Invasive%20candidiasis Treatment

Candidemia

• Existing central venous catheters should be removed, when feasible
• All patients with candidemia should undergo at least 1 ophthalmological exam to exclude the possibility of candidal endophthalmitis

Central Nervous System (CNS)

• For candidal meningitis associated with neurosurgical procedures, treatment should include removal of any prosthetic devices

Endocarditis

• Both native valve and prosthetic valve infection should be managed with surgical replacement of the infected valve, the native valve within 1 week and the prosthetic valve even earlier
• If valve replacement is not possible, the patient may require long-term suppressive therapy

Endophthalmitis

• Removal of intraocular lens implant if infection is due to implant

Genitourinary Tract (GUT)

• Removal of urinary tract instruments, including stents and Foley catheters, is often helpful
• If complete removal is not possible, placement of new devices may be beneficial
• Surgical intervention in adults with Candida UTI associated with fungal balls

Infections of the Vasculature

• Catheter removal
• Surgical incision and drainage or resection of the involved vein segment is recommended

Musculoskeletal

• Adequate drainage of involved joints is critical to successful therapy
  
  • Candida arthritis of the hip, in particular, requires open drainage

• If a prosthetic joint is involved, a resection arthroplasty is generally required

Peritonitis

• Remove peritoneal dialysis catheter, if the patient has one
  
  • After removal and a delay of at least 2 weeks, a new catheter may be placed

• Proper surgical repair and drainage must be done for patients in whom Candida peritonitis is related to intra-abdominal leakage of fecal material

• Early initiation of antifungal therapy with adequate source control is essential in the management of invasive candidiasis
  
  • Empirical antifungal therapy should be considered in patients with neutropenic fever, non-neutropenic patients who have persistent fever or unexplained hypotension despite broad-spectrum antibacterial agents, and patients with septic shock and multiorgan failure with >1 proven colonization outside of the gastrointestinal (GI) tract

• When choosing an antifungal agent, consider the following factors:
  
  • Patient’s clinical status
  • Physician’s knowledge of the species and/or antifungal susceptibility of the infecting isolate
  • Relative drug toxicity
  • Presence of organ dysfunction that would affect drug clearance
  • Available knowledge of use of the drug in the given patient population
  • Patient’s prior exposure to antifungal agents

• De-escalation from an echinocandin to Fluconazole may be considered in non-neutropenic critically ill patients if clinically stable and isolate with proven susceptibility to Fluconazole, and without central venous catheter or any other foreign material
• Step-down to Fluconazole may also be considered in patients with persistent neutropenia who are clinically stable, with Fluconazole-susceptible isolates and documented clearance of Candida sp from the bloodstream
• Treatment duration depends on extent of involved organs
  
  • Treat for 14 days after resolution of candidemia for uncomplicated cases (eg end of candidemia documented by a negative BC and absence of organ involvement)
  • Oral therapy may start after 10 days of IV therapy

• Premature discontinuation of antifungal therapy may lead to recurrent infection
  
  • May consider discontinuation of antifungal therapy once with negative BC results in previously suspected patients

• Routine antifungal prophylactic or pre-emptive therapy for critically ill patients at high risk for severe infection is not recommended
  
  • Only patients with risk factors for invasive disease (eg central venous catheters, parenteral nutrition, hemodialysis, trauma, broad-spectrum antibiotics, recent surgery) should be considered
  • Immunosuppressed patients anticipated to develop profound, protracted neutropenia and grade III/IV mucositis at high risk for invasive candidiasis may be given antifungal prophylaxis during the expected period of neutropenia

Echinocandins

• Eg Anidulafungin, Caspofungin, Micafungin
• First-line therapy for most episodes of candidemia and invasive candidiasis except for those infections in the CNS, eye and UTIs
• Agents of choice for patients with moderately severe to severe illness, critically ill patients with septic shock and multiorgan failure, or those who have had recent azole exposure
• Preferred empiric treatment in non-neutropenic intensive care unit (ICU) patients suspected with candidiasis
• Strongly recommended for targeted primary treatment of candidemia
• Only Caspofungin requires dosage reduction for moderate to severe hepatic dysfunction
• Mechanism of action: Inhibit synthesis of glucan, which is an important component of fungal cell wall

Flucytosine

• Has broad antifungal activity against most Candida sp with the exception of C krusei
• Primarily used in combination with Amphotericin B with more refractory infections such as Candida endocarditis, meningitis and endophthalmitis
• Occasionally used for symptomatic urinary tract candidiasis due to Fluconazole-resistant C glabrata
• Mechanism of action: Deaminated to 5-fluorouracil, which inhibits RNA and protein synthesis

Polyenes

• Eg Amphotericin B deoxycholate (AmB-d), lipid formulations [eg Amphotericin B lipid complex (ABLC), Amphotericin B colloidal dispersion (ABCD), liposomal Amphotericin B, lipid formulation of Amphotericin B (LFAmB)]
• Efficacious for Candida sp but has well-documented significant toxicity
• Lipid formulations are less toxic but as effective as AmB-d when used in appropriate dosages
• LFAmB is preferred over other lipid formulations for critically ill patients with history of treatment failure with echinocandins and azoles
• The cost of lipid formulations and the small number of organized clinical data tend to limit use in patients at high risk of being intolerant of AmB-d
• Urinary candidiasis may be the only candidal infection where lipid-associated formulas are contraindicated
  
  • It is theorized that the lipid-associated formulas will potentially reduce delivery of Amphotericin B and thus slow the pace of response

• Used as alternative treatment in patients who are intolerant with other antifungal agents
• Mechanism of action: Increase cytoplasmic permeability

Triazoles

• Mechanism of action: Inhibit synthesis of ergosterol, which is a fungal cell component
• Should not be used as initial therapy in neutropenic patients who require antifungal therapy

Fluconazole

• Appropriate as initial therapy for hemodynamically stable patients with no recent exposure to azole and those who are not colonized by azole-resistant Candida sp (eg C krusei, C glabrata) if access to echinocandins is limited
  
  • Should be considered 1st-line treatment option for critically ill patients with low disease severity

• Highly effective for the treatment of superficial and invasive candidal infections
• Inferior to Anidulafungin but better than echinocandins against C parapsilosis

Itraconazole

• Itraconazole is a useful agent for dermatologic and mucosal candidal infections but its role in invasive candidal infections has yet to be determined

Posaconazole

• Posaconazole has in vitro activity against Candida sp but there is limited evidence for its use in candidal infections other than oropharyngeal candidiasis
• May be used as alternative treatment in patients who are intolerant to Voriconazole

Voriconazole

• Voriconazole is as active as Fluconazole against esophageal candidiasis
• Has been used for candidemia in non-neutropenic patients, candidal infection in the CNS and for other deep tissue Candida infections
• Also used as step-down oral therapy in patients with candidal infection caused by C krusei and Fluconazole-resistant, Voriconazole-susceptible C glabrata
• Should not be used for urinary candidiasis as it does not accumulate in active form in the urine

Other Triazole

Isavuconazole

• An expanded-spectrum triazole with good in vitro activity against Candida sp
• Clinical trials are ongoing to prove the use of Isavuconazole for the treatment of candidiasis
  
  • It is suggested by preliminary analysis of the recently completed international double-blind trial that compared Isavuconazole to an echinocandin that Isavuconazole did not meet criteria for noninferiority

± with or without

Treatments Under Investigation

• Rezafungin, a novel semi-synthetic 1,3-β-D-glucan synthase-targeting echinocandin, is undergoing clinical trials for its use in the treatment of candidiasis