Antifungal Prophylaxis in At-Risk Patients

The evaluated treatment was antifungal prophylaxis with azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or an amphotericin B formulation compared with placebo or no prophylaxis controls.

The search used MEDLINE and EMBASE (1966–2000); additional studies were identified from bibliographies/reference lists of articles, topical reviews, and information from the pharmaceutical industry and investigators in the field.

38 randomized, controlled trials

7,014 patients who received cytotoxic therapy for acute leukemia or hematopoietic stem cell transplantation (HSCT) sufficient to result in neutropenia (an absolute neutrophil count [ANC] of less than 1,000) lasting one week or more.

In severely neutropenic patients (ANC less than 1,000 for a week or more), antifungal prophylaxis reduced the use of:

• Parenteral antifungal therapy by 43% (prophylaxis success).
• Superficial fungal infection by 71%.
• Invasive fungal infection by 56%.
• Fungal infection-related mortality by 42%.

In subgroup analyses, superficial fungal infections were not reduced for:

• HSCT recipients overall.
• Patients receiving low-dose amphotericin B formulations.
• Patients in a single, small miconazole trial.

However, superficial fungal infections were reduced in HSCT recipients on azoles.

In subgroup analyses, fluconazole was more effective than itraconazole or low-dose amphotericin B formulations to prevent superficial fungal infections.

In subgroup analyses, a reduction in fungal infection-related mortality was not observed in:

• Pediatric trials.
• Non-HSCT trials.
• Trials comparing azoles with polyene controls.
• Trials comparing low-dose amphotericin B formulations with placebo.
• Trials with itraconzaole, ketoconazole, or miconazole.

There was a reduction in fungal infection-related mortality in trials using fluconazole for antifungal prophylaxis.
Antifungal prophylaxis did not affect:

• Overall mortality, except in subsets of HSCT recipients or patients in which the mean duration of neutropenia was longer than two weeks.
• The incidence of aspergillosis, perhaps because the overall incidence was low (1%) in both groups; therefore, a treatment effect could not be detected.

Primary antifungal prophylaxis with fluconazole, itraconazole, or an amphotericin B product were evaluated in neutropenic patients with hematologic malignancies.

Not described.

Thirty-eight randomized, controlled trials of primary antifungal prophylaxis and 13 historically controlled or uncontrolled trials of primary antifungal prophylaxis.

More than 9,000 neutropenic patients with hematologic malignancies.

Recommended antifungal prophylactic regimens for patients with hematologic malignancies and their level of evidence:

Conventional chemotherapy

• Fluconazole 50–400 mg every day by mouth (CI)
• Itraconazole oral suspension 5 mg/kg every day (BI)
• Amphotericin B desoxycholate 1.0 mg/kg every 48 hour by IV (CII)
• Amphotericin B desoxycholate 20 mg inhalation (CI)

Allogeneic transplantation

• Fluconazole 400 mg every day by mouth (AI)
• Fluconazole 50–200 mg every day by mouth (CI)
• Liposomal amphotericin B 1.0 mg/kg every day by IV (CI)

To research the evidence regarding the use of mold-active versus fluconazole prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients.

Databases searched were Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials.  The authors also searched ClinicalTrials.gov, study reference lists via handsearching, Web of Science, and abstracts from the American Society of Clinical Oncology annual meetings for the past two years.

Search keywords were fluconazole, aspergillus or mycoses, prevention or prophylaxis, neoplasm, stem cell transplantation, and neutropenia.

Sources were included if they

• Were randomized, controlled trials comparing mold-active to fluconazole prophylaxis.
• Included randomization between fluconazole and any mold-active agent.
• Included patients of any age undergoing chemotherapy or HSCT.

Sources were excluded if more than one systemic prophylactic antifungal agent was given in a single study arm; pre-emptive or empiric therapy or antifungal treatment was reported; and if they did not report primary or secondary outcomes of invasive fungal infection (IFI) proven or probable, IFI-related mortality, all cause mortality, and adverse events.

Nine hundred eighty-four references were retrieved. Risk of bias was evaluated using definitions derived from the Cochrane Handbook for Systematic Reviews of Interventions.

• The final number of studies included was 20, with 5,725 total patients. Sample sizes per study ranged from 24 to 882.
• All participants had hematologic malignancies or had received allogeneic or autologous HSCT.
• Age ranged from 6 months to 82 years.
• Fifty percent were multi-center studies.
• Children were included in four trials.

• The phase of care was active antitumor treatment.
• The application was for pediatrics.

Study regimens included amphotericin B formulations, micafungin, posaconazole, voriconazole, and itraconazole. 

The majority of studies did not provide adequate information on randomization and allocation concealment. Six of 20 studies completed intention-to-treat analysis. 

Mold-active prophylaxis compared to fluconazole significantly reduced the risk of IFI (relative risk [RR] = 0.71; 95% confidence interval [CI], [0.52, 0.98]; p = 0.03). Mold-active prophylaxis decreased the risk of aspergillus infection (RR = 0.53; 95% CI [0.37, 0.75]) and IFI-related mortality (RR = 0.67; 95% CI [0.47, 0.96]); however, it did not influence overall mortality. Use of mold-active agents was associated with more adverse events leading to discontinuation of antifungal prophylaxis (RR = 1.95; 95% CI [1.24, 3.07]; p = 0.004). Types of adverse events are not described.

Prophylaxis with mold-active agents compared with fluconazole prophylaxis significantly reduced the number of proven and probable IFI and aspergillus infections in these types of patients. However, these agents were also associated with increased adverse events that necessitated stopping antifungal prophylaxis. Findings also suggested that use of mold-active agents did not affect overall mortality, although use did affect IFI-related mortality. Fluconazole is generally less expensive than some mold-active agents, and amphotericin B is not available in an oral form. Further study of the relative benefits and harms with various approaches for antifungal prophylaxis in this group of patients is warranted, and additional study is needed to better understand the full role of antifungal prophylaxis in overall survival in these patients.

Many studies had design issues regarding the description of randomization and lack of blinding. The types of adverse events observed were not provided, and clinical severity leading to study discontinuation are not described. The prophylaxis endpoint of included studies varied—some were based on absolute neutrophil count (ANC), and some were simply time-limited. ANC endpoints varied across studies. It is unclear if all studies involved primary prophylaxis or included secondary prophylaxis.

Findings suggested that antifungal prophylaxis with agents, such as amphotericin B, micafungin, posaconazole, voriconazole, and itraconazole, appears to be more effective in the prevention of invasive fungal infection and aspergillus infection than routine prophylaxis with fluconazole; however, these agents were also associated with a much greater risk of adverse events. Selection of approach for antifungal prophylaxis necessitates weighing the risks and benefits of both approaches for individual patients. Findings suggest that this type of comparison for secondary prophylaxis is worth evaluating as well.

The purpose of the study was to evaluate itraconazole solution or capsules compared with control (no treatment, placebo, oral polyenes, or fluconazole).

Searches were conducted through Cochrane Central Register of Controlled Trials and MEDLINE (January 1966 to July 2003); abstracts from the annual meetings of the American Society of Hematology, Interscience Conference on Antimicrobial Agents and Chemotherapy, European Hematology Association, European Group for Blood and Marrow Transplantation, German and Austrian Society of Hematology and Oncology, and the British Society for Hematology (1994–2003). Reference lists of relevant studies were reviewed. The pharmaceutical manufacturer of itraconazole was contacted.

13 randomized, controlled trials.

3,597 patients (1,812 on itraconazole and 1,785 controls) with hematologic malignancies who were neutropenic (absolute neutrophil count less than 500) following chemotherapy or bone marrow transplantation.

• A statistically significant decrease was found in the incidence of invasive fungal infections in the itraconazole solution group (49% reduction), but not in the itraconazole capsule group.
• A statistically significant decrease existed in the incidence of invasive yeast infections in the itraconazole solution group (60% reduction), but not in the itraconazole capsule group.
• A statistically significant decrease was found in the incidence of proven invasive aspergillus infections in the itraconazole solution group (48% reduction), but not in the itraconazole capsule group
• A statistically significant decrease was noted regarding mortality in the itraconazole solution group (42% reduction), but not in the itraconazole capsule group.
• No significant difference existed between the groups regarding mortality from any cause during the study period.

Antifungal prophylaxis with an itraconazole solution for neutropenic patients with hematologic malignancies reduces invasive fungal infections, invasive yeast infections, invasive aspergillus infections, and mortality. Bioavailability and dosing are significant factors because benefits are only derived from the oral or IV cyclodextrin solution and not the capsules.

The capsules are not recommended and the dosing should be at least 400 mg per day of the oral cyclodextrin solution or 200 mg per day of the IV solution.

STUDY PURPOSE: To determine if nystatin prophylaxis or treatment for fungal infection decreases morbidity and mortality in immunocompromised patients

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 14
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,569
• KEY SAMPLE CHARACTERISTICS: Twelve of the 14 trials studied nystatin prophylaxis, and two studied nystatin treatment. Eleven trials included patients with acute leukemia, solid cancer, or bone marrow transplantation. One trial involved patients with liver transplantation, one trial involved patients who were critically ill from surgery and/or trauma, and one trial involved patients with AIDS.

PHASE OF CARE: Active antitumor treatment

Nystatin cannot be recommended for prophylaxis or the treatment of Candida infections in immunodepressed patients.

Nystatin is no more effective than placebo for the prevention or treatment of fungal infections in immunocompromised patients.

The purpose of this systematic review was to evaluate studies conducted with various antifungal agents to determine whether or not commonly used antifungals decrease mortality in patients with cancer.

The search strategy used databases such as the Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed, as well as the reference lists of articles attached to the publications identified. Also reviewed were the proceedings of the ICAAC (from 1990–2007), General Meeting of the ASM (from 1990–2007), and the European Congress of Clinical Microbiology and Infectious Diseases (1995–2007). The authors also contacted expert researchers in the field.

Key words included random,  control,  blind,  nystatin,  amphotericin,  fluconazole, itraconazol,  ketoconazole,  miconazol,  voriconazol,  bone-marrow, cancer, fungemia, hematologic, fumalignan, neoplasm, neutropenia,  granulocytopenia,  leukemia,  or lymphoma

Randomized trials of antifungal treatments that were experimental in nature for patients with cancer were included. Studies that applied to treatment or prevention of oral candidiasis were excluded, as well as any non-randomized trials or randomized trials with noncancer patients.
 

Forty-four articles were retrieved. The authors reviewed the identified studies for mortality, mortality associated with a fungal infection, invasive fungal infection, colonization, use of additional antifungal therapy, and harm to patients.

The final article sample size was 32, with total subjects numbering 4,287.

Active treatment

Amphotecerin B was the only antifungal studied that showed reduced mortality significantly and consistently, used either prophylactically or empirically. Ketaconozole, fluconazole, and amhotercerin B were shown to be significant in overall effect for prophylactic administration. Itraconozole, fluconazole, and amphotecerin B all showed effectiveness in treating invasive fungal infection.

Amphotecerin B is highly effective in reducing mortality associated with fungal infection in patients with cancer. More studies should be done with large sample sizes to effectively compare amphotecerin B to other anti-fungals.

The article evaluated lipid-soluble formulations of amphotericin B compared with conventional amphotericin B.

The Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed (through November 2007) databases were searched, as were the proceedings from the Interscience Conference on Antimicrobial Agents and Chemotherapy (1990–2007), the General Meeting of the American Society of Microbiology (1990–2007), and European Congress of Clinical Microbiology and Infectious Diseases (1995–2007). In addition, the reference lists of articles were searched, and researchers in the field were contacted.

12 randomized trials

• 1,895 neutropenic patients with cancer.
• Most patients had acute leukemia or were undergoing hematopoietic stem cell transplantation (HSCT).

• Lipid-based amphotericin B was not more effective than conventional amphotericin B for mortality.
• Lipid-based amphotericin B decreased invasive fungal infections by 35%.
• Lipid-based amphotericin B decreased nephrotoxicity by 55%.
• Lipid-based amphotericin B decreased dropouts from the study by 22%.

There was no significant difference in mortality for the drug used in most patients, AmBisome (three trials, 1,149 patients), whereas it tended to be more effective than conventional amphotericin B for invasive fungal infection (RR = 0.63, 0.39 to 1.01, p = 0.053).

Despite a significant reduction in invasive fungal infections and nephrotoxicity seen with lipid-based amphotericin B formulations, the authors concluded that an advantage was unclear regarding the use of lipid-based amphotericin B formulations if conventional amphotericin B is administered under optimal circumstances.

In the trials reviewed, amphotericin B rarely was administered under optimal circumstances (routine premedication for the prevention of infusion-related toxicity and supplementation with fluid, potassium, and magnesium for the prevention of nephrotoxicity).

To examine fluconazole (oral or intravenous [IV]) compared with amphotericin B (oral or IV) in patients with cancer who were neutropenic.

Databases searched were The Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed (through November 2007).  The authors also searched the proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) (1990–2007), the General Meeting of the American Society for Microbiology (ASM) (1990–2007), and the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (1995–2007). In addition, the authors contacted researchers in the field and industry and reviewed reference lists to identify unpublished trials.

• Seventeen randomized, controlled trials were reviewed.
• The total number of participants was 3,798.
• The sample consisted of patients with cancer who were neutropenic.
• Most patients had acute leukemia or were undergoing hematopoietic stem cell transplantation.

No significant difference was found between fluconazole and amphotericin B with regard to

• Mortality
• Invasive fungal infection
• Colonization
• Use of rescue therapy
• Dropouts.

The major adverse effects were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment, and gastrointestinal adverse effects with amphotericin B.

Considerable heterogeneity existed in the studies, and amphotericin B was not favored in several of the largest trials through the trial design or data analysis.  Of particular concern was that seven trials compared oral fluconazole to oral amphotericin B. Oral amphotericin B is poorly absorbed and is not recommended for prophylaxis or the treatment of systemic fungal infections. No trial report offered a rationale for this design, and attempts by the authors to obtain additional information from the investigators were unsuccessful.

In the 10 trials that compared oral or IV fluconazole to IV amphotericin B, the design disfavored the amphotericin B arm. Clinicians familiar with the optimal administration of amphotericin B routinely prescribe premedication to prevent infusion-related toxicity and fluids (potassium and magnesium) to prevent nephrotoxicity. Supplemental fluids (i.e., potassium and magnesium) were not prescribed in any trial reviewed, and premedication was prescribed in only two trials. 

The majority of these trials were sponsored by the company that manufactured fluconazole, and the authors were unable to obtain additional information or access to certain trial data held by the company.

The authors concluded that there was not sufficient data from the available trials to judge the effectiveness of fluconazole compared with amphotericin B. Amphotericin B should be preferred because it is the only antifungal for which evidence suggests an effect on mortality.

• FINAL NUMBER STUDIES INCLUDED = 3
• TOTAL PATIENTS INCLUDED IN REVIEW = 391
• SAMPLE RANGE ACROSS STUDIES: 849–1,840 patients
• KEY SAMPLE CHARACTERISTICS: Two studies included immunosuppressed men and women with cancer and the third investigated immunosuppressed men and women with cancer who had undergone allogeneic hematopoietic cell transplantations (HCTs).

PHASE OF CARE: Active antitumor treatment

A trial comparing voriconazole to liposomal amphotericin B as an empirical treatment for suspected fungal infection in neutropenic patients with cancer in which 6.8% of the patients died showed a significant benefit of using liposomal amphotericin B over voriconazole. No benefits were found between antifungal agents in the other two trials evaluated.

For the empirical treatment of patients with cancer who are immunosuppressed, liposomal amphotericin B is significantly more effective than voriconazole. Voriconazole and fluconazole did not have different outcomes in patients undergoing allogeneic HCT who were given either of these antifungal agents prophylactically. Treatment of aspergillosis comparing voriconazole with amphotericin B was not investigated.

Overall, there were so few trials comparing these antifungal agents (though large sample sizes) that except for one finding, results were inconclusive. These trials also could not be pooled for analysis due to their heterogeneity in study design.

For treatment of suspected fungal infections (neutropenic fever without overt fungal infection), liposomal amphotericin B is recommended. Careful evaluation for side effects of visual disturbances, dyspnea, and hypokalemia is critical.

To evaluate the efficacy of fluconazole prophylaxis during chemotherapy-induced neutropenia.

Databases searched were MEDLINE, CancerLit, and the Pfizer company database through April 1999 (no start date was provided). The search was not restricted to the English language or published trials.

Sixteen trials were evaluated.

Studies were included if they

• Were prospective and randomized.
• Compared oral fluconazole with placebo, no treatment, or oral polyenes (nystatin, oral amphotericin B).
• Used a neutropenia definition of less than 1000/mcl and did not use intravenous (IV) antifungals.
• Reported the incidence of fungal infection.

Data from the meta-analyses reported the combined population, bone marrow transplant (BMT) recipients only, and non-BMT recipients only.

A total of 3,734 patients were evaluated. Some studies exclusively examined BMT recipients, others studied non-BMT recipients, and others evaluated a combined population.

Prophylactic fluconazole was not effective in

• Reducing fungal-related death in non-BMT recipients (although it was effective in BMT recipients).
• Reducing proven systemic fungal infections in non-BMT recipients (although it was effective in BMT recipients).

Prophylactic fluconazole was effective in

• Reducing superficial fungal infections in non-BMT and BMT recipients.
• Reducing the use of amphotericin B for persistent neutropenic fever in the BMT population (this could not be concluded for the non-BMT group).

Prophylactic fluconazole did not increase rates of proven systemic infection with resistant strains in the non-BMT or BMT populations.

Colonization of fluconazole-resistant fungi increased with prophylactic treatment in BMT recipients; however, information about non-BMT recipients is inconclusive because of lack of power and paucity of data.

• 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: Transition phase after active treatment
 
APPLICATIONS: Elder care

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.

• 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

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. 

STUDY PURPOSE: To compare second-generation azoles with first-generation azoles in patients with hematologic malignancies by comparing rates of proven or probable invasive fungal infections (IFIs), invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from studies related to development of adverse effects

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: MEDLINE, EMBASE, and Cochrane Registry of Controlled Trials databases; conference proceedings from the American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, and European Group for Blood and Marrow Transplantation from 2002–2012

KEYWORDS: voriconazole or posaconazole and prophylaxis or prevention

INCLUSION CRITERIA: Studies written in English; prospective and randomized controlled trials comparing second-generation and first-generation azole antifungal agents with regards to antifungal prophylaxis in patients with hematologic malignancies who were neutropenic following cytotoxic chemotherapy or hematopoietic stem cell transplantation, or receiving immunosuppressive therapy

EXCLUSION CRITERIA: IV administration of azole antifungal agents, unless the IFI was proven or suspected; prospective studies in which the control arm used a historical cohort; ongoing trials

TOTAL REFERENCES RETRIEVED = 168 reviewed (Of these, 18 were identified as potentially relevant; of these, 14 were screened out.)

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two reviewers independently screened the literature for eligibility for inclusion, and two other reviewers independently extracted the data from included studies and assessed for quality parameters.

• FINAL NUMBER STUDIES INCLUDED = 4
• SAMPLE RANGE ACROSS STUDIES = 465–602
• TOTAL PATIENTS INCLUDED IN REVIEW: 2,267 patients (Although elsewhere in the article, the authors note 2,165 patients.)
• KEY SAMPLE CHARACTERISTICS: Multi-center, two-arm, parallel, prospective, randomized controlled trials. Three of the four studies included patients who received allogeneic stem cell transplantation. The fourth study included patients experiencing prolonged neutropenia following induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.

PHASE OF CARE: Transition phase after active treatment

Prophylaxis using second-generation azole antifungal agents significantly reduced IFIs as compared to first-generation agents (OR = 0.47, 95% CI 0.32–0.69, I² = 0%, p = 0.0001; four trials, 2,267 patients) and also significantly reduced invasive aspergillosis (OR = 0.28, 95% CI 0.17–0.48, I² = 28%, p < 0.00001; four trials, 2,267 patients). Additionally, posaconazole significantly reduced the incidence of fungal infection (OR = 0.40, 95% CI 0.19–0.87, I² = 52%, p = 0.02; two trials, 1,202 patients), but voriconazole did not (OR = 0.56, 95% CI 0.30–1.04, I² = 0%, p = 0.06; two trials, 1,065 patients). Second-generation azoles significantly reduced IFIs (OR = 0.47, 95% CI 0.31–0.71, I² = 0%, p = 0.0003; three trials, 1,744 patients) and invasive aspergillosis (OR = 0.31, 95% CI 0.13–0.52, I² = 44%, p < 0.0001; three trials, 1,744 patients) when compared to fluconazole. When compared to itraconazole, second-generation azoles resulted in significantly fewer IFIs (OR = 0.35, 95% CI 0.14–0.87, I² = 35%, p = 0.02; two trials, 827 patients) and cases of invasive aspergillosis (OR = 0.11, 95% CI 0.03–0.40, I² = 0%, p = 0.0008; two trials, 827 patients).

Significantly fewer patients receiving prophylaxis with second-generation azoles required empirical antifungal therapy (OR = 0.62, 95% CI 0.50–0.77, I² = 0%, p < 0.0001; three trials, 1,667 patients). Despite these findings, no difference was noted in overall mortality in patients receiving antifungal prophylaxis with second-generation or first-generation azoles (OR = 0.81, 95% CI 0.64–1.01, I² = 0%, p = 0.06; three trials, 1,802 patients).

Patients with hematologic malignancies are at increased risk of IFIs, with invasive aspergillosis being particularly worrisome. Second-generation azoles appear to be superior to first-generation azoles in regards to prevention of IFIs, including invasive aspergillosis, without increased risk of adverse events. Second-generation agents also have better bioavailability and fewer drug-drug interactions than first-generation agents.

• Small number of studies (four)
• Variation between studies regarding duration of administration of antifungal agents
• No subgroup analysis of specific study populations
• The risk of heterogeneity is moderate to low, as significant heterogeneity appeared in only a portion of subgroup analyses.

This meta-analysis suggests that antifungal prophylaxis with second-generation azoles is more effective than first-generation azoles in prevention of IFIs, and without increase in adverse events. Interestingly, no difference was observed in overall mortality.

To determine the effect of antifungal prophylaxis on all-cause mortality, invasive fungal infections (IFIs), and adverse events in patients with cancer treated with chemotherapy or hematopoietic stem cell transplantation (HSCT).

Databases searched were PubMed (January 1966–January 2007) and the Cochrane Library (CENTRAL) (through 2007).  Conference proceedings in oncology, hematology, and infectious diseases were also searched. The references of all included trials and reviews were searched for additional studies.

Search keywords were neutropenia, chemotherapy and similar, specific antifungals or antifungal and similar, and prophylaxis and similar.

The authors included studies that were randomized, controlled trials comparing a systemic antifungal drug with placebo, no intervention, or other antifungal agents for prophylaxis of fungal infections in afebrile patients with cancer after chemotherapy or hematopoietic cell transplantation (HCT).

Studies were excluded if they lacked a randomized, controlled design or used empiric or pre-emptive antifungal therapy.

• One hundred twenty-four studies were initially reviewed.
• Sixty-four studies were included in the report.
• Study quality was evaluated using the Oxford scale.

• The total sample size comprised 64 randomized, controlled trials. 
• The sample size across all included studies ranged from 24 to 889.
• Thirty-five trials included a majority (>70%) of patients with hematologic malignancies (mostly acute leukemia but also lymphoma, chronic myelocytic leukemia in blast crisis, high-risk myelodysplastic syndromes, and multiple myeloma).
• Fifteen studies included patients who underwent bone marrow transplantation.
• Fourteen trials included a mixed population of patients with solid tumors or hematologic malignancies and those who had undergone HSCT.
• Children were included in five trials.

Systemic Antifungals Versus Placebo, No Treatment, or Nonsystemic Antifungals All-Cause Mortality

• In 31 trials that reported all-cause mortality, antifungal prophylaxis decreased the risk of mortality significantly at the end of follow-up (relative risk [RR] = 0.84; 95% confidence interval [CI] [0.74, 0.95]), with no significant heterogeneity (p = 0.46; I² = 0.7%).
• The number of patients needed to treat to prevent one death at end of follow-up was 43 (95% CI, [26, 138], with a control group mortality rate of 15%). 

Subgroup Analysis

• Antifungal prophylaxis resulted in a significant reduction in mortality in allogeneic HSCT (four trials; RR = 0.62; 95% CI [0.45, 0.85]) and autologous HSCT (one trial; RR = 0.27; 95% CI [0.08, 0.9526]).
• One trial, which included 52% autologous and 48% allogeneic HSCT recipients, showed no survival advantage with prophylaxis.
• There was a borderline statistically significant reduction in mortality at the end of follow-up among patients with acute leukemia, mostly undergoing induction therapy (24 trials; RR = 0.88; 95% CI [0.74, 1.06]).
• There was a nonsignificant reduction in mortality in other malignancies (12 trials; RR = 0.83; 95% CI [0.62, 1.11]).  

Specific Antifungals

• Fluconazole prophylaxis reduced early (day 30 posttreatment) mortality significantly (13 trials; RR = 0.78; 95% CI [0.64, 0.95]) and with borderline significance (15 trials; RR = 0.88; 95% CI [0.75, 1.02]) at the end of follow-up.
• Intravenous (IV) amphotericin B significantly reduced mortality at the end of follow-up (two trials; RR = 0.31; 95% CI [0.13, 0.72]).
• Trials in which itraconazole was administered as oral suspension demonstrated a significant reduction of documented IFIs (RR = 0.58; 95% CI [0.34, 0.98]) and of documented candida infections (RR = 0.35; 95% CI [0.14, 0.84]) in the itraconazole group. In this subset of trials, there was a trend toward more invasive aspergillus infections in the fluconazole arm (RR = 1.35; 95% CI [0.82, 2.21]).
• The RRs for the indirect comparison of fluconazole versus itraconazole for mortality was 1.0 (22 trials; 95% CI [0.67, 1.33]); the same comparison for IFIs was 0.68 (27 trials; 95% CI [0.18, 1.19]).

Fluconazole Versus IV Amphotericin B

• Three trials (two included patients undergoing HSCT and one included patients with acute leukemia) compared oral fluconazole versus low-dose IV amphotericin B (0.2 mg/kg once daily or 0.5 mg/kg three times a week), and no difference was noted in all-cause mortality, fungal-related mortality, any (documented, probable, and possible) IFIs, documented candida or aspergillus infections, and superficial fungal infections.
• Fluconazole resulted in a significant reduction of documented IFIs (RR = 0.49; 95% CI [0.28, 0.86]).
• There were more adverse events in the amphotericin group, necessitating discontinuation of the drug (RR = 6.67; 95% CI [2.6, 16.7]).

Posaconazole Versus Fluconazole or Itraconazole

• Two studies compared oral posaconazole with oral fluconazole or itraconazole (itraconazole in a small subgroup in one trial; 58 of 298 patients in the non-posaconazole arm) in patients with acute leukemia undergoing induction chemotherapy and patients after HSCT with graft-versus-host disease.
• The use of posaconazole compared with fluconazole or itraconazole resulted in a reduction in all-cause mortality of borderline statistical significance (RR = 0.77; 95% CI [0.59, 1.01]).
• When posaconazole was compared with fluconazole alone (data provided from the author), there was a significant reduction in all-cause mortality (RR = 0.74; 95% CI [0.56, 0.98]).
• Posaconazole prophylaxis also resulted in a significant reduction in fungal-related mortality (RR = 0.25; 95% CI [0.11, 0.57]) and in documented or probable IFIs (RR = 0.47; 95% CI [0.3, 0.74]).
• Posaconazole prophylaxis yielded a significant reduction in documented invasive aspergillus infections (RR = 0.22; 95% CI [0.11, 0.42]).
• There was no difference in the prevalence of adverse reactions causing discontinuation of the study drug (RR = 0.88; 95% CI [0.66, 1.17]).

Fluconazole Versus Antifungals with Antimold Activity

• There was a trend toward higher all-cause mortality with fluconazole (12 trials; RR = 1.14; 95% CI [0.95, 1.37]), which originated mostly from the comparison with posaconazole (two trials) and micafungin (one trial).
• Compared with antifungals that have antimold activity, fluconazole was associated with a significantly higher rate of fungal-related mortality, any IFI, and IFIs caused by the aspergillus species.

Other Trials

• Seven trials compared two regimens of systemic antifungals—comparisons that were not repeated in other trials.
• In patients undergoing HSCT, micafungin prophylaxis was superior to fluconazole in overall success rate, with no difference in mortality, and the combination of micafungin and fluconazole versus fluconazole alone showed similar efficacy. 
• A comparison of a low dose (200 mg) versus a high dose (400 mg) of fluconazole resulted in comparable efficacy. 
• In patients with high-risk acute leukemia, voriconazole prophylaxis decreased IFIs at the cost of more adverse reactions when compared with itraconazole.
• One study that compared amphotericin B colloidal dispersion with fluconazole was terminated prematurely because of a high rate of adverse events with amphotericin B colloidal dispersion.
• IV caspofungin and itraconazole provided similar protection against IFIs, and liposomal amphotericin B prophylaxis resulted in similar efficacy as the combination of itraconazole and fluconazole.

Current data support the use of fluconazole, itraconazole suspension, or posaconazole for prophylaxis.

Antifungal prophylaxis in patients with solid tumors and autologous HCT is not recommended. Prophylaxis should be administered to patients with acute leukemia during induction chemotherapy and to other patients with high-risk leukemia.

The study aim was to evaluate the comparative safety and effectiveness of fluconazole versus itraconazole as primary prophylaxis in neutropenic patients with cancer. The main outcomes of the study were withdrawals from the studies because of adverse effects, documented fungal infections, invasive fungal infections, differentiation between mold and yeast invasive infections, and overall mortality. Secondary outcomes were total fungal infections, suspected fungal infections, superficial fungal infections, and mortality attributed by the authors of each randomized, controlled trial (RCT) to fungal infections.

PubMed (until March 2005), Current Contents Connect, and the Cochrane Central Register for Controlled Trials databases were searched, as were the references from relevant articles, including review papers, to identify relevant RCTs. Two independent reviewers performed literature searches and examined the identified relevant RCTs for evaluation of data on toxicity and effectiveness.
   

Search terms included prophylaxis, prevention, antifungal, azoles, fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole, neutropenia, granulocytopenia, bone marrow transplantation (BMT) and stem cell transplantation (SCT)
   

A study was considered eligible if it was an RCT, it compared the effectiveness of prophylactic fluconazole with prophylactic itraconazole in neutropenic patients, and it assessed toxicity, effectiveness of azoles, or mortality. Concurrent use of topical antifungal agents, such as nystatin or amphotericin B, were permitted. The administration of IV amphotericin B was not permitted unless an invasive fungal infection was documented or suspected.

RCTs comparing the effectiveness of fluconazole or itraconazole with placebo or no treatment or polyenes were excluded. RCTs comparing other azoles also were excluded.

Seven refernece were retreived.

Statistical analyses were performed using meta-analyst software. The heterogeneity between RCTs was assessed by using a chi-square test; a p value lower than 0.1 was defined to note statistical significance in the analysis of heterogeneity. Publication bias was assessed by the funnel plot method using Egger’s test. Pooled odds ratios (OR) and 95% confidence intervals (CIs) for all primary and secondary outcomes were calculated, by using both the Mantel-Haenszel fixed effects and the DerSimonian-Laird random effects models. Results from the fixed effects model are presented only when no heterogeneity between RCTs was observed; otherwise, results from the random effects model are presented. A methodologic quality assessment of each trial was performed. Details of randomisation, the use of double blinding, handling of withdrawals, concealment of allocation, and generation of allocation sequences were awarded one point, for a maximum achievable score of five points. High-quality RCTs scored more than two points, while low-quality RCTs scored two or less points, according to the reported methodology.

• Five total studies were reviewed.
• Sample sizes per article ranged from 59–581.
• Key characteristics indluded neutropenic patients with cancer treated with fluconazole or itraconazole for the prevention of fungal infections.

Active treatment

No statistically significant differences were noted between prophylaxis with fluconazole and itraconazole regarding documented fungal infections (OR = 1.51, 95% CI [0.97, 2.35], five RCTs), invasive fungal infections (OR = 1.44, 95% CI [0.96, 2.17], four RCTs), development of mold infections (OR = 1.36, 95% CI [0.83, 2.24], four RCTs), development of yeast infections (OR = 2.28, 95% CI [0.92, 5.666], three RCTs), and all-cause mortality (OR = 0.89, 95% CI [0.63, 1.24], five RCTs).

Prophylactic use of fluconazole resulted in significantly more fungal infections (OR = 1.62, 95% CI [1.06, 2.48], four RCTs). However, no statistical difference was noted between fluconazole and itraconazole in the development of suspected fungal infections (OR = 1.23, 95% CI [0.74, 2.02], four RCTs), superficial fungal infections (OR = 1.49, 95% CI [0.67, 3.31], three RCTs), and mortality attributed by the authors to fungal infections (OR = 1.3, 95% CI [0.75, 2.25], five RCTs). Significantly fewer patients were withdrawn from the studies due to the development of adverse effects with fluconazole prophylaxis when compared with itraconazole (OR = 0.27, 95% CI [0.18, 0.41], five RCTs). Gastrointestinal complaints were the most common reason for withdrawal from the studies because of adverse effects. The main reason for withdrawal from the RCTs because of an adverse effect was hepatic or renal dysfunction.

Fluconazole was associated with slightly more fungal infections, but there was no difference in mortality between fluconazole and itraconazole, and fluconazole was associated with fewer adverse effects.

Fluconazole and itraconazole are both effective for primary antifungal prophylaxis.

The purpose of this study was to assess the efficacy of fluconazole compared to itraconazole in neutropenic patients with hematologic malignancies.

MEDLINE, EMBASE, the Cochrane-controlled trials register, and the Cochrane Library and Science Citation Index were searched.

Key words included itraconazole, fluconazole, hematologic malignancies, meta-analysis.

Only studies published as an abstract or journal article after 2009 were included. Studies not published as an abstract or in a journal were excluded, as were any studies prior to 2009.

6,574 total reference were retreived. 

Two independent reviewers extracted data and entered that data into a freeware program (Review Manager 5.0). Differences expressed as the risk ratio with 95% confidence interval (CI); heterogeneity was checked by using a Q-test; random effects model was used prior to pooling of data; sensitivity analysis to assess if modification of inclusion criteria affected final result; publication bias was assessed by funnel plots.
 

• After exclusion, 9 studies remained in the total sample. 
• Total amount of subjects was 2,254.
• Size of the sample ranged across studies from 59–581.
• Fluconazole dosing ranged from 100 mg PO daily to 400 mg daily; itraconazole dosing ranged from 2.5 mg/kg every 12 hours to 400 mg per day; no other sample characteristics were given (i.e., age, gender, etc.).

Active treatment

Results suggested that prophylaxis with itraconazole is more effective than prophylaxis with fluconazole in prevention of fungal infections and invasive fungal infections (RR = 1.33, 95% CI [1.02, 1.73], p = 0.03). No differences were noted in overall mortality, fungal-related mortality, or proven fungal infections. Fewer patients on fluconazole were withdrawn from studies due to adverse events (RR = 0.45, 95% CI [0.27, 0.75], p = 0.002).

 As there were no differences in mortality or proven fungal infections, it is unclear what outcome was used that showed a difference in efficacy.

• Heterogeneity is a potential problem
• Dosages and duration of both itraconazole and fluconazole were varied throughout.
• No definitions of outcomes used is provided.

While the results support itraconazole, the medication is associated with higher adverse effects.

STUDY PURPOSE: To examine the efficacy and cost-effectiveness of various azoles for antifungal prophylaxis in patients with hematologic malignancies undergoing chemotherapy or cell transplantation

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 21
• TOTAL PATIENTS INCLUDED IN REVIEW = 5,505
• SAMPLE RANGE ACROSS STUDIES: Not provided
• KEY SAMPLE CHARACTERISTICS: Duration of antifungal prophylaxis and follow-up ranged from 70–100 days; 39% underwent hematopoietic cell transplantation (HCT), and the most common disease was acute myeloid leukemia (AML).

PHASE OF CARE: Active antitumor treatment

Overall, proven or probable fungal infection occurred in 5% of the study population—45% were Candida and 49% were Aspergillus. All triazoles were better than placebo, except for itraconazole. Various triazoles differed in terms of tolerability and specific treatment-related side effects. Comparative efficacy analysis was in favor of posaconazole based on numerous outcomes evaluated. Itraconazole was associated with more study withdrawals but was also the least costly. Incremental cost-effectiveness ratios (ICER) were calculated for each agent. This analysis showed that posaconazole had a higher ICER than comparators. All triazoles except for intraconazole capsules were found to be effective in reducing fungal infection.

The findings suggest that posaconazole may more cost-effective for antifungal prophylaxis than the other triazoles examined. Itraconazole capsules were not shown to be effective.

• Low sample sizes
• Did not include patients of other high risk groups, such as GVHD. No direct head-to-head comparison of individual azoles, though the network meta-analysis approach was used to enable this comparison. The study was done in Singapore, so cost, etc., information may not be applicable in other areas.

The findings showed that all azoles other than itraconzole capsules were effective for antifungal prophylaxis, and that posaconazole may be the most cost-effective agent.

To estimate the impact of antifungal prophylaxis on the occurrence of proven systemic fungal infections in patients with neutropenia and to quantify its effect on mortality attributed to these infections.

Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through September 15, 2010.  In addition, proceedings of the annual meetings of the Infectious Diseases Society of America (2001–2009), the American Society of Hematology (2000–2009), and the European Society of Clinical Microbiology and Infectious Diseases (2000–2010) were manually reviewed.

Search keywords were clinical trial(s), neutropenia, neoplasms, malignant, malignant neoplasm, mycoses, candida, aspergillus, zygomycosis, antifungal agents/antifungal, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, amphotericin B, miconazole, and micafungin.

Articles were included if they focused on patients undergoing treatment for cancer who received prophylactic antifungal medications.

Articles were excluded if they directly compared systemic antifungal prophylactic agents, evaluated nonabsorbable polyenes or oral antifungal formulations of amphotericin B, and did not evaluate antifungals prophylactically (i.e., those that included empirical, pre-emptive, or salvage therapies for fungal mycoses).
 

A total of 11,418 references were retrieved.

A meta-analysis method of study was used. In specific, statistical analysis was performed to compare study results, including effects of antifungal prophylaxis using random effects and reported as pooled odds ratios (ORs) and 95% confidence intervals (CIs) using the Robins-Breslow-Greenland formula.  For study cells with zero events, an ad hoc treatment arm continuity correction was used.  Findings in which the 95% CI crossed 1 were not considered statistically significant. Statistical heterogeneity was assessed using the I² statistic and Cochrane Q test. The Petro method was used for sensitivity analysis, and the Harbord modification of the Egger test was used to evaluate small study effects for major outcomes.

• After exclusion factors, 26 articles remained in total and 25 were included in the analysis of the outcomes.  
• The total sample across all articles was 3,979.
• Sample sizes per article ranged from 25 to 405.
• Median age ranged from 7 to 65 years across studies. The majority of patients had hematologic malignancies treated with or without hematopoietic stem cell transplantation (HSCT), and five studies included patients with solid tumors. Specific diagnoses were not disclosed.

Patients were undergoing the active treatment phase of care.

Antifungal prophylaxis was associated with statistically significant reductions in proven fungal infections (OR = 0.43; 95% CI [0.31, 0.6]; number needed to treat [NNT] = 20) and mortality attributed to fungal infections (OR = 0.49; 95% CI [0.3, 0.8]; NNT = 53), reduction in risk for proven candida infections (OR = 0.28; 95% CI [0.2, 0.38]), and a decreased need for antifungal therapy (OR = 0.64; 95% CI [0.48, 0.86]). Explanatory subanalysis of major outcomes showed a reduced risk for proven infections among HSCT recipients only (OR = 0.27; 95% CI [0.16, 0.44]) and infection-related mortality (OR = 0.41; 95% CI [0.21, 0.81]). Not statistically significant were overall mortality (OR = 0.92; 95% CI [0.74, 1.14]) or reduction of aspergillosis or zygomycosis. Meta-regression analysis showed that multi-center and double-blind designs were significant moderators of the effect of antifungal prophylaxis on overall mortality and proven systemic fungal infections.

Systemic antifungal prophylaxis was associated with decreased proven fungal infections and fungal infection-related mortality in patients with neutropenia following chemotherapy.  Antifungal prophylaxis was also associated with decreased proven infections and infection-related mortality in HSCT recipients.  Overall mortality was not improved through the use of antifungal prophylactic therapy.

 The use of prophylactic antifungal therapy should be considered for patients receiving neutropenic-inducing chemotherapy and/or those undergoing HSCT.

The study analyzed the relative effectiveness and safety of azole antifungal prophylaxis with particular attention to the tri-azoles compared to fluconazole/itraconazole.

Patients at the Royal Melbourne Hospital with AML/MDS undergoing remission-induction chemotherapy from December 1998–January 2010 who received one day or more of azole prophylaxis were included.  Prophylaxis consisted of fluconazole 400 mg daily, itraconazole sodium 2.5 mg/kg twice daily, voriconazole 200 mg twice daily or posaconazole 200 mg three times daily with fatty food. These were started 1–2 days prior to chemotherapy and continued until neutrophil recovery (greater than 0.5 cells/L), occurrence of a confirmed or suspected invasive fungal infection, drug-related toxicity/intolerance, or the patient’s condition becoming palliative. Oral administration was preferred, fluconazole or voriconazole could be given via IV when a patient’s gastrointestinal absorption was considered inadequate.

216 patients were evaluated (57 in the fluconazole group, 59 in the itraconazole group, 82 in the voriconazole group, and 68 in the posaconazole group).

The median age per group was: fluconazole, 57 (range = 20–79); itraconazole, 55 (range = 20–79); voriconazole, 51 (range = 17–81); posaconazole, 51 (range = 19–78).

Regarding key disease characteristics, 197 patients had AML and 18 had transformed MDS. Median duration of neutropenia ranged from 13–16 days. 

Patient receiving TPN per group: fluconazole, 38%; itraconazole, 40%; voriconazole, 21%; posaconazole, 31%.

Fluconazole was used from December 1998 to September 2008, itraconazole was used from May 1999 to January 2003, voriconazole was used from November 2002 to August 2008, posaconazole was used from September 2006 to January 2010.
 

• Single site 
• Inpatient 
• Royal Melbourne Hospital

Active antitumor treatment

The study was a retrospective review.

• Receipt of total parenteral nutrition (TPN) was a marker of severe mucositis.
• Invasive fungal infection onset was defined as the first day of suspicious CT abnormality or positive microbiology or pathological test.  
• Breakthrough invasive fungal infections were defined as occurrence of invasive fungal infection in patients during \"-azole\" prophylaxis or within seven days of drug cessation.   
   

The majority of patients (213/216) underwent chemotherapy for remission-induction or re-induction or relapsed disease. The median duration of neutropenia for fluconazole/itraconazole was significantly longer than voriconazole/posaconazole (16 days versus 14 days, p = 0.003). TPN requirement was 39% versus 26% (p = 0.001), and median duration of prophylaxis was 18 days versus 22 days (p < 0.001).   
Breakthrough invasive fungal infection occurred in 27 patients comprising of probable/proven (11) and possible (16). The incidence of breakthrough invasive fungal infection was significantly lower in the voriconazole/posaconazole group (10 of 125; 8%) versus fluconazole/itraconazole (17 of 85; 20%) (p = 0.011). All probable/proven invasive fungal infections were molds, most commonly aspergillosis.  
Sub-therapeutic drug levels were common in itraconazole (42%), voriconazole (38%), and posaconazole (69%).  
 

In this institution, the use of voriconazole/posaconazole coincided with a significant decrease in the incidence of breakthrough invasive fungal infections.

Risk of bias:

• No control group
• No blinding
• No random assignment
• No appropriate attentional control conditions
• Sample characteristics*
• Findings not generalizable*

*Findings generalizable to only hematologic malignancies. The retrospective nature is not as strong in this study and, although some good information was shared, the results are not as useful to change practice.

This study compared different agents used for antifungal prophylaxis. There is always the need for education of patients and staff of the signs on infection while on prophylactic therapy and the education of taking the medication correctly and changing to an alternate therapy if the risk of impaired gastrointestinal function is greater for particular patients (i.e., severe mucositis).

To evaluate the feasibility and tolerability of prophylactic administration of a single, very high dose of liposomal amphotericin B (L-AmB) in adult patients newly diagnosed with acute myeloid leukemia (AML) and undergoing induction chemotherapy

The study was a pilot, phase II, single-center trial. The L-AmB was used to evaluate its efficacy and the level of toxicity. The study enrolled patients with AML undergoing first remission induction chemotherapy from January 2004–January 2011.

• N = 48      
• AGE = 32–78 years
• MALES: 61.7%
• KEY DISEASE CHARACTERISTICS: Induction chemotherapy; type of AML; toxicity level

• SITE: Not stated/unknown   
• SETTING TYPE: Inpatient   
• LOCATION: Not specific

• PHASE OF CARE: Transition phase after active treatment
• APPLICATIONS: Palliative care

• Phase II, single-center trial

• Common toxicity criteria (CTC)
• Pharmacokinetic study

Overall, 18 of the 48 (37.5 %) patients experienced at least one adverse effect (all CTC grade) after the first or second L-AmB, and only six of them (12.5%) reported CTC grade 3 adverse events related to L-AmB administration.

The study demonstrates the feasibility and safety of a single, very high dose of L-AmB as antifungal prophylaxis in patients with AML undergoing induction chemotherapy.

• Small sample (less than 100)
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Measurement/methods not well described
• Measurement validity/reliability questionable

This study basically determines the use of L-AmB to be used safely in patients with AML undergoing induction chemotherapy and does not have enough specification related to nursing.

To evaluate the safety and efficacy of micafungin for antifungal prophylaxis in pediatric patients at high risk for fungal infection

Children who were intolerant to polyenes and axoles or in whom theses were otherwise contraindicated were given 3–4 mg/kg micafungin twice weekly. Micafungin was begun when the patient could not take other antifungals and was continued until hematopoetic recovery after chemotherapy or until 100 days after HCT. Trough concentrations were determined from blood drawn prior to micafungin infusion, and peak levels were obtained 30 minutes after the end of the infusion.

• N = 21
• MEDIAN AGE = 9 years
• AGE RANGE = 0.2–16 years
• MALES: 66.6%, FEMALES: 33.4%
• KEY DISEASE CHARACTERISTICS: All relapse, Non-Hodgkin lymphoma, AML, or undergoing allogeneic HCT

• SITE: Single site  
• SETTING TYPE: Multiple settings  
• LOCATION: Germany

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Pediatrics

• Observational retrospective

• IFD defined according to European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG)
• Peak and trough micafungin concentrations

There was no premature discontinuation of micafungin due to related adverse events. Proven or probably invasive fungal infection did not occur in any patients.

Findings suggest that intermittent micafungin for antifungal prophylaxis can be safe and effective in high-risk pediatric patients. Additonal larger studies are needed to confirm these results.

• Small sample (less than 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 

There are a number of limitations to the use of oral triazoles for routine antifungal prophylaxis, and micfungin has been used for prevention and treatment of candida infections in children. This study showed that a larger dose, delivered intermittently, may be a safe and effective alternative for antifungal prophylaxis in high-risk children with cancer. The ability to not have to provide infusions daily can be an attractive and convenient alternative to daily treatment. This study has several important limitations, so additional well-designed research to confirm these findings in larger samples is needed.

To examine the incidence and outcomes related to the treatment of invasive fungal infection (IFI) with posaconazole versus fluconazole prophylaxis

Records of patients undergoing remission induction chemotherapy were reviewed for data collection. Results of those who received fluconazole versus posaconazole antifungal prophylaxis were compared. Both agents were begun 1–2 days prior to chemotherapy and continued until the patients' absolute neutrophil count (ANC) was > 500/mm³.

• N = 424
• MEAN AGE = 45.6 years
• MALES: 56.1%, FEMALES: 43%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All had either acute myeloid leukemia (AML) or myelodysplastic syndrome

• SITE: Single site
• SETTING TYPE: Not specified
• LOCATION: Korea

• PHASE OF CARE: Active antitumor treatment

• Retrospective cohort comparison

• Neutropenia defined as ANC < 500/mm³ and severe neutropenia as < 100 500/mm³
• IFI categorized according to European Organization for Research and Treatment of Cancer (EORTC) criteria
• Breakthrough IFIs were defined as proven or probable if developed after at least seven days of antifungal prophylaxis.
• Charlson comorbidity index

The incidence of breakthrough IFIs and the use of empirical antifungal treatment were lower in those who received posaconazole (p < 0.001). Overall, IFI-related mortality was 1.9% in the posaconazole group compared to 12.1% in the fluconazole group (p = 0.028). No difference existed between groups in overall survival.

The findings suggest that posaconazole was more effective than early generation azoles for antifungal prophylaxis in at-risk patients with cancer.

• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Measurement/methods not well described
• Length of follow-up for data collection was not described.

The findings suggest that newer azoles may be more effective for antifungal prophylaxis in at-risk patients with cancer.

Study patients received  200 mg of posaconazole in an oral suspension three times daily, 400 mg of fluconazole in an oral suspension once daily, or 200 mg of itraconazole in an oral solution twice daily.

Patients who were unable to tolerate the oral study drug could receive IV prophylaxis at the same dose for three days or less per chemotherapy cycle. Patients in either group were permitted to receive amphotericin B or another systemic agent as empirical antifungal therapy for a suspected invasive fungal infection.

Antifungal prophylaxis was administered with each chemotherapy cycle, starting either 24 hours after the last anthracycline dose or, in patients not  receiving an anthracycline-based regimen, on the first day of chemotherapy.

Prophylaxis was continued until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks from randomization, whichever came first. Patients were followed for 100 days after randomization and for 30 days after the last dose of the study drug administered during the last chemotherapy cycle.

• 602 total patients
• Patients aged 13 years or older who had or were anticipated to have neutropenia with an absolute neutrophil count of 500 cells/mcl or lower for seven days or longer resulting from remission-induction chemotherapy for newly diagnosed or the first relapse of acute myelogenous leukemia or myelodysplastic syndrome.
• Exclusion criteria included an invasive fungal infection within the previous 30 days.
   

Eighty-nine centers worldwide.

Prospective, randomized trial.

An independent data review committee of infectious disease experts who were unaware of the treatment assignments reviewed and classified all cases of fungal infection as proven, probable, or possible, according to the consensus criteria of the European Organisation for the Research and Treatment of Cancer and the Mycoses Study Group.

• Incidence of proven or probable invasive fungal infection during the treatment phase.
• Incidence of invasive aspergillosis.
• Incidence of invasive fungal infection within 100 days after randomization and treatment success (versus failure) during the treatment phase. Treatment failure was defined as the occurrence of a proven or probable invasive fungal infection; receipt of an IV study drug for four consecutive days or more, or 10 days in total; receipt of any other systemic antifungal agent for four days or more for suspected invasive fungal infection; the occurrence of an adverse event possibly or probably related to the study treatment, resulting in the discontinuation of treatment; or withdrawal from the study with no additional follow-up.
• Survival was evaluated 100 days after randomization.
   

Proven or probable invasive fungal infections occurred during the treatment phase in 7 of the 304 patients (2%) in the posaconazole group and in 25 of the 298 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group = –6%; 95% confidence interval [CI] [–9.7, –2.5]; p < 0.001).

During the 100-day period after randomization, 14 of 304 patients (5%) in the posaconazole group had a proven or probable fungal infection, as compared with 33 of 298 patients (11%) in the fluconazole or itraconazole group (p = 0.003).

The mean time to invasive fungal infection was 41 (SD = 26) days in the posaconazole group and 25 (SD = 26) days in the fluconazole or itraconazole group.

Kaplan-Meier analysis of the time to invasive fungal infection showed a significant difference in favor of posaconazole (p = 0.003).

The analysis of the time to first use of empirical antifungal therapy during the 100-day period revealed a significant difference in favor of posaconazole over fluconazole or itraconazole (p = 0.02).

Of the 304 patients in the posaconazole group, 49 (16%) died during the study period, as did 67 of 298 patients (22%) in the fluconazole or itraconazole group (p = 0.048); 44 patients (14%) and 64 patients (21%), respectively, died within 100 days.

The relative reduction in mortality at day 100 in the posaconazole group, as compared with the fluconazole or itraconazole group, was 33%.

The analysis of the time to invasive fungal infection or death also showed a significant benefit in favor of posaconazole (p = 0.01).

The incidence of treatment-related adverse events was similar among the treatment groups.

• All 602 patients in the intention-to-treat population were included in the safety evaluation.
• The different dosing schedules of the three study drugs and the logistics of their IV alternatives precluded a double-blind design.

To investigate practices for antifungal prophylaxis and incidence of invasive fungal disease (IFD)

A retrospective chart review was conducted to collect data on patients from beginning of induction to completion of consolidation regarding the use of antifungal prophylaxis and IFD outcomes. Cost analysis was included.

• N = 98   
• MEDIAN AGE = 43 years
• MALES: 65%, FEMALES: 35%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All had acute lymphoblastic leukemia

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: Australia

PHASE OF CARE: Active antitumor treatment

Retrospective

European Organization for Research and Treatment of Cancer (EORTC) criteria for proven, possible, or probable IFD

Ninety-eight percent had neutropenia ranging from 18–45 days in duration. Prophylactic antifungal agents were given to 85% of patients. The only significant difference between those who developed IFD and those who did not was the use of antifungal prophylaxis. Those receiving prophylaxis had a lower incidence of proven or probable IFD  (2.6%) than others (21.4%) (p = 0.024). IFD incidence was highest in patients receiving BFM95 treatment (hyper-CVAD: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). Cost of care for those with IFD was significantly higher from hospitalization, diagnostic testing, and antifungal treatment costs (p < 0.001).

The use of antifungal prophylaxis was associated with a lower incidence of IFD and associated healthcare costs.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Antifungal prophylaxis in at-risk patients was shown to be effective in reducing the incidence of IFD and associated healthcare costs.

200 mg of oral posaconazole was started three times daily on patients on the first day after their chemotherapy ended. Treatment was started prophylactically and was independent of a specific cycle of chemotherapy (i.e., some patients started after cycle 1, some started after cycle 2). A total of 76 chemotherapy cycles were included among these 40 patients.

• Forty participants with an age range of 38–76 years.
• 65% were male, 35% were female
• Key disease characterisitcs included acute myelogenous leukemia (30 of the participating patients), acute myelogenous leukemia after MDS conversion (9 patients), and one patient with chronic myeloid leukemia with biphenotypic blast crisis.

A single site in Heidelberg, Germany.
 

Active treatment

Retrospective, observational study.

• Development of fungal Infection in patients receiving posaconazole as prophylaxis.   
• Development of sepsis in patients receiving posaconazole as prophylaxis.
   

23 patients enrolled in the study developed pneumonia, with 13 being possible invasive fungal disease and 1 being proven aspergillosis. Single-agent posaconazole as prophylaxis was interrupted in 25 of the 40 enrolled patients due to various causes; one patient was unable to swallow due to mucositis, two developed adverse reactions. One third of the patients (25 cycles of the 76 studied) had systemic therapy of different types started during the study time period because of signs and symptoms of fungal infection or due to adverse events.

Based on the findings of the study, posaconzole may show promise for prevention of fungal infection in the immunocompromised patient, although it cannot be relied on as monotherapy for all patients due to the limitations of it being only PO and the use of other systemic anti-fungal prophylaxis. More studies are needed with posaconazole to determine its effectiveness as sole prophylaxis.

Some patients included were receiving additional prophylactic treatment other than posaconazole, making it hard to determine which drug was the most effective in prevention of invasive fungal infection.

Posaconazole may be an effective treatment prophylactically for fungal infection if patients are able to take oral medications, but further studies are needed to determine how effective it can be. The fact that it only comes as an oral product limits the population that may benefit.

To evaluate the effectiveness of antifungal prophylaxis in children with acute myeloid leukemia (AML)

Medical data for children newly diagnosed with AML were obtained from a database of hospitals associated with the Children's Hospital Association nationwide. Only patients with AML receiving induction therapy involving cytarabine, aunorubicin, and etoposide regimens were included. Patients were followed until inpatient death, loss to follow-up, or completion of induction. Data for antibiotic use, blood cultures, and chest CTs were obtained. Exposure to antifungal prophylaxis with any agent was obtained, and decision rules were used to ensure antifungals were used for prophylaxis rather than empiric therapy. Those who did not receive any antifungal agent during the first 21 days of induction chemotherapy were considered “no prophylaxis” patients. Outcomes were analyzed and compared for those who did and did not receive prophylaxis

• N = 871
• MEAN AGE = Not provided
• AGE RANGE = younger than 1 year to younger than 19 years
• MALES: 53.4%, FEMALES: 46.6%
• KEY DISEASE CHARACTERISTICS: All had AML and were receiving induction chemotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: 69% were Caucasian

• SITE: Multi-site  
• SETTING TYPE: Inpatient  
• LOCATION: United States of America

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

• Retrospective cohort comparison

Of those who did not get antifungal prophylaxis, 5.32% died during induction compared to 2.42% of those receiving prophylaxis (RR = 0.42, 95% CI [0.19, 0.9]). Those receiving prophylaxis had less use of antibiotics and fewer blood cultures and CT scans. There was no significant difference in mortality between those receiving anti-mold prophylaxis and others.

Findings show that primary antifungal prophylaxis was associated with lower mortality and utilization of resources during induction for AML among pediatric patients.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• There was no demonstration of mortality related to invasive fungal infection.
• Cause of mortality is not discussed.

Findings suggest that primary antifungal prophylaxis among pediatric patients may reduce mortality and resource utilization. These findings support the use of antifungal prophylaxis among at-risk pediatric patients.

To assess the effect of primary prophylaxis with posaconazole and levofloxacin on the incidence of invasive fungal infections (IFI) and bacteremia

This was a retrospective, single-center study that evaluated two groups of adult patients with acute myeloid leukemia/acute promyelocytic leukemia (AML/APL) and high-grade myelodysplastic syndrome (MDS) receiving intensive chemotherapy. The primary endpoint was IFI and bacteremia with secondary endpoints of overall survival at day 100 and at two years, time from the initiation of chemotherapy to the onset of IFI, the use of intravenous and oral antifungal and antibacterial therapy, and total duration of antifungal and antibacterial medication.

• N = 88 (43 no prophylaxis and 45 prophylaxis)
• AVERAGE AGE = 49.8 years (no prophylaxis); 53.5 years (prophylaxis)
• MALES: 51.2% (no prophylaxis); 51.1% (prophylaxis)
• KEY DISEASE CHARACTERISTICS: Patients with AML, APL, or high-grade MDS receiving intensive chemotherapy

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: University Hospital Zurich

• PHASE OF CARE: Active antitumor treatment

Retrospective 

• Radiologic diagnosis of IFI determined by two independent evaluators
• Possible or proven IFI defined according to European Organisation for Research and Treatment of Cancer and ​Mycoses Study Group (EORTC/MSG) criteria

IFIs were significantly less common in the prophylaxis group after the first chemotherapy cycle (33.3% versus 65.8%; p = 0.0088). IFIs were significantly less common in the prophylaxis group after the last chemotherapy cycle (53.9% versus 88.9%; p = 0.0021). Chemotherapy cycles that were complicated with bacteremia occurred at a rate of 34.6% with prophylaxis and 32.3% in the nonprophylaxis group; p = 0.8. Positive blood cultures were 50 and 43, respectively, with a nonsignificant trend to more gram-negative infections in the nonprophylaxis group (42% versus 14%; p = 0.073) and to more gram-positive infection in the prophylaxis group (86% versus 58%; p = 0.092). Overall survival at 100 days and at two years, as well as the use of antiviral medications, did not differ between the two arms. Fewer fever days (5.6 versus 9.2;  p = 0.00032) and less cytarabine toxicity (18.3% versus 35%; p = 0.025) were observed in the prophylaxis arm.

This single-center retrospective study of posaconazole prophylaxis was efficient in reducing the possible IFIs with a number needed to treat to prevent one IFI of only three. This institution had a relatively high rate of IFIs when compared to published data. Posaconazole for prophylaxis was cost-effective. There was no benefit seen in the use of levofloxacin in preventing bacteremia.

• Small sample (< 100)
• Measurement/methods not well described
• Findings not generalizable
• Other limitations/explanation: The rate of IFIs in this institution was higher compared to other published data, and the inclusion of possible IFIs may have led to an overdiagnosis of IFIs, which might not reflect the true outcomes of IFI.

Oncology nurses should be aware of facility policies relating to the use of prophylaxis for IFI and bacteremia and should understand the local climate that may affect the rate of IFIs. This facility used posaconazole and levofloxacin as prophylaxis agents. Other agents exist and are currently in use that may produce different outcomes.

To analyze risk factors for breakthrough invasive fungal infection (IFI) in patients receiving remission-induction chemotherapy and evaluate effects of echinocandin versus triazole prophylaxis

Data were obtained from patients’ electronic medical records for antifungal use, documented IFI, type of chemotherapy, use of HEPA air filtration, duration of hospitalization, and neutropenia and mortality. Kaplan-Meier curves were used to estimate the probability of remaining IFI free based on prophylaxis strategy. Patient data were used up to IFI diagnosis, loss to follow-up, death, or completion of 120 days post-induction, whichever came first.

• N = 125
• MEDIAN AGE = 64 years
• AGE RANGE = 51–73 years
• MALES: 55%, FEMALES: 45%
• KEY DISEASE CHARACTERISTICS: AML undergoing remission induction. The majority were on cytarabine-based regimens.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Texas

• PHASE OF CARE: Active antitumor treatment

• Retrospective

• None—no definition of IFI provided

Those receiving echinocandin versus mold active triazole had higher incidence of IFI (0% in the triazole group, 8% in the echinocandin group, p = 0.09). All cause mortality did not differ between groups. Regimens containing clofarabine for induction was also an independent predictor of IFI (p = 0.004). Patients who died within 120 days of beginning induction chemotherapy were more likely to be female, had prior chemotherapy-related AML, had lung disease or infection, or had cardiovascular disease as a comorbid condition. Those receiving echinocandin also had more breakthrough yeast infections.

Findings suggest that primary antifungal prophylaxis during remission induction with echinocandin may be less effective in preventing IFI than prophylaxis with mold-active triazoles.

• Risk of bias (no control group)
• Risk of bias (no random assignment) 
• There were very few fungal infections overall, and a much lower sample size that received echinocandin.

Patients with AML undergoing remission-induction chemotherapy are at high risk for developing IFIs, particularly mold infections. Findings from this study suggest that the class of antifungal prophylaxis agent used influences the patient’s risk of IFI. Nurses should be aware of the potential increased risk for fungal and yeast infections in patients getting echinocandin prophylaxis. Further research in this area is warranted given the limitations of this study.

The primary aim of this study was to determine if micafungin is an effective and safe antifungal prophylaxis to be used for neutropenic pediatric patients undergoing chemotherapy treatment or stem cell transplantation treatment for cancer.  

Patient records were reviewed for pediatric oncology patients who received micafungin via IV (3 mg/kg per day) while they were neutropenic from May 2006 to September 2008. A total of 40 children were included in a record review that encompassed 146 patient cycles of chemotherapy.

• The sample consisted of 40 patients.
• Ages ranged from 1–17 years old.
• Key disease characteristics included acute leukemia, non-Hodgkin lymphoma, and solid tumors.
• Although 40 patients were treated prophylactically with micafungin, 39 of them received chemotherapy or stem cell transplantation for their disease. One did not receive either chemotherapy or stem cell transplantation as treatment for their cancer.
   

A single-site setting.

• The phase of care was active treatment
• The application was pediatrics
   

 Retrospective

Development of probable, proven, or suspected invasive fungal infection.

Of the 40 records reviewed, a total of 131 patient cycles were noted for chemotherapy and 15 patient cycles for those undergoing stem cell transplantation. Thirty of 40 patients had successful prevention of invasive fungal infection. Only one patient developed a diagnosed fungal infection, the rest of the failures were suspected fungal infections.

Based on this study, it appears that micafungin may be a safe and effective prophylactic treatment for fungal infection in pediatric patients with cancer. A larger randomized study would be beneficial to prove the success rates in a larger randomized group.

•  The study had a small sample size (less than 100).
•  Invasive fungal infections are more prominent in hematologic malignancies as opposed to solid tumors, thus combining these two populations in a study may skew the results for positive benefit.
   

Micafungin is generally tolerated well with minor side effects and minimal drug-to-drug interactions as opposed to other treatment for fungal prophylaxis. More exclusive, randomized studies are needed to determine if it is appropriate for all patient populations and demographics.

To investigate efficacy of various secondary antifungal prophylaxis regimens

Patients with hematological malignancy that had a previous diagnosis of probable or proven invasive fungal disease were reviewed retrospectively and followed for 180 days post-chemotherapy or transplantation. Antifungal prophylaxis was provided with voriconazole, itraconazole, amphotericin B, liposome, or caspofungin. Secondary prophylaxis began on the first day of conditioning or within two days before chemotherapy and was continued throughout the duration of neutropenia. It was ended when immunosuppression was finished in all patients undergoing HCT, or neutrophil recovery or failure of the prophylaxis.

• N = 164
• AGE = 51% were older than age 40 years
• MALES: 51%, FEMALES: 49%
• KEY DISEASE CHARACTERISTICS: 90% had acute leukemia. More than one-third had acute or chronic graft-versus-host disease.
• OTHER KEY SAMPLE CHARACTERISTICS: All had prior pulmonary invasive fungal disease.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: China

• PHASE OF CARE: Multiple phases of care

• Retrospective

Not applicable.

121 patients received secondary antifungal prophylaxis. The recurrence rates were 16.5% and 46.5% in those receiving and not receiving prophylaxis, respectively (p = 0.000). There was no difference in recurrence rates according to the specific prophylactic agents used.

Findings suggest that secondary antifungal prophylaxis is beneficial in reducing the rate of recurrent fungal infections in patients with cancer.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Specific definition of fungal infection are not provided, and most only had probable infection due to lack of diagnostic data.

Secondary antifungal prophylaxis in patients who had previous invasive fungal infections was shown to be effective in reducing the rate of new fungal infections; however, it did not prevent fungal infection in all patients. Nurses need to closely monitor and assess these types of patients for signs of infection so that they can be treated aggressively when needed.

The purpose of the study was to compare the efficacy and toxicity of oral voriconazole to IV low-dose amphotericin B in pediatric patients with acute leukemia.   

Oral variconazole was administered at a dose of 6 mg/kg per dose for initial two doses followed by 4 mg/kg per dose twice daily one hour before meals. Low-dose IV amphotericin B was administered at a dose of 0.5 mg/kg per day three times a week. Before administration of amphotericin B all patients received diphehydramine IV and oral paracetamol as premedication and saline hydration post infusion. Systemic antifungals were not allowed for use before patients underwent the trial. Complete blood count, liver function tests, and renal function tests were done at least twice weekly until seven days after completion or failure.

• The sample consisted of 100 patients aged 15 years or younger. 
• Males were 75% of the sample, females were 25%
• Key disease characteristics included acute myeloid and acute lymphoblastic leukemias.
• Before induction chemotherapy, patients were eligible if they had no pneumonia on chest radiograph and no systemic antifungal therapy within seven days of randomization. Febrile patients who were hemodynamicaly stable with a normal chest radiograph also were included in the study.

• Single site
• Inpatient
• New Dehli, India
   

• The phase of care was active treatment
• The application was pediatrics.
   

Randomized, non-stratified, open-label, single-institution pilot study.

• EORTC/MSG criteria for definition and classification of proven, probable, and possible invasive fungal infection.    
• Hepatic toxicity was defined as liver function test values greater than 5 times the upper limit of normal.
• Renal toxicity is defined as creatinine greater than 2 mg/dl.
   

The overall probable, proven, and possible fungal infections were 5% in the study.  In the voriconazole arm, 28% had failure of prophylaxis compared to 34% failure rate in the amphotericin B arm. No differences were noted between groups in proven, probable, and possible fungal infections. Those receiving the voriconazole had significantly less toxicity, with 6% of patients in variconazole arm having any serious adverse event (SAE)  compared to 31% in the amphotericin B arm (hypokalemia) (p < 0.001). With the amphotericin B arm, 50% had infusion reactions.

 Oral voriconazole seemed to be comparable with amphotericin B, with less toxicity and more convenience.

• The empirical dose of varicanozole is an extrapolation of adult dose.
• The authors did not perform pharmacokinetics of the patients to show whether the empirical dose of variconazole administered was efficacious or not.
• There was no blinding in the study, with inherent risk of bias.

Potential increased need for patient and caregiver education regarding oral medication administration. Continued research in comparable efficacy of antifungal agents will be helpful in order to select effective agents that are least toxic, practical, and cost effective.

To determine the safety of voriconazole (VRC) as antifungal prophylaxis (AFP) in pediatric hematology/oncology patients.

Patients received IV VRC 5-7 mg/kg every 12 hours as AFP, not as empiric treatment. Dosing and duration of VRC therapy was at the discretion of the treating physician. Median VRC dose = 7 mg/kg. Median duration of VRC = 17 days (range = 1-31 days). Median number of AFP courses = 1.7 (range = 1-6) per patient.

• N = 249   
• AGE: Median = 6; range not specified. Inclusion criteria states ages 0-17.
• MALES: 55%      
• FEMALES: 45%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Pediatric cancer patients (any malignancy), although the majority had acute lymphoblastic leukemia, non-Hodgkin lymphoma, or acute myeloid leukemia.
• OTHER KEY SAMPLE CHARACTERISTICS: Researchers assessed risk factors for IFIs in the two weeks prior to initiation of VRC treatment. These risk factors included corticosteroid use, severity of neutropenia, grading of mucositis, type of surgery, ICU transfer, chemotherapy, and previous antibiotic therapy.

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: Greece

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Pediatrics

Retrospective chart review

Researchers assessed the rate of breakthrough IFIs during AFP and tabulated the incidence, time of onset, and severity of all AEs related to VRC.

Only one breakthrough IFI was found in the 429 courses of VRC given to 249 unique patients. Median duration of AFP with VRC was 17 days (range = 1-31 days). Median number of courses of VRC was 1.7 (range = 1-6) per patient. Females required more courses of VRC (median = 2, range = 1-4) than males (median = 1, range = 1-6) (p > 0.05). The underlying malignancy had a significant effect on the number of courses of VRC, with patients with leukemia receiving a median of 2 courses (range = 1-6). Patients without leukemia required a median of one course (range = 1-4) (odds ratio = 0.47; 95% CI [0.047, 0.5]; p = 0.019).

Seventy AEs of any grade were reported (a rate of 16.3%). There was no significant correlation between age, sex, and type of AEs. Of the 70 AEs, 38.5% were grade I, 48.4% were grade II, and 12.8% were grade III. Severity of AEs was not impacted by sex (p = 0.745), age (p = 0.78), and type of AE (p = 0.365). None of the AEs was severe enough to warrant discontinuation of VRC.

VRC provides effective prophylaxis in pediatric hematology/oncology patients at risk for IFIs. AEs were tolerable and manageable. However, the pediatric population may not be able to report subjective AEs, which could result in underdiagnosis of AEs. The risk of long-term AEs remains unknown.

Risk of bias (no control group)

Although AFP with VRC is effective, safe, and fairly well-tolerated, nurses should monitor their patients for early signs of AEs.

To evaluate the impact of antifungal prophylaxis in patients with hematologic cancers

Retrospective analysis of medical records was used to compare invasive fungal infection outcomes among patients who received prophylactic posaconazole and a historical cohort treated prior to the implementation of standard prophylaxis. Prophylaxis was used in high-risk patients.

• N = 200 (100 historical controls)
• MEAN AGE = 51 years
• AGE RANGE = 18–77 years
• MALES: 50%        
• FEMALES: 50%
• KEY DISEASE CHARACTERISTICS: Patients had acute myeloid leukemia or myelodysplastic syndromes or received hematopoietic cell transplantation 

• SITE: Single site 
• SETTING TYPE: Multiple settings 
• LOCATION: Germany

• PHASE OF CARE: Active antitumor treatment

• Retrospective, descriptive with historical control comparison

• Aspergillus testing
• Weekly stool samples and mouth swabs
• European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for possible, probable, or proven invasive fungal disease (IFD)

Mean duration of posaconazole prophylaxis was 21.7 days. Comparisons showed that 43% of controls had no IFD, compared to 72% of those with prophylaxis. Possible IFD was seen in 43% of controls and 24% of those on posaconazole.  Probable IFD was 7% in controls, compared to 4% of those getting prophylaxis. No cases of IFD were proven among patients receiving prophylaxis, compared to 7% of controls with proven IFD. Forty-one percent of those on prophylaxis required antifungal therapy, compared to 91% of controls.

Findings showed that routine posaconazole prophylaxis in high-risk patients was associated with substantial reduction in the incidence of IFD and treatment with antifungal therapy.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: The definition of high-risk used for the intervention was not specifically described.

Findings support the routine use of antifungal prophylaxis in high-risk patients with cancer.

To examine effectiveness of oral suspension posaconazole for antifungal prophylaxis

Consecutive patients were examined retrospectively. All received intensive-induction chemotherapy. All were given oral suspension posaconazole at 200 mg three times daily. All received antibacterial and antiviral prophylaxis. All infectious workups, empiric treatment, and second-line treatment were standard.

• N = 79
• MEDIAN AGE = 58 years
• AGE RANGE = 22–73 years
• MALES: 38.5%, FEMALES: 62.5%
• KEY DISEASE CHARACTERISTICS: All patients had acute myeloid leukemia; 40% were secondary due to prior therapy.

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: Germany

• PHASE OF CARE: Transition phase after active treatment

• Retrospective

• Not applicable.

Seventy percent did not develop invasive fungal infection during AML induction chemotherapy. Twenty-one percent had possible infection, and one-third underwent empiric first-line antifungal treatment because of persistent fever of unknown origin or presence of pulmonary infiltrates. Fourteen patients with possible infection received either liposomal amphotericin B or caspofungin. Only those receiving caspofungin required second-line antifungal treatment.

A high proportion of patients received consecutive antifungal treatment. Optimal protection against fungal infection in patients with AML undergoing induction chemotherapy is not clear.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Measurement/methods not well described

Prevention of infection, and invasive fungal infection in particular, is a challenge in patients undergoing induction chemotherapy for AML. Findings from this retrospective review suggest that a high proportion of patients routinely given oral suspension posaconazole required additional treatment for possible invasive fungal infection. The authors noted that there is uncertain bioavailability of posaconazole given as oral suspension, suggesting that evaluation of various formulations is needed, and that this may not be the most effective approach for antifungal prophylaxis.

To compare the efficacy and safety of posaconazole and fluconazole in the prevention of invasive fungal infection (IFI) in Chinese patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) receiving chemotherapy

Patients in China with MDS or AML with persistent chemotherapy-induced neutropenia (expected to last longer than seven days) were enrolled. Posaconazole or fluconazole was administered for a maximum of 12 weeks, or until recovery from neutropenia and complete remission or until IFI was diagnosed. The endpoint was incidence of proven, probable, or possible IFI during treatment.

• N = 244  
• AGE = 18–70 years; median in posaconazole group was 40 years (range: 17–61 years), median in fluconazole was 40 years (range: 15–68 years)
• MALES: Posaconazole, 55%; fluconazole, 52%  
• FEMALES: Posaconazole, 62%; fluconazole, 65%
• KEY DISEASE CHARACTERISTICS: De novo AML (posaconazole, 56%; fluconazole, 60%; relapsed AML (posaconazole, 46%; fluconazole, 45%); MDS (posaconazole, 15%; fluconazole, 12%)
• OTHER KEY SAMPLE CHARACTERISTICS: Duration of neutropenia in posaconazole (less than two weeks, 52%; more than two weeks, 65%); in fluconazole (less than two weeks, 55%; more than two weeks, 62%)

• SITE: Multi-site   
• SETTING TYPE: Outpatient   
• LOCATION: China

• PHASE OF CARE: Active antitumor treatment

• Prospective, randomized study

• Fisher’s method was used for analyzing between-group comparison. 
• A Kaplan-Meier analysis was used to calculate time-related parameters, including the time to first onset of proven, probable, or possible IFI, and time to first use of empirical antifungal therapy (from day of randomization).
• Log-rank tests were used for comparison between groups.

Two hundred forty-five patients entered safety analysis (124 in posaconazole and 121 in fluconazole). After exclusions, 117 patients were included in each set. Incidence of IFI was 9.4% and 22.2% in the posaconazole and fluconazole groups, respectively. There was a difference in rates of -12.8% in favor of posaconazole. There was an incidence of 3.42% when only proven and probable diagnoses were considered. Noninferiority of posaconazole compared with fluconazole was established with a difference in incidence rate of -5.98%. The 100-day time to first onset of proven, probable, or possible IFI was 13.8 (SD = 3.5%) in the posaconazole group and 29.2 (SD = 4.6%) in the fluconazole/itraconazole group.

Antifungal prophylaxis has been shown to be a successful strategy in patients at high risk for IFI. Posaconazole showed significant advantage compared with fluconazole in reducing the incidence of IFI. The advantage of posaconazole in decreasing the incidence may translate into reduced need for systemic antifungal treatment.

The study raises awareness of the potential for use of posaconazole as a reasonable prophylactic medication for IFI. There is some evidence that second-generation azoles may be more effective for prophylaxis in high-risk patients.

The purpose of the study was to Investigate efficacy of secondary antifungal prophylaxis (SAP) .  

Primary antifungal prophylaxis was fluconazole 200 mg PO daily. Patients with documented IFI were treated with intensive antifungal therapy. Two of these had complete response prior to futher treatment of primary disease. Thirty-three patients received prophylaxis with voriconazole, 21 received itraconazole, two received micafungin, and one received amphotericin B. The antifungal prophylaxis continued through time of neutropenia and ended when eradication of residual diseases or initiation of salvage therapy due to failure of SAP.

• 57 patients were included.
• 149 cycles of therapy
• Ages ranged from 14-77 years
• 56% were male, 44% were female
• 21 patients had AML, 23 had ALL, 2 had NHL, and 1 patient had MDS-RAEB
• 70% were in complete remission, 30% identified as uncontrolled disease.
• Medical records for all patients hospitalized for more than two weeks were reviewed.
• 57 patients who received 149 cycles of therapy were included.
   

• Single site  
• Inpatient stem cell transplantation center  
• Tianjin, China
   

Active treatment (i.e., chemotherapy or stem cell transplantation)

Retrospective chart review

• Diagnosis of IFI was according to revised EORTC/MSG criteria: proven cases diagnosed according to pathologic or microbiological evidence.  Probably and possible cases documented by radiological and/or microbiological evidence.
• Response to antifungal treatment graded according to criteria defined by complete response (CR), pratical response (PR), stable disease (SD), or progressive disease (PD).
• Relapse defined as recurrence of fungal lesions in historical foci.
• Breakthrough infection defined as emergence of fungal lesions in other than historical foci.

Median follow-up 120 days (12–1,080) revealed 11 failures of SAP, representing 7.4 per 100 cycles of therapy and cumulative incidence of 24.5% at end of follow-up. Four experienced infection progression, three had infection recurrence, and the other four had breakthrough infection. Of the 11 failures, five occurred in the allo-HSCT and six during chemotherapy. High-dose steroids and neutropenia of more than 14 days were identified as risk factors for SAP failure.

SAP demonstrated high efficacy and can protect further chemotherapy and SCT. Two risk factors, high-dose steroids and neutropenia longer than 14 days, were identified as factors of prophylaxis failure and these patients were deemed to require special consideration.

• Small sample size
• Retrospective study design
   

Based on small sample size and study design, evidence is weak in recommendation for practice. 

To investigate the effectiveness of antibiotic and antifungal prophylaxis during intensive chemotherapy for acute leukemia in children and to assess the impact on days of intensive care, changes in antibiotic resistance, and medical cost

Oral ciprofloxacin 300 mg/m²every 12 hours was given when patients became neutropenic and when seven days of neutropenia were expected. Oral voriconazole 4 mg/kg every 12 hours was initiated at the onset of neutropenia in patients with acute myeloid leukemia (AML) and after seven days of neutropenia in patients with acute lymphoblastic leukemia (ALL). IV micafungin was substituted for oriconazole during induction and reinduction chemotherapy. Prophylaxis was discontinued when patients' absolute neutrophil counts recovered to > 100/mcL. Probable invasive fungal infection (IFI) was not included in analysis. Data were analyzed from patients prior to the use of prophylaxis and from patients during the prophylaxis period.

• N = 113  
• MEAN AGE: 4.4 years (range = 0.2–18 years)
• MALES: 40%, FEMALES: 60%
• KEY DISEASE CHARACTERISTICS: AML or ALL

• SITE: Single-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Taiwan

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

Retrospective cohort comparison study

• Bloodstream infection was defined by the isolation of bacteria from blood cultures and clinical signs of systemic infection.
• IFI was diagnosed according to the culture or histology of infected tissue.

In the preprophylaxis period, there were 25 episodes of bloodstream infection among 62 patients, and in the prophylaxis period there were five episodes among 51 patients (p < .01). Preprophylaxis, there were 12 episodes of IFI compared to zero episodes during prophylaxis (p < .01). There were fewer episodes of febrile neutropenia with prophylaxis (p = .01). Ciprofloxacin resistance of E-coli Klebsiella pneumoniae, pseudomonas aeruginosa, and serratia marcescens was significantly reduced during the prophylaxis period. Other gram-negative bacilli did not change with regard to ciprofloxacin resistance between the two periods of time. 39% of patients had hepatotoxicity during prophylaxis with micafungin leading to dose modification in three patients and discontinuation in seven patients. Intensive-care stays due to infection and total cost were significantly lower during the prophylaxis period.

Prophylaxis decreased the occurrence of febrile neutropenia, bloodstream infections, IFI, intensive care length of stay due to infection, and cost for patients with ALL and AML. There was no increase in ciprofloxacin resistance associated with prophylaxis with this agent.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)

This study demonstrates the efficacy of antibiotic and antifungal prophylaxis in children receiving intensive chemotherapy for ALL and AML. There has been limited evidence of prophylaxis use and outcomes in children. Children safely received ciprofloxacin for antibiotic prophylaxis. In this particular study, there was no increase in ciprofloxacin resistant organisms during the time prophylaxis was used; however, analysis was done over a limited period of time and is not seen as conclusive. Continued monitoring for the development of drug resistance is important in organizations providing this type of prophylaxis as a routine. Findings here support the cost effectiveness of prophylaxis, showing lower intensive care stay lengths and overall cost during the time prophylaxis was used.

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Active antitumor treatment

An initial search resulted in 1,162 citations, which were delimited to 277 references that contributed to these guidelines. High-level evidence findings were included as well as a review of lower-level evidence by panel members in areas where high-level evidence was lacking.

Algorithms were established for the use of antifungal and antiviral therapies and the use of vaccinations, specifically therapeutic drug monitoring of azoles; enhanced recommendations for HBV, HCV, and HIV; and vaccination utilization (outlined by disease/therapies and level of risk, p. 884–890). Overall, infection control should include prophylactic anti-infective therapies, per protocol per case, as well as ensure standards of care (e.g., hand hygiene). Considerations for susceptibility and resistance are paramount.

• No major limitations were noted. These werecomprehensive guidelines from a national work group.

Assessment of patient diagnosis, treatment, and preexisting comorbidities (e.g., HSV, HIV, CMV) can guide proper prophylactic anti-infective agents and vaccines. Together with following standards of practice (e.g., hand hygiene), nurses can optimize infection control.

The purpose of this article was to study the primary prophylaxis of invasive fungal infections (IFI) in patients with hematologic malignancies. Eighty-six trials were reviewed, with a total patient population of 16,922.

In order to compile this resource, data were extracted and a draft manuscript was written by two of the authors and reviewed by a committee of hematologists and infectious disease specialists assigned by the Infectious Diseases Working Party of the German Society for Haematology and Oncology. The consensus draft was secondarily reviewed by the review committee of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. In cases where uniform consensus was not reached, the majority vote was adopted. Treatment recommendations were categorized using the evidence categories of the Infectious Disease Society of America ( IDSA). The categories indicate the strength of evidence and the quality of evidence. 

• A: Good evidence to support  a recommendation for use.
• B: Moderate evidence to support a recommendation for use.
• C: Poor evidence to support a recommendation for use.
• D: Moderate evidence to support a recommendation against use.
• E: Good evidence to support a recommendation against use.

I = evidence from at least one properly randomized, controlled trial; II = evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), from multiple time series, or from dramatic results of uncontrolled experiments; III = evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

For the search stragety, the following databases were used: Medline, CancerLit, Embase, Cochrane Library and conference proceedings of Advances Against Aspergillosis, ASH, EBMT, ECCMID, ESMO, Focus on Fungal Infections, and ICAAC/IDSA. Keywords included invasive fungal infection, antifungal prophylaxis, itraconazole, fluconazole, posaconazole, amphotericin B, and liposomal. Inclusion was based on the research being clinical trials on antifungal prophylaxis. Exclusion criteria were trials published as abstracts, only, and meta-analyses.

Active treatment

Fluconazole 400 mg per day was significantly superior to placebo in both the reduction of breakthrough invasive fungal infection and the decrease of IFI attributable mortality; showed a lower incidence of intestinal graft-versus-host disease (GVHD); and is protective against cyclophosphamide toxicity. Doses lower than 400 mg per day failed to show a marked benefit. Also, breakthrough infections are seen with molds and Candida krusei due to their intrinsic resistance to fluconazole. Itraconazole is broader in spectrum than fluconazole, but has a start-up delay; therefore, it is not recommended as a start-up for prophylaxis of invasive fungal infection.

One study found itraconazole suspension at a dose of 2.5 mg/kg bid plus nystatin 500,000 IU qid versus nystatin alone to be a more effective reduction in the rate of fatal candidemia from 2% to 0; however, invasive mold infections and death due to fungal infection were not prevented. Itraconazole was not shown to be more effective than fluconazole in patients with hematologic malignancies and was associated with more adverse outcomes.

At a dose of 600 mg per day, posaconazole resulted in a significant reduction in proven and probable IFIs, mainly by reducing the incidence rate of aspergillosis along with an attributable and overall mortality reduction. Safety, including the overall rate of patients with serious adverse events, was comparable between posaconazole, flucanazole, and itraconazole. The only difference was a higher rate of patients on posaconazole experiencing possibly or probably related serious adverse events than patients on fluconazole or itraconazole prophylaxis. Posaconazole 600 mg per day was associated with decreased mortality associated with GVHD in HCT recipients.

Voriconazole exposure has been associated with a reduction of invasive aspergillosis, but an increase in breakthrough zygomycosis.

Ketoconazole, miconazole, and clotrimazole have not been proven effective.

Amphotericin B, a broad spectrum anti-fungal, does not appear to be significantly effective and is associated with adverse events in all forms (inhalation, deoxycholate infusion, and lipid-based formulations).

Primary prophylaxis with fluconazole 400 mg per day is recommended since it reduces the incidence of invasive candidiasis and mortality after HSCT (AI). The recommended antifungal prophylaxis in patients with neutropenia (ANC < 500 cell/mcl for more than seven days): posaconazole 200 mg PO TID for patients with AML/MDS receiving induction chemotherapy (AI); liposomal amphotericin B 12.5 mg twice a week by inhalation (BII); liposomal amphotericin B 50 mg q 48 hours via IV (CII); itraconazole oral solution 2.5–7.5 mg/kg/d (CI), fluconazole 400 mg per day PO (CI), itraconzole capsules, any dose (CI); caspofungin 50 mg per day IV (CI); conventional amphotericin, any dose IV or 20 mg per day inhalation (EI). 

The recommended antifungal prophylaxis in patients undergoing allogeneic HSCT: fluconazole 400 mg per day PO (until the development of GVHD) (AI); posaconazole 200 mg TID PO (in the setting of GVHD) (AI); itraconazole oral solution 400 mg per day PO (CI); micafungin 50 mg per day IV (CI).

Other recommendations for antifungal prophylaxis: itraconazole, any dose of capsules (CI); voriconazole (CII), fluconazole less than 400 mg per day (EI); ketoconazole, any dose (EII); miconazole, any dose (EII); clotrimazole, any dose (EII); nystatin, any dose (EII).

Fluconazole 400 mg per day is recommended to prevent IFIs in allogeneic stem cell recipients until the development of GVHD. Posaconazole is recommended to prevent IFI in allogeneic stem cell recipients with severe GVHD, and in patients with acute myelogenous leukemia or myelodysplastic syndrome undergoing induction chemotherapy. There is no benefit to the use of  fluconazole in the non-transplantation setting to prevent IFI. Itraconazole, voriconazole, caspofungin, and micafungin are not recommended to prevent IFI since there is limited data. Aerosolized liposomal amphotericin B appears to be effective to reduce the risk of invasive pulmonary aspergillosis in patients with prolonged neutropenia, but it was given with concomitant fluconazole. Conventional amphotericin B is strongly NOT recommended due to toxicity and the availability of other less-toxic effective agents.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Not fully described. Provides only search terms used

Not stated

• Identifies high-risk factors as low neutrophil counts; unrelated or mismatched HCT; a combination of systemic steroid use and low neutrophil counts; high-dose cytarabine, fludarabine, or alemtuzumab; and those with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML)
• Recommends prophylaxis for patients undergoing allogeneic HCT until at least day 75 or for 16 weeks in patients with graft-versus-host disease
• Recommends mold active prophylaxis for high-risk patients
• Recommends anticandida prophylaxis for low-risk patients
• Provides a review of individual prophylactic medications and application with specific antitumor agents used
• Recommends secondary prophylaxis in those with previous invasive fungal disease

No quality grading of evidence

Provides information regarding risk factors for consideration in determining the specific type of prophylactic agent to be used, and provides comprehensive information regarding metabolism, etc., of individual antifungals.

To provide a guide for the use of antimicrobial agents for chemotherapy-induced fever and neutropenia in patients with cancer. The patient population targeted included adult and pediatric patients with neutropenia.

For this guideline document, the IDSA Standards and Practice Guidelines Committee reconvened many members of their original guideline panel, together with additional experts, in the management of patients with fever and neutropenia. The committee included experts in infectious diseases, oncology, and hematopoietic stem cell transplantation (HSCT) in both adult and pediatric patients. The literature was reviewed and graded according to a systematic weighting of the level and grade of the evidence for making a recommendation.

Patients were undergoing the active treatment phase of care.

Antibiotic Prophylaxis 

Fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients (patients expected to have absolute neutrophil counts (ANCs) of 100 cells/mm³ or lower for more than seven days. Levofloxacin and ciprofloxacin are the agents that have been evaluated the most and are generally equivalent, although levofloxacin is preferred for patients at risk for oral mucositis-related invasive viridans group streptococcal infection (B-1). The addition of a gram-positive active agent to fluoroquinolone prophylaxis is not recommended (A-1). Antibacterial prophylaxis is not indicated for low-risk patients anticipated to be neutropenic for less than seven days (A-III). 

Antifungal Prophylaxis

Patients at high risk for candida infection, such as recipients of allogeneic HSCT and patients with acute leukemia undergoing intensive chemotherapy, should be treated with antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin (A-I). Patients aged 13 years or older who are undergoing intensive chemotherapy for acute leukemia or myelodysplastic syndrome who are at high risk for aspergillus infection may be treated with posaconazole for antifungal prophylaxis (B-I). Prophylaxis against aspergillus infection is not effective in recipients of pre-engraftment HSCTs, but it is recommended for patients with a prior history of invasive aspergillosis (A-III), anticipated neutropenia of at least two weeks (C-III), or a prolonged period of neutropenia prior to transplantation (C-III). Antifungal prophylaxis is not recommended for patients with an anticipated duration of neutropenia of less than seven days (A-III). 

Antiviral Prophylaxis

Herpes simplex virus–positive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Annual influenza vaccination is recommended for all patients being treated for cancer (A-II). The optimal timing has not been established, but serologic responses may be best between chemotherapy cycles (more than seven days after the last treatment) or more than two weeks prior to the start of therapy (B-III). 

Colony-Stimulating Factors

Colony-stimulating factors are recommended for prophylaxis against neutropenia when the anticipated risk of fever and neutropenia is 20% or greater.

Prevention of Catheter-Related Bloodstream Infections

Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine are recommended for all central venous catheter insertions (A-I). 

Hand Hygiene

Hand hygiene is the most effective means of preventing infection in the hospital (A-II).

Environment

HSCT recipients should be in private rooms (B-III). Patients with neutropenia do not need to be placed in single-patient rooms. Allogeneic HSCT recipients should be in rooms with more than 12 air exchanges, high-efficiency particulate absorption filtration, and positive pressure (A-III). Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III). 

Isolation and Barrier Precautions

No specific protective gear (gowns, gloves, or masks) are necessary during the routine care of neutropenic patients. Standard barrier precautions should be used for all patients when contact with body fluids is anticipated.

Food

In general, food should be well cooked. Well-cleaned uncooked fruits and vegetables are acceptable.

Skin and Oral Care

Daily showers are recommended to maintain skin integrity (expert opinion). Patients should brush their teeth two times per day or more with a regular toothbrush, and flossing can be performed if it can be performed without trauma (expert opinion). Patients with mucositis should rinse their mouths with sterile water, saline, or sodium bicarbonate rinses four to six times per day (expert opinion). Menstruating immunocompromised women should avoid tampons (expert opinion). Rectal thermometers, enemas, suppositories, and rectal examinations are contraindicated for patients with neutropenia (expert opinion).

This was a comprehensive guideline developed by the Infectious Diseases Society of America (IDSA) to guide clinicians in the care of patients with chemotherapy-induced neutropenia and in the management of febrile neutropenia. The full guide can be located at http://cid.oxfordjournals.org/content/52/4/e56.full.

To determine if there is sufficient evidence that pre-emptive antifungal treatment is as effective as antifungal prophylaxis with posaconazole. The patient populations addressed included patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and allogeneic hematopoietic stem cell transplantation (HSCT) recipients with significant graft-versus-host disease.

Prophylactic antifungal therapy is defined as the initiation of an antifungal agent to high-risk patients to prevent a fungal infection. Pre-emptive antifungal therapy is defined as the initiation of antifungal therapy in high-risk patients based on laboratory markers, radiologic monitoring, or both to identify early ​invasive fungal infections (IFIs) before clinically overt disease develops. The authors based their evaluation on the principle that prophylaxis of fungal infections is important due to the significant morbidity and mortality associated with fungal infections, the incidence in high-risk patients, the safety of available antifungal agents, and the lack of sensitive methods of early detection. A pre-emptive approach is limited by the sensitivity and specificity of available detection methods. The authors reviewed the current literature on posaconazole prophylaxis and pre-emptive antifungal therapy.

No databases used for a search were listed, nor were any inclusion or exclusion criteria mentioned. However, keywords searched were invasive fungal infection, prophylaxis, pre-emptive therapy, and aspergillosis.

One prospective, randomized trial compared posaconazole with fluconazole or itraconazole as a primary antifungal prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia. Proven or probable IFIs occurred in seven (2%) patients in the posaconazole group and 25 (8%) patients in the fluconazole or itraconazole group (p < 0.001). Significantly fewer patients in the posaconazole group had invasive aspergillosis. Survival was improved in posaconazole recipients (p = 0.04). Serious adverse events possibly related to treatment occurred in 6% of patients in the posaconazole group and in 2% in the fluconazole or itraconazole group (p = 0.01).

One prospective, randomized trial compared primary antifungal prophylaxis with posaconazole versus fluconazole in allogeneic HSCT recipients with significant graft-versus-host disease on immunosuppression. Posaconazole was at least as effective as fluconazole in preventing IFIs during the prespecified period of observation (incidence, 5.3% versus 9%, respectively; p = 0.07) but was superior in preventing invasive aspergillosis and deaths caused by IFIs. If the analysis was restricted to the period in which patients received the study drug, posaconazole was considered superior to fluconazole in preventing IFIs (incidence, 2.4% versus 7.6%; p = 0.004), particularly invasive aspergillosis (incidence, 1% versus 5.9%; p = 0.001). Treatment-related adverse events were similar between the groups. One peer-reviewed publication reported pre-emptive antifungal therapy. The study was a feasibility study in which a total of 136 treatment episodes for patients with neutropenia at high risk for IFI were screened with daily serum galactomannan testing. There was a diagnostic algorithm that included chest computed tomography (CT) scans and bronchoalveolar lavage. Patients who met prespecified criteria for probable or proven invasive fungal infection received pre-emptive therapy with liposomal amphotericin B; neutropenic fever alone did not trigger modification in the antifungal regimen. Although this approach was successful in identifying early invasive aspergillosis and avoiding amphotericin B use in most patients with persistent neutropenic fever of unknown origin, invasive aspergillosis developed in 17 patients and zygomycosis in one patient among 136 chemotherapy treatment episodes. All cases of invasive aspergillosis were identified through positive antigenemia results. Seven (41%) deaths occurred in patients with positive serum galactomannan results; of these, six had autopsy-proven invasive aspergillosis. However, only two patients were considered to have died directly because of invasive aspergillosis.

The authors believe that insufficient evidence exists to recommend a pre-emptive antifungal therapy approach in place of posaconazole prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and allogeneic hematopoietic cell transplantation (HCT) recipients with significant graft-versus-host disease.

No conflict of interest was stated.

Posaconazole is recommended as a primary antifungal prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and in allogeneic HCT recipients with significant graft-versus-host disease. Pre-emptive treatment is not recommended in these patient populations.

PURPOSE: To provide guidance for the clinical practice of preventing and treating infection in patients with cancer

PHASE OF CARE: Multiple phases of care

One thousand one hundred sixty-two publications were retrieved. No method of study quality evaluation or results were reported.

The combination of evidence- and consensus-based recommendations and the differentiation between them are not clearly stated. For vascular access device prevention of infection, the guidelines only address antimicrobial-coated catheters and not any other aspect of management.

The guidelines provide a comprehensive reference to assess patient risk of infection and expert recommendations regarding interventions aimed at the prevention and treatment of infection in patients with cancer. They do not discuss long-term survivorship issues in this area.

PURPOSE: To provide healthcare providers with evidence-based recommendations on the use of primary antifungal prophylaxis in children with cancer and undergoing hematopoietic stem cell transplantation (HSCT)

TYPES OF PATIENTS ADDRESSED: Allogeneic and autologous HSCT recipients, children with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), and pediatric patients with anticipated neutropenia for longer than seven days

RESOURCE TYPE: Evidence-based guideline 

PROCESS OF DEVELOPMENT: Literature search was done, and included studies were evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation system. Recommendations were established by a panel discussion. Guidelines then were externally reviewed by another interprofessional expert panel and provided to Canadian pediatric tertiary hospitals for stakeholder review.

DATABASES USED: MEDLINE, EMBASE, Cochrane Collaboration, proceedings of the American Society of Clinical Oncology and American Society of Hematology    

KEYWORDS: Not stated

INCLUSION CRITERIA: RCTs involving patients of any age with cancer or undergoing HSCT that compared antifungal agents with another antifungal agent, placebo, or no prophylaxis; no language exclusions

EXCLUSION CRITERIA: Trials involving nonsystemic antifungal treatment

• PHASE OF CARE: Multiple phases of care            
• APPLICATIONS: Pediatrics

Initially, 7,869 references were retrieved and screened. A final set of 47 studies were included.

The following are strong recommendations.

• Children one month to 19 years undergoing allogeneic HSCT should have fluconazole daily from the start of conditioning until engraftment (high-quality evidence).
• When fluconazole is contraindicated, echinocandin should be used as an alternative (moderate-quality evidence).
• Children undergoing autologous HSCT with anticipated neutropenia for longer than seven days should receive fluconazole daily from the start of conditioning until engraftment (moderate-quality evidence).
• Children with AML or MDS should receive fluconazole daily during chemotherapy-associated neutropenia (moderate-quality evidence).

Additional weak recommendations also are outlined in the guidelines.

Although these guidelines are aimed at pediatric patients, 17 studies included did not include children in the sample.

These evidence-based guidelines clearly recommend primary antifungal prophylaxis in at-risk children. Specific dosages recommended are identified in this reference.

PHASE OF CARE: Multiple phases of care

This update includes information from 14 clinical trials (eight randomized) involving 2,899 patients published since 2009. The quality of evidence and the strength of recommendations were guided by criteria from the Infectious Diseases Society of America and the United States Public Health Service grading systems and are presented in table format.

Only eight of the 14 studies considered were randomized, controlled trials.

Unlike previous versions, the newest guidelines provide separate recommendations for allogeneic HSCT in the pre- and postengraftment phases and in the presence or absence of GVHD. If GVHD is present, posaconazole is considered the drug of choice while fluconazole use is discouraged. Because the labeling of antifungal compounds can vary by country, the guidelines may not necessarily follow approved indications. They do, however, reflect published evidence.