Synthomycin

Uses

Synthomycin is used for the treatment of individuals with moderate to severe infections caused by susceptible strains of microorganisms in the specific conditions listed below:

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. Synthomycin is also used for therapy of tuberculosis when one or more of the above drugs is contraused 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.

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.

• Pasteurella pestis (plague)
• Francisella tularensis (tularemia)
• Brucella
• Calymmatobacterium granulomatis (donovanosis, granuloma inguinale)
• H. ducreyi (chancroid)
• H. influenzae (in respiratory, endocardial, and meningeal infections - concomitantly with another antibacterial agent)
• K. pneumoniae pneumonia (concomitantly with another antibacterial agent)
• E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections
• Streptococcus viridans, Enterococcus faecalis (in endocardial infections - concomitantly with penicillin)
• Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of streptomycin and other antibacterial drugs, streptomycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy

Synthomycin is also used to associated treatment for these conditions: Bacteremia, Bacterial Infections caused by susceptible bacteria, Chancroid, Disseminated mycobacterium avium complex infection, Flu caused by Influenza, Granuloma Inguinale, Menière's Disease, Mycobacterium avium complex infection, Mycobacterium kansasii infection, Mycobacterium marinum infection, Plague, Pneumonia, Tuberculosis (TB), Tularemia, Urinary Tract Infection

How Synthomycin works

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry.

The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane. Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified.

Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model.

Inhibition of protein synthesis is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, elongation, and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation. Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.

Dosage

Synthomycin dosage

Tularaemia:

• Adult: 1-2 g daily in divided doses for 7-14 days until the patient is afebrile for 5-7 days.
• Child: 15 mg/kg bid for at least 10-14 days. Max: 2 g daily

Bacterial endocarditis:

• Adult: Streptococcal endocarditis: 1 g bid for 1 wk, then 500 mg bid for the 2nd wk. Enterococcal endocarditis: 1 g bid for 2 wk then 500 mg bid for an additional 4 wk. Doses are given in combination with penicillin.
• Child: Enterococcal endocarditis: 20-30 mg/kg daily in 2 divided doses, in combination w/ penicillin.
• Elderly: Streptococcal endocarditis: >60 yr 500 mg bid for the entire 2 wk period.

Tuberculosis:

• Adult: 15 mg/kg as a single dose daily. Max: 1 g daily. As part of intermittent regimen: 25-30 mg/kg 2-3 times wkly. Max: 1.5 g/dose.
• Child: 20-40 mg/kg as a single dose daily. Max: 1 g daily. As part of intermittent regimen: 25-30 mg/kg 2-3 times wkly. Max: 1.5 g/dose.
• Elderly: >40 yr Max: 500-750 mg daily.

Plague:

• Adult: 2 g daily in 2 divided doses for a minimum of 10 days.
• Child: 30 mg/kg daily in 2-3 divided doses. Max: 2 g daily.

Bacteraemia, Brucellosis, Meningitis, Pneumonia, Urinary tract infections:

• Adult: For concomitant use with other agents and as 2nd line agent: 1-2 g daily in divided doses 6-12 hrly. Max: 2 g daily.
• Child: 20-40 mg/kg daily in divided doses 6-12 hrly.

Add 4.2 mL, 3.2 mL, or 1.8 mL of sterile water for inj to prepare a soln containing approx 200 mg, 250 mg, or 400 mg, respectively, of streptomycin per mL.

Side Effects

Neurotoxic reactions (e.g. vestibular and cochlear function disturbance, optic nerve dysfunction, peripheral neuritis, arachnoiditis, encephalopathy); paraesthesia of face, rash, fever, angioneurotic oedema, eosinophilia; exfoliative dermatitis, azotemia, leucopenia, thrombocytopenia, pancytopenia, haemolytic anaemia, muscular weakness, amblyopia.

Toxicity

The most common symptoms of streptomycin overdose are ototoxicity and vestibular impairment. Synthomycin is also associated with nephrotoxicity which presents as mild elevations in blood urea, mild proteinuria, and excess cellular excretion. While in severe cases, streptomycin may lead to permanent hearing loss and vestibular dysfunction, any associated nephrotoxicity is typically transient. In cases of toxicity, streptomycin serum concentrations may be lowered with dialysis.

Precaution

Patient with neuromuscular disorders (e.g. myasthenia gravis), pre-existing vertigo, or hearing loss. Renal impairment. Elderly, childn. Pregnancy and lactation.

Interaction

Additive neurotoxic and nephrotoxic effect with neomycin, kanamycin, gentamicin, cefaloridine, paronomycin, viomycin, polymyxin B, colistin, tobramycin, and ciclosporin. Enhanced ototoxic and nephrotoxic effect with ethacrynic acid, mannitol, furosemide and possibly other diuretics. May enhance the resp depressant effect of neuromuscular blockers. Increased risk of nephrotoxicity with cephalosporins. Reduced excretion with NSAIDs.

Food Interaction

Synthomycin Drug Interaction

Moderate: aspirin, ceftriaxoneUnknown: amoxicillin, sulfamethoxazole / trimethoprim, calcium / vitamin d, ciprofloxacin, albuterol / ipratropium, sulfamethoxazole / trimethoprim, multivitamin with minerals, acetaminophen, procaine penicillin, valproic acid, thiamine, cyanocobalamin, riboflavin, pyridoxine, ascorbic acid, cholecalciferol, phytonadione, levalbuterol

Synthomycin Disease Interaction

Major: dehydration, neuromuscular blockade, ototoxicity, renal dysfunction

Elimination Route

Due to poor oral absorption, aminoglycosides including streptomycin are administered parenterally. Synthomycin is available as an intramuscular injection, and in some cases may be administered intravenously. A peak serum concentration of 25-50 mcg/mL is achieved within 1 hour after intramuscular administration of 1 gram of streptomycin.

Half Life

Synthomycins serum half-life is estimated to be 2.5 hours.

Elimination Route

Approximately 50% of streptomycin is eliminated in the urine within 24 hours after intravenous or intramuscular administration.

Pregnancy & Breastfeeding use

Synthomycin 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.

Contraindication

Hypersensitivity to streptomycin and other aminoglycosides.

Special Warning

Renal Impairment: Dosage adjustment needed.

Storage Condition

Store between 15-30°C. Protect from light.

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