The aminoglycosides are a group of drugs sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. At present, the group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, arbekacin, and dibekacin. Sisomicin, arbekacin, and dibekacin are available outside of the United States. All inhibit protein synthesis of bacteria by attaching to and inhibiting the function of the 30S subunit of the bacterial ribosome. Resistance is based on (1) a deficiency of the ribosomal receptor (mutation or methylation of 16S rRNA binding site), (2) enzymatic destruction of the drug (plasmid mediated transmissible resistance of clinical importance), or (3) lack ofpermeability to the drug molecule and lack of active transport into the cell or active efflux pumps. Anaerobic bacteria are often resistant to aminoglycosides because transport through the cell membrane is an energy-requiring process that is oxygen dependent.

All aminoglycosides are more active at alkaline pH than at acid pH. All are potentially ototoxic and nephrotoxic, although to different degrees. All can accumulate in renal failure; therefore, marked dosage adjustments must be made when nitrogen retention occurs. Aminoglycosides are used most widely against Gram-negative enteric bacteria or when there is suspicion of sepsis. In the treatment of bacteremia or endocarditis caused by streptococci, enterococci, or some Gram-negative bacteria, the aminoglycoside is given together with a penicillin that facilitates the entry of the aminoglycoside. Aminoglycosides are selected according to recent susceptibility patterns in a given area or hospitals until susceptibility tests become available on a specific isolate. The clinical usefulness of aminoglycosides has declined with the advent of cephalosporins and quinolones, but they continue to be used in combinations (eg, with cephalosporins for multidrug-resistant Gram-negative bacteremias). All positively charged aminoglycosides are inhibited in blood cultures by sodium polyanetholsulfonate and other polyanionic deter gents. Some aminoglycosides (especially streptomycin) are useful as antimycobacterial drugs.

Neomycin and Kanamycin

Kanamycin is a close relative of neomycin with similar activity and complete cross-resistance. Paromomycin is also closely related and is used in amebiasis. These drugs are stable and poorly absorbed from the intestinal tract and other surfaces. Neither drug is used systemically because of ototoxicity and neurotoxicity. Oral doses of both neomycin and kanamycin are used for reduction of intestinal microbiota before large bowel surgery, often in combination with erythromycin. Otherwise, these drugs are mainly limited to topical application on infected surfaces (skin and wounds).

Amikacin

Amikacin is a semisynthetic derivative of kanamycin. It is relatively resistant to several of the enzymes that inactivate gentamicin and tobramycin and therefore can be used against some microorganisms resistant to the latter drugs. However, bacterial resistance caused by impermeability to amikacin is slowly increasing. Many Gram-negative enteric bacteria are inhibited by amikacin in concentrations obtained after injection. CNS infections require intrathecal or intraventricular injection.

Similar to all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Its level should be monitored in patients with renal failure.

Gentamicin

 In concentrations of 0.5–5 μg/mL, gentamicin is bactericidal for many Gram-positive and Gram-negative bacteria, including many strains of Proteus, Serratia, and Pseudomonas. Gentamicin is ineffective against streptococci and Bacteroides species.

Gentamicin has been used in serious infections caused by Gram-negative bacteria resistant to other drugs. Penicillins may precipitate gentamicin in vitro (and thus must not be mixed), but in vivo, they may facilitate the aminoglycoside entrance into streptococci and Gram-negative rods and result in bactericidal synergism, which is beneficial in sepsis and endocarditis.

Gentamicin is toxic, particularly in the presence of impaired renal function. Gentamicin sulfate, 0.1%, has been used topically in creams or solutions for infected burns or skin lesions. Such creams tend to select gentamicin-resistant bacteria.

Tobramycin

This aminoglycoside closely resembles gentamicin, and there is some cross-resistance between them. Separate susceptibility tests are desirable. Tobramycin has slightly enhanced activity against P. aeruginosa when compared with gentamicin. Inhaled formulations of the drug have been used to treat chronic pseudomonas infections in patients with cystic fibrosis.

The pharmacologic properties of tobramycin are virtually identical to those of gentamicin. Most of the drug is excreted by glomerular filtration. In renal failure, the drug dosage must be reduced, and monitoring of blood levels is desirable.

Similar to other aminoglycosides, tobramycin is ototoxic but perhaps less nephrotoxic than gentamicin. It should not be used concurrently with other drugs having similar adverse effects or with diuretics, which tend to enhance aminoglycoside tissue concentrations.

Netilmicin

Netilmicin shares many characteristics with gentamicin and tobramycin, but it is not inactivated by some bacteria that are resistant to the other drugs.

The principal indication for netilmicin may be iatrogenic infections in immunocompromised and severely ill patients at very high risk for Gram-negative bacterial sepsis in the hospital setting.

Netilmicin may be somewhat less ototoxic and nephrotoxic than the other aminoglycosides.

Streptomycin

Streptomycin was the first aminoglycoside—it was discovered in the 1940s as a product of Streptomyces griseus. It was studied in great detail and became the prototype of this class of drugs. For this reason, its properties are listed here, although widespread resistance among microorganisms has greatly reduced its clinical usefulness.

After intramuscular injection, streptomycin is rapidly absorbed and widely distributed in tissues except the CNS. Only 5% of the extracellular concentration of streptomycin reaches the interior of the cell. Absorbed streptomycin is excreted by glomerular filtration into the urine. After oral administration, it is poorly absorbed from the gut; most of it is excreted in feces.

Streptomycin may be bactericidal for enterococci (eg, in endocarditis) when combined with a penicillin. In tularemia and plague, it may be given with a tetracycline. In tuberculosis, it is used in combination with other antituberculous drugs (INH, rifampin). Streptomycin should not be used alone to treat any infection.

The therapeutic effectiveness of streptomycin is limited by the rapid emergence of resistant mutants. All microbial strains produce streptomycin-resistant chromosomal mutants with relatively high frequency. Chromosomal mutants have an alteration in the P 12 receptor on the 30S ribosomal subunit. Plasmid-mediated resistance results in enzymatic destruction of the drug. Enterococci resistant to high levels of streptomycin (2000 μg/mL) or gentamicin (500 μg/mL) are resistant to the synergistic actions of these drugs with penicillin.

Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin. These occur most frequently upon prolonged contact with the drug, in patients receiving a protracted course of treatment (eg, for tuberculosis), or in personnel preparing and handling the drug. (Personnel preparing solutions should wear gloves.)

Streptomycin is markedly toxic for the vestibular portion of the eighth cranial nerve, causing tinnitus, vertigo, and ataxia, which are often irreversible. It is moderately nephrotoxic.

Spectinomycin

Spectinomycin is an aminocyclitol antibiotic (related to aminoglycosides) for intramuscular administration. Its sole application was in the single-dose treatment of gonorrhea caused by β-lactamase-producing gonococci or occurring in individuals hypersensitive to penicillin. About 5–10% of gonococci are probably resistant. There is usually pain at the injection site, and the patient may have nausea and fever. However, nephrotoxicity and ototoxicity do not occur. This drug is no longer available in the United States.

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مواضيع ذات صلة

Sulfonamides and Trimethoprim

Quinolones

Glycopeptides, Lipopeptides, Lipoglycopeptides antibiotics

Macrolides

Chloramphenicol

Tetracyclines

Other β-Lactam Drugs

Cephalosporins

Penicillins

Many Antibiotics work by Selectively Inhibiting Protein Synthesis in Bacteria

Antimicrobial Drugs: Inhibition of nucleic acid synthesis

Antimicrobial Drugs: Inhibition of Protein Synthesis