Prophylaxis, Pre-emptive, or Empiric Antifungal Strategies? Dr Asok - - PowerPoint PPT Presentation

Prophylaxis, Pre-emptive, or Empiric Antifungal Strategies?

Dr Asok Kurup Dept of Infectious Diseases Singapore General Hospital

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

Trends: USA 2004- 2007

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

preventive administration of an antifungal agent to patients at risk of IFI without attributable signs and symptoms initiation of antifungal tx in patients at high risk of IFIs and established clinical s/s, but without microbiological documentation when the decision to tx is based on early diagnostic test

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

Clinical Infectious Diseases 2007; 44:373–

• 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

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

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 2005;41:1242–1250

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

Clinical Infectious Diseases 2009; 48:265–73 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.

• 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

Koh LP, Kurup A et al. Am J Hematol 2002

Fluconazole vs Ampho B as Prophylaxis in HSCT Recipients

Itracoconazole vs Ampho B in HSCT Recipients Infection

Itraconazole Ampho B p 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

Total

9 (10.1%) 9 (12.5%) 0.47 Invasive fungal infections diagnosed during the first 100 days of transplant.

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

• vertreatment.
• Pre-emptive treatment may reduce this

limit, but its role remains to be established.

Infection Control

Terima Kasih!