Abstract
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 hyperkalaemia to be associated with co‐trimoxazole, which may stem from an amiloride‐like potassium‐sparing effect. The current study investigated changes in serum potassium in patients without acute infections, and the influence of concomitant antikaliuretic drugs on this effect.
Methods
A post hoc analysis was carried out of a randomized controlled trial in patients with interstitial lung disease who were assigned to placebo or 960 mg co‐trimoxazole twice daily. Serum potassium and creatinine were measured at baseline, 6 weeks, and 6, 9 and 12 months. The primary outcome was the difference in mean serum potassium concentrations between co‐trimoxazole and placebo at 6 weeks.
Results
Mean serum potassium levels were similar at baseline: 4.24 (± 0.44) mmol l–1 in the 87 co‐trimoxazole group participants and 4.25 (± 0.39) mmol l–1 in the 83 control participants. Co‐trimoxazole significantly increased mean serum potassium levels at 6 weeks, with a difference between means compared with placebo of 0.21 mmol l–1 [95% confidence interval (CI) 0.09, 0.34; P = 0.001). This significant increase in serum potassium was detectable even after exclusion of patients on antikaliuretic drugs, with a difference between means for co‐trimoxazole compared with placebo of 0.23 mmol l–1 (95% CI 0.09, 0.38; P = 0.002). There were 5/87 (5.7%) patients on co‐trimoxazole whose serum potassium concentrations reached ≥5.5 mmol l–1 during the study period.
Conclusions
Co‐trimoxazole significantly increases serum potassium concentration, even in participants not using antikaliuretic drugs. While the magnitude of increase was often minor, a small proportion in our outpatient cohort developed hyperkalaemia of clinical importance.
Keywords: adverse effect, co‐trimoxazole, hyperkalaemia, serum potassium
What is Already Known about this Subject
Co‐trimoxazole has an established role in treating urinary tract, Pneumocystis jirovecii and Toxoplasma gondii infections.
Observational studies have suggested that a combination of co‐trimoxazole and antikaliuretic medications is associated with sudden death through severe hyperkalaemia.
There are no placebo‐controlled randomized trials with data on serum potassium levels to demonstrate these changes.
What this Study Adds
Our trial demonstrates a significant increase in serum potassium in co‐trimoxazole users compared with placebo.
These findings were also seen in patients after accounting for prescribed concomitant antikaliuretic medications.
The magnitude of increase was not large but would be of importance to patients with serum potassium at the higher end of normal.
Tables of Links
| TARGETS | |
|---|---|
| G protein‐coupled receptors 2 | Enzymes 5 |
| Angiotensin receptor | Angiotensin‐converting enzyme |
| β1‐adrenoceptor | Cyclooxygenase 1 |
| Nuclear hormone receptors 3 | Cyclooxygenase 2 |
| Glucocorticoid receptor | Dihydrofolate reductase |
| Mineralocorticoid receptor | Thymidylate synthetase |
| Transporters 4 | Voltage‐gated ion channels 6 |
| Kidney‐specific Na‐K‐Cl symporter | Calcium‐activated potassium channel |
| Na‐Cl symporter |
| LIGANDS |
|---|
| Folinic acid |
These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2, 3, 4, 5, 6.
Introduction
Co‐trimoxazole (a combination of the antibiotics trimethoprim and sulfamethoxazole) is a commonly used treatment in the United States for urinary tract infections 7, and a reported 4000 prescriptions a month are dispensed in Canada. Following concerns in the UK of antibiotic‐related Clostridium difficile colitis from other broad‐spectrum antibiotics, co‐trimoxazole is regaining favour 8 and maintains a well‐established role in the treatment and prophylaxis of Pneumocystis jirovecii and Toxoplasma gondii infections 9.
The link between this drug and hyperkalaemia lies in trimethoprim's mechanism of action, which has been described by laboratory and animal studies as being akin to the potassium‐sparing effect of amiloride, where sodium channel activity is inhibited 10, 11, 12. Earlier studies identified that those with more inherent defects in potassium homeostasis had a higher risk of exacerbation of this antikaliuretic effect, including patients with acquired immunodeficiency syndrome 13 and acutely unwell hospitalized patients with mild renal insufficiency 10, 11, 14. Recently, there has been a focus in the literature on evaluating the effects of concomitant medication such as inhibitors of the renin–angiotensin system 15, 16, spironolactone 17 and beta‐adrenoceptor antagonists 18 on precipitating sudden, severe hyperkalaemia, which might be a mechanism behind the increased risk of sudden death in co‐trimoxazole users, especially in elderly patients. It is speculated that the interactions between these drugs and co‐trimoxazole may exacerbate the amiloride‐like inhibition of sodium channels in the luminal membrane of the distal tubule, resulting in impaired potassium secretion.
However, much of the data are observational in nature 15, 17, and few studies have had access to or reported serum potassium levels obtained through protocolized long‐term follow‐up in a high‐quality randomized controlled trial. We undertook a post hoc analysis of a placebo‐controlled randomized controlled trial with 12 months’ follow‐up, to evaluate the effect of standard‐dose co‐trimoxazole on serum potassium concentrations. We also aimed to evaluate the change in serum potassium concentrations in separate subgroups of participants according to their baseline history of concomitant medications that can increase serum potassium concentrations – namely, angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and potassium‐sparing diuretics.
Methods
The present study was a post hoc analysis of a multicentre randomized, placebo‐controlled, double‐blinded, parallel‐arm trial of the use of co‐trimoxazole for the treatment of idiopathic pulmonary fibrosis. Briefly, the trial recruited patients from 28 university and district hospitals in England and Wales between January 2008 and 2009. Patients randomized to the treatment arm received the standard dose of 960 mg (two tablets of 480 mg each) co‐trimoxazole twice daily (320 mg trimethoprim, 1600 mg sulfamethoxazole) plus folic acid. Controls were given placebos of identical appearance, plus folic acid. Laboratory testing, including determination of urea and electrolytes, was performed at baseline, 6 weeks and 6, 9 and 12 months as part of the safety monitoring of the study. The full methodology is reported by Shulgina et al. 19. Ethical approval for the research was obtained from the Cambridgeshire 4 Research Ethics Committee (reference number: 07/MRE05/45). The study was adherent to the Declaration of Helsinki and conducted in accordance with good clinical practice. The safety of the trial was monitored by independent oversight committees [Data Monitoring and Ethics Committee (DMEC) and Trial Steering Committee (TSC)], which had access to all serious adverse events reporting and withdrawals. All patients gave written informed consent. Age, gender, comorbidities and concurrent medications were recorded at baseline.
The primary outcome of the trial was the change in forced vital capacity (FVC) after 12 months. For the present post hoc analysis, the main outcome of interest was the first follow‐up serum potassium measurement at 6 weeks after study entry. Secondary outcomes included serum potassium concentrations at later time points, as well as serum creatinine concentrations.
Statistical analysis
All analyses were conducted using IBM SPSS Statistics 22, IBM Corporation (Armonk, New York City, United States). We calculated mean values and standard deviations (SD) for serum potassium and creatinine concentrations over the study period at each measurement point. We assessed the homogeneity of variance using Levene's test and used the independent t‐test to evaluate differences between the two intervention arms. For categorical adverse events, we used the chi‐squared test to evaluate differences between groups. Pearson's correlation coefficient was used to describe the relationship between two continuous variables in the trial participants.
The main outcome was the difference in mean potassium concentrations between the treatment and placebo groups at the 6‐week follow‐up. We also calculated the change in potassium concentrations against baseline at all time points for each individual patient, and compared the mean change between the two groups.
In a preplanned analysis, we evaluated the primary outcome in subgroups of patients who were or were not using drugs that retain potassium (ACEIs, ARBs or potassium‐sparing diuretics) at baseline.
Results
A total of 181 patients were enrolled onto the original study, of whom 86 were randomized into the placebo group and 95 into the treatment group. These groups were stratified for azathioprine and mycophenolate mofetil use only. Table 1 summarizes the baseline characteristics of patients included in the complete case analysis, where both baseline and 6‐week follow‐up potassium levels were available in included patients. Appendix S1 lists the baseline characteristics of the entire treatment and placebo group. Baseline mean potassium, serum creatinine and the number of patients taking medications that could alter potassium homeostasis were distributed equally between the groups. All patients enrolled in the study provided a serum potassium and creatinine level at baseline. The availability of follow‐up data diminished as the study progressed, owing to adverse events, discontinuation of interventions and withdrawal of consent (n = 83, 65, 57 and 54 in the placebo group, and n = 87, 63, 51, 53 in the treatment group at 6 weeks, 6 months, 9 months and 12 months, respectively). Blinded interim analysis showed no significant difference in the percentage of patients dying, or average number of adverse or serious adverse events between the two groups.
Table 1.
Baseline characteristics of complete case analysis
| Placebo (n = 83) | Co‐trimoxazole (n = 87) | |
|---|---|---|
| Characteristic | Mean/number (SD/%) | Mean/number (SD/%) |
| Age (years), mean ± SD | 70.86 (8.25) | 72.54 (8.45) |
| Number or women (%) | 20 (24.1) | 29 (33.3) |
| Number of patients with hypertension (%) | 22 (26.5) | 19 (21.8) |
| Number of patients taking potassium‐altering drugs (%) | 66 (76.7) | 61 (64.2) |
| ACE inhibitors | 13 (15.7) | 13 (14.9) |
| Angiotensin receptor blockers | 8 (9.6) | 15 (17.2) |
| Potassium‐sparing diuretics | 0 (0) | 1 (1.1) |
| Potassium supplements | 0 (0) | 1 (1.1) |
| Loop diuretics | 10 (12.0) | 15 (17.2) |
| Thiazide diuretics | 5 (6.0) | 7 (8.0) |
| Aspirin | 27 (32.5) | 33 (37.9) |
| NSAIDs (not including aspirin) | 1 (1.2) | 1 (1.1) |
| Beta‐adrenoceptor antagonists | 15 (18.1) | 13 (14.9) |
| Prednisolone | 51 (61.4) | 49 (56.3) |
| Mean K+ concentration, mmol l–1 (SD) | 4.25 (0.39) | 4.24 (0.43) |
| Mean serum creatinine level, mmol l–1 (SD) | 89.0 (21.8) | 88.96 (25.0) |
| ACE, angiotensin‐converting enzyme; NSAID, nonsteroidal anti‐inflammatory drug; SD, standard deviation |
Main outcome: difference in means between groups
At the 6‐week follow‐up, the mean serum potassium concentration in the treatment group (4.46 ± 0.41 mmol l–1) was significantly higher than in the placebo group (4.24 ± 0.40 mmol l–1), which represents a difference between means of 0.21 [95% confidence interval (CI) 0.09, 0.34] mmol l–1; P = 0.001.
The mean serum potassium concentrations recorded at the four study follow‐up visits are shown in Figure 1 and Appendix S2. The data showing the changes from baseline serum potassium are shown in Figure 3 and Appendix S3, and indicate significant incremental rises in serum potassium with co‐trimoxazole compared with placebo at all follow‐up points.
Figure 1.
Mean serum potassium in the co‐trimoxazole and placebo arms of the study. The Illustrated error bars depict the standard error for each measurement
Figure 3.
Mean serum creatinine in co‐trimoxazole and placebo arms. The illustrated error bars depict the standard error for each measurement
The largest increase in serum potassium over the entire trial was 1.7 mmol l–1, which was recorded in a patient receiving co‐trimoxazole. We found that 15/87 (17%) patients on co‐trimoxazole experienced a change of ≥ +1 mmol l–1 in serum potassium at any point in the study, compared with 3/83 (3.6%) in the control arm. The relative risk of a rise of ≥ +1 mmol l–1 in serum potassium with co‐trimoxazole was 4.77 (95% CI 1.43,15.88) compared with placebo.
We found that 25/87 (29%) of patients in the treatment group had a peak serum potassium ≥5.0 mmol l–1 at any point in the follow‐up, compared with 15/83 (18%) patients in the control arm. The relative risk of a serum potassium level of ≥5.0 mmol l–1 at any point in the trial was 1.59 (95% CI 0.90, 2.80) with co‐trimoxazole compared with placebo.
Overall, 5/87 (5.7%) patients in the co‐trimoxazole arm had a serum potassium level of ≥5.5 mmol l–1, compared with 1/83 (1.2%) in the control arm. There were no reports of hyperkalaemia as a cause of a serious adverse event or a reason for patient withdrawal.
A preplanned analysis on mean serum potassium from baseline to 6 weeks was performed on a subgroup of patients, whereby we excluded baseline users of (ACEIs), ARBs or potassium‐sparing diuretics (n = 28). Figure 2 illustrates our finding of a significant increase in serum potassium concentrations in the treatment group compared with placebo [0.23 mmol l–1 (95% CI 0.09, 0.38); P = 0.002], even in the absence of concomitant use of drugs that have been implicated in hyperkalaemia. When we considered the small subgroup comprising users of ACEIs, ARBs or potassium‐sparing diuretics, the difference in mean potassium concentrations between co‐trimoxazole and placebo arms was not statistically significant [0.14 mmol l–1 (95% CI –0.10, 0.38); P = 0.24].
Figure 2.
Mean serum potassium in users and non‐users of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers or potassium‐sparing diuretic users at baseline and 6 weeks. The illustrated error bars depict the standard error for each measurement
Secondary outcomes
Figure 3, Appendix S2 and Appendix S3 illustrate the mean serum creatinine concentrations in treatment and placebo group at 6 weeks, and 6, 9 and 12 months. At the 6‐week follow‐up, the mean serum creatinine concentration in the treatment group (105.79 ± 33.43 mmol l–1) was significantly higher than in the placebo group (89.81 ± 18.10 mmol l–1), which represents a difference between means of 15.99 (95% CI 7.88, 24.09) mmol l–1 (P = 0.005).
The elevation in creatinine was persistent at further follow‐up measurements (Appendix S2 and S3). We found a moderate positive correlation between the change from baseline in potassium and creatinine concentrations at 6 weeks [r(168) = 0.383; P < 0.0005].
Renal adverse events
On reviewing reported adverse events in patients in the co‐trimoxazole group, 10/95 (11%) patients were reported to have a deterioration in renal function compared with 3/86 (3.5%) in the placebo group (P = 0.78). Seven of these 10 patients in the co‐trimoxazole group went on to complete the study while three were unable to continue after the 6‐week follow‐up. There was a downward trend in serum creatinine for these patients on follow‐up testing up to 2 months later. Renal impairment was specifically mentioned in the original study publication; however, individual electrolyte levels have not previously been published.
Discussion
Main findings
In the present post hoc analysis of a blinded, placebo‐controlled, randomized controlled trial, we demonstrated a significant increase in measured serum potassium at 6 weeks in patients taking co‐trimoxazole compared with those on placebo. We note that the significant increase in serum potassium concentrations occurred even in patients who were not taking concomitant ACEIs, ARBs or potassium‐sparing diuretics with co‐trimoxazole, thus indicating that this adverse effect was not due to a specific drug interaction. Although the magnitude of the increase was clinically modest in most patients, we found that about one in seven patients in the treatment group were affected by increases of ≥1.0 mmol l–1. Approximately one in 25 patients receiving co‐trimoxazole had a peak serum potassium level that exceeded 5.5 mmol l–1, which is a concentration that we would consider to be of major clinical concern. We also noted a concurrent increase in serum creatinine with co‐trimoxazole therapy within the first 6 weeks of starting treatment.
Comparison with the literature
Co‐trimoxazole has been linked to sudden death through the postulated mechanism of precipitating life‐threatening hyperkalaemia. The precise renal mechanism has been previously described 10, through human and animal studies. Trimethoprim inhibits renal potassium excretion by blocking sodium channels in the distal nephron and decreasing the electrical driving force favouring potassium secretion. We report findings which can be attributed to the described mechanism. There was a significant rise in mean serum potassium at 6 weeks, followed by a sustained increase from baseline at the three further potassium measurements. This trend appeared to be replicated in serum creatinine measurements. A rise in serum creatinine is secondary to a well‐described mechanism related to the trimethoprim component of co‐trimoxazole, which competitively inhibits tubular creatinine secretion 20. Previous studies have demonstrated a rise in serum creatinine with a concomitant fall in creatinine clearance and no significant change in glomerular filtration rate 21. The mechanism for the moderate correlation between the increase in potassium and creatinine concentrations is not clear, and further research into the possibility of a nephrotoxic effect may be indicated.
Four large population studies have examined this life‐threatening complication of hyperkalaemia, thought to be induced by a drug interaction with co‐trimoxazole. Antoniou et al. reported the highest risk of hospital admission with hyperkalaemia 17 or sudden death 22 in patients concurrently taking spironolactone. The same group also reported a higher risk of hospitalization with hyperkalaemia and sudden death in patients taking co‐trimoxazole alongside inhibitors of the renin–angiotensin system in comparison with those prescribed other antibiotics. This reaction is thought to be linked to the amiloride properties of trimethoprim, which are further perpetuated by the antagonistic effects of ACEIs, ARBs and potassium‐sparing diuretics on aldosterone. By contrast, the present study did not demonstrate evidence of life‐threatening serum potassium concentrations across all patients, even in those taking medications whose mechanisms of action involve aldosterone.
The strength of previous studies lies in the large amount of data that they captured in electronic databases over a significant period of time. However, none of these studies had access to serum potassium measurements. There also remains an important question of whether confounding was adequately accounted for in the previous observational datasets.
Strengths and limitations of the present study
Unlike in the current work, few studies have had access to serial serum potassium measurements in a protocolized manner with a randomized controlled trial. A large analysis of 6162 patients prescribed high‐ and standard‐dose co‐trimoxazole 23 has been reported; however, serum potassium measurements in that study were recorded, if available, at variable times up to 30 days after the initial prescription was made, making it difficult to comprehend the context in which the serum potassium was measured. Similarly, a retrospective analysis of the serum potassium of 53 patients while on co‐trimoxazole 24 showed significant increase in serum potassium to a mean of 4.67 mmol l–1 (P = 0.017). Again, serum potassium recordings were taken within 5 days of prescription or as close as possible to that time window, with no knowledge of the patient's medical situation at the time. To our knowledge, there has only been one randomized controlled trial including prospective serum potassium measurements 25. The latter was an unblinded randomized controlled trial of 97 outpatients, where patients randomized to the control group were those treated with other antibiotics. All patients in that study had one follow‐up serum urea and electrolyte measurement taken, on day 5 of treatment. Only 6% (n = 3) of their cohort developed severe hyperkalaemia ≥5.5 mmol l–1, which is comparable to the 2.6% of patients in the study by Gentry et al. 23 who developed grade 1 hyperkalaemia (5.6–6.0 mmol l–1). Unlike the present study, this study was not blinded, and patients were receiving active control drugs rather than placebo.
The results of the present study were comparable with those reporting serum potassium measurements in an outpatient setting. The present study built on those previously described as it was performed on well patients, with no acute infections, in a blinded, randomized, placebo‐controlled setting. We were able to account individually for all potassium‐altering medications in each patient, and for the first time report on the sustained, longer‐term effects of co‐trimoxazole on a patient's serum potassium and creatinine levels. We recognize that our study was limited by the small sample size, a time‐varying effect, and losses to follow‐up that led to fewer available serum potassium measurements as the study progressed. However, we are able to report definitively that the withdrawal of patients was not precipitated by clinically relevant hyperkalaemia. Only three of the 10 patients with reported renal deterioration were unable to complete the study after 6 weeks. It was also reassuring to note the improvement in their RF after withdrawal from treatment, confirming the reversible nature of the impairment. Finally, we did not have sufficient numbers of patients with markedly elevated potassium concentrations to be able to identify reliably the patient risk factors that predispose to this adverse effect. The mean age of the co‐trimoxazole group was 72.38 (SD 8.45) years; we were unable to investigate the effect of age on the increase in serum potassium. The older age of the study population might have contributed to a larger increase in serum potassium, independently of concomitant antikaliuretic medication use. It is also possible that there is an underlying genetic predisposition that renders some patients susceptible to hyperkalaemia with co‐trimoxazole but the present trial was not designed to investigate such pharmacogenetic markers.
Conclusion
Over the course of our study, we did not identify a significant risk of patients developing life‐threatening hyperkalaemia, even with up to a year's exposure, and we found no evidence of an interaction with antikaliuretic agents. However, we are conscious that a small minority of patients experienced potassium elevations to a degree that may raise clinical concern. Therefore, there should be far greater caution in those who already have serum potassium concentrations at the top end of the normal range.
Competing Interests
A.P.C. (a TIPAC investigator; see Appendix S4) is an employee of GlaxoSmithKline but has no conflict of interest to declare. The study was funded by East Anglia Thoracic Society, the National Institute for Health Research for Patient Benefit (RfPB) Programme (grant reference number PB‐PG‐0906‐11 116) and a Boehringer Ingelheim noncommercial educational grant. The funding source had no input regarding the design, conduct or interpretation of this study. This article presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Contributors
The original study was conceived and designed by the TIPAC investigators. W.Y.C. and Y.K.L. designed the current evaluation. TIPAC investigators were involved in original data acquisition. Y.K.L. conducted the statistical analysis. W.Y.C., A.B.C., A.M.W. and Y.K.L. were involved in the interpretation of the data. W.Y.C. and Y.K.L. drafted the manuscript. All co‐authors contributed to and approved the final manuscript.
Supporting information
Appendix S1 Baseline characteristics of all individuals
Appendix S2 Follow‐up values for primary and secondary outcomes
Appendix S3 Change from baseline results of primary and secondary outcomes
Appendix S4 TIPAC investigators
Chan, W. Y. , Clark, A. B. , Wilson, A. M. , Loke, Y. K. , and on behalf of the TIPAC investigators (2017) The effect of co‐trimoxazole on serum potassium concentration: safety evaluation of a randomized controlled trial. Br J Clin Pharmacol, 83: 1808–1814. doi: 10.1111/bcp.13263.
References
- 1. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP, et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 2016; 44 (Database Issue): D1054–D1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE, et al. The concise guide to PHARMACOLOGY 2015/16: G protein‐coupled receptors. Br J Pharmacol 2015; 172: 5744–5869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Alexander SPH, Cidlowski JA, Kelly E, Marrion N, Peters JA, Benson HE, et al. The concise guide to PHARMACOLOGY 2015/16: Nuclear hormone receptors. Br J Pharmacol 2015; 172: 5956–5978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, et al. The concise guide to PHARMACOLOGY 2015/16: Transporters. Br J Pharmacol 2015; 172: 6110–6202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. The concise guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 2015; 172: 6024–6109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Alexander SPH, Catterall WA, Kelly E, Marrion N, Peters JA, Benson HE, et al. The concise guide to PHARMACOLOGY 2015/16: Voltage‐gated ion channels. Br J Pharmacol 2015; 172: 5904–5941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Hicks LA, Taylor TH, Hunkler RJ. US outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 368: 1461–1462. [DOI] [PubMed] [Google Scholar]
- 8. Barton E, Macgowan AP. Use of intravenous co‐trimoxazole to treat bacterial infection: analysis of 50 treatment episodes. J Chemother 2010; 22: 267–269. [DOI] [PubMed] [Google Scholar]
- 9. Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, et al. Centers for Disease Control and , Prevention, National Institutes of Health , HIV Medicine Association of the Infectious Diseases Society of America . Guidelines for prevention and treatment of opportunistic infections in HIV‐infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009; 58: 1–207. [PubMed] [Google Scholar]
- 10. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim‐induced hyperkalemia. Ann Intern Med 1993; 119: 296–301. [DOI] [PubMed] [Google Scholar]
- 11. Schlanger LE, Kleyman TR, Ling BN. K+‐sparing diuretic actions of trimethoprim: inhibition of Na + channels in A6 distal nephron cells. Kidney Int 1994; 45: 1070–1076. [DOI] [PubMed] [Google Scholar]
- 12. EiamOng S, Kurtzman NA, Sabatini S. Studies on the mechanism of trimethoprim‐induced hyperkalemia. Kidney Int 1996; 49: 1372–1378. [DOI] [PubMed] [Google Scholar]
- 13. Perazella MA, Brown E. Electrolyte and acid–base disorders associated with AIDS: an etiologic review. J Gen Intern Med 1994; 9: 232–236. [DOI] [PubMed] [Google Scholar]
- 14. Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med 1997; 12: 646–656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM. Trimethoprim‐sulfamethoxazole‐induced hyperkalemia in patients receiving inhibitors of the renin‐angiotensin system: a population‐based study. Arch Intern Med 2010; 170: 1045–1049. [DOI] [PubMed] [Google Scholar]
- 16. Fralick M, Macdonald EM, Gomes T, Antoniou T, Hollands S, Mamdani MM, et al. Canadian Drug Safety and Effectiveness Research Network . Co‐trimoxazole and sudden death in patients receiving inhibitors of renin‐angiotensin system: population based study. BMJ 2014; 349: g6196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Antoniou T, Gomes T, Mamdani MM, Yao Z, Hellings C, Garg AX, et al. Trimethoprim‐sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case–control study. BMJ 2011; 343: d5228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Weir MA, Juurlink DN, Gomes T, Mamdani M, Hackam DG, Jain AK, et al. Beta‐blockers, trimethoprim‐sulfamethoxazole, and the risk of hyperkalemia requiring hospitalization in the elderly: a nested case–control study. Clin J Am Soc Nephrol 2010; 5: 1544–1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Shulgina L, Cahn AP, Chilvers ER, Parfrey H, Clark AB, Wilson EC, et al. Treating idiopathic pulmonary fibrosis with the addition of co‐trimoxazole: a randomised controlled trial. Thorax 2013; 68: 155–162. [DOI] [PubMed] [Google Scholar]
- 20. Delanaye P, Mariat C, Cavalier E, Maillard N, Krzesinski JM, White CA. Trimethoprim, creatinine and creatinine‐based equations. Nephron Clin Pract 2011; 119: c187–c193; discussion c93‐4. [DOI] [PubMed] [Google Scholar]
- 21. Kalowski S, Nanra RS, Mathew TH, Kincaid‐Smith P. Deterioration in renal function in association with co‐trimoxazole therapy. Lancet 1973; 1: 394–397. [DOI] [PubMed] [Google Scholar]
- 22. Antoniou T, Hollands S, Macdonald EM, Gomes T, Mamdani MM, Juurlink DN, et al. Canadian Drug Safety and Effectiveness Research Network . Trimethoprim‐sulfamethoxazole and risk of sudden death among patients taking spironolactone. CMAJ 2015; 187: E138–E143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim‐sulfamethoxazole with and without concomitant medications. Ann Pharmacother 2013; 47: 1618–1626. [DOI] [PubMed] [Google Scholar]
- 24. Mori H, Kuroda Y, Imamura S, Toyoda A, Yoshida I, Kawakami M, et al. Hyponatremia and/or hyperkalemia in patients treated with the standard dose of trimethoprim‐sulfamethoxazole. Intern Med 2003; 42: 665–669. [DOI] [PubMed] [Google Scholar]
- 25. Alappan R, Buller GK, Perazella MA. Trimethoprim‐sulfamethoxazole therapy in outpatients: is hyperkalemia a significant problem? Am J Nephrol 1999; 19: 389–394. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1 Baseline characteristics of all individuals
Appendix S2 Follow‐up values for primary and secondary outcomes
Appendix S3 Change from baseline results of primary and secondary outcomes
Appendix S4 TIPAC investigators