Pediatrics

Candidiasis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Candidiasis? What are the typical findings for this disease?

This chapter will focus on the invasive presentations of Candidiasis seen in the hospital setting and their management.

Candidiasis is a term that encompasses all infections caused by organisms in the genus Candida,which includes several species known to cause disease in humans. Candida species are the most common cause of invasive fungal infections. Entities from oropharyngeal candidiasis and diaper dermatitis to candidemia and disseminated disease are caused by Candida.

Infections due to Candidal have increased in incidence over the last two decades due to increasing numbers of immunocompromised hosts and increased survival of the pediatric populations at highest risk for invasive disease, including premature infants and oncology patients.

Candidal infections have multiple different presentations, ranging from superficial to severe invasive disease. Superficial mucocutaneous disease presents as nail, mucous membrane and skin disease, such as diaper dermatitis and oropharyngeal Candidiasis (thrush). Congenital cutaneous candidiasis is seen in term neonates; whereas, a more severe manifestation can be seen in premature infants.

Chronic mucocutaneous candidiasis is a unique presentation seen in patients with defects in cell-mediated immunity and a resultant poor proliferative response specifically to Candida. The more severe manifestations of disease due to Candida species involve infection of sterile sites or organs, such as candidemia, esophagitis, endocarditis, intra-abdominal infections, musculoskeletal disease, disseminated disease, CNS, hepatosplenic and renal disease, along with other forms of invasive candidiasis (IC).

The signs and symptoms for candidiasis are dependent on the site of infection and extent of disease. Candida may cause disease at any body site; however, some sites are more commonly affected than others:

Oral Candidiasis, or thrush, is the most common presentation of Candida in infants and children. It presents as white patches, resembling curdled milk, on the buccal and gingival mucosa, along with the tongue, palate and pharynx. The lesions can coalesce to form a pseudomembrane. Thrush may be asymptomatic or painful. In infants, prolonged thrush can lead to decreased oral intake. Persistent or recurrent thrush without predisposing factors is worrisome for an underlying immunodeficiency, such as primary immunodeficiency or HIV infection.

Angular cheilosis, where fissuring and erythema are noted at the corners of the mouth, can be due to Candida.

Candidal esophagitis most commonly presents with dysphagia in patients who may or may not have oral candidiasis. Additional complaints can include nausea, vomiting, and pain (retrosternal, paravertebral, intrascapular or subscapular in location). Esophagitis is seen in severely immunocompromised patients. Hoarseness can also be seen in immunocompromised hosts due to candidal plaques on the vocal cords.

Cutaneous - diaper dermatitis and other sites may be involved. Diaper dermatitis is characterized by an erythematous, "beefy red", confluent rash with satellite lesions or intertriginous areas with white curdled appearance and underlying erythema.

Ungual and periungual Infections. Paronychia and onychomycosis can be caused by Candida, but more often are due to Trichophyton and Epidermophyton. When due to Candida, the finger rather than the toe nails are more often involved.

Vulvovaginitis presents with pruritus, pain, a white or watery discharge and dysuria. On physical examination, the vaginal mucosa is erythematous with white lesions. Vaginitis occurs commonly in pubertal and post-pubertal females and with increased frequency in those with risk factors, such as HIV infection, diabetes mellitus, pregnancy, oral contraceptive use, and those recently treated with broad-spectrum antibiotics.

Candidemia presents with symptoms similar to those seen in patients with bacteremia, often non-specific symptoms. However, some features that may help distinguish candidal from bacterial BSI include an increased association with thrombocytopenia. Also, the presence of ongoing fever in at-risk patients despite broad-spectrum antimicrobial therapy raises the suspicion for Candidal infection.

Ophthalmologic complications can be seen in the setting of disseminated candidiasis and in patients receiving parenteral nutrition. They may complain of eye pain, blurred vision, scotoma and photophobia. Both endophthalmitis and chorioretinitis (manifested as fluffy white retinal lesions) are seen. Rates of chorioretinitis are decreasing.

Hepatosplenic candidiasis is usually seen in patients with leukemia; however, others can also present with hepatosplenic disease. Children may not have specific symptoms or may present with right upper quadrant pain, nausea, vomiting, hepatomegaly, splenomegaly, and - in some - persistent fever despite granulocyte recovery.

Peritonitis due to Candida may manifest as fever, vomiting and abdominal pain and can occur in patients with a history of peritoneal dialysis, intestinal surgery or bowel perforation.

Disseminated candidiasis - Candida can disseminate to one or multiple organs, including the brain, heart, lungs, liver, kidneys, spleen, eyes, bones and joints. Persistent candidemia in a patient with a central venous catheter and immunosuppression were independent risk factors for disseminated disease in children. Cardiac and CNS candidiasis frequently occur together in the setting of disseminated disease. Endocarditis presents similar to subacute bacterial endocarditis, except that blood cultures are more often sterile. 5% or less of candidemia cases have documented endocarditis.

The presence of a central venous catheter increases the risk of cardiac involvement. The valves more commonly involved are the aortic and mitral. Bone and joint disease may present days to weeks after the original bloodstream infection. The knee is the most common joint in fungal arthritis; the spine, upper and lower extremities, ribs, mandible and sternum are the sites most frequently involved in candidal osteomyelitis. Young infants have a higher incidence of candidal osteomyelitis than other groups.

Central nervous system involvement in the form of meningitis, encephalitis, demyelination, transverse myelitis, vasculitis and parenchymal lesions (abscesses, granulomas and nodules) can be seen in patients with disseminated candidiasis or, much less commonly, as isolated disease. Patients who have CNS involvement may not have specific signs or may manifest non-specific symptoms of meningitis or encephalitis. Additionally, CSF parameters can be normal in those with encephalitis.

Renal and urinary tract infections due to Candida have similar manifestations to those with bacterial infections. Candida is often cultured in those who have been receiving antibiotics, with indwelling urinary catheters, and in immunocompromised hosts.

Respiratory tract disease generally presents with tachypnea and fever. However, lower respiratory tract disease due to Candida is uncommon; histopathologic evidence is needed to confirm the diagnosis. When pulmonary disease does occur, it may present as localized or diffuse pneumonia, nodular lesions, abscesses or empyema.

Chronic mucocutaneous candidiasis refers to persistent or recurrent Candidal infections of the skin, nails and mucous membranes. It is an uncommon presentation and is seen in patients who have cell-mediated immune defects and an impaired T cell response to Candida antigens.

What other disease/condition shares some of these symptoms?

Differential Diagnosis:

Candidemia and disseminated candidiasis: The signs and symptoms commonly seen in patients with bacterial bloodstream infection, urinary tract infection, peritonitis, bone or joint disease, and endocarditis due to bacteria are very similar to those seen in patients with these infections due to candidiasis.

Renal disease: Renal ultrasound may demonstrate fungal parenchymal involvement; however, other considerations for these sonographic findings include blood clots, tumors and renal stones.

What caused this disease to develop at this time?

The source of the Candida organism is most often dissemination from a gastrointestinal or a cutaneous source. Therefore, it is most commonly due to the patient's own endogenous flora. However, it has been reported as a nosocomial pathogen, especially in premature infants in the neonatal intensive care unit.

Certain patient groups are at higher risk for Invasive candidiasis (IC), including premature infants - especially those receiving hyperalimentation - and others in neonatal intensive care units, hosts with primary or secondary immunodeficiencies, patients in pediatric intensive care units - especially those with prolonged ICU stays, patients with neoplastic disease, and those who have undergone instrumentation.

Procedures associated with an increased risk of candidiasis in children include vascular catheterization, mechanical ventilation, dialysis and gastrointestinal procedures. Additional risk factors in children are administration of parenteral nutrition and of prior antibacterial therapy .

The risk factors that place pediatric ICU patients at the highest risk for Candidemia are those with prior bacterial infection, immunosuppression, prolonged ICU stay, and the presence of a central venous catheter, as reported by Zaoutis et al in 2010.

Factors that predispose to the development of candidiasis include the following:

  • Indwelling vascular catheters (central catheters) and hardware/instrumentation; Candida can adhere to the thrombin sheath and grow.

  • Treatment with broad-spectrum antibiotics

  • Receipt of parenteral nutrition

  • Deficiencies in the number or function of phagocytic cells; patients with prolonged neutropenia or with congenital immunodeficiencies involving phagocytes

    • Invasive candidiasis in neutropenic children receiving chemotherapy may present as catheter-associated candidemia, disseminated candidiasis, or deep single organ candidal infection. Risk of candidal infections increases after 5 days of neutropenia and fever. Overall frequency is 5 - 10% in children with high risk leukemia or those status-post bone marrow transplantation.

    • Bone marrow transplant recipients are at high risk of fungal infections due to the prolonged duration of neutropenia seen in some.

  • Hyperglycemia

  • Skin, mucous membrane, endotracheal colonization with Candida. The risk of invasive disease increases with each additional site of colonization per some studies; however, others have not demonstrated colonization as an independent risk factor.

  • Acid-reducing medications have been shown to increase candidal overgrowth and H 2 blockers were linked to increased risk of candidemia in infants. Conversely, gastric acidity is thought to be protective in that it suppresses candidal growth in the upper GI tract.

  • Corticosteroid use predisposes to candidal infections due to the resulting immune system suppression, hyperglycemia, and some have demonstrated that they upregulate Candida virulence genes

  • Tissue disruption or damage

  • Intra-abdominal surgery or intraabdominal processes, such as perforation, diarrhea, friable mucosa, or candidal overgrowth in the gastrointestinal tract

  • Also at higher risk for candidal disease are immunocompromised hosts, both those with primary and with secondary immunodeficiencies, including HIV, oncology patients, premature infants, and recipients of bone marrow and solid organ transplants (liver, pancreas, others).

  • Patients with chronic mucocutaneous candidiasis

  • Patients receiving hemodialysis

  • Patients in the neonatal and pediatric Intensive care units; increased length of stay in an ICU

  • Critically ill patients requiring intensive care have in increased risk of invasive candidiasis due to invasive procedures, indwelling vascular and urinary catheters, use of broad-spectrum antibiotics and steroids, mechanical ventilation and parenteral feeding, along with prolonged length of stay

  • A recent retrospective chart review demonstrated that the combination of > 4 days in an ICU, the presence of a central line, and treatment with broad-spectrum antibiotics was associated with a 10% incidence of Candidiasis and a relative risk for Candidiasis of 4.4 (Mycoses 2011)

  • Patients with candidal urinary tract infection, who are not severely ill or immunocompromised, often have anatomic anomalies, such as congenital malformations, neurogenic bladder or anatomic obstruction.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Definitive diagnosis of candidal infection is often difficult as Candida frequently colonizes various body sites. However, isolation of the organism from a sterile body site in a severely ill or immunocompromised patient with a presentation consistent with candidiasis would be diagnostic.

Microscopic examination of specimens may demonstrate 3 - 7 mm in diameter ovoid budding yeast cells or pseudohyphae. Skin lesion scrapings can be suspended in KOH and will demonstrate fungal forms. Candida species stain well using Gram stain, Periodic acid-Schiff, Gomori methenamine silver nitrate, and toluidine blue stains. A positive stain provides a presumptive diagnosis; however, growth of the organism is necessary to differentiate Candida from other yeast and some molds which can stain similarly.

Cultures from the affected site may confirm the diagnosis; however, non-sterile sites may be colonized by Candida. Therefore, a positive culture may not indicate actual disease secondary to Candida. Candida will grow on routine blood agar but use of Sabouraud dextrose media prevents bacterial overgrowth on the plate, making it easier to recognize growth of yeast.

The germ tube test is a rapid way to make a presumptive diagnosis of Candida albicans and to distinguish C. albicans from other species of candida. When the organism growing on the plate is suspended in rabbit or human serum and incubated for 1 - 4 hours, C. albicans forms germ tubes. To definitively identify the species of Candida, the lab uses biochemical fermentation and assimilation tests, which can take 2 - 3 days.

Biopsy of lesions or the affected area may be the best method for diagnosis, especially in a severely ill or immunocompromised host where the results of pathology and cultures could drastically change management. Blood cultures may be negative, so biopsy of lesions is considered the gold standard. For example, in hepatosplenic candidiasis, blood cultures are positive in only approximately 20% of patients. Pathology demonstrates acute suppuration early on and subsequently granulomatous changes and microabscesses can be seen; pseudohyphae and yeast can be seen on biopsy.

Routine blood cultures: the sensitivity and specificity varies if the candidal infection is line-associated versus disseminated or hepatosplenic. Candida sp grow on routine blood culture media and the sensitivity of standard bacterial blood cultures is equivalent to specific fungal cultures; hence, fungal cultures need not be ordered if you suspect Candida as the pathogen. Currently, blood culture is the gold standard for diagnosis of invasive candidiasis but it takes 24 - 72 hours to detect a positive culture and further candidal speciation can take several days.

However, both standard bacterial and fungal cultures have lower sensitivity for fungal compared to bacterial pathogens. This is likely related to the often small amount of blood obtained from pediatric patients and to candidal deep organ infection without sustained candidemia. An adult study demonstrated increased sensitivity of blood cultures with the increasing number of organs infected.

Previously, blood cultures in the setting of candidemia were negative up to 50% of the time; however, now, due to more sensitive culture techniques, approximately 70 - 80% of the time blood cultures are positive. 90% of blood cultures that are positive will be positive within 72 hours. Of note, the specificity of a positive blood culture for Candida is very high; therefore, when positive, the result should not be considered a contaminant.

CBC with differential: 84% of VLBW infants with Candidiasis had low platelets; however, this is non-specific as other infections are also associated with thrombocytopenia.

Biomarkers for early detection of candidiasis include immunologic/serologic (mannan, B-D-glucan) and molecular nucleic acid-based tests (PCR-based). Unfortunately, currently these tests lack standardization and validation. Additionally, there are several technical issues that limit the performance of these tests, including false positive and false negative results, low yeast burden, detection of non-viable organisms, and human versus yeast genes. See section on Additional Laboratory studies below for more details.

In patients with persistent candidemia or disseminated candidiasis, most experts recommend obtaining a cardiac chocardiogram, abdominal ultrasound (focusing on the liver, spleen and kidneys), ophthalmologic examination, and urine culture to determine the extent of disease and, therefore, the duration of therapy. Additionally, rates of meningitis are higher in pediatric oncology patients with candidemia than adults, and symptoms may be nonspecific or subtle. Therefore, head imaging and evaluation of the CSF should be considered.

Would imaging studies be helpful? If so, which ones?

Abdominal ultrasound or computed tomogram (focusing on the liver, spleen and kidneys) are important to obtain early on in the setting of persistent candidemia or in high risk patients with prolonged fever and neutropenia, in order to make the diagnosis of disseminated disease. In patients with severe prolonged neutropenia, these studies may be less sensitive.

Ultrasound, high resolution computed tomography (CT) or magnetic resonance imaging (MRI) are key tools for the diagnosis and monitoring of tissue-invasive candidiasis.

Esophagitis can be definitively diagnosed via endoscopy with biopsy; however, sometimes an upper GI or esophagram may demonstrate mucosal irregularities or ulcerations in a cobblestone appearance. Many choose to initiate empiric therapy if the clinical setting is consistent with candidal esophagitis without an endoscopy-proven diagnosis. If the response is delayed, then an endoscopy is performed.

Echocardiogram to evaluate for an endovascular site.

CT or MRI are indicated in cases of suspected CNS candidiasis.

Renal ultrasound in those with candiduria to evaluate for renal involvement.

If you are able to confirm that the patient has Candidiasis, what treatment should be initiated?

Patients with invasive Candidiasis can be severely ill and may require fluid resuscitation, vasopressors and intensive care support.

Consideration should be given early to removal of the central catheter, urethral catheter or other potentially infected foreign material (see below for more details regarding patients with CVC).

Reversal of underlying impairment of host defense when possible.

Antifungal Therapy:

Unfortunately, there are less data to guide therapy in children with Candidal infections than there is in adults. There are four different categories of antifungal agents: the polyenes, triazoles, echinocandins, and flucytosine. See Table I below.

Table I.

Antifungal Agents for use outside the neonatal period
Antifungal Agent (route) Dosage and Interval Advantages Disadvantages
Polyenes Fungicidal against Candida Infusion-related toxicity (fevers, rigors, chills, myalgias, arthralgias, nausea, vomiting, headaches, hypotension);Electrolyte wasting and nephrotoxicity especially when administered with other nephrotoxic drugs.Hypokalemia and hypomagnesemia can be seen.Better tolerated in children than adults.
Amphotericin B deoxycholate (IV) (0.6 - 1 in guidelines) 1 mg/kg/day In children, usually less toxicity than in adults Approximately 20% of C. lusitaniae strains are resistant to conventional and lipid formulation Ampho B
Lipid formulations of Amphotericin B (LFAmBs) (IV) (3-5 in guidelines) 5 mg/kg/day Increased daily dose tolerated & less toxicity compared to conventional Amphotericin; higher tissue concentrations Expensive; Protection of kidney may decrease delivery of LFAmBs to the urinary tract; not recommended for treatment of urinary tract Candidiasis.
Triazoles 2nd generation azoles (vori conazole and posaconazole) have an extended spectrum of antifungal activity Fungistatic against Candida.Metabolized through the hepatic CYP enzyme system, resulting in the potential for multiple drug interactions. Less activity against C. glabrata and C. krusei.
Fluconazole (IV, PO) 25 mg/kg loading dose on day 1, followed by 12 mg/kg/day.Maximum daily dose 400mg/d.Esophageal candidiasis: 3 - 6mg/kg/day IV or po; ~90% oral bioavailability; absorption not affected by food or gastric pH.CSF and vitreous body penetration ~80% of blood levels; 10-20 fold higher concentrations in urine than blood C. krusei resistant, C. glabrata with increasing azole resistance (5 - 25% C. glabrata strains are resistant).Side effects uncommon but include nausea, vomiting, diarrhea and rash.
Itraconazole* (IV, PO) 2.5 mg/kg/day every 12 hours IV or po; used more for mucosal candidiasis.High volume of distribution and accumulation in tissues. Variable oral absorption; absorption affected by gastric pH, so decreased capsule absorption in patients receiving Histamine receptor antagonists or proton pump inhibitors. The liquid formulation is better absorbed than the capsules and is best taken on an empty stomach.To enhance absorption, capsules should be taken with acidic beverages, carbonated drinks or cranberry juice, and with food.Side effects are few and include nausea and vomiting (10%), elevated transaminases (5%), and peripheral edema.
Voriconazole*(IV, PO) 9 mg/kg IV loading dose every 12 hrs x 2 doses, followed by 8 mg/kg/day IV every 12 hours; If convert to oral therapy, use 9mg/kg/dose q12hrs. IV or po (oral tablet or suspension); > 90% oral bioavailability, best on empty stomach; excellent CSF and vitreous penetration. Main side effects include dosage-dependent reversible visual disturbances in up to 1/3rd of patients (blurred vision, increased brightness), elevated transaminases, and probably photosensitization skin reactions.IV voriconazole is complexed to a cyclodextrin molecule which can accumulate in patients with renal dysfunction; therefore, IV voriconazole not recommended if creatinine clearance ≤ 50 mL/min.Oral voriconazole requires dose reduction when mild to moderate hepatic impairment present.
Posaconazole* (PO) 12 - 24 mg/kg/day every 8 hours.Max adult dosage 800mg/dy Prolonged half-life of 25 hours.High oral bioavailability, especially with fatty foods and acidic gastric pH. Only available as an oral suspension. Absorption is enhanced when taken with food and acidic beverages and in the abscence of proton pump inhibitors.Side effects include mild to moderate elevations in transaminases, total bilirubin and alkaline phosphatase.
* Therapeutic drug monitoring recommended
Echinocandins Fungicidal against Candida. Overall few adverse effects. Only available in intravenous form. Not first line in patients with C. parapsilosis infection due to higher MICs and decreased susceptibility.
Caspofungin (IV) Loading dose 70 mg/m2/day, followed by maintenance dose of 50 mg/m2/day;Max dose 70 mg/dayNot well studied in young infants Well-tolerated. C. parapsilosis with decreased susceptibility.
Micafungin (IV) Age-related dosing:4 - 12 mg/kg/day depending on age:Neonates 10-12mg/kg;Children <8yo - 4mg/kg/day once a day;Children >8yo - adult dosageof 150 mg daily Well-tolerated. Most common adverse events are nausea and diarrhea. Hypersensitivity reactions and elevated transaminases (~5%) have been reported.Hyperbilirubinemia, renal impairment and hemolytic anemia were noted in post-marketing surveillance.
Anidulofungin (IV) 3 mg/kg loading dose, followed by 1.5 mg/kg/day for all ages, except neonates Longest half-life of the echinocandins, ~18hrs. Small study in children reported facial erythema, rash, elevated BUN, fever and hypotension in a subset.
Pyrimidine Analogs Fungistatic
5-Fluorocytosine (Flucytosine, 5-FC)(PO)* 150 mg/kg/day in 4 divided doses 80-90% bioavailability. Penetrates well into most body sites; Broad anti-Candidal activity except against C krusei po only; used in combination therapy for IC, such as meningitis or endocarditis; resistance develops rapidly with monotherapy. Less active against C. krusei.Can exacerbate myelosuppression in neutropenic patients.Toxicities include azotemia, renal tubular acidosis, leukopenia, thrombocytopenia, etc can be seen in up to 50% of patients within 2 weeks of therapy.Less commonly used.Clearance directly proportional to GFR.

Early and appropriate antifungal therapy has been shown to improve outcomes. Delays in initiation of antifungal therapy of 12 - 28 hours in adults have been associated with increased mortality. In 2006, a study in adult patients demonstrated increased mortality when antifungal therapy was delayed. ("A delay in the initiation of fluconazole therapy in hospitalized patients with candidemia significantly impacted mortality. New methods to avoid delays in appropriate antifungal therapy, such as rapid diagnostic tests or identification of unique risk factors, are needed.")

Mechanism of Action:

Polyenes: Amphotericin B binds to ergosterol and creates transmembrane channels, ultimately leading to cell death. The lipid formulations of Amphotericin B (LFAmBs) are less nephrotoxic; however, as a result they do not penetrate the kidneys well so are not recommended for urinary tract involvement.

Azoles: inhibit the fungal cytochrome P45014DM, which catalyzes a late step in fungal cell membrane ergosterol biosynthesis. Azoles are less active against C. glabrata and C. krusei.

Echinocandins: interfere with cell wall biosynthesis through non-competitive inhibition of 1,3-beta-D-glucan synthase, a fungal enzyme not present in mammals. 1,3-beta-glucan is a fungal cell wall polysaccharide necessary for cell wall integrity. Echinocandins were found to be less active against C. parapsilosis in some studies due to higher MICs for echinocandins.

Flucytosine: 5-Fluorocytosine (5-FC) - converted to fluorouracil by the fungal cytosine deaminase enzyme; a fungus-specific synthetic base analog that acts by causing RNA-miscoding and inhibition of DNA synthesis.

Topical agents: Nystatin, Clotrimazole; Gentian violet is used less commonly.

Considerations for choosing an antifungal:

Considerations when choosing an antifungal include the patient's renal and hepatic status, pharmacokinetics and site of infection, drug interactions, local candidal epidemiology and susceptibilities, and the cost of antifungal agents at your institution.

Within the echinocandin group, micafungin has been most extensively studied in the pediatric population.

Current candidiasis guidelines recommend fluconazole or amphotericin B for initial therapy of C. parapsilosis infections.

Fluconazole is not ideal for therapy of C. krusei or C. glabrata (see Table I). Treatment with an echinocandin or amphotericin B is recommended for these species.

For further details regarding therapy for candidiasis, please refer to the Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America.

Therapy falls into different categories (Prophylaxis, pre-emptive, empirical and treatment):

Prophylaxis for high risk hosts where prophylaxis shown to make a difference.

Pre-emptive therapy describes initiation of antifungal therapy in an asymptomatic patient whose surveillance blood culture or beta-glucan is positive.

Empiric therapy is considered in a patient at high risk for candidemia who has signs and symptoms consistent with this diagnosis. It is generally begun in the setting of a high risk host who has been on broad-spectrum antibiotics but has persistent fevers. Antifungal therapy is begun to empirically cover possible Candidal infection. Increased mortality is seen when antifungal therapy is delayed.

Treatment is indicated in a symptomatic patient with a positive culture from a sterile body site.

General Guidelines when choosing antifungals:

Fluconazole has comparable efficacy to Amphotericin for Candidemia. Considered standard therapy for oropharyngeal, esophageal, and vaginal candidiasis.

Itraconazole reserved for patients with persistent mucosal candidiasis; few data on use in invasive candidiasis.

Voriconazole is effective for invasive and mucosal candidiasis.

Posaconazole without current indication for primary candidiasis therapy.

Echinocandins demonstrated to be effective in the treatment of esophageal and invasive candidiasis. They are fungicidal against Candida.

Flucytosine has broad antifungal activity against most Candida species, except C. krusei. However, resistance develops rapidly when used as monotherapy.

Prophylaxis of Candidal infections (See section "How disease can be prevented"):

Empirical therapy for suspected Invasive Candidiasis:

-Consider empiric therapy with fluconazole or an echinocandin in a non-neutropenic patient at high risk for candidemia, based on risk factors delineated above, who has signs and symptoms consistent with the diagnosis.

-Empirical therapy is usually added in a neutropenic host who remains febrile for > 5 days while on broad-spectrum antibiotics.

Key recommendations from the 2009 Update of the Clinical Practice Guidelines for the Managment of Candidiasis by the Infectious Diseases Society of America (IDSA). For full recommendations on treatment of specific infections due to Candida, refer to the Guidelines themselves.

Candidemia in Non-Neutropenic Host; documented blood culture positive for yeast:

-Fluconazole or an echinocandin is recommended for initial treatment. An echinocandin was favored by the Expert Panil in patients with moderately severe to severe illness or for patients with recent azole exposure. Fluconazole is recommended for those less critically ill and without recent azole exposure.

►One consideration not included in the current guidelines is the difference in the epidemiology of Candida species that commonly infect children versus those that commonly infect adults. In children, the second most common Candidal pathogen after C. albicans is C. parapsilosis; whereas in adults, it is C. glabrata. Therefore, in children the use of fluconazole may actually be preferred over an echinocandin pending culture results, since C. parapsilosis is less susceptible to echinocandins. However, the local epidemiology and susceptibilities should be taken into account when choosing antifungal therapy.)

-Transition to fluconazole is recommended for those with isolates likely to be fluconazole-susceptible.

-Treatment with fluconazole is recommended for C. parapsilosis infections.

-Treatment with an echinocandin is recommended for C. glabrata infections; this can be transitioned to fluconazole if the organism is susceptible.

-Amphotericin B or a LFAmB are recommended alternatives if there is intolerance to or limited availability of other antifungals.

-Intravenous catheter removal is strongly recommended. The reasoning behind line removal is that Candida is more likely to originate from a line infection than many other pathogens. Since many Candida species adhere to foreign material, removal is recommended to remove the source. Otherwise, the line can seed other sites and result in disseminated Candidiasis.

-Usual treatment duration for Candidemia is 2 weeks after documented clearance of Candida from the bloodstream and resolution of symptoms related to candidemia.

Candidemia in Neutropenic Host:

-Blood culture positive for Yeast in immunocompromised host:

-An echinocandin is recommended for initial treatment in most neutropenic patients, since echinocandins are fungicidal.

-Fluconazole is a reasonable alternative for those less critically ill without recent azole exposure. For those less critically ill without recent azole exposure, fluconazole is a reasonable alternative. For additional mold coverage, voriconazole can be subsituted.

-C. parapsilosis infections: treatment with fluconazole or LFAmB are recommended for initial therapy.

-C. glabrata infections: treatment with an echinocandin is recommended, and LFAmB is an alternative. If fluconazole was initiated and patient is clinically improved with clearance of the organism, then the azole can be continued.

-C. krusei infections: treatment with an echinocandin, LFAmB or voriconazole is recommended by the Expert panel.

-Intravenous catheter removal should be considered. This issue is more complex in neutropenic patients as the source of the Candidemia (line versus gut-associated) is often difficult to ascertain. Neutropenic patients with candidemia who have an intravascular catheter are more challenging in that their candidemia could be associated with the line or not. Therefore, the data regarding line removal is more variable. Given that patients with neutropenia may not have line-associated disease as their candidemia may result from another source and that removal of their catheter may result in challenging venous access issues, the Expert Panel "suggests consideration of venous catheter removal for neutropenic patients who have persistent candidemia and in whom it is logistically feasible".

-Since peripheral cultures may not have been performed, it is difficult to distinguish if the infection is line-associated. A study of pediatric oncology paitents who had double lumen catheters found a > 5-fold difference in colony count between the two lumens in patients who had catheter-related infections. This distinction could prove to be very helpful; however, further studies will need to confirm this finding.

-The usual treatment duration for Candidemia without disseminated disease is 2 weeks after documented clearance of Candida from the bloodstream and resolution of neutropenia and of symptoms related to candidemia.

Empirical therapy for suspected Invasive Candidiasis:

Non-neutropenic patient: consider empirical therapy with fluconazole or an echinocandin in a non-neutropenic patient at high risk for candidemia who has signs and symptoms consistent with the diagnosis. For example, consideration should be given in febrile, critically ill patients with risk factors for invasive disease and no other identified cause of fever. The decision should be based on risk factors, serological markers for invasive disease, and/or culture data from non-sterile sites.

-Fluconazole or an echinocandin is recommended for initial therapy. In the setting of recent azole exposure, moderately severe or severe illness, or high risk for C. glabrata or C. kruseiinfection, an echinocandin is the preferred initial therapy.

-AmB-d or LFAmB are alternatives in the setting of intolerance or limited availability of other antifungal agents.

Neutropenic patient: Neutropenic or Immunocompromised Host: Empirical therapy is usually added in a neutropenic host who remains febrile for > 5 days while on broad-spectrum antibiotics.

-LFAmB, an echinocandin or Voriconazole are recommended.

-Fluconazole and Itraconazole are considered alternative antifungal agents.

-AmB-d is also an alternative but is associated with a higher risk of toxicity.

-Azoles are not recommended in patients who have had recent azole exposure.

Combination Antifungal Therapy:

For invasive candidiasis, only a few trials have studied combination therapy in humans with invasive candidiasis; however, given the lack of data in children and current lack of evidence that combination therapy changes outcomes, combination antifungal therapy is not recommended for invasive candidiasis.

For CNS candidiasis, based on a case series demonstrating a benefit to those patients wtih candidal meningitis who received combination AmB and 5-FC, current guidelines' primary therapy recommendation is use of LFAmB with or without 5-FC for initial therapy of CNS candidiasis.

For Candida endocarditis, the current guidelines also recommend use of LFAmB with or without 5-FC as primary therapy.

Candidemia in patient with Central Venous Catheter (CVC):

Compared to other pathogens, Candida is more likely to originate from the central line. Additionally, depending on the Candida spp., it can rapidly form biofilms on foreign material.

Delayed removal of the CVC has been associated with increased morbidity and mortality in infants and older children, in addition to a low success rate in eradicating Candida from the catheter. In neonates, delay in removing the CVC was associated with an increased risk of disseminated disease, worsened neurodevelopmental outcomes, and increased mortality.

-Removal of catheters is recommended in the setting of non-neutropenic patients with candidemia; however, removal is not always possible in all cases due to the risk of severe complications, lack of other intravenous access in a severely ill child, or lack of other sites for CVCs in a child who has had multiple lines previously.

Catheter-associated BSI may be due to biofilm formation, for which much higher antifungal levels are needed to clear the organism.

Not all cases of candidemia are catheter-related; however,

-if catheter-related, removal of catheter is strongly recommended in non-neutropenic patients. Catheter removal shortened the duration of candidemia and decreased mortality in adults and neonates. A recent study by Pasqualotto et al identified failure to remove the central line as a risk factor for early mortality in their multivariate analysis of pediatric patients.

-In neutropenic patients, consider line removal if symptoms persist or blood cultures continue to be positive.

Candida biofilms adhere to abiotic surfaces. There are differences between species with respect to biofilm formation; C. albicans and tropicales form robust biofilms; whereas, C. glabrata does not form the most robust biofilms. There are some preliminary data on the role of antimicrobial lock therapy as an adjunct to systemic therapy in the setting of Candidemia:

-Due to the high density of organisms and the complex microbial community, a drug resistant population can develop within the biofilm.

-Azoles are poorly active versus Candidal biofilms; whereas, echinocandins retain activity in the presence of biofilms.

-Amphotericin B has decreased activity against biofilms; liposomal Amphotericin formulations are more active.

-Preliminary in vitro data has demonstrated that doxycycline and tegecycline have activity against Candida biofilms. Additionally, high dose heparin decreases biofilm formation.

-Data on effectiveness of caspofungin lock, streptokinase, minocycline, EDTA, ethanol, and others.

Treatment failure:

Candida biofilms adhere to abioticsurfaces. There are differences between species with respect to biofilm formation; C. albicans and tropicales form robust biofilms; whereas, C. glabrata does not form the most robust biofilms. There are some preliminary data on the role of antimicrobial lock therapy as an adjunct to systemic therapy in the setting of Candidemia:

-Due to the high density of organisms and the complex microbial community, a drug resistant population can develop within the biofilm.

-Azoles are poorly active versus Candidal biofilms; whereas, Echinocandins retain activity in the presence of biofilms.

-Amphotericin B has decreased activity against biofilms; liposomal Amphotericin formulations are more active.

-Preliminary in vitro data has demonstrated that Doxycycline and Tegecycline have activity against Candida biofilms. Additionally, high dose heparin decreases biofilm formation.

-Data on effectiveness of Caspofungin lock, Streptokinase, Minocycline, EDTA, Ethanol, etc

-Three of 3 pediatric patients with CVC-Associated infection cleared using ethanol lock (plus systemic therapy in a preliminary study).

-Two recent studies of Catheter-associated Candidemia describe a high cure rate using antifungal lock therapy when the catheter could not be removed, but the current Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America states that the data are insufficient to recommend catheter salvage routinely, and this approach should only be considered when there are unusual extenuating circumstances.

-Several ongoing studies are evaluating combinations, such as L-AMB lock or 70% EtOH lock plus IV Amphotericin.

-The data is insufficient at this point; however, in challenging situations where line removal is contraindicated, one might consider the off-label use of lock therapy in addition to systemic antifungal therapy, such as Amph lock or EtOH (25% with brief dwell) plus systemic antifungal therapy, likely with an echinocandin. However, there remain concerns about the use of EtOH locks and the risk of the EtOH harming the integrity of lonterm CVCs.

If the patient remains febrile and or persistently candidemic, one should consider retained foreign bodies, an endovascular thombus, an undrained abscess, resistance to the antifungal agent, inappropriate dosing of the antifungal agent due to different pharmocokinetics in children, biofilm formation resulting in protection from immunologic attack and from antifungal activity, a new intercurrent infection or other causes of fever.

At this point a thorough evaluation for other sites of infection should be pursued, and one should consider changing to a new antifungal agent, or possibly beginning combination antifungal therapy. Of note, the average time to clear the bloodstream in the setting of candidemia is longer than clearing a bacterial bloodstream infection.

What are the adverse effects associated with each treatment option?

Refer to Table I. on Antifungal Agents for additional details.

Amphotericin B infusion-related toxicity (fevers, rigors, chills, myalgias, arthralgias, nausea, vomiting, headaches, hypotension) appears to occur less frequently in children and rarely in neonates. To blunt these reactions, the infusion rate can be slowed but often patients require pre-medication with acetaminophen, corticosteroids, or meperidine.

Amphotericin B-associated azotemia can be lessened by administering a normal saline bolus (10-15ml/kg) before the dose and assuring appropriate hydration.

What are the possible outcomes of Candidiasis?

Invasive forms of Candidiasis are associated with both morbidity and mortality. Overall mortality rates due to Candidemia in children range from 11 to 25%, with rates as high as 37 - 45% in pediatric intensive care units and 56 - 80% in pediatric cancer and bone marrow transplant patients.

Mortality varies by species and by inpatient setting. A recent study describing the epidemiology of Candidemia in adult and pediatric patients by Horn et al, reported an overall 12 week crude mortality rate of 35.2% in those with a single episode of Candidemia. The lowest mortality was seen with Candida parapsilosis (23.7%) and the highest with C. krusei (52.9%) candidemia, likely related to the types of underlying disease seen in patients at risk for C. krusei, namely hematologic malignancy and stem cell transplantation.

Another study demonstrated mortality varies by species, with crude mortality secondary to C. krusei (59%) and C. glabrata (50%) higher than that of C. albicans (36%). Adult and pediatric patients with candidiasis in intensive care units have a mortality approaching 50%; even in non-intensive care unit settings, mortality is estimated at 29%. For pediatric ICU patients, a 2010 study by Zaoutis and colleagues reported a 44% 30-day mortality rate versus 14% in controls.

In 2005 and 2006 two adult studies demonstrated that mortality of candidemic patients was negatively impacted by delayed initiation of appropriate antifungal therapy. Additionally, candidiasis in neonates accounts for excess costs of $28,000 per case of candidiasis based on 1998-2000 data from neonatal units in the United States.

In a recent meta-analysis, the prognosis of Candidemia is worse when associated with immunosuppression, C. tropicalis, central line retention, steroid therapy and inadequate dosing. Mortality due to Candidemia in pediatric patients has been associated with neutropenia, endotracheal intubation, intensive care, and the presence of an arterial catheter.

In patients with a central catheter and bacteremia due to candida, the risks and benefits of removal of the line must be discussed with the family.

What causes this disease and how frequent is it?

Candida is the third most common etiology of pediatric bloodstream infections (BSI) in hospitals based on a prospective study by Wisplinghoff and colleagues. They found that Candida accounts for 8 - 9% of all pediatric BSIs. It is the third most common agent seen in intensive care units. The incidence of candidal BSI in the US was 8.0 per 10,000 admissions based on 1998-2000 data; however, the incidence is even higher in other countries, with 24.9 cases reported per 10,000 admissions from Brazil's 2003-04 data, and 8 - 21 per 10,000 admissions in South Africa in 2009.

Of note, even within the United States, there are differences in the overall incidence of candidiasis, with higher rates reported in Baltimore and increasing rates noted in Atlanta. However, in children less than 1 year of age, Atlanta reported a recent drop in the incidence of candidiasis from 97/100,000 to 42/100,000. Candidemia in children is associated with high morbidity and mortality, increased length of hospital stays, and higher healthcare costs. Zaoutis and colleagues reported a mean increase in length of hospital stay of 21.1 days due to Candidal infection and a mean increase in hospital charges of $92K per patient.

Although there has been an overall increase in the incidence of invasive candidal disease, fortunately, many new antifungal agents have been developed to add to our armamentarium against these pathogens. However, concomitantly there has also been an increase in resistance to these agents even in strains that were previously susceptible, making therapeutic decisions more challenging.

Candida albicans is still the most common of the Candida species that cause disease in humans; however, other species are being seen more frequently, especially Candida parapsilosis, tropicalis and glabrata. Other less common Candidal species that cause disease in children include C. krusei, C. lusitaniae, C. stellatoidea, C. kefyr, C. pseudotropicalis, C. dubliniensis, C. intermedia and C. guillermondi.

In neonates, C albicans accounts for approximately 70% of the candidiasis cases; in both neonates and children C. parapsilosis is the next most common pathogen and is being seen increasingly more frequently. It is more often a line-related pathogen and is thought to be somewhat less virulent than other strains. In adults, however, C glabrata is the most common non-albicans cause of invasive disease. C. tropicalis is also common in chidlren. C. albicans and tropicalis are generally thought to be the most virulent species.

As a result of increased use of azoles, those Candida species that are more likely to be fluconazole-resistant, namely C. krusei and C. glabrata, are causing disease more frequently. In the study by Horn et al, C. krusei was associated with the highest mortality rate of all species. Given different susceptibilities depending on the Candidal species, identification of the species has become more important.

Other clinical manifestations that might help with diagnosis and management

In patients with disseminated candidiasis, an ophthalmologic examination, an echocardiogram, and an abdominal ultrasound (evaluating the liver, spleen and kidneys) should be performed to determine the extent of disease and duration of therapy.

For patients with line-associated candidemia, most experts recommend line removal as delayed removal has been associated with increased mortality and morbidity.

Are additional laboratory studies available; even some that are not widely available?

Therapeutic Drug Monitoring:

For patients receiving voriconazole, itraconazole or posaconazole, therapeutic drug monitoring should be obtained to ensure optimal therapy and assure therapeutic levels, especially in patients receiving therapy for a prolonged course, who are receiving medications metabolized by the same hepatic CYP enzyme system, or who have deep-seated or refractory candidiasis.

Antifungal Susceptibility Testing:

Antifungal susceptibility testing for Candida species to fluconazole, itraconazole, voriconazole, the echinocandins and flucytosine are now available. MIC testing is generally inexpensive, and the results aided in the management of approximately 10% of patients in a recent small study.

Antifungal susceptibility testing should be considered in the setting of non-albicans Candida infections, severe infections, and for Candidal infections that are not responding to initial therapy. Some experts recommend testing all C. glabrata isolates for fluconazole susceptibility.

Non-culture Techniques:

Biomarkers for early detection of candidiasis include immunologic/serologic (mannan, B-D-glucan) and molecular nucleic acid-based tests (PCR-based). Unfortunately, currently these tests lack standardization and validation. Additionally, there are several technical issues that limit the performance of these tests, including false positive and false negative results, low yeast burden, detection of non-viable organisms, and human versus yeast genes.

Antigen Assays:

Two antigen assays that detect Candida are (1,3)-Beta-D glucan and mannan.

(1,3)-Beta-D glucan is a cell wall component in most Candidal species and studies of adult patients with invasive disease have shown this antigen is elevated in their serum. Sensitivity ranged from 70 - 93% and specificity was 87 - 100%; however, there were false positive results in bacteremic patients and in patients receiving hemodialysis. Fungitec and Fungitell are commercially available kits that test for (1,3)-Beta-D glucan.

The presence of mannan correlates with invasive disease; however, current assays have low sensitivity and low specificity.

At present there remain several limitations to these current antigen assays.

Fungal Metabolite:

D-arabinitol is a fungal metabolite that can be measured in the serum or urine. It is a sugar alcohol produced by Candida albicans, parapsilosis and tropicalis. Some studies demonstrate elevated urine ratios of D- over L-arabinitol in patients with Candidiasis; however, specificity was found to be low, as it is elevated in colonized patients also. Additionally, this test is not helpful for several of the other Candida species that cause disease in patients. It is not commercially available at this time.

Nucleic Acid Amplification Based Systems; DNA Polymerase Chain Reaction (PCR) and Real-time PCR:

Several different PCR assays have been developed to enhance yield and efficiency in the diagnosis of Candida. Others have been developed to shorten the time to species identification.

A multiplex PCR (light cycler SeptiFast test) was compared to routine blood cultures in newborns and children with suspected sepsis. The rate of positive results was significantly higher and the number of contaminants significantly lower with SeptiFast than blood culture. The SeptiFast (June 2011, J Clin Micro) also detected several specific pathogens that blood culture failed to detect, including Candida sp. SeptiFast in addition to blood culture could provide added diagnostic value and shorten the time to result when it is more widely available.

A meta-analysis in the Journal of Clinical Microbiology in Februrary 2011 describes a systematic review to assess the diagnostic accuracy of PCR-based methods to detect Candida spp. directly from blood samples. In patients with suspected invasive candidiasis, they found that the pooled sensitivity for the diagnosis of candidemia was 0.95 (CI, 0.88 - 0.98) and the pooled specificity was 0.92 (CI 0.88 to 0.95). Overall positivity rates for patients with proven or probable invasive candidiasis were 85% (78 - 91%) for PCR versus 38% (29 - 46%) for blood culture.

These diagnostic techniques hold promise for more sensitive and more rapid diagnosis of Candidiasis. Of note, PCR is faster than blood culture only if the laboratory has the expertise, dedicated personnel, and space to run PCR batches frequently throughout the week. Regardless, these techniques are not routinely available in most centers at the present time and standardization of the various PCR methodologies is needed.

Species identification:

PNA FISH is a commercial peptide nucleic acid fluorescent in situ hydbridization method which can distinguish C. albicans from C. glabrata and from C. dubliniensis. It is rapid but costly and not widely available at present. However in the future, tests for rapid species identification will optimize the selection of antifungal therapy.

How can Candidiasis be prevented?

Prophylaxis has been studied in certain high risk groups, such as neonates, patients on chemotherapy, and those undergoing transplantation. Agents used included topical nystatin, fluconazole and others. These studies have demonstrated that fluconazole prophylaxis decreases the incidence of candidemia in bone marrow transplant recipients and in liver transplant recipients, along with decreasing candidal colonization and invasive disease in very low birth weight infants.

However, increases in the incidence of azole-resistant Candida spp. have been reported in some studies of azole antifungal prophylaxis. Additionally, a study of adults in intensive care units demonstrated that fluconazole prophylaxis decreased the number of infections but had no effect on mortality, and an increase in fluconazole-resistant candidal infections was seen.

The current 2009 Candidiasis guidelines recommend prophylaxis in the following settings:

-Solid organ transplant recipients: post-operative fluconazole or LAmB prophylaxis for high-risk liver, pancreas and small bowel transplant recipients.

-Chemotherapy-induced neutropenia: fluconazole, posaconazole or echinocandin prophylaxis for patients receiving induction chemotherapy for the duration of their neutropenia. Oral Itraconazole is cited as an effective but less ideal alternative.

-Stem-cell transplant recipients with neutropenia: fluconazole, posaconazole or micafungin prophylaxis is recommended during the risk period of neutropenia.

Avoid broad-spectrum antibiotics, central venous catheters, and TPN when possible. In high risk patients - and in reality all patients - narrow antibiotics as soon as bacterial culture and susceptibility results return.

What is the evidence?

Zaoutis, T. "Review: Candidemia in Children". Current Medical Research and Opinion. vol. 26. 2010. pp. 1761-68.

Steinbach, WJ, Cohen-Wolkoweiz, M, Benjamin, DK. "Chapter 225: Principles of Antifungal Therapy in Nelson Textbook of Pediatrics".

Pappas, PG, Kauffman, CA, Andes, D. "Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America". Clinical Infectious Diseases. vol. 48. 2009. pp. 503-335.

Knapp, KM, Flynn, PM. "Chapter 212: Candidiasis". Feigin and Cherry's Textbook of Pediatric Infectious Diseases. pp. 2741-2751.

Avni, T, Leibovici, L, Paul, M. "PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis". Journal of Clinical Microbiology. vol. 49. 2011. pp. 665-670.

Groll, AH, Koehler, J, Walsh, TJ. "Invasive fungal infections in children: advances and perspectives". Ped Infectious Diseases Revisited 2007, ed Horst Schroten, Stefan Wirth. pp. 405-472.

Mermel, LA, Allon, M, Bouza, E. "Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America". Clinical Infectious Diseases. vol. 49. 2009. pp. 1-45.

Zaoutis, TE, Prasad, PA, Localio, R. "Risk Factors and Predictors for Candidemia in Pediatric Intensive Care Unit Paitents: Implications for Prevention". Clinical Infectious Diseases. vol. 51. 2010. pp. e38-e45.

Ongoing controversies regarding etiology, diagnosis, treatment

See above regarding considerations related to central intravenous catheter removal in neutropenic and non-neutropenic hosts.

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