Streptomycin

Description

The antibiotic streptomycin is an important and effective chemical for the management of bacterial diseases of fruit trees (especially apple), woody ornamentals, and vegetables. Streptomycin was initially discovered in 1944 and was one of the first antibiotics to be utilized in clinical medicine to control human diseases, and is still important as a feed amendment for growth promotion in agricultural animals. The widespread and diverse usage of streptomycin has contributed to the currently observed global streptomycin resistance (SmR) problem. This problem is especially critical in plant disease management, as there are few alternatives to streptomycin available and, as a consequence of increased usage, SmR has been increasingly observed among bacterial plant pathogens.

Chemical Properties

Crystalline Powder

Originator

Streptomycin,MSD,US,1945

History

Streptomycin is discovered in 1944 of streptomycin drew immediate interest because it was the least toxic of the broad-spectrum antibiotics known at that time. Indeed, streptomycin was used to treat many gram-negative microbial infections, but because of the ease with which organisms developed resistance to it during treatment, many of these applications were abandoned when the tetracyclines, discussed later, became available. Streptomycin was the first parenterally administered antibiotic active against many microorganisms, but during the last several years, its use has been limited essentially to three situations: (1) the initial treatment of serious tuberculous infections, when the principal drugs of choice (isoniazid, rifampin) cannot be used because of their adverse effects on a particular patient; (2) treatment of enterococcal and other infections, in which synergism between a penicillin and an aminoglycoside is desired; and (3) treatment of certain uncommon infections (plague and tularemia).

Uses

Antibiotic substance produced by aerobic fermentation. Antibacterial (tuberculostatic).

Uses

Control of bacterial shot-hole, bacterial rots, bacterial canker, bacterial wilts, fire blight, and other diseases caused by gram-positive species of bacteria in pome fruit, stone fruit, citrus fruit, olives, vegetables, potatoes, tobacco, cotton, and ornamentals. Chlorosis may occur on grapes, pears, peaches, and some ornamentals. Formulation types WP; Liquid. Incompatible with pyrethrins and alkaline materials. A mixture of streptomycin and oxytetracycline is highly effective for the control of bacterial canker of peach, citrus canker, soft rot of vegetables, and various other bacterial diseases. Selected tradenames “Agrimycin 17” (sesquisulfate); “AS-50” (sesquisulfate).

Uses

Streptomycin is the most commonly utilized bactericidal antibiotic for the management of plant pathogens and has been used most frequently on apple, pear, sweet pepper, and ornamental trees.

Definition

ChEBI: A amino cyclitol glycoside that consists of streptidine having a disaccharyl moiety attached at the 4-position. The parent of the streptomycin class

Indications

Streptomycin, an aminoglycoside antibiotic was the first drug shown to reduce tuberculosis mortality. Streptomycin is bactericidal against M. tuberculosis in vitro but is inactive against intracellular organisms. Most M. tuberculosis strains and nontuberculosis species, such as M. kansasii and M. aviumintracellulare, are sensitive. Spontaneous resistance to streptomycin, seen in approximately 1 in 106 tubercle bacilli, is related to a point mutation that involves the gene (rpsl or rrs) that encodes for ribosomal proteins and binding sites.About 80% of strains that are resistant to isoniazid and rifampin are also resistant to streptomycin.

Manufacturing Process

A medium is prepared having the following composition in tap water: 1.0% glucose; 0.5% peptone; 0.3% meat extract; and 0.5% NaCl. This medium is distributed in appropriate vessels to a depth of 1 to 2 inches, sterilized at 10 pounds steam pressure for 45 to 50 minutes, and then cooled.
The medium in each vessel is then inoculated with a heavy aqueous suspension of spores of a strain of Actinomyces griseus, and the inoculated media are maintained at an incubation temperature of 22° to 28°C for 10 days. The growth is then filtered off and the filtrates are combined for further treatment.
To a batch of approximately 10 liters of filtered broth is added 150 grams of activated charcoal. The mixture is stirred continuously for about 5 minutes and is then filtered. The slightly yellowish (almost colorless) filtrate is discarded and the charcoal residue is washed several times with distilled water and finally with 95% ethanol. The washed material is then suspended in 1.5 liters of 95% ethanol, made 0.15 normal with hydrochloric acid. The suspension is stirred for about an hour and allowed to stand in the cold for about 10 hours more with occasional stirring. The suspension is then filtered, the charcoal residue discarded, and the yellowish clear filtrate thus obtained is poured into 10 liters of ether, with stirring. A brown-colored aqueous layer separates and is drawn off.
The alcohol-ether solution is washed with 100 cc of water and the brown aqueous layer is drawn off and added to the first aqueous layer. The aqueous solution is neutralized to pH 6 to 7 with dilute sodium hydroxide and any precipitate that forms is filtered off and discarded. A faintly colored aqueous solution containing streptomycin is thus obtained.

brand name

Antidiarrhoicum;Bio hubber fuerte;Bio hubbersimple;Cidan est;Darostrep;Derbitan antibiotico;Diastat;Direver;Estrepromade;Estrepromicina;Estrepto e;Estrepto level;Estrepto ph;Estrepto wolner;Estreptomicina normon;Gamafin;Injectin;Neodistreptotab;Neodualtrepto;Novostrep;Novo-strep;Servistrep;Solustrep;Solvo-strep-s;Solvo-strept-s;Strep-diva;Strepolin;Streptan;Streptaquaine;Streptocal;Strepto-fatal;Streptosol 25;Streptothenat;Stretobretin;Sul-mycin ii.

Therapeutic Function

Antitubercular

World Health Organization (WHO)

Oral preparations of streptomycin, an aminoglycoside antibiotic isolated from streptomyces griseus in 1944, were formerly widely used to treat intestinal infections. There is no evidence that streptomycin is effective in this indication and its widespread use promotes the emergence of resistant strains of bacteria. The World Health Organization recommends that streptomycin should not be used for the treatment of diarrhoea. (Reference: (WHORUD) The Rational Use of Drugs, , , 1990)

Antimicrobial activity

It is less active than gentamicin group compounds against most micro-organisms within the spectrum,but it is particularly active against mycobacteria, including M. kansasii and most strains of M. ulcerans. Brucella (MIC 0.5 mg/L), Francisella, Pasteurella spp. and Yersinia pestis are susceptible.
It is actively bactericidal, the speed of killing increasing progressively with concentration. The antibacterial activity is greatest in a slightly alkaline medium (pH 7.8) and is considerably reduced below pH 6.0. It is so sensitive to the effect of pH that the natural acidity of a solution of streptomycin sulfate may be sufficient to depress its antibacterial activity.

Acquired resistance

In contrast to most other aminoglycosides, high level resistance can result from a single-step mutation in the gene encoding ribosomal protein S12 (rpsL), which alters the protein so that binding is reduced. Resistance in some clinical isolates of M. tuberculosis is associated either with missense mutations in the rpsL gene, or with base substitutions at position 904 in the 16S rRNA.
Resistance can also be caused by aminoglycosidemodifying enzymes: phosphotransferases that modify the 3″-hydroxyl group in both Gram-negative and Grampositive organisms; a phosphotransferase that modifies the 6-hydroxyl group in Pseudomonas spp.; and a nucleotidyltransferase that modifies the 3″-hydroxyl group in Gramnegative organisms.
Increase in resistance often occurs within a few days (for M. tuberculosis a few weeks) of the beginning of treatment, and resistance of many species is now common. Primary streptomycin resistance in M. tuberculosis is much more common in the Far East and less developed countries than in the UK and USA. However, several clusters of multidrug-resistant tuberculosis have been identified among hospital patients with AIDS in the USA.
Strains of streptococci and enterococci showing moderate resistance (MIC 6–500 mg/L) exhibit synergy with penicillin, but strains showing high levels of resistance (MIC >500 mg/L) have ribosomes that are resistant to streptomycin and simultaneous treatment with penicillin is without effect.
It is not uncommon to find strains of bacteria, including M. tuberculosis, that are actually favored by the presence of the antibiotic or completely dependent on it. Isolated ribosomes from streptomycin-dependent Esch. coli show a change in the same single ribosomal protein that determines resistance and synthesize peptides only in the presence of the drug.
Streptomycin-resistant bacteria usually remain sensitive to other aminoglycosides. Enterococci with high-level resistance to gentamicin, and consequent resistance to gentamicin–β- lactam synergy, may show synergy between the β-lactam and streptomycin.

Hazard

Damage to nerves and kidneys may result from ingestion. Use restricted by FDA.

Mechanism of action

The mechanism of action of STM and the aminoglycosides in general has not been fully elucidated. It is known that the STM inhibits protein synthesis, but additional effects on misreading of an mRNA template and membrane damage may contribute to the bactericidal action of ST M. Streptomycin is able to diffuse across the outer membrane of Mycobacterium tuberculosis and, ultimately, to penetrate the cytoplasmic membrane through an electrondependent process. Through studies regarding the mechanism of drug resistance, it has been proposed that STM induces a misreading of the genetic code and, thus, inhibits translational initiation. In ST M-resistant organisms, two changes have been discovered: First, S12 protein undergoes a change in which the lysine present at amino acids 43 and 88 in ribosomal protein S12 is replaced with arginine or threonine, and second, the pseudoknot conformation of 16S rRNA, which results from intramolecular base pairing between GCC bases in regions 524 to 526 of the rRNA to CGG bases in regions 505 to 507, is perturbed. It is thought that S12 protein stabilizes the pseudoknot, which is essential for 16S rRNA function. By some yet-to-be-defined mechanism, STM interferes with one or both of the normal actions of the 16S protein and 16S rRNA.

Pharmacology

Ototoxicity and nephrotoxicity are the major concerns during administration of streptomycin and other aminoglycosides. The toxic effects are dose related and increase with age and underlying renal insufficiency.All aminoglycosides require dose adjustment in renal failure patients. Ototoxicity is severe when aminoglycosides are combined with other potentially ototoxic agents.

Clinical Use

Streptomycin is indicated as a fourth drug in combination with isoniazid, rifampin, and pyrazinamide in patients at high risk for drug resistance. It is also used in the treatment of streptomycin-susceptible MDR tuberculosis.

Clinical Use

Tuberculosis (in combination with other antituberculosis drugs) Infections caused by M. kansasii (in combination with other antimycobacterial agents)
Plague and tularemia, including tularemia pneumonia Bacterial endocarditis (in combination with a penicillin) Brucellosis
Whipple’s disease (in combination with other antibiotics)
The most important use of streptomycin is in the treatment of tuberculosis . Depression of vestibular function by streptomycin has been used in the treatment of patients suffering from Ménière’s disease.

Side effects

Pain and irritation at the site of injection are common, and sterile inflammatory reactions or peripheral neuritis from direct involvement of a nerve sometimes occur. Many patients experience circumoral paresthesia, vertigo and ataxia, headaches, lassitude and ‘muzziness in the head’. Renal dysfunction is rare but has been described in patients receiving 3–4 g per day.
Ototoxicity
The most common serious toxic effect is vestibular disturbance, which is related to total dosage and excessive blood concentrations, and hence to the age of the patient and the state of renal function. In older patients the risk of damage is higher and compensation is less than in young patients. Persistence of the drug in the perilymph after the plasma concentration has fallen may play an important part in such ototoxicity. There is no significant relation between incidence of dizziness and peak streptomycin concentration, but a highly significant relation to plasma concentrations exceeding 5 mg/L at 24 h. The risk to hearing is much less, but damage sometimes occurs after only a few doses. Congenital hearing loss or abnormalities in the caloric test or audiogram have been described several times in children born to women treated with streptomycin in pregnancy. There is considerable individual variation in susceptibility to its toxic effects, which may be partly genetically determined.
Allergy
In addition to eosinophilia unassociated with other allergic manifestations, rashes and drug fever occur in about 5% of treated patients. These are usually trivial and respond to antihistamine treatment, so that in most cases therapy can be continued, although this should be done with caution, since occasionally severe and even fatal exfoliative dermatitis may develop. Skin sensitization is also common in nurses and dispensers who handle streptomycin and may lead to severe dermatitis, sometimes associated with periorbital swelling and conjunctivitis. Reactions most frequently develop between 4 and 6 weeks, but may appear after the first dose or after 6 months’ treatment. Patients who develop hypersensitivity during prolonged therapy can generally be desensitized by giving 20 mg prednisolone daily plus 10 daily increments from 0.1 to 1.0 g streptomycin when normal dosage will usually be tolerated, or by giving increased doses of streptomycin every 6 h.
Neuromuscular blockade
It is rare for neuromuscular blockade to develop in those whose neuromuscular mechanisms are normal, but patients who are also receiving muscle relaxants or anesthetics, or are suffering from myasthenia gravis are at special risk.
Other effects
Rare neurological manifestations include peripheral neuritis and optic neuritis with scotoma. Other rare effects have been aplastic anemia, agranulocytosis, hemolytic anemia, thrombocytopenia, hypocalcemia and severe bleeding associated with a circulating factor V antagonist.

Safety Profile

Poison by intravenous and subcutaneous routes. Moderately toxic by ingestion and intraperitoneal routes. An experimental teratogen. Human systemic effects by ingestion and intraperitoneal routes: change in vestibular functions, blood pressure decrease, eosinophilia, respiratory depression, and pulmonary changes. Human reproductive and teratogenic effects by unspecified routes: developmental abnormalities of the eye and ear and effects on newborn including postnatal measures or effects. Toxic to hdneys and central nervous system. Has been implicated in aplastic anemia. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOX.

Synthesis

Streptomycin, trans-2,4-diguanidino-3,5,6-trihydroxycyclohexyl-5-deoxy-2- O-(2-deoxy-2-methylamino-α-L-glucopyranosyl)-3-C-hydroxymethyl-β-L-lyxo-pentofuranoside (32.4.1), is isolated from a culture liquid of the vital activity of the actinomycete S. griseus.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of nephrotoxicity with colistimethate or polymyxins and possibly cephalosporins; increased risk of ototoxicity and nephrotoxicity with capreomycin or vancomycin.
Ciclosporin: increased risk of nephrotoxicity.
Cytotoxics: increased risk of nephrotoxicity and ototoxicity with platinum compounds.
Loop diuretics: increased risk of ototoxicity.
Muscle relaxants: enhanced effects of nondepolarising muscle relaxants and suxamethonium.
Parasympathomimetics: neostigmine and pyridostigmine antagonised by aminoglycosides.
Tacrolimus: increased risk of nephrotoxicity.

Environmental Fate

The mechanism of toxicity for aminoglycosides has not been fully explained and is therefore unclear. It is known that the drug attaches to a bacterial cell wall and is drawn into the cell via channels made up of a protein, porin. Once inside the cell, aminoglycoside attaches to the 30S bacterial ribosomes. Ribosomes are the intracellular structures responsible for manufacturing proteins. This attachment either inhibits protein biosynthesis or causes the cell to produce abnormal, ineffective proteins. The bacterial cell cannot survive with this impediment. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity.
Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobic bacteria (bacteria that cannot grow in the presence of oxygen), viruses, and fungi. And only one aminoglycoside, paromomycin, is used against parasitic infection. Like all other antibiotics, aminoglycosides are not effective against influenza, the common cold, or other viral infections.

Metabolism

Streptomycin inhibits protein synthesis in bacterial cells by binding to the 30S ribosomal subunit and causes misreading of the genetic codes in protein synthesis (29). Streptomycin-resistant strains are distributed in a wide range of plant pathogenic bacteria, such as Xanthomonas oryzae, X. citri, Pseudomonas tabaci, and P. lachrymans. In agricultural use, the alternative or combined applications of streptomycin and other chemicals with different action mechanisms is recommended in order to reduce the development of streptomycin-resistant strains in the field. Mutants of E. coli highly resistant to streptomycin are known to involve modification of the P10 protein of the bacterial ribosome 30S subunit.

Toxicity evaluation

Streptomycin: Acute oral LD₅₀ for mice >10 g/kg. Acute percutaneous LD₅₀ for male mice 400, female mice 325 mg/kg. May cause allergic skin reaction. NOEL: 125 mg/kg. Acute i.p. LD₅₀ for male mice 340, female mice 305 mg/kg. Streptomycin sesquisulfate: Acute oral LD₅₀ for rats 9, mice 9, hamsters 0.4 mg/kg.