Deep Seated Candidiasis

Deep seated candidiasis is infection of a normally sterile organ or space by Candida, arising from haematogenous seeding after candidaemia, from direct inoculation at surgery or trauma, or by extension from a mucosal or device source.

The common syndromes are intra-abdominal candidiasis, hepatosplenic (chronic disseminated) candidiasis, endogenous endophthalmitis, endocarditis and device infection, central nervous system candidiasis, osteoarticular candidiasis, and renal candidiasis. These infections are difficult to diagnose because blood cultures are often negative, and treatment is prolonged and often needs surgery or drainage.

Peritoneal Candida infection follows gut perforation, anastomotic leak, repeated laparotomy, necrotising pancreatitis, and peritoneal dialysis. It accounts for about 20 to 30 percent of invasive candidiasis in high income intensive care units. Candida albicans predominates, with Candida glabrata common in recurrent or hospital acquired disease.

Diagnosis rests on culture of peritoneal fluid or pus, ideally intra-operative or percutaneously collected, with yeast on Gram stain or fungal stain. Beta D glucan has a good negative predictive value but is raised by intra-abdominal surgical materials. Blood cultures are positive in a minority.

Treatment requires source control (drainage, repair of leak, and debridement of infected necrosis). Antifungal therapy is an echinocandin first line, with step down to fluconazole 400 mg (6 mg per kg) daily for susceptible isolates once the patient is stable, and liposomal amphotericin B 3 to 5 mg per kg daily where resistance or intolerance occurs.

Duration is determined by drainage and clinical response, commonly 2 weeks after adequate source control, longer for pancreatic necrosis. Candida isolated from the peritoneum in a patient with community onset perforation and no other risk factors is often a colonising organism and may not need therapy, while recurrent perforation, upper gastrointestinal perforation, and healthcare associated peritonitis do need it.

This syndrome affects patients with acute leukaemia and haematological malignancy, usually when neutropenia recovers. Fungal seeding of the liver and spleen occurs during neutropenia, and the inflammatory reaction as counts recover makes the lesions visible.

• Presentation: persistent fever after neutrophil recovery, right upper quadrant pain, hepatosplenomegaly, nausea, and a markedly raised alkaline phosphatase.
• Imaging: multiple small (under 2 cm) lesions in the liver, spleen, and sometimes kidneys. Ultrasonography shows a bull's eye pattern, computed tomography shows low attenuation lesions, and magnetic resonance imaging (T2 and post contrast) is the most sensitive.
• Microbiology: blood cultures are usually negative. Biopsy shows yeast and pseudohyphae with granulomas, and culture is positive in a minority. Beta D glucan can be raised.
• Treatment: liposomal amphotericin B 3 to 5 mg per kg daily or an echinocandin for several weeks (usually 2 to 4 weeks), then fluconazole 400 mg (6 mg per kg) daily until lesions resolve or calcify, typically for 3 to 6 months or longer. Chemotherapy or transplantation may continue during antifungal therapy.
• Immune reconstitution: persistent fever with progressive lesions despite therapy can reflect an inflammatory response, and prednisolone 20 to 40 mg daily for 1 to 2 weeks is used alongside antifungal therapy in this setting, with limited evidence.

Candida chorioretinitis occurs in about 10 percent of candidaemia, and vitreous extension (endophthalmitis) in 1 to 3 percent. It is the most feared metastatic complication because it threatens vision and can occur with negative blood cultures at the time of presentation.

• Detection: every patient with candidaemia has a dilated fundus examination by an ophthalmologist within the first week and after neutrophil recovery in neutropenic patients. Routine examination of the intubated or sedated patient matters, because symptoms are absent.
• Findings: white, fluffy, cotton wool like chorioretinal lesions with overlying vitreous haze, sometimes a string of pearls pattern in the vitreous.
• Treatment, chorioretinitis without macular involvement or vitritis:
  • Fluconazole 800 mg (12 mg per kg) loading, then 400 to 800 mg (6 to 12 mg per kg) daily.
  • Or voriconazole 400 mg (6 mg per kg) every 12 hours for 2 doses, then 200 mg (3 mg per kg) every 12 hours.
  • Or liposomal amphotericin B 3 to 5 mg per kg daily, with or without oral flucytosine 25 mg per kg every 6 hours.
• Echinocandins penetrate the eye poorly and are avoided as sole therapy.
• Endophthalmitis, with vitreous involvement or macular threat: systemic therapy with the same agents and doses, plus intravitreal injection of amphotericin B deoxycholate 5 to 10 micrograms in 0.1 mL, or voriconazole 100 micrograms in 0.1 mL, and early vitrectomy for vitreous involvement. Intravitreal dosing is specialist administered.
• Duration: at least 4 to 6 weeks, until the ophthalmological lesions resolve.

Endocarditis is uncommon but carries 30 to 60 percent mortality. Risk factors are prosthetic valves, previous bacterial endocarditis, injection drug use, central venous catheters, cardiac surgery, and prolonged candidaemia. Vegetations are large and bulky, emboli are common (large vessel emboli especially), and blood cultures can be negative in half of cases. Candida parapsilosis and Candida albicans are the commonest species.

• Treatment: surgical valve replacement is recommended in almost all cases. Antifungal therapy is liposomal amphotericin B 3 to 5 mg per kg daily with or without flucytosine 25 mg per kg every 6 hours, or a high dose echinocandin (caspofungin 150 mg, micafungin 150 mg, or anidulafungin 200 mg daily) with limited evidence.
• Step down and duration: fluconazole 400 to 800 mg (6 to 12 mg per kg) daily for susceptible isolates, for at least 6 weeks after surgery, and longer with perivalvular abscess or delayed clearance. If surgery is impossible, lifelong fluconazole suppression 400 to 800 mg daily is used.
• Device infection: pacemaker and defibrillator leads, ventricular assist devices, and vascular grafts require device removal, with antifungal therapy for 4 to 6 weeks after removal (longer for bloodstream persistence), and chronic suppression with fluconazole in patients with a device that cannot be removed.
• Mediastinitis and sternal wound infection need debridement, with therapy for at least 6 weeks.
• Infected aneurysm and suppurative thrombophlebitis need surgical excision.

Candida meningitis follows candidaemia in premature neonates (about 15 percent of neonatal candidaemia has meningitis), neurosurgical procedures, ventriculoperitoneal shunts, and external ventricular drains, and sometimes in injection drug users. Microabscesses and brain parenchymal lesions, and occasionally vasculitic stroke, occur.

• Diagnosis: cerebrospinal fluid with a pleocytosis (neutrophils early, mononuclear later), low glucose, and raised protein. Culture is positive in under half. Repeat sampling and large volumes help, and imaging may show microabscesses or hydrocephalus.
• Treatment: liposomal amphotericin B 5 mg per kg daily, with or without flucytosine 25 mg per kg every 6 hours (dose adjusted to renal function and serum levels).
• This is followed by fluconazole 400 to 800 mg (6 to 12 mg per kg) daily for susceptible isolates, until all signs, symptoms, cerebrospinal fluid abnormalities, and imaging findings have resolved, commonly for weeks to months.
• Devices: infected shunts and ventricular drains are removed, because failure to remove them leads to relapse.
• Neonates: liposomal amphotericin B 5 mg per kg daily, or amphotericin B deoxycholate 1 mg per kg daily, with or without flucytosine 100 mg per kg daily in 4 divided doses, followed by fluconazole 12 mg per kg daily, with 4 weeks as the minimum.
• Echinocandins reach low concentrations in cerebrospinal fluid, although high dose micafungin is used in neonates, and they are not first line for meningitis.

Candida osteomyelitis and arthritis arise from candidaemia (vertebral and long bone disease in injection drug users and in the premature), contiguous infection, trauma, and joint arthroplasty.

• Vertebral osteomyelitis and discitis: back pain, with fever in a minority; magnetic resonance imaging shows disc and vertebral involvement. Surgical debridement is used with neurological compromise or instability.
• Septic arthritis: knees and hips, with synovial culture positive. Drainage and debridement with joint lavage are required.
• Treatment: fluconazole 400 mg (6 mg per kg) daily for 6 to 12 months for osteomyelitis, or an echinocandin or liposomal amphotericin B 3 to 5 mg per kg daily for at least 2 weeks followed by fluconazole.
• Septic arthritis needs at least 6 weeks.
• Prosthetic joint infection needs removal of the prosthesis, with at least 6 weeks of therapy and then suppressive fluconazole 200 to 400 mg daily where the prosthesis stays.

Renal candidiasis follows candidaemia (renal cortical microabscesses), or ascending infection with obstruction, diabetes, or instrumentation. Obstruction by fungus balls, papillary necrosis, and renal abscess are features. Imaging by ultrasonography or computed tomography shows hydronephrosis and filling defects.

Treatment is relief of obstruction (nephrostomy, stent removal, or surgery) with fluconazole 200 to 400 mg (3 to 6 mg per kg) daily for 2 weeks or until clinical resolution. Amphotericin B deoxycholate 0.3 to 0.6 mg per kg daily, with or without flucytosine, is used for resistant isolates.

Echinocandins penetrate urine poorly, and they are not used for urinary tract disease.

• Peritoneal dialysis peritonitis: Candida parapsilosis and Candida albicans are the common organisms. The catheter is removed promptly, and therapy continues for 2 weeks after removal with an echinocandin, or fluconazole 200 mg daily for susceptible isolates, before reinsertion is considered.
• Candida pneumonia: rare and difficult to prove. A positive respiratory culture is nearly always colonisation, and diagnosis needs histology.
• Pancreatic necrosis infection: managed with percutaneous or endoscopic drainage and necrosectomy, with an echinocandin or fluconazole 400 mg daily for susceptible isolates, for several weeks guided by drainage and imaging.
• Candida pericarditis and myocarditis: rare; treated with drainage or pericardiectomy and prolonged antifungal therapy.