Streptomycin Monograph – Pharmacology Chapter

Introduction / Overview

Streptomycin, discovered in the late 1940s, represents the first clinically useful aminoglycoside antibiotic. It has retained clinical relevance primarily in the management of severe mycobacterial infections, notably tuberculosis, and in certain Gram‑negative bacterial infections. The drug’s pharmacological profile is distinctive due to its selective interaction with the bacterial ribosome and its narrow therapeutic index. This chapter is structured to provide a systematic review of streptomycin, focusing on its classification, mechanism of action, pharmacokinetics, therapeutic applications, adverse effect spectrum, drug interactions, and special patient populations. The content is intended to enhance understanding of streptomycin’s role within the broader context of antimicrobial therapy for medical and pharmacy students.

Learning Objectives

• Identify the chemical and pharmacological classification of streptomycin.
• Explain the molecular basis of streptomycin’s antibacterial activity.
• Describe the pharmacokinetic parameters influencing dosing regimens.
• Summarize approved therapeutic indications and common off‑label uses.
• Recognize major adverse effects, drug interactions, and special considerations in vulnerable populations.

Classification

Drug Class and Category

Streptomycin falls under the antibiotic class of aminoglycosides. Within this group, it is distinguished as a 3‑aminoside of streptomycin A. Aminoglycosides are characterized by their tricyclic structure and the presence of amino sugars linked via glycosidic bonds. The drug’s activity is mediated predominantly by the interaction of its aminocyclitol moiety with the bacterial ribosomal machinery.

Chemical Classification

From a structural standpoint, streptomycin is a cyclic aminocyclitol derivative, specifically an adenosine derivative with a unique 3‑amino‑3′‑hydroxyl group. Its molecular formula is C₁₇H₃₅N₆O₁₀, and it possesses a molecular weight of approximately 389.4 g/mol. The drug is naturally produced by the soil bacterium Streptomyces griseus and is available commercially as an injectable solution and a crystalline powder for reconstitution.

Mechanism of Action

Pharmacodynamics

Streptomycin exerts its antibacterial effect by binding to the 30S subunit of the bacterial ribosome. This binding interferes with the initiation complex formation and induces misreading of mRNA, thereby producing aberrant proteins. The resulting cytotoxicity leads to bacterial death, characterizing streptomycin as a bactericidal agent. The drug’s action is concentration‑dependent; peak concentrations correlate with the magnitude of bacterial killing, whereas exposure time has a lesser influence.

Receptor Interactions

At the molecular level, streptomycin associates with the A site of the 30S ribosomal subunit, specifically interacting with the 16S rRNA. The aminoglycoside’s positively charged amino groups form hydrogen bonds with the phosphate backbone of the rRNA, stabilizing a conformational state that hampers translocation. This interaction disrupts the fidelity of protein synthesis and impairs bacterial growth.

Molecular/Cellular Mechanisms

Beyond ribosomal binding, streptomycin induces the formation of reactive oxygen species (ROS) within bacterial cells. The generation of ROS contributes to DNA damage and membrane destabilization, amplifying the bactericidal effect. Additionally, the drug can inhibit bacterial ATP synthesis indirectly by compromising the integrity of the proton motive force. These ancillary mechanisms reinforce streptomycin’s potency against susceptible organisms.

Pharmacokinetics

Absorption

Oral bioavailability of streptomycin is negligible due to poor gastrointestinal absorption and extensive first‑pass extraction. Consequently, the drug is administered parenterally, primarily via intramuscular or intravenous routes. Intramuscular injections yield peak serum concentrations (C_max) within 1–2 hours, whereas intravenous administration achieves immediate systemic exposure.

Distribution

Following parenteral administration, streptomycin distributes extensively into extracellular fluid but demonstrates limited penetration into lipophilic tissues such as the central nervous system and ocular compartments. The volume of distribution (V_d) approximates 0.4 L/kg, reflecting its confinement to the interstitial space. Protein binding is minimal (<5 %), facilitating rapid tissue uptake and clearance.

Metabolism

Streptomycin undergoes negligible hepatic metabolism. The drug remains chemically unchanged throughout its circulation, which simplifies the prediction of pharmacokinetic parameters in patients with hepatic dysfunction.

Excretion

Renal excretion dominates the elimination of streptomycin, with a glomerular filtration rate (GFR) acting as the primary determinant of clearance (Cl). The drug is largely unaffected by tubular secretion or reabsorption. In patients with normal renal function, the half‑life (t_1/2) ranges from 2.5 to 4 hours. Dose adjustments are required in renal impairment to avoid accumulation and toxicity.

Half‑Life and Dosing Considerations

Given the concentration‑dependent killing profile, dosing strategies emphasize achieving high peak concentrations while allowing sufficient drug clearance between doses. A typical regimen for tuberculosis involves a loading dose of 15–20 mg/kg IV or IM once daily, followed by a maintenance dose of 15 mg/kg. In patients with reduced renal function (creatinine clearance < 30 mL/min), the maintenance dose is decreased by approximately 50 % and the dosing interval extended to every other day. Monitoring of serum concentrations is advisable when therapeutic drug monitoring facilities are available.

Therapeutic Uses / Clinical Applications

Approved Indications

Streptomycin remains a cornerstone in the multidrug regimen for drug‑susceptible pulmonary tuberculosis. It is routinely combined with isoniazid, rifampicin, pyrazinamide, and ethambutol during the intensive phase. Additionally, streptomycin is indicated for severe infections caused by Gram‑negative bacilli, such as Pseudomonas aeruginosa, when other agents are contraindicated or ineffective.

Off‑Label Uses

In certain clinical contexts, streptomycin is employed off‑label to treat:

1. Complicated urinary tract infections resistant to other agents.
2. Severe septicemia from Enterobacteriaceae when alternative antibiotics are unavailable.
3. Certain ocular infections, such as endophthalmitis, when delivered via intravitreal injection.

These applications are guided by susceptibility testing and risk‑benefit considerations, given the drug’s narrow therapeutic window.

Adverse Effects

Common Side Effects

Patients frequently experience nephrotoxic changes, manifested as an acute rise in serum creatinine and reduced glomerular filtration. Ototoxicity, presenting as tinnitus, vertigo, or hearing loss, is also common, particularly with prolonged therapy or high cumulative doses. Other reported side effects include gastrointestinal disturbances (nausea, vomiting), injection site reactions, and dermatologic manifestations such as rash.

Serious / Rare Adverse Reactions

Serious complications, though uncommon, encompass irreversible sensorineural hearing loss, vestibular dysfunction, and severe allergic reactions (anaphylaxis). In rare instances, streptomycin has been associated with neurotoxicity, characterized by seizures and altered mental status.

Black Box Warning

Streptomycin carries a black‑box warning for potential ototoxicity, emphasizing the necessity of baseline hearing assessment and periodic audiometric monitoring during treatment. The risk of nephrotoxicity is also highlighted, urging careful dose adjustment in patients with renal impairment.

Drug Interactions

Major Drug‑Drug Interactions

Streptomycin’s aminoglycoside structure predisposes it to synergistic nephrotoxic effects when combined with other nephrotoxic agents such as loop diuretics (furosemide) or amphotericin B. Concurrent administration with other aminoglycosides (gentamicin, tobramycin) may potentiate ototoxicity. Additionally, neuromuscular blocking agents can experience enhanced blockade due to streptomycin’s potentiation of neuromuscular transmission inhibition.

Contraindications

Absolute contraindications include documented hypersensitivity to streptomycin or other aminoglycosides, severe renal failure (creatinine clearance < 30 mL/min) without dose adjustment, and pregnancy, due to potential fetal ototoxicity. Caution is warranted in patients with vestibular disorders or concomitant use of ototoxic drugs.

Special Considerations

Use in Pregnancy / Lactation

Streptomycin is classified as category D for pregnancy. It can cross the placenta and may cause irreversible fetal hearing loss. Use is generally reserved for life‑threatening maternal infections where no safer alternatives exist. Lactation is also contraindicated due to potential ototoxicity to the infant via breast milk.

Pediatric / Geriatric Considerations

In pediatric patients, dosing is weight‑based (15–20 mg/kg). Monitoring for ototoxicity is particularly important, as children are more susceptible to auditory damage. In geriatric patients, renal function often declines with age; thus, dose adjustments and therapeutic drug monitoring are essential to avoid accumulation and toxicity.

Renal / Hepatic Impairment

Renal impairment necessitates dose reduction proportional to the decrease in creatinine clearance. Hepatic impairment has minimal impact on streptomycin pharmacokinetics, given the drug’s negligible hepatic metabolism. Nevertheless, caution is advised in patients with concomitant hepatic dysfunction, as renal clearance may be affected by altered volume status.

Summary / Key Points

• Streptomycin is an aminoglycoside antibiotic with a concentration‑dependent bactericidal action mediated by ribosomal interference and ROS generation.
• Parenteral administration is mandatory due to poor oral absorption; renal excretion dominates elimination, necessitating dose adjustments in renal impairment.
• Approved indications include drug‑susceptible tuberculosis and severe Gram‑negative infections; off‑label uses are guided by susceptibility data.
• Key adverse effects involve nephrotoxicity and ototoxicity; a black‑box warning underscores the need for baseline and periodic hearing assessments.
• Drug interactions with other nephrotoxic or ototoxic agents heighten risk; contraindications include pregnancy and severe renal failure.
• Special populations require careful monitoring: pregnant and lactating women are contraindicated, pediatric dosing is weight‑based, and geriatric patients may need dose reductions.

Clinicians and pharmacists should integrate these pharmacological insights into individualized treatment plans, balancing therapeutic efficacy against the narrow safety margin inherent to streptomycin therapy.

References

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