para>Fever is common.
Macronodular skin lesions (10%)
Candidal endophthalmitis (10-28%)
Patients are ill and may present in septic shock.
Hematogenous Candida meningoencephalitis (HCME) is a syndrome unique to premature infants (15-20%).
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DIFFERENTIAL DIAGNOSIS
Includes a variety of cryptic bacterial infections and, in the neutropenic host, multiple opportunistic infections á
DIAGNOSTIC TESTS & INTERPRETATION
- Diagnosis confirmed by culturing the causative organism from blood or other sterile body sites or by demonstrating organisms in histopathologic specimens from normally sterile tissues. Candida species isolated from a normally sterile site should be identified to the species level.
- Plasma 1,3-β-D-glucan assay-sensitivity 50-85%, specificity 80-99% (4). Can provide diagnosis up to 5 to 10 days earlier than cultures. F results from hemodialysis, blood products, concurrent use of β-lactams
- Polymerase chain reaction (PCR)-sensitivity 73-100%, specificity 92-100% (4). Can provide diagnosis up to 3 days earlier than culture
- Combining biomarkers (such as 1,3- assay and C. albicans germ tube antibody [CAGTA]) improves sensitivity and negative predictive value (8).
- Isolation of Candida from multiple sites raises likelihood of hematogenously disseminated invasive candidiasis.
- Because fluconazole-resistant C. albicans and nonalbican sp. are reported with increasing frequency, susceptibility testing should be performed before treatment with fluconazole.
Initial Tests (lab, imaging)
- CBC (may show leukocytosis)
- Blood cultures (may be negative-serial cultures recommended if suspicion is high)
- Imaging is not specifically useful in diagnosis of hematogenously invasive disseminated candidiasis.
- In patients with persistent fever and liver dysfunction who have recently recovered from neutropenia, imaging of the liver and spleen by liver scan, ultrasound (US), CT, or MRI may identify hepatosplenic candidiasis.
Diagnostic Procedures/Other
- If blood cultures remain negative, consider aspiration or excisional biopsy of focal sites of infection.
- Aspiration and biopsy of skin lesions can yield organisms in hematogenously disseminated candidiasis.
- Procalcitonin can help distinguish invasive fungal infection from bacterial sepsis (9)[B]. Procalcitonin often shows quicker response to bacterial infection.
Test Interpretation
Characteristic histopathology of lesions of Candida invasion of visceral organs is microabscess formation. á
TREATMENT
Inpatient for hematogenously disseminated invasive candidiasis á
GENERAL MEASURES
- Remove all intravenous (IV) catheters if possible. Removing central venous catheter decreases morbidity and mortality. (10).
- Hemodynamic and respiratory support as needed
- Perform a dilated ophthalmologic exam to exclude Candida endophthalmitis.
- Begin empiric therapy (11).
- Intra-abdominal infections often require surgical intervention with systemic antifungal therapy (12).
- Increasing resistance to echinocandins and azoles is seen in both C. albicans and nonalbican species (13).
MEDICATION
First Line
- Echinocandins
- Initial therapy of choice for moderately severe to severe candidemia, neutropenic patients, or patients with prior azole exposure. Confers best outcomes with least side effects and improved mortality benefit (5)[A],(10). Preferred for use with C. glabrata or C. krusei (10).
- Caspofungin: 70 mg IV dose on day 1 followed by 50 mg/day IV. Continue for 2 weeks after last positive sterile site culture if no evidence of metastatic infection (11)[A]. Monitor for hepatic impairment and adjust dose accordingly.
- The echinocandins anidulafungin and micafungin have similar efficacy.
- Transition from an echinocandin to fluconazole if organism is sensitive (e.g., C. albicans) and patient is clinically stable (11)[B].
- Treat neutropenic patients without metastatic complications for 14 days after first negative blood culture result. Continue until symptoms and neutropenia resolve.
- Echinocandins associated with improved survival and greater clinical success in adults.
- Pregnancy Category C
- Triazoles: fluconazole, itraconazole, voriconazole
- Fluconazole is the initial therapy of choice for nonneutropenic patients.
- May be used in stable neutropenic patients with no recent azole exposure
- First-line for C. parapsilosis infections (11)[B]
- Not recommended for treatment of C. glabrata; however, for patients initially receiving fluconazole who are clinically improved and whose follow-up culture results are negative, continuing to completion is acceptable.
- Fluconazole 800 mg (12 mg/kg) PO or IV loading dose, then 400 mg (6 mg/kg) PO or IV once daily. Oral fluconazole has <90% bioavailability of IV dosing.
- Duration of treatment for nonneutropenic candidemia is 14 days after first negative blood culture result. Continue to resolution of symptoms in patients without obvious metastatic complications.
- Other azole antifungals, depending on activity and safety (itraconazole and voriconazole), have been used as well.
- Liposomal amphotericin B (L-AmB)
- Can be used as an initial therapy. Only recommended if there is intolerance to or limited availability of other antifungal medications. Higher risk of toxicity compared with alternative medications.
- Usual dosage is 3 to 5 mg/kg/day IV.
- Consider higher doses for C. krusei or C. glabrata (5 to 10 mg/kg/day).
- Contraindications
- Safety in pregnancy has not been established.
- Precautions
- L-AmB
- Acute reactions (fever, rigors, and hypotension) may occur during the initiation of therapy. Ameliorate by premedication with acetaminophen or ibuprofen. Use meperidine to abort rigors.
- Azotemia may occur. Maintain optimal fluid status and prevent dehydration to minimize risk of azotemia. "Sodium loading"Ł with 1 L half-normal saline daily may decrease renal toxicity.
- Hypokalemia and renal tubular acidosis may develop. Hypomagnesemia may worsen hypokalemia.
- Anemia is common during protracted therapy but is almost always reversible.
- Headache and phlebitis are common.
- Central venous access is necessary for administration.
- Significant possible drug-drug interactions
- Echinocandins
- Potential interactions with carbamazepine, phenytoin, cyclosporine, tacrolimus, sirolimus, nonnucleoside reverse transcriptase inhibitors, and rifampin
- L-AmB
- 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 with oral hypoglycemics, Coumadin anticoagulants, phenytoin, cyclosporine, rifampin, theophylline
- These drug-drug interactions are more likely with itraconazole and voriconazole than with fluconazole.
ISSUES FOR REFERRAL
Manage invasive Candida infections in consultation with an infectious disease specialist. á
SURGERY/OTHER PROCEDURES
Drain abscesses for resolution. Remove indwelling devices or catheters. á
INPATIENT CONSIDERATIONS
Hemodynamic and respiratory support in critically ill á
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patients should have follow-up visit 6 weeks after end of therapy to evaluate for complications of metastatic infection. á
Patient Monitoring
- Evaluate CBC, serum electrolytes, and serum creatinine at least twice weekly in patients on liposomal amphotericin B therapy.
- Obtain follow-up blood cultures for all patients with candidemia to ensure eradication from the bloodstream.
PATIENT EDUCATION
Advise patients of the nature of the infection and the toxicities associated with therapy. á
PROGNOSIS
- Mortality from candidemia is ~29-40% and has not changed significantly over the past 20 years (2,4,10).
- Infection with C. parapsilosis confers a lower mortality than other types of Candida infection (24% vs. 46%) (6).
COMPLICATIONS
- Systemic inflammatory response syndrome
- Pyelonephritis
- Endophthalmitis
- Endocarditis, myocarditis, pericarditis
- Arthritis, chondritis, osteomyelitis
- Pneumonitis
- CNS infection
REFERENCES
11 Zaoutis áT, Argon áJ, Chu áJ, et al. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis. 2005;41(9):1232-1239.22 Chalmers áC, Guar áS, Chew áJ, et al. Epidemiology and management of candidaemia-a retrospective, multicentre study in five hospitals in the UK. Mycoses. 2011;54(6):e795-e800.33 Muskett áH, Shahin áJ, Eyres áG, et al. Risk factors for invasive fungal disease in critically ill adult patients: a systematic review. Crit Care. 2011;15(6):R287.44 Kale-Pradhan áPB, Morgan áG, Wilhelm áSM, et al. Comparative efficacy of echinocandins and nonechinocandins for the treatment of Candida parapsilosis infections: a meta-analysis. Pharmacotherapy. 2010;30(12):1207-1213.55 Kanji áJN, Laverdi Ęre áM, Rotstein áC, et al. Treatment of invasive candidiasis in neutropenic patients: systematic review of randomized controlled treatment trials. Leuk Lymphoma. 2013;54(7):1479-1487.66 Pappas áPG, Rex áJH, Lee áJ, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37(5):634-643.77 Chahoud áJ, Kanafani áZA, Kanj áSS. Management of candidaemia and invasive candidiasis in critically ill patients. Int J Antimicrob Agents. 2013; (42 Suppl):S29-S35.88 Mart şnez-Jim ęnez áMC, Mu ▒oz áP, Valerio áM, et al. Candida biomarkers in patients with candidaemia and bacteraemia. J Antimicrob Chemother. 2015;70(8):2354-2361. doi: 10.1093/jac/dkv090.99 Dou áYH, Du áJK, Liu áHL, et al. The role of procalcitonin in the identification of invasive fungal infection-a systematic review and meta-analysis. Diagn Microbiol Infect Dis. 2013;76(4):464-469.1010 Andes áDR, Safdar áN, Baddley áJW, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110-1122.1111 Pappas áPG, Kauffman áCA, Andes áD, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503-535.1212 Rebolledo áM, Sarria áJC. Intra-abdominal fungal infections. Curr Opin Infect Dis. 2013;26(5):441-446.1313 Sanguinetti áM, Posteraro áB, Lass-Fl Ârl áC. Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses. 2015;58(Suppl 2):2-13.
ADDITIONAL READING
- Flevari áA, Theodorakopoulou áM, Velegraki áA, et al. Treatment of invasive candidiasis in the elderly: a review. Clin Interv Aging. 2013;8:1199-1208.
- Morrissey áCO. Advancing the field: evidence for new management strategies in invasive fungal infections. Curr Fungal Infect Rep. 2013;7(1):51-58.
CODES
ICD10
- B37.7 Candidal sepsis
- P37.5 Neonatal candidiasis
- B37.89 Other sites of candidiasis
- B37.0 Candidal stomatitis
- B37.49 Other urogenital candidiasis
- B37.2 Candidiasis of skin and nail
- B37.9 Candidiasis, unspecified
- B37.81 Candidal esophagitis
- B37.42 Candidal balanitis
ICD9
- 112.5 Disseminated candidiasis
- 771.7 Neonatal Candida infection
- 112.89 Other candidiasis of other specified sites
- 112.0 Candidiasis of mouth
- 112.3 Candidiasis of skin and nails
- 112.2 Candidiasis of other urogenital sites
- 112.84 Candidal esophagitis
- 112.9 Candidiasis of unspecified site
SNOMED
- Disseminated candidiasis (disorder)
- Neonatal systemic candidosis (disorder)
- candidemia (disorder)
- Sepsis due to Candida (disorder)
- candidiasis of skin (disorder)
- Pharyngeal candidiasis (disorder)
- Anogenital candidiasis (disorder)
- candidiasis of urogenital site (disorder)
CLINICAL PEARLS
- Consider invasive candidemia in high-risk febrile patients not responding to appropriate antibiotic treatment.
- Start antifungal therapy on all candidemic patients within 24 hours of a positive blood culture. Delays increase mortality.
- Treat for 14 days after first negative blood culture result and continue until symptoms and neutropenia (if present) resolves.
- Fluconazole prophylaxis in high-risk ICU patients reduces the incidence of invasive candidiasis.