Fungal Infections	53
Subhash Todi and Rajesh Chawla

A 50-year-old diabetic male patient was admitted to hospital with pancreatitis. He had received imipenem for 2 weeks. He had spiking fever and abdominal CT showed peripancreatic collection. Growth of Candida species was found in his urine.

With increasing incidence of elderly patient population, comorbidities, prolonged ICU stay, invasive therapies, and use of broad-spectrum antibiotics, there is a rising incidence of fungal infection and use of antifungal drugs. Candidemia is the most common invasive fungal infection encountered in the ICU and is the fourth most common cause of bloodstream infection. Candida albicans is the most common identified species, but there is an increasing shift to non-albicans Candida species. Attributable mortality with candidemia could be as high as 47%. Other fungal infections seen in the ICU are invasive aspergillosis and zygomycosis. With increasing threat of developing resistance, antifungal drugs should be used judiciously, either prophylactic, empiric, or as a definitive therapy.

Step 1: Take focused history and perform physical examination to identify the patient at risk of candidemia

•Classical risk factors described for candidemia are as follows:

–Prolonged ICU stay

–Use of broad-spectrum antibiotics

S. Todi, M.D., M.R.C.P. (*)

Critical Care & Emergency, A.M.R.I. Hospital, Kolkata, India e-mail: [e-mail]

R. Chawla, M.D., F.C.C.M.

Department of Respiratory, Critical Care & Sleep Medicine, Indraprastha Apollo Hospitals, New Delhi, India

e-mail: [e-mail]

R. Chawla and S. Todi (eds.), ICU Protocols: A stepwise approach,	417
DOI 10.1007/978-81-322-0535-7_53, © Springer India 2012

418	S. Todi and R. Chawla

–Central venous catheters

–Parenteral nutrition

–Neutropenia

–Candida colonization

–Diabetes

–Renal replacement therapy

–Pancreatitis

–Implantable prosthetic devices

–Immunosuppressive agents (glucocorticoid, chemotherapeutic agents, immunomodulating agents)

–Abdominal surgery

•All patients with suspected candidemia should have an ophthalmological examination to rule out endophthalmitis.

•Cardiac examination should be performed to look for features suggestive of endocarditis.

•Abdominal examination is required for hepatosplenomegaly suggestive of visceral candidiasis.

•Neurological examination is performed to look for features of meningoencephalitis in patients with intraventricular catheters.

•Cutaneous examination to look for skin changes of disseminated candidiasis.

Step 2: Send blood for fungal cultures for persistent fever

•Presence of Candida in blood culture is usually pathological.

•Fungal cultures can be obtained in the aerobic culture bottles used for aerobic bacterial cultures.

•Blood cultures are positive in only 50–70% of patients with invasive candidiasis.

•In patients with documented candidemia, repeat blood cultures should be obtained frequently, preferably daily or alternate days, till they become negative.

Step 3: Differentiate colonization from infection with Candida

•Growth of Candida from respiratory secretions usually represents colonization, and therefore, it should not be treated.

•In the absence of systemic features, growth of Candida in the urine often represents colonization.

Step 4: Identify patients in whom empiric antifungal therapy should be considered

•Early empirical therapy in patients with candidemia has been proved to reduce mortality.

•Empirical antifungal therapy should be considered in patients with one or more risk factors for invasive candidiasis and if they show one or more of the following features:

–Persistent fever without a definite source

–Fever not responding to antibiotics

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–Positive serological markers for systemic fungal infection (b-D-glucan)

–Candida colonization of one or more sites (e.g., urine, sputum, and skin)

Step 5: Get familiar with antifungal agents used in patients with suspected or proven candidemia

•Choice of antifungal agents in candidemia is guided by many factors:

–History of recent azole exposure—avoid azoles.

–Local epidemiological data from the ICU regarding predominant Candida species and susceptibility pattern—choose most effective antifungal agents initially pending culture results.

–Severity of illness—use fungicidal drugs in severely ill patients.

–Comorbidity—check renal and hepatic function and avoid amphotericin deoxycholate and voriconazole respectively.

–Involvement of CNS, cardiac valves, and eyes—choose antifungal agents for penetration at the infected site.

–History of intolerance to any antifungal agent or drug interactions.

•Antifungal agents used for candidemia are triazoles, echinocandins, and amphotericin B.

Triazoles

–Triazoles include fluconazole, itraconazole, voriconazole, and posaconazole. In the ICU, fluconazole and voriconazole are used most often.

–They all have similar activity against most Candida species and are fungistatic. They have less activity against Candida glabrata and Candida krusei.

–They inhibit cytochrome P450 and are prone to drug–drug interaction.

–Fluconazole is available both as an oral and as intravenous formulations. It is readily absorbed orally. It has the greatest penetration into the cerebrospinal fluid and vitreous body.

–In patients with invasive candidiasis, fluconazole should be administered with a loading dose of 800 mg (12 mg/kg), followed by a daily dose of 400 mg (6 mg/ kg); a lower dosage is required in patients with creatinine clearance of less than 50 mL/min.

–Voriconazole is available in both oral and intravenous forms. It is used mainly for infection with Aspergillus. Its clinical use in candidiasis has been primarily for step-down oral therapy for patients with infection due to C. krusei and fluconazoleresistant, voriconazole-susceptible C. glabrata.

–In adults, the recommended oral dosing regimen includes a loading dosage of 400 mg twice daily for 1 day, followed by 200 mg twice daily.

–Intravenous voriconazole is complexed to a cyclodextrin molecule; after two loading dosages of 6 mg/kg every12 h, a maintenance dosage of 3–4 mg/kg every 12 h is recommended. Because of the potential for cyclodextrin accumulation among patients with significant renal dysfunction, intravenous voriconazole is not recommended in patients with a creatinine clearance less than 50 mL/min.

420	S. Todi and R. Chawla

–Oral voriconazole does not require dosage adjustment for renal insufficiency, but it is the only triazole that requires dosage reduction for patients with mild-to- moderate hepatic impairment.

–Common polymorphisms in the gene encoding the primary metabolic enzyme for voriconazole result in wide variability of serum levels. Therapeutic drug level monitoring is advisable when using voriconazole.

–Drug–drug interactions are common with voriconazole and should be considered when initiating and discontinuing treatment with this compound.

Echinocandins

–Echinocandins are caspofungin, anidulafungin, and micafungin and are available only as parenteral preparations.

–These are fungicidal drugs and have equal efficacy.

–All echinocandins have a few adverse effects and minimal drug–drug interaction.

–The pharmacological properties in adults are also very similar, and echinocandins are administered intravenously once daily.

–None of the echinocandins require dosage adjustment for renal insufficiency or dialysis.

–Caspofungin is the only echinocandin for which dosage reduction is recommended for patients with moderate-to-severe hepatic dysfunction.

–Intravenous dosing regimens for invasive candidiasis with the three compounds are as follows: caspofungin, loading dose of 70 and 50 mg daily thereafter; anidulafungin, loading dose of 200 and 100 mg daily thereafter; and micafungin, 100 mg daily.

–All echinocandins have a broad-spectrum activity against most of the Candida species.

Amphotericin B (Amph B)

–This is available in non-lipid formulation (Amph B deoxycholate AmB-d) or lipid formulation (ABLC, ABCD, and L-AmB).

–These are fungicidal drugs.

–The three lipid formulations have different pharmacological properties and rates of treatment-related adverse events and should not be interchanged.

–All amphotericin preparations have a very broad-spectrum activity against most Candida species.

–For most forms of invasive candidiasis, the typical intravenous dosage for AmB-d is 0.5–0.7 mg/kg daily, but dosages as high as 1 mg/kg daily should be considered for invasive Candida infections caused by less susceptible species, such as

C. glabrata and C. krusei.

–The typical dosage for liposomal preparations of AmB is 3–5 mg/kg daily when used for invasive candidiasis.

–Nephrotoxicity is the most common serious adverse effect associated with AmB-d therapy, resulting in acute renal failure in up to 50% of recipients. This can be minimized by avoiding concomitant use of other nephrotoxic agents,

53 Fungal Infections	421

proper hydration, and saline loading prior to use of AmB-d. Its use is associated with hypokalemia and hypomagnesemia due to renal wasting, and levels of these electrolytes should be monitored and replaced.

–Liposomal preparations of AmB are considerably more expensive than AmB-d, but all have considerably less nephrotoxicity.

–AmB-d and other liposomal preparations have infusion-related toxicity with fever and rigor and require pretreatment with antipyretics.

Step 6: Choose appropriate antifungal regimen for patients with suspected or proven candidemia

•Fluconazole is recommended in patients who are less critically ill and who have no recent azole exposure and no known resistance to fluconazole.

•Echinocandins are recommended in patients with moderately severe to severe illness or patients who have had recent azole exposure and in neutropenic patients.

•Amphotericin B, preferably lipid formulation, may replace echinocandins in patients with normal renal function, cost consideration, and nonavailability of echinocandins.

•Amphotericin B, preferably liposomal preparations, may be considered in neutropenic patients where invasive Aspergillus or mucormycosis is a possibility.

•Transition from an echinocandin to fluconazole is recommended for patients who have isolates that are likely to be susceptible to fluconazole (e.g., C. albicans) and who are clinically stable.

•Combination antifungal therapy is sometimes used in the following situations:

–Invasive aspergillosis refractory to amphotericin B—voriconazole with caspofungin.

–Central nervous system infection (cryptococcal meningitis)—amphotericin B with flucytosine.

•Voriconazole is recommended as step-down oral therapy for selected cases of candidiasis due to C. krusei or voriconazole-susceptible C. glabrata.

•Recommended duration of therapy for candidemia without obvious metastatic complications is 2 weeks after documented clearance of Candida species from the bloodstream (last negative blood culture) and resolution of symptoms attributable to candidemia.

•Intravenous catheter removal is strongly recommended for nonneutropenic patients with candidemia.

•In patients with endophthalmitis, consider amphotericin B deoxycholate along with flucytosine for 4–6 weeks. Consider early partial vitrectomy in severe cases.

Step 7: Manage persistent candiduria in a catheterized patient

•Avoid treating with antifungal drugs in an asymptomatic, afebrile, stable patient.

•Remove the catheter if possible.

•In high-risk patients such as neutropenic, urological surgery, consider fluconazole therapy if the species is susceptible.

422	S. Todi and R. Chawla

Step 8: Consider central nervous system candidiasis in patients with an intraventricular device

•Consider liposomal amphotericin B at a dosage of 3–5 mg/kg/day with or without flucytosine at a dosage of 25 mg/kg/dose four times daily.

•After initial response, deescalate to fluconazole 400–800 mg daily.

•Remove the infected ventricular device.

Step 9: Consider azole prophylaxis in the selected group of patients

•Prophylactic antifungal therapy has not been proven to decrease mortality from invasive candidiasis in medical/surgical ICU patients and should be avoided.

•For high-risk patients such as neutropenic, solid organ transplant, or stem cell transplant, fluconazole 400 mg (6 mg/kg) daily, posaconazole 200 mg three times a day, or an echinocandin is recommended during the period of neutropenia.

Step 10: Consider possibility of invasive aspergillosis in some situations

•Invasive aspergillosis should be suspected in the following group of patients:

–Prolonged neutropenia more than 10 days

–Hematopoietic stem cell transplantation

–Solid organ transplantation

–Corticosteroid therapy

•Look for involvement of lungs and paranasal sinuses by CT scan, which may show a “halo sign,” a haziness surrounding nodular pulmonary infiltrate.

•Serum galactomannan assay has a moderate sensitivity and specificity for diagnosing invasive aspergillosis. It will be falsely positive in patients treated with piperacillin–tazobactam.

•Isolation of Aspergillus hyphae from nonsterile sites like respiratory secretions may represent colonization. Demonstration of the organism in tissue biopsy is considered a gold standard, but it is difficult to perform in ICU patients.

•Voriconazole is considered a first-line agent for treatment of invasive aspergillosis. Echinocandins have in vitro sensitivity against Aspergillus and may be considered in selected cases.

•In nonresponder combination, antifungal therapy may be tried.

Step 11: Consider zygomycosis (mucormycosis) in some specific situations

•Consider this mould infection in patients with uncontrolled diabetes presenting with rhinocerebral disease.

•This mould also infects immunosuppressed patients and mainly involves the lung.

•Diagnosis is based mainly on tissue biopsy.

•High-dose amphotericin B is considered standard first-line therapy (amphotericin B deoxycholate 1–1.5 mg/kg body wt/day or lipid amphotericin preparation at 5 mg/kg body wt/day).

•Echinocandins and azoles are ineffective against zygomycosis.

•Surgical intervention is usually required in this angioinvasive disease.