Monograph of Streptomycin

1. Introduction and Overview

Streptomycin, an aminoglycoside antibiotic discovered in the 1940s, remains a cornerstone in the treatment of certain severe bacterial infections. Its unique bactericidal activity, particularly against intracellular pathogens, has sustained its relevance in modern clinical practice, especially in resource‑limited settings and for infections refractory to first‑line agents. The pharmacological profile of streptomycin offers valuable educational insights into the interplay between drug structure, mechanism of action, pharmacokinetics, and clinical application.

Learning Objectives

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

2. Classification

2.1 Drug Class and Category

Streptomycin belongs to the aminoglycoside class of antibiotics, characterized by a tricyclic ring system and multiple amino sugar moieties. Within this class, it is classified as a first‑generation aminoglycoside, distinguished by its relative susceptibility to inactivation by bacterial enzymes compared with later generations.

2.2 Chemical Classification

Structurally, streptomycin is a glycosylated derivative of streptidine, comprising a 2,3‑diaminopropane moiety bound to a 1‑hydroxy‑3‑deoxy‑ribose and a 1‑amino‑1‑deoxy‑glucose component. The presence of multiple hydroxyl, amino, and amide functional groups confers high polarity and limits its lipophilicity, influencing its distribution and excretion profiles.

3. Mechanism of Action

3.1 Pharmacodynamic Overview

Streptomycin exerts bactericidal effects by binding to the 30S subunit of the bacterial ribosome. This interaction induces misreading of messenger RNA during translation, leading to the synthesis of aberrant proteins that compromise cellular integrity. The concentration of streptomycin required to inhibit growth (MIC) is typically in the low micromolar range for susceptible organisms.

3.2 Receptor Interactions

Binding occurs at the A site of the 30S subunit, adjacent to the decoding center. The drug’s amino groups form electrostatic interactions with the phosphate backbone of rRNA, while hydroxyl groups engage in hydrogen bonding with ribosomal proteins. These interactions stabilize a conformational state that prevents accurate codon‑anticodon pairing.

3.3 Molecular and Cellular Mechanisms

Upon attachment to the ribosome, streptomycin promotes the incorporation of incorrect amino acids into the nascent polypeptide chain. Consequences include premature termination, formation of nonfunctional proteins, and induction of the bacterial SOS response. The resulting cellular stress triggers membrane depolarization and loss of proton motive force, ultimately leading to cell death. The drug’s activity is concentration‑dependent; peak concentrations above the MIC are associated with enhanced killing, whereas sustained exposure may be required for slower‑growing organisms.

4. Pharmacokinetics

4.1 Absorption

Oral absorption of streptomycin is limited, with bioavailability reported at less than 10 %. Consequently, intravenous or intramuscular administration is preferred for therapeutic purposes. When administered intramuscularly, peak plasma concentrations (C_max) are achieved within 30–60 minutes, reflecting rapid release from the injection site.

4.2 Distribution

Streptomycin exhibits extensive volume of distribution (V_d ≈ 0.7 L/kg), attributable to its hydrophilic nature and limited protein binding (< 5 %). The drug penetrates well into most body fluids, including cerebrospinal fluid, aqueous humor, and synovial fluid, although penetration into lung alveolar lining fluid is modest. Tissue distribution is also influenced by the presence of active transporters in renal tubular cells.

4.3 Metabolism

Unlike many antibiotics, streptomycin undergoes negligible hepatic metabolism. It is predominantly excreted unchanged, with minimal biotransformation mediated by gut flora or phase II conjugation pathways.

4.4 Excretion

Renal clearance is the primary route of elimination. Glomerular filtration and active tubular secretion via organic cation transporters determine the overall clearance (Cl). In patients with normal renal function, the elimination half‑life (t_1/2) ranges from 2.5–3 hours. Reduced renal function lengthens t_1/2 proportionally, necessitating dose adjustment based on creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR).

4.5 Half‑Life and Dosing Considerations

Given its concentration‑dependent killing, once‑daily dosing maximizes peak concentrations while minimizing exposure to toxic thresholds. Typical dosing regimens involve 15–20 mg/kg/day divided into single or multiple administrations, adjusted for renal function. The relationship between dose, plasma concentration, and therapeutic effect can be approximated by the equation:

C_t = C₀ × e^-k_tt

where C_t is the concentration at time t, C₀ is the initial concentration, and k_t is the elimination rate constant. The area under the concentration‑time curve (AUC) is calculated as AUC = Dose ÷ Clearance, providing a useful metric for assessing cumulative exposure.

5. Therapeutic Uses and Clinical Applications

5.1 Approved Indications

Streptomycin is indicated primarily for the treatment of:

• Infections caused by susceptible strains of Mycobacterium tuberculosis, often in combination with other antitubercular agents.
• Severe infections due to Pseudomonas aeruginosa, particularly in burn patients and individuals with cystic fibrosis.
• Gram‑negative sepsis when other agents are contraindicated or ineffective.

5.2 Off‑Label Uses

Clinically, streptomycin is sometimes employed for:

• Intracellular bacterial infections such as Tularemia and Brucellosis.
• Treatment of certain fungal infections, including Candida species, when combined with other antifungals.
• Adjunctive therapy in septic shock or multi‑organ failure scenarios where broad spectrum coverage is required.

These off‑label applications are guided by susceptibility testing and clinical judgment.

6. Adverse Effects

6.1 Common Side Effects

Patients frequently experience ototoxicity, manifested as tinnitus, hearing loss, or vestibular disturbances. These effects are dose‑dependent and may progress to irreversible damage. Nephrotoxicity, characterized by elevated serum creatinine and decreased glomerular filtration, is also a recognized complication, particularly with prolonged or high‑dose therapy.

6.2 Serious or Rare Adverse Reactions

Serious reactions include anaphylactic hypersensitivity, manifested by urticaria, angioedema, and bronchospasm. Rare but notable adverse events encompass neurotoxicity, leading to paresthesia or muscle weakness, and ocular toxicity, presenting as retinal pigmentary changes.

6.3 Black Box Warnings

Given the potential for irreversible ototoxicity and nephrotoxicity, prescribing information includes a black box warning highlighting the importance of monitoring auditory function and renal parameters. Dose adjustments and therapeutic drug monitoring are recommended to mitigate these risks.

7. Drug Interactions

7.1 Major Drug‑Drug Interactions

Concomitant use of other nephrotoxic agents (e.g., amphotericin B, cisplatin) or ototoxic drugs (e.g., gentamicin, vancomycin) may synergistically increase the risk of renal impairment or hearing loss. Additionally, drugs that affect renal tubular secretion, such as loop diuretics or cimetidine, can alter streptomycin clearance, leading to elevated plasma concentrations.

7.2 Contraindications

Streptomycin is contraindicated in patients with known hypersensitivity to aminoglycosides. It is also generally avoided during pregnancy and lactation unless benefits outweigh risks, given the potential for ototoxicity in the fetus and infant. Use in patients with significant renal impairment is contraindicated without dose adjustment, as accumulation can precipitate toxicity.

8. Special Considerations

8.1 Use in Pregnancy and Lactation

Animal studies have indicated potential teratogenic effects, particularly on the auditory system of the fetus. Consequently, streptomycin should only be prescribed during pregnancy if alternative agents are unsuitable. Lactation may result in drug excretion into breast milk, posing a risk of auditory toxicity in nursing infants; thus, alternative therapies are preferred.

8.2 Pediatric and Geriatric Considerations

In children, the volume of distribution is larger, and renal clearance is higher, necessitating weight‑based dosing. Geriatric patients often exhibit reduced renal function and increased sensitivity to ototoxicity; dosing must be carefully adjusted and monitored.

8.3 Renal and Hepatic Impairment

Renal dysfunction prolongs t_1/2 and reduces clearance, requiring lower doses or extended dosing intervals. Hepatic impairment has minimal impact on streptomycin pharmacokinetics due to negligible metabolism, but monitoring for cumulative toxicity remains essential.

9. Summary and Key Points

• Streptomycin is a first‑generation aminoglycoside with potent bactericidal activity against intracellular and Gram‑negative bacteria.
• Its mechanism hinges on misreading of mRNA via binding to the 30S ribosomal subunit, leading to defective protein synthesis.
• High volume of distribution and renal elimination characterize its pharmacokinetic profile; dose adjustments are guided by renal function.
• Clinically, it is primarily used for tuberculosis, Pseudomonas infections, and certain intracellular bacterial diseases.
• Ototoxicity and nephrotoxicity remain the most significant adverse effects; monitoring of auditory and renal function is essential.
• Drug interactions with other nephrotoxic or ototoxic agents can amplify toxicity; careful selection of concomitant therapies is advised.
• Special populations—including pregnant women, lactating mothers, children, and the elderly—require individualized dosing and vigilant monitoring.

Clinical pearls for practitioners include: administering the drug as a single daily dose to maximize peak concentrations while minimizing exposure, performing baseline and periodic audiometry in patients at high risk for ototoxicity, and employing therapeutic drug monitoring in patients with fluctuating renal function. By integrating pharmacodynamic insights with pharmacokinetic principles, clinicians can optimize streptomycin therapy while mitigating potential harms.

References

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