STREPTOMYCIN
DESCRIPTION:
WARNING
THE RISK OF SEVERE NEUROTOXIC REACTIONS IS
SHARPLY INCREASED IN PATIENTS WITH IMPAIRED
RENAL FUNCTION OR PRE-RENAL AZOTEMIA. THESE
INCLUDE DISTURBANCES OF VESTIBULAR AND
COCHLEAR FUNCTION. OPTIC NERVE DYSFUNCTION,
PERIPHERAL NEURITIS, ARACHNOIDITIS, AND
ENCEPHALOPATHY MAY ALSO OCCUR. THE
INCIDENCE OF CLINICALLY DETECTABLE,
IRREVERSIBLE VESTIBULAR DAMAGE IS
PARTICULARLY HIGH IN PATIENTS TREATED WITH
STREPTOMYCIN.
RENAL FUNCTION SHOULD BE MONITORED
CAREFULLY; PATIENTS WITH RENAL IMPAIRMENT
AND/OR NITROGEN RETENTION SHOULD RECEIVE
REDUCED DOSAGES. THE PEAK SERUM
CONCENTRATION IN INDIVIDUALS WITH KIDNEY
DAMAGE SHOULD NOT EXCEED 20 TO 25 MCG/ML.
THE CONCURRENT OR SEQUENTIAL USE OF OTHER
NEUROTOXIC AND/OR NEPHROTOXIC DRUGS WITH
STREPTOMYCIN SULFATE, INCLUDING NEOMYCIN,
KANAMYCIN, GENTAMICIN, CEPHALORIDINE,
PAROMOMYCIN, VIOMYCIN, POLYMYXIN B,
COLISTIN, TOBRAMYCIN AND CYCLOSPORINE
SHOULD BE AVOIDED.
THE NEUROTOXICITY OF STREPTOMYCIN CAN
RESULT IN RESPIRATORY PARALYSIS FROM
NEUROMUSCULAR BLOCKAGE, ESPECIALLY WHEN THE
DRUG IS GIVEN SOON AFTER THE USE OF
ANESTHESIA OR OF MUSCLE RELAXANTS.
THE ADMINISTRATION OF STREPTOMYCIN IN
PARENTERAL FORM SHOULD BE RESERVED FOR
PATIENTS WHERE ADEQUATE LABORATORY AND
AUDIOMETRIC TESTING FACILITIES ARE
AVAILABLE DURING THERAPY.
Streptomycin is a water-soluble aminoglycoside derived from Streptomyces
Griseus. It is marketed as the sulfate salt of streptomycin. The chemical name
of streptomycin sulfate is D-Streptamine, O- 2-deoxy-2-(methylamino)-alpha-L-
glucopyranosyl-(1 right arrow 2)-O-5-deoxy-3-C-formyl-alpha-L- lyxofuranosyl-(1
right arrow 4)-N,N'-bis(aminoiminomethyl)-, sulfate (2:3) (salt). The empirical
formula for Streptomycin Sulfate is (C21H39N7O12)2.3H2SO4 and the molecular
weight is 1457.38. It has the following structure:
Streptomycin Sulfate Injection, 1 g/2.5 mL (400 mg/mL), is supplied as a
sterile, nonpyrogenic solution for intramuscular use.
Each mL contains: Streptomycin sulfate equivalent to 400 mg of streptomycin,
sodium citrate dihydrate 12 mg, phenol 0.25% w/v as preservative, sodium
metabisulfite 2 mg in Water for Injection. pH range 5.0 to 8.0.
ACTIONS/CLINICAL PHARMACOLOGY:
Following intramuscular injection of 1 g of streptomycin, as the sulfate, a peak
serum level of 25 to 50 mcg/mL is reached within 1 hour, diminishing slowly to
about 50 percent after 5 to 6 hours.
Appreciable concentrations are found in all organ tissues except the brain.
Significant amounts have been found in pleural fluid and tuberculous cavities.
Streptomycin passes through the placenta with serum levels in the cord blood
similar to maternal levels. Small amounts are excreted in milk, saliva, and
sweat.
Streptomycin is excreted by glomerular filtration. In patients with normal
kidney function, between 29% and 89% of a single 600 mg dose is excreted in the
urine within 24 hours. Any reduction of glomerular function results in decreased
excretion of the drug and concurrent rise in serum and tissue levels.
Microbiology
Streptomycin sulfate is a bactericidal antibiotic. It acts by interfering with
normal protein synthesis.
Streptomycin has been shown to be active against most strains of the following
organisms both In Vitro and in clinical infection. (See INDICATIONS AND USAGE.):
Brucella (brucellosis),
Calymmatobacterium Granulomatis (donovanosis, granuloma inguinale),
Escherichia Coli, Proteus Spp., Aerobacter Aerogenes, Klebsiella Pneumoniae, and
Enterococcus Faecalis in urinary tract infections,
Francisella Tularensis,
Haemophilus Ducreyi (chancroid),
Haemophilus Influenzae (in respiratory, endocardial, and meningeal infections- -
concomitantly with another antibacterial agent),
Klebsiella Pneumoniae pneumonia (concomitantly with another antibacterial
agent),
Mycobacterium Tuberculosis,
Pasteurella Pestis
Streptococcus viridans, Enterococcus Faecalis (in endocardial infections--
concomitantly with penicillin).
SUSCEPTIBILITY TESTS: Diffusion Techniques
Quantitative methods that require measurement of zone diameters give the most
precise estimate of the susceptibility of bacteria to antimicrobial agents. One
such standard procedure1 which has been recommended for use with disks to test
susceptibility of organisms to streptomycin uses the 10 mcg streptomycin disk.
Interpretation involves the correlation of the diameter obtained in the disk
test with the minimum inhibitory concentration (MIC) for streptomycin.
Reports from the laboratory giving results of the standard single disk
susceptibility test with a 10 mcg streptomycin disk should be interpreted
according to the following criteria:
Zone Diameter (mm) Interpretation
>/=15 (S) Susceptible
11-12 (I) Intermediate
=10 (R) Resistant
A report of "Susceptible" indicates that the pathogen is likely to respond to
monotherapy with streptomycin. A report of "Intermediate" indicates that the
result be considered equivocal, and, if the organism is not fully susceptible to
alternative clinically feasible drugs, the test should be repeated. This
category provides a buffer zone which prevents small uncontrolled technical
factors from causing major discrepancies in interpretations. A report of
"Resistant" indicates that achievable drug concentrations are unlikely to be
inhibitory and other therapy should be selected.
Standardized procedures require the use of laboratory control organisms. The 10
mcg streptomycin disk should give the following zone diameter:
Organism Zone diameter (mm)
E. Coli ATCC 25922 12-20
S. Aureus ATCC 25923 14-22
Methods Section:
Two standardized In Vitro susceptibility methods are available for testing
streptomycin against Mycobacterium Tuberculosis organisms. The agar proportion
method (CDC or NCCLS M24-P) utilizes middlebrook 7H10 medium impregnated with
streptomycin at two final concentrations, 2.0 and 10.0 mcg/mL. MIC90 values are
calculated by comparing the quantity of organisms growing in the medium
containing drug to the control cultures. Mycobacterial growth in the presence of
drug >/= 1% of the control indicates resistance.
The radiometric broth method employs the BACTEC 460 machine to compare the
growth index from untreated control cultures to cultures grown in the presence
of 6.0 mcg/mL of streptomycin. Strict adherence to the manufacturer's
instructions for sample processing and data interpretation is required for this
assay.
Susceptibility test results obtained by these two different methods cannot be
compared unless equivalent drug concentrations are evaluated.
The clinical relevance of In Vitro susceptibility test results for mycobacterial
species other than M. Tuberculosis using either the BACTEC or the proportion
method has not been determined.
INDICATIONS AND USAGE:
Streptomycin is indicated for the treatment of individuals with moderate to
severe infections caused by susceptible strains of microorganisms in the
specific conditions listed below:
1. Mycobacterium tuberculosis: The Advisory Council for the Elimination of
Tuberculosis, the American Thoracic Society, and the Center for Disease Control
recommend that either streptomycin or ethambutol be added as a fourth drug in a
regimen containing isoniazid (INH), rifampin and pyrazinamide for initial
treatment of tuberculosis unless the likelihood of INH or rifampin resistance is
very low. The need for a fourth drug should be reassessed when the results of
susceptibility testing are known. In the past when the national rate of primary
drug resistance to isoniazid was known to be less than 4% and was either stable
or declining, therapy with two and three drug regimens was considered adequate.
If community rates of INH resistance are currently less than 4%, an initial
treatment regimen with less than four drugs may be considered.
Streptomycin is also indicated for therapy of tuberculosis when one or more of
the above drugs is contraindicated because of toxicity or intolerance. The
management of tuberculosis has become more complex as a consequence of
increasing rates of drug resistance and concomitant HIV infection. Additional
consultation from experts in the treatment of tuberculosis may be desirable in
those settings.
2. Non-tuberculosis infections: The use of streptomycin should be limited to the
treatment of infections caused by bacteria which have been shown to be
susceptible to the antibacterial effects of streptomycin and which are not
amenable to therapy with less potentially toxic agents.
a. Pasteurella Pestis (plague),
b. Francisella Tularensis (tularemia),
c. Brucella,
d. Calymmatobacterium Granulomatis (donovanosis, granuloma inguinale),
e. H. Ducreyi (chancroid),
f. H. Influenzae (in respiratory, endocardial, and meningeal infections--
concomitantly with another antibacterial agent),
g. K. Pneumoniae pneumonia (concomitantly with another antibacterial agent),
h. E. Coli, Proteus, A. Aerogenes, K. Pneumoniae, and Enterococcus Faecalis in
urinary tract infections,
i. Streptococcus viridans, Enterococcus Faecalis (in endocardial infections--
concomitantly with penicillin),
j. Gram-negative bacillary bacteremia (concomitantly with another antibacterial
agent).
CONTRAINDICATIONS:
A history of clinically significant hypersensitivity to streptomycin is a
contraindication to its use. Clinically significant hypersensitivity to other
aminoglycosides may contraindicate the use of streptomycin because of the known
cross- sensitivity of patients to drugs in this class.
WARNINGS:
WARNINGS
THE RISK OF SEVERE NEUROTOXIC REACTIONS IS
SHARPLY INCREASED IN PATIENTS WITH IMPAIRED
RENAL FUNCTION OR PRE-RENAL AZOTEMIA. THESE
INCLUDE DISTURBANCES OF VESTIBULAR AND
COCHLEAR FUNCTION. OPTIC NERVE DYSFUNCTION,
PERIPHERAL NEURITIS, ARACHNOIDITIS, AND
ENCEPHALOPATHY MAY ALSO OCCUR. THE
INCIDENCE OF CLINICALLY DETECTABLE,
IRREVERSIBLE VESTIBULAR DAMAGE IS
PARTICULARLY HIGH IN PATIENTS TREATED WITH
STREPTOMYCIN.
RENAL FUNCTION SHOULD BE MONITORED
CAREFULLY; PATIENTS WITH RENAL IMPAIRMENT
AND/OR NITROGEN RETENTION SHOULD RECEIVE
REDUCED DOSAGES. THE PEAK SERUM
CONCENTRATION IN INDIVIDUALS WITH KIDNEY
DAMAGE SHOULD NOT EXCEED 20 TO 25 MCG/ML.
THE CONCURRENT OR SEQUENTIAL USE OF OTHER
NEUROTOXIC AND/OR NEPHROTOXIC DRUGS WITH
STREPTOMYCIN SULFATE, INCLUDING NEOMYCIN,
KANAMYCIN, GENTAMICIN, CEPHALORIDINE,
PAROMOMYCIN, VIOMYCIN, POLYMYXIN B,
COLISTIN, TOBRAMYCIN AND CYCLOSPORINE
SHOULD BE AVOIDED.
THE NEUROTOXICITY OF STREPTOMYCIN CAN
RESULT IN RESPIRATORY PARALYSIS FROM
NEUROMUSCULAR BLOCKAGE, ESPECIALLY WHEN THE
DRUG IS GIVEN SOON AFTER THE USE OF
ANESTHESIA OR OF MUSCLE RELAXANTS.
THE ADMINISTRATION OF STREPTOMYCIN IN
PARENTERAL FORM SHOULD BE RESERVED FOR
PATIENTS WHERE ADEQUATE LABORATORY AND
AUDIOMETRIC TESTING FACILITIES ARE
AVAILABLE DURING THERAPY.
Ototoxicity: Both vestibular and auditory dysfunction can follow the
administration of streptomycin. The degree of impairment is directly
proportional to the dose and duration of streptomycin administration, to the age
of the patient, to the level of renal function and to the amount of underlying
existing auditory dysfunction. The ototoxic effects of the aminoglycosides,
including streptomycin, are potentiated by the co-administration of ethacrynic
acid, mannitol, furosemide and possibly other diuretics.
The vestibulotoxic potential of streptomycin exceeds that of its capacity for
cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting
and disequilibrium. Early cochlear injury is demonstrated by the loss of high
frequency hearing. Appropriate monitoring and early discontinuation of the drug
may permit recovery prior to irreversible damage to the sensorineural cells.
Sulfites: Streptomycin contains sodium metabisulfite, a sulfite that may cause
allergic type reactions including anaphylactic symptoms and life-threatening or
less severe asthmatic episodes in certain susceptible people. The over- all
prevalence of sulfite sensitivity in the general population is unknown and
probably low. Sulfite sensitivity is seen more frequently in asthmatic than in
non-asthmatic people.
Pregnancy: Streptomycin can cause fetal harm when administered to a pregnant
woman. Because streptomycin readily crosses the placental barrier, caution in
use of the drug is important to prevent ototoxicity in the fetus. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus.
PRECAUTIONS:
General: Baseline and periodic caloric stimulation tests and audiometric tests
are advisable with extended streptomycin therapy. Tinnitus, roaring noises, or a
sense of fullness in the ears indicates need for audiometric examination or
termination of streptomycin therapy or both.
Care should be taken by individuals handling streptomycin for injection to avoid
skin sensitivity reactions. As with all intramuscular preparations, Streptomycin
Sulfate Injection should be injected well within the body of a relatively large
muscle and care should be taken to minimize the possibility of damage to
peripheral nerves. (See DOSAGE AND ADMINISTRATION.)
Extreme caution must be exercised in selecting a dosage regimen in the presence
of pre-existing renal insufficiency. In severely uremic patients a single dose
may produce high blood levels for several days and the cumulative effect may
produce ototoxic sequelae. When streptomycin must be given for prolonged periods
of time alkalinization of the urine may minimize or prevent renal irritation.
A syndrome of apparent central nervous system depression, characterized by
stupor and flaccidity, occasionally coma and deep respiratory depression, has
been reported in very young infants in whom streptomycin dosage had exceeded the
recommended limits. Thus, infants should not receive streptomycin in excess of
the recommended dosage.
In the treatment of venereal infections such as granuloma inguinale, and
chancroid, if concomitant syphilis is suspected, suitable laboratory procedures
such as a dark field examination should be performed before the start of
treatment, and monthly serologic tests should be done for at least four months.
As with other antibiotics, use of this drug may result in overgrowth of
nonsusceptible organisms, including fungi. If superinfection occurs, appropriate
therapy should be instituted.
Drug Interactions: The ototoxic effects of the aminoglycosides, including
streptomycin, are potentiated by the co-administration of ethacrynic acid,
furosemide, mannitol and possibly other diuretics.
Pregnancy: Category D: See WARNINGS section.
Nursing Mothers: Because of the potential for serious adverse reactions in
nursing infants from streptomycin, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use: (See DOSAGE AND ADMINISTRATION.)
DRUG INTERACTIONS:
The ototoxic effects of the aminoglycosides, including streptomycin, are
potentiated by the co-administration of ethacrynic acid, furosemide, mannitol
and possibly other diuretics.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following reactions are common: vestibular ototoxicity (nausea, vomiting,
and vertigo); paresthesia of face; rash; fever; urticaria; angioneurotic edema;
and eosinophilia.
The following reactions are less frequent: cochlear ototoxicity (deafness);
exfoliative dermatitis; anaphylaxis; azotemia; leukopenia; thrombocytopenia,
pancytopenia; hemolytic anemia; muscular weakness; and amblyopia.
Vestibular dysfunction resulting from the parenteral administration of
streptomycin is cumulatively related to the total daily dose. When 1.8 to 2
g/day are given, symptoms are likely to develop in the large percentage of
patients--especially in the elderly or patients with impaired renal function--
within four weeks. Therefore, it is recommended that caloric and audiometric
tests be done prior to, during, and following intensive therapy with
streptomycin in order to facilitate detection of any vestibular dysfunction
and/or impairment of hearing which may occur.
Vestibular symptoms generally appear early and usually are reversible with early
detection and cessation of streptomycin administration. Two to three months
after stopping the drug, gross vestibular symptoms usually disappear, except for
the relative inability to walk in total darkness or on very rough terrain.
Although streptomycin is the least nephrotoxic of the aminoglycosides,
nephrotoxicity does occur rarely.
Clinical judgment as to termination of therapy must be exercised when side
effects occur.
DOSAGE AND ADMINISTRATION:
Intramuscular Route Only
Adults: The preferred site is the upper outer quadrant of the buttock, (i.e.,
gluteus maximus), or the mid-lateral thigh.
Children: It is recommended that intramuscular injections be given preferably
in the mid-lateral muscles of the thigh. In infants and small children the
periphery of the upper outer quadrant of the gluteal region should be used only
when necessary, such as in burn patients, in order to minimize the possibility
of damage to the sciatic nerve.
The deltoid area should be used only if well developed such as in certain adults
and older children, and then only with caution to avoid radial nerve injury.
Intramuscular injections should not be made into the lower and mid-third of the
upper arm. As with all intramuscular injections, aspiration is necessary to help
avoid inadvertent injection into a blood vessel.
Injection sites should be alternated. As higher doses or more prolonged therapy
with streptomycin may be indicated for more severe or fulminating infections
(endocarditis, meningitis, etc.), the physician should always take adequate
measures to be immediately aware of any toxic signs or symptoms occurring in the
patient as a result of streptomycin therapy.
1. TUBERCULOSIS: The standard regimen for the treatment of drug susceptible
tuberculosis has been two months of INH, rifampin and pyrazinamide followed by
four months of INH and rifampin (patients with concomitant infection with
tuberculosis and HIV may require treatment for a longer period). When
streptomycin is added to this regimen because of suspected or proven drug
resistance (see INDICATIONS AND USAGE section), the recommended dosing for
streptomycin is as follows:
Daily Twice Weekly Thrice Weekly
Children 20-40 mg/kg 25-30 mg/kg 25-30 mg/kg
Max 1 g Max 1.5 g Max 1.5 g
Adults 15 mg/kg 25-30 mg/kg 25-30 mg/kg
Max 1 g Max 1.5 g Max 1.5 g
Streptomycin is usually administered daily as a single intramuscular injection.
A total dose of not more than 120 g over the course of therapy should be given
unless there are no other therapeutic options. In patients older than 60 years
of age the drug should be used at a reduced dosage due to the risk of increased
toxicity. (See BOXED WARNING.)
Therapy with streptomycin may be terminated when toxic symptoms have appeared,
when impending toxicity is feared, when organisms become resistant, or when full
treatment effect has been obtained. The total period of drug treatment of
tuberculosis is a minimum of 1 year; however, indications for terminating
therapy with streptomycin may occur at any time as noted above.
2. TULAREMIA: One to 2 g daily in divided doses for 7 to 14 days until the
patient is afebrile for 5 to 7 days.
3. PLAGUE: Two grams of streptomycin daily in two divided doses should be
administered intramuscularly. A minimum of 10 days of therapy is recommended.
4. BACTERIAL ENDOCARDITIS:
a. Streptococcal Endocarditis: In penicillin- sensitive alpha and non-
hemolytic streptococcal endocarditis (penicillin MIC=0.1 mcg/mL),
streptomycin may be used for 2-week treatment concomitantly with penicillin.
The streptomycin regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d.
for the second week. If the patient is over 60 years of age, the dosage
should be 500 mg b.i.d. for the entire 2-week period.
b. Enterococcal Endocarditis: Streptomycin in doses of 1 g b.i.d. for 2 weeks
and 500 mg b.i.d. for an additional 4 weeks is given in combination with
penicillin. Ototoxicity may require termination of the streptomycin prior to
completion of the 6-week course of treatment.
5. CONCOMITANT USE WITH OTHER AGENTS: For concomitant use with other agents to
which the infecting organism is also sensitive: Streptomycin is considered a
second-line agent for the treatment of gram-negative bacillary bacteremia,
meningitis, and pneumonia; brucellosis; granuloma inguinale; chancroid, and
urinary tract infection.
For adults: 1 to 2 grams in divided doses every six to twelve hours for
moderate to severe infections. Doses should generally not exceed 2 grams per
day.
For children: 20 to 40 mg/kg/day (8 to 20 mg/lb/day) in divided doses every 6
to 12 hours. (Particular care should be taken to avoid excessive dosage in
children.)
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
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