Fungal Infections

Dr P. JaninRNSH

Introduction

• Complex names, description, and classification

• Difficult diagnosis

• Difficult treatment strategy

Importance

• More than 100 000 species• Small subset can cause human disease

• Increasing incidence• Disease of modern Medicine• Aspergillosis:

10 000 hospitalization /year (USA)20% increase compared with previous 2

decades.

• Mortality ~100% if left untreated.

• Substantial financial burden• Annual cost for candidemia: $44-320 million (USA)• Hospitalization for Aspergillosis: >$60 000

Principles

• Subcutaneous, Cutaneous, Superficial mycosis

• Endemic mycoses• Histoplasma, Bastomyces, Coccidioides• Restricted to specific areas. Less relevant in Australia.• Wide variety of syndromes

• Opportunistic fungal infections• The most relevant category in ICU patients• Both yeasts and moulds• Associated with many difficulties

Principles

• Many species are free living in the environment (moulds), or are part of the normal flora (candida)• Continuous exposure• Normally well controlled in immunocompetent host

• Many fungi are saprohytes• Disease when tissue becomes “inert”: profound

immunosuppression• Direct inoculation

• Diagnostic problem• Colonization vs Invasive infection

Principles• Protagonists in ICU :

• Invasive Candidiasis• Represents over 10% of infections in ICU• Rates in the ICU >10-fold those on the wards• Probably underestimated

• Invasive Aspergillosis and other mould pathogens• Transplant patients, haematological conditions, immunosuppressed• Other patients (lung disease, liver failure). Uncommon.• Fusarium, Scedosporium, Zygomycetes

• Pneumocystis

• Cryptococcus

Candidiasis

• Emergence :

• Normal colonizer of GI tract. Most infections are endogenous.

• GI tract surgery

• Immunosuppression, including :• Broad spectrum antibiotics• Neutropenia and Decreased T-cell immunity• Invasive devices (CVC, Dialysis, TPN)

• Extensive candidiasis develops early when integrity of natural barriers is compromised• Risk assessment

• Culture from normally sterile sites, including blood cultures• Newer techniques not sufficiently validated

• High mortality rate (25-38% for candidemia, at least in part due to the infection itself)

• Many species• Different susceptibility profiles• No prediction model shown accurate

Candidiasis• Invasive Candidiasis :• May affect virtually every organ (micro-abscesses)• Vulnerable sites : endophtalmitis, meningitis, vertebral

osteomyelitis, hepatosplenic abscesses, endocarditis (prosthetic valves)

Candidiasis• Echinocandin (Caspofungin, Anidulafungin,

Micafungin) as initial choice

• Many patients have prior Azole exposure. Selection of resistant organism• C. glabrata• C. krusei (intrinsic)

• Clinical superiority compared to Azoles?• Theoretical fungicidal benefit• Anidulafungin vs Fluconazole

C. Reboli & Al. – NEJM 2007;356:2472-2482Non inferiority trial

D. R. Andes & Al. - Clinical Infectious Disease 2012;54(8):1110-1122

• Other considerations:

• Bypasses the problem of drug interactions

• Caspofungin: agent with extensive data in Neutropenic patients• Amphotericin B still preferred ?

• C. parapsilosis: higher MIC ; no outcome implication?

Candidiasis• Echinocandin (Caspofungin, Anidulafungin,

Micafungin) as initial choice

Candidiasis• Echinocandin (Caspofungin, Anidulafungin, Micafungin) as initial

choice

• Other considerations:

• Only Fluconazole can achieve sufficient concentrations in urine• Problem of fungal balls

• Eye/CNS diffusion: Flucytosine, Fluconazole, Amphotericine B

• Hepatotoxicity …

• Removal of CVC: associated with decreased mortality

• Mortality benefit of early treatment implementation• Days rather than hours

Candidiasis

• Combination therapy ?

• CNS infections

• Prosthesis (prosthetic joints, …)• Flucytosine better than Fluconazole on biofilms

• Endocarditis

Moulds

• Diagnostic problem• Infect areas in direct contact with the environment• Culture and examination of superficial specimen : contaminants• Biopsy

• Treatment problem• Resistant organism• Empirical treatment: risk of inadequacy• Conservative treatment: often insufficient

• Aspergillus• Zygomycetes (Mucor, Rhizopus)• Other (Scedosporium, Fusarium)

Aspergillus

• Haematology patients: 2 waves• Neutropenia• Post-acute phase: Steroids (GVHD)

• Epidemiology• Important data to identify patients at risk• Derives the required pre-test probability• Very difficult

• By far the most common opportunistic mould• Invasive pulmonary Aspergillosis• Aspergilloma

Aspergillus

• Diagnostic issues• Halo sign only if neutropenic• Sputum production is minimal if neutropenic• Poor performance of testing

• Limitations of empirical approach• Selection of rare pathogens (underlying condition, antifungal

prophylaxis)• No satisfying broad empirical coverage• Interfere with future diagnostic attempts

• Strategy• Empirical approach• Diagnostic approach• No very satisfying guideline

Pre-disease Tests

• ß-D-Glucan• Attempt to solve issue of slow growth of Candida from BC• False positive common. Moderate performance (PPV ~55%).• May exclude Pneumocystis if negative?

• Galactomannan• Proposed as screening test for high risk patients• Interference with ß-Lactams (Tazocin), and fungal prophylaxis• Non reproducible results on Australian samples• Role when used on BAL samples ?

• Highly standardized technique (120mL, Centrifugation)• Cut-off? 1.0?

• Good negative predictive value

• Serologic tests• ß-D-Glucan: fungus (non Cryptococcus,

Zygomycetes)• Galactomannan: Aspergillus• PCR: not validated

Anti-fungals• Difficult use• Spectrum inadequate for empirical use• Which end-points? (fever not reliable, …)• Side effects• Drug interactions• Pharmacodynamics/Pharmacokinetics

• Diffusion problem• Dose adjustment

• 3 major classes• Triazoles

• Fluconazole, Itraconazole, Voriconazole, Posaconazole• Echinocandins

• Caspofungin, Anidulafungin, Micafungin• Amphotericin B• Flucytosine

Fluconazole• Linear pharmacokinetics. Predictable levels.• Loading dose

• Tubular reabsorption• Increased clearance in CVVH

• Non optimized dosing accounts for treatment failure ?

Other Triazoles• Itraconazole• Concominant use of PPI: major impingement on absorption• Cyclodextrine

• Increased absorption• Increased nausea/diarrhea• Accumulation in renal failure

• Voriconazole• Complex pharmacokinetics• No impact of PPI• Large individual variations (CYP2C19):

• Poor (Chinese) vs high metabolizers• Highly variable concentrations

• Very often under-dosed• 4 mg/Kg q12h, after loading dose• Saturable excretion: risk of overdosing!

• Interactions: Phenytoin, Rifampicin, Corticosteroids

Other Triazoles

• Posaconazole• IV formulation available in the future• Interference by PPI, mucositis, fatty meal• Limited benefit in acute setting

• 100h for steady state

Conclusion• An expanding problem of modern medicine• Vulnerable host• predisposing holes in the normal barrier• Holes in the prophylactic “immune system replacement therapy”

• True impact on outcome• more than just the effect of the underlying advanced disease

• Difficult diagnosis. Host is predisposed to a wide array of injuries.• Value of tissue / deep specimen collection

• Inconvenient empirical treatment• Difficult drugs. Difficult endpoints.• Role of TDM