[Show abstract][Hide abstract] ABSTRACT: This report discusses the present status of antifungal therapy and treatment options for candidaemia, considered by experts in the field in Europe. A conference of 26 experts from 13 European countries was held to discuss strategies for the treatment and prevention of invasive candidiasis, with the aim of providing a review on optimal management strategies. Published and unpublished comparative trials on antifungal therapy were analysed and discussed. Commonly asked questions about the management of candidaemia were selected, and possible responses to these questions were discussed. Panellists were then asked to respond to each question by using a touchpad answering system. After the initial conference, the viewpoint document has been reviewed and edited to include new insights and developments since the initial meeting. For many situations, consensus on treatment could not be reached, and the responses indicate that treatment is likely to be modified on a patient-to-patient basis, depending on factors such as degree of illness, prior exposure to azole antifungals, and the presence of potentially antifungal drug-resistant Candida species.
[Show abstract][Hide abstract] ABSTRACT: Little is known about the incidence and clinical impact of cytomegalovirus (CMV) infection in patients with acute myeloid leukemia at the time of diagnosis and during chemotherapy. The aims of the present study were to assess prospectively the incidence of active CMV infection in 69 consecutive patients with acute myeloid leukemia and to describe the outcomes of treatment. pp65 antigenemia was monitored at diagnosis, post-induction and post-consolidation chemotherapy, and whenever CMV reactivation was suspected. Patients with pp65 antigenemia received pre-emptive anti-CMV treatment. Fifty-nine patients achieved complete remission. Baseline CMV serology results were available for 56 of the 59 patients: 52 patients (93%) were IgG positive. The overall incidence of pp65 antigenemia in patients in complete remission after chemotherapy was 35% (21/59): 9 patients after induction and 12 post-consolidation. Sixteen of the 21 pp65-positive patients received anti-CMV treatment: 15 as pre-emptive therapy and 1 for interstitial CMV pneumonitis. Five patients received no anti-CMV treatment and did not develop CMV disease. Patients with pp65 antigenemia had more hospital admissions (2.57 vs. 2.16; P = 0.009), while patients with >10 pp65-positive cells had more clinical complications (8/9 vs. 2/12; P = 0.002). In conclusion, patients with acute myeloid leukemia receiving chemotherapy should be monitored for active CMV infection. CMV reactivation in these patients was associated with an increased number of hospital admissions, and high levels of pp65 antigenemia were associated with more clinical complications. Controlled studies are needed to assess the relevance of pre-emptive anti-CMV therapy in patients with acute myeloid leukemia receiving chemotherapy.
Journal of Medical Virology 07/2010; 82(7):1201-7. · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preemptive strategies in neutropenic patients based on serum galactomannan (GM) -guided triggering of diagnostic work-up may be time-consuming and expensive when applied to the entire population. We have assessed the feasibility of a clinically driven diagnostic strategy without GM screening.
Patients with neutropenic fever underwent a baseline diagnostic work-up (BDWU; three blood cultures and other examinations as indicated). An intensive diagnostic work-up (IDWU; GM for 3 days, chest computed tomography and other examinations as indicated) was reserved for patients with 4 days of persisting or relapsing fever or with other clinical findings possibly related to an invasive fungal diseaser (IFD). Antifungal therapy was administered to patients diagnosed with IFD and empirically (negative IDWU) only to those with persisting neutropenic fever and worsening clinical conditions.
Of 220 neutropenia episodes, fever occurred in 159 cases and recurred in 28 cases. Overall, 49 IFDs were diagnosed (two by BDWU and 47 by IDWU) during 48 episodes (21.8%). Diagnostic-driven therapy was administered to 48 patients with IFDs; one patient with zygomycosis died without treatment. Only one patient received empirical therapy. IDWU was required in 40% of neutropenia episodes, and only 1.4 mean blood samples per neutropenia episode were tested for GM. Our strategy allowed a 43% reduction in antifungal treatments compared with a standard empirical approach. At 3-month follow-up, 63% of patients with IFD survived, and no undetected IFDs were found.
A clinically driven diagnostic approach in selected neutropenia episodes offered effective antifungal control and reduced the exposure to unnecessary antifungal treatment.
Journal of Clinical Oncology 10/2009; 28(4):667-74. · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: CMV infection may occur in 25- 60% of patients (pts) receiving alemtuzumab(anti-CD52)-based therapy; the efficacy of prophylaxis in preventing CMV reactivation is not well defined.In a prospective single-center study, we evaluated the efficacy and safety of VACV in the prevention of CMV infection in CLL pts who received alemtuzumab-based therapy. Methods: From June 2004 to February 2008,17 resistant/relapsed CLL pts received alemtuzumab-based therapy. Patients received oral VACV 6 g daily during alemtuzumab-based therapy and for at least 2 months after the last alemtuzumab dose. Symptomatic CMV reactivation was defined as fever with positive pp65-antigenemia (pp65-AG) and no other causes of fever. Patients were weekly monitored by pp65-AG until 2 months after alemtuzumab treatment had been discontinued. The pp65-AG results were reported as the number of positive cells/200,000 peripheral blood leukocytes (PBL) examined. Patients with positive pp65-AG (=/>1 positive cell per 200,000 PBL) discontinued both alemtuzumab and VACV,and were treated with intravenous ganciclovir (GCV) for 14-21 days. Results: All pts had negative CMV pp-65AG at baseline.Three of 17 (17%) pts had asymptomatic CMV reactivation (one or more pp65-AG positive result, with a median of 3 positive cells, range 1-20), none of 17 pts had symptomatic CMV infection or disease.The pp65-AG assay was positive at a median of 7 weeks of alemtuzumab therapy (range 4-12 weeks). All 4 asymptomatic CMV infected pts were treated with GCV and all recovered; only 1 fludarabine-alemtuzumab refractory patient had a second episode of positive pp65-AG and was successfully retreated with GCV. Alemtuzumab and VACV were restarted without further CMV reactivations.No patient discontinued VACV for other adverse events. Conclusions: Our findings suggests that VACV (6 g daily) may prevent CMV infection effectively and safely in CLL pts receiving alemtuzumab-based therapy
Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
[Show abstract][Hide abstract] ABSTRACT: Cytomegalovirus infection and disease is associated with poor prognosis and steroid refractoriness in inflammatory bowel disease patients. The unfavourable effect of steroids and immunosuppressive therapy on CMV infection is well known but few data are available concerning anti-TNFalpha therapy (Infliximab). Aim of the study was to evaluate the presence and severity of CMV infection and disease in Infliximab-treated IBD patients.
The severity of active CMV infection and disease was assessed in 11 consecutive patients with ileocolonic/colonic disease and 4 patients with ulcerative colitis before and after a standard 3-infusion course of Infliximab. Active CMV infection was evaluated by serology and diagnosed by means of pp65-antigenemia (pp65 AG), and quantification of CMV DNA isolated from biopsy specimens of colonic tissue. CMV disease was assessed on haematoxylin/eosin-stained colonic biopsies and immunohistochemical stains.
Of the 11 patients, nine were CMV seropositive. As far as concerns CMV infection, only one patient had positive pp65 AG, before and after Infliximab. CMV DNA was detected in the colonic biopsies of three patients. In 2, CMV DNA persisted also after therapy with 410 and 1300 copies/microg of DNA, respectively, albeit with no evidence of worsening of the colonic disease. In the remaining patient, CMV DNA load became undetectable. Conventional histology and immunohistochemical stains were negative for CMV in all the patients, without evidence of CMV disease.
Active CMV infection did not progress to disease following Infliximab therapy. Although these preliminary observations require confirmation, the response to Infliximab therapy does not appear to be influenced by, or influence the course of, CMV infection/disease.
Journal of Clinical Virology 08/2008; 43(2):180-3. · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the outcomes of patients with hematologic diseases diagnosed with acute invasive Aspergillus rhinosinusitis comparing a group of patients diagnosed after voriconazole was available at our center with a historical group of patients diagnosed before voriconazole was available. Voriconazole use was associated with a decrease in mortality and earlier clinical response.
[Show abstract][Hide abstract] ABSTRACT: During the last 15 years, we have used the National Cancer Institute (NCI) 89-C-41 protocol in patients aged younger than 21 years with Burkitt's leukemia/lymphoma (BLL) and diffuse large B-cell lymphoma (DLBCL). According to the Magrath staging system, patients were classified as low and high risk. Low-risk received three cycles of the CODOX-M regimen; high-risk patients received four alternating cycles with the CODOX-M and IVAC regimens. Thirty-five patients entered the study: 32 (91%) achieved complete remission (CR); three were non-responders and died and one patient died in CR. Two responders relapsed after 2 months and one presented early B acute lymphoblastic leukemia 33 months from the end of therapy. The 5-year overall survival and event free-survival are 83% and 80%, respectively. No late toxicity was registered. In our experience with a median follow-up of 11 years, the NCI 89-C-41 protocol has confirmed its high cure rate in BLL and DLBCL children and adolescents.
Leukemia and Lymphoma 04/2007; 48(3):551-9. · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report three cases of invasive Geotrichum capitatum infection in patients with acute leukemia for which an enzyme-linked immunosorbent assay (ELISA) for Aspergillus galactomannan was positive, with no evidence of aspergillosis. Supernatants obtained from suspensions of 17 G. capitatum strains gave positive reactions with the Aspergillus galactomannan ELISA. These clinical and laboratory data seem to suggest that G. capitatum produces a soluble antigen that is cross-reactive with Aspergillus galactomannan.
Journal of Clinical Microbiology 10/2006; 44(9):3432-4. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The microbiological, clinical, and epidemiological features of most non-Candida albicans Candida species are well known, but much less is known about species such as Candida guilliermondii, an uncommon pathogen causing a variety of deep-seated infections in immunocompromised hosts. To characterize C. guilliermondii fungemia in patients with hematological malignancies and its susceptibility to antifungal drugs, all cases of C. guilliermondii fungemia diagnosed in our department between 1983 and 2005 were retrospectively analyzed and the literature was reviewed. C. guilliermondii caused 29/243 (11.7%) candidemia episodes diagnosed during the study period. Central venous catheters were the documented sources of candidemia in 19/29 episodes (65.5%), and invasive tissue infections were documented in 2 (6.9%). In the remaining eight, the catheter was not removed and the source of the fungemia remained obscure. Seven episodes ended in death, but only one could be attributed to invasive C. guilliermondii infection. Molecular typing data reveal no evidence of common infection sources. Isolates displayed high rates of in vitro susceptibility to amphotericin B (100%), voriconazole (95%), and fluconazole (90%) and lower rates of in vitro susceptibility to flucytosine (86%), itraconazole (76%), and caspofungin (33%). Our literature review confirms that C. guilliermondii is a significantly more frequent cause of candidemia among cancer patients compared with the general hospital population. It accounted for <1% of the total number of Candida bloodstream isolates reported in the articles we reviewed, with higher rates in Europe (1.4%) and Asia (1.8%) compared with North America (0.3%).
Journal of Clinical Microbiology 08/2006; 44(7):2458-64. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low levels of Cytomegalovirus (CMV) viral load are frequently detected following allogeneic stem cell transplantation (SCT) and CMV disease may still develop in some allogeneic SCT patients who have negative pp65-antigenemia (pp65-Ag) or undetectable DNA. Pp65Ag is a sensitive method to diagnose CMV infection. Quantitative CMV-DNA PCR assay in plasma has been proposed to monitor CMV infection in SCT patients. We evaluated the clinical utility of pp65Ag and PCR assay in plasma of SCT recipients.
In a prospective longitudinal study, 38 consecutive patients at risk of CMV infection (donor and/or recipient CMV seropositive) were weekly monitored for CMV infection by both quantitative CMV-PCR in plasma (COBAS AMPLICOR CMV MONITOR) and pp65 Ag, during the first 100 days after SCT.
A total of 534 blood samples were simultaneously analysed for pp65Ag and PCR. Overall, 28/38 patients (74%) had active CMV infection within 100 days from SCT. In 16 patients, CMV was first detected by pp65 Ag alone; in 5 patients by both methods and in 6 by PCR assay alone; one patient had CMV biopsy-proven intestinal disease without pp65Ag and PCR assays positivity before CMV disease. Overall, three patients developed intestinal CMV disease (7.9%): one had negative both pp65Ag and PCR assays before CMV disease, one had disease and concomitant positivity of both methods, while in the remaining patient, only pp65Ag was positive before CMV disease.
Plasma PCR(COBAS AMPLICOR CMV MONITOR) and pp65Ag assays were effective in detecting CMV infection, however, discordance between both methods were frequently observed. Plasma PCR and pp65Ag assays may be complementary for diagnosis and management of CMV infection.
[Show abstract][Hide abstract] ABSTRACT: Several studies have suggested that hydration and sodium load might reduce nephrotoxicity related to amphotericin B-deoxycholate (AmB-d). However, a schedule of these nephroprotective measures has not been standardized until now. A protocol of hydration and electrolyte supplementation was used prospectively in patients with hematological malignancies receiving empirical AmB-d treatment to evaluate its effect on AmB-d-related renal toxicity.
A total of 77 consecutive patients received AmB-d (1 mg/kg per day) in association with an initial intravenous hydration of at least 1 l/m2 body surface, containing at least 1 l of 0.9% saline daily. Hydration was increased when serum creatinine levels showed a 20% increase from baseline. Serum electrolytes were replaced when indicated.
The median duration of AmB-d therapy was 14 days. The mean intravenous hydration and the mean diuresis were 1530 and 1970 ml/m2 of body surface per day, respectively. Overall, 55 patients (71.4%) received a mean of 18.5 days of therapy without dose-limiting adverse events. Despite significant increases in mean creatinine serum levels and decreases in mean creatinine clearance observed early in the whole population, in only six patients (7.8%) was therapy discontinued due to renal failure, which always recovered after treatment discontinuation. In eight patients (10.4%) therapy was stopped due to infusion-related side effects. Seven patients died while under antifungal therapy without relevant signs of AmB-d-associated toxicity.
Our prospective experience confirms that adequate hydration (about 1500 ml/m2 of body surface) and careful electrolyte supplementation are simple measures able to contain nephrotoxicity and to permit adequate antifungal therapy at least in the empirical setting.
Supportive Care Cancer 01/2006; 13(12):987-92. · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a case of breakthrough invasive zygomycosis in a stem cell transplant recipient who was receiving caspofungin for treatment of a breakthrough Candida krusei fungemia that occurred during fluconazole prophylaxis. Also, patients receiving the echinocandin caspofungin remain at risk for pathogens, such as zygomycetes, that are intrinsically resistant to this agent.
Journal of Clinical Microbiology 11/2005; 43(10):5395-6. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary infections are second in importance only to septicemia as a cause of infectious morbidity and mortality in patients with hematological disorders. The differential diagnosis of the pneumonitis syndrome includes not only infection but also a multitude of noninfectious causes. In addition, the diagnosis may be difficult, owing to the subtlety of the clinical signs as a consequence of the impaired inflammatory response. Radiographic findings are often nonspecific, and invasive procedures and microbiological exams are required to establish the cause of pulmonary disease and to choose a specific therapy. However, invasive diagnostic procedures are often precluded by the poor general conditions and (particularly in acute leukemia patients) by concurrent thrombocytopenia. The approach to all infectious complications, including those of the lower respiratory tract, in immunocompromised patients with hematological diseases, is based on aggressive prevention strategies and the empirical administration of broad-spectrum antimicrobials eventually followed by a clinically or microbiologically guided treatment modification. With regard to the antimicrobial treatment, given the variety of infectious and noninfectious causes of pulmonary infiltrates in patients with hematological diseases, the diversity of the underlying immunocompromised state, and the spectrum of clinical findings, no single general therapeutic algorithm can be applied.
Seminars in Respiratory and Critical Care Medicine 11/2005; 26(5):445-57. · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prophylactic use of fluoroquinolones in patients with cancer and neutropenia is controversial and is not a recommended intervention.
We randomly assigned 760 consecutive adult patients with cancer in whom chemotherapy-induced neutropenia (<1000 neutrophils per cubic millimeter) was expected to occur for more than seven days to receive either oral levofloxacin (500 mg daily) or placebo from the start of chemotherapy until the resolution of neutropenia. Patients were stratified according to their underlying disease (acute leukemia vs. solid tumor or lymphoma).
An intention-to-treat analysis showed that fever was present for the duration of neutropenia in 65 percent of patients who received levofloxacin prophylaxis, as compared with 85 percent of those receiving placebo (243 of 375 vs. 308 of 363; relative risk, 0.76; absolute difference in risk, -20 percent; 95 percent confidence interval, -26 to -14 percent; P=0.001). The levofloxacin group had a lower rate of microbiologically documented infections (absolute difference in risk, -17 percent; 95 percent confidence interval, -24 to -10 percent; P<0.001), bacteremias (difference in risk, -16 percent; 95 percent confidence interval, -22 to -9 percent; P<0.001), and single-agent gram-negative bacteremias (difference in risk, -7 percent; 95 percent confidence interval, -10 to -2 percent; P<0.01) than did the placebo group. Mortality and tolerability were similar in the two groups. The effects of prophylaxis were also similar between patients with acute leukemia and those with solid tumors or lymphoma.
Prophylactic treatment with levofloxacin is an effective and well-tolerated way of preventing febrile episodes and other relevant infection-related outcomes in patients with cancer and profound and protracted neutropenia. The long-term effect of this intervention on microbial resistance in the community is not known.
New England Journal of Medicine 10/2005; 353(10):977-87. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the prevalence of human herpesvirus 8 (HHV-8) infection, the rate of HHV-8 seroconversion, and the presence of serum HHV-8 DNA after bone marrow transplantation (BMT), we evaluated sera from 187 Italian BMT donor-recipient pairs. Antibodies to lytic and latent HHV-8 antigens were detected by immunofluorescence. Sera of donor-recipient pairs who seroconverted were examined by real-time polymerase chain reaction (RT-PCR). Before BMT, 24 (13%) of 187 donors and 20 (11%) of 187 recipients were seropositive; after BMT, 28 (15%) of 187 recipients were seropositive. Seroconversion occurred in 19 (11%) of 167 recipients seronegative at baseline: 14 (9%) from 149 seronegative donors and five (28%) from 18 seropositive donors (relative risk of seroconversion with BMT from a seropositive donor = 2.96, 95% confidence interval = 1.21 to 7.25; P = .02, two-sided Fisher's exact test). One donor and two recipients who seroconverted after BMT were positive for HHV-8 by RT-PCR. No HHV-8-related complications were observed after a median follow-up of 6 years. BMT-associated HHV-8 seroconversion is relatively common in seronegative recipients from seropositive donor, but factors other than BMT may also contribute to seroconversion.
[Show abstract][Hide abstract] ABSTRACT: Trichosporonosis is an uncommon but frequently fatal mycosis in immunocompromised patients. A multicenter retrospective study was conducted to characterize cases of proven or probable invasive trichosporonosis diagnosed over the past 20 years in Italian patients with hematological diseases. Of the 52 cases identified, 17 were classified as Trichosporon sp. infections and 35 were attributed to Geotrichum capitatum. Acute myeloid leukemia accounted for 65.4% of the cases. The incidence rates of Trichosporon sp. and G. capitatum infections in acute leukemia patients were 0.4 and 0.5%, respectively. Overall, 76.9% of cases had positive blood cultures. Pulmonary involvement was documented in 26.9% of cases. Death was reported for 57.1% of G. capitatum infections and for 64.7% of Trichosporon sp. infections. A literature review on trichosporonosis in patients with any underlying disease or condition reveals G. capitatum as a predominantly European pathogen, particularly in certain Mediterranean areas, while Trichosporon sp. infections are seen with similar frequencies on all continents. The majority of published Trichosporon sp. and G. capitatum infections occurred in patients with hematological diseases (62.8 and 91.7%, respectively). Well over half of these were suffering from acute leukemia (68 and 84% of patients with Trichosporon sp. and G. capitatum infections, respectively). Crude mortality rates were 77% for Trichosporon spp. and 55.7% for G. capitatum. The optimal therapy for trichosporonosis has yet to be identified; however, in vitro experiences are providing encouraging evidence of the potential role of the new triazoles, in particular, voriconazole.
Journal of Clinical Microbiology 05/2005; 43(4):1818-28. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endoscopic procedures are the gold standard for the diagnosis of esophageal varices but these invasive methods are complex to perform in hemophilic patients co-infected with hepatitis C virus/human immunodeficiency virus (HCV/HIV). Real-time ultrasonography has been reported to be an effective, non-invasive procedure able to monitor patients with chronic liver disease and to give useful information for the diagnosis of liver cirrhosis, portal hypertension and the presence of esophageal varices.
Seventy patients with severe hemophilia were evaluated by esophago-gastro-duodenoscopy (EGDS) and ultrasonography; 40 had HCV/HIV co-infection and 30, comparable for age and HCV exposure time, were HCV+/HIV-. Hepatic longitudinal diameter, splenic longitudinal diameter, portal vein diameter and the average speed of portal flow were measured. The congestion index was calculated.
Thirteen out of 40 (32.5%) HCV/HIV coinfected patients had esophageal varices. None out of 30 HCV+/HIV- patients had esophageal varices (p< 0.001). Univariate analysis showed that the 13 HCV/HIV coinfected patients with esophageal varices had significantly higher hepatic longitudinal diameter (p=0.006), splenic longitudinal diameter (p=0.0002), portal vein diameter (p=0.0005) and congestion index (p=0.0001) than did the remaining 27 HCV/HIV coinfected patients. The stepwise logistic regression analysis indicated that, of the various ultrasonographic parameters evaluated, splenic longitudinal diameter and portal vein diameter had the greatest diagnostic efficiency in diagnosing a high proportion of patients with esophageal varices. The diagnostic efficiency of the combined criterion expressed by the area under the ROC curve was 0.8803. Interpretation and Conclusions. Real-time ultrasonography, by evaluation of splenic longitudinal diameter and portal vein diameter, is an effective non-invasive technique able to classify correctly a large proportion of HCV/HIV co-infected hemophilic patients with esophageal varices.