Aminoglycosides

Mechanism of resistance
Three principal mechanisms have been established:
(1) production of a transferase enzyme or enzymes inactivates the aminoglycoside by
adenylylation, acetylation, or phosphorylation. This is the principal type of resistance
encountered clinically.
(2) There is impaired entry of aminoglycoside into the cell. This may be genotypic, resulting
from mutation or deletion of a porin protein or proteins involved in transport and maintenance of
the electrochemical gradient; or phenotypic, e.g, resulting from growth conditions under which
the oxygen-dependent transport process described above is not functional.
(3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a
mutation.
Clinical Uses

 Aminoglycosides are mostly used against gram-negative enteric bacteria, especially when
the isolate may be drugresistantand when there is suspicion of sepsis.
 They are almost always used in combination with a βlactam antibiotic to extend coverage
to include potential gram-positive pathogens and to take advantage of the synergism
between these two classes of drugs.
 Penicillin-aminoglycoside combinations also are used to achieve bactericidal activity in
treatment of enterococcal endocarditis and to shorten duration of therapy for viridans
streptococcal and some patients with staphylococcalendocarditis.
Streptomycin

 Streptomycin was isolated from a strain of Streptomyces griseus.

 The antimicrobial activity of streptomycin is typical of that of other aminoglycosides.
Ribosomal resistance to streptomycin develops readily, limiting its role as a single agent.
Clinical Uses
A. Mycobacterial Infections

 Streptomycin is mainly used as a second-line agent for treatment of tuberculosis. The

dosage is 0.5–1 g/d (7.5– 15 mg/kg/d for children),which is given intramuscularly or
intravenously. It should be used only in combination with other agents to prevent
emergence of resistance.
B. NontuberculousInfections
  In plague, tularemia, and sometimes brucellosis, streptomycin, 1 g/d (15 mg/kg/d for
children), is given intramuscularlyin combination with an oraltetracycline.
 Penicillin plus streptomycin is effective for enterococcal endocarditis and 2-week therapy
of viridans streptococcal endocarditis. Gentamicin has largely replaced streptomycin for
these indications.
 Streptomycin remains a useful agent for treating enterococcal infections, however,
because approximately 15% of enterococcal isolates that are resistant to gentamicin (and
therefore resistant to netilmicin, tobramycin, and amikacin) will be susceptible to
streptomycin.
Adverse Reactions

 Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to
streptomycin. This occurs most frequently with prolonged contact with the drug either in
patients who receive a prolonged course of treatment (eg, for tuberculosis) or in medical
personnel who handle the drug.
 Pain at the injection site is common but usually not severe. The most serious toxic effect
with streptomycin is disturbance of vestibular function—vertigo and loss of balance. The
frequency and severity of this disturbance are in proportion to the age of the patient, the
blood levels of the drug, and the duration of administration.
 Vestibular dysfunction may follow a few weeks of unusually high blood levels (e.g, in
individuals with impaired renal function) or months of relatively low blood levels.
 Vestibular toxicity tends to be irreversible.
 Streptomycin given during pregnancy can cause deafness in the newborn and, therefore,
is relatively contraindicated.
Gentamicin:

 Gentamicin is an aminoglycoside isolated from

Micromonosporapurpurea.
 It is effective against both gram-positive and gramnegative organisms. Sisomicin is very
similar to the C1a component of gentamicin.
Antimicrobial Activity

 Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many strains of staphylococci and
coliforms and other gramnegative bacteria.
 It is active alone, but also with β-lactam antibiotics, against Escherichia coli, Proteus,
Klebsiella pneumoniae, Enterobacter, Serratia, Stenotrophomonas, and other gram-
negative rods that may be resistant to multiple other antibiotics.
Resistance
  Streptococci and enterococci are relatively resistant to gentamicin owing to failure of the
drug to penetrate into the cell. Ribosomal resistance is rare.
 Among gram-negative bacteria, resistance is most commonly due to
plasmid-encoded aminoglycoside-modifying enzymes.
 The enterococcal enzyme that modifies gentamicin is a bifunctional enzyme that also
inactivates amikacin, netilmicin, and tobramycin, but not streptomycin.
Clinical Uses
A. Intramuscular or Intravenous Administration

 Gentamicin is used mainly in severe infections (eg, sepsis and pneumonia) caused by
gram-negative bacteria that are likely to be resistant to other drugs, especially P
aeruginosa, Enterobacter sp, Serratia marcescens, Proteus sp, Acinetobacter sp, and
Klebsiella sp.
 Aminoglycosides also should not be used for single-agent therapy of pneumonia because
penetration of infected lung tissue is poor and local conditions of low pH and low oxygen
tension contribute to poor activity. Gentamicin 5– 6 mg/kg/d traditionally is given
intravenously in three equal doses, but once daily administration is just as effective for
some organisms and less toxic.
 Gentamicin, in combination with a cell wallactive antibiotic, is also indicated in the
treatment of endocarditis caused by gram positive bacteria (streptococci, staphylococci,
and enterococci).
 The doses of gentamicin used for synergy against gram-positive bacteria are lower than
traditional doses. Typically the drug is administered at a dose of 3 mg/ kg/day in three
divided doses.
 Peak levels should be approximately 3 mcg/mL, while trough levels should be < 1
mcg/mL.
B. Topical and Ocular Administration

 Creams, ointments, and solutions containing 0.1–0.3% gentamicin sulfate have been used
for the treatment of infected burns, wounds, or skin lesions. Topical gentamicin is partly
inactivated by purulent exudates. 10mg can be injected subconjunctivally for treatment of
ocular infections.
C. Intrathecal Administration

 Meningitis caused by gram-negative bacteria has been treated by the intrathecal injection
of gentamicin sulfate, 1–10 mg/d.
 Moreover, the availability of third-generation cephalosporins for
gram-negative meningitis has rendered this therapy obsolete in most cases.
Adverse Reactions
  Nephrotoxicity is usually reversible and mild. It occurs in 5–25% of patients receiving
gentamicin for longer than 3–5 days. Measurement of gentamicin serum levels is
essential. Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular
dysfunction.
 Loss of hearing can also occur.
 Hypersensitivity reactions to gentamicin are uncommon.
 This aminoglycoside has an antibacterial spectrum similar to that of gentamicin.
Although there is some cross resistance between gentamicin and tobramycin, it is
unpredictable in individual strains.
 The pharmacokinetic properties of tobramycin are virtually identical with those of
gentamicin.
 The daily dose of tobramycin is 5–6 mg/kg intramuscularly or intravenously, traditionally
divided into three equal amounts and given every 8 hours.
 Monitoring blood levels in renal insufficiency is an essential guide to proper dosing.

Tobramycin:

 Tobramycin has almost the same antibacterial spectrum as gentamicin with a few
exceptions.
 Gentamicin is slightly more active against S marcescens, whereas tobramycin is slightly
more active against P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin
and tobramycin, but E faecium is resistant to tobramycin.
 Like other aminoglycosides, tobramycin is ototoxic and nephrotoxic.
 Nephrotoxicity of tobramycin may be slightly less than that of gentamicin, but the
difference is clinically nconsequential.
 Tobramycin is also formulated in solution (300 mg in 5 mL) for inhalation for treatment
of P aeruginosa lower respiratory tract infections complicating cystic fibrosis.
 The drug is recommended as a 300-mg dose regardless of the patient’s age or weight for
administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days
off therapy.
 Caution should be used when administering tobramycin to patients with preexisting renal,
vestibular, or hearing disorders.
Amikacin

 Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent

molecule. It is resistant to many enzymes that inactivate gentamicin and tobramycin, and
it therefore can be used against some microorganisms resistant to the latter drugs.
 Many gram-negative bacteria, including many strains of Proteus, Pseudomonas,
Enterobacter, and Serratia, are inhibited by 1–20 mcg/mL amikacin in vitro.
  After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak
levels in serum are 10– 30 mcg/mL.
 Strains of multidrug-resistant Mycobacterium tuberculosis, including streptomycin-
resistant strains, are usually susceptible to amikacin.
 Kanamycin-resistant strains may be cross-resistant to amikacin. The dosage of amikacin
for tuberculosis is 7.5–15 mg/kg/d as a once-daily or two to three times weekly injection
and always in combination with other drugs to which the isolate is susceptible.
 Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the
auditory portion of the eighth nerve).
Netilmicin

 Netilmicin shares many characteristics with gentamicin and tobramycin. However, the
addition of an ethyl group to the 1-amino position of the 2-deoxystreptamine ring (ring II)
sterically protects the netilmicin molecule from enzymatic degradation at the 3-amino
(ring II) and 2hydroxyl (ring III) positions.
 Consequently, netilmicin may be active against some gentamicin-resistant and
tobramycin-resistant bacteria.
 The dosage (5–7 mg/kg/d) and the routes of administration are the same as for
gentamicin.
Neomycin and Kanamycin

 Neomycin and kanamycin are closely related. Paromomycin is also a

member of this group. All have similar properties.
Antimicrobial Activity & Resistance

 Drugs of the neomycin group are active against grampositive and gram-negative bacteria
and some mycobacteria. P aeruginosa and streptococci are generally resistant.
Mechanisms of antibacterial action and resistance are the same as with other
aminoglycosides.
 Cross-resistance between kanamycin and neomycin is complete.

Pharmacokinetics

 Drugs of the neomycin group are poorly absorbed from the gastrointestinal tract. After
oral administration, the intestinal flora is suppressed or modified, and the drug is excreted
in the feces. Excretion of any absorbed drug is mainly through glomerular filtration into
the urine.
Clinical Uses
  Neomycin and kanamycin are now limited to topical and oral use. Neomycin is too toxic
for parenteral use. With the advent of more potent and less toxic aminoglycosides,
parenteral administration of kanamycin has also been largely abandoned.
 Paromomycin has recently been shown to be effective against visceral leishmaniasis
when given parenterally.
A. Topical Administration
 Solutions containing 1–5 mg/mL are used on infected surfaces or injected into joints, the
pleural cavity, tissue spaces, or abscess cavities where infection is present.
 The total amount of drug given in this fashion must be limited to 15 mg/kg/d because at
higher doses enough drug may be absorbed to produce systemic toxicity.
 Ointments, often formulated as a neomycin-polymyxinbacitracin combination, can be
applied to infected skin lesions or in the nares for suppression of staphylococci but they
are largely ineffective.
Adverse Reactions

 All members of the neomycin group have significant nephrotoxicityand ototoxicity.

 Auditory functionis affected more than vestibular function.
 Deafness has occurred, especially in adults with impaired renal function and
prolongedelevationof drug levels.
 The sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity
(3–5 g) has resulted in curare-like neuromuscularblockade and respiratoryarrest.
 Although hypersensitivity is not common, prolonged application of neomycin-containing
ointments to skin and eyes has resulted in severe allergic reactions.
Spectinomycin

 Spectinomycin is an other aminocyclitol antibiotic that is structurally related to

aminoglycosides. It lacks amino sugars and glycosidic bonds.
 Spectinomycin is active in vitro against many grampositive and gram-negative
organisms.
 The majority of gonococcal isolates are inhibited by 6 mcg/mL of spectinomycin.
 Strains of gonococci may be resistant to spectinomycin, but there is no cross-resistance
with other drugs used in gonorrhea.
 Spectinomycin is rapidly absorbed after intramuscular injection. A single dose of 40
mg/kg up to a maximum of 2 g is given. There is pain at the injection site.
 Nephrotoxicity and anemia rarely observed.