This document discusses aminoglycosides, a class of antibiotics. It describes their modes of antibacterial action including being concentration and time dependent, having a post-antibiotic effect, and toxicity depending on plasma concentration over time. Common aminoglycosides like gentamicin and tobramycin are used to treat infections from various aerobic gram-negative bacteria. Their mechanisms of action and resistance are explained. The document also covers the clinical uses, toxicities including ototoxicity and nephrotoxicity, and precautions for aminoglycoside administration.

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