Trimethoprim–sulfamethoxazole-induced refractory hypoglycaemia successfully treated with octreotide
- 1 Department of Internal Medicine, McGill University, Montreal, Quebec, Canada
- 2 Endocrine Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada
- 3 Division of Endocrinology, Department of Medicine, King Saud bin Abdulaziz University for Health Sciences College of Medicine, Jeddah, Saudi Arabia
- 4 Division of Endocrinology, McGill University, Montreal, Quebec, Canada
- Correspondence to Dr Suhaib Radi; suhaibradi@gmail.com
Abstract
Trimethoprim–sulfamethoxazole (TMP–SMX) is a commonly prescribed antimicrobial agent for a wide variety of infections. It is generally well tolerated in a majority of patients; however, serious adverse effects have been described with its usage. Hypoglycaemia is an exceedingly rare but potentially life-threatening side effect of this antimicrobial agent due to its sulfonylurea-like effect. We describe a case of symptomatic, refractory hypoglycaemia secondary to TMP–SMX in a patient being treated for Stenotrophomonas maltophilia bacteraemia, which required treatment with 10 hours of intravenous dextrose (including several 50% dextrose boluses), as well as intramuscular glucagon and octreotide. We reviewed previous case reports described in the literature of TMP–SMX-induced hypoglycaemia, in which renal insufficiency was noted to be a common predisposing risk factor in an overwhelming majority of cases. In refractory cases of TMP–SMX-induced hypoglycaemia, intravenous octeotride may be considered for treatment.
Background
Trimethoprim–sulfamethoxazole (TMP–SMX), first introduced in 1968, remains a commonly prescribed antimicrobial in clinical practice due to its effectiveness, low cost and familiarity with clinicians.1 2 It is used to treat a wide variety of infections and is considered a first-line agent for urinary tract infections, uncomplicated sinusitis and acute exacerbations of chronic bronchitis.1–5 Other indications include treatment of Pneumocystis jirovecii, Toxoplasma gondii and Stenotrophomonas maltophilia.1 2
TMP–SMX is generally well tolerated; however, there are several potentially serious adverse reactions. The most common side effects include dermatological manifestations, hyperkalaemia and drug interactions given cytochrome P450 inhibition.1 2 The more severe but uncommon adverse reactions associated with TMP–SMX include aseptic meningitis, bone marrow suppression, toxic epidermal necrolysis and hypersensitivity reactions.1 2 Hypoglycaemia as a result of TMP–SMX is common when there is concomitant use of sulfonylureas or meglitinides, resulting in drug–drug interactions.6 In the absence of these agents, hypoglycaemia induced solely by TMP–SMX is rare, with cases sporadically reported in the literature.7 Of cases where this was prevalent, risk factors leading to this complication included chronic kidney disease (CKD) and treatment with high-dose TMP–SMX.7 Management of this complication involves intravenous glucose, cessation or dose reduction of TMP–SMX, and rarely administration of glucagon.7
Case presentation
In March 2020, a 73-year-old man was admitted to hospital for urinary sepsis. He had an extensive medical history, which included rheumatoid arthritis, previous ventricular tachycardia arrest from drug-induced long QT syndrome, chronic obstructive pulmonary disease, previously treated prostate cancer, chronic urinary retention with an indwelling Foley catheter and stage IIIa CKD with a baseline creatinine of 130 µmol/L (glomerular filtration rate of 47 mL/min). He was a previous smoker, with an 80 pack-year smoking history, and denied alcohol or intravenous drug use.
The patient was started on broad spectrum antibiotics with intravenous piperacillin–tazobactam and given intravenous fluids. Blood cultures drawn from initial presentation grew Klebsiella pneumoniae and later S. maltophilia. A CT scan of the thorax and abdomen revealed a left pleural effusion and bladder wall thickening suspicious for cystitis without any other intra-abdominal source. Intravenous TMP–SMX (960 mg/day trimethoprim component) was later added for S. maltophilia, to finish a 14-day antibiotic course. The patient was later stepped down after 2 days of parenteral therapy to amoxicillin–clavulanate 875/125 mg per os two times per day and TMP–SMX two double strength tablets per os three times a day. Repeated blood cultures were subsequently negative. His clinical status improved and remained medically stable.
Eight days into his TMP–SMX course, the patient developed mild lethargy and subtle visual hallucinations and was found to have a capillary blood glucose of 2.5 mmol/L. This hypoglycaemia was confirmed on chemistry and blood gas analysis. There were no focal neurological deficits nor symptomatology suggestive of a seizure. The patient was afebrile and haemodynamically stable.
Investigations
Laboratory investigations revealed normal liver enzyme tests, an appropriately high cortisol and normal Thyroid Stimulating Hormone. Beta-hydroxybutyrate was undetectable, with insulin and C peptide values of 229 pmol/L (N: <20.8) and 1.5 nmol/L (N: <0.2), respectively. A venous blood gas revealed a pH of 7.40 with a pCO2, bicarbonate and lactate levels within normal limits. His creatinine was at baseline (112 µmol/L) with a creatinine clearance (CrCl) of 59.2 mL/min. He had a septic work-up including a chest X-ray, urine culture and two sets of blood cultures which were negative.
Differential diagnosis
The differential diagnosis for hypoglycaemia in adults is broad and can be initially divided by those who are ill and/or medicated versus those who are seemingly well.8 For those who are ill and/or medicated, the differential for hypoglycaemia includes drug-induced, critical illness and hormone deficiency.8 In the seemingly well individual, causes of hypoglycaemia include endogenous hyperinsulinism and factitious hypoglycaemia.8
The patient was not known for diabetes previously and review of the medication administration history confirmed that no insulin, sulfonylurea or meglitinides were given to the patient. Other typical medications that have been described to cause hypoglycaemia including non-selective β-blockers, angiotensin-converting enzyme inhibitors and intravenous pentamidine were not present.8 The patient had been taking a cardioselective β-blocker, bisoprolol, but this was deemed unlikely to be the cause given that he had been taking this medication for over 2 years. With regards to critical illness, the patient had a septic work-up which was ultimately negative, and did not have any prior history suggestive of chronic liver disease, chronic alcohol usage nor signs of malnutrition. Testing for hormone deficiency including hypothyroidism and adrenal insufficiency was negative.
Our patient’s investigations eventually revealed inappropriately high insulin and C peptide levels with negative ketones, suggesting a non-ketotic hyperinsulinaemic hypoglycaemic state. This carries a differential diagnosis including insulinoma, insulin autoimmune hypoglycaemia and nesidioblastosis.8 Review of abdominal CT imaging during his admission revealed a normal pancreas without any mass. The patient did not have symptoms to suggest multiple endocrine neoplasia type 1. Additionally, the absence of previous hypoglycaemic episodes and presentation at the seventh decade of life, as opposed to the second to fourth, reduced the probability of an insulinoma.8 Finally, factitious hypoglycaemia was deemed highly unlikely given the pattern of insulin and C peptide levels (self-administration of insulin would have resulted in low C peptide and high insulin levels), the patient’s level of functional impairment (requiring one person assist for transfer out of bed), and the fact that the patient did not receive any visitors nor did he have access to medications during his hospital stay. Given the patient’s old age, acute onset of hypoglycaemia in hospital after starting antibiotics and resolution of hypoglycaemia after switching antibiotics, the patient’s presentation was not consistent with the above aforementioned diagnoses.
One of the other causes of hyperinsulinaemic hypoglycaemia in our patient was TMP–SMX. Our patient developed hypoglycaemia on the eighth day of TMP–SMX, and it was likely renal insufficiency which resulted in sufficient drug accumulation to exert a sulfonylurea-like effect. This was consistent with previous literature reporting a median duration of therapy prior to the onset of hypoglycaemia of 7 days.7 The protracted nature of the hypoglycaemia, refractoriness to treatment and need for octreotide supports the hypothesis of TMP–SMX accumulation. Furthermore, the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 7 points, suggesting that TMP–SMX was a probable culprit (table 1).9
The Naranjo Adverse Probability Scale
| No. | Question | Yes | No | Do not know | Score |
| 1 | Are there previous conclusive reports on this reaction? | 1 | 0 | 0 | 1 |
| 2 | Did the adverse event appear after the suspected drug was administered? | 2 | −1 | 0 | 2 |
| 3 | Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? | 1 | 0 | 0 | 1 |
| 4 | Did the adverse reaction reappear when the drug was readministered? | 2 | −1 | 0 | 0 |
| 5 | Are there alternative causes (other than the drug) that could on their own have caused the reaction? | −1 | 2 | 0 | 2 |
| 6 | Did the reaction reappear when a placebo was given? | −1 | 1 | 0 | 0 |
| 7 | Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? | 1 | 0 | 0 | 0 |
| 8 | Was the reaction more severe when the dose was increased or less severe when the dose was decreased? | 1 | 0 | 0 | 0 |
| 9 | Did the patient have a similar reaction to the same or similar drugs in any previous exposure? | 1 | 0 | 0 | 0 |
| 10 | Was the adverse event confirmed by any objective evidence? | 1 | 0 | 0 | 1 |
| Total | 7 | ||||
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This scale asks a series of questions which helps to estimate the probability that a drug causes an adverse clinical event. Definite is if the overall score is 9 or greater; probable is for a score of 5–8; possible is for a score of 1–4; doubtful is if the score is 0. This table was taken with permission from Naranjo et al. 9 Copyright (1981) by The C. V. Mosby Co.
Treatment
Initially, the patient was given oral glucose, orange juice and 12.5 g of dextrose. He then developed another episode of symptomatic hypoglycaemia of 2.3 mmol/L requiring another 37.5 g of dextrose. He was given 100 mg intravenous of hydrocortisone and 10% dextrose was started at 100 mL/hour. TMP–SMX was subsequently stopped and the patient’s antibiotics were changed to vancomycin and ceftazidime.
The patient remained symptomatic with hypoglycaemia for the next 14 hours with capillary blood glucose measurements ranging from 2.1 to 3.3 mmol/L despite 6 ampules of 50% dextrose, 1 mg of intramuscular glucagon, 100 mg of intravenous hydrocortisone, two 250 mL boluses of intravenous 10% dextrose, then intravenous 10% dextrose at 100 mL/hour. The patient was later started on 100 mcg of octreotide intravenously every 8 hours. The temporality of various treatment regimens is displayed graphically in figure 1.
Serum glucose concentrations over time, with the administration of various medications. The patient’s serum glucose concentration was plotted against time. The various types of medications are denoted by different colour coded symbols found in the legend to visualise the temporal relationship of different medications versus serum glucose concentrations. D10 continuous infusion was given at 100 mL/hour while D50 push consisted of 25 g of dextrose.
Outcome and follow-up
Fourteen hours following the onset of hypoglycaemia, and an hour after the first dose of octreotide, the patient’s symptoms and blood glucose levels began to improve. The octreotide was stopped first, followed by the intravenous hydrocortisone (figure 1). The 10% dextrose intravenous infusion was switched to 5% which was slowly weaned off with careful monitoring of blood glucose over the next 12 hours. He did not have a recurrence of a hypoglycaemia episode throughout the rest of his hospital stay. His repeat insulin level 48 hours after stopping TMP–SMX decreased to 15 pmol/L. Vancomycin and ceftazidime were stopped and the patient was treated with oral levofloxacin 750 mg every 48 hours, to finish a 14-day course. The patient’s clinical status continued to improve and he remained medically stable. He remained in hospital for 1 month due to deconditioning and malnourishment but was eventually discharged home in stable condition. Follow-up revealed that the patient had passed away 4 months later from an underlying multiple myeloma for which the patient requested palliative care.
Discussion
Hypoglycaemia due to TMP–SMX alone is rare, with approximately 25 cases documented in literature.7 10–38 In the majority of cases, development of hypoglycaemia with TMP–SMX was associated with at least one predisposing risk factor, including CKD or malnutrition.7 10–38
TMP–SMX is a sulfonamide sharing a similar biochemical structure to sulfonylurea.1 2 TMP–SMX has a sulfonylurea-like action on pancreatic islet cells, increasing endogenous insulin levels.1 27 It is renally excreted and in an individual with normal renal function, the half-life is 8–15 hours.3 In end-stage renal disease, the half-life can extend to 20–50 hours.3 In the product monograph, elimination of TMP–SMX is not affected if the CrCl is >30 mL/min, dosage adjustments are recommended if CrCl is 15–30 mL/min and if CrCl is <15 mL/min, the Food and Drug Administration discourages its usage.3 39 Our patient’s renal insufficiency likely contributed to sufficient TMP–SMX accumulation to result in hypoglycaemia.
In our case, despite continuous intravenous 10% dextrose, six boluses of 50% dextrose, intravenous hydrocortisone and intramuscular glucagon, our patient had refractory hypoglycaemia. While we did not have the C peptide or insulin levels at this time, we had a strong clinical suspicion of TMP–SMX-induced hypoglycaemia.
Review of the management from previous cases in literature revealed that all cases required administration of intravenous glucose to correct the hypoglycaemia.7 10–38 40 In roughly half of the cases, TMP–SMX was discontinued whereas in the other half, TMP–SMX was continued but at a reduced dose.7 10–37 40 Only nine cases, including ours, had a protracted course, defined as greater than 12 hours of hypoglycaemia, despite ongoing intravenous glucose administration.7 11 13 15 19 24 28 30 38 Of the cases that had refractory hypoglycaemia, two cases reported treatment with intramuscular glucagon while another case described usage of diazoxide in 5 months old.11 13 None of the reviewed cases used octreotide for the treatment of refractory hypoglycaemia.7 10–37 40
We decided to use octreotide, a somatostatin analogue, commonly used to treat sulfonylurea overdose.41 The temporal improvement of the hypoglycaemia following octreotide strongly suggests its role in the treatment of our patient’s refractory hypoglycaemia. Octreotide is thought to decrease calcium influx through voltage-gated channels in beta islet cells, thereby reducing pancreatic calcium-mediated insulin release.42 We hypothesised that octreotride could be used in TMP–SMX-induced hypoglycaemia, given that it is employed for treatment of refractory hypoglycaemia in sulfonylurea overdose and that both conditions share a similar pathophysiologic mechanism. We report that this is the first time that octreotide was used to successfully treat refractory TMP–SMX-induced hypoglycaemia.
Patient’s perspective
I am glad that this rare side effect was caught by my doctors and hope that my case can be used to educate doctors all around the world.
Learning points
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The sulfamethoxazole component of trimethoprim–sulfamethoxazole (TMP–SMX) can directly cause pancreatic insulin release resulting in hypoglycaemia.
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Clinicians should consider this adverse reaction in patients taking TMP–SMX who have renal impairment.
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In most cases of TMP–SMX-induced hypoglycaemia, management includes administration of intravenous glucose with discontinuation or dose reduction of TMP–SMX.
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In severe, refactory cases of TMP–SMX-induced hypoglycaemia, octeotride may be used for treatment.
Acknowledgments
We would like to thank the Department of Internal Medicine at the Jewish General Hospital at McGill University for supporting us.
Footnotes
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Contributors JKM and DN wrote the original draft of the manuscript. SR and SC contributed to the writing-review and editing.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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