This document discusses aminoglycoside antibiotics. It begins by listing the key learning objectives which include explaining the mechanisms of action and resistance of aminoglycosides, describing different dosing regimens, monitoring therapy to avoid toxicity, and the unique features of individual drugs. It then covers the common structural features and characteristics of aminoglycosides, their mechanisms of action, and causes of resistance. The advantages and disadvantages of different dosing regimens are outlined. Signs of ototoxicity and nephrotoxicity are described along with monitoring therapy. Individual drugs like gentamicin, streptomycin, and amikacin are discussed in terms of their uses, doses, and spectra of activity.

1. AMINOGLYCOSIDES
Dr. Mukundam Borah
Assistant Professor of Pharmacology
SMCH, Silchar

2. OBJECTIVES
At the end of the class, you should be able to ..
1.42.14 Explain aminoglycoside mechanisms of action and resistance.
1.42.15 Describe the advantages and disadvantages of multiple daily
dosing versus once daily extended-interval dosing regimens for
aminoglycosides.
1.42.16 Describe the rationale and the methods of plasma concentration
monitoring of aminoglycoside therapy.
1.42.17 Describe the causes and clinical signs of aminoglycoside
ototoxicity and nephrotoxicity and the best means of monitoring therapy to
avoid these serious toxicities.
1.42.18 Explain the unique clinical differences among the aminoglycosides.

3. COMMON FEATURES OF AMINOGLYCOSIDES
STRUCTURE
 Chemically, they are polycations containing amino-
sugars in glycoside linkage.
aminosugar -0- 2-deoxystreptamine -0- aminosugar
aminocyclitol moiety

4. Streptidine—o—Streptose aminosugar—o— N-methyl-
L-Glucosamine
aminosugar
Streptobiosamine
(Streptomycin)

5. COMMON FEATURES OF AMINOGLYCOSIDES contd..
They are bactericidal and have maximum
activity in alkaline medium.
Simiar spectrum of activity and highly effective
aglinst Gram negative microorganisms.
Hiaghly polar and are not absorbed orally,
distributed extracellularly (mostly), and have
poor penetration into CSF and eyes.

6.  Excreted unchanged relatively rapidly by the kidneys by
glomerular filtration and dosage adjustment is a must in
renal impairment and elderly.
 Bacteria develop resistance fairly rapidly (with cross-
resistance).
 Exhibit synergism when combined with a beta-lactam
antibiotic.
 Cause nephrotoxicity and ototoxicity, along with curari
mimetic properties.
 Should be avoided in pregnancy.

7. AMINOGLYCOSIDE DRUGS
Systemic aminoglycosides Topical aminoglycosides
 Streptomycin
 Kanamycin
 Gentamicin
 Tobramycin
 Netilmicin
 Amikacin
 Paromomycin
 Abekacin
•Neomycin
•Framycetin

8.  1.42.14 Explain aminoglycoside mechanisms of
action

9. Passive diffusion
Bacterial Cell wall

10.  The formation of improper "initiation complex” also blocks
the movement of ribosomes, resulting in a mRNA chain
attached with single ribosomes (monosomes). Thus
aminoglycosides also interfere in the assembly of
polysomes, which results in the accumulation of
nonfunctional ribosomes.

12. 1.42.14 Explain aminoglycoside mechanisms of
resistance
ANTIBACTERIAL SPECTRUM
 Primarily directed against Gram-negative aerobic bacilli (E. coli,
Klebsiella, Shigella, Proteus, including Enterobacter and
Pseudomonas aeruginosa, except Salmonella).
 Most enterobacteriaçeae are sensitive to aminoglycosides. Only a
few Gram-positive cocci (aureus, Streptococcus viridans and
faecalis, not others) are inhibited by these drugs.
 Aminoglycosides are not effective against Gram-positive bacilli,
Gram negative cocci and anaerobes.

13. MECHANISMS OF RESISTANCE:
 Three principal mechanisms identified:
1. ‘R’ factor-mediated resistance: The conjugative
plasmids, that contain the r- gene transferred during
conjugation confers on the recipient cell the capacity to
synthesize specific enzymes which destroy the
aminoglycosides.
Synthesis of plasmid-mediated bacterial transferase
enzymes that can inactivate aminoglycosides by
acetylation, phosphorylation and adenylylation.

14. 2. Due to decreased transport of aminoglycoside into the
bacterial cytosol.
3. By deletion or alteration of the receptor protein on 30S
ribosomal unit because of mutations to prevent
attachment of the drug with the 30S ribosomal

15. PHARMACOKINETICS
 Aminoglycosides are highly polar, basic and have very poor
oral bioavailability.
 Given parenterally (l.V. or l.M.) or applied locally (as
ointments or eye drops).
 These are poorly distributed insynovial, pleural and
peritoneal compartments and poorly protein bound.
 Aminoglycosides are not metabolized in the body, and are
excreted unchanged in urine by Glomerular filtration.

16.  Hence dose adjustment is needed to avoid toxicity in patients
with renal insufficiency.
 Dose in renal insufficiency = Regular therapeutic dose / Serum
creatinine value
 However, the most precise method for calculating the dose for
such patient must use creatinine clearance.
 Though normal half-life varies from 1.5-3 hrs, it may increase to
24- 48 hrs in patients with renal insufficiency.

17. 1.42.15 Describe the advantages and
disadvantages of multiple daily dosing versus
once daily extended-interval dosing regimens
for aminoglycosides

18. DOSING REGIMENS:
 For an average adult with normal renal function (CLcr > 70
ml/min), the usual doses are:
 Gentamicin/tobramycin/ 3- 5 mg/kg/day
sisomicin/netiImicin
 Streptomycin/ 7.5- 15 mg/kg/day
kanamycin/amikacin
 Considering the short t½ (2-4 hr) of aminoglycosides
the daily doses are conventionally divided into 3 equal
parts and injected i.m. (or i.v. slowly over 60 min)
every 8 hours.
 However, most authorities now recommend a single
total daily dose regimen for patients with normal
renal function.

19. Advantages of once daily extended-interval dosing regimens:
 They exhibit concentration dependent killing (CDK) and also
have a post antibiotic effect, depending on concentration.
 Increased concentration kills an increasing proportion of
bacteria at a rapid rate.(CDK)
 Post-antibiotic Effect (PAE): A persistent suppression of bacterial
growth after a brief exposure of an antimicrobial agent is known as
post-antibiotic effect (PAE).
 In PAE, the inhibition of bacterial growth is seen even when the
antibacterial agent is no longer present in the bacterial medium or
even when its concentration is well below MIC.

20.  Reduced incidence of ototoxicity and nephrotoxicity.
 Better patient compliance and Cost-effective .
Disdvantages of once daily extended-interval dosing
regimens:
 May require Therapeutic Drug Monitoring.
 Patients who are pregnant or have liver failure, severe renal
insufficiency, serious illness are not appropriate candidates
for once-daily dosing.

21. 1.42.16 Describe the rationale and the methods of plasma
concentration
Monitoring of aminoglycoside therapy
For once daily injections, plasma trough concentrations are
measured which should be <1mcg/ml. Sample is collected after 2
hr and 12 hr following a dose.
Dose of aminoglycosides should be reduced in renal impairment.
Calculation:
Dose in renal insufficiency = Regular therapeutic dose / Serum
creatinine value

22.  PRECAUTIONS AND INTERACTIONS
 Avoid aminoglycosides during pregnancy due to risk of foetal
ototoxicity.
 Avoid concurrent use of other nephrotoxic drugs, e.g. NSAIDs,
amphotericin B, vancomycin, cyclosporine and cisplatin.
 Cautious use of other potentially ototoxic drugs like vancomycin,
minocycline and furosemide, though clinical evidence of
potentiated ototoxicity is meagre.
 Cautious use in patients >60 years age and in those with kidney
damage.
 Do not mix aminoglycoside with any drug in the same
syringe/infusion bottle.

23. ADVERSE DRUG REACTIONS
Neomycin, Kanamycin and Amikacin are the most ototoxic
(Cochlear toxicity) while Streptomycin and Gentamicin are the
most vestibulotoxic.
Neomycin, Tobramycin and Gentamicin are the most
nephrotoxic .
Neuromuscular Blockade
 The neuromuscular blockade is more with neomycin and
streptomycin as compared to amikacin, gentamicin,
tobramycin and netilmicin.

24. 1.42.17 Describe the causes and clinical signs of aminoglycoside
ototoxicity and the best means of monitoring therapy to avoid
these serious toxicities
OTOTOXICITY CLINICAL SIGNS:
 Dependent on the drug, dose and duration of therapy
 Greater in infants, elderly and in renal impaired .
 High concentrations are found in the endolymph and perilymph
of the inner ear  cochlear or vestibular dysfunction or both
 Reversible or irreversible.

25.  Cochlear damage:
Hearing loss affects the high frequency sound first, then
progressively encompasses the lower frequencies.
Initially, the cochlear toxicity is asymptomatic and can be
detected only by audiometry.
Tinnitus then appears, followed by progressive hearing loss.
On stopping the drug, tinnitus disappears in 4--10 days, but
frequency loss persists.

26.  Vestibular damage:
 Headache is usually first to appear, followed by nausea,
vomiting, dizziness, nystagmus, vertigo and ataxia.
 When the drug is stopped at this stage, it passes into a
chronic phase lasting 6 to IO weeks in which the patient is
asymptomatic while in bed and has difficulty only during
walking.
 Compensation by visual and proprioceptive positioning
tends to allay symptoms and recovery (often incomplete)
occurs over 1-2 years.

27. 1.42.17 Describe the causes and clinical signs of aminoglycoside
nephrotoxicity and the best means of monitoring therapy to avoid
these serious toxicities
Nephrotoxicity :
 Accumulate in the proximal tubular cells and cause damage to
them.
 Also reduce the sensitivity of the collecting ducts to vasopressin.
Nephrotoxicity Clinical signs:
 Mild albuminuria, cylindruria (renal casts), or acute tubular
necrosis (rarely azotemia)
Nephrotoxicity monitoring:
 Dosage adjustment in renal insufficiency.
 Withdrawal causes reversal.

28. INDIVIDUAL DRUGS AND CLNICAL USES
1. GENTAMICIN
 Currently, it is the most commonly used aminoglycoside for
acute infections and may be considered prototype of the class.
 Because of low therapeutic index, its use should be restricted to
serious gram-negative bacillary infections.

29. USES:
1. Gentamicin is very valuable for preventing and treating
respiratory infections in critically-ill patients,
postoperative pneumonias; patients with implants and in
intensive care units.
 It is mostly combined with a penicillin/cephalosporin or
another antibiotic in these situations.
 Aminoglycosides should not be used to treat community
acquired pneumonias (CAPs) which are mostly caused
by gram-positive cocci and anaerobes.

30. 2. Pseudomonas, Proteus or Klebsiella infections:
 Burns, urinary tract infection, pneumonia, lung abscesses,
osteomyelitis, middle ear infection, septicaemia, etc.,
caused mostly by the above bacteria are an important area
of use of gentamicin. It may be combined with piperacillin
or a third generation cephalosporin for serious infections.
3. Meningitis caused by gram negative bacilli:
 Third generation cephalosporin with an aminoglycoside are
favoured for this purpose.

31. 4. Subacute bacterial endocarditis (SABE):
Gentamicin (1 mg/kg 8 hourly i.m.) is generally combined
with penicillin/ampicillin/vancomycin.
STREPTOMYCIN
 Ribosomal resistance to streptomycin develops fast, which has
limited its usefulness as a single agent except for few indications .
 Uses:
I. Tuberculosis .
2. Subacute bacterial endocarditis (SABE)

32. 3. Plague: Streptomycin is rapidly curative (in 7- 12 days).
Given alone or combined with a tetracycline. it is employed
only in confirmed cases.
4. Tularemia: Streptomycin is the drug of choice for this rare
disease; effects cure in 7-10 days. Tetracyclines arc the
alternative drugs, especially in milder cases.

33. Tobramycin
 It is 2-4 times more active than gentamicin against
Pseudomonas and Proteus.
 However, tobramycin is not useful for combining with
penicillin in the treatment of enterococcal endocarditis.
Kanamycin
 Similar to streptomycin in all respects but is more toxic.
 Kanamycin is occasionally used as a Second line drug in
resistant tuberculosis.

34. AMIKACIN
 It is a semisynthetic derivative of kanamycin to which it
resembles in pharmacokinetics, dose and toxicity.
 The outstanding feature of amikacin is its resistance to
bacterial aminoglycoside modifying enzymes. Thus, it has
the widest spectrum of activity.
 The range of conditions in which amikacin can be used is
the same as for gentamicin.
 It is recommended as a reserve drug for empirical
treatment of hospital acquired gram-negative bacillary
infections.
 Amikacin is also used for multidrug resistant TB.

35. NEOMYCIN
 Obtained from S. fradiae, it is a wide-spectrum aminoglycoside
active against most gram negative bacilli and some gram-positive
cocci.
 However, Pseudomonas and Strep. Pyogenes are not sensitive.
 Because of ototoxicity and nephrotoxicity, not used systemically.
 Absorption from the g.i.t. is minimal. Oral and topical
administration does not ordinarily cause systemic toxicity.
 Dose: 0.25- 1 g Q ID oral, 0.3--0.5% topical.

36.  Uses
I. Topically (often in combination with polymyxin, bacitracin
etc.) for infected wound, ulcers, burn, external ear infections,
conjunctivitis.
II. Used orally as preoperative intestinal antiseptic (1 g TDS or
QID) a day before surgery along with erythromycin (250 mg
QID) to reduce aerobic bowel flora.
III. Neomycin (1 g TDS or QID with reduced protein intake) is
useful in hepatic coma, as it suppresses ammonia-producing
coliform bacterial flora. Blood ammonia levels therefore get
decreased and encephalopathy is thus prevented.

37.  Adverse effects
 Oral neomycin for prolonged time has a damaging effect
on intestinal villi.
 Due to marked suppression of gut flora superinfection by
Candida can occur.
 Contraindicated if renal function is impaired.
Framycetin
 Ointment is used for skin infections, otitis externa,
furunculosis, burns and scalds. Eye drops are used for
ophthalmic infections.

38. ARBEKACIN
 It is a semisynthetic aminoglycoside of the kanamycin
family.
 It has a broad spectrum activity covering many gram +ive
and gram -ve bacteria including MRSA, E. coli,
P.aeruginosa. K. pneumoniae, etc. and is stable to many
commonly occurring aminoglycoside modifying enzymes,
confering activity against many bacteria resistant to
gentamicin and tobramycin.

39.  It synergises with B-lactam antibiotics, and the combination
may be useful in treating multidrug resistant Pseudomonas
and Acinetobacter infections.
 Dose: 1- 3 mg/kg/day i.m. or slow i.v. injection.
PAROMOMYCIN
 Paromomycin (1 g QID orally for 2 weeks) can be used to
treat Intestinal amoebiasis.
 It is also used orally to treat cryptosporidiosis in
immunocompromised patients.

40. 1.42.18 Explain the unique clinical differences
among the aminoglycosides
 Streptomycin is bacteriostatic in low and bactericidal in
high concentrations.
 Kanamycin is used in MDR & XDR TB but is much more
toxic.
 Gentamycin acts synergistically with beta-lactam
antibiotics and metronidazole. Its urinary concentration is
50-100 times that in plasma.
 Tetracycline and chloramphenicol to be avoided with
gentamicin as they reduce its therapeutic efficacy.

41.  Tobramycin is highly active against Pseudomonas, relatively
less toxic.
 Amikacin has the broadest spectrum antibacterial activity;
is expensive and is usually reserved for hospital-acquired
Gram-negative infections and in MDR TB.
 Neomycin is administered orally for sterilization of bowels
prior to surgery (though is poorly absorbed orally); not used
systemically due to more severe ADRs.

42. THANK YOU