AMINOGLYCOSIDESAMINOGLYCOSIDES

Anita Q. Sangalang, MD, FPOGSFACULTY OF PHARMACY

UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION Treatment of microbial infection with

antibiotics

• Multiple daily dosing

• Maintain serum concentration level

above the minimum inhibitory concentration (MIC)

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION

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

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION

TIME DEPENDENT Any antibiotics, including penicillin and

cephalosporins

• Directly related to time above MIC

• Independent of concentration once

the MIC is reached

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION

POSTANTIBIOTIC EFFECT Aminoglycosides’ killing action continues

when the plasma levels have declined

below measurable levels

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION

POSTANTIBIOTIC EFFECT Greater efficacy when administered as

a single large dose than when given as multiple smaller doses

AMINOGLYCOSIDESAMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION 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

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS Structurally related amino sugars

attached by glycosidic linkages Polar compounds Not absorbed orally

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS Given intramuscularly or intravenously

for systemic effects Limited tissue penetration Do not readily cross the blood-brain

barrier

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS Major mode of excretion

• Glomerular filtration Plasma levels are affected by changes

in renal function

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS Excretion is directly proportional to

creatinine clearance With normal renal function, elimination

half-life is 2-3 h

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS 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

AMINOGLYCOSIDESAMINOGLYCOSIDES

PHARMACOKINETICS For traditional dosing regimens

• 2 or 3 times daily

• Peak serum levels

•Measured at 30-60 minutes after administration

• Trough serum levels

•Measured just before the next dose

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISM OF ACTION Bactericidal (irreversible) inhibitors of

protein synthesis Penetration of bacterial cell wall is partly

dependent on O2-dependent active

transport

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISM OF ACTION Minimal activity against strict anaerobes Transport is enhanced by cell wall

synthesis inhibitors

• Antimicrobial synergism

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISM OF ACTION 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

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISMS OF RESISTANCE Resistant due to failure to penetrate

into the cell

• Streptococci, including S. pneumoniae

• Enterococci

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating

enzymes

• Primary mechanism of resistance

• Varying susceptibility to the enzyme

AMINOGLYCOSIDES

MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating

enzymes

• Group transferases

•Catalyze the acetylation of amine functions

•Transfer of phosphoryl or adenyl groups to the O2 atoms of hydroxyl groups on the aminoglycoside

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating

enzymes• Transferases produced by enterococci

can inactivate •Amikacin•Gentamicin•Tobramycin •Not streptomycin

AMINOGLYCOSIDESAMINOGLYCOSIDES

MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating

enzymes

• Netilmicin is less susceptible and is active against more strains of organisms

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

GENTAMICIN, TOBRAMYCIN, and AMIKACIN Serious infections caused by aerobic

gram (-) bacteria

• E. coli Enterobacter

• Klebsiella Proteus

• Providencia Pseudomonas

• Serratia

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

GENTAMICIN, TOBRAMYCIN, and AMIKACIN Used for the following but is not the drug of

choice

• H. influenzae

• M. catarrhalis

• Shigella species

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

ANTIBACTERIAL SYNERGY Not effective for gram (+) cocci when

used alone Combination of aminoglycoside and

cell wall synthesis inhibitors

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

ANTIBACTERIAL SYNERGY Combined with penicillin in the treatment

• Pseudomonal

• Listerial

• Enterococcal infections

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

STREPTOMYCIN Tuberculosis Plague Tularemia Multi-drug-resistant (MDR) strains of M. tb

resistant to streptomycin maybe susceptible

to amikacin

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

NEOMYCIN Used topically Locally

• In the GIT

• Eliminate bacterial flora

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

NETILMICIN Reserved for serious infections resistant

to other aminoglycosides

AMINOGLYCOSIDESAMINOGLYCOSIDES

CLINICAL USES

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

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

A. OTOTOXICITY Auditory or vestibular damage (or both)

maybe irreversible

• Auditory impairment

• Amikacin and kanamycin

• Vestibular dysfunction

• Gentamicin and tobramycin

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

A. OTOTOXICITY 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

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

B. NEPHROTOXICITY Acute tubular necrosis Reversible Most nephrotoxic

• Gentamicin and tobramycin

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

B. NEPHROTOXICITY More common in elderly patients Patients concurrently receiving

• Amphotericin B

• Cephalosporins

• Vancomycin

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

C. NEUROMUSCULAR BLOCKADE Rare Curare-like block may occur at high doses

• Respiratory paralysis Reversible

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

C. NEUROMUSCULAR BLOCKADE Treatment

• Calcium

• Neostigmine

• Ventilatory support

AMINOGLYCOSIDESAMINOGLYCOSIDES

TOXICITY

D. SKIN REACTIONS Neomycin

• Allergic skin reactions like contact dermatitis