Cotrimoxazole

Trimethoprim was specifically developed in the late 1960s as a sulphonamide potentiator and was launched in combination with sulfamethoxazole as cotrimoxazole. Laboratory data showed synergy of antimicrobial action for the combination and suggested that the use of both agents would delay the emergence of resistance. However, the tissue distribution of trimethoprim and sulfamethoxazole does not favour synergy, and resistance among common pathogens to sulfamethoxazole is high. Clinical studies comparing trimethoprim alone with cotrimoxazole for the treatment of respiratory tract and urinary tract infections have failed to show any benefit from the combination. The development of delayed resistance by use of the combination has not been substantiated. The common adverse effects seen with cotrimoxazole are gastrointestinal disturbances and skin rashes which are well described adverse effects of sulphonamides. Comparative studies suggest that these are less common with trimethoprim alone. Serious adverse effects such as liver disorders and Stevens-Johnson syndrome appear more common with cotrimoxazole. Where there is little evidence for benefit from the use of the combination, the exposure of patients to the additional risk from the adverse effects and drug interactions of 2 drugs cannot be justified. Therefore use of cotrimoxazole should be restricted to those situations such as Pneumocystis carnii pneumonia where the combination has been shown to be beneficial.

Sulfamethoxazole (SMX) and trimethoprim (TMP) individually and a combination known as cotrimoxazole (SMX-TMP) are widely used for the treatment of protozoan and bacterial infections. SMX-TMP is also one of the widely used antibiotics administered orally in neonates, along with gentamicin injection, for treating pneumonia and sepsis by home-based healthcare providers in Asian countries. Although the use of this drug has successfully reduced neonate mortality, there is a concern for it causing neurotoxicity. Previous clinical studies with sulfisoxazole have demonstrated occurrence of kernicterus in neonates. This sulfonamide is thought to displace bilirubin from its albumin-binding sites in plasma leading to an elevation of plasma bilirubin, which crosses the blood-brain barrier, reaches central neurons to cause kernicterus. We performed an extensive review of clinical and animal studies with cotrimoxazole, which showed no reported incidences of kernicterus with SMX-TMP use in neonates. EndNote, BasicBiosis, Embase, PubMed and Toxline database searches were conducted using specific keywords yielding 74 full-length articles relevant to the review. This review has taken into account various factors, including the disease itself, direct effects of the drug and its metabolism through conjugation and acetylation through a thorough review of the literature to examine the potentials of SMX-TMP to cause kernicterus in neonates. SMX-TMP in oral doses administered to neonates for 7-10 days is unlikely to cause kernicterus. Also, this review recommends warranting the need of future studies using animal models and clinical studies in humans to address SMX-TMP toxicity.

A70-year-old man, with established hypoadrenalism due to a previous bilateral adrenalectomy, was admitted with recurrent episodes of postural dizziness and presyncope. He had been discharged from hospital 3 weeks earlier on a 1-month course of cotrimoxazole following a diagnosis of prostatitis. His electrolytes on admission showed new onset hyponatraemia and hyperkalaemia.His usual glucocorticoid replacement dose was doubled in view of a presumed diagnosis of hypocortisolaemia. However, the hyperkalaemia persisted. On rereviewing his treatment, we suspected a possible diagnosis of cotrimoxazole-induced hyperkalaemia. Cotrimoxazole was stopped and ciprofloxacin started instead. His fludrocortisone replacement was doubled for 3 days after stopping treatment to decrease his postural symptoms. His postural symptoms improved, his serum potassium decreased to normal levels and he was safely discharged.It is essential to remember that cotrimoxazole, a commonly used antibiotic, can induce a potentially fatal hyperkalaemia especially in patients with known hypoadrenalism.