1. Empirical versus Preemptive Antifungal Therapy for High-Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial Clinical Infectious Diseases 2009;48:1042-51 경희대학교 동서신의학병원 감염내과 R2 최재호 / 교수 손준성

2. Background Empirical antifungal tx – invasive fungal infection(IFI) among neutropenic, persistent or recurrent fever despite broad-spectrum antibacterial tx. criterion for initiation of antifungal Tx – fever : not specific to IFI, CT galactomannan assay for Aspergillus infection Liposomal amphotericin B, caspofungin- safety gain, cost increase In open study, preemptive Tx reduced antifungal drug use by 78%

3. Background randomized trial – compare survival empirical Tx vs preemptive Tx prim.end point : Survival at 2 wks after recovery from neutropenia

4. METHODS -design overview 1.Prospective, randomized, open-label non inferiority trial 2.April 2003 ~ February 2006 3.13 French teaching hospitals Prim. Objective : compare survival Sec. objective : compare the incidence of IFI, adverse events, antifungal drug consumption and costs

5. METHODS -paricipants 1. >=18yrs 2. Hematological malignancy. --Scheduled for CTx or autologous stem cell transplantation (expected to cause neutropenia) Exclusion criteria 1.Allogenic transplanation 2.Hx of or sx consistent IFI 3.Previous severe toxicity from IV polyenes 4.Karnofsky score < 30% 5.HIV seropositivity

6. METHODS -Randomization and interventions. Enrolled at initiation of CTx No lather than 48h into 1 st febrile episode Stratified by risk factors for IFI – induction vs consolidation or stem cell transplanation systemic antifungal tx was used At least 2 blood Cx Urine Cx Other microbiological tests Tx with a broad spectrum B-lactam +-AG 1 ST line GlycoPeptide Tx – shock, grade 4 mucositis, colonization with MRSA or PRSP, or catheter infection(met IDSA criteria) Persistent fever at 48h after starting a B-lactam with no GP  add on GPs No further changes allowed to, w/o microbiological guidance

7. METHODS- Randomization and interventions. Randomly antifungal strategy started on day 4 of persistent fever and antibacterial Tx on day of recur : recurrent fever between day 4 & day 14 Empirical Tx persistent or recurrent fever Preemptive Tx at any time after 4 days of fever and antibacterial Tx 1.Clinically and imaging –documented pneumonia 2.Acute sinusitis 3.Mucositis of grade >3 4.Septic shock 5.Skin lesion suggesting IFI 6.Unexplained CNS Sx 7.Periorbital inflammation 8.Splenic or hepatic abscess 9.Severe diarrhea 10.Aspergillus colonization or ELISA (+) for galactomannan antigenemia

9. METHODS- Randomization and interventions. 1 st IV antifungal Tx was same in both arms Amphotericin B deoxycholate (1mg/kg/day) : CrCl > 60 ml/min > 40-59 ml/min w/o nephrotoxic drug Liposomal amphotericin (3mg/kg/day) : CrCl 26-39 ml/min 40-59 ml/min with nephrotoxic drug CrCl < 25 ml/min = severe adverse event(SAE) In the absence of SAEs, antifungal Tx was continued until recovery from neutropenia

10. METHODS- OUTCOMES AND FOLLOW-UP Prim.efficacy outcome : proportion of patients alive at 14 days after recovery from neutropenia  persistent neturopenia, SAE : censored Sec.efficacy outcome : fever duration proportion of proven or probable IFI Also Surivival assessed at 4 months after inclusion

11. METHODS- OUTCOMES AND FOLLOW-UP Safety outcome : 1. change in CrCl (<60 mL/min) 2. proportion of SAE (CrCl <25 or septic shock) Economic outcome 1. proportion of receiving systemic antifungal Tx 2. duration & cost of antifungal Tx 3. length of hospital stay Possible infections were not considered Baseline IFI cases : before or within 24 h after the first dose Breakthrough IFI cases : performed at > 24h

12. METHODS -Sample size and statistical analysis -10% noninferiority margin Efficacy outcome : Cochran-Mantel-Haenszel x 2 test Differences in survival times : log –rank test Incidence of IFI : Gray’s test All analyses were performed using SAS

13. RESULTS -Patient population Total 293 patients 150 in the empirical Tx 143 in the preemptive Tx Median duration of neutropenia = 18 days only one in the empirical arm was still neutropenic on day 60 because rescue CTx was given after failure of 1 st -line CTx

15. RESULTS -Primary efficacy end point,overall survival, and cause of death Overall survival preemptive Tx (95.1%) 〈 empirical Tx(97.3%) : significant Cause of death In 293, 11 died IFI (3, all in preemptive) bacterial sepsis (4) nondocumented sepsis(2) cardiogenic shock(1) coma of unknown origin(1) Proportion of survivors at 4 months : not different

16. RESULTS -Proven and probalbe IFIs Incidence of IFI preemptive Tx (9.1%) 〉 empirical Tx(2.7%) 17 IFI cases 12 case : aspergillosis 5 case : candidiasis 32 pneumonia before antifungal Tx  proven or probable aspergillosis 3 of 6 in empirical 7 of 26 in preemptive

18. RESULTS -Safety CrCl decreased significantly The mean decrease +- SD : larger in empirical  not significant SAEs in similar proportions in 2 groups 101(34.5%) of the 293 had CrCl < 60mL/min

19. RESULTS -Use of antifungal agents Significantly lower in the preemptive Tx 55 (59.8%) of 92 in empirical 〉 1(1.8%) of 56 in preemptive (P<.001) ‘Total days’ and ‘mean cost’ of antifungal Tx lower for the preemptive Tx liposomal amphotericin B had been used for all treated the cost differece would have been 40%

21. RESULTS -Subgroup analysis Survival For induction Tx subgroup Preemptive Tx group 93.2% 〈 empirical Tx group 94.9% For consolidation Tx subgroup Preemptive Tx group 97.1% 〈 empirical Tx group 100% 17 IFI cases, 15 occurred in the induction Tx group 2 occurred in the consolidation Tx group (16.4% vs. 3.9% ; P<.01)

23. Cumulative incidence of antifungal Tx and IFI during netropenia

24. Conclusions Preemptive Tx increased the incidence of invasive fungal disease, w/o increasing mortality, and decreased the costs of antifungal drugs. Empirical Tx may provide better survival rates for patients receving induction ChemoTx.