STREPTO 1

Indications

• Tuberculosis, resistant to other treatment
• Brucellosis (as an adjunct to doxycycline)
• Severe gram-negative infections (specific cases)

Dosage

Adults: For tuberculosis: 15 mg/kg daily (maximum 1 g per dose), reduce in those under 50 kg and over 40 years. For other infections: 3 mg/kg daily in 3 divided doses, increased if necessary up

Mechanism of action

Streptomycin enters bacterial cells through a three-phase process. Initially, it binds electrostatically to negatively charged components of bacterial cell membranes, increasing permeability and allowing entry. This is followed by energy-dependent transport into the cytoplasm where it binds to the 30S ribosomal subunit, causing mistranslation of proteins and disrupting membrane integrity. The resultant damage leads to concentration-dependent bactericidal effects, including immediate and delayed actions due to impaired protein synthesis.

Pharmacodynamics

Streptomycin has a narrow spectrum of activity, effective against susceptible strains of Yersinia pestis, Francisella tularensis, Brucella, and certain strains of gram-negative bacilli and gram-positive cocci. Resistance has reduced its effectiveness against many pathogens, and it is not effective against Pseudomonas aeruginosa. The drug's therapeutic index is narrow, necessitating close monitoring for toxic effects, particularly nephrotoxicity and ototoxicity.

Pharmacokinetics

Streptomycin is administered parenterally due to poor oral absorption. After intramuscular injection, it achieves peak plasma concentrations within 1-2 hours. It is distributed widely in body tissues and fluids, but does not penetrate well into the central nervous system. The drug is primarily eliminated unchanged by the kidneys, necessitating dosage adjustments in renal impairment. The half-life is approximately 2-3 hours in individuals with normal renal function.

Contra-indications

• Hypersensitivity to streptomycin or other aminoglycosides
• Myasthenia gravis (due to risk of neuromuscular blockade)
• Pregnancy (especially in the second and third trimesters due to risk of auditory or vestibular nerve damage)

Adverse effects

• Nephrotoxicity
• Ototoxicity
• Nausea
• Vomiting
• Diarrhea
• Electrolyte imbalance
• Blood disorders
• Confusion
• Paraesthesia
• Drowsiness
• Respiratory disorders
• Hearing loss
• Vestibular dysfunction

Interactions

• Other nephrotoxic drugs (e.g., vancomycin, furosemide)
• Neuromuscular blocking agents
• Other ototoxic agents

Precautions

• Caution in renal impairment due to increased risk of nephrotoxicity and ototoxicity
• Monitor renal function and auditory function before and during treatment
• Use with caution in patients with existing hearing loss

Pregnancy

There is a risk of auditory or vestibular nerve damage in the infant when aminoglycosides, including streptomycin, are used during the second and third trimesters of pregnancy.

Breast-feeding

Streptomycin is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store below 25°C, protect from light, and keep out of reach of children.

Formulations

• Streptomycin sulfate injection (various concentrations)
• Streptomycin for inhalation (nebulized form)
• Streptomycin oral solution

Mechanism of action

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. The primary intracellular site of action of the aminoglycosides is the 30 S ribosomal subunit, which consists of 21 proteins and a single 16 S molecule of RNA. at least three of these proteins and perhaps the 16 S ribosomal RNA as well contribute to the streptomycin binding site, and alterations of these molecules markedly affect the binding and subsequent action of streptomycin. For example, a single amino acid substitution of asparagine for lysine at position 42 of one ribosomal protein (S12) prevents binding of the drug; the resultant mutant is totally resistant to streptomycin. Another mutant, in which glutamine is the amino acid at this position, is dependent on streptomycin. During protein synthesis, the ribosome selects aminoacyl-transfer RNAs with anticodons matching the messenger RNA codon present in the A site of the small ribosomal subunit. The aminoglycoside antibiotic streptomycin disrupts decoding by binding close to the site of codon recognition. Here we use X-ray crystallography to define the impact of streptomycin on the decoding site of the Thermus thermophilus 30S ribosomal subunit in complexes with cognate or near-cognate anticodon stem-loop analogues and messenger RNA. Our crystal structures display a significant local distortion of 16S ribosomal RNA induced by streptomycin, including the crucial bases A1492 and A1493 that participate directly in codon recognition. Consistent with kinetic data, we observe that streptomycin stabilizes the near-cognate anticodon stem-loop analogue complex, while destabilizing the cognate anticodon stem-loop analogue complex. These data reveal ho

Pharmacodynamics

Although streptomycin originally had broad gram-negative and gram-positive coverage, its spectrum of activity has been significantly narrowed due to antibiotic resistance. Streptomycins current spectrum of activity includes susceptible strains of Yersinia pestis, Francisella tularensis, Brucella, Calymmatobacterium granulomatis, H. ducreyi, H. influenza, K. pneumoniae pneumonia, E.coli, Proteus, A. aerogenes, K. pneumoniae, Enterococcus faecalis, Streptococcus viridans, Enterococcus faecalis, and Gram-negative bacillary bacteremia. Streptomycin is not reliably active against pseudomonas aeruginosa. Similar to other aminoglycosides, streptomycin is considered to have a narrow therapeutic index. Characteristic toxicities of streptomycin include nephrotoxicity and ototoxicity. Patients should be carefully monitored for early signs of hearing loss and vestibular dysfunction in order to prevent permanent damage to sensorineural cells. Neuromuscular blockade has also been rarely reported.