Pharmacology of Streptomycin

Introduction/Overview

Streptomycin, derived from the soil actinomycete Streptomyces griseus, represents the first discovered aminoglycoside antibiotic and a landmark agent in antimicrobial chemotherapy. Its introduction in the mid-20th century provided the first effective pharmacological intervention against tuberculosis, fundamentally altering the prognosis of a disease previously managed largely with sanatorium care. Although its clinical use has diminished in many settings due to toxicity concerns and the development of newer agents, streptomycin retains a defined role in specific therapeutic regimens, particularly for multidrug-resistant tuberculosis and certain zoonotic infections. A thorough understanding of its pharmacology remains essential for clinicians managing complex infectious diseases where alternative treatments are limited or contraindicated.

The clinical relevance of streptomycin persists primarily within the domain of infectious diseases. It is a core component of second-line antitubercular therapy and is employed against infections caused by Yersinia pestis (plague), Francisella tularensis (tularemia), and Brucella species (brucellosis), often in combination with other antimicrobials. Its importance extends beyond direct clinical application to its historical role in validating the concept of combination therapy for preventing antimicrobial resistance, a principle that underpins modern tuberculosis management. Furthermore, streptomycin serves as a prototypical model for understanding the pharmacological class of aminoglycosides, illustrating shared mechanisms of action, pharmacokinetic properties, and characteristic toxicities that inform the use of all drugs within this category.

Learning Objectives

• Describe the chemical classification of streptomycin as an aminoglycoside and its historical significance as the first agent of its class.
• Explain the detailed molecular mechanism of action, including irreversible binding to the bacterial 30S ribosomal subunit and the consequent inhibition of protein synthesis.
• Analyze the pharmacokinetic profile of streptomycin, with emphasis on its concentration-dependent bactericidal activity, poor oral bioavailability, and predominantly renal excretion.
• Identify the approved clinical indications for streptomycin, its role in combination therapy for tuberculosis, and its use in treating specific zoonotic infections.
• Evaluate the major adverse effects, notably ototoxicity and nephrotoxicity, including their risk factors, monitoring parameters, and potential irreversibility.

Classification

Streptomycin is classified definitively within the aminoglycoside class of antibiotics. This classification is based on its chemical structure, which contains amino sugars linked by glycosidic bonds to a central aglycone (aminocyclitol) ring, in this case, streptidine. It belongs to the streptidine subgroup of aminoglycosides, distinguishing it from the deoxystreptamine-containing agents like gentamicin or amikacin.

Chemical Classification

Chemically, streptomycin is an aminoglycoside antibiotic. Its molecular structure consists of three components: streptidine (a diguanidinated inositol derivative), streptose (a pentose sugar), and N-methyl-L-glucosamine. This tripartite structure is essential for its antibacterial activity and its binding affinity to the target ribosomal site. The molecule is highly polar and polycationic at physiological pH, a property that dictates its pharmacokinetic behavior, including poor absorption across lipid membranes and a dependence on active transport for intracellular accumulation in renal tubular cells and the inner ear.

Mechanism of Action

The antibacterial action of streptomycin is bactericidal and results from a multi-step process that ultimately disrupts bacterial protein synthesis. Its primary target is the prokaryotic 30S ribosomal subunit. Unlike bacteriostatic protein synthesis inhibitors, aminoglycosides like streptomycin cause irreversible, concentration-dependent bacterial cell death.

Detailed Pharmacodynamics

The pharmacodynamic profile of streptomycin is characterized by concentration-dependent killing and a significant post-antibiotic effect (PAE). The rate and extent of bactericidal activity increase proportionally with drug concentration, particularly when the peak serum concentration (C_max) to minimum inhibitory concentration (MIC) ratio exceeds 8-10. This relationship supports the use of once-daily or high-dose intermittent dosing regimens to maximize efficacy while potentially mitigating toxicity. Furthermore, streptomycin exhibits a prolonged PAE against susceptible bacteria, meaning bacterial growth remains suppressed for a period after serum concentrations fall below the MIC. This allows for less frequent dosing intervals without loss of therapeutic effect.

Molecular and Cellular Mechanisms

The mechanism initiates with the energy-dependent uptake of the polycationic streptomycin molecule across the bacterial outer membrane and cytoplasmic membrane, a process facilitated by the electron transport chain and referred to as the “energy-dependent phase I transport.” This step is oxygen-dependent, explaining the poor activity of aminoglycosides against anaerobic bacteria. Once inside the cell, streptomycin binds with high affinity to specific nucleotides of the 16S ribosomal RNA within the 30S subunit, primarily at the A-site (aminoacyl-tRNA binding site).

This binding induces a series of conformational changes with three critical consequences. First, it interferes with the initiation complex formation by causing misreading of the initiation codon. Second, it induces misreading of the mRNA template during elongation, leading to the incorporation of incorrect amino acids into the growing polypeptide chain and the production of nonfunctional or toxic proteins. Third, and most significantly for its bactericidal effect, the binding of streptomycin disrupts the proofreading function of the ribosome and may cause the ribosome to stall at specific codons. This stalling can lead to the dissociation of the ribosomal complex and the premature release of truncated polypeptide chains. The cumulative effect of these disruptions—production of aberrant proteins and interference with ribosomal integrity—triggers bacterial cell death. The process is generally irreversible, which correlates with the observed bactericidal activity.

Pharmacokinetics

The pharmacokinetic properties of streptomycin are typical of aminoglycosides, characterized by high water solubility, poor membrane penetration, and significant influence by patient physiology, particularly renal function.

Absorption

Streptomycin is not absorbed appreciably from the gastrointestinal tract due to its high polarity and polycationic nature. Oral administration yields negligible systemic bioavailability, confining its use to topical preparations for gut decontamination. For systemic effect, it must be administered parenterally, almost exclusively via the intramuscular route. Intramuscular injection results in rapid and complete absorption, with peak serum concentrations (C_max) typically achieved within 1-2 hours post-injection. Intravenous administration is less common but used in specific clinical scenarios, requiring slow infusion over 30-60 minutes to prevent neuromuscular blockade associated with rapid peak concentrations.

Distribution

Distribution is largely confined to the extracellular fluid compartment due to the drug’s hydrophilic properties. The apparent volume of distribution (V_d) approximates 0.2-0.3 L/kg, similar to the extracellular fluid volume. Protein binding is minimal, generally less than 10%. Penetration into most cells, the central nervous system, and vitreous humor is poor. However, therapeutic concentrations can be achieved in pleural, peritoneal, and synovial fluids. Notably, streptomycin distributes into the renal cortex, where concentrations can exceed plasma levels by a factor of 10-50, and into the perilymph and endolymph of the inner ear, which correlates with its major sites of toxicity. It crosses the placenta and is found in fetal serum and amniotic fluid.

Metabolism

Streptomycin is not metabolized to a significant extent in humans. It is excreted unchanged, primarily by glomerular filtration. This lack of hepatic metabolism simplifies dosing adjustments, as they are based almost entirely on renal function.

Excretion

Renal excretion is the principal route of elimination. Nearly 80-90% of an administered dose is recovered as unchanged drug in the urine within 24 hours. The elimination half-life (t_1/2) is directly dependent on glomerular filtration rate (GFR). In adults with normal renal function, the half-life ranges from 2 to 4 hours. The relationship between creatinine clearance (Cl_Cr) and drug clearance is linear, allowing for predictable dosing adjustments in renal impairment. A small fraction of the drug may be excreted in bile, but this pathway is not clinically significant for elimination.

Half-life and Dosing Considerations

The elimination half-life dictates dosing frequency. The conventional approach has involved administration in divided doses (e.g., twice daily). However, pharmacodynamic principles supporting concentration-dependent killing and a significant PAE have led to the adoption of extended-interval or once-daily dosing (ODD) regimens in many clinical situations. ODD aims to achieve a high C_max/MIC ratio for optimal bactericidal effect while allowing a prolonged drug-free period that may reduce accumulation in renal tubular cells and the inner ear, potentially lowering toxicity. Dosing must be individualized based on body weight, renal function, and the severity of infection. Therapeutic drug monitoring (TDM), specifically measuring peak and trough serum concentrations, is considered standard of care, especially in patients with unstable renal function, those on prolonged therapy, or when using conventional multi-daily dosing. Target peak concentrations (drawn 1 hour post-IM injection) for tuberculosis are typically 20-30 µg/mL, while trough concentrations (drawn just before the next dose) should be maintained below 5 µg/mL to minimize toxicity risk.

Therapeutic Uses/Clinical Applications

The clinical applications of streptomycin have narrowed over time but remain vital in specific contexts where its unique antibacterial spectrum is required.

Approved Indications

• Mycobacterial Infections: Streptomycin is a second-line agent for the treatment of all forms of tuberculosis caused by susceptible strains of Mycobacterium tuberculosis. It is used when first-line agents (isoniazid, rifampin, pyrazinamide, ethambutol) cannot be used due to resistance or intolerance. It is always used in combination with at least two other antitubercular drugs to which the organism is susceptible to prevent the emergence of resistance. It also has a role in the treatment of Mycobacterium avium complex (MAC) infections, typically as part of a multidrug regimen.
• Plague (Yersinia pestis): Streptomycin is considered a drug of choice for the treatment of plague, including both bubonic and pneumonic forms. Therapy is often initiated with streptomycin or gentamicin.
• Tularemia (Francisella tularensis): It is a first-line agent for the treatment of all forms of tularemia. Gentamicin is often used as an alternative due to wider availability.
• Brucellosis (Brucella species): Streptomycin is used in combination with doxycycline or tetracycline for a duration of 2-4 weeks as part of a classic dual-therapy regimen for brucellosis. Alternative regimens using doxycycline plus rifampin are also common.
• Bacterial Endocarditis: While largely superseded by other aminoglycosides, streptomycin, in combination with penicillin, retains a role in the treatment of endocarditis caused by Enterococcus faecalis or Streptococcus viridans strains that exhibit tolerance to penicillin alone. Its use is guided by susceptibility testing.

Off-label Uses

Off-label use is limited but may include combination therapy for other multidrug-resistant Gram-negative bacterial infections when no other options are available and susceptibility is confirmed. It is also employed occasionally in the Whipple’s disease treatment regimen (in combination with penicillin and ceftriaxone) and as part of a multi-drug regimen for peritoneal dialysis-associated peritonitis caused by certain organisms.

Adverse Effects

The clinical utility of streptomycin is significantly constrained by its potential for serious, dose-related, and often irreversible toxicities. Vigilant monitoring is a mandatory component of therapy.

Common Side Effects

• Pain and irritation at the site of intramuscular injection.
• Paresthesias, such as numbness or tingling around the mouth (perioral paresthesia) or in the extremities, which are often transient.
• Headache, dizziness, and malaise.
• Rash and drug fever, which may indicate hypersensitivity.

Serious/Rare Adverse Reactions

• Ototoxicity: This is the most characteristic and concerning toxicity. It manifests as both vestibular and cochlear damage.
  • Vestibular toxicity is more common with streptomycin than with other aminoglycosides. Symptoms include dizziness, vertigo, nausea, vomiting, nystagmus, and ataxia. The damage is often irreversible due to destruction of hair cells in the cristae ampullaris of the semicircular canals.
  • Cochlear (auditory) toxicity presents initially as high-frequency hearing loss, which may progress to involve conversational frequencies and result in permanent deafness. It results from damage to the hair cells of the organ of Corti.

  Risk factors include prolonged therapy (>10 days), high cumulative dose, advanced age, pre-existing hearing impairment, concurrent use of other ototoxic drugs (e.g., loop diuretics, platinum chemotherapy), and renal impairment.

• Nephrotoxicity: Streptomycin accumulates in renal proximal tubular cells, causing damage that can lead to acute tubular necrosis. This typically presents as a non-oliguric rise in serum creatinine and blood urea nitrogen (BUN). The toxicity is usually reversible upon discontinuation of the drug but can potentiate ototoxicity by reducing drug clearance and increasing serum levels. Risk factors are similar to those for ototoxicity and include concurrent use of other nephrotoxins (e.g., vancomycin, amphotericin B, cisplatin).
• Neuromuscular Blockade: Streptomycin can inhibit pre-synaptic acetylcholine release and postsynaptic receptor binding, leading to a curare-like effect. This may result in acute muscle weakness, respiratory depression, or apnea. The risk is heightened with rapid intravenous infusion, high doses, concurrent use of other neuromuscular blocking agents (e.g., during anesthesia), and in patients with myasthenia gravis or hypocalcemia.
• Hypersensitivity Reactions: These can range from skin rashes and drug fever to eosinophilia, serum sickness-like reactions, and rarely, anaphylaxis.
• Peripheral Neuropathy: Optic neuritis and other cranial nerve palsies have been reported, though they are rare.

Black Box Warnings

Streptomycin carries a boxed warning from regulatory agencies highlighting its potential for severe toxicity. The warning specifically emphasizes:

• The risk of ototoxicity, which can be both vestibular and auditory, and may be permanent. It can occur even with conventional doses and in patients with normal renal function.
• The risk of nephrotoxicity, which can lead to acute renal failure.
• The risk of neuromuscular blockade and respiratory paralysis, particularly when the drug is administered intravenously, in high doses, or to patients receiving anesthesia or neuromuscular blocking agents.
• The necessity for dose adjustment in patients with renal impairment and the recommendation for therapeutic drug monitoring to minimize risks.

Drug Interactions

The polycationic nature and specific toxicities of streptomycin lead to several clinically significant drug interactions.

Major Drug-Drug Interactions

• Other Nephrotoxic Agents: Concurrent use with drugs like vancomycin, amphotericin B, cisplatin, cyclosporine, and loop diuretics (e.g., furosemide) can have additive or synergistic effects in damaging renal tubules, significantly increasing the risk of acute kidney injury.
• Other Ototoxic Agents: Concomitant administration with other ototoxic drugs, such as loop diuretics (especially when given intravenously), platinum-based chemotherapeutics (cisplatin, carboplatin), and other aminoglycosides, markedly elevates the risk of permanent hearing loss or vestibular dysfunction.
• Neuromuscular Blocking Agents: Potentiation of neuromuscular blockade can occur with simultaneous use of anesthetic agents (e.g., succinylcholine, vecuronium), magnesium sulfate, and polymyxins. This can lead to profound muscle weakness and respiratory arrest.
• Penicillins (In Vitro Inactivation): When streptomycin is physically mixed in the same intravenous solution with certain beta-lactam antibiotics (e.g., penicillins, cephalosporins), chemical inactivation of the aminoglycoside can occur. These agents should be administered separately.

Contraindications

Absolute contraindications to streptomycin use include a history of documented serious hypersensitivity (e.g., anaphylaxis) to streptomycin or any other aminoglycoside antibiotic. Relative contraindications, requiring extreme caution and a strong risk-benefit assessment, include:

• Pre-existing significant auditory or vestibular impairment.
• Pre-existing severe renal impairment (unless no alternative exists and meticulous TDM is available).
• Myasthenia gravis or other neuromuscular junction disorders.
• Pregnancy (due to risk of fetal ototoxicity).
• Concurrent use of potent diuretics like ethacrynic acid.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy (Category D): Streptomycin crosses the placenta and can cause fetal harm. Exposure in utero has been associated with congenital deafness due to damage to the developing cochlea. Consequently, it is contraindicated during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus, such as in life-threatening infections like plague or multidrug-resistant tuberculosis. If used, informed consent and audiologic monitoring of the newborn are essential.

Lactation: Streptomycin is excreted in human milk in low concentrations. Because of the potential for serious adverse reactions in nursing infants, including modification of intestinal flora and theoretical risk of ototoxicity, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric and Geriatric Considerations

Pediatrics: Dosing in children is typically based on body weight or body surface area. The principles of TDM apply, though establishing therapeutic ranges can be more challenging. The risks of ototoxicity and nephrotoxicity are present, and baseline auditory testing is recommended when feasible for prolonged courses.

Geriatrics: Elderly patients are at increased risk for toxicity due to several factors: an age-related decline in renal function (even with a “normal” serum creatinine), reduced lean body mass altering volume of distribution, and possible pre-existing subclinical hearing loss. Dosing must be based on an estimated creatinine clearance (using formulas like Cockcroft-Gault), and lower initial doses with careful TDM are often warranted. Baseline and periodic audiometric and vestibular assessments are strongly recommended.

Renal and Hepatic Impairment

Renal Impairment: This is the most critical factor requiring dose modification. As streptomycin is eliminated almost exclusively by glomerular filtration, any reduction in GFR leads to drug accumulation and elevated risk of toxicity. Dosing must be adjusted based on creatinine clearance. Common strategies include extending the dosing interval (e.g., administering the usual dose every 24, 48, or 72 hours) or reducing the maintenance dose while keeping the interval constant. Therapeutic drug monitoring of both peak and trough concentrations is mandatory in this population. In patients with end-stage renal disease on hemodialysis, streptomycin is dialyzable, and a supplemental dose is usually required post-dialysis.

Hepatic Impairment: No specific dose adjustment is required for hepatic dysfunction, as streptomycin is not metabolized by the liver. However, caution is advised in patients with severe hepatic disease who may have concomitant conditions like ascites (which may alter volume of distribution) or hepatorenal syndrome.

Summary/Key Points

• Streptomycin is the prototypical aminoglycoside antibiotic, a bactericidal agent that irreversibly binds to the bacterial 30S ribosomal subunit, causing misreading of mRNA and inhibition of protein synthesis.
• Its pharmacokinetics are defined by poor oral absorption, distribution primarily in extracellular fluid, negligible metabolism, and renal excretion. The half-life is directly proportional to renal function.
• Clinical use is now restricted to specific infections: as a second-line agent for tuberculosis, and as a first-line treatment for plague, tularemia, and brucellosis (in combination regimens).
• The major dose-limiting toxicities are ototoxicity (vestibular and cochlear, often irreversible) and nephrotoxicity (usually reversible). A boxed warning highlights these risks.
• Therapeutic drug monitoring of peak and trough serum concentrations is a standard of care to optimize efficacy (high C_max/MIC) and minimize toxicity (low troughs).
• Dosing requires meticulous adjustment in renal impairment, and the drug is contraindicated in pregnancy due to risk of fetal ototoxicity. Extreme caution is warranted in the elderly and with concurrent use of other nephrotoxic or ototoxic agents.

Clinical Pearls

• Always administer streptomycin in combination with other antimicrobials for tuberculosis to prevent resistance; monotherapy is never appropriate.
• Vestibular toxicity may present subtly with mild dizziness or nausea; patients should be questioned specifically about these symptoms at each clinical encounter.
• For patients on prolonged therapy, obtain baseline audiometry and vestibular function tests if possible, and repeat them periodically during treatment.
• When calculating doses in renal impairment, use an ideal body weight or adjusted body weight formula to avoid overdosing in obese patients.
• The once-daily dosing strategy leverages concentration-dependent killing and the post-antibiotic effect, and it may reduce the risk of nephrotoxicity compared to multiple daily doses.

References

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