Early Empiric Antifungal Therapy Research Articles

Empirical antifungal therapy for health care-associated intra-abdominal infection: a retrospective, multicentre and comparative study

BackgroundCurrent guidelines recommend using antifungals for selected patients with health care-associated intra-abdominal infection (HC-IAI), but this recommendation is based on a weak evidence. This study aimed to assess the association between early empirical use of antifungals and outcomes in intensive care unit (ICU) adult patients requiring re-intervention after abdominal surgery.MethodsA retrospective, multicentre cohort study with overlap propensity score weighting was conducted in three ICUs located in three medical institutions in France. Patients treated with early empirical antifungals for HC-IAI after abdominal surgery were compared with controls who did not receive such antifungals. The primary endpoint was the death rate at 90 days, and the secondary endpoints were the death rate at 1 year and composite criteria evaluated at 30 days following the HC-IAI diagnosis, including the need for re-intervention, inappropriate antimicrobial therapy and death, whichever occurred first.ResultsAt 90 days, the death rate was significantly decreased in the patients treated with empirical antifungals compared with the control group (11.4% and 20.7%, respectively, p = 0.02). No differences were reported for the secondary outcomes.ConclusionThe use of early empirical antifungal therapy was associated with a decreased death rate at 90 days, with no effect on the death rate at 1 year, the death rate at 30 days, the rate of re-intervention, the need for drainage, and empirical antibiotic and antifungal therapy failure at 30 days.

Comparison of The Effect of Candida Score and Candida Colonization Index on Decrease in Candidemia Incidence in Our Intensive Care Unit

Aim: Since candidemia is an important cause of mortality and morbidity in hospitals, especially in intensive care units (ICU), those hospitalized in the ICU; In patients with risk factors such as invasive device use and undergoing abdominal surgery, early empirical antifungal therapy is recommended to reduce mortality according to the results of candida score (CS) and candida colonization index (CCI). In this study, the data of the patients who were followed up in the ICU, who were started on empirical treatment according to KS and CCI, were evaluated and their effects on the incidence of candidemia were analyzed. Method: Cultures taken from 100 patients hospitalized in the intensive care unit where adult patients were followed between 01.06.2018 and 01.08.2021 were examined. While investigating the colonization index of each patient, swab samples were taken once during the hospitalization from five main sites: mouth, nose, skin, perineum, and catheter. Samples taken with sterile swabs were inoculated on Sabouraud dextrose agar (SDA) plates and the plates were incubated at 35°C for 48 hours. The yeast colonies formed were defined according to their microscopic appearance and biochemical properties. CCI and CS of the patients were evaluated and fluconazole prophylaxis was started in patients with KS ≥3 or CCI ≥0.5. Results: A total of 500 culture samples from 100 non-neutropenic adult patients were analyzed (Mean of 5 cultures/patient). No growth was detected in any of the samples in 32 (32 %) of 100 patients, and growth was detected in at least one of the samples taken from 68 patients (68 %). Reproduction was detected from a total of 118 samples. Of the yeasts, 104 were identified as Candida albicans, 10 as Candida glabrata and 4 as Candida inconspicua. CS≥ 3 and CCI ≥0.5 in 11 (11%) patients, and CS≥3, CCI

Impact of early empirical antifungal therapy on prognosis of sepsis patients with positive yeast culture: A retrospective study from the MIMIC-IV database.

Mortality and other clinical outcomes of culture-negative and culture-positive among patients with fungal sepsis have not been documented, and whether antifungal therapy prior to fungal culture reports is related to decreased mortality among patients remains largely controversial. This study aimed to determine the mortality and other clinical outcomes of patients with positive yeast cultures and further investigate the effects of initial empiric antifungal therapy. A retrospective study was conducted among septic patients using the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were divided into two groups based on first fungal culture status during intensive care unit (ICU) stay, and initial empirical antifungal therapy was prescribed based on physician's experience prior to fungal culture reports within 48 h. The primary outcome was in-hospital all-cause mortality. The secondary outcomes were 30-day all-cause mortality, 60-day all-cause mortality, length of ICU stay and length of hospital stay. Multivariate logistic regression, propensity score matching (PSM), subgroup analyses and survival curve analyses were performed. This study included 18,496 sepsis patients, of whom 3,477 (18.8%) had positive yeast cultures. Patients with positive yeast cultures had higher in-hospital all-cause mortality, 60-day all-cause mortality, and longer lengths of ICU stay and hospital stay than those with negative yeast cultures after PSM (all p < 0.01). Multivariate logistic regression analysis revealed that positive yeast culture was a risk factor for in-hospital mortality in the extended model. Subgroup analyses showed that the results were robust among the respiratory infection, urinary tract infection, gram-positive bacterial infection and bacteria-free culture subgroups. Interestingly, empiric antifungal therapy was not associated with lower in-hospital mortality among patients with positive yeast cultures, mainly manifested in stratification analysis, which showed that antifungal treatment did not improve outcomes in the bloodstream infection (odds ratio, OR 2.12, 95% CI: 1.16-3.91, p = 0.015) or urinary tract infection groups (OR 3.24, 95% CI: 1.48-7.11, p = 0.003). Culture positivity for yeast among sepsis patients was associated with worse clinical outcomes, and empiric antifungal therapy did not lower in-hospital all-cause mortality in the bloodstream infection or urinary tract infection groups in the ICU.

Survival Outcome of Empirical Antifungal Therapy and the Value of Early Initiation: A Review of the Last Decade.

This rapid systematic review aimed to collect the evidence published over the last decade on the effect of empirical antifungal therapy and its early initiation on survival rates. A systematic search was conducted in PubMed, Cochrane, Medline, Scopus, and Embase, in addition to a hand search and experts' suggestions. Fourteen cohort studies and two randomized clinical trials reporting the survival outcome of empirical antifungal therapy were included in this review. Two studies reported the association between early empirical antifungal therapy (EAFT) and survival rates in a hematological cancer setting, and fourteen studies reported the outcome in patients in intensive care units (ICU). Six studies reported that appropriate EAFT decreases hospital mortality significantly; ten studies could not demonstrate a statistically significant association with mortality rates. The inconsistency of the results in the literature can be attributed to the studies' small sample size and their heterogeneity. Many patients who may potentially benefit from such strategies were excluded from these studies. While EAFT is practiced in many settings, current evidence is conflicting, and high-quality studies are needed to demonstrate the true value of this approach. Meanwhile, insights from experts in the field can help guide clinicians to initiate EAFT when indicated.

P090 Biofilm forming capabilities in multi-drug resistant Candida species with special emphasis on Candida auris isolated from intensive care unit patients

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM ObjectiveBiofilm forming capabilities of isolates obtained from intensive care unit (ICU) patientsTo study the trend of antifungal susceptibility of Candida isolates using MIC method by VITEK-2MethodsThis is a hospital-based prospective study in which Candida isolates from urine, blood, and BAL fluid of ICU patients from March 2021 to February 2022 were included. Conventional identification methods were performed for all isolates, speciation was done by MALDI-TOF. Biofilm formation by microtiter plate method and anti-fungal susceptibility was performed by VITEK-2.ResultsIn the present study, out of 360 positive fungal isolates, 20% Candida isolates (72) were obtained from the ICU patients. Candida tropicalis (45.2%) was the most common fungal isolate among all non-albicans Candida spp followed by C. parapsilosis, and C. auris. The biofilm formation was tested by microtiter plate method on Candida isolates. Candida auris showed strong biofilm formation tendency (28.5%). In this study, 16.6% of Candida isolates had resistance against fluconazole out of which 6 isolates were multiresistant to other antifungal. Use of automated machines helped in early identification of these species 24-48 h less than the conventional methods.ConclusionParallel increase in number of non-albicans Candida beside C. albicans could be because of patients on prolonged antimicrobial therapy, immunosuppressive drugs, varied comorbidities and species selection in the presence of certain antifungals, given the higher level of resistance expressed by NAC. Biofilm production a probable cause for increasing antifungal resistance and therapeutic failure. NAC species are emerging as potential threats to cause infection and posing a therapeutic challenge. Early empirical antifungal therapy and further research to improve diagnostic, prevention, and therapeutic strategies are necessary to reduce the considerable morbidity and mortality.

Diagnosis and Management of Invasive Candida Infections in Critically Ill Patients.

Invasive candidiasis (IC) has become a serious problem in the intensive care unit patients with an attributable mortality rate that can reach up to 51%. Multiple global surveillance studies have shown an increasing incidence of candidemia. Despite their limited sensitivity (21-71%), cultures remain the gold standard for the diagnosis of IC associated with candidemia. Many adjunct laboratory tests exist to support or rule out the diagnosis, each with its indications and limitations, including procalcitonin, 1,3-β-D-glucan, mannan and anti-mannan antibodies, and Candida albicans germ tube antibody. In addition, polymerase chain reaction-based methods could expedite species identification in positive blood cultures, helping in guiding early empirical antifungal therapy. The management of IC in critically ill patients can be classified into prophylactic, preemptive, empiric, and directed/targeted therapy of a documented infection. There is no consensus concerning the benefit of prophylactic therapy in critically ill patients. While early initiation of appropriate therapy in confirmed IC is an important determinant of survival, the selection of candidates and drug of choice for empirical systemic antifungal therapy is more controversial. The choice of antifungal agents is determined by many factors, including the host, the site of infection, the species of the isolated Candida, and its susceptibility profile. Echinocandins are considered initial first-line therapy agents. Due to the conflicting results of the various studies on the benefit of preemptive therapy for critically ill patients and the lack of robust evidence, the Infectious Diseases Society of America (IDSA) omitted this category from its updated guidelines and the European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) do not recommend it.

A randomized, double-blind, placebo-controlled clinical trial of fluconazole as early empiric treatment of coccidioidomycosis pneumonia (Valley Fever) in adults presenting with community-acquired pneumonia in endemic areas (FLEET-Valley Fever)

IntroductionCoccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown. MethodsPhase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness. ObjectivesThe primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality. DiscussionThis trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.

S2648 Spontaneous Peritonitis and When to Escalate Therapy From Bacterial to Fungal: A Case Report and Review of the Literature

INTRODUCTION: Spontaneous bacterial peritonitis (SBP) is a disease seen in patients with decompensated liver cirrhosis and can be deadly. Clear diagnostic criteria have been established with ascites showing >250 PMNs/mm at which point of time empiric antibiotic therapy should be initiated. Spontaneous fungal peritonitis (SFP) can present similarly to SBP, yet the diagnosis is often delayed and outcomes are poor. We present a case of a patient with SFP was misdiagnosed as SBP, followed but criteria that can distinguish those at high risk for SFP for whom early antifungal therapy could be considered. CASE DESCRIPTION/METHODS: A 67 yr old man with a history of decompensated NASH cirrhosis, CKDIII and diabetes presented to our hospital with acute kidney injury and abdominal pain, after having been discharged 2 weeks prior for a C. difficile infection and ascites requiring paracentesis. Signs and symptoms on arrival suggested spontaneous bacterial peritonitis with abdominal distension and tenderness and ceftriaxone was started empirically. Nephrology was consulted for kidney injury and diagnosed hepatorenal syndrome type 1. His initial paracentesis ascites fluid showed >4000 PMNs/mm3, confirming SBP. On day 2 he underwent hemodialysis and developed altered mental status, respiratory distress and hypotension and was emergently transferred to the ICU for intubation and antibiotic escalation to vancomycin, cefepime and metronidazole for septic shock. At 48 hours he underwent second paracentesis for which ascites fluid showed 3600 PMNs/mm3, suggesting failure of SBP therapy. Candida glabrata grew from initial paracentesis culture on day 3 and empiric micafungin was initiated. By day four with worsening clinical status and dismal prognosis, he was made comfort care after discussion with family. DISCUSSION: Effective medical therapy has been established for SBP, but such is lacking for spontaneous fungal peritonitis (SFP). In cases where SBP therapy fails, SFP should be seriously considered. Mortality for SFP remains significant at 50–100%, thought to be due to the delay in culture-based fungal therapy initiation. Literature suggests antifungal initiation at 48 hours does little to change initial prognosis and thus earlier initiation should be sought when possible. Ascitic fluid fungal PCR should be pursued for early diagnosis when SFP is suspected. We will present criteria that can delineate patients at high risk for SFP so that early empiric antifungal therapy can be initiated in attempt to improve overall prognosis.

Impact of host- and early treatment-related factors on mortality in ICU patients with candidemia: a bicentric retrospective observational study

BackgroundCandidemia is one of the most life-threatening infections among critically ill patients in the intensive care unit. However, the number of studies on the impact of host- and early treatment-related factors on mortality in this cohort is limited. The aim of this study was to investigate the relationship between clinically relevant factors, including early treatment (appropriate antifungal therapy and/or central venous catheter removal) and mortality in intensive care unit patients with candidemia.MethodsWe performed a retrospective observational study in two Japanese University hospitals between January 2007 and December 2016. Adult intensive care unit patients with candidemia who met the following inclusion criteria: (1) ≥ 18 years old; (2) admitted in intensive care unit at the time of onset; and (3) central venous catheter in situ at the time of onset were included. We performed univariate and multivariate logistic regression analysis to identify factors associated with 30-day crude mortality.ResultsA total of 68 patients met the inclusion criteria, 47 (69%) of whom were males. The median age was 68.0 (interquartile range, 61.0–76.0) years. The most common causative Candida species was Candida albicans (40 [59%] patients). With respect to the source of infection, central venous catheter-related candidemia was the most frequent (30 [44%] patients). Thirty-day crude mortality was 54% (37 patients). In multivariate logistic regression analysis, Acute Physiology and Chronic Health Evaluation II score (1-point increments) was the only factor that was independently associated with higher 30-day crude mortality. Other variables, including appropriate antifungal therapy and/or central venous catheter removal ≤ 24 h and ≤ 48 h following onset, did not significantly influence mortality.ConclusionsCandidemia in intensive care unit patients is still associated with high 30-day crude mortality rates. The only predictor of death was Acute Physiology and Chronic Health Evaluation II score ≤ 24 h following candidemia onset. Early empiric antifungal therapy and/or early CVC removal conferred no significant clinical benefit on survival in this patient population.

Isolated cerebral mucormycosis masquerading as a tumor in an immunocompetent patient

ABSTRACTMucormycosis is an opportunistic fungal disease that commonly presents as cutaneous or rhinocerebral infections associated with immunocompromised states. It may exceptionally present as isolated involvement of the brain with a varied clinical presentation, which may be difficult to diagnose early, leading to increased mortality. Herein, we report the case of a 42-year-old immunocompetent female with left-sided limb weakness and a history of recurrent vomiting and headache for the last two years. Clinically, glioma was suspected, but histopathological examination revealed a few broad aseptate fungal hyphae. As no other organ was involved, the diagnosis of isolated cerebral mucormycosis was rendered. Reporting this case, we show an unusual presentation of a central nervous system mucormycosis masquerading a tumor in an immunocompetent patient. The case also highlights the importance of a careful histopathological examination to avoid missing the presence of occasional fungal hyphae. Ideally, recognition of fungal hyphae in the brain, during intraoperative consultation, can prompt brain tissue culture for definitive diagnosis and early empirical antifungal therapy, which may prove life-saving.

Antifungal Resistant in Non-Albicans Candida Species are Emerging as a Threat to Antenatal Women with Vulvovaginal Candidiasis

Vulvovaginal candidiasis (VVC) is caused by Candida species. It has been associated with impact on economic cost. Currently, Non-albicans Candida species are more resistant to azoles and get converted from harmless to pathogenic state due to several virulence factors. Monitoring of the antifungal susceptibility pattern is important to know the resistant pattern of Candida species. Thus the objective of this research was to the identification of Candida in species level and to evaluate the antifungal resistance pattern in Candida species isolated from the vaginal discharge of antenatal women with vulvovaginal candidiasis. This prospective study was done in SRM MCH &amp; RC, Chennai, India, from March 2017 and December 2018. An aggregate of 342 vaginal swabs were gathered from antenatal women of symptomatic and asymptomatic VVC. Antifungal susceptibility test was done by the disk diffusion method as per the CLSI guidelines. A total of 112 Candida species were isolated from 342 high vaginal swabs. Out of 112 Candida isolates, 65 (58%) were Non-albicans Candida (NAC) and 47 (42%) were C. albicans. In this study, 103/112(91.6%) of Candida isolates had the highest sensitivity to voriconazole and 26/112(23.2%) of Candida isolates had the highest resistance to miconazole. NAC species are emerging as potential threats to cause infection and posing a therapeutic challenge. Early empirical antifungal therapy and further research to improve diagnostic, prevention and therapeutic strategies are necessary to reduce the considerable morbidity and mortality.

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

An Observational Study on Early Empiric versus Culture-Directed Antifungal Therapy in Critically Ill with Intra-Abdominal Sepsis.

Objective. To compare early empiric antifungal treatment with culture-directed treatment in critically ill patients with intra-abdominal sepsis. Methods. A prospective observational cohort study was conducted between August 2010 and July 2011, on SICU patients admitted after surgery for gastrointestinal perforation, bowel obstruction or ischemia, malignancy and anastomotic leakages. Patients who received antifungal treatment within two days of sepsis onset were compared to patients who received culture-directed antifungal treatment in terms of mortality rate and clinical improvement. Patients' demographics, comorbidities, severity-of-illness scores, and laboratory results were systematically collected and analysed. Results. Thirty-three patients received early empiric and 19 received culture-directed therapy. Of these, 30 from the early empiric group and 18 from culture-directed group were evaluable and analysed. Both groups had similar baseline characteristics and illness severity. Patients on empiric antifungal use had significantly lower 30-day mortality (P = 0.03) as well as shorter median time to clinical improvement (P = 0.025). Early empiric antifungal therapy was independently associated with survival beyond 30 days (OR 0.131, 95% CI: 0.018 to 0.966; P = 0.046). Conclusion. Early empiric antifungal therapy in surgical patients with intra-abdominal sepsis was associated with reduced mortality and warrants further evaluation in randomised controlled trials.

Candida in Burns: Risk Factors and Outcomes

Sepsis due to Candida is an uncommon but a significant cause of death in burns patients. Colonization is common, but consensus guidelines for prophylaxis and empirical therapy do not specifically include this cohort. Our aim was to define predictive factors for candidaemia in a burns unit, to guide protocols for prevention and early treatment. We conducted a 10-year review (July 1998-December 2007) of patients admitted to the Victorian Adult Burns Service, Melbourne, Australia. Of 1929 patients admitted with acute burn injury, 143 had Candida isolated at any site, most commonly Candida albicans. There were 12 episodes of candidaemia. Prior colonization was an important risk factor for candidaemia, and the risk increased substantially with the number of colonized sites; indeed 43% of patients colonized at more than three sites (and not on antifungals) developed candidaemia. Other risk factors were higher total burn surface area, higher full-thickness surface area, prolonged admission, number and duration of intensive care unit admissions, number of visits to the operating theatre, alcohol as a contributing factor to burn, prior treatment with total parenteral nutrition, or certain antibiotics (ceftriaxone, vancomycin, amikacin, co-trimoxazole). The attributable mortality of candidaemia was 15% (n = 2). Initiation of antifungal therapy was often delayed. Our results support early empirical antifungal therapy in septic burns patients who are colonized, before the results of cultures become known. The role of prophylactic antifungals is less clear, but should be strongly considered for patients colonized at multiple sites.

Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis

Children with acute leukemia have increased risk for invasive fungal infections (IFI) but the role of long term antifungal prophylaxis (AFP) in morbidity and mortality of IFI is not well-known. Medical records of 154 children with acute leukemia who received AFP with fluconazole during intensive chemotherapy were retrospectively reviewed to determine risk factors, clinical characteristics and outcome of IFI. The overall incidence of IFI was 13.6%. Frequencies of proven, probable and possible infections were 7.2%, 2.6%, and 3.8%, respectively. The causative agent was Candida in 12 (57.2%) and Aspergillus in 9 (42.8%) children. There were 10 children with candidemia (47.6%), 7 with pulmonary aspergillosis (33.4%), 2 with hepatosplenic candidiasis (10.0%), one with sinopulmonary aspergillosis (4.5%) and one with sinus aspergillosis (4.5%). IFI was twice as common in acute myeloid leukemia (AML) (20.7%) than in acute lymphoblastic leukemia (ALL) (10.2%). Duration of profound neutropenia (P = 0.01) and steroid medications (P = 0.001) were significantly associated with IFI in univariate but not in multivariate analysis. Liposomal amphotericin B (L-AMB) was successful in 15 of 21 children as a single agent. Voriconazole produced complete response in four children with invasive aspergillosis and two with hepatosplenic candidiasis, who were unresponsive to L-AMB. The rate of IFI attributable death was 5%. Our results indicate that AFP with fluconazole and early empirical antifungal therapy may be effective in reducing the incidence and mortality of IFI in children with acute leukemia.

Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine.

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occured in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.

Anti-infective strategies in neutropenia

Anti-infective strategies in febrile neutropenic patients have evolved continuously over the past decade. The changing spectrum of not only the infecting organisms but also of the underlying disease have necessitated different approaches. While the duration and degree of neutropenia have remained the most important risk factors for the development of invasive infections, other factors such as the presence of catheters, cytotoxic chemotherapy, mucositis, infection history, microbial colonisation and the concomitant immune dysfunction, also play a major role in the design of the anti-infective strategy. Individualisation of treatment strategy and the need for flexibility in response to local microbial ecology have also become key concepts. Controversy still surrounds the optimal prophylactic and empirical therapeutic regimens. Selective suppression of the endogenous microbial flora, particularly of the alimentary tract and other mucosal surfaces is recommended for high risk patients, such as those with anticipated profound and prolonged neutropenia, severe post chemotherapy mucositis and the presence of long-term intravenous catheters. For all other risk categories, cost benefit ratios must be carefully weighed against potential clinical benefit. Empirical monotherapy with broad-spectrum cephalosporins or a carbapenem is accepted as a cost-effective and usually well tolerated alternative to combination therapy. However, close monitoring of the patient's response is essential. Early empirical antifungal therapy also remains one of the prerequisites for a successful outcome in the management of neutropenic fever. Safer and more effective antifungal agents are urgently needed. In the future haematopoietic growth factors and other new techniques, such as peripheral blood progenitor cell transplantations, are likely to play a role in the early prophylaxis and management of severe neutropenic infective episodes. Future anti-infective strategies in the neutropenic host may not only lie with antibiotics, but also encompass successful modulation of host defences.

Interventional antimicrobial therapy in febrile neutropenic patients

In this prospective multicenter trial, treatment strategies for 1573 patients with neutropenia < 1000/microliters and fever > or = 38.5 degrees C after cytotoxic chemotherapy were compared. Patients with unexplained fever were randomized to a three-phase sequential study for different established drug regimens. If an infection could be defined microbiologically or clinically, treatment modifications were determined. In phase I, treatment for all patients consisted of acylaminopenicillin (PEN) plus aminoglycoside (AMG); or third-generation cephalosporin (CEPH) plus AMG; or PEN plus CEPH. In 800 patients with unexplained fever the response rates were: PEN/AMG (n = 258): 74.4%, CEPH/AMG (n = 252): 73.4%; PEN/CEPH (n = 290): 70.0%. Total response rate was 72.5%. In phase II, patients not responding after 3 days received PEN/CEPH/vancomycin (n = 70) or PEN/CEPH/AMG (n = 74). The respective response rates were 52.9% and 55.4%, total 54.2%. If fever did not resolve, the patients received either PEN/CEPH (n = 40) or imipenem/cilastatin (n = 59) both in combination with amphotericin-B/5-flucytosin/rifampin. The response rates were 62.5% and 79.7%, respectively (p = 0.07), total 72.7%. No significant differences between the treatment modalities compared were found. Analyzing all three phases together, 91.3% of patients with unexplained fever were cured. The response rate was also analyzed according to patients with gram-positive bacteremia (n = 183), response rate = 82.5%; gram-negative organisms (n = 145) 78.6%; fungemia (n = 51) 43.1% (p < 0.001); lung infiltrates (n = 269) 61.3% (p < 0.001); clinically documented infections (n = 198) 84.4%; and clinically and microbiologically documented infections (n = 84) 82.1%. If infections were diagnosed after at least 5 febrile days, more lung infiltrates and fungal infections occurred (p < 0.001). Leukocytes rising above 500/mu during the infection predicted better response rates (p < 0.001): in unexplained fever 97.8% vs 86.5% and lower death rates 1.5% vs 8.5%. In documented infections the response rates were then 89.9% vs 62.3% and the death rates 7.0% vs 20.5%. Therapy of neutropenic fever and infections must be adapted according to risk factors and should include early empiric antifungal therapy. The therapeutic and prophylactic use of hematopoietic growth factors to overcome neutropenia should be evaluated.

Invasive candidiasis during granulocytopenia.

Candidiasis remains the most frequently encountered fungal infection in patients with profound granulocytopenia and appears to be increasing in frequency. In addition, Candida infections are occurring earlier during remission induction chemotherapy and can be caused by a variety of species such as C. albicans, C. tropicalis, and C. krusei. The most frequent source of disseminated infection is the gastrointestinal tract, as the integrity of the epithelium is disrupted by chemotherapeutic agents. The spectrum of disseminated candidiasis comprises both an acute and a chronic presentation (also known in the literature as hepatosplenic candidiasis). The management of disseminated infection consists of early empiric antifungal therapy with a standard agent, amphotericin B. Unfortunately, responses in the setting of profound granulocytopenia appear to be poor. Other agents that appear to be useful in the management of disseminated candidiasis include 5-flucytosine and fluconazole. Based on animal experimentation, it appears that the combination of these three classes of agents might produce superior results compared with amphotericin B alone. Removal of the central venous catheter does not appear warranted in the setting of profound granulocytopenia, and the role of colony stimulating factors needs to be defined. Given the severity and high mortality associated with disseminated candidiasis in patients with hematologic malignancies, antifungal prophylaxis appears warranted.

An evaluation of empirical antibiotic therapy in febrile neutropenic patients

A prospective study was undertaken to determine the effectiveness of an empirical antibiotic therapy regimen in 34 neutropenic patients undergoing bone marrow transplantation or remission-induction chemotherapy for leukaemia. Throughout the study period a total of 90 pyrexial episodes were monitored in which organisms designated to be pathogens were isolated from blood cultures on 38 occasions. The response rate to the combination of a ureidopenicillin with gentamicin fell sharply from 50% during patients' first pyrexial episodes to zero during the third and subsequent episodes. The preponderance of Gram-positive bacteria and the high overall resistance of bacterial isolates to these antibiotics have led us to reconsider our approach to empirical therapy and to include antibiotics with greater activity against Staphylococcus epidermidis. The emergence of fungi as a major cause of morbidity in patients with prolonged neutropenia underlines the necessity to introduce early empirical antifungal therapy in this group of patients.