A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Nebcin Pharmacology, Pharmacokinetics, Studies, Metabolism - Tobramycin
Nebcin Pharmacology, Pharmacokinetics, Studies, Metabolism - Tobramycin
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 Nebcin
is administered by intravenous infusion over a 1-hour period, the serum
concentrations are similar to those obtained by intramuscular administration.
Nebcin is poorly absorbed from the gastrointestinal tract.
In patients with normal renal function, except neonates, Nebcin 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 the 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 Nebcin 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
Serratia 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 can not be used to predict susceptibility. Susceptibility
testing and tests for antibiotic synergism 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 procedure.1 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 |
| ³15 |
(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 NCCLS,2
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 |
| ³16 |
(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 ATCC29213 |
0.12-1 |
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