Fidaxomicin therapy in critically ill patients with Clostridium difficile infection.

Fidaxomicin use to treat proven Clostridium difficile infection (CDI) was compared between 20 patients receiving care in critical care units (CCUs) and 30 patients treated on general medical floors. At baseline, the CCU patients had more initial CDI episodes, more severe and complicated disease, and more concurrent broad-spectrum antibiotic coverage. On multivariate analysis, the response to fidaxomicin therapy among the critically ill patients was comparable to that among patients in the general medical wards.

Use of healthy-donor granulocyte transfusions to treat infections in neutropenic patients with myeloid or lymphoid neoplasms: experience in 74 patients treated with 373 granulocyte transfusions.

BACKGROUND/AIMS: Despite limited evidence for efficacy, granulocyte transfusions (GTX) are used to prevent and treat opportunistic infections in patients with neutropenia. METHODS: Three hundred and seventy-three GTX given to 74 patients were assessed retrospectively. RESULTS: GTX were discontinued because of clinical improvement more often in patients with severe infections than in patients without severe infections (27 vs. 12%; p ≤ 0.002), whereas deaths resulted in discontinuation of GTX therapy less often in patients with severe infections than without (8 vs. 39%; p ≤ 0.002). Patients who died by 12 weeks after GTX initiation were more likely to have leukemia (p = 0.03), not to have recovery of neutrophil counts (p < 0.0001), and to have started GTX during a critical care unit stay (p < 0.001). Uses of granulocyte colony-stimulating factor (p ≤ 0.02) and interferon-γ (p ≤ 0.04) were more common in patients who survived. In patients with comorbidities (31%; odds ratio, OR, 12.6; 95% confidence interval, CI, 2.4-65.7; p ≤ 0.003), GTX was started in the critical care unit (OR 8.8; 95% CI 2.5-30.9; p < 0.001), and a high total bilirubin level at the end of GTX (OR 2.1; 95% CI 1.1-4.2; p = 0.03) had a higher probability of death 12 weeks after GTX therapy commenced. CONCLUSIONS: The possibility that a niche population may benefit from GTX requires further assessment.

Impact of cytotoxic and targeted antineoplastic drugs on the validity of the mitogen-induced interferon-gamma release assay for latent tuberculosis infection: results of a prospective trial at a comprehensive cancer center.

Abstract The T-SPOT.TB test (TS.TB), an interferon-gamma (IFN-γ) release assay (IGRA), is superior in diagnosing latent tuberculosis infection compared with the conventional tuberculin skin test (TST). However, whether cytotoxic chemotherapy and treatment with new-generation antineoplastic monoclonal antibodies affects the TS.TB is not certain. We evaluated the feasibility of using the TS.TB in this population. Sixteen cancer patients at high risk for tuberculosis exposure were prospectively evaluated with the TST and TS.TB. Blood samples were obtained 7.5 ± 89.3 days after the most recent cycle of antineoplastic therapy. Six patients (38%) were febrile within 24 h of blood sampling; high-dose corticosteroid therapy and profound treatment-induced neutropenia were present in 1 patient each. In all patients, TS.TB showed no evidence of latent tuberculosis infection. A robust mitogen-induced IFN-γ response was seen in samples from 14 patients (88%) despite therapy with high-dose corticosteroids, cyclophosphamide, fludarabine, gemtuzumab ozogamicin, and alemtuzumab. The presence of fever or profound neutropenia did not negatively impact mitogen response by peripheral lymphocytes. The 2 patients whose peripheral blood lymphocytes (> 500 cells/ml) failed to generate a cytokine response to ex vivo mitogen stimulation had refractory advanced cancer. Unlike the TST, a negative TS.TB provided interpretable results even in cancer patients undergoing new-generation immunosuppressive therapy.

Modeling dendritic cell vaccination for influenza prophylaxis: potential applications for niche populations.

BACKGROUND: Cancer patients can exhibit negligible responses to prophylactic vaccinations, including influenza vaccination. To help address this issue, we developed in vitro and in vivo models of dendritic cell (DC) immunotherapy for the prevention of influenza virus infection. METHODS: Human cord blood (CB)-derived or mouse splenocyte-derived DCs were loaded with purified recombinant hemagglutinin (rHA). T-cell responses to HA-loaded CB-derived DCs were determined by ELISpot. Protective efficacy was determined by vaccination of BALB/c mice with a single injection of 10(6) autologous DCs. DC migration to peripheral lymphoid organs was verified by carboxyfluorescein succinimidyl ester staining, and HA-specific antibody titers were determined by enzyme-linked immunosorbent assay. Mice were then challenged intranasally with BALB/c-adapted A/New Caledonia influenza virus derived from four consecutive lung pool passages. Antigen-presenting cell (APC) dysfunction was modeled using the MAFIA transgenic system, in which the Csf1r promoter conditionally drives AP20178-inducible Fas. RESULTS: CB-derived human DCs were able to generate de novo T-cell responses against rHA, as determined by a system of rigorous controls. Mice vaccinated intraperitoneally developed HA titers detectable at serum dilutions of >1:1000. HA seroconverters survived virus challenge, whereas unvaccinated controls and vaccinated nonseroconverters lost weight and died. Furthermore, use of a model of APC-specific immunosuppression revealed that DC vaccination could generate HA-specific antibody titers under conditions in which protein vaccination could not. CONCLUSIONS: The model demonstrates that DC immunotherapy for the prevention of influenza is feasible, and studies are underway to determine whether populations of immunosuppressed individuals might ultimately benefit from the procedure.

Immunotherapy for invasive mold disease in severely immunosuppressed patients.

Response to systemic antifungal therapy alone remains disproportionately less satisfactory in immunosuppressed transplant and oncology patients. As insight in fungal immunopathogenesis forges ahead, interventions for boosting immune functions along with antimicrobial drugs has shown promise in preclinical experiments. The clinical experience with immunotherapy for invasive mold disease is limited. Most studies have involved small numbers of patients at a single institution or data collected retrospectively. An overview of various facts of immune modulatory drug intervention is presented, including major considerations in antifungal immunotherapy in immunosuppressed patients. Patients in whom immunotherapy is being considered must be critically evaluated to identify the underlying immune defects, including treatment-induced immunosuppression. Antifungal immunotherapy is appealing; however, before routine clinical use is recommended, well-designed prospective comparative clinical trials are urgently needed.

Fidaxomicin versus conventional antimicrobial therapy in 59 recipients of solid organ and hematopoietic stem cell transplantation with Clostridium difficile-associated diarrhea.

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P = 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P = 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P = 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.

Granulocyte macrophage colony-stimulating factor in 66 patients with myeloid or lymphoid neoplasms and recipients of hematopoietic stem cell transplantation with invasive fungal disease.

BACKGROUND/AIMS: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). METHODS: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. RESULTS: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21-264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66-63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27-16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1-16.2; p ≤ 0.05) predicted antifungal treatment failure. CONCLUSIONS: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.

Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects.

Infections are common in patients with hematologic neoplasms and following allogeneic hematopoietic transplantation. Neutropenia and defects in adaptive B-cell-mediated immunity and/or lack of splenic function predispose patients to a host of diverse and often serious infections. It is important to recognize that patients who undergo treatment for hematologic neoplasms may have mixed immune defects, and their vulnerability to infection may continue to change, in part as a reflection of the dynamic developments in the practice of oncology. The main obstacle in providing targeted, evidence-based antimicrobial treatment is the unpredictable results of even the new generation of diagnostic assays. A definite diagnosis for most end-organ opportunistic diseases requires tissue samples that are seldom available. Because immune defects may coexist, empirical therapy is directed toward a wide spectrum of pathogens. Real-time information about innate and adaptive immune functions and the role of acute and chronic phase molecules may improve target-specific therapy.

Human herpesvirus-6 DNAemia in immunosuppressed adult patients with leukemia at risk for mold infection.

Little is known about human herpesvirus-6 (HHV-6) in leukemia patients. We prospectively followed 37 leukemia patients at risk for mold infection. HHV-6 DNA was detected from whole blood specimens in 11 patients (30%). History of granulocyte transfusions (p=0.05) and prior relapse of leukemia (p=0.07) were the only independent predictors of HHV-6 DNAemia.

Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer.

Stenotrophomonas maltophilia colonization/infection in patients with cancer has significantly increased over the past 2 decades. Patients with prolonged neutropenia, exposure to broad-spectrum antibiotics, and those requiring mechanical ventilation have higher risk of infection. These micro-organisms are intrinsically resistant to carbapenems, and exposure to these agents has been linked to selection of S. maltophilia. Recently, these infections are being documented in patients without traditional risk factors. The spectrum of infection includes bacteremia, catheter-related infection, pneumonia, complicated biliary and urinary tract infection, and skin and skin-structure infection. Trimethoprim-sulfamethoxazole is the therapeutic agent of choice, but resistance is increasingly being reported. Susceptibility to alternative agents is unpredictable. Combination therapy and alternative routes of drug administration, such as aerosolized aminoglycoside, might be necessary. New insights into the mechanisms of drug resistance might lead to identification of new target sites. Agents that improve outer-membrane permeability and broad-spectrum beta-lactamase inhibitors may favorably impact difficult-to-treat (i.e., multidrug resistant) S. maltophilia infections.

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.

Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study.

We reviewed the records of 33 patients with leukemia who experienced influenza during the period from October 2000 to March 2004. Three (38%) of the 8 patients who did not receive neuraminidase inhibitor therapy and none of the 25 patients who received it died of influenza pneumonia (P=.001). The use of neuraminidase inhibitor therapy seems to improve the outcome of influenza in patients with leukemia.

Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine-breakthrough infections, 1989-2005.

Streptococcus pneumoniae infections can cause serious systemic disease in patients following hematopoietic stem cell transplantation (HSCT), and the response to pneumococcal vaccine is inadequate in most HSCT recipients. We evaluated the clinical spectrum of pneumococcal disease and vaccine-breakthrough infections in HSCT recipients at our cancer center in a retrospective analysis of all consecutive episodes of S. pneumoniae infection from 1989 through 2005. During the study period, 7888 patients underwent HSCT at our center; we identified 47 HSCT recipients with 54 S. pneumoniae infections. The overall incidence of S. pneumoniae infection was 7 per 1000 HSCTs. The incidence was higher in recipients of allogeneic grafts than in recipients of autologous grafts (9 vs. 5 per 1000 HSCTs, respectively; p

Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005.

Cord blood-derived stem cells are successfully used in the treatment of cancer and congenital disorders in children. This alternative source of stem cells is also explored for adult cancer patients with limited donor options. However, delayed engraftment, prolonged neutropenia, secondary graft loss, and graft-versus-host disease (GVHD) in recipients of cord blood transplantation (CBT) make opportunistic infections a serious concern. We evaluated the spectrum of infections in adults and children undergoing CBT at our National Cancer Institute-designated comprehensive cancer center. The infection incidence rate ratio (total infection episodes/days at risk [survival after CBT] x 100) was 2.4 times higher in 35 adult patients than in 62 children, especially in adults with neutropenia (3 x higher) and GVHD (1.9 x higher). Ninety-two percent of fungal infection episodes occurred within 100 days after transplantation; half of these infections occurred in the first 30 days after CBT. Most bacterial infections (80%) were also diagnosed in the first 100 days, whereas late (>100 d) post-CBT cytomegalovirus and varicella zoster virus infections occurred only in children with chronic GVHD. Multivariate analysis showed that resolution of lymphocytopenia (> or =1000 cells/microL) (hazard ratio [HR] 0.71; p < 0.0001) and successful engraftment (HR 0.20; p < 0.0001) were associated with a low risk of serious infection. Children (HR 0.36; p < 0.0002) with sustained engraftment (HR 0.39; p < 0.004) and those with cancer in remission (HR 0.47; p < 0.007) were less likely to die from infection. More effective measures for surveillance and prevention of late cytomegalovirus and varicella zoster virus infections in children with CBT and chronic GVHD are needed.

Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia.

BACKGROUND AND OBJECTIVES: Little is known about respiratory syncytial virus (RSV) infection in patients with leukemia. The aim of this study was to determine the characteristics, and the outcome of RSV infection with or without therapy with aerosolized ribavirin in leukemia patients. DESIGN AND METHODS: We reviewed the records of 52 leukemia patients with RSV infection seen at our institution between October 2000 and March 2005. RESULTS: The median age of the patients was 47 years (range, 1-83 years). Most patients were male (65%) and had acute leukemia (65%); 46% had received salvage chemotherapy and 62% corticosteroids before RSV infection. Compared to the 25 patients with upper respiratory tract infection (URI), the 27 patients with pneumonia had a higher median APACHE II score at the time of the first assessment at the hospital for respiratory symptoms (11 vs 16), and a higher rate of corticosteroid treatment in the month preceding the infection (48% vs 74%) (all p < or =0.05). Twenty-four (46%) patients received aerosolized ribavirin. Patients who presented with URI and were treated with ribavirin were less likely than non-treated patients to develop pneumonia (68% vs 96%, p<0.01) and possibly die of pneumonia (6% vs 36%, p=0.1). Multiple logistic regression analysis identified high APACHE II score and lack of ribavirin treatment as independent predictors of progression to pneumonia (p=0.01). Five patients (10%) died within 30 days of RSV infection; all had pneumonia. INTERPRETATION AND CONCLUSIONS: RSV infection is associated with significant morbidity and mortality in leukemia patients; treatment with aerosolized ribavirin at the stage of URI may prevent pneumonia in some subsets of patients.

Aerosolized ribavirin-induced reversible hepatotoxicity in a hematopoietic stem cell transplant recipient with Hodgkin lymphoma.

We describe a case of acute hepatic toxicity associated with aerosolized ribavirin in a bone marrow transplant recipient with documented respiratory syncytial virus infection. The temporal relationship with drug administration and the liver biopsy results suggested drug-induced hepatic injury. As the use of aerosolized ribavirin to treat respiratory syncytial virus infections continues, it is imperative that careful attention be paid to possible adverse effects of therapy in the high-risk population of immunosuppressed patients.

Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006.

We reviewed the records of patients with cancer who had Scedosporium infection (due to Scedosporium apiospermum and Scedosporium prolificans in 21 and 4 patients, respectively). The incidence of Scedosporium infection increased from 0.82 cases per 100,000 patient-inpatient days (in 1993-1998) to 1.33 cases per 100,000 patient-inpatient days (in 1999-2005). Cases of S. prolificans infection occurred only after 2000. Dissemination occurred in 16 patients (64%). The 12-week mortality rates were 70% and 100% for S. apiospermum and S. prolificans infection, respectively.

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