oral
500 mg po tid x7d
Oral
( Humatin ®)
( mycifrdish ®)
Oral
For hepatic encephalopathy :
4-12 gm/d
As prophylactic in GI surgery :
1.0 gm po x3 with erythromycin
Tobramycin
I.V
5.1 ( 7 if critically ill ) mg/kg q24h
Neomycin
Oral , topical
It is not given intravenously, as it is
extremely nephrotoxic
I.V , I.M , inhalation
(Tobi®)
( Nebcin ®)
Gentamicin
I.V
5.1 ( 7 if critically ill ) mg/kg q24h
I.V , I.M , Topical
( garamycin ®)
Amikacin
I.V
15mg/kg q24h
I.V , I.M
I.V
6.5 mg/kg q24h
I.V , I.M
( Amikin ® )
Netilmicin
( NETROMYCIN ®)
The lowest ototoxic AGL
Special concern in treatment:






Tobramycin is superior to gentamicin for ttt of
P.aeruginosa .
Gentamicin is the preferred AGL used in combination ttt
of enterococcal endocarditis ( with ampicillin or
vancomycin).
Streptomycin has the greatest activity of all the AGL
against M.tuberculosis.
Capreomycin is an AGL use as alternative drug to ttt
mycobacterial infection
Streptomycin & gentamicin are drugs of choice to ttt
tularemia
Streptomycin is drug of choice to ttt plague & brucellosis
Single Daily Dose (SDD) of AGL:

•
1.
2.
For Adult:
There are two main principles for the use of the SDD of AGL:
Since the AGL bactericidal effect is related to peak concentrations, higher doses
will achieve a higher peak concentration and ensure efficacy of therapy. With this
dosing, it is possible to achieve the desired peak:MIC ratio.
SDD may reduce the frequency of nephrotoxicity since low or undetectable trough
concentrations will be attained.
3.
Dose ranges from 3 to 7mg/kg/day for gentamicin & tobramycin.
o
For children:
•
The use of SDD of AGL in children has some limitation
because of:
1.
Rapid AGL clearance.
Unknown duration of post-antibiotic effect.
Safety concerns.
Limited clinical and efficacy data.
2.
3.
4.
Single Daily Dose of AGL:
cont.
•
SDD relatively contraindications :
1.
2.
S.aureus or Enterococcal infection.
Bacterial pneumonia with pathogen having high MIC.
•
Toxicity with SDD:
3.
Endotoxin like reactions with SDD AGL’s therapy:
- many patients develop rigors, fever, tachycardia.
Ototoxicity: develop vestibular dysfunction with high dose.
Nephrotoxicity decreased with the use of SDD AGL’s.
*
N.B:
*
SDD of AGL not for every infection, pathogen, or patient.
Must have therapeutic goal based on pathogen susceptibility & location
of infection.
PK’s remain useful tool to screen patients & to establish desired Cpx:MIC
ratio.
1.
2.
*
*
Aminglycosides dosage :

AGL dose depend on IBW & cretinine clerance.
IMP. Formulae:
1.
Creatinine clerance :
= (140-age)(IBW in kg) / (72)(Scr)=ml/min
x 0.85 for CrCl of women .
2.
Ideal Body Weight (IBW) :
males: 50kg + 2.3kg per inch over 5’= weight in kg
females: 45kg +2.3kg per inch over 5’= weight in kg
3.
Obesity adjustment :
use if Actual Body Weight (ABW) is >30% above IBW. To
calculate adjusted dosing weight in kg :
IBW+ 0.4 (ABW-IBW) = adjusted weight .
Aminglycosides dosage :


cont.
SARUBBI-HULL NOMOGRAM FOR AMINOGLYCOSIDES:
Drug
Therapeutic
concentration
Max. peak conc. Max. trough
conc.
Amikacin
15-25 µg/mg
35 µg/mg
5 µg/mg
Gentamicin
4-10 µg/mg
10 µg/mg
2 µg/mg
Tobramycin
4-10 µg/mg
10 µg/mg
2 µg/mg
General dosing information: The following dosing chart by Sarubbi-Hull
(Ann Intern Med 1978; 89: 612-8) may be used to provide the clinician
with an initial loading dose and maintenance dose regimen in adult
patients. Further dosage adjustments should be individualized and
based on peak/trough serum concentrations, which should be drawn
after the 3rd maintenance dose.
Aminglycosides dosage :
cont.
1- Select loading dose ( based on IBW ) to provide peak serum
concentration in the range listed below for the desired AGL:
AGL
Usual loading dose
Expected peak serum
conc.
Gentamicin, Tobramycin
1.5-2 mg/kg
4-10 µg/ml
Amikacin
5-7.5 mg/kg
15-30 µg/ml
Aminglycosides dosage :
cont.
2- Select maintenance dose ( as % of loading dose ) to maintain peak serum conc. Indicated above
according to desired dosing interval & the patient corrected CrCl:
CrCl ( ml/min )
Half-life ( hours )
% of loading dose required for dosage interval selected *
8 hours
12 hours
24 hours
90
3.1
84 %
-
-
80
3.4
80
91 %
-
70
3.9
76
88
-
60
4.5
71
84
-
50
5.3
65
79
-
40
6.5
57
72
92 %
30
8.4
48
57
81
20
11.9
37
50
75
17
13.6
33
46
70
15
15.1
31
42
67
12
17.9
27
37
61
10
20.4
24
34
56
7
25.9
19
28
47
5
31.5
16
23
41
2
46.8
11
16
30
0
69.3
8
11
21
* This chart is not applicable to children & neonate.
Side effects:
• Nephrotoxicity
• Risk of Nephrotoxicity with Cyclosporine , Vancomycin ,
Ampho B , Radiocontrast & NSAIDs .
• Risk of nephrotoxicity by once-daily dosing method.
• Ototoxicity , deafness
• Risk of ototoxicity with loop diuretic .
• Risk of nephro/ototoxicity with Cis platinum .
• Pseudomembrane colitis
• Neuromuscular toxicity
• Other drug-drug interactions:
• Neuromuscular blocking agents
• Non-polarizing muscle relaxant
• Oral anticoagulants
apnea or respiratory paralysis
apnea
prothrombin time
Note: there is no known method to eliminate risk of AGL
nephro/ototoxicity .proper Rx attempts to the % risk.
Follow up & monitoring :

Monitor patient for ototoxicity : tinnitus, vertigo,
hearing loss
• the drug should be stopped if tinnitus occurs.



Monitor patient for nephrotoxicity periodically .if serum
creatinine increases by more than 50% over baseline value
it may be advisable to discontinue drug ttt & use less
nephrotoxic agent.
Monitor neuromuscular function when administering the
drug IV. Too rapid administration may cause paralysis &
apnea. Have Ca gluconate or pyridostigmine available to
reverse such effect
Monitor patient's neurologic status if the drug is given for
hepatic encephalopathy .
Contraindications:

Hypersensitivity to AGL

Pregnancy
(AGL is class D during pregnancy )


Myasthenia gravis
Parkinsonism
(AGL may cause neuromuscular blockade, resulting in
further skeletal muscle weakness )

Fetal eight nerve damage
( AGL may cause auditory and vestibular toxicity )
Patient counseling :

Do not take AGL if you are pregnant or could become
pregnant during treatment.

Do not take AGL if you are breast-feeding a baby.

Take each dose with a full glass of water.

Take AGL with food.

Store AGL at room temperature away from moisture,
heat, and direct light.
References :
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Joel Hardman, Lee Limbird, Alferd Goodman Gilman,
eds. The Pharmacological Basis Of Theraputics.10th ed.
Mcgraw-hill;2001;p1219-1238.
Seymour Ehrenpreis, Eli Ehrenpreis, eds. Clinician’s
Handbook Of Prescription Drugs.1st ed. McGraw-hill;
2001;p959-960.
David Gilbert, Robert Moellering, George Eliopulos, Merle
Sande, eds. The Sanford Guide To Antimicrobial therapy.
35th ed. Antimicrobial Therapy, Inc;2005;p47-53.
Simeon Marglis, Rodney Friedman, Thomas Dickey,
Jermy Birch, eds. The Johns Hopikins Consumer Guide
to Drugs.1st ed. Medletter associates, Inc;2005;p766.
Frederic Vagnini, Barry Fox, eds. The Side Effects
Bible.1st ed. Random House, Inc;2005;p499-500.
http://health.yahoo.com/drug/d00014a1.
http://www.rxlist.com/cgi/generic2/streptomycin.htm.
http://www.medscape.com/viewarticle/448281_print.
http://bmj.bmjjournals.com/cgi/content/full/312/7027/338.
http://depts.washington.edu/druginfo/Formulary/Aminogl
ycosides.pdf#search='aminoglycosidenomogram.
Thank You
Ahmad Noor , PharmD