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Year : 1990  |  Volume : 56  |  Issue : 4  |  Page : 273-277

Adverse drug reactions to streptomycin-a reappraisal

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V Seth

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How to cite this article:
Seth V, Seth S D, Semwal O P, D'monty V. Adverse drug reactions to streptomycin-a reappraisal. Indian J Dermatol Venereol Leprol 1990;56:273-7

How to cite this URL:
Seth V, Seth S D, Semwal O P, D'monty V. Adverse drug reactions to streptomycin-a reappraisal. Indian J Dermatol Venereol Leprol [serial online] 1990 [cited 2018 May 20];56:273-7. Available from: http://www.ijdvl.com/text.asp?1990/56/4/273/3545

Ever since its discovery by Schatz, Bugle and Waksman in 1944[1], and profiling of clinical usefulness a little later, streptomycin has remained in use as a bactericidal antituberculosis agent. Along with its low cost and easy availability, its being injectable in nature ensures compliance and is a big point in favor for inclusion in the initial intensive phase of short course chemotherapy in the developing countries. In addition, it has limited indications in the treatment of bacterial endocarditis, tularemia and  Brucellosis More Details, and was highly effective in the treatment of all types of plague in the past. Unfortunately, it has been associated with a number of adverse reactions which limit its clinical usefulness. We intend to review them in this article.

  Adverse Reactions Top

Adverse reactions to streptomycin can be grouped as allergic and toxic.[2]

1. Allergic reactions have a variable time of onset but appear earlier, usually within three to seven weeks after starting the drug. However, anaphylactoid reaction is immediate and occurs in minutes while an occasional allergic reaction may be seen after 6 months of continuous therapy.[3],[4] These are reproducible with a single test dose within a period of 1 to 4 hours and are neither dose related nor specific for a particular drug thus making it difficult to determine their incidence and pinpoint the offending drug in combination chemotherapy.[5] In various series the allergic reactions have ranged from 3.6 to 12.9% of the patients .[2],[4],[6],[7],[8],[9],[10]

  Mechanism of Hypersensitivity Reactions Top

Anaphylactic reaction is type I and IgE mediated. Skin rashes and fever are type III reactions while blood dyscrasias are due to a type II reactions.[3] Keil and Trosow[11] thought that the streptidine portion of the streptomycin molecule was responsible for the allergic reactions since it contains guanidine groups which are skin allergens. However, Sandler[12] proposed that skin hypersensitivity was due to the sulphate radicle, since patients were able to tolerate the calcium chloride complex better.

The various allergic reactions may be listed as follows :

1) Anaphylaxis : This occurs within a few minutes of injection and may be fatal. Symptoms and signs are those of shock associated with a fall in blood pressure, dyspnea, cyanosis and collapse. Urticaria and angioedema may also occur. It is a rare complication.[13],[14],[15]

2) Exanthematous eruptions : Skin eruptions may be found in 5% of the persons being treated with streptomycin. These are hypersensitivity reactions and include morbiliform, maculopapular, erythematous and urticarial rashes, which are the most common of all the drug eruptions. Pruritus and scaling may also accompany the eruption. Exfoliative dermatitis may also be seen.

3) Serum Sickness

This is relatively uncommon. The symptoms and signs may be delayed for several days after the injection and take the form of malaise, a rise in body temperature, rigors, arthralgia, maculo-papular urticarial rash and severe conjunctivitis. Lymphadenopathy and eosinophilia are the other features. Drug fever is relatively uncommon. The increase in temperature is most likely due to sterile inflammatory reactions at the site of injection.

4) Atopy : An attack of asthma or hay fever may be precipitated by a single injection of streptomycin.

5) Local irritation at site of injection and topical application

In one Indian study it was the commonest allergic manifestation .[7]

II Toxic Reactions are quantitative, dose related, tend to occur more often with prolonged administration and occur even beyond six months of therapy. These are specific for the drug used, are not usually reproducible after a single test dose and are not treatable by means of desensitization. However they may be suppressed or overcome by a reduction of dosage. They are commoner in elderly patients. In a study by Smith and Zirk,[4] both allergic and toxic reactions to streptomycin were twice as common in women as in men. No adverse reactions (toxic or allergic) were seen in children.

The various toxic manifestations with streptomycin therapy may be listed as follows

1) Neurological

a) Ototoxicity :
Streptomycin has the potential to produce reversible and irreversible vestibular and cochlear toxicity. It progressively accumulates in the perilymph and endolymph of the inner ear when concentrations in plasma reach levels 5-6 times higher in the otic fluids than in plasma with resultant destruction of vestibular or cochlear sensory cells. With increasing dosage/exposure, damage progresses from the base of the cochlea where high frequency sounds are processed, to the apex necessary for the perception of low frequencies. Early changes may be reversible by calcium, but once sensory cells are lost, regeneration does not occur. Retrograde degeneration of the auditory nerve follows, resulting in irreversible hearing loss.

Streptomycin predominantly affects the vestibular system. Audiometry data[ 16] suggests that the incidence of ototoxicity may be as high as 25%. Nearly 20% of patients who received the drug in a dose of 500 mg twice daily for 4 weeks for enterococcal endocarditis developed clinically detectable, irreversible, vestibular damage. Upto 75% patients who received 2 gm of streptomycin for more than 60 days showed evidence of nystagmus or postural imbalance .[17] When 1 gm streptomycin was used, the incidence fell to 25%. Prazic and Salaj[18] found audiologically defined lesions in 36% of a group of 975 children treated with streptomycin sulphate for pulmonary tuberculosis. Hearing loss has also been reported in infants of tuberculous mothers treated with streptomycin during pregnancy.[19] Familial occurrence of drug induced toxicity has also been reported.[ 20] In a large Indian[21] study of short course chemotherapy regimes in the treatment of patients with pulmonary tuberculosis, 16.1% of the patients given streptomycin developed vertigo which was severe in 5% cases. In 10% of these patients the drug had to be stopped. Reduction of dosage was needed in about 20%. In another series of 1,744 patients[9] treated with various anti-tuberculous drugs, 10.3% developed intolerance to streptomycin. Involvement of the VIII cranial nerve was the commonest (46.8%) untoward reaction. Neff et a1[5] reported intolerance to streptomycin in 12.9% of their cases. In this series, also, vestibular and auditory dysfunction was the commonest.

b) Neuromuscular blockade

When administered intrapleurally or intraperitoneally in large doses, streptomycin causes neuromuscular blockade leading to acute muscular paralysis, apnoea and even death [22],[23] It acts by inhibiting prejunctional release of acetylcholine and decreasing post­synaptic sensitivity to it. Calcium overcomes this effect and is the preferred treatment of this toxicity. Acetylcholine inhibitor (edrophonium, neostigmine) have also been used.

c) . Others

Peripheral neuritis either direct or remote, paraesthesias,[24] optic nerve dysfunction[25] headache, lassitude, insomnia[25],[26] psychotic and euphoric states,[7] encephalopathy and encephalomeningitis have been described.[27]

2) Renal

Aminoglycosides are retained in the renal cortex by the proximal tubular cells causing renal impairment.[25] Streptomycin does not accumulate in the renal cortex and is the least nephrotoxic.[1]

3) Hematological manifestations

Eosinophilia,[17],[28] granulocytopenia[26] and anemia[26] have been described. Eosinophilia may be seen in 50% of the cases receiving streptomycin for an extended period of time. Neutropenia has been observed in 0.7% cases with a few cases progressing to frank agranulocytosis. Aplastic and hemolytic anemia and thrombocytopenia with purpura have also been observed in a few instances.[1]

4) Rheumatoid type of arthritis can occur from the continued use of this drug.[26]

5) Gastrointestinal nausea, vomiting, diarrhea[26] and

6) Hepatic involvement resulting in jaundice[26] may also be seen.

Recommendations for treating Adverse Drug Reactions

1) Anaphylactic shock

In anaphylactic shock, release of histamine or a histamine-like substance causes venous dilatation with an attendant increase in vascular capacity and reduction in cardiac output. It also results in arteriolar dilatation and a reduction of perfusion pressure, as well as increased capillary permeability with loss of intravascular volume.[29] The clinical features involving the­various systems are,[30] i) Bronchospasm, cyanosis, acute pulmonary edema, laryngeal edema, ii) Hypovolemia, shock, death, iii) Diffuse erythema, generalized pruritus, urticaria, angioneurotic edema, iv) Pain abdomen, vomiting, diarrhoea and v) Urgency, urinary incontinence.

Premonitory symptoms are frequent and include itching around the eyes, ears and throat, a feeling of being suddenly unwell, sneezing, hoarseness, loss of voice, coughing, anxiety, fear and lacrimation.

Since it is a catastrophic and often fatal reaction with onset within minutes of parenteral administration, its management should be immediate and intensive,[30] it requires : i) A tourniquet or band to be placed immediately above the site of injection to retard absorption, ii) Adrenaline given subcutaneously as 0.5 ml of 1 : 1000 solution in the other arm and 0.5 ml infiltrated round the site of streptomycin injection. It can be repeated after 15-20 minutes 3-5 times. It may also be administered intravenously if the patient is in shock or has hypotension. It is given as 0.5 ml of 1 : 1000 solution diluted in 10 ml of normal saline over a period of 10 minutes and can be repeated after 15-20 minutes. iii) Card iorespiratory resuscitation like a closed chest cardiac massage or mouth to mouth breathing, if needed, iv) Maintenance of airway by mechanical methods such as oral airways, endotracheal intubation or tracheostomy. Drugs such as adrenaline may be used in doses stated above for the relief of severe bronchosoasm though it is contraindicated in patients of myocardial infarction. Corticosteroids such as hydrocortisone hemisuccinate 100 mg or methylprednisolone 20-60 mg can also be administered intravenously either directly or as an infusion. They may also be given orally depending on the condition of the patient and can be repeated 6 hours for the next 24 hours. In milder cases, antihistaminics such as diohenhydramine intravenously in a dose of 60 mg may suffice. Aminophylline (250-500 mg) may also be given if needed, v) To maintain the blood pressure, the patient should be placed in shock position and intravenous vasoactive agents like dopamine in a dose of 10-20 µg/ kg/ minute may be administered. Fluid loss may be replaced by rapid intravenous administration of normal saline or plasma. Corticosteroids and adrenaline may also be given in doses stated above.

For proper management the patient may need hospitalization for 36-48 hours.

2) Drugs eruptions

The treatment of drug eruptions entails[31] discontinuation of the offending agent. In hospitalized patients, all drugs not absolutely necessary should be stopped. The treatment is essentially supportive in nature. An asymptomatic morbiliform eruption may need no intervention whereas an anaphylactic reaction necessitates prompt therapy. In case of pruritus, topical antipruritic lotions or oral antihistaminics may be administered. If epidermal barrier function is lost as in cases of exfoliative dermatitis saline or aluminum acetate compresses may be used to hasten drying and prevent infection. Special attention has to be paid to fluid and electrolyte balance and treatment of secondary infection in these cases.

Systemic corticosteroids as a modality of treatment enjoy widespread use.

Most drug eruptions have excellent prognosis and subside within 1-2 weeks after discontinuation of the drug. However, reactions may last for weeks or months. Anaphylaxis and exfoliative dermatitis may be fetal.

  References Top

1.Sande MA and Mandell GL : The aminoglycosides Antimicrobial agents, Goodman and Gilman's . The Pharmacological Basis of Therapeutics, Seventh Ed, Editors, Goodman LS, Gilman AG, Rail TW et al : MacMillan Publishing Co, New York, 1985, PP 1150.  Back to cited text no. 1    
2.Hutfield DC : Streptomycin sensitization, Brit J Vener Dis, 1965; 41 : 210-213.  Back to cited text no. 2    
3.Thompson JE : The management of hypersensitivity reactions to antituberculosis drugs, Med J Aust, 1969; 22 :1058-1063.  Back to cited text no. 3    
4.Smith JM and Zirk MH : Toxic and allergic drug reactions during the treatment of tuberculosis, Tubercle, 1961; 42 : 287-296.  Back to cited text no. 4    
5.Neff TA, and Coan BJ : Incidence of drug intolerance to antituberculosis chemotherapy, Dis Chest, 1969 : 56 : 10-12.  Back to cited text no. 5    
6.Aamodt T : Hypersensitivity reactions to streptomycin, paraaminosalicylic acid and isonicotinic acid hydrazide, Acta Tuber Scand, 1959; 37 : 195-202.  Back to cited text no. 6    
7.Chakravaarty S and Sircar DK : Allergic reaction due to streptomycin : Corroboration of clinical findings with streptomycin skin tests, Acta Tuberc Scand, 1961; 41 : 144-151.  Back to cited text no. 7    
8.Kallinowski SZ, Lioyd. TW and Moyes EN Complications in the chemotherapy of tuberculosis, Amer Rev Resp Dis, 1961; 83 : 359-371.  Back to cited text no. 8    
9.Berte SJ, Dimase JD and Christianson CS Isoniazid, paraaminosallicylic acid and streptomycin intolerance in 1,744 patients, Amer Rev Resp Dis, 1964; 90 : 598-606.  Back to cited text no. 9    
10.Deshmukh PA, Parekh KJ, Kundra N et al : Drug toxicity in tuberculosis, Ind J Tuber, 1981; 28 : 84­91.  Back to cited text no. 10    
11.Keil H and Trosow A : Eczzematous contact dermatitis due to streptomycin Ann Allergy, 1948; 6 : 435-438.  Back to cited text no. 11    
12.Sandler A : Management of hypersensitivity reaction to streptomycin. Brit J Tuber Dis Chest, 1955; a9 : 231-241.  Back to cited text no. 12    
13.Prasad R : Anaphylactic shock due too streptomycin sulphate, J Ind Med Assoc, 1984; 82 : 254-255.  Back to cited text no. 13    
14.Anzelov GO, Zolotaroviski VJ and Tvorvski AL Severe anaphylactic shock and clinical death after administration of streptomycin, Soviet Med, 1967; 30 : 114-115.  Back to cited text no. 14    
15.Basin LM: Severe anaphylactic shock after administration of streptomycin, complicated by right side hemiparesis and hearing disturbances, Antibiotic, 1969;, 13 : 53-56.  Back to cited text no. 15    
16.Moore RE, Smith CR and Lietman PS : Risk factors for the development of auditory toxicity in patients receiving aminoglycosides, J Infect Dis, 1984; 149 : 23-30.  Back to cited text no. 16    
17.Wilson WR, Wilkowski CJ, Wright AJ et al Treatment of streptomycin resistant enterococcal endocarditis, Ann Int Med, 1984; 100 : 816-823.  Back to cited text no. 17    
18.Prrazic M and Saiaj B : Ototoxicity in children caused by streptomycin, Audiology, 1975; 14 : 173­176.  Back to cited text no. 18    
19.Robinson GL and Cambon KG : Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy, N Eng J Med, 1964; 271 : 949-951.  Back to cited text no. 19    
20.Johnsonbaugh RE, Drexler HG, Light JJ et al : Familial occurrence of drug induced hearing loss, Am J Dis Child, 1974; 127 : 245-247.  Back to cited text no. 20    
21.Indian Council of Medical Research Centre Report : Study of Chemotherapy regimens of 5 and 7 months duration and the role of corticosteroids in the treatment of Sputum-positive patients with pulmonary tuberculosis in South India, Tubercle, 1983; 64:73-91.  Back to cited text no. 21    
22.Fisk GC: Respiratory paralysis after a large dose of streptomycin, Brit Med J. 1961: 556-557.  Back to cited text no. 22    
23.Mowaar SN and Mukerjee GD: Streptomycin toxicity as manifested by hypotension and complete flaccidity of muscle, J Ind Med Assoc, 1965 : 44: 557-558.  Back to cited text no. 23    
24.Doyle Jo: Unusual subjective reaction following di-hydrostreptomycin. Report of seven cases, Brit J Vener Dis, 1960; 36: 266-276.  Back to cited text no. 24    
25.Riches HRC: Streptomycin reactions; their characteristic features, incidence, etiology and means of prevention, Brit J Tuber. 1954; 48: 298­307.  Back to cited text no. 25    
26.Fein BT: Allergic and toxic reactions of prolonged chemotherapy for pulmonary tuberculosis, Dis Chest, 1959; 36: 286-292.  Back to cited text no. 26    
27.Ranger D: The dangers of streptomycin with particular reference to the Vestibular toxic effects, postgrad Med J. 1959; 35: 344-346.  Back to cited text no. 27    
28.Criep LH: Streptomycin and extrapulmonary tuberculosis-reactions to penicillin and streptomycin. Trans Nat Tubers Assoc, 1949; 45: 110-117.  Back to cited text no. 28    
29.Engelman K and Braaunwald E: Hypotesion and the shock syndrome. In: Harrison's Principles of Internal Medicine 9th ed, Editors, Isselbacher KJ, Adams RD, Braunwald E. et al; Mc Graw Hill International Book Co, Tokyo, 1981 p 178.  Back to cited text no. 29    
30.Vakil RJ: Allergic emergencies - Anaphylaxis , in Diagnosis and Management of Medical Emergencies, 3rd ed Editors Vakil Rj and Udwadia FE: Oxford Univ Press, New Delhi, 1988; pp 369­371.  Back to cited text no. 30    
31.Wintrobe BU, Schittman NJ and Arndt KA: Adverse cutaneous reactions to Drugs, in: Dermatolgy in General Medicine, 2nd ed, Editors Firzpatrick T B, Eisen AZ, Wolff K et al: McGrraw Hill Book Co, New York, 1979; p 555.  Back to cited text no. 31    


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