Near-fatal reaction associated with cotrimoxazole, metformin and kidney impairment

Case

A 78-year-old woman was brought by ambulance to the Emergency Department of a hospital in remote Cape York, Far North Queensland, with acute hypoglycaemia and a 3-week history of nausea and vomiting. The paramedic had found her blood glucose concentration to be 2.2 mmol/L and administered oral glucose.

One month earlier, the patient had been discharged from the nearest major hospital, 2 hours flight away, where she had been treated for pulmonary and bacteraemic melioidosis. Following a course of intravenous antibiotics, she had been discharged on trimethoprim 320 mg + sulfamethoxazole 1600 mg (cotrimoxazole) twice daily for 3 months.

She had a relevant medical history of type 2 diabetes, stage 2 chronic kidney disease and hypertension. Her long-term medications were metformin XR 1000 mg, amlodipine 5 mg, aspirin 100 mg, perindopril 10 mg and atorvastatin 20 mg, all taken orally once daily; and semaglutide 0.5 mg once weekly by subcutaneous injection.

Prior to the hospital admission for melioidosis, the patient's estimated glomerular filtration rate (eGFR) was 64 mL/min/1.73 m². On bloods taken just before the current presentation her eGFR was 7 mL/min/1.73 m².

At the current presentation, the patient was barely rousable. Her blood pressure was 60/30 mmHg, heart rate 64 beats per minute, respiratory rate 22 breaths per minute, and temperature 36°C. Her oxygen saturation (measured by finger-clip sensor) was 96% on room air. She was clinically profoundly volume depleted.

We only had point-of-care blood testing available. Her results showed severe lactic acidosis, acute kidney failure and hyperkalaemia, which were confirmed on retesting; the device had been calibrated (Table 1).

Table 1 Point-of-care blood test results

Parameter	Result	Reference range
pH	7.15	7.35 to 7.45
Partial pressure of carbon dioxide (pCO2)	19.8 mmHg	32 to 48 mmHg
Partial pressure of oxygen (pO2)	58 mmHg	83 to 108 mmHg
Base excess in extracellular fluid (BEecf)	−22 mmol/L	−2 to 3 mmol/L
Bicarbonate (HCO3)	6.9 mmol/L	22 to 32 mmol/L
Total carbon dioxide (TCO2)	8 mmol/L	24 to 29 mmol/L
Oxygen saturation (sO2)	82%	94 to 98%
Lactate	7.12 mmol/L	0.50 to 2.20 mmol/L
Sodium	129 mmol/L	135 to 145 mmol/L
Potassium	8.3 mmol/L	3.5 to 5.2 mmol/L
Chloride	109 mmol/L	95 to 110 mmol/L
Ionised calcium	1.21 mmol/L	1.15 to 1.32 mmol/L
Glucose	3.7 mmol/L	3.0 to 7.8 mmol/L
Urea	47.8 mmol/L	2.5 to 8.0 mmol/L
Creatinine	552 micromol/L	60 to 120 micromol/L

Her management began with crystalloid fluid resuscitation. She was given a 1 mg bolus of metaraminol and an infusion of 0.5 mg metaraminol per hour to maintain a mean arterial pressure (MAP) greater than 65 mmHg. Her systolic blood pressure increased to 90 mmHg with a MAP of 70 mmHg. She was catheterised and 100 mL of dark urine was drained.

Hyperkalaemia was managed with intravenous calcium gluconate 2.2 mmol and short-acting insulin 10 units with 50 mL of glucose 50%, plus nebulised salbutamol 20 mg. Bicarbonate was not used to manage the acidosis because it may have added risk for uncertain gain.¹

The presentation was thought to have been triggered by the patient's recently started cotrimoxazole in the context of pre-existing kidney disease, nausea and vomiting leading to dehydration, and concurrent use of metformin. Cotrimoxazole was withheld, and intravenous broad-spectrum beta-lactam therapy was started with specialist input. Metformin was also withheld.

Due to a cyclone, retrieval of the patient to the major hospital was not immediately possible. The patient was helicoptered to a centre with an onsite laboratory, and subsequently transported to the major hospital for ongoing care.

 

Comment

Melioidosis is an infectious disease that is endemic in northern Australia. It is caused by the soil and water saprophyte Burkholderia pseudomallei. People with diabetes, chronic kidney disease, chronic respiratory disease (especially cystic fibrosis), a history of hazardous alcohol consumption and those on immunosuppressive therapy are at increased risk of developing more severe melioidosis.² Pneumonia is the most common presentation, but abscesses in any organ (especially the spleen and prostate) may occur. Localised cutaneous ulcers are also common. Asymptomatic infection, latent infection and relapse can occur. Management is dependent on the site of infection but usually involves extended courses of high-dose cotrimoxazole.²

The patient described in this case developed anorexia, nausea, vomiting and worsening kidney function while taking cotrimoxazole for melioidosis. Cotrimoxazole is associated with dose-dependent kidney injury, especially in the context of pre-existing renal disease and older age.^3,4 Nausea and dehydration may have also contributed to her kidney failure. Cotrimoxazole has also been rarely associated with hypoglycaemia, usually in older people and when there are predisposing factors such as renal impairment and hypoglycaemic drugs.⁵ The patient described in this case had not been planned for early and frequent post-discharge review when she was started on cotrimoxazole, which would have been preferable.

The severe acidosis pointed to possible metformin toxicity. Metformin has been associated with the development of lactic acidosis, a rare but important adverse event that may occur especially in the presence of risk factors such as renal failure or dehydration.⁶ The patient had continued to take metformin from her blister pack (dose administration aid), which ideally would have been withheld when she became nauseated and dehydrated.

Cotrimoxazole and metformin are widely used drugs. An interaction between trimethoprim (in cotrimoxazole) and metformin may have contributed to this patient's presentation. Trimethoprim can inhibit renal elimination of metformin and increase metformin exposure by 37%, which may become clinically relevant in dehydration and renal failure.⁷ The likely mechanism for this interaction is inhibition of MATE1/2-k (multidrug and toxin extrusion) transporters. Inhibition of OCT2 (organic cation transporter 2) also likely contributes.⁷

The combination of progressive kidney failure, dehydration and consequent increased levels of trimethoprim and metformin resulted in this unfortunately severe illness.

 

Conclusion and recommendations

Trimethoprim (in cotrimoxazole) and metformin used together can cause serious toxicity in the presence of reduced oral intake, dehydration and kidney failure. Regular clinical and biochemical review is recommended when the drugs are used in combination, particularly in high-risk patients such as in this case. Monitoring kidney function in remote locations without onsite or daily pathology services is challenging but essential.

In a remote location where medication management and adherence have many challenges,⁸ and access to healthcare is limited, patients who are progressively unwell might continue to take their regular medications without review by a clinician. Patients should be advised about the potential problems arising from medications they have been prescribed and when to seek advice.

This article was finalised on 28 October 2025.

Patient consent for publication of this case study was obtained by the author.

Conflicts of interest: none declared

This article is peer reviewed.

 

References

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2. Melioidosis. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2025. [cited 2025 Oct 28]
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