Gentamicin Dailymed

To reduce the development of drug-resistant bacteria and maintain the effectiveness of gentamicin injection and other antibacterial drugs, gentamicin injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Boxed Warnings

Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use.

As with other aminoglycosides, gentamicin injection is potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high dosage or prolonged therapy.

Neurotoxicity manifested by ototoxicity, both vestibular and auditory, can occur in patients treated with gentamicin, primarily in those with pre-existing renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended. Aminoglycoside-induced ototoxicity is usually irreversible. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

Renal and eighth cranial nerve function should be closely monitored, especially in patients with known or suspected reduced renal function at onset of therapy, and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Urine should be examined for decreased specific gravity, increased excretion of protein, and the presence of cells or casts. Blood urea nitrogen (BUN), serum creatinine, or creatinine clearance should be determined periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears or hearing loss) or nephrotoxicity requires dosage adjustment or discontinuance of the drug. As with the other aminoglycosides, on rare occasions changes in renal and eighth cranial nerve function may not become manifest until soon after completion of therapy.

Serum concentrations of aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. When monitoring gentamicin peak concentrations, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.

When monitoring gentamicin trough concentrations, dosage should be adjusted so that levels above 2 mcg/mL are avoided. Excessive peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity. In the event of overdose or toxic reactions, hemodialysis may aid in the removal of gentamicin from the blood, especially if renal function is, or becomes, compromised. The rate of removal of gentamicin is considerably less by peritoneal dialysis than by hemodialysis.

In the newborn infant, exchange transfusions may also be considered.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, cephaloridine, kanamycin, amikacin, neomycin, polymyxin B, coulin, paromomycin, streptomycin, tobramycin, vancomycin, and viomycin, should be avoided. Other factors which may increase patient risk of toxicity are advanced age and dehydration.

The concurrent use of gentamicin with potent diuretics, such as ethacrynic acid or furosemide, should be avoided, since certain diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering the antibiotic concentration in serum and tissue.

Aminoglycosides can cause fetal harm when administered to a pregnant woman (see  WARNINGS  section).

Description:

Gentamicin sulfate, USP a water-soluble antibiotic of the aminoglycoside group, is derived from Micromonospora purpurea, an actinomycete.

It has the following structural formula:

Gentamicin injection, USP is a sterile, nonpyrogenic, aqueous solution for parenteral administration.

Each mL of the preservative free product contains: Gentamicin sulfate, USP equivalent to gentamicin 10 mg; water for injection q.s. sulfuric acid and/or sodium hydroxide may have been added for pH adjustment (3 to 5.5).

Clinical Pharmacology:

After intramuscular administration of gentamicin sulfate, peak serum concentrations usually occur between 30 and 60 minutes and serum levels are measurable for 6 to 8 hours. In infants, a single-dose of 2.5 mg/kg usually provides a peak serum level in the range of 3 to 5 mcg/mL. When gentamicin is administered by intravenous infusion over a two-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Age markedly affects the peak concentrations: in one report, a 1 mg/kg dose produced mean peak concentrations of 1.58, 2.03, and 2.81 mcg/mL in patients six months to five years old, 5 to 10 years old, and over 10 years old, respectively.

In infants one week to six months of age, the half-life is 3 to 3½^  _ hours. In full-term and large premature infants less than one week old, the approximate serum half-life of gentamicin is 5½ hours. In small premature infants, the half-life is inversely related to birth weight. In premature infants weighing less than 1,500 grams, the half-life is 11½ hours; in those weighing 1,500 to 2,000 grams, the half-life is eight hours; in those weighing over 2,000 grams, the half-life is approximately five hours. 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, like all aminoglycosides, may accumulate in the serum and tissues of patients treated with higher doses and/or for prolonged periods, particularly in the presence of impaired or immature renal function. In patients with immature or 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 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%.

In neonates less than three days old, approximately 10% of the administered dose is excreted in 12 hours; in infants 5 to 40 days old, approximately 40% is excreted over the same period. Excretion of gentamicin correlates with postnatal age and creatinine clearance. Thus, with increasing postnatal age and concomitant increase in renal maturity, gentamicin is excreted more rapidly. 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, but does not equal, 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 of some patients 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.

Microbiology

Mechanism of Action

Gentamicin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria. It is bactericidal in vitro against Gram-positive and Gram-negative bacteria.

Mechanism of Resistance

Bacterial resistance to gentamicin is generally developed slowly. Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides. The following bacteria are usually resistant to the aminoglycosides, including gentamicin: most streptococcal species (including Streptococcus pneumoniae and the Group D streptococci), most enterococcal species (including Enterococcus faecalis, E. faecium, and E. durans), and anaerobic organisms, such as Bacteroides species and Clostridium species.

Aminoglycosides are known to be not effective against Salmonella and Shigella species in patients. Therefore, in vitro susceptibility test results should not be reported.

Interactions with Other Antimicrobials

In vitro studies show that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some enterococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against strains of Enterococcus faecalis, E. faecium and E. 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.

Antibacterial Activity

Gentamicin has been shown to be active against most of the following bacteria, both in vitro and in clinical infections (see INDICATIONS AND USAGE ).

Gram-Positive Bacteria

Staphylococcus species

Gram-Negative Bacteria

Citrobacter species

Enterobacter species

Escherichia coli

Klebsiella species

Proteus species

Serratia species

Pseudomonas aeruginosa

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of gentamicin injection and other antibacterial drugs, gentamicin injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Gentamicin injection is indicated in the treatment of serious infections caused by susceptible strains of the following microorganisms: Pseudomonas aeruginosa, Proteus species (indole-positive and indole-negative), Escherichia coli, Klebsiella-Enterobacter-Serratia species, Citrobacter species, and Staphylococcus species (coagulase-positive and coagulase-negative).

Clinical studies have shown gentamicin injection to be effective in bacterial neonatal sepsis; bacterial septicemia; and serious bacterial infections of the central nervous system (meningitis), urinary tract, respiratory tract, gastrointestinal tract (including peritonitis), skin, bone and soft tissue (including burns).

Aminoglycosides, including gentamicin, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are susceptible to these antibiotics and are not susceptible to antibiotics having less potential for toxicity.

Specimens for bacterial culture should be obtained to isolate and identify causative organisms and to determine their susceptibility to gentamicin.

Gentamicin may be considered as initial therapy in suspected or confirmed gram-negative infections, and therapy may be instituted before obtaining results of susceptibility testing. The decision to continue therapy with this drug should be based on the results of susceptibility tests, the severity of the infection, and the important additional concepts contained in the BOXED WARNINGS  above. If the causative organisms are resistant to gentamicin, other appropriate therapy should be instituted.

In serious infections when the causative organisms are unknown, gentamicin may be administered as initial therapy in conjunction with a penicillin-type or cephalosporin type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected as etiologic agents, consideration should be given to using other suitable antimicrobial therapy in conjunction with gentamicin. Following identification of the organism and its susceptibility, appropriate antibiotic therapy should then be continued.

Gentamicin has been used effectively in combination with carbenicillin for the treatment of life-threatening infections caused by Pseudomonas aeruginosa. It has also been found effective when used in conjunction with a penicillin-type drug for the treatment of endocarditis caused by group D streptococci.

Gentamicin injection has also been shown to be effective in the treatment of serious staphylococcal infections. While not the antibiotic of first choice, gentamicin injection may be considered when penicillins or other less potentially toxic drugs are contraindicated and bacterial susceptibility tests and clinical judgment indicate its use. It may also be considered in mixed infections caused by susceptible strains of staphylococci and gram-negative organisms.

In the neonate with suspected bacterial sepsis or staphylococcal pneumonia, a penicillin-type drug is also usually indicated as concomitant therapy with gentamicin.