Fournier's gangrene and sodium–glucose cotransporter 2 inhibitors: Is there a causal association?

ObjectiveSodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier’s gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS).Research design and methodsWe mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR).ResultsWe retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.ConclusionsAlthough causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.

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Real-world evidence on sodium-glucose cotransporter-2 inhibitor use and risk of Fournier’s gangrene

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000985 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000985 ◽

Cited By ~ 3

Author(s):

Jeff Yufeng Yang ◽

Tiansheng Wang ◽

Virginia Pate ◽

John B Buse ◽

Til Stürmer

Keyword(s):

Real World ◽

Fournier’S Gangrene ◽

Sensitivity Analyses ◽

Standardized Mortality Ratio ◽

Fournier's Gangrene ◽

Diagnosis Codes ◽

Sodium Glucose Cotransporter ◽

Real World Evidence ◽

Increased Risk ◽

The Impact

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with increased occurrence of Fournier’s gangrene (FG), a rare but serious form of necrotizing fasciitis, leading to a warning from the Food and Drug Administration. Real-world evidence on FG is needed to validate this warning.MethodsWe used data from IBM MarketScan (2013–2017) to compare the incidence of FG among adult patients who initiated either SGLT2i, a dipeptidyl peptidase-4 inhibitor (DPP4i), or any non-SGLT2i antihyperglycemic medication. FG was defined using inpatient International Classification of Diseases, Ninth Edition and Tenth Edition diagnosis codes 608.83 and N49.3, respectively, combined with procedure codes for debridement, surgery, or systemic antibiotics. We estimated crude incidence rates (IRs) using Poisson regression, and crude and adjusted HRs (aHR) and 95% CIs using standardized mortality ratio-weighted Cox proportional hazards models. Sensitivity analyses examined the impact of alternative outcome definitions.ResultsWe identified 211 671 initiators of SGLT2i (n=93 197) and DPP4i (n=118 474), and 305 329 initiators of SGLT2i (n=32 868) and non-SGLT2i (n=272 461). Crude FG IR ranged from 3.2 to 3.8 cases per 100 000 person-years during a median follow-up of 0.51–0.58 years. Compared with DPP4i, SGLT2i initiation was not associated with increased risk of FG for any outcome definition, with aHR estimates ranging from 0.25 (0.04–1.74) to 1.14 (0.86–1.51). In the non-SGLT2i comparison, we observed an increased risk of FG for SGLT2i initiators when using FG diagnosis codes alone, using all diagnosis settings (aHR 1.80; 0.53–6.11) and inpatient diagnoses only (aHR 4.58; 0.99–21.21).ConclusionsNo evidence of increased risk of FG associated with SGLT2i was observed compared with DPP4i, arguably the most relevant clinical comparison. However, uncertainty remains based on potentially higher risk in the broader comparison with all non-SGLT2i antihyperglycemic agents and the rarity of FG.Trial registration numberEUPAS Register Number 30018.

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Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

10.2337/figshare.15147888 ◽

2021 ◽

Author(s):

Bao Anh Tran ◽

Wendy H. Updike ◽

Krystal Bullers ◽

Erini Serag-Bolos

Keyword(s):

Mortality Rate ◽

Case Reports ◽

Fournier’S Gangrene ◽

Boxed Warning ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene ◽

Sodium Glucose Cotransporter ◽

Potential Development ◽

Post Marketing ◽

The U.S

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective for glycemic control and have demonstrated cardiorenal benefits. The U.S. Food and Drug Administration (FDA) released a boxed warning in 2018 regarding the potential development of Fournier’s gangrene (FG) with the use of SGLT2 inhibitors. FG is a serious perineal infection with a mortality rate of up to 88% in some cases.

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Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

Clinical Diabetes ◽

10.2337/cd21-0015 ◽

2021 ◽

pp. cd210015

Author(s):

Bao Anh Tran ◽

Wendy H. Updike ◽

Krystal Bullers ◽

Erini Serag-Bolos

Keyword(s):

Case Reports ◽

Fournier’S Gangrene ◽

Fournier's Gangrene ◽

Sodium Glucose Cotransporter ◽

Post Marketing

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Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

10.2337/figshare.15147888.v1 ◽

2021 ◽

Author(s):

Bao Anh Tran ◽

Wendy H. Updike ◽

Krystal Bullers ◽

Erini Serag-Bolos

Keyword(s):

Mortality Rate ◽

Case Reports ◽

Fournier’S Gangrene ◽

Boxed Warning ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene ◽

Sodium Glucose Cotransporter ◽

Potential Development ◽

Post Marketing ◽

The U.S

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective for glycemic control and have demonstrated cardiorenal benefits. The U.S. Food and Drug Administration (FDA) released a boxed warning in 2018 regarding the potential development of Fournier’s gangrene (FG) with the use of SGLT2 inhibitors. FG is a serious perineal infection with a mortality rate of up to 88% in some cases.

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Fournier's gangrene as Amyand's hernia complication

Perspectives in Surgery ◽

10.33699/pis.2019.98.7.291-296 ◽

2019 ◽

Vol 98 (7) ◽

pp. 291-296

Keyword(s):

Case Report ◽

Case Reports ◽

Rare Condition ◽

Sporadic Case ◽

Fournier’S Gangrene ◽

Amyand’S Hernia ◽

Fournier's Gangrene ◽

Randomized Controlled Studies ◽

Based Medicine ◽

Hernia Complication

Introduction: Fournier’s gangrene is a rare but fast deteriorating and serious condition with high mortality. In most cases, it is characterized as necrotizing fasciitis of the perineum and external genitals. Amyand’s hernia is a rare condition where the appendix is contained in the sac of an inguinal hernia. Inflammatory alterations in the appendix account only for 0.1 % of the cases when Amyand’s hernia is verified. Fournier’s gangrene as a complication of a late diagnosis of appendicitis located in the inguinal canal is described in the literature as rare case reports. Case report: The case report of a 70-year-old patient with Fournier’s gangrene resulting from gangrenous appendicitis of Amyand’s hernia. Conclusion: Fournier’s gangrene as a complication of Amyand’s hernia is a rare condition. Only sporadic case reports thereof can be found in the literature. Because of the rarity of this pathology and the lack of randomized controlled studies, it is difficult to determine the optimal treatment according to the principles of evidence-based medicine. An appropriate approach for this condition appears to be the combination of guidelines developed in Amyand’s therapy according to Losanoff and Basson, along with the recommended “gold standard” therapy for Fournier’s gangrene. This means early and highly radical surgical debridement, adequate antibiotic therapy and intensive care.

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Fournier’s gangrene due to Salmonella Typhimurium in a healthy male: a rare aberrant infection

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666201117143421 ◽

2020 ◽

Vol 20 ◽

Author(s):

Varsha Gupta ◽

Lipika Singhal ◽

Kritika Pal ◽

Mani Bhushan ◽

Rajeev Sharma ◽

...

Keyword(s):

Salmonella Typhimurium ◽

Systemic Disease ◽

External Genitalia ◽

Fournier’S Gangrene ◽

The Body ◽

Healthy Male ◽

Fournier's Gangrene ◽

Salmonella Infections ◽

Chief Complaints ◽

Human Infections

Introduction: Human Salmonella infections have been classically distinguised into diseases caused by typhoidal and non-typhoidal salmonella (NTS). Typhiodal salmonella includes S. enterica serovars Typhi and Paratyphi that cause the systemic disease but are restricted to human infections, while NTS consists mainly of other serovars that predominantly cause self-limiting gastroenteritis in humans. Localisation of foci with persisting infection occurs due to dissemination of the bacteria throughout the body and can cause a variety of rare clinical syndromes at aberrant sites. Fournier’s gangrene, a rapidly progressive, often fatal, necrotizing fasciitis of the external genitalia and perineum due to Salmonella Typhimurium, is a rare manifestation and has never been reported. Case: A 22-year-old male, apparently healthy patient with no relevant past medical history presented to surgical emergency with chief complaints of swelling of bilateral scrotal area. Infective etiology was considered and a diagnosis of fournier’s gangrene was made. Pure growth of Salmonella Typhimurium was obtained after repeated subculture and was identified biochemically and on serotyping, as Salmonella enterica serotype Typhimurium using specific antisera. Conclusion: In our case report, we describe a case of fournier’s gangrene due to Salmonella Typhimurium in an otherwise healthy male to highlight the unusual presentation of Non typhoidal salmonellae at an aberrant site. We also emphasize the importance of using selective media like Selenite F broth for isolation of Salmonella Typhimurium from a pus sample.

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Gangrena de Fournier. Reporte de caso

Studies in the Economic History of Southern Africa ◽

10.22201/fm.24484865e.2020.63.5.04 ◽

2020 ◽

Vol 63 (5) ◽

pp. 26-30

Author(s):

Paloma Pérez Ladrón de Guevara ◽

Georgina Cornelio Rodríguez ◽

Oscar Quiroz Castro

Keyword(s):

Mortality Rate ◽

Necrotizing Fasciitis ◽

Broad Spectrum ◽

Soft Tissues ◽

Fournier’S Gangrene ◽

Type Ii ◽

Necrotic Tissue ◽

Fournier's Gangrene ◽

Necrotizing Fascitis ◽

Key Words Fournier's Gangrene

Fournier’s Gangrene is a type II necrotizing fascitis that leads to thrombosis of small subcutaneous vessels and spreads through the perianal and genital regions and the skin of the perineal. Most cases have a perianal or colorectal focus and in a smaller proportion it originates from the urogenital tract. The mortality rate varies between 7.8 and 50%1-3, only timely diagnosis decreases the morbidity and mortality of this condition. Treatment includes surgical debridement of all necrotic tissue and the use of broad-spectrum antibiotics. Key words: Fournier’s gangrene; gangrene; necrotizing fasciitis; infectious necrotizing of soft tissues.

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Algorithm of rational approach to reconstruction in Fournier’s disease

Open Medicine ◽

10.1515/med-2021-0294 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1028-1037

Author(s):

Domenico Tripodi ◽

Maria Ida Amabile ◽

Federica Gagliardi ◽

Federico Frusone ◽

Marzia Varanese ◽

...

Keyword(s):

Necrotizing Fasciitis ◽

Fournier’S Gangrene ◽

Rational Approach ◽

Skin Grafts ◽

Local Infection ◽

Fournier's Gangrene ◽

Rare Form ◽

Perineal Region ◽

Reconstructive Technique ◽

Diabetes And Obesity

Abstract Background Fournier’s gangrene is a rare form of necrotizing fasciitis that affects the genital area up to the perineal region and sometimes the abdominal wall. Objectives Our article aims to show that in the treatment of extensive forms of Fournier’s gangrene, correct use of flap and skin grafts and a quick reconstruction of the exposed tissues avoid scarring retraction of the testicles and deformation of the penis. Materials and methods We retrospectively reviewed the clinical and photographic data of Fournier’s gangrene cases treated at our Institute. The data were evaluated to obtain an estimate of the results of the reconstructive technique used, in terms of percentage of occurred healings and eventual complications. Results A total of 34 patients underwent surgery for Fournier’s gangrene. In nine cases (26.5%), we had minor complications: in four patients, suffering from diabetes and obesity, a retard in attachment of graft occurred, while in five patients with perianal problems there was a delay in healing due to the onset of local infection. Conclusion The reconstruction approach described here may reduce surgical times. In Fournier’s gangrene, the exposed tissues must be reconstructed as quickly as possible.

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Management of peno-scrotal wound defects in a tertiary hospital in North-Western Nigeria: a 20-year retrospective review

African Journal of Urology ◽

10.1186/s12301-021-00167-5 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Abubakar Sadiq Muhammad ◽

Ngwobia Peter Agwu ◽

Abdullahi Abduwahab-Ahmed ◽

Ahmed Mohammed Umar ◽

Muhammad Ujudud Musa ◽

...

Keyword(s):

Statistical Significance ◽

Graft Loss ◽

External Genitalia ◽

Tertiary Hospital ◽

Advancement Flap ◽

Fournier’S Gangrene ◽

Fournier's Gangrene ◽

Direct Closure ◽

Secondary Intention ◽

North Western

Abstract Background Fournier’s gangrene and trauma to the external genitalia are the commonest causes of peno-scrotal wound defects in our environment. The management of these patients includes initial resuscitation and subsequent wound care with or without wound cover. The aim of this study is to document our experience in the management of peno-scrotal defects in a tertiary hospital of North-Western Nigeria. Methods This is a 20-year retrospective study of patients managed for peno-scrotal wound defects by the Urology Unit in the Department of Surgery of our hospital from January 2001 to December 2019. Data were collected from the patients’ case notes and entered into a proforma. Data were analysed using SPSS version 25.0. Results A total number of 54 patients with peno-scrotal wound defects were managed within the study period with the mean age of 46.27 ± 22.09 years and a range of six weeks to 107 years. The wound defects were sequelae of Fournier’s gangrene in 42 patients (77.8%) and traumatic in 12 patients (22.2%). Healing by secondary intention was achieved in 20 patients (37.0%). Direct closure was done in 17 patients (31.5%), skin graft in nine patients (16.7%), and advancement flap in eight patients (14.8%) depending on the location and size of the defects. Fourteen patients (26.0%) developed surgical site infection ± wound dehiscence and partial graft loss. The complication rate was higher in post-Fournier’s gangrene wound defects, but without statistical significance (p = 0.018). Conclusion Fournier’s gangrene and trauma to the external genitalia are the commonest causes of peno-scrotal wound defects in our environment. Smaller wound defects were healed by secondary intention, while larger defects required either direct closure or the use of advancement flap or skin grafting depending on the location and size of the wound. The study reported a higher post-repair complication in patients that had Fournier’s gangrene.

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