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Streptomycin Sulfate

Streptomycin is an aminoglycoside antibiotic and antituberculosis agent.

Uses

Tuberculosis

Active Tuberculosis

Streptomycin is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.

These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months). Streptomycin is considered a second-line antituberculosis agent for use in these regimens.

Although streptomycin can be as effective as ethambutol when used in the initial phase of antituberculosis treatment and was previously included in recommendations for this phase of treatment, resistance to streptomycin has been reported with increasing frequency worldwide, which makes the drug less useful. Therefore, the ATS, CDC, and IDSA state that streptomycin is no longer recommended as being interchangeable with ethambutol unless the strain is known to be susceptible to the drug or the patient is from a population in which streptomycin resistance is unlikely.

Streptomycin can be is used in the treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis if the strain is susceptible to the drug. If streptomycin is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant tuberculosis, at least 2, preferably 3, new drugs known or expected to be active against the resistant strain should be added at the same time.

After results of in vitro susceptibility testing are available, the regimen can be adjusted accordingly. Cross resistance does not occur between streptomycin and amikacin, kanamycin, or capreomycin.

Other Mycobacterial Infections

Streptomycin also has been used in conjunction with other antituberculosis agents in the treatment of other mycobacterial diseases including infections caused by Mycobacterium kansasii.

Enterococcal and Streptococcal Infections

Most strains of enterococci are resistant to streptomycin alone, and penicillin therapy alone is usually inadequate in infections caused by these organisms.

However, because antibacterial activity may be additive or synergistic, streptomycin used concomitantly with penicillin G or ampicillin is often effective in the treatment of enterococcal endocarditis. Streptomycin-resistant strains of enterococci that do not demonstrate a synergistic effect in vitro with penicillins have been reported with increasing frequency.

However, the clinical importance of in vitro enterococcal resistance to streptomycin in the treatment of endocarditis has not been conclusively determined to date. Further study is needed to compare safety and efficacy of streptomycin versus other aminoglycosides when used in conjunction with penicillins for the treatment of enterococcal endocarditis.

Although the efficacy of concomitant therapy as compared to penicillin therapy has not been definitely established, streptomycin is also used concomitantly with penicillin G or ampicillin in the treatment of streptococcal (viridans group) endocarditis.

Urinary Tract Infections

Streptomycin is used alone or concomitantly with other anti-infective agents in the treatment of urinary tract infections caused by Escherichia coli, Proteus, Klebsiella, Enterobacter, or Enterococcus faecalis (formerly Streptococcus faecalis); gram-negative bacillary bacteremia, respiratory tract infections, meningitis, or endocarditis caused by Haemophilus influenzae; or pneumonia caused by Klebsiella pneumoniae. However, streptomycin should be used in these infections only when the causative organism is susceptible and when other aminoglycosides or other appropriate anti-infectives are ineffective or contraindicated.

Plague

Streptomycin is used for the treatment of plague caused by Yersinia pestis. Streptomycin generally has been considered the drug of choice for the treatment of plague; however, gentamicin also is considered a drug of choice since it may be as effective and is more readily available than streptomycin.

Alternative drugs recommended when aminoglycosides are not used include doxycycline (or tetracycline), chloramphenicol, or co-trimoxazole (may be less effective than other alternatives).

Based on results of in vitro and animal testing, ciprofloxacin (or other fluoroquinolones) also is recommended as an alternative for the treatment of plague. Chloramphenicol generally is considered the drug of choice for the treatment of plague meningitis.

Anti-infective regimens recommended for the treatment of naturally occurring or endemic bubonic, septicemic, or pneumonic plague also are recommended for the treatment of plague that occurs following exposure to Y. pestis in the context of biologic warfare or bioterrorism. These exposures would most likely result in primary pneumonic plague.

Prompt initiation of anti-infective therapy (within 18-24 hours of onset of symptoms) is essential in the treatment of pneumonic plague. Some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that treatment of plague in the context of biologic warfare or bioterrorism should be initiated with a parenteral anti-infective regimen of streptomycin (or gentamicin) or, alternatively, doxycycline, ciprofloxacin, or chloramphenicol, although an oral regimen (doxycycline, ciprofloxacin) may be substituted when the patient’s condition improves or if parenteral therapy is unavailable.

Postexposure prophylaxis with anti-infectives is recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague or laboratory exposure to viable Y. pestis. In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that asymptomatic individuals with exposure to plague aerosol or asymptomatic individuals with household, hospital, or other close contact (within about 2 m) with an individual who has pneumonic plague should receive postexposure anti-infective prophylaxis; however, any exposed individual who develops a temperature of 38.°C or higher or new cough should promptly receive a parenteral anti-infective for treatment of the disease. An oral regimen of doxycycline or ciprofloxacin usually is recommended for such prophylaxis.

Tularemia

Streptomycin is used in the treatment of tularemia caused by Francisella tularensis, and generally is considered the drug of choice for this infection. However, gentamicin is more readily available and may be used as an alternative drug of choice when streptomycin is unavailable.

Other alternatives for the treatment of tularemia include tetracyclines (doxycycline), chloramphenicol, or ciprofloxacin. Anti-infective regimens recommended for the treatment of naturally occurring or endemic tularemia also are recommended for the treatment of tularemia that occurs following exposure to F. tularensis in the context of biologic warfare or bioterrorism.

However, the fact that a fully virulent streptomycin-resistant strain of F. tularensis was developed in the past for use in biologic warfare should be considered. Exposures to F. tularensis in the context of biologic warfare or bioterrorism would most likely result in inhalational tularemia with pleuropneumonitis, although the organism also can infect humans through the skin, mucous membranes, and GI tract.

Postexposure prophylaxis with anti-infectives usually is not recommended after possible exposure to natural or endemic tularemia (e.g., tick bite, rabbit or other animal exposure) and is unnecessary in close contacts of tularemia patients since human-to-human transmission of the disease is not known to occur.

However, postexposure prophylaxis is recommended following a high-risk laboratory exposure to F. tularensis (e.g., spill, centrifuge accident, needlestick injury). In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that asymptomatic individuals with exposure to F. tularensis receive postexposure anti-infective prophylaxis; however, any individual who develops an otherwise unexplained fever or flu-like illness within 14 days of presumed exposure should promptly receive a parenteral anti-infective for treatment of the disease.

Oral doxycycline (or oral tetracycline) or oral ciprofloxacin usually is recommended for postexposure prophylaxis following such exposures.

Brucellosis

Streptomycin is used in the treatment of brucellosis. Tetracyclines generally are considered the drugs of choice for the treatment of brucellosis; however, concomitant use of another anti-infective (e.g., streptomycin or gentamicin and/or rifampin) may reduce the likelihood of disease relapse and usually is recommended in serious infections or when there are complications such as meningitis, endocarditis, or osteomyelitis.

Some experts recommend a 3-drug regimen that includes a tetracycline, an aminoglycoside, and rifampin for the treatment of brucellosis in patients with meningoencephalitis or endocarditis. Although data are limited, alternative regimens that have been suggested for the treatment of brucellosis include co-trimoxazole with or without gentamicin (or streptomycin) or rifampin; ciprofloxacin (or ofloxacin) and rifampin; and chloramphenicol with or without streptomycin.

Postexposure prophylaxis with anti-infectives is not generally recommended after possible exposure to endemic brucellosis; however, use of an anti-infective regimen recommended for the treatment of brucellosis (e.g., doxycycline and rifampin) should be considered following a high-risk exposure to Brucella.

These high-risk exposures include needlestick injuries involving the brucella vaccine available for veterinary use (a brucella vaccine for use in humans is not available); inadvertent laboratory exposure to the organism; or confirmed exposure in the context of biologic warfare or bioterrorism.

Burkholderia Infections

Streptomycin used in conjunction with a tetracycline is considered a regimen of choice for the treatment of glanders caused by Burkholderia mallei (formerly Pseudomonas mallei). Alternative regimens recommended for the treatment of glanders include streptomycin used in conjunction with chloramphenicol or imipenem monotherapy.

Chancroid and Granuloma Inguinale (Donovanosis)

Streptomycin has been used in the treatment of chancroid caused by Haemophilus ducreyi and in the treatment of granuloma inguinale (Donovanosis) caused by Calymmatobacterium granulomatis; however, streptomycin is not included in current US Centers for Disease Control and Prevention (CDC) guidelines for the treatment of these sexually transmitted diseases.

Administration

Reconstitution and Administration

Streptomycin sulfate is administered by deep IM injection into a large muscle mass. To minimize irritation, injection sites should be alternated. Although the manufacturers state that streptomycin is for IM administration only, the drug reportedly has been administered by IV infusion through a peripheral or central IV catheter (e.g., 12-15 mg/kg in 100 mL of 0.9% sodium chloride injection over 30-60 minutes) without unusual adverse effects in patients who could not tolerate IM injections.

Streptomycin sulfate powder for injection is reconstituted by dissolving the drug with 4.2, 3.2, or 1.8 mL of sterile water for injection to prepare a solution containing approximately 200, 250, or 400 mg, respectively, of streptomycin per mL.

Dosage

Dosage of streptomycin sulfate is expressed in terms of streptomycin and should be based on an estimate of ideal body weight.

For the treatment of moderate to severe infections caused by susceptible organisms, the usual adult dosage of streptomycin is 1-2 g daily in divided doses every 6-12 hours. Dosage of streptomycin generally should not exceed 2 g per day.

Children may receive 20-40 mg/kg daily, given in divided doses every 6-12 hours. Particular care should be taken to avoid excessive dosage in children. Whenever possible, and especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of streptomycin should be monitored frequently and dosage adjusted to maintain desired serum concentrations.

A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for aminoglycoside dosing regimens. However, an increased risk of toxicity reportedly may be associated with prolonged peak streptomycin serum concentrations greater than 40-50 mcg/mL, and trough concentrations of the drug generally should not exceed 5 mcg/mL.

Active Tuberculosis

In the treatment of clinical tuberculosis, streptomycin is considered a second-line agent for use in multiple-drug regimens for the treatment of active tuberculosis. Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).

The manufacturer states that the usual adult dosage of streptomycin for the treatment of tuberculosis is 15 mg/kg (up to 1 g) daily and the usual pediatric dosage is 20-40 mg/kg (up to 1 g) daily.

When intermittent antituberculosis therapy is used, the manufacturer recommends a dosage of 25-30 mg/kg (up to 1.5 g) 2-3 times weekly in adults and children. In addition, the manufacturer states that the total dosage of streptomycin over a course of therapy should not exceed 120 g unless there are no therapeutic options.

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that the usual dosage of streptomycin for use in conjunction with other antituberculosis agents for the treatment of active tuberculosis in adults and children 15 years of age or older is 15 mg/kg daily (up to 1 g) given as a single daily dose (usually 750-1000 mg daily) 5-7 times weekly for the first 2-4 months or until culture conversion; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.

However, these experts recommend that adults older than 59 years of age receive a dosage of 10 mg/kg (up to 750 mg) daily.

The dosage of streptomycin recommended by the ATS, CDC, IDSA, and American Academy of Pediatrics (AAP) for the treatment of active tuberculosis in pediatric patients is 20-40 mg/kg daily (up to 1 g) given once daily.

The ATS, CDC, and IDSA state that pediatric patients also can receive streptomycin in an intermittent regimen using a dosage of 20 mg/kg twice weekly.

Enterococcal and Streptococcal Infections

For the treatment of penicillin-susceptible streptococcal (viridans group) endocarditis, streptomycin, in conjunction with a penicillin, may be administered in a dosage of 1 g twice daily for 1 week followed by 500 mg twice daily for 1 week.

Patients older than 60 years of age should receive 500 mg of streptomycin twice daily for 2 weeks in conjunction with a penicillin. For the treatment of enterococcal endocarditis, streptomycin, in conjunction with a penicillin, is administered in a dosage of 1 g twice daily for 2 weeks followed by 500 mg twice daily for 4 weeks. Ototoxicity may require termination of streptomycin prior to completion of the 6-week course of therapy.

Plague

For the treatment of plague, including pneumonic plague that occurs as the result of exposure to Yersinia pestis in the context of biologic warfare or bioterrorism, the recommended adult dosage of streptomycin is 1 g (15 mg/kg) IM twice daily and the usual dosage in children is 15 mg/kg IM twice daily (maximum 2 g daily).

The usual duration of therapy for the treatment of plague is 10 days; some experts recommend a duration of 10-14 days. Tularemia For the treatment of tularemia, the usual adult dosage of streptomycin is 1-2 g daily given in divided doses.

The manufacturer recommends that streptomycin be continued for 7-14 days and until the patient is afebrile for 5-7 days. For the treatment of tularemia that occurs as the result of exposure to Francisella tularensis in the context of biologic warfare or bioterrorism, the US Working Group on Civilian Biodefense recommends that adults receive streptomycin in a dosage of 1 g IM twice daily and that children receive 15 mg/kg IM twice daily (maximum 2 g daily) for 10 days; the US Army Medical Research Institute of Infectious Diseases recommends that adults receive 7.5-10 mg/kg IM twice daily for 10-14 days.

Brucellosis

When streptomycin is used for the treatment of brucellosis in conjunction with doxycycline or tetracycline, the usual adult dosage is 1 g IM once or twice daily during the first week of therapy and once daily for at least one additional week of therapy. When streptomycin is used for treatment of brucellosis in children older than 8 years of age, 20 mg/kg (up to 1 g) is given IM daily in 2 divided doses during the first 7-14 days of tetracycline or co-trimoxazole therapy.

Streptomycin Sulfate

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of streptomycin must be modified in response to serum concentrations of the drug and the degree of renal impairment.

The manufacturer states that peak serum concentrations of streptomycin should not exceed 20-25 mcg/mL in individuals with kidney damage. When serum streptomycin concentrations are not available, dosage may be based on creatinine clearance.

Some clinicians recommend an initial loading dose of 1 g. For subsequent therapy, patients with a creatinine clearance of 50-80 mL/minute should receive 7.5-mg/kg doses at intervals of 24 hours, patients with a creatinine clearance of 10-50 mL/minute should receive the same dose every 24-72 hours, and patients with a creatinine clearance of less than 10 mL/minute should receive the dose every 72-96 hours. In patients with renal failure undergoing hemodialysis, some clinicians recommend supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period.

However, serum concentrations of the drug should be monitored in dialysis patients and dosage should be adjusted to maintain desired serum concentrations.

Pharmacokinetics

The pharmacokinetics of streptomycin are similar to those of the other aminoglycosides. In all studies described in the Pharmacokinetics section, streptomycin was administered as the sulfate salt; dosages and concentrations of the drug are expressed in terms of streptomycin.

Absorption

Following IM administration of streptomycin in adults with normal renal function, peak plasma streptomycin concentrations are attained within 1-2 hours and are reported to range from 5-20 mcg/mL after a single 500-mg dose and from 25-50 mcg/mL after a single 1-g dose. In one study in premature infants, mean peak serum concentrations of about 29 mcg/mL were attained within 2 hours following IM administration of streptomycin 10-11 mg/kg; serum concentrations averaged 11 mcg/mL at 12 hours.

Distribution

Streptomycin is distributed into most body tissues and fluids except the brain. Substantial amounts of the drug reportedly are found in pleural fluid and tuberculous cavities, and small amounts are excreted in saliva and sweat. Streptomycin crosses the placenta; serum concentrations in cord blood reportedly are similar to maternal serum concentrations. Small amounts of streptomycin are distributed into milk.

Streptomycin Sulfate

Elimination

The plasma elimination half-life of streptomycin is usually 2-3 hours in adults with normal renal function and has been reported to range up to 110 hours in adults with severe renal impairment.

The plasma elimination half-life of streptomycin has been reported to range from 4-10 hours in premature and newborn infants. In patients with impaired hepatic and renal function, the plasma elimination half-life has been reported to be more prolonged than in patients with renal impairment alone. In adults with normal renal function, approximately 30-90% of a single 600-mg IM dose of streptomycin is excreted unchanged by glomerular filtration within 24 hours with the major portion being excreted within the first 12 hours.

Urine concentrations of streptomycin reach peak concentrations of 400 mcg/mL after a single 500-mg IM dose and 1 mg/mL or more following a single 1-g IM dose.

Chemistry and Stability

Chemistry

Streptomycin is an aminoglycoside antibiotic obtained from cultures of Streptomyces griseus. The drug is commercially available as the sulfate salt. Potency of streptomycin sulfate is expressed in terms of streptomycin.

Streptomycin sulfate occurs as a white or practically white, hygroscopic powder that is odorless or has not more than a faint odor. The drug is freely soluble in water and very slightly soluble in alcohol.

Streptomycin sulfate injection is commercially available as a sterile lyophilized powder for injection without preservatives (Pharma-Tek) and as a sterile solution of the drug in water for injection (Pfizer). Following reconstitution of the sterile powder with 4.2 mL of sterile water for injection, solutions of streptomycin sulfate containing 200 mg of streptomycin per mL have a pH of 4.5-7. The injection (Pfizer) has a pH of 5-8 and contains sodium citrate dihydrate, phenol, and sodium metabisulfite.

Stability

Streptomycin sulfate powder for injection should be stored at 15-30°C and protected from light. When stored as directed, the powder for injection is stable for at least 2 years following the date of manufacture.

The manufacturer states that sterile reconstituted solutions of streptomycin sulfate are stable for 1 week when stored at room temperature and protected from light; however, streptomycin sulfate powder for injection contains no preservatives and the possibility of microbial contamination of reconstituted solutions must be considered.

Commercially available streptomycin sulfate injection should be stored at 2-8°C. For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of streptomycin, see the Aminoglycosides General Statement 8:12.02.

Preparations

Streptomycin sulfate lyophilized powder for injection (Pharma-Tek) is commercially available through regular distribution channels. Clinicians interested in prescribing streptomycin sulfate injection (as the solution) for a labeled use (see Uses) in a new patient may obtain the drug directly from the manufacturer at no cost by contacting the Pfizer Streptomycin Program at Pfizer Pharmaceuticals Inc, 235 E. 42nd Street, New York, NY 10017 or (800) 254-4445. Pfizer also should be contacted regarding procedures for obtaining the injection (as the solution) for various unlabeled uses (e.g., Mycobacterium avium complex infections, Meniere’s disease). Streptomycin Sulfate Parenteral For injection 1 g Streptomycin Sulfate for Injection, Pharma-Tek Injection, for IM 400 mg (of streptomycin) per Streptomycin Sulfate Injection use only mL , (with phenol 0.25% and sodium metabisulfite) Pfizer

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