Amar Safdar

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.

Fidaxomicin versus Conventional Antimicrobial Therapy in 59 Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation with Clostridium difficile-Associated Diarrhea

ABSTRACT 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.

Fidaxomicin Therapy in Critically Ill Patients with Clostridium difficile Infection

ABSTRACT 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.

Characteristics of, and risk factors for, infections in patients with cancer treated with dasatinib and a brief review of other complications.

Abstract Dasatinib has transformed the treatment of chronic myelogenous leukemia, resulting in durable remissions and prolonged survival. The spectrum of infectious complications during and after dasatinib therapy is not known. Retrospective analysis of records among 69 patients treated with dasatinib showed that 35 (51%) developed 57 episodes of infection. Twenty-nine (51%) episodes occurred during neutropenia, and 25 (44%) were microbiologically confirmed. Compared with patients who did not develop infection with dasatinib therapy, patients with infection were significantly more likely to have acute lymphocytic leukemia (51% vs. 18%; p ≤ 0.005) and to have received high-dose corticosteroids (51% vs. 26%; p ≤ 0.05). Patients with infection were also more likely to have received dasatinib with another antineoplastic agent (57% vs. 35% without infection; p = 0.09). On multivariate analysis, treatment with three or more cycles of dasatinib increased the risk of infection (odds ratio 11.7; 95% confidence interval 2.5–54.3; p = 0.002). The presence of comorbidities tended to increase the risk of infection (odds ratio 3.9; 95% confidence interval 0.9–17.9; p = 0.07). Interestingly, viral infections, including a single case of cytomegalovirus colitis, were uncommon (7%). The rate of death in 57 patients during follow-up was non-significantly higher in patients with infection versus those without infection (35% vs. 18%; p = 0.18). Infection-associated deaths were noted in only two patients (10%) who had an infection and died. The results of our analysis suggest that antibacterial prophylaxis is important in patients who develop neutropenia during dasatinib therapy, although routine antifungal and anti-cytomegalovirus prophylaxis may not be necessary.

Cytokine adjuvants for vaccine therapy of neoplastic and infectious disease

Vaccination, the revolutionary prophylactic immunotherapy developed in the eighteenth century, has become the most successful and cost-effective of medical remedies available to modern society. Due to the remarkable accomplishments of the past century, the number of diseases and pathogens for which a traditional vaccine approach might reasonably be employed has dwindled to unprecedented levels. While this happy scenario bodes well for the future of public health, modern immunologists and vaccinologists face significant challenges if we are to address the scourge of recalcitrant pathogens like HIV and HCV and well as the significant obstacles to immunotherapy imposed by neoplastic self. Here, the authors review the clinical and preclinical literature to highlight the manner by which the host immune system can be successfully manipulated by cytokine adjuvants, thereby significantly enhancing the efficacy of a wide variety of vaccination platforms.

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.

High-dose caspofungin as a component of combination antifungal therapy in 91 patients with neoplastic diseases and hematopoietic stem cell transplantation: a critical review of short-term and long-term adverse events.

The antifungal activity of echinocandins is concentration dependent. Previously, we demonstrated that high-dose caspofungin (HD-CSP; 100 mg daily) was well tolerated in 34 immunosuppressed patients with cancer and may have favorably influenced outcomes. We retrospectively assessed all 91 patients in whom HD-CSP was given for the treatment of invasive fungal disease (IFD). The median number of doses was 18.5 ± 21.5, and in 8 (9%) patients more than 40 doses were given. Most (62%) of the patients had leukemia. A total of 45 (49%) patients had undergone stem cell transplantation; 80% received allogeneic grafts and 47% had graft-versus-host disease. High-dose corticosteroids were given during antifungal therapy in 26 (29%) patients. In all, 8 (9%) patients had new elevation in serum bilirubin during HD-CSP therapy; normalization occurred after voriconazole and HD-CSP were discontinued in 4 patients each. No other short-term or delayed adverse events were observed. In all, 40 (44%) patients died of IFD. High-dose corticosteroids during HD-CSP (odds ratio [OR] 8, 95% confidence interval [CI] 2.1-30.4; P < .002) and starting HD-CSP in the critical care unit (OR 67.5, 95% CI 5.25-868.9; P < .001) were associated with death from fungal disease. Prolonged HD-CSP therapy was well tolerated. Drug-induced hyperbilirubinemia may pose a potential limitation for continued HD-CSP use in highly susceptible patients with hematologic neoplasms and stem cell transplantation.

Aerosolized Amphotericin B Lipid Complex as Adjunctive Treatment for Fungal Lung Infection in Patients with Cancer-Related Immunosuppression and Recipients of Hematopoietic Stem Cell Transplantation

Aerosolized amphotericin B lipid complex (aeABLC) has been successfully used to prevent fungal disease. Experience with aeABLC as treatment of fungal lung disease is limited.

Initial Therapy for Mild to Moderate Clostridium difficile Infection: Exploring the Role of Oral Metronidazole Versus Vancomycin in 168 Hospitalized Patients

BackgroundOral vancomycin is being increasingly used for treatment of Clostridium difficile infection (CDI), although the feasibility for such approach and avoidance of currently recommended oral metronidazole for mild to moderate (mm)-CDI remain uncertain. We sought to assess treatment response in hospitalized patients with mm-CDI at our university medical center. MethodsStandard Infectious Diseases Society of America and Society for Healthcare Epidemiology of America definitions were used. Primary outcomes included rate of treatment response and infection recurrence following therapy. ResultsAmong 513 total cases of CDI between 2011 and 2013, 168 were mm-CDI and were further analyzed. Overall treatment responses to oral vancomycin were 97% versus 82% in patients given metronidazole (P = 0.002). Overall rate of CDI recurrence was 13% following vancomycin versus 9% following metronidazole treatment (P = 0.4). In 85 patients with NAP1 (North American PFGE type 1) CDI, vancomycin and metronidazole yielded similar response (97% vs 98%, P = 0.13), whereas in 83 patients with non-NAP1 CDI, rate of treatment response to vancomycin was higher (98% vs 78% with metronidazole, P = 0.007). In a regression analysis, initial therapy with metronidazole was an independent predictor of treatment failure (odds ratio, 8.4; 95% confidence interval, 1.75–40; P = 0.007) after controlling for hypoalbuminemia (<3 g/dL), concurrent use of proton pump inhibitors, chronic liver disease, community-onset CDI, age older than 65 years, and presence of more than 3 comorbidities. In the subset of 91 patients treated with metronidazole, presence of chronic liver disease (odds ratio, 4.4; 95% confidence interval, 1.19–16.4; P = 0.027) was associated with treatment failure. ConclusionsOral metronidazole therapy for mm-CDI in hospitalized patients might not be optimal and needs further reassessment.

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.