A. Organisms [1]

1. Budding yeast, ubiquitous, common oral colonizer
2. Hyphal forms usually occur in invasive / pathogenic lesions
3. Candida species are 5th most common blood-borne infection in humans
   1. Usually in patients recently on antibacterial antibiotics and/or immunocompromised
   2. C. albicans was is most common species (~50%), usually sensitive to fluconazole
   3. Increasing incidence of non-albicans
4. Non-Albicans Species
   1. C. kruzei - resistant to fluconazole; sensitive to voriconazole, candins
   2. C. (Torulopsis) glabrata - ~50% resistant to fluconazole
   3. C. tropicalis - pan sensitive
   4. C. guillermondii - resistant to amphotericin B
   5. C. lusitaniae - sensitive to azoles and candins, may be resistant to amphotericin B
   6. C. parapsilosis - pan sensitive
   7. C. pseudotropicalis
5. Increased fluconazole prophylaxis is leading to increase in C. glabrata infections [3]

B. Types of Infections

1. Superficial Skin Infections
   1. Satellite lesions are common
   2. Often occur in skin folds (intetrigo), groin, scrotum, pelvic area
   3. Chronic Paronychia may also occur
2. Mucosal Lesions
   1. Oral candidiasis (thrush) - usually with HIV, inhaled steroids, immunosuppression
   2. Chronic Mucocutaneous Candidiasis (below)
   3. Vulvovaginitis - often after antibiotic therapy [19]
   4. Anal thrush - HIV, immunosuppression
3. Chronic Mucocutaneous Candidiasis
   1. Recurrent progressive candidal infections
   2. Usually in patients with underlying immune deficiency, usually cell mediated
   3. Spreading infection, skin hyperkeratosis, scarring, hair loss
4. Invasive Infections [1]
   1. Esophageal candidiasis
   2. Candidal urinary tract infections (UTI)
   3. Central venous catheter infections (often on TPN, broad spectrum anti-bacterials)
   4. Mainly occur in intensive care units and immunocompromised persons
   5. Case mortality rates ~50% despite effective therapy (delayed diagnosis, complex patients)
   6. Reduction in C. albicans with fluconazole prophylaxis [3]
   7. Increase in C. kruzei and C. glabrata which are often fluconazole resistant
   8. Disseminated infection is common in immunocompromised persons
   9. Candidal UTI's increased in catheterized patients; reduced ith nitrofurazone-impregnated catheters [21]
5. Disseminated - skin eruptions, liver, spleen, kidney abscess, endocarditis, fungemia
6. Hepatosplenic Candidiasis [1,2]
   1. Nearly always in immunocompromised patients
   2. Occurs in acute leukemia patients after chemotherapy
   3. Focal persistent microabscesses in liver, ± spleen, ± kidneys
   4. Fever, abdominal pain, anorexia, nausea and vomiting
   5. Up to 50% of patients will fail amphotericin despite high doses (>1.5gm)
   6. Fluconazole 200-400mg po qd effective and better tolerated than amphotericin
7. High risk of developing endocarditis after nosocomial candidal fungemia

C. Disseminated Infection [1,3,4]

1. Usually in immunocompromised patients
   1. Most commonly persistent fever with neutropenia after chemotherapy
   2. Occurs in patients treated with multiple broad spectrum antibiotics
   3. Patients with leukemia are at high risk
   4. Organ and hematopoietic transplant patients also at risk
2. Suspect in patients with vascular grafts, foreign bodies, treated with antibacterials [6]
3. Also associated with parenteral nutrition use over long periods
4. Candidal line sepsis generally requires removal of intravenous catheter
5. May present with diffuse skin rash, erythematous nontender maculopapular eruptions
6. Increasaing rates of non-candidal species, particularly with resistance

D. Diagnosis

1. Usually challenging and may be delayed
2. Cultures are often negative, at least in early course of disease
3. Tissue biopsies for culture are reluctantly and infrequently performed
4. Antigen- and PCR-based methods for detection are under development
5. However, culture remains the gold standard

E. Treatment [5]

1. Superficial Lesions
   1. Topical therapy is highly prefered
   2. Less resistance develops, fewer side effects and lower cost
   3. Nystatin powder is most commonly used
2. Oral Candidiasis
   1. Nystatin suspension (5cc qid)
   2. Clotrimazole troches - 1-2 po tid-qid
   3. Fluconazole (Diflucan®) - 100-200mg po bid
   4. Prophylactic 200mg/d fluconazole is good for Candida suppression in HIV disease
   5. Oral amphotericin B suspension for fluconazole resistant cases [7]
3. Vulvovaginal [8,19]
   1. Three day or one day topical azole therapy is preferred
   2. Single dose topical tioconazole (Vagistat-1®, Monistat1®) is now over the counter
   3. Butoconazole (Femstat3®, Mycelex3®), miconazole, clotrimazole, terconazole effective
   4. Tioconazole and terconazole have activity against non-albicans Candidal strains
   5. Fluconazole (Diflucan®) 150mg po x 1 is also effective and very convenient
   6. Fluconazole 150mg weekly for 6 months reduces recurrence: 72% (placebo) to 10% [13]
   7. Fluconazole weekly prophylaxis should be strongly considered in women with recurrences
4. Intertrigo
   1. Keep area dry
   2. Antifungal powder such as nystatin or cream such as clotrimazole
   3. May add low potency steroid cream to reduce pruritis (provided antifungal agent is used)
5. Disseminated C. albicans Infection [1,4]
   1. Must be treated with parenteral therapy
   2. Several options now available:
   3. Amphotericin B intravenously
   4. Antifungal Azoles
   5. Echinocandins
6. Amphotericin B
   1. Amphotericin B 0.3-1.2mg/kg/day IV to total 0.5-1gm
   2. 5-Fluocytosine (5-FC) may be added to amphotericin but only marginal benefit in severe or resistant candidemia
   3. Lipid formulations of amphotericin are better tolerated and more effective than standard
   4. Liposomal amphotericin B 3-6mg/kg IV qd is probably best tolerated
   5. Amphotericin combined with high dose fluconazole (800mg qd) may be superior to either agent alone
   6. For serious infections, amphotericin IV initially (usually for up to 4 days) followed by oral fluconazole is increasingly used [15]
7. Azoles
   1. Fluconazole and voriconazole are active an relatively well tolerated
   2. Fluconazole (Diflucan®) 400mg IV/PO qd likely as effective for mild-moderate infections as amphotericin and less toxic but does not cover non-albicans candida well
   3. Empirical fluconazole in intensive care unit patients who have not responded to antibiotics should reduce mortality [16]
   4. Voriconazole and posaconazole active against most non-albicans candida species [15,17]
   5. Voriconazole (Vfend® IV then PO) is as effective as amphotericin followed by fluconazole for candidemia in non-neutropenic patients [15]
   6. Posaconazole (Noxafil®) is an oral azole approved for prevention of Candida and Aspergillus in severe immunocompromise
   7. Dose (with food) is 200mg x 1, followed by 100mg qd x 13d for oropharyngeal candidiasis
   8. Prophylaxis against Candida with 200mg po tid posaconazole for duration of immunocompromise [17]
8. Echinocandins [4]
   1. Generally superior to azoles concerning anti-candida spectrum
   2. Reasonable alternative first line therapies to amphotericin in serious infections [9,10]
   3. Caspofungin, micafungin, anidulafungin all very effective
   4. Resistant candidal esophagitis may respond to echinocandins [9,11,14] or posaconazole [17]
9. Caspofungin (Cancidas®) [4,10]
   1. Echinocandid, about as effective as fluconazole for esophageal candidiasis
   2. More effective for non-albicans candida than fluconazole [10,11]
   3. As effective and far better tolerated than amphotericin for neutropenic or non- neutropenic patients, including non-albicans species [12]
10. Micafungin (Mycamine®) [4,14]
    1. Approved for IV treatment of esophageal candidiasis and candidal prophylaxis
    2. Active in vitro against most Candida and Aspergillus species
    3. Active in vitro against fluconazole-resistant Candida and non-albicans Candida
    4. As effective as liposomal amphotericin B, with fewer side effects, in candidemia and invasive candidosis, including across all non-albicans species [18]
    5. Generally well tolerated: fever, headache, nausea, vomiting, diarrhea, liver abnormalities
    6. Dose is 50mg/day for prophylaxis, 150mg/day for treatment, IV over 1 hour
11. Anidulafungin (Eraxis®) [4,9]
    1. Approved for IV treatment of esophageal candidiasis, candidemia, other complicated candida infections
    2. Active in vitro against most Candida and Aspergillus species
    3. Active in vitro against fluconazole-resistant Candida and non-albicans Candida
    4. Dose for esophageal candidiasis is 100mg IV day 1, then 50mg daily for 14 days
    5. Dose for complex candida infections is 200mg on day 1, then 100mg dailyfor 14 days after the last positive candida culture
    6. Invasive candidiasis treated for 10 days with IV anidulafungin (75% success) is superior to fluconazole (60% success) in mainly nonneutropenic patients [20]
    7. No clear benefits over other echinocandins
12. C. glabrata and C. krusei Infections
    1. Often resistant to fluconazole [1,5]
    2. Echinocandins are alternative first line for non-albicans candidiasis
    3. Most strains are sensitive to echinocandins [4]
    4. Voriconazole (Vfend®) is active against ~50% of isolates
    5. Posaconazole is active against most isolates [17]
    6. Amphotericin B (without 5-FC) lipid formulation is recommended
    7. Itraconazole (Sporanox®) is generally not effective because of cross resistance

References

1. Patterson TF. 2005. Lancet. 366(9490):10132
2. Kontoyiannis DP and Lewis RE. 2002. Lancet. 359(9312):1135
3. Bodey GP, Mardani M, Hanna HA, et al. 2002. Am J Med. 112(5):380
4. Bennett JE. 2006. NEJM. 355(11):1154
5. Treatment of Fungal Infections. 1996. Med Let. 38(967):10
6. Graber CJ, Lauring AS, Chin-Hong PV, et al. 2007. NEJM. 357(10):1029 (Case Discussion)
7. Amphotericin. 1997. Med Let. 39(994):16
8. Drugs for Vulvovaginal Candidiasis. 2001. Med Let. 43(1095):3
9. Anidulafungin. 2006. Med Let. 48(1235):43
10. Villanueva A, Gotuzzo E, Arathoon EG, et al. 2002. Am J Med. 113(4):294
11. Caspofungin. 2001. Med Let. 43(1108):58
12. Mora-Duarte J, Betts R, Rotstein C, et al. 2002. NEJM. 347(25):2020
13. Sobel JD, Wiesenfeld HC, Martens M, et al. 2004. NEJM. 351(9):876
14. Micafungin. 2005. Med Let. 47(1211):51
15. Kullberg BJ, Sobel JD, Ruhnke M, et al. 2005. Lancet. 366(9495):1435
16. Golan Y, Wolf MP, Pauker SG, et al. 2005. Ann Intern Med. 143(12):857
17. Posaconazole. 2006. Med Let. 48(1248):93
18. Kuse ER, Chetchotisakd P, da Cunha CA, et al. 2007. Lancet. 369(9572):1519
19. Sobel JD. 2007. Lancet. 369(9577):1961
20. Reboli AC, Rotstein C, Pappas PG, et al. 2007. NEJM. 356(24):2472
21. Stensballe J, Tvede M, Looms D, et al. 2007. Ann Intern Med. 147(5):285