Fungal Infections (Candida/molds); Candidemia, Invasive candidiasis, Candida bloodstream infection

Table II.

Condition	First-line Therapy	Alternative	Comment
Candidemia	Fluconazole 400 mg/d x 14 daysCaspofungin 70 mg load x1, then 50 mg/d x 14 daysAnidulafungin 200 mg load x1, then 100 mg/d x 14 daysMicafungin 100 mg/day x 14 days	Liposomal amphotericin 3-5 mg/kg/day x 14 daysVoriconazole 400 mg (6 mg/kg) bid for 2 doses, then 200 mg (3 mg/kg) bid x 14 days	-Fluconazole if known sensitive species or clinically stable, non-neutropenic patient, and not already receiving an azole-Voriconazole can be considered if need to also cover mold (e.g., neutropenic fever in stem cell transplant recipient).-Consider changing to fluconazole if starting with another Rx and isolate is sensitive to fluconazole.-Oral fluconazole and voriconazole are well absorbed and are reasonable alternatives to IV administration.
Urinary tract infection	Fluconazole 200 mg/d x 2 weeks	-Amphotericin B 0.3-0.6 mg/kg/d x 7 days-Amphotericin bladder irrigation-Echinocandin	-Asymptomatic candiduria is usually not significant (neutropenic hosts are an exception).-Remove indwelling Foley catheter if possible, and repeat urine culture.-Treatment if symptoms, fever and candiduria and pyuria
Chronic, disseminated candidiasis	Fluconazole 400 mg/d until resolution of signs and symptoms	An echinocandinAmphotericinVoriconazole	Response to therapy may be protracted and require a long duration of Rx.
Candida endophthalmitis	Amphotericin B 0.7-1 mg/kg/d + 5-FC 25 mg/kg QIDFlucoanzole 6-12 mg/kg/d	Liposomal amphotericin 3-5 mg/kg/dVoriconazole 6 mg/kg q 12h for 2 doses, then 3-4 mg/kg q 12hrEchinocandiin	-Some patients require surgical intervention.-Treat for at least 4-6 weeks and until resolution.
Candida endocarditis	Liposomal amphotericin 3-5 mg/kg/d +/- 5-FC 25 mg/kg QIDEchinocandin	Fluconazole 400-800 mg (6-12 mg/kg) daily	-Fluconazole once blood cultures are negative if organism is susceptible-Valve replacement recommended for cure. If not possible, consider lifelong suppression with fluconazole.-Consider higher doses of echinocandin (caspofungin 50-150 mg/d).
Bone and joint infection	Fluconazole 400 mg daily for at least 6 weeks for arthritis and 6-12 months for osteomyelitis	EchinocandinAmphotericin	-Surgical debridement is recommended.
Suppurative thrombophlebitis	Liposomal amphotericin 3-5 mg/kg/d x 2 weeksFluconazole 400-800 mg/dEchinocandin		Surgical incision and drainage or vein resection is recommended.

Antifungal agents: dosing, side effects and drug interactions

Amphotericin B preparations & dosing for candidemia

Drugs:

• Amphotericin B deoxycholate 0.5-1.0 mg/kg/d IV

• Liposomal amphotericin B 3-5 mg/kg//d IV

• Amphotericin B lipid complex 3-5 mg/kg/d IV

• Amphotericin B colloidal dispersion 3-5 mg/kg/d IV

Spectrum:

Most candida species (except for
Candida lusitaniae), broad-spectrum activity against many other yeasts and molds.

Side effects:

Nephrotoxicity (usually reversible), less frequent with lipid preparations.

Infusion-related toxicity: fever, chills, pulmonary infitrates.

Renal tubular acidosis–usually mild.

Pharmacokinetics and Bioavailability:

Poorly understood.

Reduced delivery to kidney in lipid preparations compared to amphotericin

B deoxycholate.

Drug Interactions:

May have additive nephrotoxicity with other agents–avoid co-administration with aminoglycosides.

Adjustments in Patients with Reduced Creatinine Clearance:

Avoid if possible.

Additional Points:

Maintain adequate hydration

If infusion-related toxicity, consider premedication with Tylenol +/- Benadryl.

Infusion-related toxicity tends to become milder with subsequent administrations.

Lipid preparations are more expensive and associated with less toxicity, but have not been demonstrated to have improved efficacy.

Triazoles & dosing for candidemia

Drugs:

• Fluconazole: 800 mg x 1 load, then 400 mg QD.

• Itraconazole: 200 mg tid x 3 days, then 200 mg QD or bid. Not well studied in candidemia. Usually reserved for mucosal disease only.

• Voriconazole: 400 mg bid x 1 day load, then 200 mg po bid; IV preparation: 6 mg/kg q 12 h x 1 day, then 3-4 mg/kg Q 12 h.

• Posaconazole: Approved for prophylaxis in stem cell transplant (200 mg QID or 400 mg bid oral suspension), but not for candidemia.

Spectrum:

Fluconazole: resistance mostly in C. glabrata and C. kruseii. Resistance less common but can potentially occur with other species. No activity against molds.

Itraconazole: similar to fluconazole against candida, with activity against some molds

Voriconazole: similar to fluconazole, but may also have activity against C.kruseii or fluconazole-resistant C. glabrata. Activity against a variety of molds (not Rhizopus or Mucor).

Posaconazole: similar to voriconazole with added activity against Rhizopus and Mucor.

Side Effects:

As a class: hepatotoxicity, QT prolongation, rash.

Voriconazole: phototoxicity, visual symptoms: most commonly altered color perception or halos around lights; rarely, visual hallucinations.

Pharmacokinetics and Bioavailability:

Fluconazole and voriconazole: excellent oral bioavailability, considered equivalent to IV administration. Oral absorption not affected by gastric pH, but may be diminished with food.

IV voriconazole is compexed to a cyclodextrim molecule, which may accumulate in patients with renal dysfunction.

Itraconazole: oral suspension has much better bioavailability than capsules (capsule absorption inhibited by drugs that raise gastric pH; absorption improved with acidic and carbonated drinks). Oral solution better absorbed without food; capsule has better absorption with food.

Drug Interactions:

All inhibit cytochrome P450 enzymes. Carefully review all other medications for potential drug interactions based on P450.

Adjustments in patients with reduced creatinine clearance:

Voriconazole: no adjustment for oral preparation. Intravenous voriconazole is not recommended if CrCl < 50 mL/min.

Additional points:

Large variety in blood levels with voriconazole (see Therapeutic Drug Monitoring)

Echinocandins &dosing for candidemia

Drugs:

Caspofungin: 70 mg load x 1 , then 50 mg/d.

Anidulafungin: 200 mg load x 1, then 100 mg daily.

Micafungin: 100 mg daily.

Spectrum:

Activity against most candida species.

C. parapsilosis has diminished in vitro activity; clinical significance is unclear.

Partial list of side effects:

Minimal/well tolerated: hepatotoxicity (usually mild), infusion related.

Pharmacokinetics and Bioavailability:

Available only for IV administration.

Drug Interactions:

Minimal.

Adjustments in patients with reduced creatinine clearance:

No dose adjustment for renal dysfunction or dialysis, but dose reductions necessary with caspofungin only in patients with hepatic dysfunction.

fWhen to request susceptibility testing

Standardized susceptibility testing is available for Candida species to fluconazole, itraconazole, voriconazole, flucytosine, and the echinocandins.

Consider susceptibility testing in the following patients:

• Failure to respond to treatment.

• C. glabrata isolates.

Therapeutic drug monitoring

Available for itraconazole, voriconazole and posaconazole.

For itraconazole, steady-state levels may take up to 2 weeks to acheive. Drug levels should not be obtained prior to this time period.

For voriconazole, serum concentrations vary widely. Drug levels can be obtained after 4-5 days.

Suspected candidemia: empiric antifungal therapy in the ICU

Neutropenic patients with peristent fever after 4-7 days should receive empiric antifungal therapy per published guidelines.

Empiric treatment for candidemia in non-neutropenic ICU patients is controversial. There are conflicting studies in the literature.

Consider empiric therapy in patients with:

• Persistent fever on broad-spectrum antibiotics.

• Multiple risk factors for candidemia.

• Colonization with candida from multiple non-sterile sites, or positive beta-D-glucan.

5. Disease monitoring, follow-up and disposition

Obtain daily blood cultures until they are clear.

Dilated funduscopic exam should be performed in all patients to look for candida retinitis/endophthalmitis.

Follow renal and hepatic function as well as CBC for signs of toxicity.

Clinical monitoring for signs/sx’s of recurrance or metastati cfoci of infection–further work-up is indicated if recurrent fever, anorexia or focal symptoms

Follow-up imaging of all previously abnormal findings related to candida infection. For example, in disseminated, hepatosplenic candidiasis, obtain periodic abdominal CT or US to follow the response to therapy. For endophthalmitis, perform periodic funduscopic exam.

Complications

Potential Complications:

Septic shock

Endocarditiis – more common in patients with prosthetic heart valves

Suppurative thrombophlebitis

Disseminated infection: deep organ infection

• Retinitis/endophthalmitis–incidence 10-25%

• Arthritis, osteomyelitis—knees and vertebrae most common sites

What's the evidence

Wisplinghoff, H, Bischoff, T, Tallent, SM. “Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study”. Clin Infect Dis. vol. 39. 2004. pp. 309(Epidemiology of Candidemia.)

Chow, JK, Golan, Y, Ruthazer, R. “Risk factors for albicans and non-albicans candidemia in the intensive care unit”. Crit Care Med. vol. 36. 2008. pp. 1993(Risk factors for candidemia.)

Blumberg, HM, Jarvis, WR, Soucie, JM. “Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey”. Clin Infect Dis. vol. 33. 2001. pp. 177(Risk factors for candidemia.)

Pappas, PG, Kauffman, CA, Andes, D. “Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 48. 2009. pp. 503(Guidelines for the treatment of candidemia.)

Schuster, MG, Edwards, JE, Sobel, JD, Darouiche, RO, Karchmer, AW. “Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial”. Annals of Internal Medicine. vol. 149. 2008. (Empiric antifungal therapy in high risk ICU patients.)