Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study.

Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20-year period (1989-2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004-2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004-2008 (0.02-0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.

An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection.

A continuous dosing schedule of aerosolized ribavirin has been used for respiratory syncytial virus (RSV) upper respiratory tract infection and lower respiratory tract infection (LRTI) but is associated with high cost and inconvenient administration. We conducted an adaptive randomized trial to evaluate the effectiveness of an intermittent dosing schedule of ribavirin versus that of a continuous dosing schedule of ribavirin in preventing RSV LRTIs in 50 hematopoietic stem cell transplant recipients or patients with hematologic malignancies. LRTI occurred in 3 patients (9%) receiving the intermittent schedule and in 4 (22%) receiving the continuous schedule, with a 0.889 posterior probability. Because the intermittent schedule is easy to administer and has a higher efficacy than the continuous schedule, we recommend the intermittent schedule for patients who are at risk for RSV LRTI. Clinical Trials Registration. NCT00500578.

The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Fever and neutropenia: the early years.

The importance of neutropenia as a predisposing factor for infection in patients with haematological malignancies was not clearly appreciated until effective therapeutic agents became available. This led to the important advance of administering antibiotics promptly to neutropenic patients when they developed fever, before a diagnosis was established. Although some antibiotics available in the 1960s had activity against many pathogens in vitro, they were ineffective against infections in neutropenic patients. The development of methods to administer white blood cell transfusions along with antibiotics was beneficial to some patients. The development of new antibiotics was of critical importance, such as methicillin for treatment of Staphylococcus aureus and carbenicillin for Pseudomonas aeruginosa. Prevention of infection was attempted, using isolation rooms, air filtration and prophylactic antibiotics. All of these early efforts laid the foundations for the many important current investigations.

Polymicrobial infection in patients with cancer: an underappreciated and underreported entity.

Polymicrobial infections account for ~15% of infections in immunocompromised patients with cancer. However, limited information exists regarding the spectrum and microbiology of these infections, even in severely neutropenic patients. Most studies describe only monomicrobial bloodstream infections in detail, and information regarding polymicrobial infections and nonbacteremic infections is often incomplete or not provided at all. The current lack of well-established definitions for various infections in the immunocompromised host, including pneumonia, neutropenic enterocolitis, and polymicrobial infections, probably plays an important role in the paucity of published information. In this review, we briefly describe the limited information available regarding polymicrobial infections in patients with cancer and address the need for establishing consensus definitions for site-specific polymicrobial infections in neutropenic and nonneutropenic patients. We anticipate that, as factual information regarding such infections becomes available, a more comprehensive understanding of the true scope and impact of these infections will emerge, leading to appropriate modifications in the diagnostic work-up and in the therapeutic approaches used in treating these patients.

Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center.

Community respiratory viruses (CRVs) have been recognized as a potential cause of pneumonia and death among hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancies. We reviewed the Microbiology Laboratory records dated from July 1, 2000, to June 30, 2002, to identify patients who had respiratory specimens positive for influenza, parainfluenza, respiratory syncytial virus, or picornavirus. We identified 343 infections among patients with underlying hematologic malignancies and HSCT. We collected data on type of disease, age, sex, type of infection, neutrophil and lymphocyte counts, therapy, and outcome. Influenza, parainfluenza, and respiratory syncytial virus accounted for most cases and were approximately equal in frequency. Most infections occurred predominantly among recipients of allogeneic transplants. Infection progressed to pneumonia in 119 patients (35%) and occurred with similar frequency for the 3 viruses. Patients at greatest risk for developing pneumonia included those with leukemia, those aged more than 65 years, and those with severe neutropenia or lymphopenia. Lack of respiratory syncytial virus-directed antiviral therapy (p=0.025) and age (p=0.042) were associated with development of respiratory syncytial virus pneumonia, and an absolute lymphocyte count

Culture-positive and culture-negative endocarditis in patients with cancer: a retrospective observational study, 1994-2004.

Endocarditis is uncommon in patients with cancer. The characteristics of culture-positive (CPE) and culture-negative endocarditis (CNE) in high-risk cancer patients are not known; therefore we sought to evaluate the disease characteristics in patients with endocarditis at a comprehensive cancer center. We retrospectively reviewed the transthoracic (TTE) and transesophageal (TEE) echocardiograms obtained from 654 consecutive cancer patients in whom endocarditis was suspected between 1994 and 2004. Endocarditis was confirmed in 45 (7%) of 654 patients using modified Duke University criteria based on information obtained from hospital records and computerized data systems. In 21 (95%) of 22 cases, TEE examinations were diagnostic, and 16 (42%) of 38 patients with initially nondiagnostic TTE studies had the diagnosis confirmed by TEE study; this difference between diagnostic TEE and initial nondiagnostic TTE was significant (p < 0.0001). Among the 26 (58%) patients with CPE, Staphylococcus aureus (35%) was the most common organism isolated, followed by coagulase-negative Staphylococcus species (23%). Eighteen (78%) of 23 patients with a central venous catheter had CPE, whereas only 8 (36%) of 22 patients without a central venous catheter had CPE (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.69-23.53; p < 0.006). Vegetations were larger in patients with CPE than in patients with CNE (median +/- standard deviation, 10 +/- 8.8 vs. 8.7 +/- 3.9 mm). Fifteen patients (58%) with CPE and 10 (53%) with CNE had embolic complications. We note that cutaneous and septic pulmonary emboli were more common in patients with CPE than in patients with CNE (31% vs. 11% and 15% vs. 0%, respectively), whereas embolic cerebrovascular and fatal embolic coronary events were more common in patients with CNE than in those with CPE (37% vs. 12% and 21% vs. 0%, respectively; p = 0.026). The 4-week endocarditis-attributable death rate did not differ significantly between the groups (CPE, 15% vs. CNE, 32%; p = 0.28). On stepwise multivariate regression analysis, patients with neutropenia (OR, 22.52; 95% CI, 2.25-225.48; p < 0.008) and those with embolic cerebrovascular events (OR, 17.07; 95% CI, 1.63-178.45; p < 0.01) had an increased probability of death due to endocarditis. The clinical spectrums of CPE and CNE differed in these patients with cancer. In patients with CNE, embolic cerebrovascular and fatal myocardial infarction were relatively common.

Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003).

We evaluated autopsy-proven invasive fungal infections (IFI) in patients with hematologic malignancies over three periods (1989-1993, 1994-1998, and 1999-2003). The autopsy rate declined significantly (67%-34%-26%, respectively p<0.0001). IFI were identified in 314 (31%) of 1017 autopsies. Most IFI (75%) were not diagnosed antemortem. The prevalence of invasive mold infections increased significantly (19%-24%-25% p=0.05) in parallel with the emergence of Zygomycetes (0.9%-4%-3%; p=0.03). The prevalence of all other IFI remained relatively constant. Among patients with invasive pulmonary aspergillosis, those with graft-versus-host disease had a histopathological pattern distinct from those with neutropenia. The complex and evolving epidemiology of IFI in severely immunocompromised patients is not well captured by current diagnostic methods.

Cutaneous fungal infections in the oncology patient: recognition and management.

There are two main types of fungal infections in the oncology patient: primary cutaneous fungal infections and cutaneous manifestations of fungemia. The main risk factor for all types of fungal infections in the oncology patient is prolonged and severe neutropenia; this is especially true for disseminated fungal infections. Severe neutropenia occurs most often in leukemia and lymphoma patients exposed to high-dose chemotherapy. Fungal infections in cancer patients can be further divided into five groups: (i) superficial dermatophyte infections with little potential for dissemination; (ii) superficial candidiasis; (iii) opportunistic fungal skin infections with distinct potential for dissemination; (iv) fungal sinusitis with cutaneous extension; and (v) cutaneous manifestations of disseminated fungal infections. In the oncology population, dermatophyte infections (i) and superficial candidiasis (ii) have similar presentations to those seen in the immunocompetent host. Primary cutaneous mold infections (iii) are especially caused by Aspergillus, Fusarium, Mucor, and Rhizopus spp. These infections may invade deeper tissues and cause disseminated fungal infections in the neutropenic host. Primary cutaneous mold infections are treated with systemic antifungal therapy and sometimes with debridement. The role of debridement in the severely neutropenic patient is unclear. In some patients with an invasive fungal sinusitis (iv) there may be direct extension to the overlying skin, causing a fungal cellulitis of the face. Aspergillus, Rhizopus, and Mucor spp. are the most common causes. We also describe the cutaneous manifestations of disseminated fungal infections (v). These infections usually occur in the setting of prolonged neutropenia. The most common causes are Candida, Aspergillus, and Fusarium spp. Therapy is with systemic antifungal therapy. The relative efficacies of amphotericin B, fluconazole, itraconazole, voriconazole, and caspofungin are discussed. Recovery from disseminated fungal infections is unlikely, however, unless the patient's neutropenia resolves.

Managing infections in the immunocompromised patient.

Increasingly aggressive practices for treatment of patients with hematologic malignancies create challenges for successful management of infectious complications in immunocompromised patients. Infectious diseases practitioners face changing patterns of causative pathogens in their patients with febrile neutropenia, as well as evolving standards for empirical use of antimicrobial agents. The articles in this supplement issue of Clinical Infectious Diseases review these issues and their implications for current clinical practice.

Gastrointestinal cytomegalovirus disease in patients with cancer: a two decade experience in a tertiary care cancer center.

Although gastrointestinal cytomegalovirus disease (GI-CMVd) is not common in cancer patients, it is associated with high morbidity and mortality. Herein, we review our 2-decade experience with GI-CMVd in such patient population at The University of Texas M.D. Anderson Cancer Center. Forty-seven patients were identified. Thirty-four patients (72%) had an underlying haematological malignancy, and 18 patients (38%) developed GI-CMVd following hematopoietic stem cell transplantation (HSCT). Nine (25%) of the 36 cancer patients with data available had AIDS. Upper-GI tract involvement was more common in patients with haematological malignancies than in those with solid tumours (P=0.02). Patients with AIDS were more likely to have colonic involvement than were those without AIDS (67% vs. 15%, P=0.006), and patients without AIDS were more likely to have gastric involvement (59% vs. 11%, P=0.01). The CMV-attributable mortality rate was 42%. Independent predictors of death by multivariate analysis included disseminated CMV and AIDS (P<0.01). The presentation of GI-CMVd varies according to the type of cancer, and AIDS. GI-CMVd is associated with a high mortality among cancer patients, particularly those with disseminated CMV disease or AIDS.

Management of central venous catheters in patients with cancer and candidemia.

To determine the need and appropriate timing of catheter removal in patients with candidemia, the records for 404 patients with cancer and central venous catheters (CVCs) who developed candidemia during the period of 1993-1998 were retrospectively reviewed. Of the total 404 cases of candidemia, 241 (60%) were due to a primary source, 111 (27%) were catheter related, and 52 (13%) were secondary cases of candidemia caused by a source other than the catheter. Multivariate analysis showed that catheter removal < or =72 h after onset improved response to antifungal therapy exclusively in patients with catheter-related candidemia (P=.04). Clinical characteristics that suggested a noncatheter source for the candidemia were disseminated infection (P<.01), previous chemotherapy (P<.01), previous corticosteroid therapy (P=.02), and poor response to antifungal therapy (P<.03). CVC removal < or =72 h after onset should be considered in patients with suspected catheter-related candidemia who have no evidence of dissemination, recent corticosteroid therapy, or chemotherapy.

Nocardiosis in cancer patients.

Nocardiosis (NOC) is an important cause of infection in immunocompromised patients. However, large series in patients with cancer have not been described. We review the records of patients with cancer and NOC who were evaluated at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, between 1988 and 2001, and we describe the incidence, microbiologic and clinical characteristics, treatment, and outcome of NOC in this population. Forty-two patients with a total of 43 episodes of NOC were identified (incidence of 60 cases of NOC per 100,000 admissions). Twenty-seven patients (64%) had hematologic malignancies. In 13 patients, NOC complicated bone marrow transplantation. Neutropenia was observed in 4 (10%) of 40 episodes with information available, and lymphopenia in 20 (50%) of 40 episodes. Patients had received steroids for 25 episodes (58%) and had received chemotherapy for 10 episodes (23%) within 30 days before the onset of NOC. Nine episodes of breakthrough NOC were identified in 7 (23%) of the 40 patients with information available. Pulmonary NOC was seen in 30 (70%) of 43 cases; soft-tissue NOC in 7 (16%); central venous catheter-related nocardemia in 3 (7%); and disseminated NOC, central nervous system NOC, and a perinephric abscess each in 1 (2%). Twenty-three percent of patients with pulmonary NOC had an acute presentation. complex was the most common causative species (77%). Therapy for NOC was mainly concurrent trimethoprim/ sulfamethoxazole and either a tetracycline or a beta-lactam. The median duration of treatment was 113 days (range, 10-600 d). Nine (60%) of 15 patients with outcome data died from NOC. NOC, although infrequent, is an important cause of morbidity and mortality in patients with cancer. It has pleomorphic manifestations, and it can be seen as a breakthrough infection. The present study confirms that timely diagnosis, the site of NOC, the type of, the presence of comorbidities, and cytomegalovirus coinfection influence the outcome of patients with cancer and NOC.

Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy.

Since the 1990s, changing trends have been documented in species distribution and susceptibility to bloodstream infections caused by Candida species in cancer patients. However, few data are available regarding the association between in vitro antifungal susceptibility and outcome of candidemia in this patient population. We therefore evaluated the association of in vitro antifungal susceptibility and other risk factors with failure of initial antifungal therapy in cancer patients with candidemia. Candidemia cases in cancer patients from 1998 to 2001 (n = 144) were analyzed retrospectively along with their in vitro susceptibility to amphotericin B, fluconazole, and itraconazole (National Committee for Clinical and Laboratory Standards M27-A method). Patients were evaluable for outcome analysis if they received continuous unchanged therapy with either fluconazole or amphotericin B for >/=5 days. We excluded cases of mixed candidemia. In vitro susceptibility testing data of the first Candida bloodstream isolate were analyzed. Appropriate therapy was defined as that using an active in vitro antifungal for >/=5 days. For fluconazole susceptible-dose dependent Candida species, we defined appropriate therapy as a fluconazole dose of >/=600 mg/day. The Candida species distribution was 30% Candida albicans, 24% Candida glabrata, 23% Candida parapsilosis, 10% Candida krusei, 9% Candida tropicalis, and 3% other. Overall, amphotericin B was the most active agent in vitro, with only 3% of the isolates exhibiting resistance to it (>1 mg/L). Dose-dependent susceptibility to fluconazole and itraconazole was seen in 13% and 21% of the isolates, respectively, while resistance to fluconazole and itraconazole was seen in 13% and 26%, respectively.Eighty patients were evaluable for outcome analysis. In multivariate analysis, the following factors emerged as independent predictors of failure of initial antifungal therapy: leukemia (p = 0.01), bone marrow transplantation (p = 0.006), and intensive care unit stay at onset of infection (p = 0.02). Inappropriate antifungal therapy, as defined by daily dose and in vitro susceptibility, was not shown consistently to be a significant factor (it was significant in multivariate analysis, p = 0.04, but not in univariate analysis), indicating the complexity of the variables that influence the response to antifungal treatment in cancer patients with candidemia.

The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer.

PURPOSE: Candida glabrata is an increasing cause of candidemia, especially at cancer and bone marrow transplant centers where fluconazole is used for antifungal prophylaxis. This yeast is less susceptible to fluconazole in vitro than is Candida albicans. We compared the characteristics of patients who had C. glabrata and C. albicans candidemia at a large cancer center. SUBJECTS AND METHODS: We searched the microbiological laboratory reports and identified 116 cases of C. glabrata candidemia between 1993 and 1999. The 116 cases of C. albicans candidemia that occurred most closely in time (before or after each case of C. glabrata candidemia) served as the control group. Data were collected from patients' medical records. RESULTS: When compared with patients who had C. albicans infection, patients with C. glabrata candidemia more often had an underlying hematologic malignancy (68 [59%] vs. 26 [22%], P = 0.0001), had an Acute Physiology and Chronic Health Evaluation (APACHE) II score > or =16 (55 [48%] vs. 28 [25%], P = 0.0002), and received fluconazole prophylaxis (57 [49%] vs. 8 [7%], P = 0.0001). Patients with C. albicans candidemia more often had concomitant infections (101 [87%] vs. 78 [67%], P = 0.0003) and septic thrombophlebitis (11 [10%] vs. 2 [2%], P = 0.01). Among patients treated with antifungal therapy, those with C. albicans candidemia had a significantly greater overall response to therapy (83/104 [80%] vs. 60/97 [62%], P = 0.005) and to primary therapy (74/104 [71%] vs. 45/97 [46%], P = 0.0003). Amphotericin B preparations were not more effective than fluconazole (19/45 [42%] vs. 20/38 [53%], P = 0.5) in patients with C. glabrata candidemia. Fluconazole was less effective against C. glabrata than against C. albicans (20/38 [53%] vs. 57/74 [77%], P = 0.008). CONCLUSION: C. glabrata has emerged as an important cause of candidemia, especially among neutropenic patients who receive fluconazole prophylaxis.

Evaluation of the silver iontophoretic catheter in an animal model.

Silver iontophoretic catheters (SIC) were shown to be highly efficacious in preventing catheter infections in vitro and in a rabbit model (J. Infect. Dis. 173 (1996) 495). Furthermore, we sought to determine the safety and durability of SIC prior to use in humans. A total of 30 New Zealand white rabbits (3-4 kg) were randomly assigned to one of three groups whereby SIC or Arrow Guard (AG) catheters were tunneled and inserted in the jugular vein. All animals were followed for 2-12 weeks after catheter implantation. Blood was collected from each rabbit for assessment of toxicity and determination of silver levels. The electrical current generated by each SIC was measured once daily. At the end of the follow-up period, tissue samples were collected from the skin surrounding the catheter, the lungs, spleen, and liver. Microscopically, none of the tissues examined from any of the animals showed evidence of silver deposits, silver toxicity, thermal or electrical injury. The silver levels in the animals that received the SIC ranged from 0.1 to 2.23 microg/l with a mean of 0.62 (+/-0.44 SD). In conclusion SIC were safe with normal serum silver levels and were not associated with any local or systemic toxicity.

Breakthrough candidemia in patients with cancer differs from de novo candidemia in host factors and Candida species but not intensity.

OBJECTIVES: To evaluate the risk factors associated with breakthrough candidemia in patients with cancer and to compare them with those of de novo candidemia in this patient population. DESIGN: Retrospective case series of 120 episodes of candidemia, 90 de novo and 30 breakthrough candidemias. SETTING: University-affiliated, tertiary-care cancer center in Houston, Texas. PATIENTS: All patients with cancer who acquired candidemia between January 1993 and December 1998 were included if they had non-catheter-related candidemia and information about quantitative blood cultures. RESULTS: Although less frequent, breakthrough candidemia was seen more often in neutropenic patients with leukemia. The intensity of breakthrough candidemia was comparable to that of de novo candidemia. Most (70%) of the breakthrough candidemias were due to Candida glabrata or C. krusei. CONCLUSIONS: In breakthrough candidemia, the same risk factors seen in de novo candidemia were encountered, although more frequently. C. glabrata and C. krusei are the leading causes of breakthrough candidemia in patients with cancer.

Masking of neutropenic patients on transport from hospital rooms is associated with a decrease in nosocomial aspergillosis during construction.

To prevent nosocomial pulmonary aspergillosis during hospital construction, neutropenic patients with hematologic malignancy were required to wear high-efficiency masks when leaving their rooms. The rate of nosocomial aspergillosis decreased from 0.73 per 1,000 hospital patient-days during fiscal years 1993 to 1996 to 0.24 per 1,000 hospital patient-days during fiscal years 1996 to 1999 (P < .001). High-efficiency masks reduced nosocomial aspergillosis during hospital construction.