Prophylaxis, Pre-emptive, or Empiric Antifungal Strategies? Dr Asok Kurup Dept of Infectious Diseases Singapore General Hospital
Trends: USA 2004-2007 Clinical Infectious Diseases 2009; 48:265 – 73
Trends: USA 2004- 2007 Distribution of infecting fungal pathogens and sp observed in 234 HSCT recipients with a total of 250 IFIs Clinical Infectious Diseases 2009; 48:265 – 73
Mould Infections in HSCT 1999-2003 • N=3228 (1249 allo, 1979 auto) HSCT patients admitted to 11 Italian HSCT centres • Incidence of proven/probable IA among alloHSCT: 8% • Attributable mortality rate of IA in alloSCT recipients: 77% Pagano et al. Clin Infect Dis 2007: 45:1161-70
The Continuum of IFI from Colonisation to Disease when the decision to tx is based on early diagnostic test initiation of antifungal tx in patients at high risk of IFIs and established clinical s/s, but without microbiological documentation preventive administration of an antifungal agent to patients at risk of IFI without attributable signs and symptoms
Rationale for Prophylaxis • Outcome of IFI has been suboptimal and a/w high fatality rates – Early diagnosis is difficult to make – Best available rx: 52% CR/PR (IA) 65% (IC) – Host defences important for resolution of infection
Primary AF Prophylaxis in Haem Malignancies/HCST Patients
Updated Guidelines for Primary AF Prophylaxis Cornely et al. Hematologica 2009:94;113-22
Considerations for Systemic Antifungal Prophylaxis • Risks: • Emergence of multi-azole resistance • Effect on patterns of breakthrough infections • Adverse effects • Potentially deleterious side effects of drug interactions
Empirical Therapy • Difficult to diagnosis fungal infections in neutropenic patients • Delays in instituting target therapy associated with increased mortality concept of empirical antifungal therapy emerged
Vancomycin in Neutropenic Patients with Fever Persisting After Pip-tazo monotx (48-60 hrs) • Randomized DBPC Study • P/T + Vanco (n=86) vs P/T + placebo (n=79) • Duration of neutropenia < 500 ANC/ul:14 days Clin Infect Dis 2003:37: 382-9
Empiric Antifungal Rx in High Risk Patients with Persistent Fever • AmB>effective than antibiotics (Pizzo 1982, EORTC 1989) • Liposomal AmB Vs AmB: less toxic and less breakthrough IFI (Prentice 1997, Walsh 1989) • Voriconazole Vs L-AmB: less toxic and less breakthrough IFI (Walsh 2002) • Caspofungin Vs L-AmB: less toxic and at least as efficacious (Walsh 2004)
Pre-emptive Therapy • Rx of a suspected or presumed FI in advance of confirmation – High morbidity/mortality a/w established FI – High costs a/w IFIs – Difficulty and uncertainty of diagnosis – Rapid progression of disease – Early rx a/w improved outcomes
• Compared response to treatment and survival after 12 weeks of treatment • 143 patients who presented with a halo sign and in 79 patients with other imaging findings. Clinical Infectious Diseases 2007; 44:373 –
The finding of a halo sign at baseline was strongly associated with improved responses to treatment and better survival Clinical Infectious Diseases 2007; 44:373 –
Algorithm for the clinical mx of patients with fever and lung infiltrates Eur J Cancer 2009:45:2462-72
Pre-emptive Tools • Galactomannan detection – variable sensitivity (affected by prior AF) – false positivity (piperacillin-tazobactam, etc) • (1,3)-b-d glucan in blood useful preliminary screening tool for IA – present in many pathogenic fungi • PCR
Clinical Infectious Diseases 2005;41:1242 – 1250 Feasibility study: a pre-emptive approach based on the routine incorporation of non-invasive diagnostic tests (i.e., GM assay or abnormalities in chest CT-scan findings) an ideal strategy that can reduce exposure to expensive and potentially toxic antifungal drugs
Clinical Infectious Diseases 2009; 48:1042 – 51 Length of neutropenia was a crucial discriminating factor empirical antifungal tx may result in higher survival rates than preemptive treatment among AMLs receiving induction chemotherapy Pre-emptive therapy safe and cost-effective only for neutropenic patients with an expected neutropenia of < 15 days (i.e., patients receiving consolidation chemotherapy or auto-HSCT)
Pre-emptive Vs Empiric Strategies Clin Infect Dis 2009; 48:1042 – 51 ASH 2004 #192 Clin Infect Dis 2005: 41:1242-50
IA in allogeneic (37.1%) and autologous (48.9%) HSCTs were observed 40 days after transplantation IA remains a significant problem soon after transplantation, despite routine prophylactic tx and the aggressive monitoring of these patients. Clinical Infectious Diseases 2009; 48:265 – 73
• Posaconazole appears to be the drug of choice for prophylaxis • whereas voriconazole remains the preferred treatment for proven or probable aspergillosis • Leaving caspofungin and liposomal amphotericin B as the options for empirical therapy unfortunate consequence of mixing efficacy studies that should explore the options and limitations of a drug with strategic trials that, ideally, should assess the appropriate moment to administer a drug with an established efficacy
What is the best approach? Variables that influence strategies • What is your local epidemiology? – Heterogeneity of risk – Rates of IFI in acute leukemia 2-29% – Rates in alloSCT 10-15% – Other groups 5% or less
Fluconazole vs Ampho B as Prophylaxis in HSCT Recipients Koh LP, Kurup A et al. Am J Hematol 2002
Itracoconazole vs Ampho B in HSCT Recipients Invasive fungal infections diagnosed during the first 100 days of transplant. Itraconazole Ampho B p Infection Proven 4 (4.5%) 2 (2.8%) 0.57 Probable 2 (2.2%) 1 (1.4%) 0.69 Possible 3 (3.4%) 6 (8.3%) 0.31 9 (10.1%) 9 (12.5%) 0.47 Total Koh et al. ASH 2003
What is the best approach? Variables that influence strategies • Prophylaxis not beneficial if prevalence <5% • Biomarkers not cost effective if prevalence <10% – Or in patients on mould effective prophylaxis
What is the best approach? • The antifungal prophylaxis is indicated in patients at high risk for IFI (AML induction, allo-HSCT) • The best prophylactic antifungal agent should confer protection against either molds or yeasts • At present, the best results have been provided by posaconazole prophylaxis
What is the best approach? • The availability of newer, less toxic drugs, laid the basis for empirical antifungal treatment. • Empirical treatment should be considered a valid option in particular subsets of patients (i.e., AML in first induction of remission), even with the risk of overtreatment. • Pre-emptive treatment may reduce this limit, but its role remains to be established.
Infection Control
Terima Kasih!
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