Empirical Antifungal Therapy In Patients Research Articles

Empiric antifungal therapy in patients with cutaneous and subcutaneous phaeohyphomycosis.

We encountered two cases of phaeohyphomycosis caused by Exophiala jeanselmei and E. oligosperma that were treated with fosravuconazole and terbinafine, respectively. Our cases were successfully treated with empiric therapy before the pathogen's species or antifungal sensitivity had been determined. We summarized 32 cases of cutaneous and subcutaneous phaeohyphomycosis caused by Exophiala species in Japan. The patients received antifungals, including itraconazole, terbinafine, voriconazole, and fosravuconazole, and the treatment success rates of these monotherapies were 77% (17/22), 67% (8/12), 100% (5/5), and 50% (1/2), respectively. Although the broad-spectrum azole antifungal itraconazole is the first choice for treatment, terbinafine at 125mg/day might exert the same efficacy. Fosravuconazole is a novel broad-spectrum azole and a moderate inhibitor of Cyp3A4 that causes fewer drug interactions than itraconazole and voriconazole, indicating a promising drug for this disease.

Role of Empiric Antifungal Therapy in Patients with Perforated Peptic Ulcers

Background: It is unclear if the addition of antifungal therapy for perforated peptic ulcers (PPU) leads to improved outcomes. We hypothesized that empiric antifungal therapy is associated with better clinical outcomes in critically ill patients with PPU. Patients and Methods: The 2001-2012 Medical Information Mart for Intensive Care (MIMIC-III) database was searched for patients with PPU and the included subjects were divided into two groups depending on receipt of antifungal therapy. Propensity score matching by surgical intervention, mechanical ventilation (MV), and vasopressor administration was then performed and clinically important outcomes were compared. Multiple logistic regression was performed to calculate the odds of a composite end point (defined as "alive, hospital-free, and infection-free at 30 days"). Results: A total of 89 patients with PPU were included, of whom 52 (58%) received empiric antifungal therapy. Propensity score matching resulted in 37 pairs. On logistic regression controlling for surgery, vasopressors, and MV, receipt of antifungal therapy was not associated with higher odds (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.5-4.7; p = 0.4798) of the composite end point. Conclusions: In critically ill patients with perforated peptic ulcer, receipt of antifungal therapy, regardless of surgical intervention, was not associated with improved clinical outcomes. Selection bias is possible and therefore randomized controlled trials are required to confirm/refute causality.

Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation.

Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.

Risk Factors for Invasive Candida Infection in Critically Ill Patients: A Systematic Review and Meta-analysis

BackgroundCurrent guidelines recommend empirical antifungal therapy in patients with sepsis with high risk of invasive Candida infection. However, many different risk factors have been derived from multiple studies. These risk factors lack specificity, and broad application would render most ICU patients eligible for empirical antifungal therapy.Research QuestionWhat risk factors for invasive Candida infection can be identified by a systematic review and meta-analysis?Study Design and MethodsWe searched PubMed, Web of Science, ScienceDirect, Biomed Central, and Cochrane and extracted the raw and adjusted OR for each risk factor associated with invasive Candida infection. We calculated pooled ORs for risk factors present in more than one study.ResultsWe included 34 studies in our meta-analysis resulting in the assessment of 29 possible risk factors. Risk factors for invasive Candida infection included demographic factors, comorbid conditions, and medical interventions. Although demographic factors do not play a role for the development of invasive Candida infection, comorbid conditions (eg, HIV, Candida colonization) and medical interventions have a significant impact. The risk factors associated with the highest risk for invasive Candida infection were broad-spectrum antibiotics (OR, 5.6; 95% CI, 3.6-8.8), blood transfusion (OR, 4.9; 95% CI, 1.5-16.3), Candida colonization (OR, 4.7; 95% CI, 1.6-14.3), central venous catheter (OR, 4.7; 95% CI, 2.7-8.1), and total parenteral nutrition (OR, 4.6; 95% CI, 3.3-6.3). However, dependence between the various risk factors is probably high.InterpretationOur systematic review and meta-analysis identified patient- and treatment-related factors that were associated with the risk for the development of invasive Candida infection in the ICU. Most of the factors identified were either related to medical interventions during intensive care or to comorbid conditions.

1167. Got Micafungin? The Incidence of Fungemia in Patients with Septic Shock

BackgroundTimely administration of antibiotics in patients presenting with sepsis decreases mortality, however evidence evaluating empiric antifungal coverage has been inconclusive. Recent data have shown no mortality benefit of empiric antifungal therapy in patients with ICU-acquired sepsis. Despite the lack of data, the Surviving Sepsis Campaign recommends empiric coverage for all suspected pathogens, including fungi. The purpose of this study is to determine the frequency of concomitant septic shock and fungemia at UMass Memorial Medical Center, a large tertiary care center.MethodsThis was a retrospective cohort study that included adult patients with a discharge diagnosis of severe sepsis or septic shock and/or fungemia admitted to UMMMC between October 2017 and October 2019. Patients with positive fungal blood cultures were further reviewed to identify if septic shock was present within 24 hours of blood culture collection. Additionally, risk factors for fungemia and 30-day mortality were assessed. Exclusion criteria included pregnancy, cultures from outside hospitals, incarceration, and hospice care.ResultsIn the analysis period, 4,253 patients had a discharge diagnosis of severe sepsis or septic shock. There were 68 cases of fungemia. In total, 54 patients with fungemia were included after applying exclusion criteria. Of the 54 patients with fungemia, 8 patients (15.1%) met criteria for septic shock at the time of positive blood culture, while 81% met SIRS criteria. Of the 4,253 total patients, 0.19% had coexisting fungemia and septic shock. At 30 days, four patients (7.4%) with both septic shock and fungemia had expired out of 12 total deaths. Three of the four deaths had multiple risk factors for fungemia including central line in place for greater than 48 hours, parenteral nutrition, and prolonged antibiotic therapy.ConclusionSeptic shock is a rare presentation of fungemia. Most patients with septic shock and fungemia have known risk factors. Despite recommendations by the Surviving Sepsis Campaign to initiate therapy for all likely pathogens, including fungal species, the incidence of fungemia presenting as septic shock at our academic medical center was very low and does not appear to warrant empiric coverage.Disclosures All Authors: No reported disclosures

A real-world prospective observational study on the efficacy and safety of liposomal amphotericin B in 426 patients with persistent neutropenia and fever

IntroductionInvasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan. MethodsAn open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection. ResultsOf the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported. ConclusionsThe safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.

Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.

SummaryBackgroundFungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required.ObjectiveWe conducted a multicentre, open‐label, randomised, non‐inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever.MethodsPatients with haematological malignancies who developed fever refractory to broad‐spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d).ResultsObserved overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model‐based estimate of a 4% difference (90% CI, −12% to 20%), did not fulfil the statistical non‐inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3‐4 hypokalaemia‐related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07).ConclusionivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non‐inferiority.

Echinocandins versus non-echinocandins for empirical antifungal therapy in patients with hematological disease with febrile neutropenia: A systematic review and meta-analysis

Empirical antifungal therapy is recommended in high-risk patients who have persistent febrile neutropenia (FN) despite broad-spectrum antibiotic therapy. Based on high-quality evidence, most guidelines recommend caspofungin. The aim of this study was to clarify whether echinocandins, including micafungin, are associated with improved clinical outcomes in patients with persistent FN. We conducted a meta-analysis of randomized controlled trials (RCTs) of empirical therapy with echinocandins and non-echinocandins for FN in patients with hematological disease. The primary outcome was all-cause mortality within 7 days after completion of therapy. Secondary outcomes included treatment success, and discontinuation of therapy because of adverse events. For subgroup analysis, we compared RCTs of echinocandins with liposomal amphotericin B. Six RCTs (four that evaluated caspofungin and two that evaluated micafungin) were included in the meta-analysis. Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with non-echinocandins [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.49–0.99; RR 0.48, 95% CI 0.33–0.71, respectively]. There was no significant difference in treatment success (RR 1.09, 95% CI 0.87–1.36). Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with liposomal amphotericin B (RR 0.68, 95% CI 0.46–0.99; RR 0.53, 95% CI 0.37–0.74, respectively). In conclusion, patients with persistent FN treated with echinocandins had decreased risk of death and adverse events. Both caspofungin and micafungin may be recommended as first-line empirical antifungal therapy in these patients. However, the small number of enrolled patients and the lack of RCTs involving pediatric patients should be considered when using micafungin.

Nephrotoxicity of Antimicrobials and Antibiotics.

Medication-induced nephrotoxicity remains one of the most common causes of acute kidney injury (AKI) among hospitalized patients. Within the extensive group of medications associated with AKI, antibiotics and other antimicrobials are well recognized triggers of structural and functional renal impairment. Clinical manifestations range from mild forms of tubular injury to significant deterioration of kidney function requiring acute renal replacement therapy. Several mechanisms are described, although the most frequent are acute interstitial nephritis, acute tubular necrosis, intratubular crystal deposition, and proximal/distal tubulopathy with electrolyte wasting abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease, and concomitant use of medication with nephrotoxic potential. Prevention and early recognition of AKI represent the standard approach to mitigate AKI and avoid morbidity.

Empirical antifungal treatment for diagnosed and undiagnosed invasive fungal disease in patients with hematologic malignancies

Background: Empirical antifungal therapy is effective in some patients with risk factors for invasive fungal disease (IFD) who do not qualify for the EORTC/MSG criteria for IFD, but who fail to respond to anti-bacterial and anti-viral therapy. Objective: This retrospective single-center study investigated the epidemiology of IFD and empirical antifungal therapy in patients with hematological malignancies. Methods: This study recruited 893 patients with hematologic malignancies who had failed to respond to anti-bacterial and anti-viral treatment and received antifungal therapy, but not for antifungal prophylaxis. Antifungal therapy regimens included amphotericin B, voriconazole, itraconazole and caspofungin. A total of 689 patients were diagnosed with proven, probable, or possible IFD, while 159 patients did not meet the EORTC/MSG criteria for IFD diagnosis but recovered with antifungal treatment, and 45 were excluded from having IFD. Effective treatment was defined as the disappearance or resolution of clinical symptoms of IFD. Results: Patients diagnosed with IFD underwent chemotherapy at a higher proportion, and had significantly higher neutrophil counts compared to those who did not qualify for the EORTC/MSG criteria for IFD but responded to antifungals. The mortality due to all causes within 3 months was significantly higher for patients diagnosed with proven IFD, compared with those who did not qualify for the EORTC/MSG criteria for IFD. There was no discontinuation reported due to adverse events of caspofungin. Conclusion: Empirical antifungal treatment could help save the lives of some patients with severe infections who are strongly suspected of having IFD.

Candida Tropicalis Cholangitis in a Patient With No Underlying Malignancy

SESSION TITLE: Critical Care 1 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Acute cholangitis is characterized by fever, jaundice and abdominal pain occurring secondary to biliary infection due to sepsis. Candida tropicalis is a rare cause of acute cholangitis, predominantly seen in patients with underlying hematological malignancies. Here, we describe a case of acute cholangitis caused by mixed organisms (Candida tropicalis, Candida albicans and Enterococcus durans) without known risk factors. CASE PRESENTATION: 78 year old Chinese female was brought in to ED after an unwitnessed fall at home. Patient was found to be febrile to 102F, hypotensive with neutrophil predominant leukocytosis and had a cholestatic picture on liver function tests. Ultrasound showed evidence of common bile duct stone and intrahepatic and common bile duct dilatation. Percutaneous Transhepatic Cholangiographic (PTCA) drain was placed and bile was sent for culture. Broad spectrum antibiotics were initiated and sepsis protocol followed. Blood cultures grew E. coli. Antibiotic regimen was switched to target the sensitivities of this organism. Workup for malignancy and other immunocompromised states was pursued with no evidence on CT scan or blood work. Despite initial improvement, the patient decompensated and expired. Bile cultures later grew Candida tropicalis, Candida albicans and Enterococcus durans. DISCUSSION: Candida in bile cultures is usually considered to be a colonization and not treated unless known risk factors are present (underlying malignancy, Diabetes Mellitus, prolonged antibiotic use history, immunosuppression, and biliary stent). We describe a case of cholangitis who decompensated on optimal antibiotic therapy and later bile cultures grew Candida tropicalis, Candida albicans and Enterococcus durans. Cholangitis secondary to Candida tropicalis has mostly been defined in patients with underlying malignancy1. Our case had a negative malignancy workup, no history of previous ERCP/EST, no history of receiving long term antibiotics or Diabetes. Blood cultures were negative for Candida which is concordant with various studies which reported sensitivity of blood cultures to detect Candida to be 50-75% or lower2. CONCLUSIONS: 1) A case of Candida tropicalis cholangitis defined in patient with no underlying malignancy or other risk factors. 2) Biliary Candidiasis as a cause of cholangitis should be considered as a differential in immunocompetent patients especially in the ICU setting. 3) Candidemia is not frequently present in patients with biliary candidiasis. 4) Consider early empiric antifungal therapy in patients with cholangitis in the ICU setting. Reference #1: 1. Ballal M, Chakraborty R, Bhandary S, Kumar P. Candida tropicalis in a case of cholangiocarcinoma with cholangitis at a tertiary care hospital in Manipal. Med Mycol Case Rep. 2013;2:95-97. Reference #2: 2. Lenz P, Eckelskemper F, Erichsen T, et al. Prospective observational multicenter study to define a diagnostic algorithm for biliary candidiasis. World J Gastroenterol. 2014 Sep 14;20(34):12260-12268. DISCLOSURE: The following authors have nothing to disclose: Arjun Saradna, Shyam Shankar, ishan malhotra, Ankur Sinha, Yizhak Kupfer, Taek Yoon No Product/Research Disclosure Information

Clinical evidence for caspofungin monotherapy in the first‐line and salvage therapy of invasive Aspergillus infections

In 2001, caspofungin received market authorisation by the FDA and EMA and is globally licensed for several indications, including candidiasis, empirical antifungal therapy in patients with neutropenic fever of unknown origin and treatment of invasive aspergillosis in patients refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or itraconazole. Despite the lack of phase III data in first-line treatment of invasive aspergillosis, increasing evidence supports the use of first-line therapy. Here, we analyse the evidence of therapeutic activity, represented by favourable response rates, of caspofungin for invasive aspergillosis. A systematic literature search was conducted to identify international presentations and papers reporting monotherapy with caspofungin. Efficacy data are summarised separately for first-line and salvage therapy. Thirty-one papers and published abstracts reported caspofungin therapy for aspergillosis. Fifteen full papers and two abstracts fulfilled the criteria of reporting significant outcome data for caspofungin monotherapy for invasive aspergillosis. Consistent with other analyses and the known safety profile, few adverse events and associated terminations of caspofungin medication have been reported. Although a randomised, comparative, prospective study using caspofungin in this indication is still lacking, growing evidence supports the efficacy of this echinocandin not only for salvage but also for first-line therapy.

Role of galactomannan assay in bronchoalveolar lavage fluid in the diagnosis of invasive aspergillosis in high risk patients with hematological disorders

Introduction: Invasive aspergillosis (IA) is the most frequent invasive fungal infection occurring in high risk patients with haematological disorders and also an important cause of morbidity and mortality in them. Lungs comprise the primary site of IA in the vast majority of cases, and the most frequently occurring form of IA. Early diagnosis followed by early initiation of therapy improves outcome. The current culture based diagnostic methods are insensitive and slow. Detection of Aspergillus galactomannan (GM) in serum using the platelia Aspergillus enzyme immunoassay (GM EIA) represents sensitive, non-culture-based tool for the early diagnosis of IA. Recent studies have shown that during IPA, GM is released earlier and in higher concentration in the BAL fluid than in serum. Thus, an early and accurate diagnosis of IPA can be reached by detecting antigen in BAL samples. Materials and Methods: Thirty consecutive high risk patients with haematological disorders satisfying the inclusion and exclusion criteria according to EORTC-MSG diagnostic criteria and undergoing indoor treatment were recruited between November 2013 and December 2014 into the study. In all the patients, bronchoalveolar lavage (BAL) fluid GM and serum GM assays were assayed. Results: The diagnostic accuracy of the two tests was measured by calculating the sensitivity, specificity, predictive values and receiver operating characteristic curve (ROC). The optimal BAL GM index for diagnosing probable and possible IPA was >1.00 OD, resulting in a sensitivity and specificity of 93.75% and 78.57% respectively. As per ROC curve, when the optimal BAL GM index for the diagnosis of probable and possible invasive pulmonary aspergillosis (IPA) was OD >0.5, it resulted in sensitivity and specificity of 50% and 71.43% respectively. BAL GM was thus found to have a significantly higher sensitivity as compared to serum GM. Conclusion: In all high-risk patients with haematological disorders where the clinical and radiological findings favour the possibility of invasive pulmonary aspergillosis, conducting a GM assay in BAL fluid sample is far more rewarding than carrying out the traditional serum GM assay. BAL GM has a high diagnostic accuracy when correlated with the EORTC/MSG diagnostic criteria, and this high diagnostic yield is useful in obviating the unnecessary widespread use and abuse of empirical antifungal therapy in patients with IPA.

Candida biomarkers in patients with candidaemia and bacteraemia

Microbiological strategies are necessary to help clinicians discontinue empirical antifungal therapy in patients with suspected invasive candidiasis. Culture methods and biomarkers each show low sensitivity. We analysed the value of combining different biomarkers as a decision-making tool for discontinuing empirical antifungal treatment. We studied stored serum samples from 31 patients with candidaemia (Candida albicans 40%, Candida tropicalis 20%, Candida parapsilosis 18%, Candida glabrata 12% and other 10%) and 50 patients with bacteraemia at Gregorio Marañón Hospital, Madrid, Spain. C. albicans germ tube antibody (CAGTA), mannan antigens (MN), antimannan antibodies (AMN) and (1→3)-β-d-glucan (BDG) were assayed using the manufacturer's and alternative cut-offs to improve the accuracy of the tests. The sensitivity of the biomarkers when used alone was low (58%-84%), but specificity was high (65.8%-92.0%). The best combinations were CAGTA and BDG using cut-offs of 1/80 and 80 pg/mL, respectively (sensitivity 96.8% and specificity 84%), and CAGTA and MN using cut-offs of 1/80 and 75 pg/mL, respectively (sensitivity 93.5% and specificity 86.0%). The sensitivity of both combinations was 100% for C. albicans, C. tropicalis and C. parapsilosis, but only combinations including BDG detected Candida krusei. The negative predictive values (NPVs) of both combinations were, respectively, 97.7% and 95.6% (prevalence of candidaemia, 23.6%). For a prevalence of candidaemia of 5% and 10%, the NPV reached 99.8% and 99.6%. The combinations of CAGTA and BDG or CAGTA and MN had a very high NPV at the alternative cut-offs and could be used in antifungal stewardship programmes as a decision-making tool for discontinuing unnecessary empirical therapy in patients with suspected candidaemia.

O2-7-4 - Micafungin Compared with Voriconazole for Empirical Antifungal Therapy in Patients with Neutropenia and Persistent Fever

Objectives: Patients with haematological malignancy who experience persistent fever and neutropenia often receive empirical antifungal therapy for the prevention and early treatment of invasive fungal infections. Micafungin (MCFG), a member of the echinocandin class of compounds, may be an effective alternative that is better tolerated than voriconazole (VRCZ).Methods: We conducted a randomised, cooperative group, open-label trial, comparing the efficacy and safety of micafungin with those of voriconazole as empirical antifungal therapy in febrile neutropenic patients with haematological malignancy. A successful outcome was defined as the fulfilment of all components of a 5-part composite endpoint.Results: Efficacy was evaluated in 100 patients (MCFG: 50, VRCZ: 50). Overall, favourable responses were observed in 52.0% of MCFG and 34.0% of VRCZ recipients (p = 0.069). There were no significant differences between the 2 groups in the rates of successful treatment of baseline fungal infection, absence of breakthrough fungal infection, survival for ≥7 days after treatment completion, or resolution of fever in the setting of neutropenia. Premature study discontinuation occurred less often in the MCFG group than in the VRCZ group (p = 0.001). Fewer patients who received MCFG experienced drug-related adverse events (p = 0.002).Conclusions: MCFG is as effective as and is generally better tolerated than VRCZ when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

Micafungin for empirical antifungal therapy in patients with febrile neutropenia: multicenter phase 2 study

Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150mg/day. Of the 78 evaluable patients, 54 (69%) achieved defervescence by the time of neutrophil recovery, and 56 (72%) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60%, with the lower limit of a 90% confidence interval (50.3%) exceeding the predefined threshold success rate (50%). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study.

The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea

To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

Empiric Antifungal Therapy in Patients with Febrile Neutropenia

Invasive fungal infections, most commonly candidiasis or aspergillosis, are a major cause of morbidity and mortality among patients with neutropenia. Difficulty in diagnosing invasive fungal infections in these patients complicates decisions regarding pharmacotherapy. Because of the difficult diagnosis and the significant morbidity and mortality of fungal infections in patients with neutropenia, systemic antifungal agents are used as empiric antifungal therapy in patients with febrile neutropenia who are not responding to antibacterial therapy. The pharmacotherapy of invasive fungal infections has evolved rapidly within the past several years as numerous antifungal agents--different formulations of amphotericin B, azoles, and echinocandins--have become available for use as empiric antifungal therapy in patients with febrile neutropenia. Various levels of evidence support the use of these agents for this indication. Their use is limited, however, by drug intolerance, drug interactions, adverse-event profiles, and limited activity with some mold species. Thus, considerations for selecting an antifungal drug for empiric use in patients with febrile neutropenia should include the epidemiology of fungal infections in the individual patient's institution and the specific clinical circumstances of the patient.

Economic evaluation of caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden

To evaluate the cost-effectiveness of caspofungin versus liposomal amphotericin B (L-AmB) for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden. With a decision-analytic model, the expected direct costs, life-years lost and quality adjusted life-years lost were estimated for an average patient in Sweden. Efficacy/tolerability data were obtained from analysis of a randomized, double-blind multinational trial. Life expectancy, medical resource use and unit costs data were gathered from the literature and expert opinion. Probabilistic sensitivity analysis was used to evaluate the impact of uncertainty in data on outcomes. The direct cost with caspofungin amounted to 233,851 SEK (95% uncertainty interval 225,091-242,210) and with L-AmB to 271,921 SEK (262,935-281,363), a difference of 38,070 SEK (31,745-44,811) favouring caspofungin. Treatment with caspofungin resulted in 0.25 (0.01-0.55) quality-adjusted life-years (QALYs) saved in comparison to L-AmB. Given the uncertainty in the estimates there is a >95% probability that caspofungin is economically dominant over L-AmB, i.e. cost-saving and QALY-saving. Given the underlying assumptions and data used, caspofungin is expected to be cost-effective with at least comparable outcomes compared to L-AmB for the empirical treatment of patients with suspected fungal infections in Sweden.

Positive Results of Serum Galactomannan Assays and Pulmonary Computed Tomography Predict the Higher Response Rate of Empirical Antifungal Therapy in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Invasive fungal disease (IFD) is a leading cause of infection-related mortality among patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the mortality of IFD has been decreased with empirical antifungal therapy in this population, overtreatment remains a problem, for the persistent or recurrent fever is nonspecific for an IFD. Hence, we explored retrospectively the value of incorporating serum galactomannan (GM) test and pulmonary high-resolution computed tomography (HRCT) as predictors for higher response rate of empirical treatment. In our study, all of 124 patients after allo-HSCT received empirical antifungal therapy when the persistent or recurrent fever developed after receiving broad-spectrum antibiotics. Meanwhile, the levels of serum GM were monitored twice weekly and pulmonary HRCT was performed serially. It showed that the response rate of empirical antifungal therapy was higher in patients with positive results of serum GM tests and/or chest CT scan than that in all patients (66.1% versus 44.6%, P = .008). Moreover, only 10 of 55 patients with both negative GM tests and pulmonary HRCT responded to empirical treatment, and 7 of these 10 patients did not take antifungal agents for prophylaxis. It suggested that these 2 diagnostic tools could not predict patients without adequate Candida prophylaxis well. Thus, we concluded that serum GM assays and pulmonary CT scan could find out patients who really need empirical antifungal therapy, which resulted in improving the efficiency of the treatment.