THE PROPER USE OF

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

By :
Postgraduate Pharmacy Student
Master of Clinical Pharmacy
University of Airlangga
2010
 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 detected in the urine for several
days  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

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

Cockroft And Gault

SARUBBI AND HULL METHOD

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

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

Nightingale., et al., 2007., Antimicrobial Pharmacodynamics in theory and Clinical Practice 2 nd 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 17 th 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