Pechlivanoglou, P., Le, H.H., Daenen, S., Snowden, J.A., & Postma, M.J. (2014). Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: A systematic review. The Journal of Antimicrobial Chemotherapy, 69, 1–11.

DOI Link

Purpose

STUDY PURPOSE: To estimate the relative effectiveness of all anti-fungal agents for a number of outcomes (mixed treatment comparison)
 
TYPE OF STUDY: Systematic review (studies included were randomized, controlled trials)

Search Strategy

DATABASES USED: MEDLINE, EMBASE, United States National Institutes of Health Clinical Trials Registry, and Google Scholar
 
KEYWORDS: (Invasive fungal infections, IFI, fungus, fungal, fungemia, mycosis, candidiasis, Candida, Aspergillus, invasive mold infections, IMI, aspergillosis) and (prophylaxis, prophylactic, prevention) and (antifungal, amphotericin, azoles, triazoles, fluconazole, itraconazole, isavuconazole, voriconazole, posaconazole, ravuconazole, echinocandin, micafungin, caspofungin, anidulafungin)
 
INCLUSION CRITERIA: All randomized, controlled trials on antifungal agents that were newly introduced or are currently being used as invasive fungal infection (IFI) prophylaxis among adult patients with hematological malignancies undergoing chemotherapy or hematopoietic stem cell transplantation (HSCT) were eligible.
 
EXCLUSION CRITERIA: Studies were limited to those written in English and published in international peer-reviewed journals. Because the focus was on IFI, studies that reported only noninvasive, single-site fungal infections were excluded. Studies that investigated antifungal agents that are not suggested for prophylactic use by current guidelines or agents of outdated formulations such as (non-liposomal) amphotericin B, ketoconazole, miconazole, and nystatin were also excluded. Studies that analyzed only graft-versus-host disease patients were excluded as this patient population is at a significantly higher risk of IFI.   

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 2,154 abstracts identified; 2,079 excluded; 75 relevant abstracts identified; 33 excluded as nonrandomized controlled trial data, not a patient population of interest, or not a prophylactic strategy; 42 potentially relevant full-text articles; 17 excluded as no IFIs were observed, not current agents for prophylactic strategy, agent combinations, or not written in English
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two investigators independently scanned all title and abstracts. The same investigators independently conducted the data extraction.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 25 studies included in mixed treatment comparison (MTC) analysis
  • TOTAL PATIENTS INCLUDED IN REVIEW = 7,062
  • KEY SAMPLE CHARACTERISTICS: Patients an average of 41.9 years of age; 53.5% of them were male and 54.4% were undergoing HSCT or bone marrow transplant at baseline; the most common underlying malignant disease was AML

Phase of Care and Clinical Applications

PHASE OF CARE: Transition phase after active treatment
 
APPLICATIONS: Elder care

Results

Through the meta-analysis, it was observed that fluconazole and liposomal amphotericin B were significantly better than placebo/no prophylaxis in reducing what were proven to be or were likely IFIs. Posaconazole prophylaxis was found to be more effective in comparison with fluconazole prophylaxis. All antifungal agents, with the exception of caspofungin and itraconazole, were observed to have a significant prophylactic effect compared to a placebo or to no prophylaxis. Posaconazole was found to be significantly more effective than fluconazole and itraconazole. For proven or probable IC, all agents with the exception of micafungin were more effective than placebo/no prophylaxis. Itraconazole solution and caspofungin had a significant advantage against IC compared to fluconazole. For IA infection, posaconazole improved prophylaxis when compared to placebo/no prophylaxis, fluconazole, and itraconazole solution. Liposomal amphotericin B and micafungin were more effective against IA infections compared to placebo/no prophylaxis and fluconazole. Voriconazole was significantly more effective than fluconazole. Posaconazole was the only agent achieving a significant reduction in the risk of all-cause mortality. For reducing IFI related mortality, all agents except micafungin and caspofungin were found to be significantly superior to a placebo. Posaconazole was found to be superior to fluconazole and itraconazole. The relative effectiveness of voriconazole was not determined.

Conclusions

IFI prophylaxis reduces IFI risk but may not affect all-cause mortality. Posaconazole is superior for prophylaxis against IFIs in neutropenic patients; its effectiveness against Aspergillus is more pronounced than against Candida. Fluconazole does not protect against Aspergillus species. Results are consistent with previous studies. The order of antifungal preference matches that recommended by the German Society for Hematology and Oncology. These results were strong, and no severe problems with inconsistency were observed. The original hypothesis that studies with a higher proportion of patients with acute myeloid leukemia (AML) would show a higher risk of acquiring an IFI compared with other types of leukemia was not supported.

Limitations

  • Studies were inconsistent in reports and reporting outcomes.
  • Inconsistencies in reporting underlying disease
  • Underlying severity of the studied population makes isolation of the treatment effect difficult.
  • Variations in dosing complicates the estimation of an aggregate prophylactic effect.
  • No distinction between patients with neutropenia or immunosuppression due to chemotherapy or due to HSCT and bone marrow transplant

Nursing Implications

Intensive head-to-head comparisons are needed using both chemotherapy populations and HSCT populations. Additionally, institutions should assess the effectiveness of prophylactic options as well as the cost effectiveness of these newer agents. 

Legacy ID

4840