The effect of co-trimoxazole on serum potassium concentration: safety evaluation of a randomized controlled trial

AIMS: Co-trimoxazole maintains a well-established role in the treatment of Pneumocystis jirovecii and Toxoplasma gondii, as well as urinary tract infections. Observational studies report hyperkalemia associated with co-trimoxazole which may stem from an amiloride-like potassium sparing effect. Our study reports on changes in serum potassium on patients without acute infections, and the influence of concomitant anti-kaliuretic drugs on this effect. 

METHODS: Post-hoc analysis of a randomised controlled trial in patients with interstitial lung disease who were assigned to placebo or 960 mg twice daily co-trimoxazole. Serum potassium and creatinine were measured at baseline, six weeks, 6, 9 and 12 months. Primary outcome was difference in mean serum potassium concentrations between co-trimoxazole and placebo at six weeks. 

RESULTS: Mean serum potassiums were similar at baseline, 4.24 (±0.44) mmol/L in the 87 co-trimoxazole group participants and 4.25 (±0.39) mmol/L in the 83 control participants. Co-trimoxazole significantly increased mean serum potassium at 6 weeks, difference between means compared to placebo of 0.21 mmol/L (95% Confidence Intervals [CI] 0.09-0.34; p = 0.001). This significant increase in serum potassium was detectable even after exclusion of patients on anti-kaliuretic drugs, difference between means for co-trimoxazole compared to placebo 0.23 mmol/L (95% CI 0.09-0.38, p = 0.002). There were 5/87 (5.7%) patients on co-trimoxazole whose serum potassium reached concentrations ≥5.5 mmol/L during the study period. 

CONCLUSIONS: Co-trimoxazole significantly increases serum potassium concentration, even in participants not using anti-kaliuretic drugs. Whilst the magnitude of increase is often minor, a small proportion in our outpatient cohort developed hyperkalaemia of clinical importance.