Aminoglycosides &

Spectinomycin
MUTUA W. MUTHEU
introduction
• Obtained from many species of streptomyces
• They share chemical,antimicrobial,pharmacologic and toxic
characteristics
• Bactericidal inhibitors of protein synthesis that interfere with
ribosomal function.
• These agents are useful mainly against aerobic Gram-negative
microorganisms especially in sepsis and bacteremea in combination
with penicillin or vancomycin
• They are used most widely in combination with other agents to treat
drug-resistant organisms including MDR tuberculosis
• The aminoglycosides include
• streptomycin,
• neomycin,
• kanamycin,
• amikacin,
• gentamicin,
• tobramycin,
• sisomicin, netilmicin, and others.
Mechanism of action

• irreversible inhibitors of protein synthesis but mechanism for bactericidal activity

is unclear.
• The initial event is passive diffusion via porin channels across the outer
membrane into periplasmic space
• Drug is then actively transported across the cell membrane into the cytoplasm by
an oxygen-dependent process.
• The transmembrane electrochemical gradient supplies the energy for this
process, and transport is coupled to a proton pump.
• This energy-dependent phase is rate limiting and can be blocked or inhibited by
divalent cations (e.g., Ca2+ and Mg2+), hyperosmolarity, a reduction in pH, and
anaerobic conditions. Thus, the antimicrobial activity of aminoglycosides is
reduced markedly in the anaerobic environment of an abscess and in
hyperosmolar acidic urine
M.O.A ctd
• Transport may be enhanced by cell wall active drugs such as penicillin or
vancomycin; this enhancement may be the basis of the synergism of those
antibiotics with aminoglycosides.
• Inside the cell, aminoglycosides bind to 30S-subunit ribosomal proteins.
• Protein synthesis is inhibited by aminoglycosides in at least three ways
• interference with the initiation complex of peptide formation
• misreading of mRNA, which causes incorporation of incorrect amino acids into the
peptide and results in a nonfunctional protein
• breakup of polysomes into nonfunctional monosomes.
• These 3 activities occur more or less simultaneously, and the overall effect
is irreversible and leads to cell death
Resistance to aminoglycosides

• production of a transferase enzyme that inactivates the aminoglycoside by

adenylylation, acetylation, or phosphorylation is the most common.
• The ability of these enzymes differ with amikacin being a suitable substrate for
only a few hence it can have activity against strains that are resistant to other
aminoglycosides
• impaired entry of aminoglycoside into the cell from mutation or deletion of a
porin protein involved in transport and maintenance of the electrochemical
gradient.
• The receptor protein on the 30S ribosomal subunit may be deleted or altered as a
result of a mutation.
• Transport of aminoglycosides across the cytoplasmic membrane is an active
process that depends on oxidative metabolism. Strictly anaerobic bacteria thus
are resistant to these drugs because they lack the necessary transport system.
Pharmacokinetics and rationale for Once-Daily
Dosing
• Aminoglycosides are absorbed very poorly from the intact gastrointestinal
tract, and almost the entire oral dose is excreted in feces
• Aminoglycosides are usually administered intravenously as a 30–60 minute
infusion.
• After intramuscular injection, aminoglycosides are well absorbed, giving
peak concentrations in blood within 30–90 minutes. After a brief
distribution phase, peak serum concentrations are identical to those
following intravenous injection.
• The normal half-life of aminoglycosides in serum is 2–3 hours, increasing to
24–48 hours in patients with significant impairment of renal function.
• Aminoglycosides are only partially and irregularly removed by hemodialysis
Pharmacokinetics
• High-dose, extended-interval administration of aminoglycosides is the
preferred means of administering aminoglycosides
• single injection may be preferred in many clinical situations in spite of the
short half life for at least two reasons
• concentration dependent killing- higher concentrations kill a larger proportion of
bacteria and kill at a more rapid rate.
• a significant post antibiotic effect,-antibacterial activity persists beyond the time
during which measurable drug is present. This last several hours
• When co-adminstered with a cell wall-active antibiotic (a β-lactam or
vancomycin) for serious infections like hospital acquired infections,MDR
gram negative organism e.g klebsiella,Enterobacter,serratia they
• expand the empiric spectrum of activity of the antimicrobial regimen
• provide synergistic bacterial killing
• prevent the emergence of resistance to the individual agents
Pharmacokinetics ….ctd
• Because of their polar nature, the aminoglycosides do not penetrate well
into most cells, the CNS, or the eye.
• Except for streptomycin, there is negligible binding of aminoglycosides to
plasma albumin.
• The apparent volume of distribution of these drugs is 25% of lean body
weight and approximates the volume of extracellular fluid.
• The aminoglycosides distribute poorly into adipose tissue, which must be
considered when using weight-based dosing regimens in obese patients.
• Concentrations of aminoglycosides in secretions and tissues are low
• High concentrations are found only in the renal cortex and the endolymph
and perilymph of the inner ear; the high concentration in these sites likely
contributes to the nephrotoxicity and ototoxicity caused by these drugs.
Pharmacokinetics …ctd
• Due to active hepatic secretion, concentrations in bile approach 30% of
plasma, but this represents a very minor excretory route
• Inflammation increases the penetration of aminoglycosides into peritoneal
and pericardial cavities.
• Concentrations achieved in CSF with parenteral administration usually are
subtherapeutic . Treatment of meningitis via IV route is thus suboptimal
• Drug clearance is slow in neonates hence need for drug level monitoring
• In cystic fibrosis clearance is increased and half life is reduced
• In burns,drug clearance is high due to loss through burn tissue,higher dose
maybe required
• Administration of aminoglycosides to women late in pregnancy may result
in accumulation of drug in fetal plasma and amniotic fluid.
• Streptomycin and tobramycin can cause hearing loss in children born to
women who receive the drug during pregnancy.
• The aminoglycosides undergo minimal metabolism and are excreted almost
entirely by glomerular filtration, achieving urine concentrations of 50–200
μg/mL.
• Partial and irrgular removal by haemodialysis and peritoneal dialysis
• Dose adjustment in patients with renal insufficiency to avoid accumulation
and toxicity
• To avoid toxicity serum drug monitoring is used
Adverse effects

• from aminoglycosides are both time- and concentration-dependent.

• Toxicity is unlikely to occur until a certain threshold concentration is
reached, This threshold is not precisely defined, but a trough
concentration above 2 mcg/mL is predictive of toxicity.
• At clinically relevant doses, the total time above this threshold is greater
with multiple smaller doses of drug than with a single large dose.
• a single daily dose of aminoglycoside is just as effective and probably less
toxic than multiple smaller doses.
• Aminoglycosides are cleared by the kidney, and excretion is directly
proportional to creatinine clearance. Renal dose and avoiding once a day
dosing in this patients
• Peak and trough levels should be assessed particularly in renal failure
Adverse Effects
• All aminoglycosides are ototoxic and nephrotoxic with risk increased if
• when therapy is continued for more than 5 days
• higher doses
• in the elderly
• and in the setting of renal insufficiency.
• Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic
antimicrobial agents (eg, vancomycin or amphotericin) can potentiate nephrotoxicity and
should be avoided if possible.
• Ototoxicity can manifest either as auditory damage, resulting in tinnitus and
high-frequency hearing loss initially, or as vestibular damage with vertigo, ataxia,
and loss of balance.
• Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory
damage.
• Streptomycin and gentamicin are the most vestibulotoxic.
Adverse effects

• Nephrotoxicity results in rising serum creatinine levels or reduced

creatinine clearance
• Neomycin, tobramycin, and gentamicin are the most nephrotoxic
• High dose aminoglycosides have curare-like effect with
neuromuscular blockade that results in respiratory paralysis reversed
by calcium gluconate or neostigmine
Clinical use

• Mostly used against aerobic Gram-negative bacteria no activity against

anaerobes
• Consider if concern for drug-resistant pathogens or in critically ill patients.
• Specific indications include
• Sepsis particular neutropenic patients
• Hospital acquired pneumonia
• Infective endocarditis
• Peritonitis
• Gram negative meningitis as intrathecal not intravenous
• Penicillin-aminoglycoside combinations used to achieve bactericidal
activity in treatment of enterococcal endocarditis and to shorten duration
of therapy for viridans streptococcal endocarditis
Clinical use
• Gentamicin, tobramycin, amikacin, and netilmicin can be used
interchangeably for the treatment of most of the infections mentioned
• Streptomycin is used as second line for treatment of tuberculosis
• Kanamycin use is limited to treatment of multi-drug-resistant tuberculosis,
although alternate agents, such as amikacin, may be preferred.
• Paromomycin has been shown to be effective against visceral leishmaniasis
when given parenterally
• Paromomycin can be used for intestinal Entamoeba histolytica infection
and is sometimes used for intestinal infections with other parasites.
Clinical use
• Neomycin have been used on infected surfaces or injected into joints,
the pleural cavity, tissue spaces, or abscess cavities
• Oral administration of aminoglycosides may be employed as “bowel
prep” prior to surgical procedures or as “selective digestive
decontamination” to reduce the risk of ventilator-associated
pneumonia
• Oral Neomycin is used for gut preparation and prevention of hepatic
encephalopathy
• Topical Applications
• Aminoglycosides, especially neomycin and paromomycin, may be employed
as topical agents in skin and mucous membrane infections.
SPECTINOMYCIN
• Spectinomycin is an aminocyclitol antibiotic that is structurally related
to aminoglycosides
• is active in vitro against many Gram-positive and Gram-negative
organisms, but it is used almost solely as an alternative treatment for
drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients.
• rapidly absorbed after intramuscular injection.
• The standard regimen is a single dose of 2–4 g/d