Tobramycin

TOBRAMYCIN — tobramycin sulfate injection
Xellia Pharmaceuticals ApS

WARNING

Patients treated with Tobramycin for Injection and other aminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity. Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth-nerve impairment and nephrotoxicity may develop, primarily in patients having preexisting renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.

Rarely, nephrotoxicity may become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible.

Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg/mL should be avoided. Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity (see Precautions). Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment.

Tobramycin for Injection should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides (eg. amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided. Other factors that may increase patient risk are advanced age and dehydration.

Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

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

DESCRIPTION

Tobramycin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derived from the actinomycete Streptomyces tenebrarius. Tobramycin for Injection, USP is supplied as a sterile dry powder and is intended for reconstitution with 30 mL of Sterile Water for Injection, USP. Sulfuric acid and/or sodium hydroxide may have been added during manufacture to adjust the pH. This Pharmacy Bulk Package contains tobramycin sulfate equivalent to 1200 mg of tobramycin. After reconstitution, the solution will contain 40 mg of tobramycin per mL. The product contains no preservative or sodium bisulfite.

Tobramycin sulfate is 0 -3-amino-3-deoxy-a -D-glucopyranosyl-(1→4)-0 -[2,6-diamino-2,3,6-trideoxy-a -D-ribo -hexopyranosyl-(1→6)]-2-deoxy-L-streptamine, sulfate (2:5)(salt) and has the chemical formula(C18H37N5O9)2•5H2SO4. The molecular weight is 1425.45. The structural formula for tobramycin is as follows:

Tobramycin

The pharmacy bulk package of Tobramycin for Injection, USP is a container of a sterile preparation for parenteral use that contains multiple single doses. It is intended for use in a pharmacy admixture program. Package use is restricted to the preparation of admixtures for intravenous infusion or to the filling of empty sterile syringes for intravenous injections for patients with individualized dosing requirements.

CLINICAL PHARMACOLOGY

Tobramycin is rapidly absorbed following intramuscular administration. Peak serum concentrations of tobramycin occur between 30 and 90 minutes after intramuscular administration. Following an intramuscular dose of 1 mg/kg of body weight, maximum serum concentrations reach about 4 mcg/mL, and measurable levels persist for as long as 8 hours. Therapeutic serum levels are generally considered to range from 4 to 6 mcg/mL. When tobramycin is administered by intravenous infusion over a 1-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Tobramycin is poorly absorbed from the gastrointestinal tract.

In patients with normal renal function, except neonates, tobramycin administered every 8 hours does not accumulate in the serum. However, in those patients with reduced renal function and in neonates, the serum concentration of the antibiotic is usually higher and can be measured for longer periods of time than in normal adults. Dosage for such patients must, therefore, be adjusted accordingly (see Dosage and Administration).

Following parenteral administration, little, if any, metabolic transformation occurs, and tobramycin is eliminated almost exclusively by glomerular filtration. Renal clearance is similar to that of endogenous creatinine. Ultrafiltration studies demonstrate that practically no serum protein binding occurs. In patients with normal renal function, up to 84% of the dose is recoverable from urine in 8 hours and up to 93% in 24 hours.

Peak urine concentrations ranging from 75 to 100 mcg/mL have been observed following the intramuscular injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood levels.

The serum half-life in normal individuals is 2 hours. An inverse relationship exists between serum half-life and creatinine clearance, and the dosage schedule should be adjusted according to the degree of renal impairment (see Dosage and Administration). In patients undergoing dialysis, 25% to 70% of the administered dose may be removed, depending on the duration and type of dialysis.

Tobramycin can be detected in tissues and body fluids after parenteral administration. Concentrations in bile and stools ordinarily have been low, which suggests minimum biliary excretion. Tobramycin has appeared in low concentration in the cerebrospinal fluid following parenteral administration, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation. It has also been found in sputum, peritoneal fluid, synovial fluid, and abscess fluids, and it crosses the placental membranes. Concentrations in the renal cortex are several times higher than the usual serum levels.

Probenecid does not affect the renal tubular transport of tobramycin.

Microbiology – Tobramycin acts by inhibiting synthesis of protein in bacterial cells. In vitro tests demonstrate that tobramycin is bactericidal.

Tobramycin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections as described in the Indications and Usage section:
Aerobic Gram-positive microorganisms
Staphylococcus aureus

Aerobic Gram-negative microorganisms
Citrobacter species Enterobacter species Escherichia coli
Klebsiella species Morganella morganii Pseudomonas aeruginosa
Proteus mirabilis Proteus vulgaris Providencia species
Serratis species
Aminoglycosides have a low order of activity against most gram-positive organisms, including Streptococcus pyogenes, Streptococcus pneumoniae , and enterococci.
Although most strains of enterococci demonstrate in vitro resistance, some strains in this group are susceptible. In vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell-wall synthesis affects some enterococcal strains synergistically. The combination of penicillin G and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of Enterococcus faecalis. However, this combination is not synergistic against other closely related organisms, eg, Enterococcus faecium. Speciation of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergisms are emphasized.

Cross resistance between aminoglycosides may occur.

Susceptibility Tests -

Diffusion techniques: Quantitative methods that require measurement of zone diameters give the most precise estimates of susceptibility of bacteria to antimicrobial agents. One such procedure is the National Committee for Clinical Laboratory Standards (NCCLS)-approved procedure1. This method has been recommended for use with disks to test susceptibility to tobramycin. Interpretation involves correlation of the diameters obtained in the disk test with minimum inhibitory concentrations (MIC) for tobramycin.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-mcg tobramycin disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation
>15 (S) Susceptible
13-14 (I) Intermediate
<12 (R) Resistant

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “Intermediate” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are obtained. A report of “Resistant” indicates that achievable concentrations are unlikely to be inhibitory and other therapy should be selected.Standardized procedures require the use of laboratory control organisms. The 10-mcg tobramycin disk should give the following zone diameters:

Organism Zone Diameter (mm)
E. coli ATCC 25922 18-26
P. aeruginosa ATCC 27853 19-25
S. aureus ATCC 25923 19-29

Dilution techniques: Broth and agar dilution methods, such as those recommended by the NCCLS2 may be used to determine MICs of tobramycin. MIC test results should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
< 4 (S) Susceptible
8 (I) Intermediate
> 16 (R) Resistant

As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Tobramycin laboratory reagent should give the following MIC values:

Organism MIC Range (mcg/mL)
E. faecalis ATCC 29212 8-32
E. coli ATCC 25922 0.25-1
P. aeruginosa ATCC 27853 0.25-1
S. aureus ATCC 29213 0.12-1
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