After intramuscular administration of gentamicin sulfate, peak serum concentrations usually occur between 30 to 60 minutes and serum levels are measurable for 6 to 8 hours. When gentamicin is administered by intravenous infusion over a two-hour period, the serum concentrations are similar to those obtained by intramuscular administration.
In patients with normal renal function, peak serum concentrations of gentamicin (mcg/mL) are usually up to four times the single intramuscular dose (mg/kg); for example, a 1 mg/kg injection in adults may be expected to result in a peak serum concentration up to 4 mcg/mL; a 1.5 mg/kg dose may produce levels up to 6 mcg/mL. While some variation is to be expected due to a number of variables such as age, body temperature, surface area and physiologic differences, the individual patient given the same dose tends to have similar levels in repeated determinations. Gentamicin administered at 1 mg/kg every eight hours for the usual 7- to 10-day treatment period to patients with normal renal function does not accumulate in the serum.
Gentamicin, like all aminoglycosides, may accumulate in the serum and tissues of patients treated with higher doses and for prolonged periods, particularly in the presence of impaired renal function. In adult patients, treatment with gentamicin dosages of 4 mg/kg/day or higher for seven to ten days may result in a slight, progressive rise in both peak and trough concentrations. In patients with impaired renal function, gentamicin is cleared from the body more slowly than in patients with normal renal function. The more severe the impairment, the slower the clearance. Dosage must be adjusted.
Since gentamicin is distributed in extracellular fluid, peak serum concentrations may be lower than usual in adult patients who have a large volume of this fluid. Serum concentrations of gentamicin in febrile patients may be lower than those in afebrile patients given the same dose. When body temperature returns to normal, serum concentrations of the drug may rise. Febrile and anemic states may be associated with a shorter than usual serum half-life. (Dosage adjustment is usually not necessary.) In severely burned patients, the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg/kg dose.
Protein binding studies have indicated that the degree of gentamicin binding is low. Depending upon the methods used for testing, this may be between 0 and 30%.
After initial administration to patients with normal renal function, generally 70% or more of the gentamicin dose is recoverable in the urine in 24 hours; concentrations in urine above 100 mcg/mL may be achieved. Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration. After several days of treatment, the amount of gentamicin excreted in the urine approaches the daily dose administered. As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys. Minute quantities of aminoglycosides have been detected in the urine weeks after drug administration was discontinued. Renal clearance of gentamicin is similar to that of endogenous creatinine.
In patients with marked impairment of renal function, there is a decrease in the concentration of aminoglycosides in urine and in their penetration into defective renal parenchyma. This decreased drug excretion, together with the potential nephrotoxicity of aminoglycosides, should be considered when treating such patients who have urinary tract infections.
Probenecid does not affect renal tubular transport of gentamicin.
The endogenous creatinine clearance rate and the serum creatinine level have a high correlation with the half-life of gentamicin in serum. Results of these tests may serve as guides for adjusting dosage in patients with renal impairment (see DOSAGE AND ADMINISTRATION).
Following parenteral administration, gentamicin can be detected in serum, lymph, tissues, sputum, and in pleural, synovial, and peritoneal fluids. Concentrations in renal cortex sometimes may be eight times higher than the usual serum levels. Concentrations in bile, in general, have been low and have suggested minimal biliary excretion. Gentamicin crosses the peritoneal as well as the placental membranes. Since aminoglycosides diffuse poorly into the subarachnoid space after parenteral administration, concentrations of gentamicin in cerebrospinal fluid are often low and dependent upon dose, rate of penetration and degree of meningeal inflammation. There is minimal penetration of gentamicin into ocular tissues following intramuscular or intravenous administration.
In vitro tests have demonstrated that gentamicin is a bactericidal antibiotic which acts by inhibiting normal protein synthesis in susceptible microorganisms. It is active against a wide variety of pathogenic bacteria including Escherichia coli, Proteus species (indole-positive and indole-negative); Pseudomonas aeruginosa, species of Klebsiella-Enterobacter-Serratia group; Citrobacter species, and Staphylococcus species (including penicillin and methicillin-resistant strains). Gentamicin is also active in vitro against species of Salmonella and Shigella. The following bacteria are usually resistant to aminoglycosides: Streptococcus pneumoniae, most species of streptococci, particularly group D and anaerobic organisms, such as Bacteroides species or Clostridium species.
In vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some group D streptococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against virtually all strains of Streptococcus faecalis and its varieties (S. faecalis var. liquifaciens, S. faecalis var. zymogenes), S. faecium and S. durans. An enhanced killing effect against many of these strains has also been shown in vitro with combinations of gentamicin and ampicillin, carbenicillin, nafcillin or oxacillin.
The combined effect of gentamicin and carbenicillin is synergistic for many strains of Pseudomonas aeruginosa. In vitro synergism against other gram-negative organisms has been shown with combinations of gentamicin and cephalosporins.
Gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides. Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides. Bacterial resistance to gentamicin is generally developed slowly.
If the disc method of susceptibility testing used is that described by Bauer et al (Am J Clin Path 45:493,1966; Federal Register 37:20527-20529, 1972), a disc containing 10 mcg of gentamicin should give a zone of inhibition of 15 mm or more to indicate susceptibility of the infecting organism. Zones greater than 12 mm and less than 15 mm indicate intermediate susceptibility. A zone of 12 mm or less indicates that the infecting organism is likely to be resistant. In certain conditions it may be desirable to do additional susceptibility testing by the tube or agar dilution method; gentamicin is available for this purpose.