Sodium–glucose cotransporter 2 inhibitor-associated severe epididymo-orchitis
- 1 Research Fellow, Hematology and Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- 2 Endocrinology, Augusta University Medical College of Georgia, Augusta, Georgia, USA
- 3 Nephrology, Pikeville Medical Center, Pikeville, Kentucky, USA
- 4 Endocrinology, Diabetes, and Metabolism, Pikeville Medical Center, Pikeville, Kentucky, USA
- 5 University of Pikeville- Kentucky College of Osteopathic Medicine, Pikeville, Kentucky, USA
- Correspondence to Dr Rishi Raj; rishiraj91215@gmail.com
Abstract
A man in his late 50s, with uncontrolled type 2 diabetes mellitus (T2DM) and morbid obesity, presented to the hospital with complicated epididymo-orchitis. The onset of symptoms (scrotal pain, erythema and swelling) occurred after the use of empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, for 2 months. His baseline antidiabetic medications were insulin, glipizide and metformin. Initially, he had failed treatment of epididymo-orchitis with oral levofloxacin for 3 weeks, followed by 2 weeks of doxycycline therapy. At the presentation to the hospital, an ultrasound of the scrotum revealed scrotal and right testicular abscess. The patient underwent right inguinal orchiectomy. Postoperatively, pus culture was positive for Enterococcus faecalis and Candida glabrata, and hence, he was treated with oral antibiotics including high-dose antifungal medications. Adequate wound care and regular follow-up demonstrated resolution of infection. This case highlights the risk of severe urogenital infection associated with the use of SGLT2 inhibitors in the setting of uncontrolled T2DM.
Background
The Food and Drug Administration had issued warnings about the increased risk of urinary tract and genital infections with sodium–glucose cotransporter 2 (SGLT2) inhibitors .1 The reported risk of empagliflozin-induced urinary tract and genital infections varies between 5.0% and 15.6% and between 2.3% and 9.5%, respectively, with very few cases of epididymo-orchitis.2 The use of SGLT2 inhibitors combined with poorly controlled type 2 diabetes mellitus (T2DM) and morbid obesity aggravates the risk of severe infection. In 2018, a notice was issued regarding rare severe genital infection (Fournier’s gangrene) following the use of SGLT2 inhibitors.3 We report a rare case of severe epididymo-orchitis requiring orchiectomy following the use of empagliflozin for 2 months.
Case presentation
A male in his late 50s, with a history of T2DM, hypertension and refractory epididymo-orchitis presented to the hospital for worsening scrotal pain and swelling. Apparently, the patient was evaluated on two separate occasions in the prior 5 weeks for scrotal pain and swelling and was managed for epididymo-orchitis with oral antibiotics (levofloxacin 500 mg/day for 3 weeks and doxycycline 100 mg two times per day for 2 weeks) without significant improvement. His symptoms of scrotal pain, redness and swelling worsened, now associated with fever and chills. He denied any penile or scrotal discharge and other systemic symptoms. There was no history of any scrotal trauma, sexually transmitted infections, dysuria or pyuria. His social history was unremarkable except for occasional alcohol consumption.
His antidiabetic medications were glipizide (10 mg two times per day), metformin (1000 mg tab/day), insulin (aspart 40/40/35 units before breakfast/lunch/supper and glargine 50 units at bedtime), and empagliflozin (25 mg/day). He was started on empagliflozin approximately 4 months prior to his current hospitalisation. However, it was stopped when he first developed symptoms of scrotal pain and swelling.
On presentation, the patient was in mild distress due to scrotal pain. His vital signs were body temperature of 98.2°F, pulse rate of 88 beats/min, blood pressure of 118/71 mm Hg, respiratory rate of 17 per minute, oxygen saturation of 98% (on room air) and body mass index of 45 kg/m2. Genitourinary examination revealed severe right scrotal oedema, erythema and tenderness on palpation, along with induration of the right testicle and cord. There was no crepitus over the genital area.
Investigations
Laboratory investigations (table 1) revealed glycated haemoglobin (HbA1C) of 110 g/L, and white blood cell of 13.8 109/L. Blood and urine cultures were negative for microbial growth. Ultrasound of the scrotum revealed diffuse scrotal wall oedema, bilateral hydrocele, and evidence of testicular and scrotal abscess (2.7×1.3×1.6 cm heterogeneous, slightly hypoechoic, hypervascular area within the posterior aspect of the right mid testicle and 6.7×5.3×4.1 cm heterogeneous, non-vascular area adjacent to the right testicle). Non-contrast CT of the abdomen and pelvis confirmed the findings of ultrasound but otherwise was negative for any gas in the soft tissues to suggest any evidence of necrotising fascitis. Pus cultures after surgical removal of abscess revealed Candida glabrata and Enterococcus faecalis.
Blood investigation on admission
| Parameter (units) | Value | Normal range |
|---|---|---|
| Albumin (g/dL) | 3.1 | 3.4–5.0 |
| Alkaline phosphatase (μ/L) | 99 | 45–117 |
| Alanine transaminase (ALT) (μ/L) | 26 | 12–78 |
| Aspartate transaminase (AST) (μ/L) | 13 | 15–37 |
| Blood Urea Nitrogen (BUN) (mg/dL) | 15 | 7–18 |
| Calcium (mg/dL) | 9 | 8.5–10.1 |
| Creatinine (mg/dL) | 1 | 0.60–1.30 |
| Potassium (mmol/L) | 4.4 | 3.6–5.2 |
| Sodium (mmol/L) | 132 | 133–144 |
| Bilirubin, total (mg/dL) | 0.5 | 0.00–1.00 |
| Glucose (mg/dL) | 327 | 70–110 |
| Protein, total (g/dL) | 8.2 | 6.4–8.4 |
| White blood cells (109/L) | 13.8 | 3.50–13.00 |
| Haemoglobin (g/L) | 141 | 110–178 |
| Platelets (109/L) | 462 | 134–412 |
| Neutrophils (%) | 66.6 | 43.0–83.0 |
| Lymphocytes (%) | 18.6 | 10.0–42.0 |
| Glomerular filtration rate (mL/min) | 78 | 60–120 |
Differential diagnosis
Our initial differential diagnosis included epididymo-orchitis, necrotising fascitis and testicular torsion. Physical examination, laboratory studies and imaging findings confirmed the diagnosis of complicated epididymo-orchitis with testicular abscess.
Treatment
The patient was started on broad-spectrum antibiotics with piperacillin/tazobactam (3.375 mg) every 8 hours and vancomycin (1750 mg) every 12 hours. Intravenous morphine was used for pain control. Due to the failure of conservative treatment and the development of a testicular abscess, surgical treatment was considered and preferred by the patient. Right-sided inguinal orchiectomy was performed, and pus culture revealed E. faecalis and C. glabrata. The patient was discharged on high-dose fluconazole (200 mg two times per day) and amoxicillin (875 mg once per day), along with a basal-bolus insulin regimen for T2DM.
Outcome and follow-up
Biopsy of the testicular specimen disclosed chronic abscess with reactive changes and atrophy. He continued to follow up with wound care and completed a course of oral antimicrobials for 6 weeks. At the 4-week follow-up visit, the patient had significant improvement in symptoms of scrotal pain. At 3 months’ visit, he had complete wound healing.
Discussion
Unfortunately, despite the great variety of medications available in the market for T2DM management, many patients are unable to achieve adequate glycaemic control. Uncontrolled T2DM increases the risk of several infections including urinary tract infections (UTIs), fungal infections and even more life-threatening infections including Fournier’s gangrene. Moreover, the risk of urogenital infections increases further with the use of SGLT2 inhibitors, which has been well documented in the literature with a particular focus on Fournier’s gangrene.4–6
SGLT2 inhibitors has major positive metabolic effects with a reduction in cardiovascular events and delay in the progression of kidney disease. These drugs increase osmotic diuresis and natriuresis with an improvement of both systolic and diastolic heart functions, hence benefiting patients with congestive heart failure. However, the pharmacologically induced glucosuria with these medications promotes the growth of commensal genital micro-organisms. This can precipitate both fungal and bacterial urinary/genital infections. Appropriate perineal hygiene measures can prevent severe genitourinary infection among patients with T2DM on SGLT2 inhibitors.7 8
Studies have reported variable incidences of genitourinary infections and UTIs with SGLT2 inhibitors. Incidence of UTIs has been reported as low as 1% or between 5% and 15.6% with empagliflozin.2 4 Moreover, some studies have shown that the SGLT2 inhibitors increases the risk of genital mycotic infection but not for UTI.9
Our case is interesting as the patient was morbidly obese, which is reported in other cases with Fournier’s gangrene with the use of SGLT2 inhibitors.5 At the same time, the patient developed a severe urogenital infection (epididymo-orchitis with testicular abscess) caused by combined bacterial (E. faecalis) and fungal (C. glabrata) infection, which is extremely rare. The infection was refractory to initial oral antibacterials, requiring orchiectomy for eradication of the infection. However, it is pertinent to note that the patient was not empirically treated with antifungals until postsurgery when the pus culture became available. The current recommendations from the Centers for Disease Control and Prevention do not suggest the empiric use of antifungal medications in treating acute epididymitis or epididymo-orchitis.10 However, based on our experience, we believe that there is a possible role of empiric antifungal medications in refractory cases of genitourinary infection, especially in those who are at increased risk of fungal genitourinary colonisation.
This case focuses on educating physicians that UTIs can be severe and different organisms can be reported with the use of SGLT2 inhibitors, especially in morbidly obese patients with uncontrolled diabetes. Adequate patient education at the start of SGLT2 inhibitors regarding proper perineal hygiene and watching for the side effects is highly recommended. Despite these adverse events, the overall cardiovascular and renal benefits of SGLT2 inhibitors, especially in patients at high cardiovascular risk, should always be considered when recommending treatment in patients with T2DM. When choosing treatment for patients with uncontrolled T2DM, clinicians should consider alternate medical management such as GLP-1 agonists, insulin, etc, until HbA1C is controlled. This strategy by clinicians would significantly reduce SGLT2 inhibitors-related genitourinary adverse events while improving glycaemic control and providing long-term renal and cardioprotective benefits to patients with diabetes.
Learning points
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Identify the increased risk of severe epididymo-orchitis with SGLT2 inhibitors and address additional risk factors (morbid obesity and uncontrolled type 2 diabetes mellitus (T2DM).
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Emphasise the importance of perineal hygiene among patients with diabetes on SGLT2 inhibitors.
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Be vigilant about timely withdrawal of SGLT2 inhibitors when concerned with associated genital infection.
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Empirical consideration of antifungal medication and early urology consultation for unresolving epididymo-orchitis among patients with uncontrolled T2DM.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @DrRishi_Raj
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Contributors RM, GE, LK and RR were directly involved in the conceptualisation of the study, data collection, literature review,and writing of the manuscript. All authors reviewed and finalised the manuscript in its current form.
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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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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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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 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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