Claudio Viscoli

Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy

BACKGROUND Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

A comparison of outcome from febrile neutropenic episodes in children compared with adults: Results from four EORTC studies

The object of this study was to determine whether there were any differences between the ‘typical’ child with fever and neutropenia and their adult counterpart with regard to infection type and outcome, by analysis of 3080 patients, including 759 children < 18 years of age and 2321 adults. These represented patients randomized in previous trials, between 1986 and 1994, which compared empirical antibiotic regimens for fever in neutropenic patients. There were fewer childhood acute myeloid leukaemia patients than adults but more acute lymphoblastic leukaemia cases and more with solid tumours undergoing intensive myelosuppressive therapy. The children were less likely to be undergoing first induction therapy but the relative incidence of patients receiving relapse schedules or maintenance therapies were not significantly different in the two age groups. Children less frequently had a defined site of infection than adults and where they had a defined site there were more upper respiratory tract but fewer lung infections. There was a similar low incidence of shock at presentation in the two groups but the childrens median neutrophil count was lower, and their median duration of granulocytopenia before the trial was shorter. The incidence of bacteraemia was similar, but clinically documented infection was less frequent and fever of unknown origin consequently more common in children. Children developed more streptococcal bacteraemias and fewer staphylococcal bacteraemias than adults (P = 0.003) but the relative incidence of various gram‐negative species was similar (P = 0.57). In general, the children had a better overall success rate and lower mortality than adults. Death from infection was only 1% in children versus 4% in adults (P = 0.001), and time to defervescence was shorter in children. In the younger age group, univariate logistic regression models showed high temperature, prolonged neutropenia before the trial and shock as prognostic indicators for the presence of bacteraemia. Solid tumour patients were significantly less likely to have a bacteraemia. Multivariate analysis confirmed the independent prognostic value of these indicators. Using the logistic equation of the selected model, the overall discriminant ability was poor. However, it was possible to identify a small subgroup without shock or high fever and with a short prior duration of neutropenia which carries a particularly low risk of bacteraemia, who could be considered for early discharge, monotherapy and shortened courses of antibodies, in prospective trials.

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

Infections in Patients with Febrile Neutropenia: Epidemiology, Microbiology, and Risk Stratification

Determinations of the type and setting of empirical therapy for immunocompromised patients with fever are complicated by the characteristics of the underlying illness and the effects of treatments already received, as well as by changing microbiological patterns and trends in drug resistance at national and institutional levels. Several systems have been proposed to distinguish patients who could benefit from outpatient antibiotic therapy from patients who require hospitalization. Practical considerations may decide whether the necessary monitoring during the period of neutropenia can be achieved.

Vancomycin versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Aspergillus Galactomannan Antigen in the Cerebrospinal Fluid of Bone Marrow Transplant Recipients with Probable Cerebral Aspergillosis

ABSTRACT The Aspergillus galactomannan test was performed on cerebrospinal fluid and serum samples from 5 patients with probable cerebral aspergillosis and from 16 control patients. Cerebrospinal fluid galactomannan levels were significantly higher in aspergillosis patients, and most galactomannan was produced intrathecally. Comparison of serum galactomannan values in pulmonary and cerebral aspergillosis patients showed significant overlapping. Detection of Aspergillus galactomannan in cerebrospinal fluid may be diagnostic of cerebral aspergillosis.

International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus

An international expert panel was convened to deliberate the management of azole-resistant aspergillosis. In culture-positive cases, in vitro susceptibility testing should always be performed if antifungal therapy is intended. Different patterns of resistance are seen, with multi-azole and pan-azole resistance more common than resistance to a single triazole. In confirmed invasive pulmonary aspergillosis due to an azole-resistant Aspergillus, the experts recommended a switch from voriconazole to liposomal amphotericin B (L-AmB; Ambisome(®)). In regions with environmental resistance rates of ≥10%, a voriconazole-echinocandin combination or L-AmB were favoured as initial therapy. All experts recommended L-AmB as core therapy for central nervous system aspergillosis suspected to be due to an azole-resistant Aspergillus, and considered the addition of a second agent with the majority favouring flucytosine. Intravenous therapy with either micafungin or L-AmB given as either intermittent or continuous therapy was recommended for chronic pulmonary aspergillosis due to a pan-azole-resistant Aspergillus. Local and national surveillance with identification of clinical and environmental resistance patterns, rapid diagnostics, better quality clinical outcome data, and a greater understanding of the factors driving or minimising environmental resistance are areas where research is urgently needed, as well as the development of new oral agents outside the azole drug class.

Fungal Infections in Children With Cancer A Prospective, Multicenter Surveillance Study

Background: Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children. Methods: A prospective, multicenter, 2-year surveillance of fungal infections in children receiving antineoplastic treatment was performed in 15 Italian centers. For each case, defined by means of EORTC-IFIG/NIAID-MSG, information was collected on age, phase of treatment, presence of neutropenia or lymphocytopenia, administration of antifungal drugs and survival. Results: Ninety-six episodes (42 proven [19 fungemias, 23 deep tissue infections], 17 probable and 37 possible invasive mycoses) were reported. Most of them (73%) followed aggressive chemotherapy, 21% allogeneic hematopoietic stem cell transplantation and only 6% moderately aggressive treatment. Neutropenia was present in 77% of the episodes, and it had a longer duration before deep tissue mycosis as compared with fungemia (P = 0.020). Lymphocytopenia was present in 75% of the episodes observed in nonneutropenic patients. As compared with children with fungemia, patients with probable invasive mycoses had a 25.7-fold increased risk of death, whereas it was 7.7-fold greater in children with possible invasive mycoses and 5-fold higher in those with proven deep tissue infection (P = 0.004). The risk of death was also 3.8-fold higher in patients already receiving antifungals at the time of diagnosis of infection as compared with those not receiving antimycotic drugs. Conclusions: In children with cancer, aggressive antineoplastic treatment, severe and longlasting neutropenia and lymphocytopenia are associated with fungal infections. These features as the clinical pictures are similar to those reported in adults, but in children, the overall and the infection-specific (fungemia or mycosis with deep tissue infection) mortalities are lower.

Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study

Caspofungin at standard dose was evaluated as first-line monotherapy of mycologically documented probable/proven invasive aspergillosis (IA) (unmodified European Organisation for Research and Treatment of Cancer/Mycosis Study Group criteria) in allogeneic hematopoietic SCT patients. The primary efficacy end point was complete or partial response at end of caspofungin treatment. Response at week 12, survival and safety were additional end points. Enrollment was stopped prematurely because of low accrual, with 42 enrolled and 24 eligible, giving the study a power of 85%. Transplant was from unrelated donors in 16 patients; acute or chronic GVHD was present in 15. In all, 12 patients were neutropenic (<500/μl) at baseline, 10 received steroids and 16 calcineurin inhibitors or sirolimus. Median duration of caspofungin treatment was 24 days. At the end of caspofungin therapy, 10 (42%) patients had complete or partial response (95% confidence interval: 22–63%); 1 (4%) and 12 (50%) had stable and progressing disease, respectively; one was not evaluable. At week 12, eight patients (33%) had complete or partial response. Survival rates at week 6 and 12 were 79 and 50%, respectively. No patient had a drug-related serious adverse event or discontinued because of toxicity. Caspofungin first-line therapy was effective and well tolerated in allogeneic hematopoietic SCT patients with mycologically documented IA.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients

OBJECTIVES Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.