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

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

3. AMINOGLYCOSIDES
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

4. AMINOGLYCOSIDES
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

5. AMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
POSTANTIBIOTIC EFFECT
 Aminoglycosides’ killing action continues
when the plasma levels have declined
below measurable levels

6. AMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
POSTANTIBIOTIC EFFECT
 Greater efficacy when administered as
a single large dose than when given as
multiple smaller doses

7. AMINOGLYCOSIDES
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

8. AMINOGLYCOSIDES
PHARMACOKINETICS
 Structurally related amino sugars
attached by glycosidic linkages
 Polar compounds
 Not absorbed orally

9. AMINOGLYCOSIDES
PHARMACOKINETICS
 Given intramuscularly or intravenously
for systemic effects
 Limited tissue penetration
 Do not readily cross the blood-brain
barrier

10. AMINOGLYCOSIDES
PHARMACOKINETICS
 Major mode of excretion
• Glomerular filtration
 Plasma levels are affected by changes
in renal function

11. AMINOGLYCOSIDES
PHARMACOKINETICS
 Excretion is directly proportional to
creatinine clearance
 With normal renal function, elimination
half-life is 2-3 h

12. AMINOGLYCOSIDES
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

13. AMINOGLYCOSIDES
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

14. AMINOGLYCOSIDES
MECHANISM OF ACTION
 Bactericidal (irreversible) inhibitors of
protein synthesis
 Penetration of bacterial cell wall is partly
dependent on O2-dependent active
transport

15. AMINOGLYCOSIDES
MECHANISM OF ACTION
 Minimal activity against strict anaerobes
 Transport is enhanced by cell wall
synthesis inhibitors
• Antimicrobial synergism

16. AMINOGLYCOSIDES
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

17. AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE
 Resistant due to failure to penetrate
into the cell
• Streptococci, including S. pneumoniae
• Enterococci

18. AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE
 Plasmid-mediated formation of inactivating
enzymes
• Primary mechanism of resistance
• Varying susceptibility to the enzyme

19. 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

20. AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE
 Plasmid-mediated formation of inactivating
enzymes
• Transferases produced by enterococci
can inactivate
• Amikacin
• Gentamicin
• Tobramycin
• Not streptomycin

21. AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE
 Plasmid-mediated formation of inactivating
enzymes
• Netilmicin is less susceptible and is active
against more strains of organisms

22. AMINOGLYCOSIDES
CLINICAL USES
GENTAMICIN, TOBRAMYCIN, and AMIKACIN
 Serious infections caused by aerobic
gram (-) bacteria
• E. coli Enterobacter
• Klebsiella Proteus
• Providencia Pseudomonas
• Serratia

23. AMINOGLYCOSIDES
CLINICAL USES
GENTAMICIN, TOBRAMYCIN, and AMIKACIN
 Used for the following but is not the drug of
choice
• H. influenzae
• M. catarrhalis
• Shigella species

24. AMINOGLYCOSIDES
CLINICAL USES
ANTIBACTERIAL SYNERGY
 Not effective for gram (+) cocci when
used alone
 Combination of aminoglycoside and
cell wall synthesis inhibitors

25. AMINOGLYCOSIDES
CLINICAL USES
ANTIBACTERIAL SYNERGY
 Combined with penicillin in the treatment
• Pseudomonal
• Listerial
• Enterococcal infections

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

27. AMINOGLYCOSIDES
CLINICAL USES
NEOMYCIN
 Used topically
 Locally
• In the GIT
• Eliminate bacterial flora

28. AMINOGLYCOSIDES
CLINICAL USES
NETILMICIN
 Reserved for serious infections resistant
to other aminoglycosides

29. AMINOGLYCOSIDES
CLINICAL USES
SPECTINOMYCIN
 Aminocylitol related to aminoglycosides
 Back-up drug
 Intramuscular as single dose for gonorrhea

30. AMINOGLYCOSIDES
TOXICITY
B. OTOTOXICITY
 Auditory or vestibular damage (or both)
maybe irreversible
• Auditory impairment
• Amikacin and kanamycin
• Vestibular dysfunction
• Gentamicin and tobramycin

31. AMINOGLYCOSIDES
TOXICITY
B. 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

32. AMINOGLYCOSIDES
TOXICITY
B. NEPHROTOXICITY
 Acute tubular necrosis
 Reversible
 Most nephrotoxic
• Gentamicin and tobramycin

33. AMINOGLYCOSIDES
TOXICITY
B. NEPHROTOXICITY
 More common in elderly patients
 Patients concurrently receiving
• Amphotericin B
• Cephalosporins
• Vancomycin

34. AMINOGLYCOSIDES
TOXICITY
B. NEUROMUSCULAR BLOCKADE
 Rare
 Curare-like block may occur at high doses
• Respiratory paralysis
 Reversible

35. AMINOGLYCOSIDES
TOXICITY
B. NEUROMUSCULAR BLOCKADE
 Treatment
• Calcium
• Neostigmine
• Ventilatory support

36. AMINOGLYCOSIDES
TOXICITY
B. SKIN REACTIONS
 Neomycin
• Allergic skin reactions like contact
dermatitis