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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Anti-Infectives

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Anti-tubercular Drugs - Antimicrobials

Millions of people worldwide are infected with tuberculosis, with at least 10 million new cases and 1 million deaths reported each year. India is one of the countries with a high incidence of this disease which is rising alarmingly with the advent of AIDS.

Anti-tubercular Drugs

Millions of people worldwide are infected with tuberculosis, with at least 10 million new cases and 1 million deaths reported each year. India is one of the countries with a high incidence of this disease which is rising alarmingly with the advent of AIDS.

Drugs used in the treatment of tuberculosis belong to two categories:

·      First-line drugs—These drugs combine the greatest level ofefficacy with a relatively low level of toxicity. Examples: isoniazid, rifampicin, ethambutol, streptomycin, and pyrazi-namide.

·      Second-line drugs—Microbial resistance or other reasons(e.g. concomitant AIDS) may necessitate the addition of these drugs. Examples: ciprofloxacin, ofloxacin, ethiona-mide, aminosalicylic acid, cycloserine, amikacin, kana-mycin, capreomycin, and thioacetazone.

Some of these drugs have been discussed elsewhere, and only the important examples from the remainingwill be discussed here.

Isoniazid (Isonicotinic Acid Hydrazide; INH)

Isoniazid or INH represents the cornerstone of the treatment of tuberculosis, and is also the drug of choice for prophylaxis in case of positive tuberculosis skin test reaction. INH is the hydrazide of isonicotinic acid, and its isopropyl derivative iproniazid is a monoamine oxidase inhibitor used in the treat-ment of depression. INH is bactericidal for both extracellular and intracellular organisms. It is usually used with other antituberculous drugs such as rifampin and pyrazinamide. Isoniazid as sole therapy is only acceptable when used prophylactically.

Isoniazid is readily absorbed on oral or parenteral admin-istration, and diffuses easily into all body fluids and tissues. Upto 95% of the drug is excreted in the urine within 24 hours, mostly as metabolites. The main metabolic pathway involves acetylation followed by hydrolysis, the rate of acetylation being genetically and racially determined. Fast acetylation is char-acteristic of Japanese, Chinese, Eskimos, and Negroes, while slow acetylation is seen mainly among Scandinavians, Jews, and North African Caucasians. Fast acetylation is inherited as an autosomal trait. The plasma half-life is 0.7 hours in rapid acetylators and 2 to 4 hours in slow acetylators. In the presence of renal or hepatic dysfunction, slow acetylators can accumulate substantial amounts of INH in the plasma.

The principal metabolites of INH include acetyl isoniazid, isonicotinic acid, isonicotinyl glycine, isonicotinyl hydrazones, and traces of methylisoniazid.

The normal therapeutic dose of INH is 5 mg/kg/day to a maximum of 300 mg/day. Up to 10 mg/kg/day (600 mg/day) is occasionally used in severely ill patients. The incidence of adverse effects is about 5.4%. Main features include rash, fever, jaundice, and peripheral neuritis. Haematological effects include eosinophilia, agranulocytosis, anaemia, and thrombocy-topenia. Vasculitis has also been reported. The neurotoxicity of INH is due to vitamin B6 (pyridoxine) depletion. In the normal course, pyridoxine is phosphorylated by a specific kinase in the liver and then oxidised to pyridoxal phosphate by a flavopro-tein. The availability of pyridoxine is affected by INH in the following ways: INH combines directly with pyridoxine and forms an isonicotinyl-hydrazide complex which is excreted in the urine; it forms hydrazones which inhibit pyridoxine phosphokinase, the enzyme that converts pyridoxine to its active form; INH hydrazides inactivate pyridoxal 5-phosphate, rendering it ineffective. The net effect is that there is a decrease in the availability of gamma-aminobutyric acid (GABA) which is the main inhibitory neurotransmitter of the CNS, since pyridoxine is necessary for the synthesis of GABA. The resultant loss of inhibitory influence of GABA on the CNS is the presumed aetiology of INH-induced convulsions. The hepa-totoxicity of INH is mediated directly by its toxic metabolites.

Acute INH overdose is characterised by the clinical triad of convulsions, metabolic acidosis, and coma. Other features include vomiting, vertigo, hyperthermia, hypotension, hyper-glycaemia, glucosuria, and ketonuria. INH-induced convulsions are often severe and do not respond to anticonvulsant therapy. They may develop abruptly within 30 minutes to 3 hours after overdose. Status epilepticus may ensue with convulsions lasting for hours and requiring aggressive treatment. Rhabdomyolysis may develop in patients with protracted convulsions. The metabolic acidosis is asociated with a high anion gap, and is mainly due to build-up of lactate secondary to seizures. Severe anion gap metabolic acidosis (pH < 7.0) is common in patients who develop convulsions after INH overdose. The acidosis is frequently refractory to IV sodium bicarbonate therapy alone, but generally reverses after pyridoxine therapy. Mild hepatic dysfunction has been reported following acute overdoses of isoniazid. Clinical hepatitis with nausea, vomiting, fatigue, fever, abdominal pain, malaise, pruritus, and elevated liver function tests is less common, occurring in 0.3 to 1.3% of patients in most studies.

Chronic effects include hepatitis, peripheral neuropathy, optic neuritis, encephalopathy, psychosis, insomnia, vertigo, arthritis, backache, anorexia, constipation, vomiting, and haematological effects (anaemia, haemolysis, agranulocytosis, eosinophilia, and methaemoglobinaemia). Peripheral neuritis occurs in about 20% of patients receiving 6 mg/kg/day of INH without supplemental pyridoxine. It occurs most often in patients who are slow acetylators, and those who are malnour-ished, alcoholic, uraemic or diabetic. It is also dose related, occurring in 44% of patients receiving more than 16 mg/kg/ day. A pellagra-like syndrome may also occur with chronic INH therapy, characterised by dermatitis, diarrhoea, and dementia. Psychosis has been reported with isoniazid therapy.

Doses as low as 1.5 grams can induce toxicity. In relation to body weight, 10 to 30 mg/kg can cause seizures, while doses in excess of 50 mg/kg can cause death.

Treatment

·              Decontamination: Stomach wash can be done if the patient is seen within 1 to 2 hours post-ingestion and is asymptom-atic. If the patient is convulsing, seizures must be controlled and the airway secured before gastric lavage. Activated charcoal has been shown to be beneficial and should be administered in the usual manner.

·              Control of convulsions: Actively convulsing patients should be given diazepam 5 to 10 mg IV at a rate of 5 mg/min, which can be repeated after 10 to 20 minutes if convul- sions persist. There are however several reported cases of INH-induced convulsions not responding to diazepam even though it is a GABA-enhancing agent and should (theoretically) be effective. Phenytoin has been proven to be useless in this setting and must not be tried at all. If convul-sions are not controlled by the above measures, consider continuous infusions of midazolam (loading dose: 0.2 mg/ kg slow bolus; infusion: 0.75 to 10 mcg/kg/min), propofol (initial: 1 to 2 mg/kg, maintenance: 2 to 10 mg/kg/hr), or pentobarbitone (loading dose: 10 to 15 mg/kg at a rate of 50mg/min until burst suppression, or electrocerebral inactivity on EEG; maintenance: 0.5 to 1 mg/kg/hr). Endotracheal intubation, mechanical ventilation, and vasopressors will be required, and consultation with a neurologist is strongly advised. Occasionally, neuromuscular paralysis may be required to avoid hyperthermia, severe acidosis, and rhab- domyolysis; continuous EEG monitoring is mandatory if neuromuscular paralysis is used.

·              Antidote: Pyridoxine should be given to all patients (symptomatic or asymptomatic) who are suspected to have ingested a large amount of INH (>80 mg/kg). The recom- mended dose is 1 gram IV for every gram of INH ingestedto a maximum of 5 grams, at a rate of 1 gram every 2 to 3minutes. If the amount of INH ingested is unknown, a doseof 5 grams may be administered to an adult, or 70 mg/kgin a child (upto a maximum of 5 gm). This can be repeated after 30 minutes if seizures persist. Combining pyridoxine with diazepam is said to be synergistic and therefore recom-mended. But while pyridoxine is a relatively safe antidote, there is some indication that it may cause severe sensory neuropathy if given in very large doses, and so caution should not be thrown to the winds while administering it.

·              Management of acidosis: If acidosis does not respond to pyridoxine, diazepam, or IV fluids, sodium bicarbonate can be given at a dose of 44 to 88 mEq/L by IV bolus. But care should be taken to see that it is not mixed with pyridoxine solution.

·              Supportive measures : If aspiration pneumonitis develops, endotracheal intubation must be done and intermittent positive pressure breathing undertaken. Hypotension can be managed by IV fluids.

·              Elimination enhancement: INH is dialysable since it has a low volume of distribution and is not much protein-bound. Haemodialysis is preferable to peritoneal dialysis. In the case of the latter, pyridoxine may be added to each litre of fluid used for dialysis. Haemoperfusion and exchange transfusion have also been successfully employed in INH overdose.

Rifampicin (Rifampin; Rifamycin)

Rifampicin is a semisynthetic derivative of rifamycin B which is one of a group of structurally similar, complex macrocyclic antibiotics produced by Streptomyces mediterranei. Rifampicin and INH (given together) are the most effective drugs avail- able for the treatment of tuberculosis. The former is also used in the prophylaxis of meningococcal disease and H.influenzae meningitis.

A related drug, rifabutin (derived from rifamycin S) is used in the prophylaxis of mycobacterium avium complex-mediated infection in AIDS patients and shares some of the toxic mani-festations of rifampicin.

Adverse effects of rifampicin include rash, fever, nausea and vomiting, and jaundice. In some patients a flu-like syndrome develops, characterised by fever, chills, and myalgia. There may also be interstitial nephritis, acute tubular necrosis, and haematological disturbances (thrombocytopenia, haemo-lytic anaemia, eosinophilia).

Rifampicin is a potent inducer of hepatic microsomal enzymes and therefore reduces the half-life of a number of drugs including anticoagulants, barbiturates, clofibrate, contraceptives (oral), corticosteroids, cyclosporine, digitoxin, fluconazole, halothane, ketoconazole, methadone, metoprolol, propranolol, quinidine, sulfonylureas, theophylline and verapamil.

Rifampicin is a hepatotoxic poison. Toxic hepatitis appears more frequently and with greater severity during combination therapy with INH. This is noted most frequently in children. Apart from liver failure, overdose of this drug produces vomiting, flushing, angioedema, periorbital and facial oedema, mental changes, and pulmonary oedema. Patients typically present with nausea, vomiting, mental status changes, and reddish discolouration of the skin. Renal failure occurs less frequently. Thrombocytopenia, haemolytic anaemia, meth-aemoglobinaemia, hypothrombinaemia, transient leukopenia,and anaemia have been reported following chronic ingestion of therapeutic doses. Hypersensitivity reactions include fever, pruritus, urticaria, various skin eruptions, polyarthropathy, and soreness of the mouth and tongue.

Overdosage can rarely result in convulsions, arrhythmias, pulmonary oedema, and death. Ingestion of more than 14 grams is potentially lethal. Since rifampicin and its metabolites are red in colour, overdose results in a characteristic orange-red staining of tissues, urine, faeces, saliva, tears, and sweat (Redman syndrome). Sclerae may also appear yellow-orange incolour. Cutaneous staining can be partially removed by washing or scrubbing.

Treatment

■■  Monitor CBC, renal and hepatic function tests in symp-tomatic patients. Elevated total bilirubin level is the most common finding, and may be due to interference of rifampicin with the bilirubin assay. Liver function tests and renal tests should be closely followed.

■■  Activated charcoal can be administered.

■■  Convulsions must be treated with benzodiazepines in the usual maner.

■■  Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases. Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 ml/kg) is preferred if ARDS develops.

■■  Since rifampicin has an extensive volume of distribution and is significantly protein-bound, it is not eliminated well by haemodialysis or haemoperfusion.

Ethambutol

Ethambutol is a synthetic bacteriostatic antituberculous drug which is effective only in actively growing cells. Ethambutol is effective as adjunctive therapy for the treatment of tuberculosis, but is not indicated as monotherapy for this disease. It is also used in combination to treat other mycobacterial infections including Mycobacterium avium-complex. It is usually given in combination with INH.

The most important adverse effects are related to the eyes: optic neuritis (resulting in diminished visual acuity and red-green discrimination), constriction in visual fields, and even blindness. These effects may be unilateral or bilateral, and are usually reversible. Optic neuritis is the principal side effect of ethambutol therapy, but usually manifests at doses in excess of 15 mg/kg. Other effects include GI upset, pruritis, arthralgia, vertigo, confusion, and peripheral neuritis. Gouty arthritis has been reported after therapeutic administration of ethambutol.

Acute overdose results in nausea, vomiting, abdominal pain, fever, confusion, hallucinations, and retrobulbar neuritis (if the dose exceeds 10 gm). Acute overdose involving both ethambutol and isoniazid may result in synergistic nervous system toxicity.

Treatment involves supportive measures. Haemo­dialysis or peritoneal dialysis may be beneficial. Patients with optic neuritis can benefit from parenteral hydroxycobalamine 40 mg/day for 10 to 28 weeks followed by a reduced dose of 20 mg/day. Deaths have so far not been reported in ethambutol overdose.

Pyrazinamide

It is an analogue of nicotinamide and is bactericidal to actively dividing tubercle bacilli. Pyrazinamide is well absorbed orally and is widely distributed throughout the body. It is partly hydrolysed to pyrazinoic acid and then hydroxylated to 5-hydroxypyrazinoic acid and excreted.

The most serious adverse effect is hepatitis with jaundice, and even death may occur from hepatic necrosis. Pyrazinamide is therefore contraindicated in individuals suffering from hepatic dysfunction or disease.

Acute overdose involving this drug has rarely been reported.

Ethionamide

It is a bacteriostatic anti-TB drug which is associated with the following adverse effects: nausea, vomiting, metallic taste, postural hypotension, mental depression, blurred vision, head-ache, tremor, skin rashes, impotence, menorrhagia, alopecia, and hepatitis. Concomitant administration of pyridoxine is advisable. Monitor liver enzyme levels after significant over-dose. Monitor electrolytes in patients with severe vomiting or diarrhoea. Monitor for evidence of encephalopathy after significant overdose. Case reports suggest that pyridoxine, nicotinamide and parenteral multiple vitamins may be useful in the treatment of ethionamide-induced encephalopathy.

Use of ethionamide should be avoided during pregnancy or in women of childbearing age, unless the benefits outweigh its potential hazards: developmental anomalies (congenital heart disease, spina bifida, spinal anomalies, Down’s syndrome and possible hydrocephalus).

Cycloserine

It is a broad-spectrum antibiotic elaborated by Strep. orchida­ceus, which acts by interfering with bacterial cell wall synthesis.Adverse effects include drowsiness, headache, tremor, dysar-thria, vertigo, confusion, psychosis, and convulsions. Other effects include megaloblastic anaemia, polyarthritis, and a pellagra-like syndrome. Concomitant administration of pyri-doxine is advisable. 

Capreomycin

It is an antimycobacterial agent elaborated by Strep. capreolus, and must be given only by intramuscular or intravenous injec-tion. Capreomycin is used concomitantly as part of a multidrug regimen to treat tuberculosis that is resistant to other therapy. It may also be used to treat infections due to other Mycobacterial species. Electrolyte abnormalities and metabolic alkalosis may occur with therapeutic use. Leukocytosis, eosinophilia, and various skin rashes may occur. Adverse effects include ototoxicity similar to streptomycin, and renal tubular damage. Severe renal tubular dysfunction and tubular necrosis have occurred. Loss of visual acuity has been rarely reported with capreomycin therapy. The ototoxicity, nephro-toxicity, and neuromuscular blocking effects of aminoglycoside antibiotics may be increased by concomitant administration of capreomycin. Capreomycin is a possible inducer of Bartter’ssyndrome.*

There is no antidote for capreomycin overdose. Treatment is symptomatic and supportive. Haemodialysis may be helpful in overdose.

Thioacetazone

It was formerly widely employed in India (in combination with INH) because of its low cost. However it is extremely toxic, and death can result even from therapeutic doses (150 mg). Patients with AIDS (or HIV seropositivity) are particularly susceptible, and therefore the drug is contraindicated. When given along with streptomycin, thioacetazone can potentiate the former’s tendency to cause ototoxicity. Adverse effects include vomiting, anorexia, conjunctivitis, mild to severe skin eruptions, vertigo, convulsions and cerebral oedema.

 

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