Pharmacotherapeutic Group: Aminoglycoside antibiotic.
Pharmacokinetics: Gentamicin is rapidly absorbed after IM injection and peak serum levels are usually achieved within 30-90 min and are measurable for 6-8 hrs. Following parenteral administration, Gentamicin can be detected in tissues and body fluids. Following absorption, Gentamicin is widely distributed into body fluid including ascitic, pericardial, pleural, synovial and abscess fluids. Concentration in bile is low. Gentamicin is excreted almost entirely by renal glomerular filtration, hence the t½ of the drug is prolonged in the presence of renal failure. Adjustments in the frequency of administration of Gentamicin are necessary to allow for the degree of renal failure. The serum t½ of Gentamicin is approximately 2-3 hrs in adults with normal renal function. It is prolonged in patients with impaired renal function and in premature or newborn infants.
Microbiology: Gentamicin is bactericidal and acts by inhibiting protein synthesis in susceptible bacteria. Cell death results. It is active against a wide range of pathogenic gram-negative organisms including Escherichia coli, Pseudomonas aeruginosa, Proteus sp (both indole-positive and -negative), Klebsiella, Enterobacter and Serratia spp. It is also active against some gram-positive organisms eg, Staphylococcus sp (including methicillin- and penicillin-resistant strains). In vitro, Gentamicin is also active against Salmonella and Shigella. Some species have demonstrated resistance to aminoglycosides including Streptococcus pneumoniae and anaerobic organisms eg, Bacteroides or Clostridium spp.
For patients using the eye drop form of Gentamicin:
For patients using the eye ointment form of Gentamicin:
To help clear up your infection completely, keep using Gentamicin for the full time of treatment, even if your symptoms have disappeared. Do not miss any doses.
The dose of Gentamicin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Gentamicin. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Gentamicin, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
IM: Administer by deep IM route if possible.
IV: Infuse over 30 to 120 minutes.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and Gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
Intraventricular (off-label route): Use preservative-free preparations only. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow Gentamicin solution to equilibrate in the cerebrospinal fluid (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]).
After intramuscular administration of Gentamicin, 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.
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.
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.
Gentamicin has been shown to be active against most of the following bacteria, both in vitro and in clinical infections.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility tests for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for treatment.
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1, 3 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Gentamicin powder. The MIC values should be interpreted according to the criteria provided in.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. The standardized procedure requires the use of standardized inoculum concentrations and paper disks impregnated with 10 mcg of Gentamicin.2, 3 The disk diffusion values should be interpreted according to the criteria provided in.
A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standard Gentamicin powder should provide the following range of MIC values provided in. For the diffusion technique using the 10-mcg Gentamicin disk the criteria provided in should be achieved.
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Information checked by Dr. Sachin Kumar, MD Pharmacology