Monograph of Streptomycin

Introduction/Overview

Streptomycin, a member of the aminoglycoside class, is a naturally occurring antibiotic derived from the soil bacterium Streptomyces griseus. It was the first antibiotic discovered that could effectively treat tuberculosis in humans, profoundly influencing infectious disease management. Over the decades, its therapeutic profile has evolved, encompassing a range of Gram‑negative infections and certain Gram‑positive pathogens susceptible to aminoglycosides. The continued relevance of streptomycin lies in its activity against resistant organisms, its role in combination regimens for mycobacterial diseases, and its utility in veterinary medicine.

Learning objectives for this chapter include:

• Describe the chemical nature and classification of streptomycin.
• Explain the pharmacodynamic mechanisms underlying its antibacterial activity.
• Summarize the pharmacokinetic parameters influencing dosing strategies.
• Identify approved therapeutic indications and common off‑label uses.
• Recognize major adverse effects, drug interactions, and special population considerations.

Classification

Drug Class and Chemical Category

Streptomycin belongs to the aminoglycoside antibiotic family, characterized by amino-modified sugars linked via glycosidic bonds. It is specifically classified as a 3‑deoxy‑6‑ketoaminocyclitol derivative, possessing a tricyclic structure with multiple amino groups. The drug is typically administered in the form of streptomycin sulfate, which enhances solubility and facilitates parenteral administration.

Structural Features Relevant to Activity

The presence of three amino groups and a hydroxyl group confers a net positive charge at physiological pH, enabling interaction with the negatively charged bacterial ribosomal RNA. The cyclitol backbone is essential for ribosomal binding and for the stabilization of the drug–ribosome complex. These structural attributes differentiate streptomycin from other aminoglycoside derivatives, such as gentamicin or amikacin, influencing both spectrum of activity and toxicity profile.

Mechanism of Action

Pharmacodynamic Overview

Streptomycin targets the bacterial 30S ribosomal subunit, binding to the 16S rRNA component of the 30S subunit. This binding induces a conformational change that interferes with the initiation complex formation, causing misreading of messenger RNA. Consequently, the synthesis of functional proteins is disrupted, leading to bactericidal effects. The drug demonstrates concentration‑dependent killing; peak concentrations relative to the minimum inhibitory concentration (MIC) correlate with therapeutic efficacy.

Receptor Interactions and Molecular Pathways

At the molecular level, streptomycin interacts primarily with residues A1492 and A1493 of the 16S rRNA. These interactions hinder accurate base pairing during translocation, effectively producing a “mistranslation” cascade. The misfolded proteins accumulate, compromising membrane integrity and cellular function. Additionally, streptomycin may interfere with the 50S subunit’s peptidyl transferase activity, further diminishing protein synthesis. The bactericidal effect is thus a composite of translational inhibition and downstream cellular dysfunction.

Cellular Mechanisms of Bactericidal Activity

Once internalized, streptomycin accumulates in bacterial cytoplasm, where it exerts its action. The drug’s positive charge facilitates uptake through the bacterial membrane via energy‑dependent transport mechanisms, including the proton motive force. In the cytosol, streptomycin induces a cascade of events: ribosomal stalling, production of misfolded proteins, oxidative stress, and eventual cell death. The time dependence of bacterial killing is minimal compared with other aminoglycosides; therefore, optimal exposure is achieved by maximizing peak concentration rather than maintaining prolonged exposure.

Pharmacokinetics

Absorption

Oral administration of streptomycin is associated with poor bioavailability, typically <10 %. Because of extensive first‑pass metabolism and limited gastrointestinal uptake, parenteral routes (intramuscular or intravenous) are preferred. Intramuscular injection results in a C_max of approximately 30–50 µg/mL within 30 minutes, whereas intravenous infusion achieves higher peak levels more rapidly.

Distribution

Streptomycin displays a volume of distribution (V_d) of roughly 0.3–0.5 L/kg, indicating limited tissue penetration. Distribution is primarily confined to extracellular fluid compartments. The drug penetrates well into sites such as the lungs, lymph nodes, and cerebrospinal fluid when administered intrathecally, but penetration into adipose tissue is minimal. Protein binding is low, around 10 %, allowing rapid clearance from plasma.

Metabolism

Streptomycin undergoes negligible hepatic metabolism, with the majority of the drug remaining unchanged. Minor oxidative pathways in the liver contribute to less than 2 % of the administered dose. Consequently, hepatic impairment has a limited effect on systemic exposure, though monitoring remains prudent in severe hepatic dysfunction.

Excretion

Renal excretion constitutes the principal elimination route, with a clearance (Cl) of approximately 0.6 L/h/kg. The drug is predominantly eliminated unchanged via glomerular filtration. The elimination half‑life (t_1/2) varies from 2.5 h in patients with normal renal function to >10 h in those with severe renal impairment. Dose adjustments are therefore essential in patients with reduced creatinine clearance to avoid accumulation and toxicity.

Dosing Considerations

Standard dosing for adult patients with adequate renal function is often 15–20 mg/kg/day divided into 3–4 equal doses. For tuberculosis therapy, a typical regimen involves 15 mg/kg/day administered intramuscularly for 2–4 weeks, followed by a continuation phase with a different antibiotic. In patients with reduced renal clearance, dosing intervals may be extended, or total daily dose may be reduced by 50‑75 %, depending on the severity of impairment. Monitoring of serum concentrations at steady state can guide individualized adjustments, particularly in prolonged therapy.

Therapeutic Uses/Clinical Applications

Approved Indications

Streptomycin is formally indicated for the treatment of multidrug‑resistant tuberculosis (MDR‑TB) when other agents are ineffective or unavailable. It is also employed in combination regimens for certain forms of leprosy, specifically in patients who exhibit resistance to first‑line agents. Veterinary indications include the treatment of respiratory infections in dogs and cats, especially those caused by Pasteurella species.

Off‑Label Uses

Clinicians sometimes prescribe streptomycin for infections caused by susceptible Gram‑negative bacilli such as Pseudomonas aeruginosa or Haemophilus influenzae, particularly in patients who have demonstrated intolerance or resistance to other aminoglycosides. Additionally, streptomycin has been used experimentally in combination with fluoroquinolones for complicated urinary tract infections, though evidence remains limited. Off‑label use is generally guided by susceptibility testing and careful risk–benefit assessment.

Adverse Effects

Common Side Effects

Patients may experience gastrointestinal disturbances, including nausea, vomiting, and diarrhea. These symptoms are usually mild and transient. Minor alterations in taste perception and metallic taste in the oral cavity have also been reported. Local reactions at the injection site, such as pain, swelling, or erythema, can occur with intramuscular administration.

Serious or Rare Adverse Reactions

Nephrotoxicity is the most significant dose‑dependent toxicity. It manifests as acute tubular necrosis, characterized by a rise in serum creatinine and reduced glomerular filtration. Ototoxicity, presenting as reversible or irreversible sensorineural hearing loss, is another major concern. Vestibular toxicity may lead to vertigo or balance disturbances. These effects are more likely in patients receiving high peak concentrations, prolonged therapy, or concurrent nephrotoxic agents.

Black Box Warnings

Regulatory authorities have issued a black box warning for streptomycin, emphasizing the risk of irreversible hearing loss and severe renal damage. Patients and prescribers are advised to monitor renal function and auditory thresholds regularly during therapy. Dose adjustments and alternative agents should be considered if baseline or emerging toxicity is detected.

Drug Interactions

Major Drug‑Drug Interactions

Concurrent administration of other nephrotoxic drugs, such as amphotericin B, cisplatin, or non‑steroidal anti‑inflammatory drugs, may amplify the risk of renal injury. Ototoxic compounds, including loop diuretics (furosemide) and certain chemotherapeutic agents (e.g., cisplatin), can synergistically elevate the potential for auditory damage. Additionally, drugs that alter the proton motive force or interfere with renal tubular secretion (e.g., cimetidine) may increase serum concentrations of streptomycin, thereby heightening toxicity.

Contraindications

Absolute contraindications include known hypersensitivity to any aminoglycoside. Relative contraindications involve pre‑existing renal insufficiency, hearing impairment, or vestibular dysfunction, as the addition of streptomycin could exacerbate these conditions. A thorough assessment of patient history and renal function is recommended before initiation.

Special Considerations

Use in Pregnancy and Lactation

Streptomycin is classified as pregnancy category C. While animal studies have not demonstrated teratogenicity, limited human data exist. Infections that pose a greater risk to maternal or fetal health may justify use under close supervision, with careful monitoring of fetal development. The drug is excreted into breast milk; therefore, breastfeeding is generally discouraged during therapy, pending evaluation of infant exposure risks.

Pediatric and Geriatric Considerations

In pediatric patients, dosing is weight‑based, and renal function is often better preserved. However, children are more susceptible to ototoxicity; thus, auditory monitoring is essential. Geriatric patients commonly exhibit reduced renal clearance and pre‑existing hearing deficits, increasing vulnerability to adverse effects. Adjusted dosing intervals and vigilant monitoring are advised in this population.

Renal and Hepatic Impairment

In patients with impaired renal function, dose adjustments are critical to avoid accumulation. A common approach is to extend dosing intervals proportionally to the decline in creatinine clearance. Hepatic impairment has a minimal impact on streptomycin pharmacokinetics; nevertheless, cautious use is warranted if severe hepatic dysfunction is present, as concomitant medications may alter overall drug exposure.

Summary/Key Points

• Streptomycin is an aminoglycoside antibiotic effective against MDR‑TB and certain Gram‑negative infections.
• Its bactericidal action results from interference with bacterial ribosomal protein synthesis, predominantly on the 30S subunit.
• Parenteral routes are preferred; oral absorption is negligible.
• Renal excretion dictates dosing; impaired renal function necessitates interval extensions or dose reduction.
• Nephrotoxicity and ototoxicity are major adverse effects; regular monitoring of renal function and auditory thresholds is essential.
• Drug interactions with other nephrotoxic or ototoxic agents can potentiate toxicity.
• Use in pregnancy, lactation, and special populations requires individualized risk–benefit evaluation and close surveillance.

Clinical pearls for practitioners include the importance of therapeutic drug monitoring, especially in prolonged treatment courses; the necessity of baseline and periodic audiometric testing; and the prudent selection of streptomycin in the context of patient comorbidities and concomitant medication profiles.

References

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7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.