THE PROPER USE OF

AMINOGLYCOSIDES
Guide of Administration to Improve Clinical Outcome and
Reduce Nephrotoxic and Ototoxic Risk

Apt. Gilang Rizki Al Farizi, M.Farm

LABORATORIUM FARMASETIKA DAN BIOLOGI

PRODI S-1 FARMASI
STIKES TELOGOREJO SEMARANG
 DEFINITION

¢ Aminoglycosides are aminocyclitol derivatives that have

concentration-dependent bactericidal activity against Gram
negative aerobic basteria via bilding to the interface between the
30S and 50S ribosomal subunits.
¢ Drugs that include : Streptomycin, Kanamycin, Neomycin,
Netilmycin, Gentamycin, Tobramycin, Amikacin

Anderson et al. Handbook of Clinical Drug Data 10th edition. 2002 . New York :McGraw Hill Inc
 AMINOGLYCOSIDE USE
¢ The aminoglycoside antibiotics are widely used for the
treatment of severe gram-negative infections such as
pneumonia or bacteremia, often in combination with a β-
lactam antibiotic
¢ Aminoglycosides are also used for gram-positive infections
such as infective endocarditis in combination with
penicillins when antibiotic synergy is required for optimal
killing
¢ Aminoglycoside antibiotics available in the Indonesia that
are in common use include gentamicin, tobramycin, and
amikacin

Bauer L.A. Applied Pharmacokinetics 2nd edition. 2008. New york : McGraw Hill Inc
PHARMACOKINETICS PROPERTIES OF
AMINOGLYCOSIDES
¢ Bioavaibility after oral or rectal administration is
about 0.2–2%
¢ Plasma protein binding is low
¢ Vd of about 0.3 ± 0.08 L/kg, which is increased by
fever, edema, ascites, and fluid overload, and in
neonates
¢ Elimination is via glomerular filtration of
unchanged drug, clearance of aminoglycosides is
about 90% of Clcr
¢ Discontinuation drug àdetected in the urine for
several days à accumulated in deep tissue
compartments
Anderson et al. Handbook of Clinical Drug Data 10th edition. 2002 . New York :McGraw Hill Inc
 PHARMACOKINETICS PROPERTIES OF
AMINOGLYCOSIDES (2)

¢ α-phase : 5–15 min

¢ β-phase : about 14 ± 0.4 hr in adult with normal renal function, can be more
variable in certain groups (eg, obstetric and burn patients), 50–70 hr in anuria.
¢ γ-phase : observed when concentrationsfall to the lower range of detectability

Bauer L.A. Applied Pharmacokinetics 2nd edition. 2008. New york : McGraw Hill Inc
 NARROW THERAPEUTIC INDEX OF
AMINOGLYCOSIDE
¢ Aminoglycoside was narrow therapeutic index
drugs which have small differences between
therapeutic and toxic doses. Toxic effect are
nephrotoxic and ototoxic.
Aminoglycoside Minimum peak Maximum peak Maximum trough
concentrations for a concentrations to concentrations to
therapeutic response avoid toxicity avoid toxicity
Gentamicin, 5 μg/mL 10 μg/mL 2 μg/mL
tobramicin,netilmicin

Amikacin, Kanamycin 20μg/mL 30 μg/mL 10 μg/mL

(Pseudomonas)

Reynolds and Aronson, 1992, ABC of Monitoring Drug Therapy;BMJ,Vol.305

 RISK FACTORS FOR AMINOGLYCOSIDE INDUCED
NEPHROTOXICITY
Increased Risk Decrease Risk
Fluid Depletion Urinary alkalinisation

Potassium Magnesium deficiency Thyroid Hormone

Endotoxaemia Potassium Loading

Pre-existingr enal disease

Advanced age

Co administrationof the nephrotoxin

Repeated courses of aminoglycoside

Liver disease
Obesity/ male sex

Sandhu,J.S., et al, 2007, AminoglycosideNephrotoxicity Revisited,Indian Academy of

Clinical Medicine, Vol.8. No.4
Anderson et al. Handbook of Clinical Drug Data 10th edition. 2002 . New York :McGraw Hill Inc
Anderson et al. Handbook of Clinical Drug Data 10th edition. 2002 . New York :McGraw Hill Inc
METHODE TO CALCULATE AMINOGLYCOSIDE
BASE ON INDIVIDUAL RENAL FUNCTION

Serum
Creatinin

Cockroft And Gault

GFR (Clearence
creatinin)

Clearence
Aminoglycoside

Dose of
Aminoglycoside
SARUBBI AND HULL METHOD

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
SARUBBI AND HULL METHOD

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
URBAN AND CRAIG NOMOGRAM

Urban, A.W. and Craig, W.A., Daily Dose of Aminoglycoside. In : Remington & Swartz. Current
Clinical Topics in Infectious Diseases 17th edition. 1997. London :Blackwell Science
URBAN AND CRAIG NOMOGRAM

Urban, A.W. and Craig, W.A., Daily Dose of Aminoglycoside. In : Remington & Swartz. Current
Clinical Topics in Infectious Diseases 17th edition. 1997. London :Blackwell Science
BAYESIAN METHOD
¢ The bayesian method calculation need a
pharmacokinetics parameters from population model
study.
¢ Approach of the Bayesian method results will be closer
to reality than the other methods.

Bauer L.A. Applied Pharmacokinetics 1st edition. 2008. New york : McGraw Hill Inc
EXTENDED DAILY DOSE
VERSUS
CONVENTIONAL DOSE
DIFFERENT BETWEEN CONVENTIONAL AND
EXTENDED INTERVAL DOSING
¢ EID is also referred to, high dose, or non-traditional dosing. EID
as once-daily dosing has become an accepted alternative method
for dosing, based on favorable pharmacodynamic and
pharmacokinetic features. It is recommended that EID be the
term used, in order to avoid confusion with patients with renal
dysfunction who may receive conventional dosing on a once-daily
basis. EID is becoming the preferred method at many institutions
based on comparable efficacy, potential reduction in toxicity, and
decreased monitoring when compared with other dosing methods

¢ Conventional dosing involves giving the total daily dose of the

aminoglycoside divided throughout the day, typically every 8 to 12
hours in patients with good renal function

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
DIFFERENT BETWEEN CONVENTIONAL AND
EXTENDED INTERVAL DOSING (CONTINUE..)

¢ Aminoglycosides exhibit concentration-dependent bactericidal

activity,meaning the bactericidal activity increases as the
concentration ofaminoglycoside increases. Utilization of EID
maximizes the concentrationdependentkilling effect of
aminoglycosides by providing the total daily dose asa single
infusion. This approach produces an elevated peak and
undetectabletrough concentrations. The significance of
undetectable trough concentrations will be discussed later. For
antimicrobials that exhibit concentration-dependent killing, a
serum concentration 10 times the minimum inhibitory
concentration (MIC) of the organism is necessary to achieve
optimal bactericidal activity.
¢ For example, a concentration of 20 mcg/mL is necessary for an
organism with an MIC of 2.

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
EXTENDED INTERVAL DOSING CONSIDERATION

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
CONCENTRATION DEPENDENT OF
AMINOGLYCOSIDE

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2nd Ed., Informa Health Care
POST ANTIBIOTIC EFFECT OF
AMINOGLYCOSIDES
¢ PAE is measured as delayed bacterial growth
after a short on-off exposure to an antibiotic for 1
or 2 h
¢ In the clinical setting, aminoglycoside
concentrations decline over time, with an
elimination half-life of several hours.
¢ PAE would significantly delay bacterial regrowth
after the antibiotic concentration falls below the
MIC
Holanderr et al. Duration and Clinical Relevance of Postantibiotic Effect in Relation to the
Dosing Interval. Antimicrobial Agents and Chemotherapy. 1998. vol 42. no 4. p 749-754
 POST ANTIBIOTIC EFFECT OF
AMINOGLYCOSIDES

Holanderr et al. Duration and Clinical Relevance of Postantibiotic Effect in Relation to the
Dosing Interval. Antimicrobial Agents and Chemotherapy. 1998. vol 42. no 4. p 749-754
 ADAPTIVE RESISTANCE
(A PHARMACODYNAMICS PROPERTIES OF
AMINOGLYCOSIDES)
• Adaptive resistance is a phenomenon recently described for
Pseudomonas aeruginosa and other gram negative bacilli following
exposure to aminoglycoside antibiotics
• It is a reversible form of resistance which develops within 1 to 2 h
of initial exposure to an aminoglycoside and disappears several
hours after removal of the antibiotic

Barclay et al. Adaptive Resistance Following Single Dose of Gentamycine in Dynamic in Vitro
Model. Antimicrobial Agents and Chemotherapy vol 36 no 9 p 1951-1957. 1992
ADAPTIVE RESISTANCE
(A PHARMACODYNAMICS PROPERTIES OF
AMINOGLYCOSIDES)

Barclay et al. Adaptive Resistance Following Single Dose of Gentamycine in Dynamic in Vitro
Model. Antimicrobial Agents and Chemotherapy vol 36 no 9 p 1951-1957. 1992
 CLINICAL EFFICACY OF CONVENTIONAL
DOSE AND EXTENDED INTERVAL DOSE

Munckof, et al. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once
daily or as divided doses. Journal of Antimicrobial Chemotherapy. 1996. vol 37 p 645-667
 TOXICITY OF CONVENTIONAL DOSE AND
EXTENDED INTERVAL DOSE

Munckof, et al. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once
daily or as divided doses. Journal of Antimicrobial Chemotherapy. 1996. vol 37 p 645-667
AMINOGLYCOSIDES DOSING
¢ Conventional Dose (Multiple Daily Dose)
Dose given every 8-12 hours

¢ Extended Interval Dose (Once Daily Dose)

Larger initial dose given less frequently

Brunton and Parker., 2008., Manual of Pharmacologic and Therapeutics., McGraw Hill
 CONTRAINDICATION FOR EXTENDED
INTERVAL DOSE OF AMINOGLYCOSIDE
Relative Contraindication
¢ Elderly (age ≥ 70 years)
¢ Pregnancy or post-partum
¢ Renal insufficiency with CrCL< 30 ml/min
¢ Dialysis
¢ Severe liver disease or ascites
¢ History or signs of hearing loss or vestibular toxicity
Absolute Contraindication
¢ Endocarditis
¢ Synergy for gram positive infections
¢ Cystic fibrosis
¢ Surgical prophylaxis
¢ Severe fluid overload states
¢ Extensive burns (> 50% total body surface area)

Blaser J, Konig C. Once-daily dosing of aminoglycosides. Eur J Clin Microbiol

Infect Dis 1995; 14: 1029-1038.
STRATEGY TO PREVENT NEPHOTOXIC EFFECT OF
AMINOGLYCOSIDE

Most to least nephrotoxic of systemically used aminoglycosides:

1. Gentamicin
2. Tobramycin
3. Amikacin
4. Netilmicin

De Broe., Porter., 2008., Clinical Nephrotoxin., Springer

SUMMARY
¢ Extended interval dose reduced risk
aminoglycoside with same efficacy to
conventional dose aminoglycoside
¢ Pharmacokinetics calculation is needed to reduce
risk of aminoglycoside toxicity,
REFERENCES
1. Anderson et al. Handbook of Clinical Drug Data 10th edition. 2002
. New York :McGraw Hill Inc
2. Bauer L.A. Applied Pharmacokinetics 2nd edition. 2008. New york :
McGraw Hill Inc
3. Sandhu,J.S., et al, 2007, Aminoglycoside Nephrotoxicity Revisited,Indian
Academy of Clinical Medicine, Vol.8. No.4
4. Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical
Practice 2nd Ed., Informa Health Care
5. Urban, A.W. and Craig, W.A., Daily Dose of Aminoglycoside. In :
Remington & Swartz. Current Clinical Topics in Infectious
Diseases 17th edition. 1997. London :Blackwell Science
6. Holanderr et al. Duration and Clinical Relevance of Postantibiotic Effect
in Relation to the Dosing Interval. Antimicrobial Agents and
Chemotherapy. 1998. vol 42. no 4. p 749-754
7. Barclay et al. Adaptive Resistance Following Single Dose of
Gentamycine in Dynamic in Vitro Model. Antimicrobial Agents and
Chemotherapy vol 36 no 9 p 1951-1957. 1992
REFERENCES
8. Munckof, et al. A meta-analysis of studies on the safety and efficacy of
aminoglycosides given either once daily or as divided doses. Journal of
Antimicrobial Chemotherapy. 1996. vol 37 p 645-667
9. Blaser J, Konig C. Once-daily dosing of aminoglycosides. Eur J Clin
Microbiol Infect Dis 1995; 14: 1029-1038.
10. De Broe., Porter., 2008., Clinical Nephrotoxin., Springer
11. Reynolds and Aronson, 1992, ABC of Monitoring Drug Therapy;
BMJ,Vol.305
THANK YOU