Aminoglycosides 23099

Aminoglycosides
Drugs in this class: streptomycin, neomycin, kanamycin, amikacin,

gentamicin, tobramycin, sisomicin, netilmicin
General Properties of Aminoglycosides
Aminoglycosides have a hexose ring, either
 streptidine (in streptomycin) or
 2-deoxystreptamine (in other aminoglycosides),
 various amino sugars are attached by glycosidic linkages
 They are water-soluble, stable in solution, and more active at
alkaline pH.
Figure: Structures of aminoglycosides
Mechanism of action
Passive diffusion across the outer membrane
Transported across the cell membrane into the cytoplasm

– by an oxygen-dependent process.
 Energy….The transmembrane electrochemical gradient transport is
coupled to a proton pump.
 The process is inhibited by
– Low extracellular pH and
– anaerobic conditions inhibit transport by reducing the gradient.
 The process is enhanced by cell wall-synthesis inhibitor drugs
(synergism)
– penicillin or
– Vancomycin
This synergy may be important in situations, such as endocarditis
Mechanism of action
Inside the cell, aminoglycosides inhibit proteins. Synthesis through
 interference with the initiation complex of peptide
 misreading of mRNA,
 breakup of polysomes into nonfunctional monosomes.
Figure: mechanisms of action of the aminoglycosides in bacteria

Mechanism of action…
Figure: mechanisms of action of the aminoglycosides in bacteria

Mechanisms of Resistance
Three principal mechanisms of resistance are :
 production of a transferase enzyme that inactivates the
aminoglycoside
– encountered clinically.
 There is impaired entry of aminoglycoside into the cell.

– Due to mutation or deletion of a porin protein
 The receptor protein on the 30S ribosomal subunit may be deleted

altered
Pharmacokinetics and once-daily dosing
 They are absorbed very poorly from the intact GIT but
ulcerations (+) absorption
 Half-life …..2–3 hours and 24–48 hours in renal impairment
 Traditionally, given BID/TID (in normal renal function). But
Once daily dosing may be preferred
– Aminoglycosides exhibit concentration-dependent killing
• higher concentrations kill a larger proportion of bacteria and kill at
a more rapid rate.
– They have a significant postantibiotic effect
• the antibacterial activity persists beyond the time during which
measurable drug is present.
– The postantibiotic effect of aminoglycosides can last several hours.
Pharmacokinetics and once-daily dosing…
 a single daily dose of aminoglycoside less toxic—than

multiple smaller doses. But
 To avoid accumulation and toxic levels, once-daily dosing should be
avoided if renal function is impaired
 Multiple dosing in combination therapy of enterococcal and

staphylococcal endocarditis……..is still recommended.
Dose adjustment
Dose adjustment based on Creatinine clearance
 If >60 mL/min,
a single daily dose of 5–7 mg/kg of gentamicin/tobramycin
(15 mg/kg for amikacin).
If <60 mL/min, in once daily dosing
 serum concentrations need not be routinely checked until the
second or third day of therapy
 unnecessary to check peak concentrations except
– high concentrations used for treating drug-resistant pathogens
Adverse Effects
 Toxicity is both time- and concentration-dependent.
All aminoglycosides are ototoxic and nephrotoxic
– Occur when therapy is >= 5 days,
– at higher doses,
– in the elderly and
– in the setting of renal insufficiency.
 potentiate nephrotoxicity occurs in concurrent use with
– loop diuretics (eg, furosemide, ethacrynic acid) or other
– nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin)
• should be avoided if possible.
 Neomycin, tobramycin, and gentamicin are the most nephrotoxic.
Adverse Effects….
 Ototoxicity manifest as auditory or as vestibular damage
– Neomycin, kanamycin, and amikacin …..most likely cause auditory

damage
– Streptomycin and gentamicin……….. vestibulotoxic
 .In very high doses, aminoglycosides can produce a curare-like effect with
neuromuscular blockade that results in respiratory paralysis.
– reversible by calcium gluconate, or neostigmine.
 Hypersensitivity occurs infrequently.
Clinical Uses…
 mostly used against aerobic Gram-negative bacteria, especially for

drug-resistant pathogens or in critically ill patients.
 Mostly used in combination with a β-lactam antibiotic
– to extend empiric coverage and
– For synergism between these two classes of drugs.
 Due to toxicity, these combinations are used less frequently when

alternate regimens are available.
 example, in enterococcal endocarditis
– ampicillin + ceftriaxone…..effective with less risk for nephrotoxicity.
Streptomycin
Clinical Uses
Mycobacterial Infections
 used as a second-line agent for treatment of tuberculosis.
 dosage…… is 15 mg/kg/d with a maximum of 1 g/d
 Children… (20–40 mg/kg/d for children)
 given IM or IV
 Given combination with other agents to prevent emergence of
resistance..
Nontuberculous Infections
 In plague, tularemia, and brucellosis
 Dose…, 1 g twice daily (15 mg/kg twice daily for children), is given
intramuscularly in combination with an oral tetracycline.
 With Penicillin….for enterococcal endocarditis
Streptomycin…
• Adverse Reactions
 Fever, skin rashes, and other allergic manifestations
 Pain at the injection site is common but usually not severe.

 The most serious toxic effect
– disturbance of vestibular function—vertigo and loss of balance and it is
irreversible.
– Streptomycin given during pregnancy can cause deafness in the
newborn.
Gentamicin
Clinical Uses
A. Intramuscular or Intravenous Administration
Dose…. 5–7 mg/kg/d
For severe infections caused by Gram-negative bacteria resistant to other drugs
– P aeruginosa,
– Enterobacter sp,
– Serratia marcescens,
– Proteus sp, Acinetobacter sp, and
– Klebsiella sp.
 Genta and other Aminoglycosides should not be used as alone for
pneumonia
– penetration of infected lung tissue is poor and
– local conditions of low pH and
– low oxygen tension contribute to limited activity.
 Gentamicin, in combination with a cell wall-active for
– endocarditis caused by Gram-positive bacteria (streptococci, staphylococci, and
enterococci)
Gentamicin…
Topical and Ocular Administration
– 0.1–0.3% gentamicin sulfatefor burns, wounds, or skin lesions
and in attempts to prevent intravenous catheter infections.
– injected intraocularly for treatment of certain eye infections.
Intrathecal Administration
. It may be used in cases of drug-resistant meningitis or severe β-
lactam allergy.
Adverse reactions
Nephrotoxicity
 reversible upon drug discontinuation.
 5–25% of patients receiving gentamicin >3-5 days.
Ototoxicity (vestibular) and loss of hearing can also
occur…..irreversible
 in 1–5% for patients receiving >5 days.
 Hypersensitivity…not common
Tobramycin
 has an antibacterial spectrum similar to that of gentamicin.
Clinical uses
IM or IV
The PK profile is similar to properties to tobramycin.
dose of tobramycin is 5–7 mg/kg (QD/TID)
 It has almost the same antibacterial spectrum to gentamicin
example….. Enterococcus faecalis is equally susceptible exceptions
– Gentamicin more active against S marcescens and tobramycin
against P. aeruginosa
– E faecium is resistant to tobramycin.
 Gentamicin and tobramycin are otherwise interchangeable clinically.
 Like other tobramycin is ototoxic and nephrotoxic..
Tobramycin…
Inhaled and Ophthalmic Administration
in solution (300 mg in 5 mL) for inhalation

 for treatment of P aeruginosa lower respiratory tract infections
complicating cystic fibrosis.
Dose…
 The drug is recommended as a 300-mg BID
 Duration of treatment….28 days
Ophthalmic
 0.3% ointment and drops for the treatment of superficial eye infections
Amikacin
 Effective against
– microorganisms resistance to gentamicin and tobramycin,
– multidrug-resistant Mycobacterium tuberculosis, including
streptomycin-resistant
• Dosage for TB…10–15 mg/kg/d as a QD-daily or two to three
times weekly
• Given combination with other drugs to which the isolate is
susceptible
 Kanamycin-resistant strains may be cross resistant to amikacin.
Netilmicin
Dose…..5–7 mg/kg/d
 netilmicin may be active against some
– gentamicin-resistant and
– tobramycin-resistant bacteria.
 interchangeable with gentamicin or tobramycin is

possible
Neomycin, kanamycin, & paromomycin
 Drugs of the neomycin group are
– active against Gram (+) and (-) and
– and some mycobacteria. But Resistance to
• P aeruginosa and streptococci
Reason for resistance ….

– widespread use in bowel preparation
– some outbreaks of enterocolitis in hospitals.
 Cross-resistance between kanamycin and neomycin is

complete and may result in amikacin cross-resistance.
Clinical uses
 Neomycin….limited to topical and oral use due to

– toxicity associated with parenteral use and
– higher resistance rates.
 Kanamycin use…. limited to treatment of MDR-TB
 Paromomycin used against
– visceral leishmaniasis (Parenteraly)
– for intestinal Entamoeba histolytica
– for intestinal infections with other parasites
Clinical uses….
Topical Administration
 Solutions containing 1–5 mg/mL neomycin
– injected into joints, the pleural cavity, tissue spaces, or abscess
cavities where infection is present.
 Dose should not be >to 15 mg/kg/d
– higher doses enough drug may be absorbed to produce systemic
toxicity.
Ointments
 as a neomycin-polymyxin-bacitracin combination,
– applied to infected skin lesions or in the nares for suppression of
staphylococci
Clinical uses….
Oral Administration
 In preparation for elective bowel surgery, 1 g of neomycin
may
– every 6–8 hours for 1–2 days, often combined with 1 g of
erythromycin base. This reduces the aerobic bowel flora
with little effect on anaerobes.
 In hepatic encephalopathy…1 g every 6–8
Adverse Reactions
All members of the neomycin group have significant nephrotoxicity
and ototoxicity.
– Auditory function is affected more than vestibular function.
– Deafness may occur, especially in impaired renal function

The sudden kanamycin from the peritoneal cavity (3–5 g) can cause
– curare-like neuromuscular blockade and
– respiratory arrest.
• Calcium gluconate and neostigmine can act as antidotes.
prolonged application of neomycin-containing ointments to skin and
eyes has resulted in severe allergic reactions.
Spectinomycin
Spectrum activity
active in many Gram(+) and (-) but it is used
– as an alternative treatment for drug-resistant gonorrhea or
– gonorrhea in penicillin-allergic patients.
Strains of gonococci may be resistant to spectinomycin, but no cross-resistance with drugs used in
gonorrhea.
Dose…single dose of 2–4 g/d (40 mg/kg in children).
Adverse effect….
There is pain at the injection site and
fever and nausea (occasionally)
Nephrotoxicity and anemia (rarely).

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Aminoglycosides

Drugs in this class: streptomycin, neomycin, kanamycin, amikacin,

Transported across the cell membrane into the cytoplasm

Figure: mechanisms of action of the aminoglycosides in bacteria

Figure: mechanisms of action of the aminoglycosides in bacteria

 There is impaired entry of aminoglycoside into the cell.

 The receptor protein on the 30S ribosomal subunit may be deleted

 a single daily dose of aminoglycoside less toxic—than

 Multiple dosing in combination therapy of enterococcal and

 Ototoxicity manifest as auditory or as vestibular damage

– Neomycin, kanamycin, and amikacin …..most likely cause auditory

 mostly used against aerobic Gram-negative bacteria, especially for

– For synergism between these two classes of drugs.

 Due to toxicity, these combinations are used less frequently when

 Pain at the injection site is common but usually not severe.

in solution (300 mg in 5 mL) for inhalation

 Duration of treatment….28 days

 interchangeable with gentamicin or tobramycin is

Reason for resistance ….

 Cross-resistance between kanamycin and neomycin is

 Neomycin….limited to topical and oral use due to

All members of the neomycin group have significant nephrotoxicity

– Auditory function is affected more than vestibular function.

– Deafness may occur, especially in impaired renal function

active in many Gram(+) and (-) but it is used

– as an alternative treatment for drug-resistant gonorrhea or

– gonorrhea in penicillin-allergic patients.

Dose…single dose of 2–4 g/d (40 mg/kg in children).

There is pain at the injection site and

fever and nausea (occasionally)

Nephrotoxicity and anemia (rarely).

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