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

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2007 Nov;86(6):324-33.

Abstract

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.

Difficulties with fungal infections in acute myelogenous leukemia patients: immune enhancement strategies.

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2007;12 Suppl 2:2-6.

Abstract

Invasive fungal infection in severely immunosuppressed patients with acute myelogenous leukemia (AML) remains a serious challenge because (a) of the higher rates of non-drug susceptible fungal sinopulmonary disease; (b) despite advances in diagnostic fungal assays, the correct identification of causative organism(s) is difficult, and antifungal drug susceptibility data are seldom available during clinical decision making; and (c) the increasing frequencies of zygomycosis, scedosporiosis, and highly virulent Candida tropicalis infection have undermined the gains attributed to effective anti-Aspergillus drug therapy. Recombinant cytokines, such as recombinant human (rh)GM-CSF and interferon (IFN)-gamma, have been explored to augment host antifungal immune responses. These cytokines promote activation and recruitment of granulocyte and mononuclear phagocytic effector cells. Prophylaxis with rhGM-CSF was associated with significantly fewer life-threatening and serious (grade > or =3) infections, especially in older patients undergoing treatment for AML. The limited experience with rhGM-CSF for the treatment of invasive fungal infections in combination with antifungal drug(s) was associated with a favorable outcome, and in contrast to Escherichia coli-derived rhGM-CSF, the new preparation (sargramostim) was well tolerated and rarely associated with serious systemic toxicities. Similarly, IFN-gamma has been successfully used in patients with antimicrobial drug-refractory and/or disseminated fungal infection. Most patients tolerate the T-helper type 1 protagonist cytokine without serious adverse events. In difficult-to-treat fungal infections, the addition of cytokines appears to improve outcome and may be considered early in severely immunosuppressed patients with AML.

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

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2008 Jan;93(1):157-8.

Abstract

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.

Fungal endophthalmitis in a tertiary care cancer center: a review of 23 cases.

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2008 May;27(5):343-7.
Abstract

Few data exist on the etiology, presentation, prognosis, and management of fungal endophthalmitis (FE) in cancer patients. FE cases were identified by reviewing the ophthalmology reports and microbiology cultures of patients at The University of Texas M. D. Anderson Cancer Center. We retrospectively reviewed the medical records and obtained information related to malignancy, fungal infection and its management, visual outcome, and mortality. We compared FE caused by Candida spp. (CE) to FE caused by molds (ME). Of the 102 cancer patients with a fungal infection for whom an ophthalmology consult was requested, 23 met the criteria for definite (N = 6) or probable (N = 17) FE (8 with CE, 15 with ME). All of the patients with ME had hematologic malignancies, whereas half of the patients with CE had solid tumor (P = .008). Only patients with CE had a history of surgery within 30 days of FE diagnosis (38%, P = .03). Fungal pneumonia [17 (74%)] and disseminated infection [14, (61%)] were common. The most common presenting symptoms were decreased vision [16 (70%)] and ocular pain [14 (61%)]. All treated patients received systemic antifungals (combination therapy in 72% of the cases). Seven patients (30%) underwent vitrectomy. Only one patient received intraocular injection of amphotericin B along with systemic antifungals. Four-week mortality was high [13 (57%)], especially in ME (73%, P = .04). Among the eight surviving patients where visual acuity could be assessed, visual outcome improved or remained stable in five (63%). FE in cancer patients occurs in the setting of severe, frequently disseminated opportunistic mycoses, is caused predominantly by hyalohyphomycetes, and is a marker for high 4-week mortality.

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

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2007 Dec 15;45(12):1602-9.

Abstract

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.

Progressive fusariosis: unpredictable posaconazole bioavailability, and feasibility of recombinant interferon-gamma plus granulocyte macrophage-colony stimulating factor for refractory disseminated infection.

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2008 Jan;49(1):163-5.

Immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed SCT recipients.

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2008 Apr;41(8):707-8.

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity.

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2008 Jul 15;113(2):383-7. doi: 10.1002/cncr.23561.

Abstract

BACKGROUND:

For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL).

METHODS:

Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF.

RESULTS:

A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination.

CONCLUSIONS:

In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00323557.

(c) 2008 American Cancer Society.

Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae.

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2008 Jul 15;198(2):186-92.

Abstract

BACKGROUND:

We investigated whether caspofungin and other echinocandins have immune-enhancing properties that influence human polymorphonuclear neutrophil (PMN)-mediated mold hyphal damage.

MATERIALS AND METHODS:

Using aniline blue staining, we compared patterns of beta-glucan exposure in Aspergillus fumigatus, Aspergillus terreus, Rhizopus oryzae, Fusarium solani, Fusarium oxysporum, Scedosporium prolificans, and Scedosporium apiospermum hyphae after caspofungin exposure. We also determined PMN-mediated hyphal damage occurring with or without preexposure to caspofungin or with preexposure to the combination of caspofungin and anti-beta-glucan monoclonal antibody, using 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-sH-tetrazolium hydroxide (XTT) assay.

RESULTS:

Preincubation with caspofungin (32 microg/mL for R. oryzae; 0.0625 microg/mL for other isolates) increased exposure to beta-glucan. PMN-induced damage increased after caspofungin exposure and was further augmented by the addition of anti-beta-glucan antibody. Preincubation with micafungin or anidulafungin had similar effects on PMN-induced damage of A. fumigatus hyphae. Finally, preexposure of A. fumigatus, but not S. prolificans, to caspofungin induced expression of Dectin-1 by PMN.

CONCLUSIONS:

The results of the present study suggest inducement of beta-glucan unmasking by echinocandins and enhancement of PMN activity against mold hyphae, thereby supporting the immunopharmacologic mode of action of echinocandins.

Comment in

Inhaled aminoglycosides in cancer patients with ventilator-associated Gram-negative bacterial pneumonia: safety and feasibility in the era of escalating drug resistance.

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2009 Mar;28(3):253-9. .

Abstract

We sought to evaluate the safety and feasibility of inhaled aminoglycosides or colistin in cancer patients with ventilator-associated pneumonia (VAP) due to Gram-negative bacteria (GNB). A retrospective case-matched study was obtained after obtaining IRB approval in patients at the intensive care unit at our NCI-designated comprehensive cancer center between 1999 and 2005. Sixteen patients with GNB-VAP who received inhaled aminoglycosides or colistin were compared with 16 patients who had received these antibiotics intravenously alone. Eligible patients were required to have received at least six doses of inhaled therapy, or 3 or more days of intravenous therapy. Clinical Pulmonary Infection Scores were used to assess pneumonia severity. Standard ATS criteria were used to define VAP. Patients treated with inhaled antibiotics were less likely to have received corticosteroids (13% vs 50%; P < 0.02) and had a higher median baseline creatinine level (0.85 vs 0.6 mg/dL; P < 0.02) than patients treated intravenously. Pseudomonas aeruginosa (69%) was the most common cause of VAP. There were no serious adverse events associated with inhaled antibiotics. Patients who received these antibiotics intravenously developed renal dysfunction (31%); none of the patients treated with inhaled antibiotics developed nephrotoxicity (P < or = 0.04). Patients treated with inhaled antibiotics were more likely to have complete resolution of clinical (81% vs 31% in the intravenous antibiotic group; P < 0.01) and microbiologic infection (77% vs 8% in the intravenous antibiotic group: P < 0.0006). In a multivariate analysis adjusted for corticosteroid use, inhaled antibiotic therapy was predictive of complete clinical resolution (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.1, 37.6; P < 0.04) and eradication of causative organisms (OR 36.7; 95% CI, 3.3, 412.2; P < 0.003). In critically ill cancer patients with Gram-negative VAP, inhaled aminoglycosides were tolerated without serious toxicity and may lead to improved outcome.