Chapter 54: Aminoglycosides Page |1

Aminoglycoside group: includes gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, paromomycin, neomycin
- Used to treat infections caused by aerobic Gram-negative bacteria
- streptomycin: treatment of tuberculosis
-paromomycine: used orally for intestinal amebiasis and in the management of hepatic coma
-bactericidal inhibitors of protein synthesis
-contain amino sugars linked to an aminocyclitol ring by glycosidic bonds
-polycations & their polarity is responsible for pharmacokinetic properties shared by all members of the group
-none is absorbed adequately after oral administration, inadequate concentrations are found in the CSF and all are excreted relatively rapidly by the normal
kidney
Chemistry -consists of 2 or more amino sugars joined in glycosidic linkage to a hexose nucleus which is usually is in central position
-hexose or aminocyclitol, is either streptidine (found in streptomycin) or 2-deoxystreptamine (found in all other available
aminoglycosides)
-compounds are aminoglycosidic amincyclitolss
-distinguished by the amino sugars attached to the aminocyclitol
-in the neomycin family: 3 amino sugars are attached to the central 2-deoxystreptamine
-kanamycin & gentamicin have only 2 amino sugars
-streptomycin differs from other aminoglycoside antibiotics that it contains streptidine rather than 2-deoxystreptamine
Mechanism of -rapidly bactericidal, bacterial killing is concentration dependent
action -post-antibiotic effect, that is, residual bactericidal activity persisting after the serum concentration has fallen below the MIC
-high-dose extended-interval dosing regimen of aminoglycosides
-diffuse through aqueous channels formed by porin proteins in the outer membrane of gram-negative bacteria to enter the periplasmic
space
-transport across the cytoplasmic (inner) membrane depends on the e- transport bec. Of recruitment for a membrane electrical potential
(interior negative) to drive permeation of these antibodies: phase of transport – energy-dependent phase I (EDP1) – rate limiting & can
be blocked by divalent cations, hyperosmolarity, reduction in pH and anaerobic conditions
-once inside the cell, aminoglycosides bind to polysomes & interfere with protein synthesis by causing misreading & premature
termination of the mRNA translation
-target: 30S ribosomal subunit w/c consists of 21 proteins & a single 16S molecule of RNA
-disrupt the normal cycle of ribosomal fxn by interfering with the initiation of protein synthesis leading to the accumulation of abnormal
initiation complexes or streptomycin monosomes
-cause misreading of the mRNA template & incorporation of incorrect amino acids into the growing polypeptide chains
Microbial -transport of aminoglycoside across the cytoplasmic membrane is oxygen-dependent active process
resistance to the -strictly anaerobic bacteria are resistant to these drugs because they lack the necessary transport system, facultative bacteria are
aminoglycosided resistant when grown under anaerobic conditions

Antibacterial -directed primarily against aerobic gram-negative bacilli

spectrum of the -kanamycin like streptomycin should not be used to treat infections caused by Serratia or P. aeruginosa
aminoglycosides -tobramycin & gentamicin exhibit similar activity against most gram-negative bacilli, although the former is more active against P.
aeruginosa, whereas the latter is more active against Serratia
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-many gram-negative bacilli are resistant to gentamicin bec. Of plasmid-mediated inactivating enzymes
-amikacin and, in some instances, netilmicin retain their activity against gentamicin-resistant strains because they are a poor substrate
for many of the aminoglycoside-inactivating enzymes
-should not be used as single agents to treat infections caused by gram-positive bacteria
-in combi. w/ a cell wall-active agent, such as penicillin or vancomycin, an aminoglycosided produces a synergistic bactericidal effect in
vitro
Absorption, -highly polar cations and therefore are very poorly absorbed for the GIT
distribution, -less that 1% is absorbed after either oral or rectal administration
dosing, elimination -not inactivated in the intestine & eliminated quantitatively in the feces
of the -absorption of gentamicin from the GI tract may be increased by GI disease
aminoglycosides -all are absorbed rapidly from the intramuscular sites of injections
-increasing use administered via inhalation for the management of patients with cystic fibrosis who have Pseudomonas aeruginosa
pulmonary infections
-amikacin & tobramycin sol’ns for injection have bee used
-do not penetrate into the most cells, the CNS or eye bec. Of their polar nature
-except for streptomycin, there is negligible binding of aminoglycosides to plasma albumin
-distribute poorly into the adipose tissue
-high concentrations are found only in the renal cortex & endolymph & perilymph of the inner ear; the high concentration contributes to
the nephrotoxicity and ototoxicity
-active hepatic secretion: minor excretory route
-penetration into the respiratory secretions is poor
-diffusion into the pleural & synovial fluid is relatively slow
-inflammation increases the penetration into the peritoneal & pericardial cavities
-conc. of aminoglycosides achieved in the CSF with parenteral administration are subtherapeutic
-administration to women late in pregnancy may result in accumulation of drug in fetal plasma & amniotic fluid
-streptomycin & tobramycin cause hearing loss in children born to women who receive the drug during pregnancy
-excreted almost entirely by glomerular filtration
-can be inactivated by various penicillins in vitro

Untoward effects -reversible & irreversible vestibular, cochlear & renal toxicity
-aminoglycoside induced otoxicity results in irreversible, bilateral high-frequency hearing loss & temporary vestibular hypofunction
-degeneration of hair cells & neurons in the cochlea correlates with the loss of hearing
-otoxicity id irreversible & results from the progressive destruction of the vestibular or cochlear sensory cells which are highly sensitive
to damage by aminoglycosides
-streptomycin & gentamicin produce predominantly vestibular effects whereas amikacin, kanamycin & neomycine primarily affect
auditory function; tobramycin affects both equallt

Clinical symptoms -high-pitched tinnitus 1st sx of toxicity

of cochlear toxicity
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C.s. of vestibular t. -moderately intense headache preceded labyrinthine dysfunction

-followed by an acute stage in w/c nausea, vomiting & difficulty with equilibrium develop & persist for 1-2 weeks
-vertigo in the upright position, inability to perceive termination of mov’t (mental past-pointing) & difficulty in sitting or standing without
visual cues
-drifting of the eyes at the end of a movement so that both focusing and reading are difficult, positive Romberg test and rarely, pendular
trunk mov’t & spontaneous nystagmus are prominent signs
Nephrotoxicity
-results from accumulation & retention of aminoglycoside in the proximal tubular cells
-initial manifestation of the damage: excretion of enzymes of the renal tubular brush border
-defect in renal concentrating ability, mild proteinuria & appearance of hyaline & granular casts
-non-oliguric phase of renal insufficiency is thought to be due to the effects of aminoglycosides on the distal portion of the nephron with
a reduced sensitivity of the collecting duct epithelium to endogenous ADH
- severe acute tubular necrosis may occur rarely, most common significant finding is mild rise in plasma creatinine
-hypo-kalemia, calcemia, phosphatemia are seen infrequently
-impairment in renal fxn almost always reversible bec. The proximal tubular cells have the capacity to regenerate
-biochemical events leading to tubular cell damage: inhibit various phospholipases, sphingomyelinase & ATPases & they alter the fxn of
the mitochondria & ribosomes
-bec. Of the ability of cationic aminoglycosides to interact with anionic phospholipids, these drugs may impair the synthesis of
membrane-derived autacoids & intracellular second messengers such as PG, inositol phosphates & DAG
-neomycin w/c concrates to the greatest degree is highly nephrotoxic in humans & should not be administered systemically
-streptomycin does not concentrate in the renal cortex & is the least nephrotoxic
Neuromuscular
blockade -neuromuscular blockade & apnea
-order of decreasing potency for blockade: neomycin, kanamycin, amikacin, gentamicin & tobramycin
-pxs with myasthenia gravis susceptible
-aminoglycosides may inhibit prejunctional release of Ach while also reducing postsynaptic sensitivity to the transmitter , but Calcium
can overcome this effect and administration of calcium salts is the preferred treatment for this toxicity
Others
-allergic potential
-cross-hypersensitivity: skin rashes, eosinophilia, fever, blood dyscrasias, angioedema, exfoliative dermatitis, stomatitis, anaphylactic
shock
-not associated with pseudomembranous colitis bec. They do not disrupt normal anaerobic flora
Therapeutic uses -gentamicin: tx of many serious gram-negative bacillary infections; it is the aminoglycoside of 1st choice bec. Of its lower cost & reliable
activity against all but the most resistant gram-negative aerobes; available for parenteral, ophthalmic & topical administration
-aminoglycosides are used in combi. with a cell wall-active agent (β-lactam or glycopeptide) for the therapy of serious proven or
suspected bacterial infections
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Gentamicin

• typical recommended intramuscular or intravenous dose of gentamicin sulfate when used for the treatment of known or suspected gram-negative
organisms as a single agent or in combination therapy for adults with normal renal function is 5-7 mg/kg daily given over 30-60 minutes.
• For patients with renal dysfunction, the interval may be extended. For patients who are not candidates for extended-interval dosing, a typical dosing
regimen for gram-negative coverage is a loading dose of 2 mg/kg and then 3-5 mg/kg per day, one-third given every 8 hours when administered as a
multiple-daily-dosing regimen.
• Several dosage schedules have been suggested for newborns and infants: 3 mg/kg once daily for preterm newborns <35 weeks of gestation 4 mg/kg
once daily for newborns >35 weeks of gestation; 5 mg/kg daily in two divided doses for neonates with severe infections; and 2-2.5 mg/kg every 8 hours
for children up to 2 years of age.
• Peak plasma concentrations range from 4-10 mg/mL (dosing: 1.7 mg/kg every 8 hours) and 16-24 mg/ mL (dosing: 5.1 mg/kg once daily).

UTI -aminoglycosides usually are not indicated for the tx of uncomplicated UTI
-single intramuscular dose of gentamicin (5mg/kg) effective in uncomplicated infections of the lower urinary tract
Pneumonia -therapy with aminoglycoside alones is ineffective due to poor penetration of drug into inflamed tissues & associated conditions of low O2 tension
and low pH - interfere with aminoglycoside antibacterial activity
-aminoglycosides are ineffective for the tx of pneumonia due to anaerobes or S. pneumonia
-they should not be considered as effective single-drug therapy for any aerobic gram-positive cocci (including S. aureus or streptococci) –
microorganisms responsible for suppurative pneumonia or lung abscess
-aminoglycoside + β-lactam antibiotic is recommended as std therapy for HAP in w/c a MDR gram-negative aerobe is likely causative agent
-once it is established that the β-lactam is active against the causative agent, there is gen. no benefit from continuing the aminoglycoside
Meningitis -availability of 3rd generation cephalosporins, esp. cefotaxime & ceftriaxone has reduced the need for tx w/ aminoglycosides except for infections
caused by gram-negative organisms resistant to β-lactam antibiotics (e.g., species of Pseudomonas and Acinetobacter).
-in adults, 5 mg of a preservative-free formulation of gentamicin is administered directly intrathecally or intraventricularly once daily
Peritonitis assoc. -treated with aminoglycoside diluted into the dialysis fluid to a concentration of 4-8 mg/L for gentamicin, netilmicin, or tobramycin or 6-12 mg/L for
with peritoneal amikacin.
dialysis -IV or IM administration of drug is unnecessary bec the serum & peritoneal fluid will equilibrate rapidly
Bacterial -synergistic or low-dose gentamicin in combi. w/ a penicillin or vancomycin: tx of infections due to gram-positive organisms primarily bacterial
endocarditis endocarditis
-penicillin & gentamicin in combination are effective as a short course regimen for uncomplicated native-valve streptococcal endocarditis
-2 week regimen of gentamicin or tobramycin in combi. w/ nafcillin is effective for the tx of selected cases of staphylococcal tricuspid valve
endocarditis
-aminoglycoside + cell wall-active agent & rifampin is recommended for tx of staphylococcal prosthetive valve endocarditis
Sepsis -inclusion of aminoglycoside in an empirical regimen is recommended for the febrile px w/ granulocytopenia & for sepsis when P. aeruginosa is a
potential pathogen
-To avoid toxicity, aminoglycosides should be used briefly and sparingly as long as other alternatives are available.
Topical -absorbed slowly when applied topically in an ointment & somewhat more rapidly when it is applied as a cream
application
Untoward effects -nephrotoxicity & irreversible otoxicity
-intrathecal or Intraventricular ad. May cause local inflammation & can result in radiculitis & other complicatiions
Chapter 54: Aminoglycosides Page |5

Tobramycin

• given either intramuscularly, intravenously, or by inhalation.

• Tobramycin also is available in ophthalmic ointments and solutions.

Therapeutic -vs P. aeuruginosa

uses -tobramycin isused with an anti-pseudomonoal β-lactam antibiotic
-vs to gentamicin, it shows poor activity in combi. with penicillin against many strains of enterococci most strains of
E. faecium are highly resistant.
-ineffective against mycobacteria
-the drug has been usefully administered by inhalation to combat P. aeruginosa infections
Untoward -nephrotoxicity & otoxicity
effects -less toxic to hair cells in the cochlear & vestibular end organs & cause less renal damage than gentamicin

Amikacin
-spectrum is the broadest of the group because of its resistance to many of the aminoglycoside-inactivating enzymes

Therapeutic -preferred agent for the initial tx of nosocomial gram-negative bacillary infections in the hospitals where resistance to gentamicin & tobramycin
uses prevails
-active vs the vast majority of aerobic gram (-) bacilli include most strains of Serratia, Proteus, P. aeruginosa
-active vs nearly all strains of Klebsiella, Enterobacter and E. coli that are resistant to gentamicin & tobramycin
-Most resistance to amikacin is found among strains of Acinetobacter, Providencia, and Flavobacter and strains of Pseudomonas other than P.
aeruginosa like tobramycin, it is less active than gentamicin vs enterococci & should not be used for this organism
-not active vs the majority of gram (+) anaerobic bacteria
-active vs M. tuberculosis including streptomycin-resistant strains & atypical mycobacteria
-used in the tx of disseminated atypical mycobacterial infections
-The recommended dose of amikacin is 15 mg/kg per day as a single daily dose or divided into two or three equal portions, which must be reduced for
patients with renal failure.
-The drug is absorbed rapidly after intramuscular injection, and peak concentrations in plasma approximate 20 μg/mL after injection of 7.5 mg/kg. An
intravenous infusion of the same dose over a 30-minute period produces a peak concentration in plasma of nearly 40 μg/mL at the end of the infusion,
which falls to ~20 μg/mL 30 minutes
-The concentration 12 hours after a 7.5 mg/kg dose typically is 5-10 μg/mL. A 15 mg/kg once-daily dose produces peak concentrations 50-60μg/mL
and a trough of <1 μg/mL
-treatment of mycobacterial infections, thrice-weekly dosing schedules of amikacin are often used, with doses up to 25 mg/kg.
Untoward -otoxicity, hearing loss & nephrotoxicity
effects
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Netilmicin
-latest of the aminoglycoside to be marketed
-similar to gentamicin & tobramycin in its pharmacokinetic properties & dosage
-antibacterial act is broad against aerobic gram (-) bacilli
-like amikacin it is not metabolized by most of the aminoglycoside inactivating enzymes & is therefore may be active vs certain bacteria that are resistant to
gentamicin
Therapeutic -useful for the tx of serious infections owing to susceptible Enterobacteriaceae & other aerobic gram (-) bacilli
uses -effective vs certain gentamicin-resistant pathogens with the exception of enterococci
-The recommended dose of netilmicin for complicated urinary tract infections in adults is 1.5-2 mg/kg every 12 hours
-serious systemic infections, a total daily dose of 4-7 mg/kg is administered as a single dose or two to three divided doses
-Children should receive 3-7 mg/kg per day in two to three divided doses;
neonates receive 3.5-5 mg/kg per day as a single daily dose
-The t1/2 for elimination is usually 2–2.5 hours in adults and increases with renal insufficiency
Untoward -otoxicity and nephrotoxicity
effects

Streptomycin
-generally less active than other members of the class vs aerobic gram(-) rods
Therapeutic -streptomycin & penicillin in combi are synergistically bactericidal in vitro & in ani. Models of infection vs strains of enterococci, group D streptococci
uses, & the various oral streptococci of the viridans group
bacterial -combi of penicillin G, w/c by itself is only bacteriostatic against enterococci, & streptomycin is effective as bactericidal therapy for enterococcal
endocarditis endocarditis
-gentamicin is preferred for lesser toxicity; also, it should be used when the strain of enterococcus is resistant to streptomycin
-streptomycin should be used instead of gentamicin when the strain is resistant to the latter
-administered by deep IM or IV
-The dose of streptomycin is 15 mg/kg per day for patients with creatinine clearances >80 mL/minute.
-1000-mg single daily dose for tuberculosis or 500 mg twice daily, resulting in peak serum concentrations of ~50-60 and 15-30 μg/mL and trough
concentrations of <1 and 5-10 μg/mL
-The total daily dose should be reduced in direct proportion to the reduction in creatinine clearance for creatinine clearances >30mL/minute
Tularemia -doc for tx of tularemia
-respond to the administration of 1-2 g (15-25 mg/kg) streptomycin per day (in divided doses) for 10-14 days
-Fluoroquinolones and tetracyclines also are effective,although the failure rate may be higher with tetracyclines
Plague -effective agent for the tx of all forms of plague
-The recommended dose is 2 g/day in two divided doses for 10 days. Gentamicin is probably as efficacious
Tuberculosis -2nd-line agent for the tx of active tuberculosis, streptomycin always should be used in combi with at least one or two other drugs to which the
causative strain is susceptible
-dose for patients with normal renal function is 15 mg/kg per day as a single intramuscular injection for 2-3 months and then two or three times a
week
Chapter 54: Aminoglycosides Page |7

Untoward -replaced by gentamicin bec. The toxicity of gentamicin is primarily renal & reversible, whereas that of streptomycin is vestibular & irreversible
effects -dysfunction of the optic nerve including scotomas presenting as enlargement of blind spot
-peripheral neuritis
Kanamycin
-among the most toxic aminoglycoside
-Kanamycin sulfate is available for injection and oral use.
-The parenteral dose for adults is 15 mg/kg per day (2-4 equally divided and spaced doses), with a maximum of 1.5 g/day. Children may be given up to 15 mg/kg
per day
Therapeutic -treat TB in combination with other effective drugs
uses
Prophylactic -administered orally as adjunctive therapy in cases of hepatic encelopathy
uses -The dose is 4-6 g/day for 36-72 hours; quantities as large as 12 g/day
Untoward -ototoxic & nephrotoxic
effects -like neomycin, its oral administration can cause malabsorption & superinfection

Neomycin
-broad spectrum antibiotic
-Gram (-) species that are highly susceptible are E. coli, Enterobacter aerogenes, K. pneumonia & P. vulgaris
-Gram (+) species that are inhibited include S. aureus, E. faecalis
-M. tuberculosis is also sensitive
-strains of P. aeruginosa is resistant
-Neomycin sulfate is available for topical and oral administration
-Neomycin currently is available in many brands of creams, ointments, and other products alone and in combination with polymyxin, bacitracin, other
antibiotics, and a variety of corticosteroids
Therapeutic uses -topical application in variety of infections of the skin & mucous membranes
-infections associated with burns, wounds, ulcers, & infected dermatoses
-oral administration of neomycin (usually in combination with erythromycin base) employed primarily for “preparation” of the bowel surgery
-therapy for hepatic encelopathy an oral daily dose of 4-12 g (in divided doses) is given
-renal insufficiency is a complication of hepatic failure & neomycin is nephrotoxic, it used rarely for this indication
-neomycin & polymyxin B: used for irrigation of the bladder; goal is to prevent bacteriuria & bacteremia associated with indwelling catheters
Absorption and -poorly absorbed from the GI tract & is excreted by the kidney
Excretion -oral dose of 3 g produces a peak plasma concentration of 1-4 μg/mL; a total daily intake of 10 g for 3 days yields a blood concentration
below that associated with systemic toxicity if renal function is normal
-97% of an oral dose of neomycin is not absorbed and is eliminated unchanged in the feces
Untoward effects -hypersensitivity reactions primarily skin rashes
-Individuals sensitive to this agent may develop cross-reactions when exposed to other aminoglycosides
-most important toxic effects of neomycin are renal damage & nerve deafness
-drug is no longer available for parenteral administration
-neuromuscular blocakdae with respiratory paralysis also has occurred after irrigation of wounds or serosal cavities
-treated with 4-6 g/day of the drug by mouth sometimes develop a sprue-like syndrome with diarrhea, steatorrhea, azotorrhea
Chapter 54: Aminoglycosides Page |8

-overgrowth of yeasts in the intestines

Clinical Summary
Aminoglycosides – narrow-spectrum agents, with their activity limited mainly to gram (-) aerobes
-most toxic
-1st line- therapy for prominent infections such as plague, tularemia & TB
-gentamicin or aminkacin: role as backup agent in the tx of nosocomial infections caused by MDR pathogens such as Pseudomonas or Acinetobacter
-gentamicin: used for the tx of serious UTI caused by enteric organisms that have acq’d resistance to sulfa drugs, penicillin, cephalosporins & fluoroquinoles
-gentamicin recommended for use in combi. w/ vancomycin or a Beta-lactam to enhance bactericidal effect, clinical benefit is unproven for most infections