Treatment with monoclonal antibodies against Clostridium difficile toxins.

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2010 Apr 15;362(15):1444-5; author reply 1445-6.

Comment on

Drug-induced nephrotoxicity caused by amphotericin B lipid complex and liposomal amphotericin B: a review and meta-analysis.

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Safdar A, Ma J, Saliba F, Dupont B, Wingard JR, Hachem RY, Mattiuzzi GN, Chandrasekar PH, Kontoyiannis DP, Rolston KV, Walsh TJ, Champlin RE, Raad II.

Medicine (Baltimore). 2010 Jul;89(4):236-44.

Lipid preparations of amphotericin B, commonly used to treat fungal infections, have been demonstrated to have reduced nephrotoxicity compared to conventional amphotericin B. However, to our knowledge, a comprehensive comparison of
nephrotoxicity induced by different lipid preparations of amphotericin B has not been performed. We conducted a meta-analysis to evaluate nephrotoxicity associated with amphotericin B lipid complex (ABLC) and liposomal amphotericin B
(L-AmB). We searched the PubMed MEDLINE database and abstracts presented at key scientific meetings, and identified 11 studies reported between 1995 and 2008 that compared nephrotoxicity resulting from the use of these agents. Eight of the
11 studies were included in the meta-analysis. The Cochran-Mantel-Haenszel test was used to determine odds ratio (OR) and relative risk (RR), and the Breslow-Day test was used to analyze homogeneity of ORs across different studies. Analysis of
all 8 studies (n = 1160) included in the meta-analysis showed an increased probability of nephrotoxicity in patients treated with ABLC versus L-AmB (OR, 1.75; RR, 1.55), but there was a significant lack of homogeneity across these studies (p < 0.001). After excluding the study by Wingard et al, the probability  of experiencing nephrotoxicity was more similar between the 2 AmB lipid preparations (OR, 1.31; RR, 1.24; n = 916), particularly when the analysis included only the salvage patient population reported by Hachem et al (OR, 1.12; RR, 1.09; n = 839); the 7 remaining studies were more homogenous by Breslow-Day test (p = 0.054). Our results suggest that nephrotoxicity is generally similar for ABLC and L-AmB in patients receiving antifungal therapy and prophylaxis.

Dendritic cell vaccines for the immunocompromised patient: prevention of influenza virus infection.

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Decker WK, Safdar A.

Expert Rev Vaccines. 2010 Jul;9(7):721-30.

Prophylactic vaccination of cancer patients and recipients of hematopoietic stem cell transplant is generally a simple, efficient and cost-effective manner by which to prevent unnecessary infection and enhance overall clinical outcomes.
However, some neoplastic conditions, particularly B-cell malignancies, impart a degree of immunosuppression that complicates traditional prophylactic approaches. Here, we make the case that the application of dendritic cell (DC) immunotherapy
for the prophylaxis of infectious disease is both appropriate and cost effective for certain niche populations who are at risk of increased morbidity and who respond poorly to traditional vaccination, particularly influenza vaccination. Here we review the full spectrum of our preclinical work in this area, results demonstrating that DCs loaded with subunit recombinant hemagglutinin can generate robust hemagglutinin-specific immune responses both in vitro and in vivo. In vivo data indicated that a single injection of hemagglutinin-loaded DC was sufficient to generate high-titer antibody responses that could mediate protective immunity to lethal influenza virus challenge. The results suggest that DC immunotherapy for influenza prophylaxis is safe and feasible and that clinical studies might be warranted.

Cytokine adjuvants for vaccine therapy of neoplastic and infectious disease.

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Decker WK, Safdar A.

Cytokine Growth Factor Rev. 2011 Aug;22(4):177-87.

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.

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

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Safdar A, Armstrong D.

Clin Infect Dis. 2011 Oct;53(8):798-806.

Infections are common in patients with hematologic neoplasms and following allogeneic hematopoietic transplantation. Neutropenia and defects in adaptiveB-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.

Aerosolized amikacin in patients with difficult-to-treat pulmonary nontuberculous mycobacteriosis.

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Safdar A.

Eur J Clin Microbiol Infect Dis. 2012 Aug;31(8):1883-7.

Patients with pulmonary nontuberculous mycobacteriosis (pNTM) may have suboptimum response to conventional antimicrobial therapy. Aerosolized amikacin (aeAmk) was  given to nine patients who had failed standard combination oral antimycobacterial drugs. A favorable toxicity profile, even in patients given aeAmk for an extended duration, median 75 ± 85 (range, 18-277) days and total cumulative dose 35,400 ±  30,568 (range, 7,600-95,400) mg, was encouraging, as was the clinical response and resolution of symptoms in 8 of 9 patients. The patient who failed therapy died due to complications arising from prior hematopoietic transplantation. The feasibility and efficacy of aeAmk in combination with oral anti-NTM drug(s) for
treatment-refractory disease and, importantly, in primary therapy for pNTM requires validation randomized trials.

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

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Rodriguez GH, Ahmed SI, Al-akhrass F, Rallapalli V, Safdar A.

Leuk Lymphoma. 2012 Aug;53(8):1530-5.

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.

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

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Konduri V, Decker WK, Halpert MM, Gilbert B, Safdar A.

J Infect Dis. 2013 Jun 1;207(11):1764-72.

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.

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Safdar A.

Clin Infect Dis. 2013 Jul;57(1):94-100.

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.

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.

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Safdar A, Rodriguez GH.

Pharmacotherapy. 2013 Oct;33(10):1035-43.

STUDY OBJECTIVE: 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.
DESIGN: We evaluated the safety and efficacy of aeABLC adjunct therapy for fungal
lung disease in a retrospective study of 32 immunosuppressed adults. All values
are given as ± standard deviation.
SETTING: National Cancer Institute-designated Comprehensive Cancer Center.
PATIENTS: Acute leukemia (69%) and severe neutropenia (63%) were common.
Fifty-six percent of patients had undergone allogeneic hematopoietic stem cell
transplantation 185 ± 424 days prior to aeABLC was commenced.
MEASUREMENT AND MAIN RESULTS: High-dose corticosteroids were administered during
aeABLC in 28% of patients. Fungal lung disease was proven or probable in 41% of
patients. Most patients (78%) received concurrent systemic antifungal therapy for
a median of 14 ± 18 days before aeABLC. The median cumulative aeABLC dose was
1050 ± 2368 mg, and the median duration of aeABLC therapy was 28 ± 130 days. Most
patients (78%) received 50 mg aeABLC twice daily. Partial or complete resolution
of fungal lung disease was noted in 50% of patients. In three patients (9%)
modest cough, mild bronchospasm, and transient chest pain with accompanying
nausea and vomiting resolved completely after discontinuation of aeABLC. No
patient required hospitalization for drug toxicity or had a serious (grade III or
IV) drug-related adverse event.
CONCLUSION: Treatment with aeABLC was tolerated without serious toxicity and may
be considered in the setting of severe immunosuppression, cancer, and/or
hematopoietic stem cell transplantation in patients with difficult-to-treat
fungal lung disease.