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 peptidyltRNA 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 Gramnegative 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 Click for Drug Monograph , tobramycin SOME TRADE NAMES

NEBCIN TOBI TOBREX Click for Drug Monograph , 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 Click for Drug Monograph 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 Click for Drug Monograph is more active against Serratia marcescens. Amikacin SOME TRADE NAMES

AMIKIN Click for Drug Monograph is frequently active against gentamicin SOME TRADE NAMES

GARAMYCIN Click for Drug Monograph - 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 Click for Drug Monograph in vitro does not rule out susceptibility of these enterococcal strains to high levels of streptomycin SOME TRADE NAMES

NO US TRADE NAME Click for Drug Monograph , 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 Click for Drug Monograph 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 Click for Drug Monograph 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 Click for Drug Monograph 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 Click for Drug Monograph , cyclosporine SOME TRADE NAMES

NEORAL SANDIMMUNE Click for Drug Monograph , amphotericin B SOME TRADE NAMES

ABELCET AMBISOME AMPHOCIN AMPHOTEC Click for Drug Monograph , 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 Click for Drug Monograph 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 Click for Drug Monograph 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 Click for Drug Monograph 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 Click for Drug Monograph

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

5.0–7.5 mg/kg

15–30 μg/mL

< 5 μg/mL

TRADE NAMES NEBCIN TOBI TOBREX Click for Drug Monograph , gentamicin SOME TRADE NAMES GARAMYCIN Click for Drug Monograph

Amikacin SOME TRADE NAMES AMIKIN Click for Drug 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 Click for Drug Monograph is a bacteriostatic antibiotic chemically related to the aminoglycosides. Spectinomycin SOME TRADE NAMES

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

SOME TRADE NAMES TROBICIN Click for Drug Monograph is excreted by glomerular filtration.

Spectinomycin SOME TRADE NAMES

TROBICIN Click for Drug Monograph 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 Click for Drug Monograph , cefpodoxime SOME TRADE NAMES

VANTIN Click for Drug Monograph , cefixime SOME TRADE NAMES

SUPRAX Click for Drug Monograph , or a fluoroquinolone.

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