Front. Endocrinol. Frontiers in Endocrinology Front. Endocrinol. 1664-2392 Frontiers Media S.A. 10.3389/fendo.2023.1059522 Endocrinology Original Research Clinical features, risk factors, diagnosis, and treatment of trimethoprim-sulfamethoxazole-induced hypoglycemia Wang Chunjiang 1 Fang Weijin 1 Li Zuojun 1 Sun Linli 2 * 1 Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China

Edited by: Shanshan Wu, Capital Medical University, China

Reviewed by: Pranjali Sharma, Parkview Health System, United States; Guangjun Fan, Second Affiliated Hospital of Dalian Medical University, China

*Correspondence: Linli Sun, sunlinli@csu.edu.cn

This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology

 08 02 2023 2023 14 1059522 01 10 2022 30 01 2023 Copyright © 2023 Wang, Fang, Li and Sun 2023 Wang, Fang, Li and Sun

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Objective

Hypoglycemia is a sporadic and serious adverse reaction of trimethoprim-sulfamethoxazole (TMP-SMX) due to its sulfonylurea-like effect. This study explored the clinical characteristics, risk factors, treatment, and prognosis of TMP-SMX-induced hypoglycemia.

 Methods

Case reports and series of TMP-SMX-induced hypoglycemia were systematically searched using Chinese and English databases. Primary patient and clinical information were extracted for analysis.

 Results

A total of 34 patients were reported from 31 studies (16 males and 18 females). The patients had a median age of 64 years (range 0.4-91), and 75.8% had renal dysfunction. The median duration of a hypoglycemic episode was six days (range 1-20), and the median minimum glucose was 28.8 mg/dL (range 12-60). Thirty-two patients (97.0%) showed neuroglycopenic symptoms, with consciousness disturbance (30.3%) and seizure (24.2%), sweating (18.2%), confusion (15.2%), asthenia (12.1%) being the most common symptoms. Fifteen patients (44.1%) had elevated serum insulin levels, with a median of 31.8 μU/mL (range 3-115.3). C-peptide increased in 13 patients (38.2%), with a median of 7.7 ng/mL (range 2.2-20). Complete recovery from symptoms occurred in 88.2% of patients without sequelae. The duration of hypoglycemia symptoms was 8 hours to 47 days after the intervention. Interventions included discontinuation of TMP-SMX, intravenous glucose, glucagon, and octreotide.

 Conclusion

Hypoglycemia is a rare and serious adverse effect of TMP-SMX. Physicians should be aware of this potential adverse effect, especially in patients with renal insufficiency, increased drug doses, and malnutrition.

 hypoglycemia trimethoprim-sulfamethoxazole pneumocystis pneumonia seizure neuroglycopenic symptoms 2021JJ30992) Natural Science Foundation of Hunan Province10.13039/501100004735 Introduction

Trimethoprim-sulfamethoxazole (TMP-SMX), AKA co-trimoxazole, was approved in 1968 for treating urinary tract infections, uncomplicated sinusitis, and chronic bronchitis (1). Oral and intravenous preparations are manufactured from a fixed ratio of 1:5 of trimethoprim to sulfamethoxazole. TMP-SMX is also the therapy for treating Pneumocystis carinii pneumonia (PCP) (2).

The most common adverse reactions of TMP-SMX are rash, allergic reaction, gastrointestinal discomfort, hyperkalemia, nephrotoxicity, and pancytopenia (3). In rare cases, TMP-SMX can also cause severe hypoglycemia that is often overlooked, leading to fatal outcomes. Current knowledge about TMP-SMX-induced hypoglycemia is based primarily on case reports, and the specific clinical features are unclear. Here, we discuss the clinical features, risk factors, treatment, and prognosis of hypoglycemia induced by TMP-SMX to provide a basis for the rational use of TMP-SMX.

 Methods Search strategy and selection criteria

Case reports, case series, and clinical studies of cotrimoxazole-induced hypoglycemia were searched from Chinese and English databases, including Wanfang, China National Knowledge Infrastructure, China Science and Technology Journal Database, PubMed, OVID, Web of Science, Embase, and Cochrane Library. The search period was limited from January 1, 1968, to July 31, 2022. The searches were performed using subject and free words, including “trimethoprim-sulfamethoxazole” [MeSH] OR “trimethoprim” [MeSH] OR “sulfamethoxazole” [MeSH] OR “SMX” [MeSH] OR “TMP” [MeSH] OR “co-trimoxazole” [MeSH] AND “hypoglycemia” [MeSH] OR “blood glucose” [MeSH] OR “glycaemia” [MeSH]. There was no language restriction. Mechanistic studies, animal studies, reviews, and duplicate reports were excluded.

 Data extraction

The following data were extracted using self-designed tables: age, sex, underlying diseases, concomitant medications, indications, dosage regimens, risk factors, clinical symptoms and signs, laboratory tests (blood glucose, insulin, C-peptide, liver function, renal function), imaging studies, treatment, and prognosis.

 Diagnostic criteria for hypoglycemia

According to the latest diagnostic criteria for hypoglycemia of the American Diabetes Association, hypoglycemia can be diagnosed when the blood glucose level of diabetic patients is ≤70 mg/dL (≤3.9 mmol/L). In contrast, the blood sugar of non-diabetic patients is less than 55 mg/dL (3.0 mmol/L) (4).

 Statistical analyses

SPSS Statistics 22.0 (IBM, Armonk, NY, USA) was used for statistical analysis. Enumeration and measurement data were represented by n (%) and the median value (range, minimum and maximum values), respectively.

 Results

A flow diagram for the study is provided in Figure 1 . According to the inclusion and exclusion criteria, 34 patients from 32 studies were included ( Table 1 ) (5–36). The basic information about these patients is summarized in Table 2 . These patients (16 men and 18 women) were mainly from North America (38.2%), Europe (44.1%), and Asia (7.6%), with a median age of 64 years (range 0.4-91). Medical history was available in 33 patients (97.1%), including 9 (27.3%) with type 2 diabetes and 2 (6.1%) with hepatitis. Ten patients (29.4%) had malnutrition. Twenty-two patients (43%) were taking concomitant drugs, including 13 (38.2%) taking drugs that could cause hypoglycemia, such as beta-adrenergic antagonists, quinolones, angiotensin-converting agent enzyme inhibitors (ACEI), propoxyphene, and hypoglycemic medications. The median daily dose of sulfamethoxazole is 3,200 mg (range 400-9,600). The median duration of TMP-SMX treatment before the hypoglycemia episode was six days (range 1-20).

Flow chart of study selection process for reported cases of trimethoprim-sulfamethoxazole-induced hypoglycemia.

Summary of clinical information of 34 patients.

reference age/sex indication daily dose (mg/d) duration(d) symptoms serum glucose (mg/dL) Insulin (μU/ml) C-peptide (ng/mL) serum creatinine (mg/dL) Management
5 65/f UTI 320/1600 po 10 seizure, dyspnea, lethargic 27 36 na 6.1 discontinued, dextrose iv
6 63/m pyogenic arthritis 960/4800 po; 320/1600 po 5/na seizures, mental status changes 26 58.7 na HD dose decreased
7 85/f UTI 320/1600 po 7 confusion, loss of consciousness 24 3 na 1.3 discontinued, dextrose iv
7 74/f UTI 320/1600 po na loss of consciousness 12 6 na 8.2 discontinued, dextrose iv
8 69/f UTI na 2 nausea, vomiting, weakness, slurred speech, numbness 48 na na normal discontinued, dextrose iv
9 62/m PCP 960/4800 po 5 consciousness disturbance 20 34.5 na 3.3 discontinued
10 64/m PCP 1280/6400 iv 2 loss of consciousness 36 na na 9.5 dextrose iv
11 34/m PCP na 6 stuporous 18 12 ↑ normal discontinued, dextrose iv
12 88/f UTI 320/1600 po 4 GTCS, incoherence, confusion 33 na NA 1.2 discontinued, dextrose iv
13 19/f na 320/1600 po 1 confusion 17 na NA PD dextrose iv
14 36/m PCP 960/4800 iv,1920/9600 po 8 tremor, loss of consciousness, seizure, sweating 28.8 na 4.3 3.6 discontinued, dextrose iv,diazepam
15 54/f PCP 1280/6400 5 neuroglycopenic symptoms 36 24.2 7.7 normal discontinued, dextrose iv
16 73/m HAP 1280/6000 iv;600/3000 iv 6/9 asymptomatic 22 na na 5.1 discontinued, dextrose iv, low-dose re-challenge
17 91/f UTI 640/3200 po 7 decreased level of consciousness 34 na na 1.7 discontinued
18 41/m PCP 640/3200 po 6 tremor, sweating, disorienting, unresponsive 18 30.2 12.6 1.4 discontinued
19 5m/f PCP 20/100 mg/kg per d 3 generalized convulsion 18 16.4 4.88 normal dose decreased, diazoxide
20 46/m PCP 1280/6400 po 18 GTCS, altered state of consciousness, falls 28.8 na na 2 discontinued, dextrose iv
21 76/m UTI 160/800 5 symptomatic hypoglycemia, inability to speak 34 na na 2 discontinued, dextrose iv
22 44/f PCP 1920/9600 iv 7 sweating, asthenia, dizziness 59 40 na normal continued, dextrose iv
22 24/m PCP 960/4800 iv 20 sweating, asthenia, confusion, nausea, dizziness 56 80 na normal discontinued, dextrose iv
23 83/m prophylaxis 160/800 na loss of muscle tone, pale skin and mucous membranes 28 3.2 2.2 1.7 discontinued, dextrose iv
24 56/f PCP no 5 coma 30.6 2ULN 2ULN CKD 5 discontinued, dextrose iv
25 52/f prophylaxis 80/400 7 dizziness, hunger, headaches, sweating. 30.6 41.1 6.1 > 60 * continued, oral sugar
26 60/f UTI 160/800 3 tremor, sweating, fatigue 60 na na normal discontinued
27 71/m PCP 1120/5600 11 coma, acute neurological deterioration, nervous breakdown, hypothermia 24 na na 3.2 discontinued, dextrose iv
28 69/m PCP 960/4800 4 Tonic clonic seizure 28.8 95.9 12.8 AKI discontinued, dextrose iv, glucagon
29 18/f prophylaxis 80/400 po 2 na 43.2 8.1 11.7 0.5 discontinued, dextrose iv
30 85/m UTI 320/1600 po 7 pale, altered state of consciousness 35 8.8 4.57 1.79 discontinued, dextrose iv
31 75/f PCP 96 mg/kg/day 10 lost consciousness 20 na na 53.7 * discontinued, oral sugar, low-dose re-challenge
32 64/m PCP 1280/6400 po 5 delirious, spoke nonsense words, displayed dancing arms, deliration 30.6 115.3 19.55 49.67* dose decreased
33 73/m bacteremia 160/800 2d, 960/4800 po 8 lethargy, visual hallucinations 45 31.8 4.5 1.3 Discontinued, hydrocortisone and dextrose iv, intramuscular glucagon and octreotide.
34 62/f Cerebral toxoplasmosis 320/1600 6 GTCS 21 99 20 na discontinued, dextrose iv, glucagon
35 64/f PCP no na confusion 21.6 no 15.5 AKI discontinued, dextrose iv, glucagon
36 79/f UTI 320/1600 po 6 consciousness disorder, coma, wandering, sweating 28.8 na na na discontinued, dextrose iv

AKI, acute kidney injury; CKD, Chronic kidney disease; GTCS, generalized tonic clonic seizure; HD, hemodialysis; na, not applicable; PCP, Pneumocystis carinii pneumonia; PD, peritoneal dialysis; iv, intravenous; ULN, upper limit of normal value; UTI, urinary tract infection.

*Represents estimated glomerular filtration rate (mL/min).

AKI, acute kidney injury; CKD, Chronic kidney disease; GTCS, generalized tonic clonic seizure; HD, hemodialysis; na, not applicable; PCP, Pneumocystis carinii pneumonia; PD, peritoneal dialysis; iv, intravenous; ULN, upper limit of normal value; UTI, urinary tract infection.

*Represents estimated glomerular filtration rate.

Summary of basic information of 34 patients.

Parameter Value
Sex FM 18 (52.3%)16 (47.1%)
Age, years 64 (0.4,91) b
Country USAUKCanadaItalyJapan, Turkey, France, ChinaPortugal, Iran, Israel, Spain, Barbados 8 (23.5%)6 (17.7%)4 (11.8%)3 (8.8%)2 (5.9%)1 (2.9%)
Onset time (days) (30) a 6 (1,20) b
Daily dose (mg) (29) a 3200 (400,9600) b
Indication (33)a PCPUTIprophylaxisHAP, pyogenic arthritis, bacteremiacerebral toxoplasmosis 16 (48.5%)10 (30.3%)3 (9.1%)1 (3.0%)
Medical history (33)a type 2 diabetesautoimmune diseaseAIDShypertensioncardiovascular diseasehematological tumorcancernervous system disease, nephrolithiasis, osteoporosis, kidney transplant, COPDepilepsy, hypothyroidism 9 (27.3%)8 (24.2%)6 (18.2%)4 (12.1%)4 (12.1%)3 (6.1%)3 (6.1%)2 (6.1%)2 (6.1%)1 (3.0%)
Combination therapy (22) a prednisoneantibioticshypoglycemic drugsdiureticspropoxypheneH2 blockersantihypertensive drugsbeta blockerImmunosuppressantantiviral drugsproton pump inhibitor 6 (27.3%)5 (22.7%)5 (22.7%)5 (22.7%)4 (18.2%)4 (18.2%)4 (18.2%)3 (13.6%)3 (13.6%)3 (13.6%)2 (9.1%)

PCP, Pneumocystis carinii pneumonia; UTI, urinary tract infection; COPD, chronic obstructive pulmonary disease; HAP, hospital acquired pneumonia; AIDS, acquired immune deficiency syndrome.

a Represents the number of patients out of 34 in whom information regarding this particular parameter was provided.

b Median (minimum-maximum).

 Clinical symptoms

Thirty-three patients had documented clinical symptoms, of which 32 (97.0%) developed neurological hypoglycemia symptoms and 1 (3.0%) had asymptomatic hypoglycemia. The most common symptoms during hypoglycemia episodes were consciousness disturbance (30.3%) and seizure (24.2%), followed by sweating (18.2%), confusion (15.2%), asthenia (12.1%), tremor (9.1%), dizziness (9.1%), coma (9.1%) and lethargic (9.1%). Other rare symptoms and signs include dyspnea, hypothermia, visual hallucinations, and numbness. Details are shown in Table 3 .

Summary of clinical symptoms and laboratory tests of 34 patients.

Parameter Value
Symptoms and signs (33)a asymptomaticneuroglycopenic symptoms 1 (3.0%)32 (97.0%)
consciousness disturbanceseizuresweatingconfusionastheniatremordizzinesscomalethargicpale skin and mucous membranesnauseadelirationother rare symptoms: dyspnea, slurred speech, numbness, incoherence, inability to speak, disorienting, nonresponsive, fall, loss of muscle tone, hunger, hypothermia, dehydration, visual hallucinations, spoke nonsense words, displayed dancing arms, headaches 10 (30.3%)8 (24.2%)6 (18.2%)5 (15.2%)4 (12.1%)3 (9.1%)3 (9.1%)3 (9.1%)3 (9.1%)2 (6.1%)2 (6.1%)2 (6.1%)1 (3.0%)
Serum glucose (mg/dL) 28.8 (12,60) b
Insulin (μU/mL) (19)a 31.8 (3,115.3) b
elevatednormal 15 (78.9%)4 (21.1%)
C-peptide (ng/mL) (13)a elevated 13 (100%)7.7(2.2,20) b
Renal (33) a normalrenal impairment* 8 (24.2%)25 (75.8%)
Liver (22)a hepatitisnormal 2 (9.1%)20 (90.1%)

* Renal impairment were categorized according to their estimated creatinine clearance at screening: normal renal function (≥ 90 mL/min/1.73 m2), mild impairment (60–89 mL/min/1.73 m2), moderate impairment (30–59 mL/min/1.73 m2) and severe impairment (15–29 mL/min/1.73 m2).

a Represents the number of patients out of 34 in whom information regarding this particular parameter was provided.

b Median (minimum-maximum).

 Laboratory test

The median lowest serum glucose measured was 28.8 mg/dL (range 12-60). Of the 19 patients measured, 15 (78.9%) had elevated serum insulin levels, with a median of 31.8 μU/mL (range 3-115.3). C-peptide levels increased in all 13 measured patients, with a median of 7.7 ng/mL (range 2.2-20). Renal impairment occurred in 25 of 33 patients (75.8%), and hepatitis occurred in 2 of 22 patients (9.1%). Details are shown in Table 3 .

 Treatment and prognosis

TMP-SMX was immediately discontinued in 27 patients (79.4%), continued in 2 patients (5.9%), and the dose decreased in 3 patients (8.8%). One case (2.9%) did not describe whether treatment was discontinued or changed information. The management of TMP-SMX was not described in one patient. Thirty patients (88.2%) received intravenous glucose immediately, 2 (5.9%) received oral glucose, and 1 (2.9%) received carbohydrate supplementation. In addition, four patients (11.8%) received glucagon, and one each (2.9%) received octreotide, diazoxide, hydrocortisone, and diazepam, respectively. Two patients (5.9%) were rechallenged with TMP-SMX at a lower dose and did not experience hypoglycemia. Despite continuous intravenous glucose injection, 11 patients (42.8%) had persistent hypoglycemia within 24 hours, 7 (26.9%) had it for 28-72 hours, and 2 (7.7%) had it for 24 days and 47 days, respectively. Ultimately, 30 patients (88.2%) recovered completely without neurological sequelae, and 1 (2.9%) did not report an outcome. Three patients (8.8%) died of hypoglycemia, potential multiple myeloma and other causes, respectively. Details are shown in Table 4 .

Summary of treatment and prognosis of 34 patients.

Parameter Value
Treatment discontinuedcontinueddose decreasednadextrose intravenouslyoral sugarcarbohydrates supplementsglucagonoctreotidediazoxidehydrocortisonediazepamlow-dose re-challenge 27 (79.4%)2 (5.9%)3 (8.8%)2 (5.9%)30 (88.2%)2 (5.9%)1 (2.9%)4 (11.8%)1 (2.9%)1 (2.9%)1 (2.9%)1 (2.9%)2 (5.9%)
Duration of hypoglycemia (26)a rapid8-24h24-48h48-72h24-47d 1 (3.8%)10 (38.4%)7 (26.9%)6 (23.1%)2 (7.7%)
Outcome recoverydeathna 30 (88.2%)3 (8.8%)1 (2.9%)

na, not applicable.

a Represents the number of patients out of 34 in whom information regarding this particular parameter was provided.

 Discussion

Hypoglycemia is characterized by low plasma glucose levels and ultimately leads to the clinical syndrome of neurological hypoglycemia with numerous etiologies (37). Patients with insulinoma, paraneoplastic hypoglycemia, hyperinsulinemic hypoglycemia syndrome, alcohol, infection, hypocortisolism, liver dysfunction, malnutrition, renal insufficiency, toxins, and drugs are associated with hypoglycemia (38). A variety of medications can induce exacerbated hypoglycemia, including acetaminophen, beta-blockers, pentamidine, ACEI, and propoxyphene (39, 40). The presence of these risk factors increases the risk of hypoglycemia in patients receiving TMP-SMX (3).

In our study, TMP-SMX -induced hypoglycemia occurred primarily in patients over 60 years of age. In these patients, the median onset of hypoglycemia was seven days. Symptoms of hypoglycemia include neurogenic (autonomic) or neuroglycopenic symptoms. The clinical signs of TMP-SMX-induced hypoglycemia are mainly neurogenic hypoglycemia. In patients with TMP-SMX-induced hypoglycemia, other factors predisposing to hypoglycemia include the use of hypoglycemic drugs (e.g., beta-blockers, ACEI, acetaminophen, propoxyphene), liver dysfunction, malnutrition, and renal insufficiency. Renal insufficiency was probably the most common risk factor for TMP-SMX-induced hypoglycemia, and 74% of patients had renal insufficiency at the time of hypoglycemia in our study. Although our retrospective analysis identified risk factors for co-trimoxazole-induced hypoglycemia, the incidence of this complication could not be determined.

About 10% to 30% of trimethoprim is metabolized to the inactive form, and the remainder is excreted unchanged in the urine. Sulfamethoxazole is mainly metabolized in the liver, and about 30% is excreted unchanged in the urine. In normal renal function, the half-life of TMP-SMX is 8-15 hours, while in end-stage renal disease, the half-life can be extended to 20-50 hours (41). Therefore, the dose of TMP-XSM should be adjusted when creatinine clearance is below 30 mL/min. This implies assessing the patient’s baseline kidney and liver function before starting co-trimoxazole is crucial. Both components of TMP-SMX can significantly affect the metabolism of concomitantly administered drugs. The trimethoprim component selectively inhibits CYP2C8, while sulfamethoxazole inhibits CYP2C9 (42). Trimethoprim may increase the risk of hypoglycemia by inhibiting repaglinide liver metabolism (21). This suggests that co-trimoxazole should be used with caution in the case of concurrent oral hypoglycemic agents.

The occurrence of hypoglycemia appears to be dose-related. Three patients had no additional hypoglycemia symptoms that occurred when the dose of co-trimoxazole was adjusted according to renal function (6, 19, 32). Hypoglycemia caused by TMP-SMX may be related to sulfamethoxazole. The possible mechanism is the structural similarity between sulfamethoxazole and sulfonylureas (10, 43). Sulfamethoxazole is postulated to increase insulin secretion, a theory supported by elevated insulin and C-peptide levels in more than 79% of patients in our study.

Currently, there is no optimal management plan for TMP-SMX-induced hypoglycemia. Opinions on continuous administration of TMP-SMX are inconsistent after hypoglycemia. The discontinuation of TMP-SMX is safe and eliminates the risk of recurrent hypoglycemia. Limited data suggest that some patients may be successfully re-challenged at lower doses. TMP-SMX remains the only option when other effective alternatives for severe PCP, such as pentamidine and primaquine, are unavailable. Intravenous glucose is needed for hypoglycemia to prevent seizures, coma, and death. Octreotide, a somatostatin analog, reduces calcium influx through voltage-gated channels in beta islet cells, thus reducing pancreatic calcium-mediated insulin release. It is commonly used in the treatment of sulfonylurea overdose (44, 45). Glucagon may be used as a treatment option in hypoglycemia refractory to glucose administration. Despite appropriate treatment, symptoms persisted for more than 8 hours in 95% of patients in our analysis.

 Conclusion

Clinicians should be aware of this rare but life-threatening hypoglycemia complication of co-trimoxazole, especially in patients with multiple risk factors. Early interventions in the event of hypoglycemia during TMP-SMX treatment are essential to prevent severe adverse outcomes. Blood glucose monitoring is feasible in patients taking long-term co-trimoxazole.

 Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

 Author contributions

LS and CW conceived of the presented idea. CW, WF, Zl and LS wrote the manuscript. All authors contributed to the article and approved the submitted version.

 Funding

This research was supported by the Inclusive Policy and Innovative Environment Construction Program of Hunan Province(Grant numbers: 2021SK53707).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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