Aminoglycosides and

SpectinomycinYjnah D. Lim BMLS III-A Riverside College Inc.

AMINOGLYCOSIDES

Streptomyces• Gram-positive rods

• Resemble filamentous fungi

• Have unique ability to produce to produce bioactive secondary metabolites such as antifungals, antivirals, antitumoral, anti-hypertensives, and mainly antibiotics and immunosuppressives.

• Streptomycin - 1st aminoglycoside; Streptomyces griseus

Micromonospora

• Gentamicin is the aminoglycoside used most often because of its low cost and reliable activity against gram-negative aerobes.

• Micromonospora purpurea

Mnemonics TimeTANGS do NOT kill anaerobes.

• Aminoglycosides

• Tobramycin

• Amikacin

• Neomycin

• Gentamicin

• Streptomycin

• Adverse Effects

• Nephrotoxicity

• Ototoxicity

• Teratogen

Aminoglycosides• Include: streptomycin, neomycin, kanamycin, amikacin,

gentamicin, tobramycin, sisomicin and netilmicin

• In vivo-effectiveness result from concentration-dependent killing action.

• Capable of exerting post-antibiotic effect.

• “Once-daily” dosing: Numerous clinical studies demonstrate that a single daily dose of aminoglycoside is just as effective—and probably less toxic— than multiple smaller doses.

• Elimination half-life of 2-3 hrs (normal renal function)

• Water soluble and more active in alkaline pH

• Poor oral absorption, poor GI absorption

• Given intramuscularly or intravenously for systemic effect

• Do not easily cross the BBB

• Given together with Beta-lactams to decrease adverse effects and increase bactericidal effect

• “Synergistic killing”

Mechanism of ActionDrug is actively

transported across the cell membrane into the

cytoplasm by an oxygen-dependent process.

Transmembrane electrochemical

gradient supplies energy for this process.

Transport is coupled to a proton pump.

Aminoglycosides bind to specific 30S-

subunit ribosomal proteins.

Protein synthesis is inhibited in at least 3 ways:

• Interference with the initiation complex of peptide formation

• Misreading of mRNA• Breakup of polysomes into

nonfunctional monosomes/Inhibiting translocation

Amikacin is not inactivated by the common enzymes that inactivate gentamicin and tobramycin.

Indications

• Aminoglycosides are mostly used against gram-negative aerobic enteric bacteria.

• In addition, some Mycobacteria, including the bacteria Mycobacterium tuberculosis, are susceptible to aminoglycosides.

• They are almost always used in combination with a β-lactam antibiotic to extend coverage to include potential gram-positive pathogens and to take advantage of the synergism between these two classes of drugs.

Example:

Aminoglycoside + Penicillin:

For pseudomonal, listerial and enterococcal infections.

• Tobramycin: Intravenous; more active than gentamicin versus Pseudomonas.

• Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin and tobramycin

• Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis.

• Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to decrease aerobic flora.

Contraindications

• In patients with mitochondrial diseases as they may result in impaired mtDNA translation, which can lead to irreversible hearing loss, tinnitus, cardiac toxicity, and renal toxicity.

• During pregnancy to prevent ototoxicity in fetus (teratogenic).

Adverse Effects• Ototoxicity

Auditory or vestibular damage (or both) may occur with any aminoglycoside and may be irreversible. Ototoxic: Amikacin, Kanamycin and Neomycin Vestibulotoxic: Gentamicin and Streptomycin Netilmicin is the least ototoxic.

• NephrotoxicityTakes the form of acute tubular necrosis. This reversible adverse effect is more common in elderly patients. Neomycin is the most nephrotoxic drug, streptomycin is the least one.

• Neuromuscular BlockadeAlthough rare, a curare-like block may occur at high doses of aminoglycosides and may result in respiratory paralysis. Reversible by treatment of calcium gluconate and neostigmine.

• Skin ReactionsAllergic reactions and contact dermatitis may occur. Neomycin

SPECTINOMYCIN

• Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides.

• Spectinomycin is rapidly absorbed after intramuscular injection.

Mechanism of ActionGlucose-6-phosphate ,

which is reduced by NADH to form a

ketone at C2

This ketone is then formed into a primary amine group through PLP and glutamine

transamination

This process is repeated again at

C4 to form a second primary amine

Once these two amines are present, the glucose ring is

ready to be methylated through two S-adenosyl methionine molecules

The glucose ring is finally ready to be converted into an

inositol ring through inositol cyclase

This can then be hydrolyzed to get rid of the phosphate group, making the inositol ring necessary

for spectinomycin

• Spectinomycin is an inhibitor of protein synthesis in the bacterial cell.

• The site of action is the 30S ribosomal subunit.

• It prevents elongation of polypeptide chain at the translocation step.

• It is bactericidal in its action.

Indications• Due to susceptible strains of Neisseria

gonorrhoeae:

• Used almost solely as an alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients.

• Male: acute gonorrheal urethritis and proctitis

• Female: acute gonorrheal cervicitis and proctitis

Contraindications

• Spectinomycin, sold under the tradename Trobicin is contraindicated in patients previously found hypersensitive to it.

Adverse Effects

• There is pain at the injection site and, occasionally, fever and nausea.

• Gastrointestinal disturbance

• Hypersensitivity

Route of Administration• Spectinomycin:

Intramuscular Injection