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AMINOGLYCOSIDES
A. Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

MODES OF ANTIBACTERIAL ACTION
Treatment of microbial infection with antibiotics
Multiple daily dosing
Maintain serum concentration level above the minimum inhibitory
concentration (MIC)

CONCENTRATION DEPENDENT
Some drugs and aminoglycosides
As the plasma level is increased above the MIC, the drug kills an
increasing proportion of bacteria at a more rapid rate

TIME DEPENDENT
Any antibiotic, including penicillins and cephalosporins
Directly related to time above MIC
Independent of concentration once the MIC is reached

POSTANTIBIOTIC EFFECT
Aminoglycosides killing action continues when the plasma levels have declined
below measurable levels
Greater efficacy when administered as a single large dose than when given as
multiple smaller doses
Toxicity (in contrast to antibacterial activity) depends on a critical plasma
concentration and on that time such a level is exceeded
Time above such threshold is shorter with single large dose
Basis for once-daily dosing protocols

PHARMACOKINETICS
Structurally related amino sugars attached by glycosidic linkages
Polar compounds
Not absorbed orally
Given intramuscularly or intravenously for systemic effects
Limited tissue penetration
Do not readily cross the blood-brain barrier
Major mode of excretion
Glomerular filtration
Plasma levels are affected by changes in renal function
Excretion is directly proportional to creatinine clearance
With normal renal function, elimination half-life is 2-3 h
Dosage adjustment must be made in renal insufficiency to avoid toxic
accumulation
Monitoring plasma levels is needed for safe and effective dosage selection and
adjustment
For traditional dosing regimens
2 or 3 times daily
Peak serum levels
Measured at 30-60 minutes after administration
2
Trough serum levels
Measured just before the next dose

MECHANISM OF ACTION
Bactericidal (irreversible) inhibitors of protein synthesis
Penetration of bacterial cell wall is partly dependent on O2-dependent active
transport
Minimal activity against strict anaerobes
Transport is enhanced by cell wall synthesis inhibitors
Antimicrobial synergism
Bind to 30S ribosomal unit
Interfere with protein synthesis
1. Block formation of initiation complex
2. Cause misreading of the code on the mRNA template
3. Inhibit translocation

MECHANISMS OF RESISTANCE
Failure to penetrate into the cell
Streptococci, including S. pneumoniae
Enterococci
Plasmid-mediated formation of inactivating enzymes
Primary mechanism of resistance
Varying susceptibility to the enzyme
Group transferases
Catalyze the acetylation of amine functions
Transfer of phosphoryl or adenyl groups to the O2 atoms of
hydroxyl groups on the aminoglycoside
Transferases produced by enterococci can inactivate
Amikacin
Gentamicin
Tobramycin
Not streptomycin
Netilmicin is less susceptible and is active against more strains of
organisms

CLINICAL USES
GENTAMICIN, TOBRAMYCIN, and AMIKACIN
Serious infections caused by aerobic gram (-) bacteria
E. coli Enterobacter
Klebsiella Proteus
Providencia Pseudomonas
Serratia
Used for the following but is not the drug of choice
H. influenzae
M. catarrhalis
Shigella species





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ANTIBACTERIAL SYNERGY
Not effective for gram (+) cocci when used alone
Combination of aminoglycoside and cell wall synthesis inhibitors
Combined with penicillin in the treatment
Pseudomonal
Listerial
Enterococcal infections
Combined with penicillin in the treatment
Pseudomonal
Listerial
Enterococcal infections

STREPTOMYCIN
Tuberculosis
Plague
Tularemia
Multi-drug-resistant (MDR) strains of M. tb resistant to streptomycin maybe
susceptible to amikacin

NEOMYCIN
Used topically
Locally
In the GIT
Eliminate bacterial flora

NETILMICIN
Reserved for serious infections resistant to other aminoglycosides

SPECTINOMYCIN
Aminocylitol related to aminoglycosides
Back-up drug
Intramuscular as single dose for gonorrhea

TOXICITY
A. OTOTOXICITY
Auditory or vestibular damage (or both) maybe irreversible
Auditory impairment
Amikacin and kanamycin
Vestibular dysfunction
Gentamicin and tobramycin
Risk is proportionate to the plasma levels
High if dosage is not modified in renal dysfunction
Increased with the use of loop diuretics
Contraindicated in pregnancy

B. NEPHROTOXICITY
Acute tubular necrosis
Reversible
Most nephrotoxic
Gentamicin and tobramycin
More common in elderly patients
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Patients concurrently receiving
Amphotericin B
Cephalosporins
Vancomycin

C. NEUROMUSCULAR BLOCKADE
Rare
Curare-like block may occur at high doses
Respiratory paralysis
Reversible
Treatment
Calcium
Neostigmine
Ventilatory support

D. SKIN REACTIONS
Neomycin
Allergic skin reactions like contact dermatitis