Candidiasis

CANDIDIASIS Presenter: SITI NORAISAH KIFLI

INTRODUCTION 

a fungal infection (mycosis) of any of the Candida species, of which Candida albicans is the most common

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Candida is a genus of “yeast-like fungi” which exist as part of the normal flora of the mouth, gastro-intestinal tract and vagina. Candidiasis occurs when there is a disturbance of local condition or impairment of immune system.

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Infections can occur anywhere and are most common in skinfolds and web spaces, on the genitals, cuticles, and oral mucosa.

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Most candidal infections are of the skin and mucous membranes, but invasive candidiasis is common in immunosuppressed patients and can be life threatening

PATHOPHYSIOLOGY Candida

is a unicellular yeast whose cells reproduce by budding.

This

organism can flourish in most environments. It frequently colonizes the oropharynx, skin, mucous membranes, lower respiratory, and gastrointestinal and genitourinary tracts. Pathogenesis:

-increased fungal burden and colonization, such as in the setting of broad-spectrum antimicrobial agents -breakdown of normal mucosal and skin barriers, which can occur with indwelling intravascular devices, recent surgery/trauma or tissue damage secondary to chemotherapy or radiation -immune dysfunction secondary to disease states or iatrogenic conditions.

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The first step in the development of a candidal infection is colonization of the mucocutaneous surfaces.

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The routes of candidal invasion include;

disruption of a colonized surface (skin or mucosa), allowing the organisms access to the bloodstream

adsorption via the gastrointestinal wall, which may occur following massive colonization with large numbers of organisms that pass directly into the bloodstream

Granulocytopenia

Hematologic

Bone

marrow transplantation

Foley

catheters

Solid

organ transplantation (liver, kidney)

Solid

neoplasms

Parenteral Acute

hyperalimentation

and chronic renal failure

Premature

birth

Gastrointestinal Recent

tract surgery

bacterial infection

Prolonged

hospitalization

Corticosteroids

Recent

malignancies

chemotherapy or radiation therapy

Hemodialysis Central

intravascular access devices

Recent

surgery

Severe

trauma

Burns Broad-spectrum Mechanical

antibiotics

ventilation for longer than 3 days

CAUSES 

Over 200 species of Candida exist in nature; thus far, only a few species have been associated with disease in humans.

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The medically significant Candida species include the following:         

C. albicans, the most common species identified (50-60%) Candida glabrata (previously known as Torulopsis glabrata) (15-20%) C. parapsilosis (10-20%) Candida tropicalis (6-12%) Candida krusei (1-3%) Candida kefyr (<5%) Candida guilliermondi (<5%) Candida lusitaniae (<5%) Candida dubliniensis, primarily recovered from patients infected with HIV

TYPES OF CANDIDIASIS Local mucous membrane Invasive candidal infections (systemic) infections •Oral candidiasis •Vulvovaginal candidiasis •Erosio interdigitalis blastomycetica •Intertrigo •Candidal paronychia •Diaper rash •Perianal candidiasis •Chronic mucocutaneous candidiasis

•candidemia •disseminated candidiasis •deep organ involvement •endocarditis •Endophthalmitis •Meningitis •isolation of Candida from a normally sterile body site,including blood, peritoneal fluid, pleural fluid, intra-articular fluid, or cerebrospinal fluid.

inflammatory lesion at the labial commissure, or corner of the mouth, and often occurs bilaterally. The condition manifests as deep cracks or splits

Perlèche (Angular cheilitis)

Oral candidiasis (Thrush)

-infection of yeast fungi of the genus Candida on the mucous membranes of the mouth. -frequently caused by C.albicans

Candidal vulvovaginitis

Diaper candidiasis

infection of the vaginal mucous membranes by C. albicans

infectious of a child's diaper area

infection of the skin by C. albicans,more specifically Candidal intertrigo located between intertriginous folds of adjacent skin

Candidal paronychia

-inflammation of the nail fold - associated with frequent hand immersion in water and diabetes mellitus

Congenital cutaneous

skin condition that results in newborn babies due to premature rupture of membranes candidiasis together with a birth canal infected with C. albicans

Perianal candidiasis

Skin maceration and pruritus are frequent with frequent extension to the perineum

Systemic candidiasis

2 primary syndromes: candidemia and disseminated candidiasis (organ infection by Candida species).

Erosio interdigitalis blastomycetica

an oval-shaped area of macerated white skin on the web between and extending onto the sides of the fingers

Antibiotic candidiasis (Iatrogenic candidiasis)

result from overuse/overpresciption of broad spectrum antibiotics

Chronic mucocuntaneous candidiasis

a heterogeneous group of Candida infections of the skin, mucous membranes, hair, and nails, which has a protracted course despite typical therapy

TREATMENT 

based on the anatomic location of the infection, the patients' underlying disease and immune status, the patients' risk factors for infection, the specific species of Candida responsible for infection, and, in some cases, the susceptibility of the Candida species to specific antifungal drugs

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4 major antifungal agents:  polyenes  azole  Glucan synthesis inhibitors (echinocandins)  Antimetabolite (flucytosine)

Polyenes   

broad-spectrum fungicidal agents MOA: insertion into fungal cytoplasmic membrane, causing increases in permeability. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations. Drugs: amphotericin B & Nystatin

Amphotericin B (Fungizone®) 

MOA: Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death

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Side effects: Fever, headache, anorexia, weight loss, GI disturbances,malaise, epigastric pain, dyspepsia, generalized pain, anaemia, abnormal renal function. Rarely cardiovascular toxicity, haematologic reactions, neurologic reactions, liver Dosing failure.

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-Adult : 0.25 mg/kg/day (IV infusion), gradually increase if tolerated to 1 mg/kg/day. Max. in severe cases : 1.5 mg/kg Drug interactions:-increased risk (blue of nephrotoxicity-nephrotoxic daily or on alternate days book)

antibiotics, cyclosporine, other nephrotoxic immunosuppressants, or parenteral -Paeds:1.5mg/kg in 50ml dex-hep at 2ml/hrpentamidine (1.5mg/kg/hr) continuous-may IV;total doseeffects 30-35mg/kg over 4-8 weeks (Frank Shann) enhance of neuromuscular-blocking drugs -Renal impairment: if due to drug,↓ doseglycosides by 50% if or dose can -may increase toxicity of digitalis

be given every other day (lexi-comp)

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Lipid formulations -Amphotericin B (Cholesteryl sulfate) (Amphotec®)-colloidal dispersion -amphotericin B lipid complex (ABLC, Abelcet®) -liposomal amphotericin B (L-AMB, AmBisome®).

Nystatin suspension (100 000u/ml) 

MOA: Binds to sterols in fungal cell membrane, changing the cell wall permeability allowing for leakage of cellular contents

Dosing

Side effects:GastrointestinaI rash. Suspension: Newborn : 50,000 - disturbances, 100,000 units daily. Child : Up to 5 yrs: 100,000 units 6hrly. 6 - 12 yrs & Adults : 500,000 units qid  Counseling points: Cream/oitment: Apply liberally to affected area bd or as required. - shake well before use has disappeared continue treatment After lesion for 10 about days to prevent -should be swished the mouthrelapses and retained in the mouth for as Tablet: 1-2possible tab (500,000 to 1,000,000 units nystatin) TDS long as (several minutes) before swallowing 

-Avoid eating for 5-10 minutes after using this medication -Wash the dropper with hot water before returning it to the bottle

Azoles MOA: inhibition of lanosterol 14-alpha-demethylase, an enzyme required for the synthesis of ergosterol, the main component of fungal cell membranes. Imidazoles

Triazoles

2 atoms of nitrogen in the azole ring

3 atoms of nitrogen

miconazole, ketoconazole, and clotrimazole

fluconazole, itraconazole, econazole, terconazole, butoconazole, and tioconazole Newer triazoles: voriconazole, posaconazole, ravuconazole

Common s/e: Clotrimazole- Local irritation, mild burning and stinging of the skin or vaginal area can occur with topical application. Miconazole -Topical: Allergic contact dermatitis, burning, maceration Ketoconazole- Oral:GI upset (nausea, vomiting, and diarrhea) and headache and dizziness ;Hepatotoxicity; Pruritus (2%) Shampoo: Abnormal hair loss, dry/oily scalp or itching may be seen following the application of the shampoo.

Common s/e: GI symptoms (nausea, abdominal pain, vomiting and diarrhea);Rash and headache; Mild elevations in liver function tests (1-7%) of cases

Drugs

Clotrimazole

Formulations & -1% Cream doses -1% Solution

Indications

Dose & durations

Imidazoles -Vaginal Tablet 200mg & 500mg

Ketoconazole

Miconazole

- Tablet 200mg - Shampoo 2%

-Cream

2% -Powder (nitrate) 2%

Cutaneous candidiasis, Tinea Tablet 200mg Cream: corporis, Tinea cruris, Tinea i) Pityriasis versicolor i) Fungal infections: Tinea pedis, pedis and Tinea versicolor ii) Systemic mycosis (other Tinea corporis, Tinea capitis and other dermatophyte infections skin mycoses) caused by Trichophyton and iii) Nail infections Epidermophyton species. ii) Antifungal agent that has been in various candida infections including vaginal candidiasis. Powder: Skin infections caused by dermatophytes or Candida

Topical:Rub in gently onto affected and surrounding skin bd-tds; continuing for 14 days after lesions have healed. Tablet:200mg pessary for 3 days

i) 200 mg with meal once dly for 14 days. ii) 200 - 400 mg dly for 4 wks - 12 mths. iii) 200 - 400 mg dly for 6 12 mths. Max 400 mg dly.

Cream: i)Skin Infection: Apply sparingly and rub gently onto affected area once daily or bd continuing for 10 days after lesions have healed. ii) Apply BD continuing for 10 days after lesions have healed Powder: Dust powder over infected area OD or bd.

Drugs

Fluconazole

Formulations & -capsule 50mg, 100mg doses -injection 2mg/ml Indications

Triazoles

Itraconazole

Voriconazole

-Oral

-Tablet

solution 10mg/ml -Capsule 100mg

i)Oropharyngeal candidiasis, Oral solution: atrophic oral candidiasis associated with dentures, other i) oral or oesophageal candidal infections of mucosa candidiasis ii) Tinea pedis, corporis,cruris, ii) fluconazole resistant versicolor and dermal and/or oesophageal candidiasis candidiasis iii) Invasive candidal & cryptococcal infections Capsule: (including meningitis) i)Dermatomycosis iv) Prevention of relapse of including Pityriasis cryptococcal meningitis in AIDS patients after completion versicolor ii) Oral Candidosis of primary therapy iii)Palmar Tinea manus v) Prevention of fungal and plantar Tinea pedis infections in immunocompromised patients iv) Fingernail considered at risk as a onychomycosis consequence of HIV infections v) Toenail or neutropenia following onychomycosis cytotoxic chemotherapy, vi) Vulvovaginal radiotherapy or bone marrow candidosis transplant

200mg, 50mg - Injection 200mg - Invasive aspergillosis - Candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds - Esophageal candidiasis - Serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of, or refractory to, other therapy

Drugs

Fluconazole

Dose & durations

i)50-100 mg daily for 7-14 day (Max. Oral solution: 14 days) except in severely i) 200 mg dly in 2 intakes, or in immunocompromised patients. 1 intake, for 1 wk. If no -Atrophic oral candidiasis response after 1 wk, associated with dentures : 50 mg continue treatment for another daily for 14 days. -Other candidal wk. infec tions of mucosa : 50 -100 mg ii) Fluconazole resistant or daily for 14-30 days. Child :3-6 mg/kg oesophageal candidiasis- 100 on first day then 3 mg/kg daily 200 mg bd for 2 (every 72 hrs in Neonate up to 2 wks. If no response after 2 wks wks old, every 48 hrs in neonate 2-4 continue treatment for another wks old ) 2 wks. ii)50 mg daily for 2-4 wks, max. 6 wks. The 400 mg daily dose should iii)400 mg initially then 200-400 mg not be used for >14 days. daily for 6-8 wks. Child: 6-12 mg/kg daily Capsule: (every 72 hrs in Neonate up to 2 wks old, every 48 hrs in neonate 2-4 i) 200 mg once dly for 7 days. ii) 100 mg daily for 15 days wks old ) iii) 200 mg bd for 7 days iv)100 - 200 mg daily. v) 50-400 mg daily. Child: 3-12 mg/kg iv) 200 mg bd for 1 wk/mth daily (every 72 hrs in Neonate up to 2 v) 200 mg bd for 1 wk/mth for 3 wks old, every 48 hrs in neonate mths 2-4 wks old). vi) 200 mg morning and evening for 1 day or 200 mg once daily for 3 days.

Triazoles

Itraconazole

Voriconazole Children > 12 y/o & adults;

-Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses -Maintenance: 4 mg/kg IV q12h infused over 2 h; switch to 200 mg PO q12h when able to tolerate; may increase to 300 mg PO q12h if inadequate response - If <40 kg: Average maintenance dose is 100 mg PO q12h (may increase to 150 mg PO q12h) Renal impairment: Crcl<50ml/min-after IV loading dose, oral voriconazole should be administered Hemodialysis: no oral dosage adjustment needed, IV not recommended *accumulation of IV vehicle

(sulfobutylether-βcyclodextrin) (SBECD).

Glucan synthesis inhibitors (echinocandins)

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MOA:inhibit the formation of fungal cell wall.

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Drugs: caspofungin, micafungin, and anidulafungin.

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Indications:have been approved for complicated forms of invasive candidiasis, candidemia, disease refractory to other systemic antifungals, and intolerance to amphotericin B.

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Spectrum activity: They are broad spectrum and fungicidal against most Candida species, except C parapsilosis and C guilliermondii.

Drugs

Caspofungin

Micafungin

Anidulafungin

Formulations & Injection (Acetate) 70mg, 50mg doses

Injection (Sodium) 50mg, 100mg

Injection 50mg

Indications

i) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation,

Echinocandins

Dose & durations

candidemia, invasive candidiasis, refractory invasive aspergillosis i)

ii) esophageal candidiasis.

i) esophageal candidiasis ii)candidemia, and other forms of candidal infections (eg, intra-abdominal abscesses, peritonitis).

iii) Also approved as empiric ii) esophageal therapy for presumed fungal candidiasis, candidemia, and invasive candidiasis infections in febrile neutropenic patients

i) I.V.: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg/day

i) 50 mg daily; median duration of therapy (from clinical trials) was 18 days

ii) I.V.: 50 mg/day ii) I.V.: 150 mg daily; iii) I.V.: Initial dose: 70 mg median duration of therapy (from clinical on day 1; subsequent trials) was 14 days dosing: 50 mg/day; may increase up to 70 mg/day if tolerated, but clinical response is inadequate.

i) I.V: 100 mg loading dose on day 1, followed by 50 mg daily for at least 14 days and for at least 7 days after symptom resolution ii) I.V: 200 mg loading dose on day 1, followed by 100 mg daily for at least 14 days after last positive culture

Antimetabolite Flucytosine MOA: deaminated to 5-fluorouracil in the fungal cell by an enzyme not present in mammalian cells, and inhibits RNA and protein synthesis Spectrum activity: against Candida and Cryptococcus species and generally used in combination with amphotericin B Formulations: injection 2.5g/250ml, tablet 500mg Indications: indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. 

Candida: Septicemia, endocarditis and urinary system infections; Limited trials in pulmonary infections justify the use of flucytosine.

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Cryptococcus: Meningitis and pulmonary infections; Studies in septicemias and urinary tract infections are limited, but good responses have been reported

Flucytosine Dosing;  Injection: Adult : 100 - 200 mg/kg daily in 4 divided doses by IV infusion over 20 - 40 mins not more than 7 days. For neonates, used primarily with Amphotericin. (Blue Book) 

Tablet: Adult : 50 - 100 mg/kg/day in 4 divided doses. 250 mg/kg/day have been recommended in severe infection (only for the treatment of fungal meningitis-blue book)

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Renal impairment: Crcl 20-40ml/min- 37.5mg/kg every 12 hours 10-20ml/min-37.5mg/kg every 24 hours <10ml/min -37.5mg/kg every 24-48 hours (lexi-comp)

Side effects:  Leucopenia, thrombocytopenia, headache, drowsiness, confusion, hallucinations, nausea, vomiting, diarrhoea, elevated liver function tests, and cutaneous reactions.

REFERENCES 

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E., E., Nwokedi & A., Omele-Ohonsi 2007. Current Clinical Review of Vulvovaginal Candidiasis. Journal of Medicine and Rehabilitation. 1(1): 28-32 Peter G. Pappas, Carol A. Kauffman, David Andes, Daniel K. Benjamin, Jr., Thierry F. Calandra, John E. Edwards, Jr., Scott G. Filler, John F. Fisher, Bart-Jan Kullberg, Luis Ostrosky-Zeichner, Annette C. Reboli, John H. Rex,Thomas J. Walsh & Jack D. Sobel. 2009. Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 48:503–35 Ministry of Health Drug Formulary 2008 Drug information Handbook 2008-2009, 17th edition http://en.wikipedia.org/wiki/Candidiasis Jose A Hidalgo & Jose A Vazquez. 2008. Candidiasis. http://emedicine.medscape.com A. Damian Dhar. 2008. Candidiasis. The Merck Manuals Online Medical Library. http://www.merck.com/mmpe

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C glabrata and C albicans account for approximately 70-80% of Candida species recovered from patients with candidemia or invasive candidiasis. C glabrata has recently become very important because of its increasing incidence worldwide, its association with fluconazole resistance in up to 20% of clinical specimens, and its overall decreased susceptibility to other azoles and polyenes. C krusei is important because of its intrinsic resistance to ketoconazole and fluconazole (Diflucan); it is also less susceptible to all other antifungals, including itraconazole (Sporanox) and amphotericin B. Another important Candida species is C lusitaniae; although not as common as other Candida species, C lusitaniae is of clinical significance because it may be intrinsically resistant to amphotericin B, although it remains susceptible to azoles and echinocandins. C parapsilosis is also an important species to consider in hospitalized patients. It is especially common in infections associated with vascular catheters prosthetic devices. Additionally, in vitro analyses have shown that echinocandins have a higher minimum inhibitory concentration (MIC) against C parapsilosis than other Candida species. The clinical relevance of this in vitro finding has yet to be determined.14 C tropicalis has frequently been considered an important cause of candidemia in patients with cancer (leukemia) and in those who have undergone bone marrow transplantation.

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Alternative options for candidemia include the following: 

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Caspofungin (Cancidas) can be initiated as a 70-mg loading dose, followed by 50 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Caspofungin is a broadspectrum semisynthetic echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans non-albicans Candida species such as C glabrata. glabrata. Anidulafungin can be initiated as a 200-mg loading dose, followed by 100 mg intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Anidulafungin is a broadspectrum echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans non-albicans Candida species such as C glabrata.24 glabrata.24 Micafungin can be administered at 100 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Micafungin is a broad-spectrum echinocandin. It has been shown to be an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans non-albicans Candida species such as C glabrata.25 glabrata.25 Voriconazole can be initiated at 6 mg/kg intravenously or orally twice per day, followed by 3 mg/kg orally twice per day or 200 mg orally twice per day. Based on the findings from a global multicenter clinical trial, voriconazole has also been approved for use in candidemia in patients who are not neutropenic.26 Amphotericin B deoxycholate can be administered at 0.7 mg/kg/d intravenously for a total dose of 1-2 g over a 4- to 6week period. Liposomal preparations of amphotericin B may also be options if (1) the infection is refractory to fluconazole or at least 500 mg of standard amphotericin B, (2) the patient has severe infusion-related toxicity, or (3) the patient develops renal insufficiency while on amphotericin B (generally with an increase in creatinine level >2.5 mg/dL).

Chronic mucocutaneous candidiasis: This condition is generally treated with oral azoles, such as fluconazole at a dose of 100-400 mg/d or itraconazole at a dose of 200-600 mg/d until the patient improves. The initial therapy for acute infection is always followed by maintenance therapy with the same azole for life.