Gentamicin is an important drug for the treatment of many serious gram-negative bacillary infections and usually is the aminoglycoside of first choice because of its low cost and reliable activity against all but the most resistant gram-negative aerobes. Gentamicin is given parenterally, oph-thalmically, and topically.
THERAPEUTIC USES OF GENTAMICIN AND OTHER AMINOGLYCOSIDES Gentamicin, tobramycin, amikacin, and netilmicin can be used interchangeably for most infections; gentamicin usually is the preferred agent. Many different types of infections can be treated successfully with these aminoglycosides; however, owing to their toxicities, prolonged use should be restricted to life-threatening infections and those for which a less toxic agent is contraindicated or less effective.
The recommended intramuscular or intravenous dose of gentamicin sulfate (garamycin) for adults is a loading dose of 2 mg/kg and then 3-5 mg/kg/day, one-third being given every 8 hours when administered as a multiple-daily-dosing regimen. The once-daily dose is 5-7 mg/kg given over 30-60 minutes for patients with normal renal function (lower if renal function is impaired). The upper limit of this dose range may be required to achieve therapeutic levels for trauma or burn patients, those with septic shock, and others in whom drug clearance is more rapid or volume of distribution is larger than normal. Several dosage schedules have been suggested for newborns and infants: 3 mg/kg once daily for preterm newborns <35 weeks' gestation; 4 mg/kg once daily for newborns older than 35 weeks' 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 ^g/mL (dosing: 1.7 mg/kg every 8 hours) and 16-24 ^g/mL (dosing: 5.1 mg/kg once daily). It should be emphasized that the recommended doses of gentamicin do not always yield desired concentrations. Periodic determinations of the plasma concentration of aminoglycosides are recommended strongly; trough concentrations consistently >2 ^g/mL are associated with toxicity.
Aminoglycosides often are combined with a penicillin or cephalosporin for the therapy of proven or suspected serious gram-negative infections, especially those due to P. aeruginosa, Enterobacter, Klebsiella, Serratia, and other species resistant to less toxic antibiotics, including urinary tract infections, bacteremia, infected burns, osteomyelitis, pneumonia, peritonitis, and otitis. With few exceptions (e.g., enterococcal endocarditis), the superiority of aminoglycoside combination therapy over an effective single drug has not been demonstrated. Because of their toxicity, aminoglycosides should not be used for more than a few days unless deemed essential. Aminoglycosides should never be mixed in the same solution with penicillins because they are inactivated by penicillin. Similar incompatibilities exist in vitro to different degrees between gen-tamicin and heparin, amphotericin B, and the cephalosporins.
Aminoglycosides usually are not indicated for the treatment of uncomplicated urinary tract infections, although a single intramuscular dose of gentamicin (5 mg/kg) can cure more than 90% of uncomplicated infections of the lower urinary tract. As strains of E. coli acquire resistance to other drugs, aminoglycoside use may increase. In the seriously ill patient with pyelonephritis, an aminoglycoside alone or in combination with a b-lactam antibiotic offers broad and effective initial coverage. Once the microorganism is isolated and its antibiotic sensitivities determined, the aminoglycoside is discontinued if the infecting microorganism is sensitive to less toxic drugs.
Organisms that cause community-acquired pneumonia will be susceptible to broad-spectrum b-lactam antibiotics, macrolides, or a fluoroquinolone, and usually it is not necessary to add an aminoglycoside. Gentamicin (or other aminoglycosides) never should be used as the sole agent to treat pneumonia acquired in the community or as the initial treatment for pneumonia acquired in the hospital.
An aminoglycoside in combination with a b-lactam antibiotic may be used for empirical therapy of hospital-acquired pneumonia in which multiple-drug-resistant gram-negative aerobes are a likely causative agent. However, provided the companion drug is active against the causative agent, there is generally no benefit from adding an aminoglycoside. One exception may be the treatment of pneumonia caused by P. aeruginosa, for which combination therapy generally is recommended, with the goal of preventing the emergence of resistance.
The availability of third-generation cephalosporins has reduced the need for aminoglycoside treatment in most cases of meningitis, except for infections caused by gram-negative organisms that are resistant to b-lactam antibiotics (e.g., species of Pseudomonas and Acinetobacter). If therapy with an aminoglycoside is necessary, in adults, 5 mg of a preservative-free formulation of gentamicin (or equivalent dose of another aminoglycoside) is administered intrathecally once daily.
Patients who develop peritonitis during peritoneal dialysis may be treated with an 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 amikacin.
"Synergistic" or low-dose gentamicin (3 mg/kg/day in three divided doses) in combination with a penicillin or vancomycin has been recommended in some circumstances for treating bacterial endocarditis. There is good evidence that penicillin and gentamicin in combination are effective as a short-course (i.e., 2-week) regimen for uncomplicated native-valve streptococcal endocarditis. In cases of enterococcal endocarditis, concomitant administration of penicillin and gentamicin for 4-6 weeks has been recommended because of an unacceptably high relapse rate with penicillin alone. A 2-week regimen of gentamicin or tobramycin in combination with nafcillin is effective for selected cases of staphylococcal tricuspid valve endocarditis in injection drug users, although the benefit of including an aminoglycoside is unproven.
Aminoglycosides have no clinically proven benefit in treatment of staphylococcal mitral or aortic valve endocarditis. Because of toxicity and limited clinical benefit, aminoglycoside combination therapy has fallen from favor as a first-line regimen for treatment of endocarditis.
In febrile patients with granulocytopenia and in infections suspected to be caused by P. aeruginosa, numerous studies using potent broad-spectrum b-lactams (e.g., carbapenems and antipseudomonal cephalosporins) have demonstrated no benefit of adding an aminoglycoside to the regimen. Most experts recommend combination therapy of documented non-urinary tract P. aeruginosa infections, particularly pneumonia with bacteremia. If there is concern that an infection may be caused by a multiple-drug-resistant organism that may be susceptible only to an aminoglycoside, then adding this antibiotic to the regimen is reasonable. Evidence that aminoglycosides are beneficial for other gram-negative infections is weak. To avoid toxicity, aminoglycosides should be used briefly and sparingly as long as other alternatives are available.
Gentamicin is absorbed slowly when it is applied topically in an ointment and somewhat more rapidly when it is applied as a cream. When the antibiotic is applied to large areas of denuded body surface (e.g., in burn patients), plasma concentrations can reach 4 mg/mL, and 2-5% of the drug may appear in the urine.
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