Aminoglycoside

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Streptomycin

An aminoglycoside is a molecule composed of a sugar group and an amino group.[1]

Several aminoglycosides function as antibiotics that are effective against certain types of
bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin,
netilmicin, paromomycin, rhodostreptomycin[2], streptomycin, tobramycin, and
apramycin.

Anthracyclines are another group of aminoglycosides. These compounds are used in

chemotherapy.

Contents
[hide]

• 1 Nomenclature
• 2 Antibiotic mechanism of action
• 3 Routes of administration
• 4 References

• 5 External links

[edit] Nomenclature
Aminoglycosides that are derived from bacteria of the Streptomyces genus are named
with the suffix -mycin, while those which are derived from Micromonospora are named
with the suffix -micin.

This nomenclature system is not specific for aminoglycosides. For example vancomycin
is a glycopeptide antibiotic and erythromycin, which is produced from a species of
Saccharopolyspora (which was previously misclassified as Streptomyces) along with its
synthetic derivatives clarithromycin and azithromycin are macrolides - all of which differ
in their mechanisms of action.

[edit] Antibiotic mechanism of action

Aminoglycosides antibiotics work by binding to the bacterial 30S ribosomal subunit[3][4]
(some work by binding to the 50S subunit[5]), inhibiting the translocation of the peptidyl-
tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the
bacterium unable to synthesize proteins vital to its growth. They kill bacteria by
inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity
of bacterial cell membrane. [6] However, their exact mechanism of action is not fully
known.

There is a significant relationship between the dose administered and the resultant plasma
level in blood. TDM, therapeutic drug monitoring, is necessary to obtain the correct dose.
These agents exhibit a post-antibiotic effect in which there is no or very little drug levels
detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is
due to strong, irreversible binding to the ribosome, and remains intracellular long after
plasma levels drop. This allows a prolonged dosage interval. Depending on their
concentration they act as bacteriostatic or bactericidal agents.

The protein synthesis inhibition of aminoglycosides does not usually produce a

bactericidal effect, let alone a rapid one as is frequently observed on susceptible Gram-
negative bacilli. Aminoglycosides competitively displace cell biofilm-associated Mg2+
and Ca2+ that link the polysaccharides of adjacent lipopolysaccharide molecules. "The
result is shedding of cell membrane blebs, with formation of transient holes in the cell
wall and disruption of the normal permeability of the cell wall. This action alone may be
sufficient to kill most susceptible Gram-negative bacteria before the aminoglycoside has
a chance to reach the 30S ribosome[7]."

Traditionally, the antibacterial properties of aminoglycosides were believed to result from

inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial
ribosome. This explanation, however, does not account for the potent bactericidal
properties of these agents, since other antibiotics that inhibit the synthesis of proteins
(such as tetracycline) are not bactericidal. Recent experimental studies show that the
initial site of action is the outer bacterial membrane. The cationic antibiotic molecules
create fissures in the outer cell membrane, resulting in leakage of intracellular contents
and enhanced antibiotic uptake. This rapid action at the outer membrane probably
accounts for most of the bactericidal activity.2 Energy is needed for aminoglycoside
uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so
aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily
in infections involving aerobic, gram-negative bacteria, such as Pseudomonas,
Acinetobacter, and Enterobacter. In addition, some Mycobacteria, including the bacteria
that cause tuberculosis, are susceptible to aminoglycosides. The most frequent use of
aminoglycosides is empiric therapy for serious infections such as septicemia, complicated
intraabdominal infections, complicated urinary tract infections, and nosocomial
respiratory tract infections. Usually, once cultures of the causal organism are grown and
their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic
antibiotics.

Streptomycin was the first effective drug in the treatment of tuberculosis, though the role
of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of
their toxicity and inconvenient route of administration) except for multiple drug resistant
strains.

Infections caused by gram-positive bacteria can also be treated with aminoglycosides, but
other types of antibiotics are more potent and less damaging to the host. In the past the
aminoglycosides have been used in conjunction with beta-lactam antibiotics in
streptococcal infections for their synergistic effects, particularly in endocarditis. One of
the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related
antibiotic) and gentamicin. Often, hospital staff refer to this combination as "amp and
gent" or more recently called "pen and gent" for penicillin and gentamicin.

Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Experimentation with aminoglycosides as a treatment of cystic fibrosis (CF) has shown

some promising results. CF is caused by a mutation in the gene coding for the cystic
fibrosis transmembrane conductance regulator (CFTR) protein. In approximately 10% of
CF cases the mutation in this gene causes its early termination during translation, leading
to the formation of is truncated and non-functional CFTR protein. It is believed that
gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading
of the termination codon, causing the ribosome to "skip" over the stop sequence and to
continue with the normal elongation and production of the CFTR protein. The treatment
is still experimental but showed improvement in cells from CF patients with susceptible
mutations.[8]

[edit] Routes of administration

Since they are not absorbed from the gut, they are administered intravenously and
intramuscularly. Some are used in topical preparations for wounds. Oral administration
can be used for gut decontamination (e.g. in hepatic encephalopathy). Tobramycin may
be administered in a nebulized form.

Aminoglycosides
Aminoglycosides (see Table 5: Bacteria and Antibacterial Drugs: Aminoglycosides ) are bactericidal. They bind to the 30S ribosome,

thereby inhibiting bacterial protein synthesis.

Pharmacology: Aminoglycosides are poorly absorbed orally but are well absorbed from the peritoneum, pleural cavity, joints (and should

never be instilled in these body cavities), and denuded skin. Aminoglycosides are distributed well into the ECF except for vitreous humor,

CSF, respiratory secretions, and bile (particularly with biliary obstruction).

Aminoglycosides are excreted by glomerular filtration and have a serum half-life of 2 to 3 h; the half-life rises exponentially as the GFR falls

(eg, in renal insufficiency or in the elderly). Peak serum levels of at least 10 times the minimum inhibitory concentration (MIC) are desirable.

When β-lactams, such as piperacillin SOME TRADE NAMES

PIPRACIL

Click for Drug Monograph

or ticarcillin SOME TRADE NAMES

TICAR

, are used in high doses, the high serum levels of the β-lactam may inactivate the aminoglycoside in vitro in serum specimens obtained for

drug level determination from patients receiving both drugs, if the serum is not assayed immediately or frozen. If patients with renal failure

are concurrently receiving both an aminoglycoside and a high-dose β-lactam, the serum aminoglycoside concentration may be lower

because of prolonged interaction in vivo.

Indications: Aminoglycosides are used for serious gram-negative infections, especially Pseudomonas aeruginosa. They are active against

most gram-negative aerobic bacilli but lack activity against anaerobes and most gram-positive bacteria, except for most staphylococci;

however, some gram-negative bacilli and methicillin-resistant staphylococci are resistant. Gentamicin SOME TRADE NAMES

GARAMYCIN

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, tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

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, and amikacin SOME TRADE NAMES

AMIKIN

Click for Drug Monograph

are active against P. aeruginosa, whereas streptomycin SOME TRADE NAMES

NO US TRADE NAME

Click for Drug Monograph

, neomycin SOME TRADE NAMES

NEO-FRADIN

NEO-RX

Click for Drug Monograph

, and kanamycin SOME TRADE NAMES

KANTREX

Click for Drug Monograph

are not. Gentamicin SOME TRADE NAMES

GARAMYCIN

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and tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

Click for Drug Monograph

have similar antimicrobial spectra against gram-negative bacilli, but tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

Click for Drug Monograph

is more active against P. aeruginosa , and gentamicin SOME TRADE NAMES

GARAMYCIN

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is more active against Serratia marcescens. Amikacin SOME TRADE NAMES

AMIKIN

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is frequently active against gentamicin SOME TRADE NAMES

GARAMYCIN

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- and tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

Click for Drug Monograph

-resistant pathogens.

Aminoglycosides are used alone infrequently, typically for plague and tularemia. They are used with a broad-spectrum β-lactam for severe

infection due to a suspected gram-negative bacillus. However, because of increasing aminoglycoside resistance, a fluoroquinolone can be

substituted for the aminoglycoside in initial empiric regimens, or the aminoglycoside can be stopped after 2 to 3 days unless an

aminoglycoside-sensitive P. aeruginosa is identified.

Gentamicin SOME TRADE NAMES

GARAMYCIN

Click for Drug Monograph

or, less commonly, streptomycin SOME TRADE NAMES

NO US TRADE NAME
Click for Drug Monograph

may be used with other antimicrobials to treat endocarditis due to streptococci or enterococci. Enterococcal resistance to aminoglycosides

has become a common problem. Because therapy of enterococcal endocarditis requires prolonged use of a potentially nephrotoxic and

ototoxic aminoglycoside combined with a bacterial cell wall–active drug (eg, penicillin or vancomycin SOME TRADE NAMES

VANCOCIN

Click for Drug Monograph

) to achieve bactericidal synergy, the choice of aminoglycoside must be based on special in vitro susceptibility testing. High-level

aminoglycoside susceptibility in vitro will predict synergy when low-dose aminoglycoside therapy is combined with a cell wall–active drug. If

the strain is susceptible to high-level gentamicin SOME TRADE NAMES

GARAMYCIN

Click for Drug Monograph

and streptomycin SOME TRADE NAMES

NO US TRADE NAME

Click for Drug Monograph

, gentamicin SOME TRADE NAMES

GARAMYCIN

Click for Drug Monograph

is preferred because serum levels can be readily determined. High-level resistance to gentamicin SOME TRADE NAMES

GARAMYCIN

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in vitro does not rule out susceptibility of these enterococcal strains to high levels of streptomycin SOME TRADE NAMES

NO US TRADE NAME

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, in which case streptomycin SOME TRADE NAMES

NO US TRADE NAME

Click for Drug Monograph

should be used. There are few therapeutic options available for endocarditis due to enterococci resistant to high levels of both gentamicin

SOME TRADE NAMES

GARAMYCIN

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and streptomycin SOME TRADE NAMES

NO US TRADE NAME

Click for Drug Monograph

, for which no synergistic cell wall–active drug/aminoglycoside combination exists. Endocarditis due to such strains has been treated with

limited success with prolonged courses of a cell wall–active drug alone or linezolid SOME TRADE NAMES

ZYVOX

Click for Drug Monograph

.
Streptomycin SOME TRADE NAMES

NO US TRADE NAME

Click for Drug Monograph

has limited uses because of resistance. It is used with other antimicrobials for TB.

Because of toxicity, neomycin SOME TRADE NAMES

NEO-FRADIN

NEO-RX

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and kanamycin SOME TRADE NAMES

KANTREX

Click for Drug Monograph

are limited to topical use in small amounts. Neomycin SOME TRADE NAMES

NEO-FRADIN

NEO-RX

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is available for eye, ear, oral, and rectal use and as a bladder irrigant. Oral use as a topical agent against intestinal flora includes bowel

preparation before surgery and treatment of hepatic coma.

Toxicity: All aminoglycosides produce renal toxicity (often reversible) and vestibular and auditory toxicity (often irreversible). Symptoms

and signs of vestibular damage are vertigo, nausea, vomiting, nystagmus, and ataxia. Risk factors for renal, vestibular, and auditory toxicity

are large doses, very high blood levels, frequent doses, longer duration of therapy (particularly > 3 days), older age, and preexisting renal

disease. Other risk factors include coadministration of vancomycin SOME TRADE NAMES

VANCOCIN

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, cyclosporine SOME TRADE NAMES

NEORAL

SANDIMMUNE

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, amphotericin B SOME TRADE NAMES

ABELCET

AMBISOME

AMPHOCIN

AMPHOTEC

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, or radiocontrast material (for renal toxicity) and preexisting hearing problems or coadministration of loop diuretics (for auditory toxicity).

Patients receiving aminoglycosides for > 2 wk or those at risk of vestibular and auditory toxicity should be monitored with serial audiograms.

At the 1st sign of toxicity, the drug is stopped (if possible) or dosing adjusted.
Aminoglycosides can prolong the effect of neuromuscular blockers (eg, succinylcholine SOME TRADE NAMES

ANECTINE

QUELICIN

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or curare-like drugs) and worsen weakness in diseases affecting neuromuscular transmission (eg, myasthenia gravis). This particularly

occurs with too-rapid administration or excessively high serum levels. It sometimes resolves more rapidly with neostigmine SOME TRADE

NAMES

PROSTIGMIN

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or IV Ca. Other neurologic effects include paresthesias and peripheral neuropathy.

Hypersensitivity reactions are uncommon. Large oral doses of neomycin SOME TRADE NAMES

NEO-FRADIN

NEO-RX

Click for Drug Monograph

can produce malabsorption.

Administration: Aminoglycosides are usually given IV. Intravitreous injection is required to treat endophthalmitis. Intraventricular injection

is often required to achieve adequate intraventricular levels for treatment of meningitis. Because toxicity depends more on the duration of

therapeutic levels than peak levels and because drug efficacy is concentration-dependent rather than time-dependent, frequent doses are

avoided. Once/day IV dosing is preferred for most indications except enterococcal endocarditis. IV aminoglycosides are given slowly (30

min for divided daily dosing or 30 to 45 min for once/day dosing). Once-daily dosing of gentamicin SOME TRADE NAMES

GARAMYCIN

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or tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

Click for Drug Monograph

is 5 to 7 mg/kg q 24 h; the higher dose is used initially in critically ill patients, who are likely to have expanded volumes of distribution, to

achieve targeted peak serum levels of 16 to 24 μg/mL and thereby facilitate concentration-dependent bactericidal activity. Peak serum

levels should be determined after the 1st dose in critically ill patients. Peak and trough levels are measured after the 2nd or 3rd dose when

the daily aminoglycoside dose is divided and the duration of therapy is > 3 days. Dosing is adjusted to ensure a therapeutic peak serum

level and nontoxic trough level (see Table 6: Bacteria and Antibacterial Drugs: Dosing for Aminoglycosides in Adults ). Trough levels

should be undetectable at 18 to 24 h after the 1st dose with once-daily dosing and between 1 and 2 mg/mL with multiple daily dosing of

gentamicin SOME TRADE NAMES

GARAMYCIN

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or tobramycin SOME TRADE NAMES

NEBCIN

TOBI

TOBREX

Click for Drug Monograph

. The peak concentration is the level 60 min after an IM injection or 30 min after the end of a 30-min IV infusion. Assuming clinical response

and continued normal renal function, the once-daily dose can be reduced after the 1st few days of therapy to 5 mg/kg. Troughs are

measured within 30 min before the next dose. Serum creatinine is measured q 2 to 3 days, and if stable, serum aminoglycoside levels need

not be repeated.

Table 6
 Dosing for Aminoglycosides in Adults
1. Choose loading dose in mg/kg (ideal weight) for peak serum

levels in range from below for desired aminoglycosides. Dose is

based on lean body weight plus 50% of adipose mass in obese

patients and total body weight in edematous patients.

Aminoglycoside Usual Loading Doses Expected Peak Serum Levels Target Serum

Trough Levels

Tobramycin SOME 1.5–2.0 mg/kg 4–10 μg/mL < 2 μg/mL

TRADE NAMES

NEBCIN

TOBI

TOBREX

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Monograph

, gentamicin SOME

TRADE NAMES

GARAMYCIN

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Monograph

Amikacin SOME 5.0–7.5 mg/kg 15–30 μg/mL < 5 μg/mL

TRADE NAMES

AMIKIN

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Monograph

2. Choose maintenance dose (as percentage of chosen loading

dose) to continue peak serum levels indicated above according to

desired interval and the patient's corrected creatinine clearance.

Calculate corrected creatinine clearance C(c)cr as follows:

Percentage of Loading Dose Required for Dosage Interval Selected

C(c)cr (mL/min) 8 h (%) 12 h (%) 24 h (%)

90 84 — —

70 76 88 —

50 65 79 —

30 48 63 86
In patients with renal insufficiency, the loading dose is the usual dose based on body weight in patients with normal renal function; usually

the dosing interval is increased rather than the dose amount decreased. Nomograms calculate maintenance doses based on serum

creatinine or creatinine clearance values (see Table 6: Bacteria and Antibacterial Drugs: Dosing for Aminoglycosides in Adults ), but they

are not precise, and measurement of blood levels is preferred.

SPECTINOMYCIN
Spectinomycin SOME TRADE NAMES

TROBICIN

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is a bacteriostatic antibiotic chemically related to the aminoglycosides. Spectinomycin SOME TRADE NAMES

TROBICIN

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binds to the 30S subunit of the ribosome, thus inhibiting bacterial protein synthesis. Its activity is restricted to gonococci. Spectinomycin

SOME TRADE NAMES

TROBICIN

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is excreted by glomerular filtration.

Spectinomycin SOME TRADE NAMES

TROBICIN

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is given for gonococcal urethritis, cervicitis, and proctitis but is not effective in gonococcal pharyngitis. It is reserved for patients who cannot

be treated with ceftriaxone SOME TRADE NAMES

ROCEPHIN

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, cefpodoxime SOME TRADE NAMES

VANTIN

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, cefixime SOME TRADE NAMES

SUPRAX

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, or a fluoroquinolone.

Adverse effects, including hypersensitivity reactions and fever, are rare.