Antifungal therapies differences in agents

The basic Fungi are eukaryotes Eukaryote = an organism whose cells contain complex structures enclosed within membrane.

Most Common Fungal Pathogens Dermatophytes Sporothrix schenckii Candida Penicillium Histoplasma Cryptococcus Aspergillus Rhizopus

Fungal Nomenclature YEASTS Moist & creamy MOULDS Filamentous fungi Candida Cryptococcus Trichosporon Curvularia Bipolaris Cladosporium Aseptate Hyphae Zygomycetes Rhizopus Mucor Dematiaceous Septate Hyphae Hyaline Histoplasma P marneffei Sporothrix Dimorphics Opportunists Dermatophytes 2 forms in 2 different temp yeast in body temp & moulds in room temp Koneman, Roberts GD, Practical laboratory mycology 1985 Aspergillus Scedosporium Fusarium Microsporum Trichophyton Epidermophyton

The basic Fungal cells = human cells designing antifungal without harm to human cells difficult! Major different btw fungi & human cells = sterol type for plasma membrane Fungal cell wall = ergosterols Human cell wall = cholesterol

The (small) world of antifungals Membrane function: Amphotericin B Cellwall synthesis: Echinocandins Ergosterol synthesis: Azoles

Antıfungal Drugs - Mode Of Action 1. Membrane disrupting agents - Amphotericin B, nystatin 2. Ergosterol synthesis inhibitors - Azoles, allylamines, morpholine 3. Glucan synthesis inhibitors -Echinocandins 5. Nucleic acid inhibitor - Flucytosine 6. Chitin synthesis inhibitor - Nikkomycin 7. Protein synthesis inhibitors - Sordarins, azasordarins 8. Anti-mitotic (spindle disruption) - Griseofulvin

Antıfungal Drugs 1. POLYENES - Amphotericin B, nystatin 2. AZOLES Ketoconazole, Fluconazole, itraconazole, voriconazole, posaconazole, 3. ECHINOCANDINS - Caspofungin, anidulafungin, micafungin 4. FLUORINATED PYRIMIDINE - Flucytosine 5. MORPHOLINE - Amorolfine 6. PEPTIDE-NUCLEOSIDE - Nikkomycin Z 7. TETRAHYDROFURAN DERIVATIVES - Sordarins, azasordarins 8. OTHER - Griseofulvin

superficial Mycoses Dermatophytosis (Tinea = Ringworm) & Pityriasis versicolor Fungal infections in human Sub-cutaneous Mycoses Sporotrichosis Systemic Mycoses Candidiasis Penicilliosis Histoplasmosis Cryptococcosis Aspergillosis Zygomycosis

Tinea Capitis Tinea Corporis Tinea Pedis Pityriasis Vesicolor

Dermatophytosis-Transmission Close human contact Sharing clothes, combs, brushes, towels, bedsheets... (Indirect) Animal-to-human contact (Zoophilic)

Dermatophytosis-Treatment 1. Topical - Miconazole, clotrimazole, econazole, terbinafine 2. Oral Griseofulvin, Ketaconazole Itraconazole, Terbinafine

Sporotrichosis - Pathogenesis Chronic infection involving cutaneous, subcutaneous and lymphatic tissue Skin: Follows minor trauma Nodule ulcer necrosis Skin/subcutaneous tissue lymphatic channels lymph nodes Systemic dissemination: bones, joints, meninges Primary pulmonary: chronic alcoholics

Lymphocutaneous sporotrichosis showing more advanced, ulcerating lesions developing along the lymph system of the forearm

Sporotrichosis-Treatment Cutaneous : Potassium iodide, local heat therapy Disseminated : Amphotericin B, Itraconazole *Spontaneous healing is possible *Treatment should be continued for 2-4 weeks after all lesions have resolved, usually for a total of 3-6 months

Candida sp Normal flora in the GIT & GUT of humans > invade & cause disease when flora imbalances occur The host immune response = important determinant of Candida infection manifestation Manifestation vary from minimal fever fullblown sepsis syndrome Candida in a blood culture should always prompt a search for the source & it is not a contaminant

Albican vs non-albicans *All C. krusei are fluconazole-resistant *A variable proportion of C. glabrata are fluconazole-resistant C. albicans *C. krusei C. tropicalis Most commonly isolated Candida sp *C. glabrata C. parapsilosis

C. albicans (green colonies), C. tropicalis (bluish-purple colonies), C. krusei (filamentous, large pink colonies) C. glabrata (pink yeast colonies)

C. krusei 1. Intrinsically resistant to fluconazole 2. Resistance cannot be overcome with use of higher drug doses 3. Decreased susceptibility to ampho B requires higher doses (1 mg/kg/day)

C. glabrata 1. Many isolates are resistant to the azoles & cross-resistance among the azoles is common 2. MICs for voriconazole are highest with C. glabrata. 3. Resistance may be overcome by higher doses of fluconazole 4. Isolates that are resistant to fluconazole are generally resistant to voriconazole, as well 5. The echinocandins have generally retained excellent activity 6. Higher doses of ampho B are recommended (1 mg/kg/day)

C. parapsilosis 1. Highly susceptible to most antifungal agents 2. MIC for all the echinocandins are higher than for other Candida species 3. The clinical implications of these in vitro data are unclear

C. parapsilosis Five trials of caspofungin use in patients with invasive candidiasis, the overall (clinical and microbiologic) success rate among patients with C. parapsilosis (74% ) was similar to patients with invasive candidiasis caused by other Candida species

Weird Candida s C. lusitaniae often resistant to or quickly becomes resistant to amp B; however, it is usually susceptible to the azoles and echinocandins C. guilliermondii more often in hematologic malignancies. Some isolates have reduced susceptibility to fluconazole and many have reduced susceptibility to echinocandins However, C. guilliermondii is usually susceptible to amp B.

Candidemia is a broad topic Candidemia Organ involvement Some trial data Mostly anecdotal Catheterrelated candidemia Acute disseminated candidiasis Chronic disseminated candidiasis Deep organ candidiasis

Risk Factors For Candidemia Immunosupressed pt hematologic malignancies solid organ or stem cell transplants recipients Pt on chemotherapeutic agents, especially if associated with extensive GIT mucosal damage In ICU CVC TPN Broad-spectrum antibiotics High APACHE scores Acute renal failure, particularly if requiring HD Abdominal surgery GIT perforations and anastomotic leaks

Through the GIT mucosal barrier Pathogenesis of Candidemia Via intravascular catheter From a localized focus of infection *Colonization with Candida sp is an independent predictor of candidemia

Oral Thrush Tiny pustular lesions Endogenous Candida endophthalmitis Splenic microabscesses

Why Echinocandins over Azoles as Primary Therapy?

ECHINOCANDIN EFFECT 1. Excellent broad spectrum antifungal activity Cidal for majority of Candida spp.) 2. Safe & Easy to use (low AEs) 3. Low drug-drug interactions

Candidemia in immunocompetent patients The echinocandins appear to be as effective as and better tolerated than amphotericin B Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347:2020.

Candidemia in immunocompetent patients 1. The echinocandins appear to be as effective as and better tolerated than amphotericin B 2. Several randomized trials have shown that fluconazole & voriconazole is as effective as amphotericin B 3. Nephrotoxicity was significantly less with fluconazole

Combination therapy 1. Has not been established & not generally given 2. A controlled trial randomly assigned 219 nonneutropenic patients with candidemia to fluconazole (800 mg/day) alone for two weeks or fluconazole (800 mg/day) plus amp B (0.7 mg/kg per day) for the first four to seven days followed by fluconazole alone to finish the two week course more rapid clearing of fungemia with initial combination therapy, but success rates were similar in the two groups

Persistent Fungemia Median time to negative BC after start drug 2.6 d with catheter exchange, 5.6 d without Fungemia that persists longer: Dirty line, endocarditis, septic phlebitis Dirty lines: breakthru infections of susceptible bugs! Persistent neutropenia

To remove lines or not? A) This ID pandai pandai ask to remove lines, not easy to put new one, very hard to find lines ok! Ask him to insert a new one then only he knows. B)What s the big deal anyway? Just leave the lines alone. He is on antifungal therapy anyway! C) Insert a new one at same site - can or not? D) I put Daktarin cream at insertion site, sure ok one!

Higher mortality if catheters remain The removal of all compromised vascular lines is independently correlated with decreased early and late mortality

No benefit if catheters removed Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis. 2010;51(3):295.

No benefit if catheters removed Some authorities have suggested that catheter removal may not be necessary in neutropenic patients with candidemia in whom the source is often the gastrointestinal tract rather than the central venous catheter Should vascular catheters be removed from all patients with candidemia? An evidence-based review. Clin Infect Dis 2002; 34:591. Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis 2010; 51:295.

% Candidemic Catheters & Candidemia Non-neutropenic #1 source! 150 100 50 All new by day 0 No change by d0 Cancer patients Tunneled lines are less often sources The gut is probably a frequent source in neutropenic patients with mucositis 0-10 0 10 20 Day of Last +BC Start Rx

Catheter removal Despite the controversy, the current consensus, including IDSA guidelines, remains that in most patients with candidemia, intravascular catheters should be removed, realizing that in some patients this may not be feasible

Now you want me to remove the line or not???#*###*x!@$%

Suggested indications for removal of tunnelled catheters Severe hypotension, shock, absence of clinical improvement after 72 h of therapy, endocarditis, septic thrombophlebitis or cellulitis

Ophthalmology Referral: Why? A)If eye involved, that need intravitreous treatment B)She is already on antifungal treatment. No Need!It wont change management!!! C) Refer cause maybe change type of antifungal D) Cause I don t like the ophthalmology MO s attitude give him some work!! E) Refer cause maybe prolong duration of treatment

Ophthalmology Referral? The frequency of endophthalmitis is relatively low (3 5% of all candidemic patients)

The reason is It requires prolonged antifungal therapy. Failure to perform this examination can result in disseminated disease and subsequent relapse. Retinal lesions as clues to disseminated bacterial and candidal infections: frequency, natural history, and etiology. Medicine (Baltimore) 2003; 82: 187 202.

When should I suspect Candida Endophthalmitis? The onset of symptoms may occur subacutely, days to several weeks after fungemia.

Candida Endophthalmitis The eye infection is often clinically silent at first Initially, may be associated with minimal eye pain, and vision decrease may be subtle until the infection is advanced Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1997; 28:185.

Multiple chorioretinal lesions

Candida Endophthalmitis Endophthalmitis: 0% to 6% ; Chorioretinitis: 2% to 26%, Characteristic findings: "cotton ball" or "string of pearls" opacities High risk for blindness Perform at a time when the candidemia appears to be controlled Neutropnia patients risk highest when neutropenia improve

Candida Endophthalmitis Favorable outcome if treatment is administered before the onset of retinal complications Recommended treatment vitrectomy, intravitreal and systemic antifungal therapy. Recommended systemic therapy: AmB-d + flucytosine for advanced lesions/macula fluconazole can be used for less severe infections Recommended duration of tx: 4 to 6 weeks.

Candida Endophthalmitis Echinocandins and Amp B have limited vitreal penetration Best drug : Fluconazole,Voriconazole,Flucytosine in terms of penetration

*All C. krusei are fluconazole-resistant *A variable proportion of C. glabrata are fluconazole-resistant

Dose and duration of therapy - not too much, not too little Data from trials on duration Generally for 14 days after last culture negative Relapse/complication rate ~1% Doses Fluco: at least 6 mg/kg. 12 mg/kg being studied and may be better for C. glabrata Ampho: at least 0.5 mg/kg. More for glabrata? Lipid ampho: ~3 mg/kg seems comparable to 0.6-1 mg/kg for Candida Walsh et al. AAC 41:1944, 1997; Linden et al. Pharmacotherapy 19:1261, 1999

Candidiemia treatment (IDSA) 1. All intravenous catheters should be removed and replaced 2. Daily or EOD cultures after starting treatment 3. Duration of therapy Minimum 2 weeks after blood c&s becomes negative

Oral step-down therapy Susceptible to fluconazole who are clinically stable can be switched from an echinocandin to fluconazole Voriconazole is recommended as oral stepdown therapy only for patients with C. krusei or voriconazole-susceptible C. glabrata.

When to consider empirical antifungal? Not debated in cancer, fever, & neutropenia. BUT, what about ICU, fever, and leukocytosis?

Empirical antifungal.. In the febrile non-neutropenic patient? Early treatment is theoretically attractive IDSA Guidelines Appropriate use has not been defined My approach & suggestions: Antibiotics, lines, no other source, and Colonized somewhere with Candida - I don t distinguish sites: anywhere works for me More sites/fungus = more risk (Pittet, Ann Surg 220:751, 1994)

Candidemia empiric choice Prior Azole prophylaxis Prior colonisation with glabrata/krusei Hemodynamically unstable Amphotericin B Caspofungin For others: Fluconazole 800mg loading dose followed by 400mg od

Candiduria So, tell me, just exactly why did you order this urine culture?

Thinking About Candiduria.. In the symptomatic or febrile patient Treat symptomatic UTI (of course!) View as a risk factor for dissemination in the febrile and critically-ill patient In the asymptomatic patient Approach as you would for bacteruria Correct anatomic factors remove CBD Treatment is probably irrelevant This is idea is now supported by data...

A very instructive study! Sobel et al., CID 30:19-24, 2000 Asymptomatic candiduria (no fever, no sx) Fluco (200/d, N = 159) vs. placebo (N = 157) x 14d Fluco cleared urine in 50%, placebo in 29% Continuous cath reduced efficacy: 63% vs. 39% 50% C. albicans, mix of others. C. tropicalis was most difficult to clear. Funguria two weeks later: Same cure rate in both groups! (60% with cath, 70% without cath)