Candidiasis

Question 1

Should candida on a blood culture ever be viewed as a contaminant? Under what conditions?

Answer 1

Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source of infection. For many patients, candidemia is a manifestation of disseminated candidiasis, whereas for others it reflects colonization of an indwelling intravenous catheter.

Question 2

How common were the various species of Candida found to be in the US?

Answer 2

In a multicenter surveillance study conducted in the United States between 2004 and 2008, 54 percent of 2019 bloodstream isolates represented non-albicans Candida spp and 46 percent represented C. albicans. C. glabrata was responsible for 26 percent of all cases of candidemia, followed by C. parapsilosis (16 percent), C. tropicalis (8 percent), and C. krusei (3 percent). Other studies have shown a similar order of frequency, although the incidence of each species varies in different patient populations and geographic regions.

Question 3

Why is important to know the prevalence of the different species?

Answer 3

Knowing the prevalence of the non-albicans Candida species is important because susceptibility to antifungal agents varies among the species. As an example, all isolates of C. krusei are fluconazole resistant, and an increasing proportion of C. glabrata are fluconazole resistant.

Question 4

What are the two most important risk factors for candidaemia?

Answer 4

Patients in the ICU and those who are immunocompromised are most at risk for the development of candidemia.

Question 5

Which ICU-related factors confer greater risk for candidaemia?

Answer 5

Patients in ICUs account for the greatest number of episodes of candidemia in most hospitals. Surgical units, especially those caring for trauma and burn patients.

Besides the risks associated with the extremes of age and trauma or burns, other factors include:
●Central venous catheters;
●Total parenteral nutrition;
●Broad-spectrum antibiotics;
●High APACHE scores;
●Acute renal failure, particularly if requiring hemodialysis;
●Prior surgery, particularly abdominal surgery;
●Gastrointestinal tract perforations and anastomotic leaks.

Question 6

What were the two most important risk factors for non-albicans candidaemia?

Answer 6

●Fluconazole exposure (odds ratio [OR] 11.6, 95% CI 2.3-58.9);
●Central venous catheter exposure (OR 2.0, 95% CI 1.1-3.5).

Question 7

Which immunocompromised patients are at greatest risk for candidaemia?

Answer 7

High-risk groups include:
●Those with hematologic malignancies;
●Recipients of solid organ or hematopoietic stem cell transplants;
●Those given chemotherapeutic agents, especially those associated with extensive gastrointestinal mucosal damage.

Neutropenia is common in these settings, and most transplant recipients are also receiving glucocorticoids.

Question 8

What are the risk factors for azole-resistant candida infection?

Answer 8

Risk factors for candidemia caused by fluconazole-resistant isolates, mostly C. glabrata, include neutropenia, chronic renal disease, chronic lung disease, male gender, and previous fluconazole or other antifungal exposure.

Question 9

What are the 3 major routes by which Candida species can gain access to the bloodstream?

Answer 9

●Through the gastrointestinal tract mucosal barrier;
●Via an intravascular catheter;
●From a localized focus of infection, such as pyelonephritis.

Question 10

How can Candida access the bloodstream via the GIT?

Answer 10

— Penetration through the gastrointestinal tract mucosa is probably the most common mechanism for Candida species to enter the bloodstream in both neutropenic patients and in intensive care unit patients. Candida species are part of the normal bowel microbiota. Chemotherapeutic agents that disrupt the intestinal mucosa play a major role in allowing Candida to escape from the bowel in patients with hematologic malignancies.

Question 11

How might Candida access the bloodstream via IV catheters?

Answer 11

Intravascular catheters, especially central venous catheters, continue to be an important source for Candida bloodstream infection. Candida colonization of indwelling vascular devices, especially central catheters, can occur at either the insertion site or the hub and lead to subsequent candidemia.

Total parenteral nutrition (TPN) is an important risk factor for candidemia. Although the mechanism by which TPN increases the risk of candidemia is not well understood, one in vitro study suggested that the lipid emulsion present in TPN solutions increases biofilm production on silicone-elastomer catheters and supports growth of C. albicans.

Question 12

How do Candida access the bloodstream from localized infections?

Answer 12

Bloodstream invasion is relatively uncommon from a localized focus of infection but has been well described with ascending Candida urinary tract infection associated with either intrinsic obstruction (eg, from a fungus ball) or extrinsic compression preventing the flow of infected urine.

Question 13

What are the subgroups of invasive Candida infection and what percentage of the total does each group comprise?

Answer 13

. Some experts have proposed dividing invasive Candida infections into three subgroups: candidemia without deep-seated or visceral involvement, candidemia with deep-seated or visceral Candida infection, and deep-seated (visceral) candidiasis without candidemia.

In at least one study, each entity was responsible for approximately one-third of cases.

Question 14

Which species is the most common cause of candidaemia?

Answer 14

Candida albicans.

Question 15

Give a broad overview of the clinical manifestations of invasive Candida infection.

Answer 15

The clinical manifestations of candidemia vary from minimal fever to a full-blown sepsis syndrome that is indistinguishable from severe bacterial infection. Invasive candidiasis is defined by hematogenous spread to multiple viscera (eg, eye, kidney, heart valves, brain).

Clinical clues on physical examination to hematogenous spread of Candida include characteristic eye lesions, skin lesions, and, much less commonly, muscle abscesses.

Question 16

How common are eye lesions in invasive Candida infection and what is the characteristic lesion?

Answer 16

The frequency of eye lesions in patients with candidemia has been variable, ranging from 2 to 26 percent in different studies.

Chorioretinitis with or without vitritis.

Question 17

What are the skin manifestations of invasive Candida infection?

Answer 17

Skin lesions tend to appear suddenly as clusters of painless pustules on an erythematous base; they can occur on any area of the body. The lesions vary from tiny pustules that can be easily missed to others that are nodular, several centimeters in diameter, and appear necrotic in the center. In severely neutropenic patients, the lesions may be macular rather than pustular. In patients with negative blood cultures, the recognition of these lesions as a manifestation of candidemia and subsequent punch biopsy may lead to the diagnosis.

Question 18

Write a very brief note on muscle abscesses in invasive Candida infection.

Answer 18

Less commonly, patients describe soreness in a discrete muscle group caused by Candida microabscesses. Examination reveals a tender muscle that may be warm and swollen.

Question 19

Outline the ways to make a diagnosis of invasive Candida infection.

Answer 19

The gold standard for the diagnosis of candidemia is a positive blood culture; blood cultures should be obtained in all patients with suspected candidemia. In patients with focal findings (eg, skin lesions or parenchymal involvement), biopsy should be performed for staining, culture, and histopathologic evaluation. When available, we suggest sending the beta-D-glucan assay because it can be a useful adjunct to blood cultures and biopsy and can be particularly useful in patients with deep-seated invasive candidiasis (eg, intraabdominal candidiasis).

Question 20

Write short notes on the culture and stain of biopsy material in the diagnosis of invasive Candida infection.

Answer 20

Directed biopsy of sites of involvement often leads to a definitive diagnosis. Material obtained by scraping the base of a pustule should be submitted to the microbiology laboratory for Gram stain and culture.

Punch biopsies of skin or tissue biopsy will show microabscesses, and special stains will show budding yeasts and often pseudohyphae or hyphae that are characteristic of Candida species.

Clinicians frequently must rely upon clinical judgment about the probability of candidemia as an explanation for a patient’s symptoms while awaiting the return of blood cultures. Certain findings on physical examination, especially the presence of suggestive skin or eye lesions, can alert the clinician to the possibility of Candida infection.

Question 21

Write short notes on the use of blood cultures in the diagnosis of invasive Candida infection.

Answer 21

The most obvious method to detect candidemia is to grow the organism from the blood. Unfortunately, blood culture techniques are relatively insensitive. Studies from several decades ago showed that blood cultures were positive in only approximately 50 percent of patients who were found to have disseminated candidiasis at autopsy.

A drawback of all blood culture systems for the diagnosis of candidemia is that one to three days are required for growth and an additional one to two days for identification of the organism after subculture onto agar medium. For a seriously ill patient, more rapid and more sensitive techniques are essential.

Question 22

Write short notes on the non-culture modalities used in the diagnosis of invasive Candida infection. Include:

• Beta-D-glucan
• PCR

Answer 22

• The most promising antigen assay is based upon the detection of beta-D-glucan, which is present in the cell wall of many fungi. Thus, this assay is not specific for Candida. As noted above, when available, we suggest sending the beta-D-glucan assay because it can be a useful adjunct to blood cultures and biopsy and is particularly useful in patients with deep-seated invasive candidiasis (eg, intraabdominal candidiasis).

Another study showed that a combination of blood cultures with the beta-D-glucan assay or the polymerase chain reaction increases the sensitivity of diagnostic testing compared with blood cultures alone.

• One current focus of non-culture methods is on the development of a PCR assay for candidemia and invasive candidiasis. As is true of cultures, PCR can identify Candida to the species level. However, to date, there is no commercially available approved PCR test to detect Candida species.

Question 23

Which classes of antifungals are available to treat invasive Candida infection. Give examples from each class.

Answer 23

The most common antifungal agents used for the treatment of candidemia are the echinocandins (caspofungin, micafungin, anidulafungin) and fluconazole (an azole). Formulations of amphotericin B (a polyene) are given less often due to the risk of toxicity.

Question 24

Which few general facts are important to know when treating invasive Candida infection?

Answer 24

In all cases, candidemia requires treatment with an antifungal agent; it should never be assumed that removal of a catheter alone is adequate therapy for candidemia. Several studies have noted the high mortality rates associated with candidemia and have shown that mortality is highest in those patients who were not treated with an antifungal drug. Furthermore, prompt initiation of therapy is crucial.

Question 25

What are the broad therapeutic categories in the management of invasive Candida infection?

Answer 25

• Non-neutropaenic patients
• Neutropaenic patients
• Non-albicans candida, esp. C. glabrata and C. krusei.

Question 26

What are the options for initial therapy in someone with invasive Candidiasis who isn’t neutropaenic?

Answer 26

●In nonneutropenic patients with candidemia, we suggest initial therapy with an echinocandin (table 1) [3].
The doses of the echinocandins are:
•Anidulafungin: 200 mg loading dose, then 100 mg daily intravenously (IV);
•Caspofungin: 70 mg loading dose, then 50 mg daily IV;
•Micafungin: 100 mg daily IV.

●Fluconazole (800 mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] orally or IV daily) can be used as an alternative agent in patients who are not critically ill and who are unlikely to have a fluconazole-resistant organism, such as C. glabrata or C. krusei. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill.

●Lipid formulation amphotericin B (3 to 5 mg/kg IV daily) is an alternative if there is intolerance, limited availability, or resistance to other antifungal agents.

Question 27

What are the options for initial therapy in someone with invasive Candidiasis who is neutropaenic?

Answer 27

●In neutropenic patients with candidemia, we suggest initial therapy with an echinocandin at the doses noted in the previous flashcard
.
●An alternative is a lipid formulation of amphotericin B (3 to 5 mg/kg daily), but this regimen has more toxicity.

●Fluconazole (800 mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] orally or IV daily) should be restricted to clinically stable patients who have not had prior azole exposure. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill.

Question 28

What are the options for initial therapy in someone with invasive Candidiasis secondary to either C. glabrata or C. krusei?

Answer 28

●An echinocandin is preferred over amphotericin B for treatment of candidemia due to C. glabrata and C. krusei. Voriconazole is approved for this indication, but there is likely to be cross-resistance between fluconazole and voriconazole among C. glabrata isolates. This cross-resistance does not occur with C. krusei.

●Some studies have shown increased rates of echinocandin resistance among C. glabrata bloodstream isolates. Resistance should be suspected in patients who have received echinocandins in the recent past and in patients who develop candidemia while receiving an echinocandin for prophylaxis or empiric therapy (eg, for neutropenic fever); in these situations, an amphotericin B formulation should be used until antifungal susceptibility testing results are available.

●Candida krusei is usually susceptible to echinocandins and voriconazole but is uniformly resistant to fluconazole. These isolates can also demonstrate high minimum inhibitory concentrations (MICs) to amphotericin B, and, for this reason, higher doses of this drug should be used for C. krusei infection (5 mg/kg daily of lipid-based formulations).

Question 29

Write short notes on stepping down to oral therapy in patients with invasive Candidiasis.

Answer 29

Nonneutropenic and neutropenic patients who are clinically stable, who have Candida isolates that are susceptible to fluconazole, and who have negative repeat blood cultures can be transitioned to oral fluconazole after five to seven days
.
For most Candida species, fluconazole should be given at a dose of 400 mg (6 mg/kg) orally once daily for step-down therapy. For C. glabrata infection, higher-dose fluconazole 800 mg (12 mg/kg) orally daily or voriconazole 200 to 300 mg (3 to 4 mg/kg) orally twice daily should be used for patients with fluconazole-susceptible or voriconazole-susceptible isolates. Voriconazole is recommended as oral step-down therapy for patients with C. krusei, as this species is intrinsically resistant to fluconazole.

Question 30

What is the recommended duration of therapy for patients with invasive Candidiasis?

Answer 30

The appropriate duration of therapy for candidemia has not been studied. For patients without metastatic complications, a minimum of two weeks of therapy after blood cultures become negative has been used in most clinical trials and is the recommended duration in the 2016 Infectious Diseases Society of America (IDSA) guidelines. Blood cultures should be performed daily or every other day after initiating therapy in order to determine the date of sterilization. If blood cultures remain positive, then a search for a metastatic focus, such as an abscess or endocarditis, must be undertaken. In addition, all patients should have resolution of symptoms attributable to candidemia and resolution of neutropenia (eg, absolute neutrophil count >500 cells/microL and a consistent increasing trend) before antifungal therapy is discontinued.

A longer duration of therapy and consultation with an infectious disease specialist are warranted in patients who have metastatic foci of infection, such as endophthalmitis or endocarditis.

Question 31

Which combinations of therapy have been shown to be effective?

Answer 31

Whether more than one antifungal agent should be used together for the treatment of candidemia has not been established, although combination therapy is generally not given for the treatment of candidemia.

Question 32

Comment on the relative effectiveness of the three classes of antifungals used for invasive Candidiasis.

Answer 32

Several randomized trials have shown that fluconazole is as effective as amphotericin B for the treatment of candidemia in immunocompetent patients. The echinocandins appear to be as effective as and better tolerated than amphotericin B formulations and, in one study, more effective than fluconazole.

Question 33

Write short notes on the use of the echinocandins in the management of invasive Candidiasis. Mention:

• Examples of drugs
• Mechanism of action
• Spectrum of action
• Resistance patterns
• Dosing
• Adverse effects

Answer 33

The echinocandins include caspofungin, anidulafungin, and micafungin. Echinocandins are noncompetitive inhibitors of the synthesis of 1,3-beta-D-glucan, which is an integral component of the fungal cell wall.

They are cidal for most Candida species, have favorable toxicity profiles, and are approved for the treatment of candidemia and other forms of invasive candidiasis. The echinocandins are preferred over azoles for the initial treatment of candidemia if C. glabrata or C. krusei is identified or suspected or if the patient has been previously treated with an azole agent.

Due to their broad-spectrum activity against Candida species, the echinocandins are used extensively for candidemia and invasive candidiasis. The highest echinocandin MICs are found for C. parapsilosis and C. guilliermondii. Resistance to echinocandins has been noted in only a few individual cases until recently. However, acquired resistance has been increasingly reported, especially in C. glabrata.

When an isolate demonstrates resistance to one echinocandin with acquired mutations in FKS gene “hot spots,” it is typically resistant to the entire class.

The echinocandins are administered intravenously as follows:
●Caspofungin is given at an initial dose of 70 mg on the first day of treatment, followed by 50 mg daily; dose reduction is required with hepatic dysfunction.
●Anidulafungin is given at an initial dose of 200 mg on the first day, followed by 100 mg daily.
●Micafungin is given at a dose of 100 mg daily for candidemia; no loading dose is needed.

Adverse effects of all echinocandins are generally mild and include fever, thrombophlebitis, headache, and elevated aminotransferases.

Question 34

Write short notes on the use of the azoles in the management of invasive Candidiasis. Mention:

• Examples of drugs
• Mechanism of action
• Bioavailability
• Relative activity of fluconazole and voriconazole
• Effect on P450 enzymes

Answer 34

The azoles work primarily by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is necessary for the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi.

Fluconazole has an excellent safety profile and is available in intravenous and oral formulations and is also inexpensive, since it is now generic. Fluconazole is highly bioavailable, making oral dosing appropriate for most patients.

Other available azoles include voriconazole, posaconazole, itraconazole, and isavuconazole.

●The activity of voriconazole against Candida species is superior to that of fluconazole, with minimal inhibitory concentrations that are a log or more lower than fluconazole. However, cross-resistance between fluconazole and voriconazole is seen frequently, especially with C. glabrata. Voriconazole has significantly greater in vitro activity against C. krusei isolates compared with fluconazole because of more effective binding of its cytochrome P450 isoenzyme.

Azoles interact with multiple different cytochrome P450 enzymes; alternative antifungal agents, such as echinocandins, may be preferred if patients are taking other medications that utilize P450 pathways.

Question 35

Write short notes on the use of polyene antifungals in the management of invasive Candidiasis. Mention:
* Examples of drugs and preference of use
* Mechanism of action
* Dosing
*

Answer 35

Amphotericin B is a polyene antifungal agent that disrupts fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the formation of pores that allow leakage of cellular components. Amphotericin B deoxycholate, which was the standard drug for the treatment of candidiasis for decades, demonstrates rapidly cidal in vitro activity against most species of Candida, but it is associated with significant nephrotoxicity. Because of this, it is rarely used anymore. Instead, most physicians use a lipid-based amphotericin B formulation, either liposomal amphotericin B or amphotericin B lipid complex (ABLC).

The recommended doses for candidemia follow:
●Lipid formulations of amphotericin B (liposomal amphotericin B [AmBisome], amphotericin lipid complex [Abelcet]) – 3 to 5 mg/kg intravenously daily.
●Amphotericin B deoxycholate – 0.5 to 1 mg/kg intravenously daily (recommended only if a lipid formulation of amphotericin B is not available).

Amphotericin B formulations have been proven to be effective in several randomized trials. However, amphotericin B formulations are often avoided due to their increased toxicity compared with azoles and echinocandins. They remain useful in cases when resistance to the other antifungal classes is suspected or proven.

Question 36

When is susceptibility testing recommended for Candida infections?

Answer 36

Susceptibility testing for Candida species is becoming more readily available and widely used. Antifungal susceptibility testing for azoles is recommended for all bloodstream isolates and other clinically significant Candida isolates.

Question 37

Comment on the susceptibililty patterns of the following Candida species;

• C. albicans
• C. krusei
• C. glabrata

Answer 37

• The incidence of C. albicans resistance remains low. An analysis of in vitro susceptibilities of approximately 90,000 isolates of C. albicans collected from 40 countries from 1997 to 2005 demonstrated that only 1.5 percent were resistant to fluconazole.
• C. krusei is intrinsically resistant to fluconazole due to an altered cytochrome P450 isoenzyme. In the large surveillance study described above, all C. krusei isolates were susceptible to the echinocandins (caspofungin, micafungin, and anidulafungin). However, individual cases of resistance to the echinocandins have been reported. C. krusei demonstrates decreased susceptibility to amphotericin B, requiring higher doses (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations) to be used for treatment. C. krusei is usually resistant to flucytosine.
• Many C. glabrata isolates are resistant to the azoles, mostly due to changes in drug efflux. The echinocandins have generally retained excellent activity against C. glabrata, but resistance to this class of antifungal agents appears to be increasing among C. glabrata isolates Amphotericin B has delayed killing kinetics against C. glabrata in vitro; higher doses of amphotericin B are recommended when treating known C. glabrata infection (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations).

Question 38

What is the name of the recently-identified, multidrug-resistant Candida species?

Answer 38

C. auris.

Question 39

Which investigation should all patients with invasive Candidiasis undergo (not a diagnostic test; complication-related)?

Answer 39

All patients who have candidemia, whether or not they have ocular symptoms, should undergo an ophthalmologic examination by an ophthalmologist to look for evidence of endophthalmitis, as recommended in the Infectious Diseases Society of America guidelines for treatment of candidiasis.

Question 40

Write short notes on the removal of CVCs in Candidaemia.

Answer 40

The 2016 Infectious Diseases Society of America guidelines for the management of candidiasis gives different recommendations for nonneutropenic patients and neutropenic patients; many neutropenic patients have chemotherapy-induced mucositis and a likely gastrointestinal source for candidemia.

For nonneutropenic patients, the central venous catheter (CVC) should be removed in most cases and as early as it is possible to do safely when the source is presumed to be the CVC. For neutropenic patients, CVC removal should be considered on an individual basis, taking into account the feasibility and risk of removal.

Clearance of candidemia occurs more quickly when CVCs are removed, and higher mortality has been documented if they remain. In addition, treatment with an antifungal agent is required; it should never be assumed that removal of a catheter alone is adequate therapy for candidemia.

Some authorities have suggested that catheter removal may not be necessary in patients who have a gastrointestinal source of candidemia, such as patients with chemotherapy-induced mucositis. Some clinicians will attempt to retain the catheters in such patients, particularly given the risk of CVC removal in the setting of thrombocytopenia, which is common following cytotoxic chemotherapy.

Question 41

Comment on the use of granulocyte transfusions in the management of Candidaemia.

Answer 41

Limited data suggest that granulocyte transfusions may be beneficial in patients with persistent candidemia and prolonged neutropenia. However, the benefit of granulocyte transfusions has not been clearly established. A multicenter randomized controlled trial was stopped prematurely and did not show benefit.

Question 42

Outline the use of empiric antifungal therapy in suspected/possible Candidaemia.

Answer 42

Empiric antifungal therapy is given routinely to patients with neutropenic fever since they are at substantial risk for invasive candidiasis. This is discussed in detail separately.

In addition, nonneutropenic patients who have persistent fever or unexplained hypotension despite broad-spectrum antibacterial agents may have candidemia or invasive candidiasis. These patients may benefit from empiric therapy with an antifungal agent. In general, the approach to the use of antifungal agents for empiric therapy in nonneutropenic patients is the same as that for treatment of candidemia.

Criteria for the need for empiric therapy remain poorly defined and should include the clinical assessment of risk factors (eg, central venous catheters, parenteral nutrition, hemodialysis, trauma, broad-spectrum antibiotics, recent surgery [particularly abdominal surgery]), non–culture-based surrogate markers for invasive candidiasis (eg, beta-D-glucan), and culture data regarding Candida colonization at nonsterile sites.

Empiric therapy should be started as soon as possible in patients with risk factors for invasive candidiasis and signs of septic shock because of the high mortality in this group of patients.

It is not clear whether the empiric use of antifungal agents is beneficial in intensive care unit (ICU) patients.

For empiric therapy in ICU patients, we recommend an echinocandin. Fluconazole can be used as an alternative in patients who have not received prior fluconazole and who are colonized with fluconazole-susceptible species.

Question 43

Comment on prophylactic antifungal use in the ICU.

Answer 43

— Because mortality remains high in patients with candidemia, antifungal prophylaxis has been studied as a means to prevent its occurrence. However, the optimal approach remains unclear. We suggest not routinely using prophylactic antifungal agents in the intensive care unit (ICU) setting. However, consideration can be given to the use of prophylaxis in selected patients in ICUs that have high rates (>5 percent) of invasive candidiasis.

Question 44

What are the outcomes in Candidaemia like?

Answer 44

Untreated candidemia has a mortality rate of over 60 percent. With treatment, the overall mortality of candidemia is approximately 30 to 40 percent. A delay in treatment can increase mortality. As an example, in one retrospective cohort study of 230 patients with candidemia, the number of days that passed from notification of the first positive culture for yeast to the initiation of fluconazole correlated with increased mortality rates as follows: zero days (15 percent); one day (24 percent); two days (37 percent); three days (41 percent).

Among candidemic patients with septic shock, the outcomes are even poorer.

Question 45

What are the risk factors for oropharyngeal candida?

Answer 45

Oropharyngeal candidiasis, or thrush, is a common local infection seen in infants, older adults who wear dentures, patients treated with antibiotics, chemotherapy, or radiation therapy to the head and neck, and those with cellular immune deficiency states, such as AIDS. Patients with xerostomia and those treated with inhaled corticosteroids for asthma or rhinitis are also at risk.

Question 46

What is the usual causative species in oropharyngeal candidiasis?

Answer 46

The usual causative agent is Candida albicans, but other species, including C. glabrata, C. krusei, and C. tropicalis, have been isolated from cases of thrush or esophagitis. These other species are usually present along with C. albicans, which is the probable cause of the symptoms in most patients. However, in highly immunosuppressed AIDS patients, non-albicans species appear to cause disease.

Question 47

What are the two major clinical forms of oropharyngeal candidiasis?

Answer 47

●The pseudomembranous form is the most common and appears as white plaques on the buccal mucosa, palate, tongue, or the oropharynx.
●The atrophic form, also called denture stomatitis, is the most common form in older adults. It is often found under upper dentures and is characterized by erythema without plaques.

Question 48

What are the typical symptoms experienced by those who have oropharyngeal candidiasis?

Answer 48

Many patients with oropharyngeal candidiasis are asymptomatic. The most common symptoms that do occur are a cottony feeling in the mouth, loss of taste, and in some cases, pain during eating and swallowing. Patients who have denture stomatitis usually experience pain.

Question 49

Which three Candida-caused conditions may accompany oropharyngeal candidiasis?

Answer 49

• Oesophageal candidiasis
• Laryngeal candidiasis
• Angular cheilitis

Question 50

How is a diagnosis of oropharyngeal candidiasis made?

Answer 50

The diagnosis of oropharyngeal candidiasis is usually suspected clinically and is readily confirmed by scraping the lesions with a tongue depressor and performing a Gram stain or KOH preparation on the scrapings. Budding yeasts with or without pseudohyphae are seen.

Although culture of the lesions can be performed, it is rarely indicated unless the disease is recalcitrant or recurrent. Such lesions are likely to be caused by an unusual and/or azole-resistant species.

Question 51

What are the two broad therapeutic groups in oropharyngeal candidiasis?

Answer 51

HIV negative and HIV positive.

Question 52

How is oropharyngeal candidiasis in HIV-negative patients managed? Address the following:

• Treatment of the two major clinical groups
• Recurrence
• Resistant infections

Answer 52

The treatment of oropharyngeal candidiasis in patients without AIDS is usually accomplished with local therapy for 7 to 14 days. For topical agents, successful therapy depends on adequate contact time between the agent and the oral mucosa. Options include:
●Clotrimazole troches (one 10-mg troche dissolved slowly five times daily) are effective, but can be difficult to adhere to due to frequent dosing.
●Miconazole mucoadhesive buccal tablets (50 mg once daily applied to the mucosal surface over the canine fossa) are as effective as clotrimazole, but may be more expensive.
●Nystatin swish and swallow (400,000 to 600,000 units four times daily).

If the patient does not respond to these local measures, the preferred therapy is oral fluconazole (200 mg loading dose, then 100 to 200 mg daily). Clinical symptoms and signs resolve in more than 90 percent of patients taking fluconazole.

Therapy for denture stomatitis requires treatment of the device as well as the oral cavity to avoid relapse. The dentures must be removed before going to bed, brushed vigorously, and then soaked in a solution of chlorhexidine gluconate or a dilute solution of bleach (10 drops in a denture cup filled with water). Other products (sold as Polident or Efferdent) can also be used but may not be as effective.

Recurrence is common if the underlying risk factors are still present, (eg, ongoing steroid use or chemotherapy). In these patients, oral troches are a reasonable first approach; for more persistent infections, prophylactic therapy with 100 mg fluconazole daily is a good option. Some patients with radiation-induced xerostomia have recurrent episodes of candidiasis after the radiation therapy is finished. It is probably better to treat when symptoms appear than to give continuous fluconazole suppression, which increases the risk of developing azole resistance. Drug-resistant Candida glabrata infection in patients with head and neck cancer has been described in two case series, and in both, higher dosages of fluconazole were required for eradication of disease.

Question 53

How is oropharyngeal candidiasis in HIV-positive patients treated? Give an overview.

Answer 53

The approach to treatment of oropharyngeal candidiasis can include topical agents or azole therapy. We recommend use of topical agents for a patient with their first presentation of mild thrush. For patients with moderate to severe oropharyngeal candidiasis or for those with recurrent disease, we recommend fluconazole. We also recommend fluconazole rather than topical therapy in patients who are at risk of developing esophageal candidiasis (CD4 count <100 cells/microL).

Question 54

Discuss the use of topical treatments in the management of oropharyngeal candidiasis in HIV-positive patients.

Answer 54

For patients presenting with an initial episode of mild thrush, topical therapy can be administered for 7 to 14 days. We prefer clotrimazole troches (one 10 mg troche five times daily), but miconazole mucoadhesive buccal tablets (50 mg once daily applied to the mucosal surface over the canine fossa) can also be used.

Studies that have compared clotrimazole troches or nystatin to fluconazole found that clotrimazole had comparable effectiveness to fluconazole, whereas nystatin was clearly inferior.

Other topical therapies, such as antifungal creams, are suitable for the treatment of angular cheilitis, which can be seen as a manifestation of candida infection in immunosuppressed hosts. Angular cheilitis manifests as bilateral, bright red erythematous fissures at the angles of the mouth.

Question 55

Discuss the use of azole therapy in the management of oropharyngeal candidiasis in HIV-positive patients.

Answer 55

Fluconazole is the most commonly used azole and the dose recommended is 200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days.

Posa-, itra- and voriconazole may be used if fluconazole therapy fails.

Question 56

What are the risk factors for oesophageal candidiasis?

Answer 56

Esophageal candidiasis is most common in HIV-infected patients, in whom it is an AIDS-defining illness and primarily occurs at CD4 cell counts below 200/microL, and in patients with hematologic malignancies. Invasive candida infections can also be seen in patients with Idiopathic CD4+ lymphocytopenia.

Question 57

What are the typical species isolated in oesophageal candidiasis?

Answer 57

The causative organism is almost always C. albicans although other species are occasionally found.

Question 58

What are the symptoms associated with oesophageal candidiasis?

Answer 58

The hallmark of esophageal candidiasis is odynophagia or pain on swallowing. Patients usually localize their pain to a discrete retrosternal area.

Question 59

Comment on the relationship between oesophagitis and thrush.

Answer 59

Esophagitis and thrush often occur together in immunosuppressed patients and the presence of thrush may help determine the cause of esophageal symptoms. However, the absence of thrush does not preclude the diagnosis of esophagitis.

Question 60

How is a diagnosis of oesophageal candidiasis made?

Answer 60

The diagnosis of Candida esophagitis is usually made at endoscopy when white mucosal plaque-like lesions are noted. Confirmatory biopsy shows the presence of yeasts and pseudohyphae invading mucosal cells, and culture reveals Candida.

An alternative diagnostic approach that has been used in AIDS patients is to treat with systemic antifungal agents on the basis of the patient’s history. Odynophagia due to candidiasis should improve within several days.

If symptoms do not improve within three to four days, endoscopy and biopsy must be performed since it is likely that a disease other than or in addition to Candida esophagitis is present. The frequency of coinfection was illustrated in a study of 110 HIV-infected patients presenting with esophageal symptoms, 72 of whom were diagnosed with esophagitis. Among the 52 patients with Candida esophagitis, concomitant infection with cytomegalovirus was noted in 22 and with herpes simplex virus in two.

Question 61

Which conditions should be considered in the differential diagnosis of oesophageal candidiasis?

Answer 61

The differential diagnosis of esophageal candidiasis includes other infectious etiologies (eg, cytomegalovirus, herpes simplex virus), medication-induced esophagitis, and inflammatory conditions such as eosinophilic esophagitis.

Question 62

Outline the general approach to the management of oesophageal candidiasis.

Answer 62

Candida esophagitis requires systemic antifungal therapy; it should never be managed with local agents.

The threshold for doing endoscopy is lower in patients without evidence of oral thrush, since other etiologies may be causing the patient’s symptoms. The general duration of treatment is 14 to 21 days. Intravenous therapy may be required initially in patients with severe disease who cannot take oral therapy.

The treatment of esophageal candidiasis can include azoles, echinocandins, or amphotericin B, as discussed below. We recommend fluconazole for the treatment of esophageal candidiasis due to its excellent efficacy, ease of administration, and low cost. For patients with documented esophageal candidiasis that is refractory to fluconazole after one week of treatment, we recommend voriconazole or posaconazole in outpatients. Itraconazole oral suspension is also effective, but causes more nausea. In patients in whom intravenous therapy is necessary, we suggest use of an echinocandin, rather than amphotericin B.

Question 63

How is fluconazole dosed in oesophageal candidiasis?

Answer 63

The dose is 400 mg as a loading dose and then 200 to 400 mg daily for 14 to 21 days given orally or intravenously, as tolerated.

Question 64

How is oesophageal candidiasis resistant to fluconazole treated?

Answer 64

• Use a different azole, such as itraconazole, voriconazole or posaconazole.
• The echinocandins (caspofungin, micafungin, and anidulafungin) are also effective for the treatment of Candida esophagitis. All of the echinocandins must be given intravenously, and therefore, are used mostly in the treatment of hospitalized patients and those patients who have esophageal candidiasis refractory to azole therapy; they are also much more expensive than fluconazole. Most studies have shown higher relapse rates with echinocandins than with azoles except at higher dosages of the echinocandins. For this reason, the recommended doses of some echinocandins for the treatment of esophageal candidiasis are higher than those used for candidemia.
• Amphotericin B deoxycholate (0.3 to 0.7 mg/kg daily) is also an effective agent for Candida esophagitis. The clinical indications for amphotericin B therapy include, drug resistant Candida infections and esophageal candidiasis during pregnancy.

Question 65

How is oesophageal candidiasis in pregnancy treated?

Answer 65

Azoles are teratogenic and should not be used during the first trimester for the treatment of mucosal candidiasis. There are no data regarding the use of echinocandins in pregnancy. Amphotericin B is recommended.

Question 66

Write short notes on the adverse effects of therapy for oesophageal candidiasis.

Answer 66

Short courses of topical therapy rarely result in adverse effects.

Azole therapy can be associated with gastrointestinal upset; prolonged administration can cause hepatotoxicity; periodic monitoring of aminotransferases is prudent with chronic administration. Voriconazole is the only azole associated with visual disturbances and has a higher risk of rash, including photosensitivity, than other azoles.

Echinocandins are very well tolerated, but require intravenous administration. Drug interactions are uncommon because, unlike the azoles, these drugs are not metabolized via the cytochrome p450 pathway.

Question 67

Comment on the finding of funguria in hospitalized patients and list some of the causative organisms.

Answer 67

Funguria is common in hospitalized patients and is generally benign. Invasive infection of the kidney is unusual and is difficult to treat. The vast majority of fungal infections of the kidney and bladder result from Candida albicans and other Candida species. A variety of other fungi can rarely involve the kidney as a result of disseminated infection. These include:
●Aspergillus species
●Fusarium species
●Trichosporon species
●Mucorales (eg, Rhizopus, Mucor species)
●Dematiaceous molds
●Cryptococcus neoformans
●Dimorphic fungi (eg, Histoplasma capsulatum, Coccidioides species, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, and Penicillium marneffei)

Question 68

How does Candida enter the urinary tract?

Answer 68

There are two mechanisms by which Candida spp infect the urinary tract: infections can begin in the lower urinary tract and ascend to the upper urinary tract, and infection can also occur via hematogenous dissemination to the kidneys.

Question 69

How common is candiduria?

Answer 69

A European observational study found that Candida was the third most common organism isolated from urine in hospitalized patients.

Question 70

Which Candida species predominate in instances of candiduria?

Answer 70

A prospective multicenter surveillance study evaluated 861 hospitalized patients with candiduria [8]. Candida albicans was found in 52 percent of these patients and Candida glabrata in 16 percent.

Question 71

What are the risk factors for candiduria?

Answer 71

The following risk factors were noted: urinary tract drainage devices (83 percent), prior antibiotic therapy (90 percent), diabetes (39 percent), urinary tract pathology (38 percent), and malignancy (22 percent). Only 11 percent had no underlying predisposing factors for funguria.

Candiduria is especially common among patients in intensive care units (ICUs); older age, diabetes mellitus, length of stay, ventilator support, and parenteral nutrition were found to be risk factors in one study.

Community-based studies have been reported infrequently, but they generally note similar risk factors (eg, diabetes, antimicrobial use, indwelling bladder catheters) as those in hospitalized patients.

Question 72

Comment on the infection/colonization dilemma.

Answer 72

Most patients with candiduria are asymptomatic, and the yeasts merely represent colonization. However, it is difficult to differentiate between colonization and bladder infection.
●Infected patients may have dysuria, frequency, and suprapubic discomfort, but others have no symptoms.
●Pyuria is so common in patients with a chronic indwelling bladder catheter that it cannot be used to indicate infection.
●Neither the presence of pseudohyphae in the urine nor the number of colonies growing in culture (unlike bacterial urine cultures) help to distinguish colonization from infection.

Question 73

Describe the natural history of candiduria.

Answer 73

There are several concerns in patients with asymptomatic candiduria: the development of ascending infection of the kidney, the development of candidemia, and the possibility that candiduria is a manifestation of disseminated candidiasis. These complications should be considered in the appropriate host:
●Ascending involvement of the kidneys usually occurs in the setting of urinary tract obstruction, which may be caused by formation of fungus balls. Complications of upper tract infection, such as emphysematous pyelonephritis and papillary necrosis, are rare.
●Candiduria as a source of candidemia typically occurs in patients who have urinary tract abnormalities, most often urinary tract obstruction, and/or in those who have undergone a urinary tract procedure. Candidemia as a consequence of asymptomatic candiduria without obstruction or surgery is uncommon in hospitalized patients, including those in the intensive care unit setting.
●The kidneys are the most commonly involved organ in disseminated candidiasis. Although candiduria can be seen in systemic infection, it is usually accompanied by many other signs and symptoms of disseminated infection.

Question 74

What do the clinical manifestations of renal candidiasis depend on?

Answer 74

The clinical characteristics of kidney infections depend on whether the disease presents secondary to candidemia or from an ascending bladder infection.

Question 75

Describe candidaemia-associated renal candidiasis.

Answer 75

Infection of the kidney associated with candidemia is usually bilateral, consisting of multiple microabscesses in the cortex and medulla.

The kidney is the most common organ involved in systemic Candida infections. This was illustrated in a review of 45 autopsies of patients with disseminated candidiasis: 40 had histological evidence of renal involvement compared with 26 with evidence of invasion of the heart, the next most commonly involved organ.

When present, symptoms and signs referable to renal infection include the following:
●Flank and/or abdominal pain
●Costovertebral angle tenderness
●Abdominal tenderness

Renal function is only rarely compromised in adults.

Papillary necrosis can occur, and the sloughed papillae may serve as a nidus for fungus ball formation. Although it is uncommon for Candida to invade vascular structures and cause infarction, there are reports of renal infarction secondary to emboli in patients with Candida endocarditis.

Question 76

Describe the clinical manifestations of renal candidiasis secondary to an ascending infection.

Answer 76

Ascending Candida infection of the kidney usually has a subacute to chronic course. Invasion of the renal parenchyma in such patients tends to involve the renal pelvis and medulla with sparing of the cortex. The kidney is usually the only organ involved and the infection tends to be unilateral. Fungus balls and perinephric abscesses can occur, as can emphysematous pyelonephritis; the latter complication occurs rarely.

Ascending infections occur mostly in patients with diabetes or anatomic abnormalities of the urinary tract.

Predisposing urinary tract abnormalities include:
●Renal stones causing obstruction
●Renal stone manipulation with percutaneous lithotripsy or ureteroscopy
●Nephrostomy tubes
●Prostatic hypertrophy
●Neurogenic bladder
●Infected penile prosthesis
●Chronic bladder catheterization

Flank pain may be present for days to weeks and costovertebral angle tenderness can be elicited in some patients. Fever or other signs of systemic infection are usually absent.

Question 77

Discuss the diagnosis of renal candidiasis.

Answer 77

When only isolated candiduria is found, it can be difficult to distinguish among contamination of the urine sample, colonization of the bladder, local bladder infection, and upper tract disease involving the renal parenchyma.

Urine characteristics, such as the number of yeast or the presence of pyuria, do not distinguish fungal colonization from fungal infection. Although uncommonly found, the identification of fungal casts in urine cytology specimens stained with periodic acid-Schiff or silver stains is diagnostic of kidney involvement. Since the kidneys are seeded from the bladder, blood cultures are generally negative for fungi.
Persistent candiduria, especially in diabetics, should prompt radiologic imaging of the kidneys with ultrasound or computed tomography (CT) to evaluate for renal involvement. Abdominal CT scans or sonography may show hydronephrosis, fungus balls, or perinephric abscesses associated with ascending infection.

Patients with candiduria who have systemic signs or symptoms should be evaluated for disseminated infection with imaging and blood cultures. Among patients with known disseminated candidiasis, the finding of renal involvement has no specific treatment implications unless renal function deteriorates or flank pain develops.

Question 78

What are the two therapeutic groups in the treatment of renal candidiasis?

Answer 78

• Asymptomatic candiduria;

* Symptomatic candiduria.

Question 79

How is asymptomatic candiduria treated? Include a discussion of therapy in renal transplant patients and the management of urinary catheters/devices.

Answer 79

Asymptomatic candiduria rarely requires antifungal therapy unless it occurs in the setting of a condition that confers high risk of dissemination (neutropenia, very low birthweight infants (<1500 g), or urinary tract manipulation)
.
Antifungal therapy is not recommended unless the patient belongs to one of the groups listed above.
In contrast, patients who have a risk factor for disseminated infection should be treated as follows:
●Neutropenic patients and very low birthweight infants (<1500 g) with asymptomatic candiduria should be assumed to have disseminated infection and should be treated with an antifungal regimen recommended for candidemia.
●Patients with asymptomatic candiduria who will be undergoing a urologic procedure should be treated with oral fluconazole 400 mg (6 mg/kg) or amphotericin B deoxycholate 0.3 to 0.6 mg/kg intravenously (IV) daily for several days before and after the procedure.

Renal transplantation is no longer an absolute indication for treatment of asymptomatic candiduria, but therapy can be considered on a case-by-case basis. Candiduria is most often treated in renal transplant recipients when there is a high risk for graft or device involvement, such as early after transplant when ureteral stents are in place.

If complete removal of bladder catheters or urologic stents is not possible, placement of new devices or intermittent bladder catheterization may decrease colonization.

Question 80

Give a broad overview of the management of symptomatic candiduria.

Answer 80

Symptomatic candiduria should be treated.

While awaiting species identification and susceptibility results, we give an antifungal agent that will target the most likely species (which will depend on the patient’s medical history and past microbiology data) and that will achieve adequate concentrations in the urine. For patients who are not at risk for fluconazole-resistant Candida infection, we give fluconazole. For patients at risk for fluconazole-resistant Candida infection, we give amphotericin B deoxycholate.

Treatment of candiduria should be tailored according to the identified Candida species and according to whether localized or disseminated infection is present. For patients with candiduria with suspected disseminated candidiasis, treatment should be chosen according to the recommendations for systemic infection.

Question 81

How is fluconazole-susceptible renal candida treated?

Answer 81

For cystitis due to fluconazole-susceptible Candida spp, we recommend fluconazole (200 mg [3 mg/kg] orally daily). For pyelonephritis due to fluconazole-susceptible Candida, we recommend fluconazole (200 to 400 mg [3 to 6 mg/kg] orally daily). Therapy should be continued for 14 days for both cystitis and pyelonephritis.

Dosing of fluconazole should be reduced in patients with renal insufficiency.

Question 82

How is fluconazole-resistant renal candida treated?

Answer 82

Patients with cystitis or pyelonephritis caused by fluconazole-resistant Candida spp can be treated with intravenous amphotericin B deoxycholate (0.3 to 0.6 mg/kg per day) for one to seven days. Lipid formulations of amphotericin B should not be used to treat urinary tract infections because they do not penetrate the kidney or achieve adequate concentrations in the urine.

Bladder irrigation with amphotericin B will clear funguria, but the effect is transient, and this treatment is not recommended for cystitis; it will clearly not be effective for pyelonephritis.

Question 83

Comment on the use of agents other than fluconazole and amphotericin B in the management renal candidiasis.

Answer 83

There is little clinical experience in treating Candida infections of the kidney or bladder with the echinocandins, voriconazole, posaconazole, or isavuconazole, none of which achieve adequate concentrations in the urine for treating infection. However, these drugs perhaps could achieve appropriate levels in patients with invasive infections involving the renal or bladder parenchyma. Their use should only be considered in the absence of alternative therapies.

Question 84

What complications may follow renal candidiasis?

Answer 84

Complications associated with fungal infections of the kidneys include perinephric abscess and fungus ball formation. Additional complications, such as renal arteritis with aneurysm formation, have been observed in renal transplant recipients who have acquired Candida infections at the time of transplantation.

Question 85

How are candida perinephric abscesses managed?

Answer 85

With fungal perinephric abscesses, drainage is preferred and can often be performed with percutaneous catheters. Large bore catheters and irrigation may be required since the abscess material can be especially thick and tenacious. Patients with multiple loculations or fistulae may require open drainage for complete evacuation.

Although some patients have been cured with drainage alone, it is recommended that systemic antifungal drugs should be given to all patients with perinephric abscesses .

Question 86

How are renal fungal balls managed?

Answer 86

Fungus balls (sometimes called fungal bezoars) should be managed with a combination of surgical and medical therapy
.
We recommend fluconazole (200 to 400 mg [3 to 6 mg/kg] orally once daily). We suggest amphotericin B deoxycholate (0.3 to 0.6 mg/kg intravenously daily) with or without flucytosine (100 mg orally per day divided into four doses) as an alternative regimen. Therapy should be continued until a surgical or endoscopic procedure to remove the fungus ball has been accomplished, symptoms have resolved, and urine cultures are negative.

The following represents a sequential approach to the surgical management of fungus balls:
●Systemic therapy with an antifungal agent is imperative during any manipulation of the urinary tract to prevent hematogenous dissemination.
●The first step is obtaining access to the involved upper tract with either percutaneous nephrostomy tubes or retrograde catheters passed through the ureter.
●If a nephrostomy tube is present, irrigation of the involved upper tract with amphotericin B deoxycholate (25 to 50 mg in 200 to 500 mL sterile water) should be performed.
●Debulking by extraction of the fungus ball through the catheters and lavage should be attempted.
●After debulking, some authorities suggest irrigation via the catheters until urine cultures are negative and there is no radiologic evidence of persistent disease.
●Balloon dilatation of inflammatory strictures may be required to reestablish drainage through the ureters; some infections will need open pyelotomy for debridement.