CANDIDIASIS

CANDIDIASIS - Brock D. Lutz, MD; Ronald A. Greenfield, MD
BASICS
DESCRIPTION
Candida albicans and related species cause a variety of infections
• Cutaneous syndromes include erosio interdigitalis blastomycetica, folliculitis, balanitis, intertrigo, paronychia, onychomycosis, diaper rash, perianal candidiasis, and the syndromes of chronic mucocutaneous candidiasis.
• Mucous membrane infections include oral candidiasis (thrush), esophagitis, and vaginitis.
• The most serious manifestations of candidiasis are candidemia and hematogenously disseminated invasive candidiasis.
The remainder of this chapter discusses candidemia and hematogenously disseminated candidiasis.
GENERAL PREVENTION
• Polyenes, azoles, and echinocandins reduce the incidence of candidiasis in patients undergoing induction therapy for acute leukemia or bone marrow or stem cell transplantation. (4)[A]
• Fluconazole prophylaxis in high-risk ICU patients reduces the incidence of invasive candidiasis. (6)[A]
EPIDEMIOLOGY
• Predominant age: All ages are susceptible to hematogenously disseminated candidiasis; premature neonates are at particularly high risk.
• Predominant sex: Male = Female (hematogenously disseminated candidiasis)
Incidence
20/100,000 persons per year
RISK FACTORS
• Neutropenia
• Corticosteroid treatment
• HIV infection
• Diabetes mellitus
• Mucocutaneous colonization/infection
• Broad-spectrum antibacterial chemotherapy
• Indwelling intravascular access devices
• Cardiothoracic or abdominal surgery
• Parenteral nutrition
• Prolonged hospital stay
• ICU stay
• Burns
• Premature birth
PATHOPHYSIOLOGY
An acute suppurative infection in which polymorphonuclear host defense is the critical element.
ETIOLOGY
• Candida albicans is the most frequent pathogen. Other important human pathogens include C. tropicalis, C. krusei, C. stellatoidea, C. pseudotropicalis, C. guilliermondi, C. parapsilosis, C. lusitaniae, C. rugosa, C. lambica, and C. glabrata.
• Candida species colonize human mucocutaneous surfaces; most infections are endogenously acquired from this reservoir.
• Human-to-human transmission of Candida occurs in some settings.
ASSOCIATED CONDITIONS
See "Risk Factors."


DIAGNOSIS
SIGNS AND SYMPTOMS
• Fever
• Malaise
• Tachycardia
• Hypotension
• Altered mental status
• Hepatosplenomegaly
• Maculopapular or nodular skin rash
ALERT
Pediatric Considerations
For an infant with thrush, be sure to also check for candidal diaper dermatitis. Also, there is often a concomitant infection.
TESTS
• The diagnosis is established by isolating the causative organism from blood cultures or other normally sterile body sites, or by demonstration of organisms in histopathologic specimens of normally sterile tissues.
• Isolation of Candida from multiple sites should raise the diagnostic suspicion of hematogenously disseminated invasive candidiasis.
• Candida species isolated from a normally sterile site should be identified to the species level. (4)[A]
• Because fluconazole-resistant C. albicans and particularly non-albicans species are reported with increasing frequency, fluconazole susceptibility testing should be performed before treatment with fluconazole. (4)[B]
Imaging
• Generally not specifically useful in diagnosis of hematogenously invasive disseminated candidiasis.
• In the syndrome of hepatosplenic candidiasis (chronic systemic candidiasis) imaging of the liver and spleen by liver scan, ultrasound, CT, or MRI may suggest this syndrome as the cause of persistent fever and liver dysfunction in patients who have recently recovered from neutropenia.
Diagnostic Procedures/Surgery
• If blood cultures remain consistently negative, aspiration or excisional biopsy of sites of focal infection may be useful in diagnosis.
• Aspiration and biopsy of skin lesions occasionally seen with hematogenously disseminated candidiasis are also useful.
Pathological Findings
Characteristic histopathology of lesions of Candida invasion of visceral organs is microabscess formation.
DIFFERENTIAL DIAGNOSIS
Includes a variety of cryptic bacterial infections and, in the neutropenic host, multiple opportunistic infections.
TREATMENT
Inpatient for hematogenously disseminated invasive candidiasis
GENERAL MEASURES
• Fluid and electrolyte therapy are often required.
• Hemodynamic and respiratory support may be required in seriously ill patients.
• The removal of potentially infected intravascular access devices is imperative.
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Caspofungin
- An initial therapy of choice for any patient with candidemia (4)[A].
- Administer 70 mg IV dose on day 1 followed by 50 mg IV daily for 2 weeks after last positive sterile site culture if no evident metastatic infection
- Modify dose for severe hepatic insufficiency.
- C. parapsilosis has reduced sensitivity to echinocandins.
• Fluconazole
- An initial therapy of choice for some patients (4)[A]
- Because it is fungistatic rather than fungicidal, it should not be used for treatment of patients with severe neutropenia or severe immunosuppression.
- It should only be used after confirmation of in vitro susceptibility in patients with azole therapy in prior 3 months
- Should be used empirically only in institutions with a very low prevalence of resistance
- Useful for switch therapy after demonstration of in vitro susceptibility after initial therapy with amphotericin or an echinocandin.
- For 1st week, administer daily 400-800 mg intravenously, followed by additional IV or oral therapy at the same dose for 2 weeks after the last positive blood culture or last evidence of infection. Higher doses of fluconazole may be required if non-albicans species are known or suspected, because they carry a higher likelihood of drug resistance.
- C. krusei and many C. glabrata are resistant to fluconazole.
• Liposomal amphotericin B
- An initial therapy of choice for any patient with candidemia (4)[A]
- Usual dosage is 3 mg/kg IV daily.
- Substantially more expensive than conventional amphotericin B deoxycholate, but also substantially less toxic
- C. lusitaniae may be resistant.
- Consider higher doses for C. krusei or C. glabrata (5-10 mg/kg/day).
Second Line
• Although caspofungin is the only echinocandin approved by the FDA for this indication, preliminary data suggest that micafungin and anidulafungin have similar efficacy and safety for treatment of hematogenously disseminated invasive candidiasis. (B)
• Other azole antifungals depending on activity and safety (itraconazole and voriconazole). (B)
• Contraindications
- The safety of amphotericin B therapy in pregnant patients has not been established.
- Echinocandins are pregnancy category C.
• Precautions
- Liposomal amphotericin B
 The toxicity is less common than with conventional amphotericin B, but may still be formidable. Acute reactions (fever, rigors, and hypotension) may occur during the initiation of therapy. Ameliorate or eliminate by premedication with acetaminophen or ibuprofen. Use meperidine if needed to abort rigors.
 Azotemia may occur; there may be an indication for reducing dose in some patients (to reduce toxicity). Maintenance of optimal fluid status and prevention of dehydration help minimize the risk of azotemia. "Sodium loading" with 77 mEq (77 mmol) sodium daily (= 1 L half-normal saline) may decrease renal toxicity.
 Significant hypokalemia and renal tubular acidosis) may develop. Significant hypomagnesemia may worsen hypokalemia.
 Anemia commonly develops in patients on protracted therapy, but is almost always reversible.
 Headache and phlebitis are common.
 Leukopenia, thrombocytopenia, and liver function abnormalities are rarely encountered.
• Itraconazole, voriconazole, and caspofungin and other echinocandins do not enter the urinary stream in sufficient concentrations to treat UTIs.
• Significant possible drug-drug interactions
- Caspofungin and other echinocandins
 Potentially important interactions with carbamazepine, phenytoin, cyclosporine, tacrolimus, sirolimus, non-nucleoside reverse transcriptase inhibitors, and rifampin
- Liposomal amphotericin B
 Concomitant therapy with cyclosporine or other nephrotoxic agents, such as aminoglycosides or vancomycin, may increase the risk of amphotericin-induced nephrotoxicity.
- Fluconazole and other azoles
 Potentially important drug-drug interactions may occur in patients receiving oral hypoglycemics, coumarin-type anticoagulants, phenytoin, cyclosporine, rifampin, theophylline, or terfenadine or astemizole.
 These drug-drug interactions are more likely with itraconazole and voriconazole than with fluconazole.
FOLLOW-UP
Patients should receive followup visit approximately 6 weeks after end of therapy and be screened for metastatic infection complications by history and physical exam
PROGNOSIS
Overall mortality for patients with hematogenously disseminated candidiasis is 40-75%, with mortality attributable to candidemia being 15-37%.
COMPLICATIONS
• Systemic inflammatory response syndrome
• Pyelonephritis
• Endophthalmitis
• Endocarditis, myocarditis, pericarditis
• Arthritis, chondritis, osteomyelitis
• Pneumonitis
• Central nervous system infection
PATIENT MONITORING
• Evaluate CBC, serum electrolytes, and serum creatinine at least twice weekly in patients on liposomal amphotericin B therapy.
• If blood cultures are positive, they should be repeated until negative.
REFERENCES
1. Benjamin DK Jr., Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: Risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117:84-92.
2. Golan Y, Wolf MP, Pauker SG, Wong JB, Hadley S. Empirical anti-Candida therapy among selected patients in the intensive care unit: a cost-effectiveness analysis. Ann Intern Med. 2005;143:857-869.
3. Ostrosky-Zeichner L, Pappas PG. Invasive candidiasis in the intensive care unit. Crit Care Med. 2006;34:857-863.
4. Spellberg BJ, Filler SG, Edwards JE Jr. Current treatment strategies for disseminated candidiasis. Clin Infect Dis. 2006;42:244-251.
5. Uzon D, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Am Oncol. 2000;11:1517-1521.
6. Varadakas KZ, Samonis G, Michalopoulos A, et al. Antifungal prophylaxis with azole in high-risk, surgical intensive care unit patients: A meta-analysis of randomized, placebo-controlled trials. Crit Care Med. 2006;34:1216-1224.
MISCELLANEOUS
• Other candidal infections
- Intraperitoneal infection in patients with major abdominal surgery
- Biliary tract candidiasis
- Isolated lower UTI
• See also: Candidiasis; Mucocutaneous; Vulvovaginitis; Candidal