Candida – MD Nexus

Epidemiology

Prevalence

Candidiasis is the Most Common Opportunistic Fungal Infection
- Due to Candida Being Normal Flora and Increasing Numbers of Patients with Risk Factors for Candidal Infection)

Risk Factors for Candidal Infection

Drugs

Anti-Tumor Necrosis Factor-α (Anti-TNF) Therapy (see Anti-Tumor Necrosis Factor-α Therapy) [MEDLINE] [MEDLINE]
- Relative Risk: infliximab > etanercept > adalimumab (see Infliximab, Etanercept and Adalimumab)
- All Patients were bone marrow transplants being treated with anti-TNFα medications for graft vs host disease (see Graft vs Host Disease)
- Most cases were extra-pulmonary Candidiasis: esophagitis, thrush, Candidemia
Broad-Spectrum Antibiotics
Corticosteroids (see Corticosteroids)

Hematologic Disease

Acute Myeloid Leukemia (AML) (see Acute Myeloid Leukemia)
Acute Lymphocytic Leukemia (ALL) (see Acute Lymphocytic Leukemia)
Chronic Lymphocytic Leukemia (ALL) (see Chronic Lymphocytic Leukemia)
Hematopoietic Stem Cell Transplant (HSCT) (Bone Marrow Transplant, BMT) (see Hematopoietic Stem Cell Transplant)
Lymphoma (see Lymphoma)
Multiple Myeloma (see Multiple Myeloma)
Neutropenia (see Neutropenia): predisposes to Candidemia

Other

Central Venous Catheter (CVC) (see Central Venous Catheter)
- Epidemiology
  - A Central Venous Catheter is Present at the Time Diagnostic Blood Culture is Obtained in Approximately 70% of Non-Neutropenic Patients with Candidemia
Heroin Abuse (see Heroin)
- Heroin Injection Predisposes to Candidemia
High Apache II Score
Hospitalization in ICU [MEDLINE]
- Hospitalization is ther Highest Risk Factor, Especially in Burn, Trauma, and Neonatal Intensive Care Units
Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
Mucositis (see Mucositis)
Prior Surgery
Renal Failure (see Chronic Kidney Disease)
- Especially Requiring Hemodialysis
Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)
- Total Parenteral Nutrition Predisposes to Candidemia

Medically-Relevant Members of Candida Genus

Candida Albicans
Candida Auris
Candida Dubliniensis
Candida Glabrata
Candida Krusei
Candida Parapsilosis
Candida Tropicalis

Physiology

Presence of Candida in the Environment
- Candida are Ubiquitous in Nature
Presence in Candida in Normal Human Flora
- Candida are Normal Oral and Gastroinestinal Flora
Source of Candida Infection
- Candida Usually Originates from the Gastrointestinal Tract or from a Central Venous Catheter
- Although Candiduria is Common in the Intensive Care Unit, the Urinary Tract is an Uncommon Source of Candidal Infection in the Intensive Care Unit
Relative Prevalence of Candida Species
- Candida Albicans is the Most Common Candida Isolate
- In the Last Decade, Infections Due to Non-Albicans Species have Increased
- Candida Glabrata is relatively resistant to Fluconazole
  - There is an Association Between Fluconazole Use and the Frequency of Candida Glabrata Infection

Clinical and Treatment

Invasive Candidiasis

Types of Invasive Candidiasis
- Deep-Seated Candidiasis with Candidemia
- Deep-Seated Candidiasis without Candidemia
- Candidemia without Deep-Seated Candidiasis
Risk Factors for Invasive Candidiasis
- Candida Colonization
- Corticosteroids (see Corticosteroids)
- Dialysis (see Hemodialysis and Peritoneal Dialysis)
- Exposure to Broad-Spectrum Antibiotics
- Necrotizing Pancreatitis (see Acute Pancreatitis)
- Presence of Central Venous Catheter (CVC) (see Central Venous Catheter)
- Recent Major Surgery (Particularly Abdominal Surgery)
- Severe illness
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)

Oropharyngeal Thrush/Candidiasis

Epidemiology
- Common in Human Immunodeficiency Virus (HIV) Infection (see Human Immunodeficiency Virus)
  - Oropharyngeal Thrush/Candidiasis Represents a Harbinger of Progression to Acquired Immunodeficiency Syndrome (AIDS)
- Thrush Occurring in Presence of Known Acquired Immunodeficiency Syndrome (AIDS) Almost Always Indicates Presence of Candida Esophagitis
Clinical
- Pharyngitis (see Pharyngitis)
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Options For Mild Disease
  - Clotrimazole Troch (10 mg 5x Per Day) (Strong Recommendation, High-Quality Evidence)
  - Miconazole Mucoadhesive Buccal Tablet (50 mg Applied to Canine Fossa qday x 7–14 Days) (Strong Recommendation, High-Quality Evidence)
  - Nystatin Suspension (100k Units/mL, 4–6 mL 4x Per Day) (Strong Recommendation, Moderate-Quality Evidence)
  - Nystatin Pastilles (200k Units Each 4X Per Day x 7–14 Days) (Strong Recommendation, Moderate-Quality Evidence)
- Options for Moderate-Severe Disease
  - Fluconazole (100–200 mg PO qday x 7–14 Days) (Strong Recommendation, High-Quality Evidence)
- Options for Fluconazole-Refractory Disease
  - Itraconazole Solution (200 mg PO qday) (Strong Recommendation, Moderate-Quality Evidence)
  - Posaconazole Suspension (400 mg PO BID x 3 Days, Then 400 mg PO qday for Up to 28 Days) (Strong Recommendation, Moderate-Quality Evidence)
  - Voriconazole (200 mg PO BID) (Strong Recommendation, Moderate-Quality Evidence)
  - Amphotericin B Deoxycholate Oral Suspension (100 mg/L 4x Per Day) (Strong Recommendation, Moderate-Quality Evidence)
  - Echinocandins (see Echinocandins) (Weak Recommendation, Moderate-Quality Evidence)
    - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
    - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
    - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
  - Amphotericin B Deoxycholate IV (0.3 mg/kg IV qday) (Strong Recommendation, Moderate-Quality Evidence)
- Chronic Suppressive Therapy is Usually Unnecessary, Although Fluconazole (100 mg PO 3x Per Week) Can Be Used, if Required (Strong Recommendation, High-Quality Evidence)
- In HIV Infected Patients, Antiretroviral Therapy is Recommended to Decrease the Incidence of Recurrent Oropharyngeal Candidaisis (Strong Recommendation, High-Quality Evidence)
- For Denture-Related Candidiasis, Both Disinfection of the Denture and Antifungal Therapy is Recommended (Strong Recommendation, Moderate-Quality Evidence)

Vulvovaginal Candidiasis

Clinical
- Vaginal Pruritus/Discharge
Treatment Options
- Clotrimazole Cream (Gyne-Lotrimin) (see Clotrimazole)
- Fluconazole (Diflucan) (see Fluconazole): 150 mg total dose
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Options for Uncomplicated Candida Vulvovaginitis
  - Topical antifungal agents, with no one agent superior to another, are recommended (Strong Recommendation, High-Quality Evidence)
  - Single 150-mg oral dose of fluconazole (Strong Recommendation, High-Quality Evidence)
- Options for Severe Acute Candida Vulvovaginitis
  - Fluconazole, 150 mg, given every 72 hours for a total of 2 or 3 doses (Strong Recommendation, High-Quality Evidence)
- C. glabrata vulvovaginitis that is unresponsive to oral azoles (Strong Recommendation, Low-Quality Evidence)
  - Topical intravaginal boric acid, administered in a gelatin capsule, 600 mg daily, x 14 days (Strong Recommendation, Low-Quality Evidence)
  - Nystatin intravaginal suppositories, 100 000 units daily for 14 days (Strong Recommendation, Low-Quality Evidence)
  - Topical 17% flucytosine cream alone or in combination with 3% AmB cream administered daily for 14 days* (Weak Recommendation, Low-Quality Evidence)
- Options for Recurring Vulvovaginal Candidiasis
  - 10–14 days of induction therapy with a topical agent or oral fluconazole, followed by fluconazole, 150 mg weekly for 6 months (Strong Recommendation, High-Quality Evidence)

Candida Esophagitis (Esophageal Candidiasis)

Clinical
- Odynophagia (see Odynophagia)
Treatment Options
- Fluconazole (Diflucan) (see Fluconazole): 200 mg/day x 2–3 wks
- Itraconazole (Sporanox) (see Itraconazole): 200 mg/day x 2–3 wks
- Caspofungin (see Caspofungin): 50 mg/day x 2–3 wks
- Micafungin (see Micafungin)
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Systemic Antifungal Therapy is Always Required (Strong Recommendation, High-Quality Evidence)
- Diagnostic Trial of Empiric Antifungal Therapy is Appropriate Before Esophagogastroduodensocopy (Strong Recommendation, High-Quality Evidence)
- First Choice Therapy
  - Fluconazole PO (200–400 mg, 3–6 mg/kg PO qday x 14–21 Days) is Recommended (Strong Recommendation, High-Quality Evidence)
- Alternatives
  - Fluconazole IV (400 mg, 6 mg/kg IV qday) (Strong Recommendation, High-Quality Evidence)
  - Echinocandins (see Echinocandins) (Strong Recommendation, High-Quality Evidence)
    - Anidulafungin (Eraxis) (see Anidulafungin): 200 mg IV qday
    - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
    - Micafungin (Mycamine) (see Micafungin): 150 mg IV qday
  - Amphotericin B Deoxycholate IV (0.3–0.7 mg/kg IV qday) (Strong Recommendation, Moderate-Quality Evidence): less preferred alternative
- Stepdown Therapy
  - Consider De-Escalating to Oral Fluconazole (200–400 mg, 3–6 mg/kg qday) Therapy Once the Patient is Able to Tolerate Oral Intake (Strong Recommendation, Moderate-Quality Evidence)
- Options for Fluconazole-Refractory Disease
  - Itraconazole Solution (200 mg PO qday) x 14–21 Days (Strong Recommendation, High-Quality Evidence)
  - Voriconazole (200 mg, 3 mg/kg PO or IV BID) x 14–21 Days (Strong Recommendation, High-Quality Evidence)
  - Echinocandins (see Echinocandins) (Strong Recommendation, High-Quality Evidence)
    - Anidulafungin (Eraxis) (see Anidulafungin): 200 mg IV qday x 14–21 days
    - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday x 14–21 days
    - Micafungin (Mycamine) (see Micafungin): 150 mg IV qday x 14–21 days
  - Posaconazole Suspension (400 mg PO BID) or Extended Release Tablets (300 mg PO qday) (Weak Recommendation, Low-Quality Evidence)
- For Patients with Recurrent Candidal Esophagitis, Chronic Suppressive Fluconazole (100–200 mg 3x Per Week) is Recommended (Strong Recommendation, High-Quality Evidence)
- In HIV Infected Patients, Antiretroviral Therapy is Recommended to Decrease the Incidence of Recurrent Candidal Esophagitis (Strong Recommendation, High-Quality Evidence)

Allergic Bronchopulmonary Candidiasis

Clinical
- Allergic Bronchopulmonary Candidiasis is Similar to Allergic Bronchopulmonary Aspergillosis (ABPA) (see Allergic Bronchopulmonary Aspergillosis)
- Asthma-Like Symptoms (see Obstructive Lung Disease)
- Pneumonia-Like Infiltrates (see Pneumonia)
Treatment
- Corticosteroids (see Corticosteroids)
- Omalizumab (Xolair) (see Omalizumab) (J Investig Allergol Clin Immunol, 2009) [MEDLINE]
  - Case Report of Use of Omalizumab

Candida Pneumonia (see Pneumonia)

Epidemiology
- Uncommon (Clin Infect Dis, 2002) [MEDLINE] and (Intern Med, 2012) [MEDLINE]
Physiology
- Due to Aspiration
Diagnosis
- Open Lung Biopsy
  - Required to Demonstrate Yeast and Pseudohyphae (Uniquely, Occur Together in the Same Specimen)
Clinical
- Pneumonia-Like Syndrome
  - Difficult to Diagnose Pre-Mortem (Due to Frequent Presence of Candida in Sputum Due to Oral Contamination and Previous Treatment with Antibiotics)
  - Patchy or Lobar Infiltrates
    - Chest X-Ray May Be Normal in Some Cases
  - Cough (see Cough)
  - Sputum
  - Dyspnea (see Dyspnea)
  - Fever (see Fever)
Treatment Options
- Lipid Formulation Amphotericin B with or without Flucytosine (see Amphotericin and Flucytosine)
- Fluconazole (Diflucan) (see Fluconazole)
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Growth of Candida from Respiratory Secretions Usually Indicates Colonization and Rarely Requires treatment with Antifungal Therapy (Strong Recommendation, Moderate-Quality Evidence)

Candida Urinary Tract Infection (UTI) (see Urinary Tract Infection)

Epidemiology

Most Fungal Infections of the Kidneys/Bladder are Due to Candida Albicans and Other Candida Species
- Urinary Tract is the Most Common Site of Infection in the Medical Intensive Care Unit
- Candiduria is Common in Hospitalized Patients and in the Intensive Care Unit: the significance of Candiduria is Difficult to Determine, Since it May Occur Due to Contamination or Colonization
- Candida Albicans is the Most Common Pathogen Isolated from the Urine of Patients in the Medical Intensive Care Unit
Risk Factors for Funguria in Hospitalized Patients (Clin Infect Dis, 2000) [MEDLINE]: Candida Albicans was the most commonly fungal species isolated (51.8% of cases), with Candida Glabrata being the second most commonly isolated fungal species (15.6% of cases)
- Diabetes Mellitus (DM) (see Diabetes Mellitus): 39% of cases
  - Glucosuria promotes the chronic presence of Candida in the urine
- Prior Systemic Antibiotics: 90% of cases
- Malignancy: 22% of cases
- Urinary Drainage Devices: 83% of cases
  - Cystostomy (see Cystostomy)
  - Foley Catheter (see Foley Catheter)
  - Nephrostomy (see Nephrostomy)
- Urinary Tract Pathology: 38% of cases
  - Infected Penile Prosthesis
  - Neurogenic Bladder
  - Renal Stone Manipulation: due to ureteroscopy or percutaneous lithotripsy
  - Urinary Tract Obstruction: due to nephrolithiasis, prostatic hypertrophy, etc
Risk Factors for Candiduria in Intensive Care Unit Patients (Intensive Care Med. 2003) [MEDLINE]
- Advanced Age
- Diabetes Mellitus (DM) (see Diabetes Mellitus)
  - Glucosuria promotes the chronic presence of Candida in the urine
- Increased Length of Stay
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)
- Ventilator Support

Physiology

Mechanisms of Candida Infection of the Urinary Tract
- Ascent from Lower Urinary Tract to the Upper Urinary Tract via Vesicoureteral Reflux: presence of Foley catheter allows the formation of biofilm, which allows the persistent colonization of the catheter by Candida
  - Renal Involvement Due to Ascending Candida Infection is Usually Unilateral with Isolated Involvement of the Kidney
    - Fungus Ball Involving the Renal Pelvis and Medulla (with Sparing of the Renal Cortex)
    - Perinephric Abscess
    - Emphysematous Pyelonephritis
- Hematogenous Dissemination: see Disseminated Candidiasis below
  - Kidneys are the Most Commonly Involved Organ in Disseminated Candidiasis
  - Renal Involvement Due to Hematogenous Candida Dissemination is Usually Bilateral with Multiple Microabscesses in the Renal Cortex and Medulla
Relationship of Candiduria to Subsequent Candidemia
- Most Patients with Candidemia Have Antecedent Candiduria
- However, Candiduria Results in Subsequent Candidemia in Only 1.3% of Cases
- Candiduria is a Marker for Increased Mortality: however, death is not related to Candida infection and treatment of Candiduria does not decrease the mortality rate

Diagnosis

Urinalysis (seeUrinalysis)
- Pyuria in a Patient with an Indwelling Bladder Catheter Cannot Differentiate Candida Infection From Colonization
Urine Culture (see Urine Culture)
- Candida Colony Count in the Urine Cannot Be Used to Differentiate Candida Infection From Colonization (Especially When an Indwelling Bladder Catheter is Present)
Abdominal/Pelvic CT and Renal Ultrasound (see Abdominal-Pelvic Computed Tomography and Abdominal/Pelvic Ultrasound)
- Imaging is Useful to Diagnose Structural Urinary Tract Abnormalities, Hydronephrosis, Renal Abscess, Emphysematous Pyelonephritis, and Fungus Ball Formation
- Aggregation of Mycelia/Yeast (Fungus Balls) in Bladder/Kidney Leads to Obstruction and Precludes Successful Treatment of Infection with Antifungal Agents Alone

Clinical

General Comments
- Candidal Urinary Tract Infection vs Colonization
  - Most Patients with Candiduria are Asymptomatic: in most cases, presence of Candida reflects colonization, not infection
  - Pyuria is Common in Patients with Chronic Indwelling Bladder Catheters and Therefore, Cannot Be Used to Diagnose Candida Infection
  - Number of Yeast in the Urine Cannot Be Used to Diagnose Candida Infection
  - Presence of Fungal Casts in the Urine is Diagnostic of Renal Involvement Due to Ascending Infection: renal imaging is indicated to evaluate for fungal balls, perinephric abscesses, or hydronephrosis
  - Persistent Candiduria (Especially in Diabetics) is an Indication for Renal Imaging to Rule Out the Presence of a Fungus Ball, Perinephric Abscess, and/or Hydronephrosis
- Ascending Candida Infection of the Urinary Tract Usually Has a Subacute-Chronic Course
Presentations
- Emphysematous Pyelonephritis: air within the renal collecting system or renal parenchyma
  - Fever (see Fever)
  - Flank Pain (see Flank Pain)
- Epididymitis (see Epididymitis)
  - Rarely Due to Candida
- Fungus Ball Involving the Renal Pelvis and Medulla (with Sparing of the Renal Cortex)
  - Fungus Ball is an Uncommon Complication of Candida UTI (Except in Neonates, Where Fungus Balls Can Occur in the Collecting System with Disseminated Candidiasis)
  - Flank Pain (see Flank Pain)
- Orchitis (see Orchitis): rarely due to Candida
  - Testicular Pain (see Testicular Pain)
- Perinephric Abscess
  - Flank Pain (see Flank Pain)
- Prostatitis (see Prostatitis): rarely due to Candida
- Pyelonephritis
  - Fever (see Fever)
  - Flank Pain (see Flank Pain)

Treatment

Clinical Efficacy
- French EMPIRICUS Trial of Empirical Micafungin Treatment in Non-Neutropenic, Non-Transplanted Patients with ICU-Acquired Sepsis, Multiple Sites of Candida Colonization, Multiple Organ Failure, and Exposure to Broad-Spectrum Antibacterial Agents (JAMA, 2016) [MEDLINE]
  - Empirical Micafungin Decreased the Rate of New Invasive Fungal Infections (3%), as Compared to Placebo (12%)
  - However, Empirical Micafungin Treatment Did Not Increase Fungal Infection-Free Survival (68%) at Day 28, as Compared to Placebo (60.2%)
General Principles
- The Only Agents Which are Useful in Treating Candida UTI are Fluconazole, Amphotericin, and Flucytosine
  - All of the Other Antifungal Drugs (Including the Other Azole Agents and Echinocandins) Have Minimal Excretion of Active Drug into the Urine and are Generally Ineffective in Treating Candida Urinary Tract Infection
- Infection Localized to the Kidney (Due to Hematogenous Spread) Probably Can Be Treated with an Echinocandin, Because Tissue Concentrations are Adequate Even Though These Agents Do Not Achieve Adequate Urine Concentrations
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Asymptomatic Candiduria
  - Indications for Imaging in Patients with Persistent Candiduria
    - Diabetes Mellitus (DM) (see Diabetes Mellitus)
    - Neonate
    - Presence of Urologic Abnormalities
  - Indications for Treatment of Asymptomatic Candiduria (Strong Recommendation, Low-Quality Evidence)
    - Treatment is recommended in these patients with asymptomatic Candiduria due to their high risk for dissemination, but the treatment of other patient populations is not recommended (due to the rapid recurrence of Candiduria, high risk for true development of Candida resistance, and no improvement in clinical outcomes)
    - Low Birth Weight Infant (<1500 g)
    - Neutropenia (see Neutropenia)
    - Planned Urologic Procedure: treatment (Fluconazole 400 mg, 6 mg/kg qday PO or Amphotericin B Deoxycholate 0.3–0.6 mg/kg IV qday for several days prior) should precede the procedure
    - Renal Transplant (see Renal Transplant): this is a relative indication, with treatment generally recommended only in cases with a high risk of graft or device involvement (such as early after transplant, when ureteral stents are present)
  - Measures to Decrease Candiduria (Strong Recommendation, Low-Quality Evidence)
    - Discontinue Antibiotics
    - Remove (or Replace) Bladder Catheters
    - Remove (or Replace) Ureteral Stents
- Symptomatic Candida Cystitis
  - Removal of an Indwelling Bladder Catheter, if Feasible, is Strongly Recommended (Strong Recommendation, Low-Quality Evidence)
  - Fluconazole-Susceptible Candida
    - Fluconazole (200 mg, 3 mg/kg qday PO) x 2 wks is Recommended (Strong Recommendation, Moderate-Quality Evidence)
  - Candida Glabrata (Typically Fluconazole-Resistant)
    - Amphotericin Deoxycholate (0.3–0.6 mg/kg IV qday x 1–7 days) is Recommended (Strong Recommendation, Low-Quality Evidence)
    - Flucytosine Monotherapy (25 mg/kg QID PO for 7–10 Days) is Recommended (Strong Recommendation, Low-Quality Evidence)
    - Amphotericin Deoxycholate Bladder Irrigation (50 mg/L Sterile Water qday x 5 days) May Be Used (Weak Recommendation, Low-Quality Evidence)
  - Candida Krusei (Typically Fluconazole-Resistant)
    - Amphotericin Deoxycholate (0.3–0.6 mg/kg IV qday x 1–7 Days) is Recommended (Strong Recommendation, Low-Quality Evidence)
    - Amphotericin Deoxycholate Bladder Irrigation (50 mg/L Sterile Water qday x 5 days) May Be Used (Weak Recommendation, Low-Quality Evidence)
- Symptomatic Ascending Candida Pyelonephritis
  - Elimination of Urinary Tract Obstruction is Strongly Recommended (Strong Recommendation, Low-Quality Evidence)
  - Consider Removal/Replacement of Nephrostomy Tubes/Stents, if Feasible (Weak Recommendation, Low-Quality Evidence)
  - Fluconazole-Susceptible Candida
    - Fluconazole (200–400 mg, 3–6 mg/kg PO qday) x 2 wks is Recommended (Strong Recommendation, Low-Quality Evidence)
  - Candida Glabrata (Typically Fluconazole-Resistant)
    - Amphotericin B Deoxycholate (0.3–0.6 mg/kg IV qday) x 1–7 days with/without Flucytosine (25 mg/kg QID PO), is Recommended (Strong Recommendation, Low-Quality Evidence)
    - Flucytosine Monotherapy (25 mg/kg QID PO) x 2 wks, Could Be Considered (Weak Recommendation, Low-Quality Evidence)
  - Candida Krusei (Typically Fluconazole-Resistant)
    - Amphotericin B Deoxycholate (0.3–0.6 mg/kg IV qday) x 1–7 days is Recommended (Strong Recommendation, Low-Quality Evidence)
- Renal Fungal Ball (Fungal Bezoar)
  - Surgical Intervention is Strongly Recommended in Adults (Strong Recommendation, Low-Quality Evidence)
  - Antifungal Treatment as Noted Above for Cystitis or Pyelonephritis is Recommended (Strong Recommendation, Low-Quality Evidence)
  - Irrigation Through Nephrostomy Tubes, if Present, with Amphotericin B Deoxycholate (25–50 mg in 200–500 mL Sterile Water), is Recommended (Strong Recommendation, Low-Quality Evidence)
- Perinephric Abscess
  - Percutaneous (or Open) Drainage + Systemic Antifungal Therapy is Recommended

Intra-Abdominal Candidiasis (see Peritonitis)

Epidemiology

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Clinical

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Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Empiric Antifungal Therapy Should Be Considered for Patients with Clinical Evidence of Intra-Abdominal Infection and Significant Risk Factors for Candidiasis, Including Recent Abdominal Surgery, Anastomotic Leaks, or Necrotizing Pancreatitis (Strong Recommendation, Moderate-Quality Evidence)
- Treatment of Intra-Abdominal Candidiasis Should Include Source Control, with Appropriate Drainage and/or Debridement (Strong Recommendation, Moderate-Quality Evidence)
- Echinocandins (see Echinocandins): recommended empiric therapy (Strong Recommendation, Moderate-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
- Fluconazole (Diflucan) (see Fluconazole): alternative empiric therapy (PO or IV: load with 800 mg, 12 mg/kg, then 400 mg, 6 mg/kg qday) for those who are not critically ill and who are unlikely to have a Fluconazole-resistant Candida species (Strong Recommendation, Moderate-Quality Evidence)
- Lipid Formulation Amphotericin B (see Amphotericin): lipid formulation Amphotericin B (3–5 mg/kg qday) is an alternative empiric therapy if there is intolerance, limited availability, or resistance to other antifungal agents (Strong Recommendation, Moderate-Quality Evidence)
- Duration of Empiric Antifungal Therapy Should Be Determined by the Adequacy of Source Control and Clinical Response (Strong Recommendation, Low-Quality Evidence)

Candida Suppurative Thrombophlebitis

Epidemiology

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Clinical

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Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Catheter Removal and Incision and Drainage or Resection of the Vein, if Feasible, is Recommended (Strong Recommendation, Low-Quality Evidence)
- Echinocandins (High-Dose) (see Echinocandins)
  - Echicandins are the Recommended Empiric Therapy (Strong Recommendation, Low-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): 200 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): 150 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 150 mg IV qday
- Fluconazole (Diflucan) (see Fluconazole)
  - Fluconazole is an Alternative Empiric Therapy
    - PO or IV: 400–800 mg qday (Strong Recommendation, Low-Quality Evidence)
- Lipid Formulation Amphotericin B (see Amphotericin)
  - IV: 3–5 mg/kg qday (Strong Recommendation, Low-Quality Evidence)
- Options for Stepdown Therapy
  - Fluconazole (Diflucan) (see Fluconazole)
    - PO or IV: 400–800 mg (6–12 mg/kg) qday should be considered for patients who initially responded to an Echinocandin or Amphotericin B, are clinically stable, and have a Fluconazole-susceptible isolate (Strong Recommendation, Low-Quality Evidence)
- Resolution of the Thrombus Can Be Used as Evidence to Discontinue the Antifungal Therapy if the Clinical and Culture Data are Supportive (Strong Recommendation, Low-Quality Evidence)

Candida Endocarditis (see Endocarditis)

Epidemiology

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Clinical

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Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Options for For Native Valve Endocarditis (Strong Recommendation, Low-Quality Evidence)
  - Echinocandins (High-Dose) (see Echinocandins)
    - Anidulafungin (Eraxis) (see Anidulafungin): 200 mg IV qday
    - Caspofungin (Cancidas) (see Caspofungin): 150 mg IV qday
    - Micafungin (Mycamine) (see Micafungin): 150 mg IV qday
  - Lipid Formulation Amphotericin B (3–5 mg/kg qday) with/without Flucytosine (25 mg/kg QID)
- Options for Stepdown Therapy
  - Fluconazole (Diflucan) (see Fluconazole): PO or IV: 400–800 mg (6–12 mg/kg) qday for those with susceptible Canida isolate, clinical stability, and Candida cleared from the bloodstream (Strong Recommendation, Low-Quality Evidence)
  - Voriconazole (Vfend) (see Voriconazole): 200–300 mg (3–4 mg/kg) PO BID can be used for Candida isolates which are susceptible for this agent, but not to Fluconazole (Weak Recommendation, Very Low-Quality Evidence)
  - Posaconazole (Noxafil, Posanol) (see Posaconazole): 300 mg PO qday can be used for Candida isolates which are susceptible for this agent, but not to Fluconazole (Weak Recommendation, Very Low-Quality Evidence)
- Valve Replacement is Recommended with Treatment Continuing for at Least 6 wks Post-Operatively (and for a LOnger Duration in Patients with Perivalvular Abscess or Other Complications) (Strong Recommendation, Low-Quality Evidence)
  - If Patient Cannot Undergo Valve Replacement, Long-Term Fluconazole Suppression (400–800 mg, 6–12 mg/kg qday) is Recommended if the Isolate is Susceptible (Strong Recommendation, Low-Quality Evidence)
- For Prosthetic Valve Endocarditis, Same Options as Above are Recommended with the Addition of Long-Term Fluconazole Suppression (400–800 mg, 6–12 mg/kg qday) to Prevent Recurrence (Strong Recommendation, Low-Quality Evidence)

Candida Infection of Implantable Cardiac Devices (see Endocarditis)

Epidemiology

xxxxx

Clinical

xxxxx

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- For Pacemaker and Implantable cardiac Defibrillator Infections, the Entire Device Should Be Removed (Strong Recommendation, Moderate-Quality Evidence)
- Antifungal Therapy is the Same as that Recommended for Native Valve Endocarditis (Strong Recommendation, Low-Quality Evidence)
- For Infections Limited to Generator Pockets, 4 wks of Antifungal Therapy After Removal of the Device is rRcommended (Strong Recommendation, Low-Quality Evidence)
- For Infections Involving the Wires, at Least 6 wks of Antifungal Therapy After Wire Removal is Recommended (Strong Recommendation, Low-Quality Evidence)
- For Ventricular Assist Devices Which Cannot Be Removed, the Antifungal Regimen is the Same as that Recommended for Native Valve Endocarditis (Strong recommendation, Low-Quality Evidence)
  - Chronic Suppressive Therapy with Fluconazole is Recommended if the Candida Isolate is Susceptible, for as Long as the Device Remains in Place (Strong Recommendation, Low-Quality Evidence)

Candida Osteomyelitis (see Osteomyelitis)

Epidemiology

xxxxx

Clinical

xxxxx

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Options
  - Fluconazole (400 mg, 6 mg/kg qday) x 6–12 mos (Strong Recommendation, Low-Quality Evidence)
  - Echinocandin x 2 wks, Followed by Fluconazole (400 mg, 6 mg/kg qday) x 6–12 mos (see Echinocandins) (Strong Recommendation, Low-Quality Evidence)
    - Anidulafungin (Eraxis) (see Anidulafungin): 100 mg IV qday
    - Caspofungin (Cancidas) (see Caspofungin): 50–70 mg IV qday
    - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
  - Lipid Formulation Amphotericin B (3–5 mg/kg qday) for at least 2 wks, Followed by Fluconazole (400 mg, 6 mg/kg qday) x 6–12 mos is a Less Attractive Alternative (Weak Recommendation, Low-Quality Evidence)
- Surgical Debridement is Recommended in Selected Cases (Strong Recommendation, Low-Quality Evidence)

Candida Septic Arthritis (see Septic Arthritis)

Epidemiology

XXXXX

Clinical

XXXXX

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Options
  - Fluconazole (400 mg, 6 mg/kg qday) x 6 wks (Strong Recommendation, Low-Quality Evidence)
  - Echinocandin x 2 wks, Followed by Fluconazole (400 mg, 6 mg/kg qday) x 4 wks (see Echinocandins) (Strong Recommendation, Low-Quality Evidence)
    - Anidulafungin (Eraxis) (see Anidulafungin): 100 mg IV qday
    - Caspofungin (Cancidas) (see Caspofungin): 50–70 mg IV qday
    - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
  - Lipid Formulation Amphotericin B (3–5 mg/kg qday) for at least 2 wks, Followed by Fluconazole (400 mg, 6 mg/kg qday) x 4 wks is a Less Attractive Alternative (Weak Recommendation, Low-Quality Evidence)
- Surgical Drainage is Indicated in All Cases of Septic Arthritis (Strong Recommendation, Moderate-Quality Evidence)
- For Septic Arthritis Involving a Prosthetic Device, Device Removal is Recommended (Strong Recommendation, Moderate-Quality Evidence)
- If the Prosthetic Device Cannot Be Removed, Chronic Suppression with Fluconazole (400 mg, 6 mg/kg qday) is Recommended if the Candida Isolate is Susceptible (Strong Recommendation, Low-Quality Evidence)

Candida Endophthalmitis (see Fungal Endophthalmitis)

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- All Patients with Candidemia Should Have a Dilated Retinal Examination, Preferably Performed by an Ophthalmologist, Within the First Week of Therapy in Non-Neutropenic Patients to Establish if Endophthalmitis is Present (Strong Recommendation, Low-Quality Evidence)
  - For Neutropenic Patients, it is Recommended to Delay the Retinal Examination Until Neutrophil Recovery (Strong Recommendation, Low-Quality Evidence)
- The extent of ocular infection (chorioretinitis with or without macular involvement and with or without vitritis) should be determined by an ophthalmologist (Strong Recommendation, Low-Quality Evidence)
- Decisions Regarding antifungal treatment and surgical in- tervention should be made jointly by an ophthalmologist and an infectious diseases physician (Strong Recommendation, Low-Quality Evidence)

Candida Chorioretinitis without Vitritis (see Chorioretinitis)

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- For Fluconazole/Voriconazole-Susceptible Candida Isolates, Fluconazole (Load 800 mg, 12 mg/kg, then 400–800 mg, 6–12 mg/kg qday) or Voriconazole (Load 400 mg, 6 mg/kg IV BID x 2 Doses, then 300 mg, 4 mg/kg IV or PO BID is Recommended (Strong Recommendation, Low-Quality Evidence)
- For Fluconazole/Voriconazole-Resistant Candida Isolates, Lipid Formulation Amphotericin B (3–5 mg/kg qday) with/without Flucytosine (25 mg/kg QID PO) is Recommended (Strong Recommendation, Low-Quality Evidence)
- With Macular Involvement, Antifungal Agents as Noted Above Plus Intravitreal Injection of Either Amphotericin B Deoxycholate (5–10 μg/0.1 mL Sterile Water) or Voriconazole (100 μg/ 0.1 mL Sterile Water or Normal Saline) to Ensure a Prompt High Level of Antifungal Activity is Recommended (Strong Recommendation, Low-Quality Evidence)
- Duration of Antifungal Treatment Should Be at Least 4–6 wks, with the Final Duration Depending on Resolution of the Lesions as Determined by Repeated Ophthalmological Examinations (Strong Recommendation, Low-Quality Evidence)

Candida Chorioretinitis with Vitritis (see Chorioretinitis)

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Antifungal Therapy as Detailed Above for Chorioretinitis without Vitritis, Plus Intravitreal Injection of Either Amphotericin B Deoxycholate (5–10 μg/0.1 mL Sterile Water) or Woriconazole (100 μg/0.1 mL Sterile Water or Normal Saline) is Recommended (Strong Recommendation, Low-Quality Evidence)
- Vitrectomy Should Be Considered to Decrease the Burden of Organisms and to Allow the Removal of Fungal Abscesses that are Inaccessible to Systemic Antifungal Agents (Strong Recommendation, Low-Quality Evidence)
- Duration of Antifungal Treatment Should Be at Least 4–6 wks, with the Final Duration Depending on Resolution of the Lesions as Determined by Repeated Ophthalmological Examinations (Strong Recommendation, Low-Quality Evidence)

Candida Central Nervous System Infection

Epidemiology

XXXX

Clinical

XXXX

Treatment

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- For Initial Treatment, Lipid Formulation Amphotericin B (5 mg/kg qday) with/without oral flucytosine, 25 mg/kg QID is Recommended (Strong Recommendation, Low-Quality Evidence)
- For Step-Down Therapy After the Patient has Responded to Initial Treatment, Fluconazole (400–800 mg, 6–12 mg/kg qday) is Recommended (Strong Recommendation, Low-Quality Evidence)
- Duration of Therapy Until All Signs/Symptoms and Cerebrospinal Fluid and Radiological Abnormalities Have Resolved (Strong Recommendation, Low-Quality Evidence)
- Infected Central Nervous System Devices (Ventriculostomy Drains, Shunts, Stimulators, Prosthetic Reconstructive Devices, and Biopolymer Wafers Which Deliver Chemotherapy) Should Be Removed, if Possible (Strong Recommendation, Low-Quality Evidence)
- For Patients in Whom a Ventricular Device Cannot Be Removed, Amphotericin B Deoxycholate Could Be Administered Through the Device into the Ventricle (Dose Range 0.01–0.5 mg in 2 mL 5% Dextrose in Water) (Weak Recommendation, Low-Quality Evidence)

Disseminated Candidiasis

Epidemiology

Risk Factors for Disseminated Candidiasis
- Heroin Abuse (see Heroin)
- Neutropenia (see Neutropenia)
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)

PICTURE

Risk Factors for Invasive Candida Infection in Critically Ill Patients (From Systematic Review and Meta-Analysis of 34 Studies) (Chest, 2022)[MEDLINE]
- Broad-Spectrum Antibiotics (OR 5.6; 95% CI: 3.6- 8.8)
- Blood Transfusion (OR 4.9; 95% CI: 1.5–16.3)
- Candida Colonization (OR 4.7; 95% CI: 1.6- 14.3)
- Central Venous Catheter (CVC) (OR 4.7; 95% CI: 2.7–8.1)
- Total Parenteral Nutrition (TPN) (OR 4.6; 95% CI: 3.3–6.3)
- Mechanical Ventilation (OR 4.4; 95% CI: 2.60–7.44)
- Bacteremia (OR 4.2; 95% CI: 1.92–8.97)
- Human Immunodeficiency Virus (HIV) Infection (OR 3.9; 95% CI: 1.47–10.38)
- Sepsis (OR 3.66; 95% CI: 2.01–6.66)
- Renal Replacement Therapy (OR 3.3; 95% CI: 2.59–4.22)
- Shock (OR 3.1; 95% CI: 2.61–3.79)
- Colonization Index (OR 3.1; 95% CI: 1.95–4.93)
- Abdominal Surgery (OR 2.5, 95% CI: 1.84–3.49)
- Hematologic Disease (OR 2.3: 95% CI: 1.54–3.35)
- Neutropenia (OR 2.2; 95% CI: 1.43–3.27)
- Transplantation (OR 2.1, 95% CI: 0.94–4.67)
- Immunosuppression (OR 2.0, 95% CI: 1.60–2.53)
- Corticosteroids (OR 1.8; 95% CI: 1.32–2.32)
- Renal Disease (OR 1.6; 95% CI: 1.19–2.14)
- Malignancy (OR 1.5, 95% CI: 1.11–2.07)
- Surgery (OR 1.4, 95% CI: 1.05–1.89)
- Diabetes Mellitus (OR 1.4; 95% CI: 1.14–1.64)
- Urinary Catheter (OR 1.2; 95% CI: 0.68–2.25)

Physiology

Mechanisms of Candida Infection of the Urinary Tract
- Ascent from Lower Urinary Tract to the Upper Urinary Tract via Vesicoureteral Reflux: presence of Foley catheter allows the formation of biofilm, which allows the persistent colonization of the catheter by Candida
  - Renal Involvement Due to Ascending Candida Infection is Usually Unilateral with Isolated Involvement of the Kidney
    - Fungus Ball Involving the Renal Pelvis and Medulla (with Sparing of the Renal Cortex)
    - Perinephric Abscess
    - Emphysematous Pyelonephritis
- Hematogenous Dissemination
  - Kidneys are the Most Commonly Involved Organ in Disseminated Candidiasis
  - Renal Involvement Due to Hematogenous Candida Dissemination is Usually Bilateral
    - Multiple Microabscesses in the Renal Cortex and Medulla
Relationship of Candiduria to Subsequent Candidemia
- Most Patients with Candidemia Have Antecedent Candiduria
- However, Candiduria Results in Subsequent Candidemia in Only 1.3% of Cases

Diagnosis

Blood Culture (see Blood Culture)
- Sensitivity of Blood Culture in Diagnosing Invasive Candidiasis: approximately 50%
- Limit of Detection of Blood Culture: ≤1 colony forming unit/mL
  - Limit of Detection of Blood Culture is At or Below that for PCR
  - As Such, Blood Cultures Should Be Positive During the Vast Majority of Active Candida Bloodstream Infections
    - However, Blood Cultures May Be Negative in Cases with Extremely Low Level Candidemia, Intermittent Candidemia, Deep-Seated Candidiasis Which Persists After Sterilization of Candidemia, or Deep-Seated Candidiasis Resulting from Direct Inoculation of Candida in the Absence of Candidemia
- Blood Cultures Have Slow Turnaround Time
  - Median Time to Positivity: 2–3 days (range: 1 to ≥7 days)
Serum (1,3)-β-D-Glucan (see Serum (1–3)-β-D-Glucan)
- Rationale
  - β-D-Glucan is a Cell Wall Component of Candida, Aspergillus, Pneumocystis Jirovecii, and Several Other Fungi
- Technique
  - Sensitivity for Invasive Candidiasis: 75–80%
  - Specificity for Invasive Candidiasis: 85%
  - Testing of Samples Other than Serum: not well established
    - Testing of Cerebrospinal Fluid: sensitivity of 100% and specificity of 95%–98% for the diagnosis of non-Candida fungal central nervous system infections
Candida Polymerase Chain Reaction (PCR)
- Technique
  - Using Blood Sample

Clinical

Abdominal Pain (see Abdominal Pain)
Costovertebral Angle Tenderness (see Costovertebral Angle Tenderness)
Flank Pain (see Flank Pain)
Blood Cultures Positive for Candida (see Blood Culture): Candida isolated from blood cultures is always pathologic
- However, Even Patients with Extensive Disseminated Visceral Candidiasis May Not Have Positive Blood Cultures
Hematogenous Micro-Abscesses to Eyes/Lungs/Bones/Joints/Skin
- Endophthalmitis (see Fungal Endophthalmitis)
- Joint Micro-Abscesses
- Non-Painful, Non-Pruritic Pustular Skin Lesions (see xxxx)
- Osteomyelitis (see Osteomyelitis)
- Pulmonary Infiltrates (see Pneumonia)
- Retinal Lesions

Prophylaxis to Prevent Invasive Candidiasis in the Intensive Care Unit (ICU) Setting

Clinical Efficacy
- Systematic Review and Meta-Analysis of the Use of Antifungal Agents to Prevent Fungal Infections in Non-Neutropenic Critically Ill and Surgical Patients (J Antimicrob Chemother, 2006) [MEDLINE]
  - Fluconazole/Ketoconazole Prophylaxis in Critically Ill Patients Decreased Invasive Fungal Infections by 50% and Mortality Rate by 25%
  - Although No Significant Increase in Azole-Resistant Candida Species was Found with the Use of Prophylaxis, the Trials Were Not Powered to Exclude Such an Effect
- Trial of Daily Chlorhexidine Gluconate Bath in Preventing the Acquisition of Multidrug-Resistant Organisms and Bloodstream Infections (NEJM, 2013) [MEDLINE]
  - Daily Chlorhexidine Gluconate Bath Prevented the Acquisition of Multidrug-Resistant Organisms and Decreased the Risk of Bloodstream Infections (Including Candidemia)
General Indications for Empiric Antifungal Therapy in Immunocompromised Patients in the Intensive Care Unit
- Persistent Fever without Source in Patient Already on Antibiotics
- Presence of Likely Source for Candidemia
  - Indwelling Central Venous Catheter (CVC) (see Central Venous Catheter)
  - Gastrointestinal Perforation
  - Gastrointestinal Surgery
  - Mucosal Defects/Mucositis
- Documented Candidal Colonization at Several Sites
  - Presence of Candida in Sputum and Bronchoalveolar Lavage (BAL) Has a Low Positive Predictive Value for Candidal Pulmonary Infection
  - Absence of Candidal Colonization in Sputum and BAL has a High Negative Predictive Value in Ruling Out Candidal Pulmonary Infection [MEDLINE]
Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Echinocandins (see Echinocandins): can be considered in high-risk patients in adult ICU’s with a high rate (>5%) of invasive candidiasis (Weak Recommendation, Low-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
- Fluconazole (Diflucan) (see Fluconazole): can be considered in high-risk patients in adult ICU’s with a high rate (>5%) of invasive candidiasis (Weak Recommendation, Moderate-Quality Evidence)
  - PO or IV: load with 800 mg (12 mg/kg), then 400 mg (6 mg/kg) qday
- Daily Chlorhexidine Bath Can Be Considered to Decrease the Incidence of Bloodstream Infections (Including Candidemia) (see Chlorhexidine Gluconate) (Weak Recommendation, Moderate-Quality Evidence)

Empiric Treatment for Suspected Invasive Candidiasis in Non-Neutropenic Patient in the Intensive Care Unit Setting

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Empiric Antifungal Therapy Should Be Considered in Critically Ill Patients with Risk Factors for Invasive Candidiasis and No Other Known Cause of Fever and Should Be Based on Clinical Assessment of Risk Factors, Surrogate Markers for Invasive Candidiasis, and/or Culture Data from Non-Sterile Sites (Strong Recommendation, Moderate-Quality Evidence): empiric antifungal therapy should be started as soon as possible in patients with these risk factors and septic shock
- Echinocandins (see Echinocandins): preferred empiric therapy (Strong Recommendation, Moderate-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
- Fluconazole (Diflucan) (see Fluconazole): alternative empiric therapy (PO or IV: load with 800 mg, 12 mg/kg, then 400 mg, 6 mg/kg qday) for those who have not recent azole antifungal exposure and are not colonized with an azole-resistant Candida species (Strong Recommendation, Moderate-Quality Evidence)
- Lipid Formulation Amphotericin B (see Amphotericin): lipid formulation Amphotericin B (3–5 mg/kg qday) is an alternative therapy if there is intolerance, limited availability, or resistance to other antifungal agents (Strong Recommendation, Low-Quality Evidence)
- Recommended Duration of Empiric Antifungal Therapy is 2 wks in Patients Who Improve on the Therapy (Weak Recommendation, Low-Quality Evidence)
- For Patients Who Do Not Have a Clinical Response to Empiric Therapy at 4–5 Days and Who Do Not Have Subsequent Evidence of Invasive Candidiasis After the Start of Empiric Therapy or Have a Negative Non-Culture-Based Diagnostic Assay with a High Negative Predictive Value, Consideration Should Be Given to Stopping the Empiric Antifungal Therapy (Strong Recommendation, Low-Quality Evidence)

Treatment of Candidemia in Non-Neutropenic Patient

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Echinocandins (see Echinocandins): recommended initial therapy (Strong Recommendation, High-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
- Fluconazole (Diflucan) (see Fluconazole)
  - Alternative initial therapy (PO or IV: load with 800 mg, 12 mg/kg, then 400 mg, 6 mg/kg qday) for those who are not critically ill and who are unlikely to have a Fluconazole-resistant Candida species (Strong Recommendation, High-Quality Evidence)
- Voriconazole (Vfend) (see Voriconazole)
  - Voriconazole 400 mg (6 mg/kg) BID x 2 Doses, then 200 mg (3 mg/kg) BID is Effective for Candidemia, But Offers Little Advantage Over Fluconazole as Initial Therapy (Strong Recommendation, Moderate-Quality Evidence)
  - Voriconazole is Recommended as Step-Down Oral Therapy for Selected Cases of Candidemia Due to Candida Krusei (Strong Recommendation, Low-Quality Evidence)
- Lipid Formulation Amphotericin B (see Amphotericin)
  - Lipid formulation Amphotericin B (3–5 mg/kg qday) is a reasonable alternative therapy if there is intolerance, limited availability, or resistance to other antifungal agents (Strong Recommendation, High-Quality Evidence)
  - With Suspected Azole and Echinocandin-Resistant Candida, Lipid Formulation Amphotericin B (3–5 mg/kg qday) is Recommended (Strong Recommendation, Low-Quality Evidence)
- Susceptibility Testing
  - Testing for Echinocandin Susceptibility is Suggested for All Patients Who Have Had Prior Echinocandin Therapy and in Those with Candida Glabrata or Candida Parapsilosis (Strong Recommendation, Low-Quality Evidence)
  - Testing for Azole Susceptibility is Recommended for All Bloodstream and Clinically-Relevant Candida Isolates (Strong Recommendation, Low-Quality Evidence)
- Transitioning of Antifungal Therapy
  - Transition from Echinocandin to Fluconazole (Usually within 5–7 Days) is Recommended for Fluconazole-Susceptible Isolate (Candida Albicans), Clinically Stability, and Repeat Negative Cultures on Antifungal Therapy (Strong Recommendation, Moderate-Quality Evidence)
  - For Candida Glabrata, Transition to Higher-Dose Fluconazole (800 mg, 12 mg/kg Daily) or Voriconazole (200–300 mg, 3–4 mg/kg BID) Should Only Be Considered Among Patients with Fluconazole-Susceptible or Voriconazole-Susceptible Isolates (Strong Recommendation, Low-Quality Evidence)
  - Transition from Liposomal Amphotericin B to Fluconazole is Recommended After 5–7 Days with Fluconazole-Susceptible Isolate, Clinically Stability, and Repeat Negative Cultures on Antifungal Therapy (Strong Recommendation, High-Quality Evidence)
- Follow-Up Blood Cultures Should Be Performed Every Day or Every Other Day to Establish the Time Point at Which Candidemia Has Been Cleared (Strong Recommendation, Low-Quality Evidence)
- Ophthalmological Examination (Preferably by an Ophthalmologist) is Recommended within the First Week After Diagnosis for All Non-Neutropenic Patients with Candidemia (Strong Recommendation, Low-Quality Evidence)
- Central Venous Catheters Should Be Removed as Early as Possible in the Course of Candidemia When the Source if Presumed to the Catheter (and the Catheter Can Be Removed Safely) (Strong Recommendation, Moderate-Quality Evidence)
- Recommended Duration of Therapy for Candidemia without Obvious Metastatic Complications is 2 wks After Documented Clearance of Candida Species from the Bloodstream and Resolution of Symptoms Attributable to Candidemia (Strong Recommendation, Moderate-Quality Evidence)

Treatment of Candidemia in Neutropenic Patient

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Echinocandins (see Echinocandins): recommended initial therapy (Strong Recommendation, Moderate-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
  - Echinocandins Can Be Used for Candidemia Due to Candida Krusei (Strong Recommendation, Low-Quality Evidence)
- Lipid Formulation Amphotericin B (see Amphotericin): lipid formulation Amphotericin B (3–5 mg/kg qday) is an alternative therapy if there is intolerance, limited availability, or resistance to other antifungal agents (Strong Recommendation, Moderate-Quality Evidence)
  - Lipid Formulation Amphotericin B Can Be Used for Candidemia Due to Candida Krusei (Strong Recommendation, Low-Quality Evidence)
- Fluconazole (Diflucan) (see Fluconazole): alternative initial therapy (PO or IV: load with 800 mg, 12 mg/kg, then 400 mg, 6 mg/kg qday) for those who are not critically ill and have had no prior azole antifungal exposure (Weak Recommendation, Low-Quality Evidence)
- Voriconazole (Vfend) (see Voriconazole)
  - Voriconazole 400 mg (6 mg/kg) BID x 2 Doses, then 200–300 mg (3–4 mg/kg) BID Can Be Used in Situations Where Additional Mold Coverage is Desired (Weak Recommendation, Low-Quality Evidence)
  - Voriconazole Can Be Used as Step-Down Oral Therapy During Neutropenia with Voriconazole-Susceptible Isolate, Clinical Stability, and Documented Bloodstream Clearance on Antifungal Therapy (Weak Recommendation, Low-Quality Evidence)
  - Voriconazole iCan Be Used for Candidemia Due to Candida Krusei (Strong Recommendation, Low-Quality Evidence)
- Transitioning of Antifungal Therapy
  - Transition from Echinocandin to Fluconazole (400 mg, 6 mg/kg day) Can Be Used During Persistent Neutrophilia with Fluconazole-Susceptible Isolate (Candida Albicans), Clinically Stability, and Repeat Negative Cultures on Antifungal Therapy (Weak Recommendation, Low-Quality Evidence)
- Ophthalmological Findings of Choroidal/Vitreal Infection are Minimal Until Recovery from Neutropenia, Necessitating Dilated Funduscopic Examination Within the First Week After Recovery from Neutropenia (Strong Recommendation, Low-Quality Evidence)
- In Neutropenic Candidemia, Non-Catheter Sources (Gastrointestinal Tract, etc) Tend to Predominate, Suggesting that Central Venous Catheters Should Be Removed on an Individualized Basis (Strong Recommendation, Low-Quality Evidence)
- Granulocyte Colony-Stimulating Factor (G-CSF)-Mobilized Granulocyte Transfusions Can Be Considered in Cases of Persistent Candidemia with Anticipated Protracted Neutropenia (Weak Recommendation, Low-Quality Evidence)
- Recommended Duration of Therapy for Candidemia without Metastatic Complications is 2 wks After Documented Clearance of Candida Species from the Bloodstream, Resolution of Neutropenia, and Resolution of Symptoms Attributable to Candidemia (Strong Recommendation, Low-Quality Evidence)

Prognosis

Retrospective Cohort Study of Hospitalized Patients with Septic Shock and Candidemia (Clin Infect Dis, 2012) [<a href=“https://www.ncbi.nlm.nih.gov/pubmed/22423135” title=“MEDLINE”>MEDLINE]
- Mortality Rate in Septic Shock Due to Candida: 63.5%
  - Mortality Rate for Patients with Adequate Source Control and Antifungal Therapy within 24 hrs of the Onset of Shock was 52.8%, as Compared to Patients Who Did Have These Goals Mets (97.6%)

Chronic Disseminated (Hepatosplenic) Candidiasis

Treatment of Chronic Disseminated (Hepatosplenic) Candidiasis

Recommendations (Infectious Diseases Society of America, 2016 Guidelines for the Management of Candidiasis) (Clin Infect Dis, 2016) [MEDLINE]
- Remove Vascular Access Devices
- Echinocandins (see Echinocandins): initial therapy (Strong Recommendation, Low-Quality Evidence)
  - Anidulafungin (Eraxis) (see Anidulafungin): load 200 mg IV, then 100 mg IV qday
  - Caspofungin (Cancidas) (see Caspofungin): load 70 mg IV, then 50 mg IV qday
  - Micafungin (Mycamine) (see Micafungin): 100 mg IV qday
- Lipid Formulation Amphotericin B (see Amphotericin): lipid formulation Amphotericin B (3–5 mg/kg qday) as initial therapy (Strong Recommendation, Low-Quality Evidence)
  - Transitioning of Antifungal Therapy
  - After Several Weeks of Echinocandin or Lipid Formulation Amphotericin B, Transition to Oral Fluconazole (400 mg, 6 mg/kg qday) is Suggested for Patient Who is Unlikely to have a Fluconazole-Resistant Isolate (Strong Recommendation, Low-Quality Evidence)
- Recommended Duration of Therapy is Until All Lesions Resolve on Imaging (Usually Several Months): premature discontinuation of therapy can result in relapse (Strong Recommendation, Low-Quality Evidence)
- If Chemotherapy/Hematopoietic Stem Cell Transplantation is Required, it Should Not Be Delayed Due to the Presence of Chronic Disseminated Candidiasis and Antifungal Therapy Should Be Continued Throughout the Period of High Risk to Prevent Relapse (Strong Recommendation, Low-Quality Evidence)
- For Patients with Debilitating Persistent Fevers, Short-Term (1–2 wk) Non-Steroidal Anti-Inflammatory (NSAID) or Corticosteroid Therapy Can Be Considered (Weak Recommendation, Low-Quality Evidence)

References

General

Allergic bronchopulmonary candidiasis: case report and suggested diagnostic criteria. J Allergy Clin Immunol. 1987 Dec;80(6):816–20 [MEDLINE]
Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis 1996; 22:30–35 [MEDLINE]
Nosocomial infections in medical intensive care units in the United States. Crit Care Med 1999; 27:887–892 [MEDLINE]
Prospective multicenter surveillance study of funguria in hospitalized patients. Clin Infect Dis 2000; 30:14–18 [MEDLINE]
Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. Clin Infect Dis 2000; 30:19–24 [MEDLINE]
Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis. 2000;30(1):14 [MEDLINE]
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