Fournier’s Gangrene and Intravenous Drug Abuse: an Unusual Case Report and Review of The Literature

Abstract Fournier’s gangrene is a potentially fatal emergency condition characterized by necrotizing fasciitis and supported by an infection of the external genital, perineal and perianal region, with a rapid and progressive spread from subcutaneous fat tissue to fascial planes. In this case report, a 52-year-old man, with a history of hepatitis C-virus (HCV)-related chronic liver disease and cocaine use disorder for which he was receiving methadone maintenance therapy, was admitted to the Emergency Department with necrotic tissue involving the external genitalia. Fournier’s gangrene is usually due to compromised host immunity, without a precise cause of bacterial infection; here it is linked to a loco-regional intravenous injection of cocaine. A multimodal approach, including a wide surgical debridement and a postponed skin graft, was needed. Here we report this case, with a narrative review of the literature.


Introduction
Fournier's gangrene was described for the first time in 1764 by Baurienne as an idiopathic, necrotizing lethal process in a man affected by gangrene of the genitalia. However, the origin of this clinical condition must be linked to Jean Alfred Fournier who described a series of fatal cases of idiopathic gangrene of the genitalia with a sudden onset in 5 young men in 1883 [1]. Fournier's gangrene is a potentially fatal condition; it is characterized by necrotizing fasciitis and supported by an infection of the external genital, perineal and perianal region, with a rapid and progressive spread from subcutaneous fat tissue to fascial planes [2].
This emergency condition always requires a multimodal approach: antibiotic therapy, surgery followed by intensive care, and oxygen hyperbaric therapy [3].
Because of its rarity, most of the limited knowledge about Fournier's gangrene derives from case reports and retrospective studies with small sample size [4].
Here, in order to improve the knowledge concerning Fournier's gangrene, we describe an unusual case due to injection of cocaine into the superficial dorsal vein of the penis, followed by a comprehensive literature review.    Kahn et al. [    ICU=intensive care unit ND=not defined Table 1 continued: review of the Literature up-to-date to July 2019 3 Case report A 52-year-old man with a history of a cocaine use disorder, who was in methadone maintenance therapy and affected by HCV-related chronic liver disease, was admitted to the Emergency Department of a high-volume hospital. At admission to our institution, he presented with fever, acute renal impairment, anuria, poor hygienic conditions, and necrotic tissue involving the external genitalia ( Figure  1). The laboratory tests showed 29 x 10 9 /L white blood cells with 95% neutrophils, haemoglobin 15.6 g/dl, glucose 103 mg/dl, aspartate transaminase 79 UI/L, alanine transaminase 68 UI/L, creatinine 2.58 mg/dl, C-reactive protein 56.2 mg/dl, procalcitonin >100 ng/ml. HIV testing was negative. The patient reported no other urological symptoms at hospital afdmission. He had a Charlson Comorbidity Index score of 2 and an Eastern Cooperative Oncology Group (ECOG) of 1, with no referring major comorbidities.
A scrotal ultrasound examination was performed. It showed the right testis augmented in volume with completely altered echogenicity, augmented vascular sign and hypoechoic areas. The left epididymis and involucres had irregular echogenicity. The left testis appeared to have irregular echogenicity and was hypervascularized with hypoechoic areas. A left hydrocele was present. Computed tomography (CT) was performed. It confirmed phlogosis and edema of the scrotum, with the right testis unrecog-nizable. Skin, subcutaneous planes, spermatic cord were thickened. Inguinal bilateral and right external iliac lymphadenopathy was described on CT.
The patient underwent resuscitation intravenous fluid support; antibiotic therapy was administered with tigecycline and meropenem. A single, prompt, extended surgical debridement of external genital, perineal, perianal and infrapubic regions to healthy tissue was performed. The patient also underwent at the same time right orchiectomy.
The microbiologic culture of the wound specimen revealed Staphylococcus lugdunensis with tigecycline susceptibility. Urine and blood samples cultures were negative. Tigecycline and meropenem were administered until discharge.
The anuric condition persisted for 24 hours; then polyuria developed, but with a renal impairment that required treatment with dialysis.
Five days after the surgical debridement the patient reported the injection of cocaine into the superficial dorsal vein of the penis.
The histologic report confirmed an inflammatory necrotizing process of subcutaneous tissue that expanded to skin, testicular and epididymis parenchyma, rete testis and peritesticular tissue.
The physical examination was notable for necrotic-appearing tissue in the entire penis and scrotum, with areas of induration and crepitus No other wound treatments were performed for the wide extension of involved cutaneous area and the correct development of granulation tissue.
The patient was discharged 17 days after the surgical debridement and was admitted to the waiting list for a skin graft, which was successfully performed 1 month later.

Ethical approval:
The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the authors' institutional review board of Perugia University.
Written informed consent was obtained from the patient.

Discussion
Fournier's gangrene is a surgical emergency characterized by necrotizing fasciitis of the genital, perineal and perianal soft tissue. It is a rare condition, representing 0.02% of hospitalizations, with an estimated incidence of 1.6 for 100.000 males/year [5]. This condition affects both males and females. Males are more affected than females with a ratio 10:1, and age of onset is becoming older (between 60s and 70s) [6].
The patient in our case of necrotizing fasciitis was 52 years old. Fournier's gangrene was initially described as an idiopathic process, which has been found to be true in only a few cases. Often the initial cause is an infection involving the ano-rectum (30-50%), uro-genitalia (20-40%) and genital skin (20%). [7][8][9]. Infection results in inflammation and edema, which leads to obliterating endarteritis of the subcutaneous vessels [10]. The resulting lower blood support leads to peripheral dissection, with consequent spread of infection between the subcutaneous tissue and the skin. The reduction of the blood supply therefore generates gancrena [11].
This necrotizing fasciitis may be due to a condition of compromised host immunity, like diabetes, alcoholism, human immunodeficiency syndrome (HIV), lymphoproliferative diseases, arterial hypertension, renal and hepatic insufficiency, obesity, dementia, tobacco consumption, chronic steroid abuse, chemo-and radiotherapy, or cancer and surgical treatment [12][13][14][15][16][17][18][19][20]. In our case, a correlation between gangrene and a patient with a history of cocaine abuse undergoing methadone substitution treatment has been highlighted. The patient was also affected by HCV-related chronic liver disease.
The pathogen involved is both aerobic and anaerobic, gram-negative and gram-positive. Some authors suggest the use of three different antibiotic classes to start an empiric treatment to cover all types of pathogen. In most of the cases, a polymicrobial infection (54%) is demonstrated, and Escherichia coli is the most frequently isolated pathogen (46.6%). The pathogens with a lower incidence are the streptococcus, bacteroides, enterobacter, staphylococcus, enterococcus, pseudomonas, corynebacterium, and Klebsiella pneumoniae [21]. Our review confirms that E. coli is the most involved pathogen (53,1%) and a polymicrobial infection the most common cause (68%) of Fournier's gangrene. However, many authors suggest the use of broad-spectrum penicillin or third-generation cephalosporins, an aminoglycoside (e.g. gentamicin) and metronidazole or clindamycin [11]. In our case tigecycline and meropenem were administered to cover aerobic gram-positive and gram-negative pathogens, as well as anaerobic gram-positive and gram-negative pathogens. The administration was related to renal-function impairment.
The risk of a fatal event makes this necrotizing fasciitis an emergency clinical condition. Prompt management is mandatory; hemodynamic support with resuscitation with fluids, board-spectrum parental antibiotics and surgical debridement of the involved region are the main procedures [22,23]. Thanks to these approaches, the mortality linked to Fournier's gangrene has dropped from between 20% and 88% to lower than 10% [24,25]. On the basis of the data we collected, the reported mortality was 14,1 %. In our case, the patient survived the acute condition, and he is still alive.
The surgical debridement must be performed within a few hours of hospitalization, and the removal of necrotic tissue helps in stopping progression of necrotizing fasciitis and in reducing the risk of death [26]. Nevertheless, Proud et al, in a retrospective study of 219 patients found no differences in mortality in patients treated within 24 hours and those not treated. The authors linked this result to the severity of the infection [27]. For some authors (Chowla et al), more than one surgical debridement is necessary to obtain adequate infection control [28]. From our review of literature, more than one surgical debridement was performed in more than 60% of cases. In our case, we performed one surgical debridement, with the goal of obtaining a partial resection of viable tissue adjacent to the necrotic one.
Negative pressure wound therapy (NPWT) may represent a solution to the risk of infection of the large open wound that usually remains after a surgical debridement, since the patient's poor condition it may be difficult to create a skin flap with which to cover the wound [29]. In NPWT the wound is exposed to a sub-atmospheric pressure between 50 and 125 mm Hg in order to increase blood supply, migration of inflammatory cells, and removal of exudates [11]. According to Chang et al, NPWT allows less frequent wound medication and reduction of pain and length of hospital stay [30].
The use of hyperbaric oxygen therapy (HBOT) is increasing in the management of Fournier's gangrene, but evidence of efficacy is lacking [31]. In the HBOT treatment, the patient inhales 100% O2 in increased ambient pressure (2 -3 atmospheres). HBOT has bactericide and bacteriostatic effects on anaerobic pathogens, in particular. It also improves bacterial lysis by leukocytes and stimulates collagen formation and superoxide dismutase with tissue survival [11,13]. Some authors have reported the range of mortality to be between 16% and 30%, whereas for the patients who undergo HBOT, the mortality is found to be approximately 17.6%.
In our case, our patient obtained a complete resolution of the necrotizing process without NPWT or HBOT, and a skin graft was then performed.
Cocaine, as described by Burnett [32], could be associated with priapism, and when administered into the corpora cavernosa, it could produce a prolonged erection [33]. In our knowledge, only two other cases of Fournier's gangrene associated with penile injection of cocaine [33,34] and three cases of penile necrosis [35] have been described. In both cases of Fournier's gangrene, the necrosis was limited to the penis. The mechanism behind the necrotizing fasciitis after intra-corpora cavernosa injection of cocaine could be dual: cocaine has an intensive vasoconstrictive action that could lead to dermal necrosis that could be complicated by superinfection [33] or by inoculation of infective agents [34]. In our case, we believe that the inoculation of infective agents was the most plausible mechanism, since a skin commensal bacterium was involved.

Conclusion
Fournier's gangrene is a potentially fatal condition that must be treated in a multimodal setting.
Here we report a rare case of genital and perineal necrotizing fasciitis after a loco-regional intravenous injection of cocaine.
To offer the patient the possibility of survival, a prompt application of a multimodal approach with intravenous fluid support, antibiotic therapy and aggressive surgical debridement is mandatory.