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ABSTRACT: Development of invasive fungal infection is the result of the complex interaction between fungal and host factors. The outcome
of infection, once it has developed, depends upon appropriate use of antifungal therapy, surgical debridement as indicated,
and improvement of host defenses. Thus, there have been major efforts for development of new strategies for immunomodulation
and augmentation of host defenses in prevention and treatment of invasive mycoses. These modalities include granulocyte and
granulocyte-macrophage colony-stimulating factors, interferon-γ, granulocyte transfusions, immunotherapy with infusion of
dendritic cells and T cells, anti-heat shock protein 90 monoclonal antibodies, long pentraxin 3, mannose-binding lectin, and
deferasirox. Although major strides in our understanding of augmentation of host response to invasive fungal infections are
opening up novel avenues of therapy to harness patients’ innate immune systems against these frequently lethal pathogens,
well-designed clinical trials are needed to demonstrate safety and efficacy of these new approaches.
Current Fungal Infection Reports 04/2012; 3(3):186-191.
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Jeffrey W Shupp,
Ruta Petraitiene,
Amin D Jaskille,
Anna R Pavlovich,
Sarah E Matt,
Do T Nguyen,
Melissa A Kath,
James C Jeng,
Marion H Jordan,
Malcolm Finkelman,
Thomas J Walsh, Shmuel Shoham
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ABSTRACT: Serum (1→3)-β-D-glucan (BG) is increasingly used as diagnostic marker for invasive fungal infections. Exposure to gauze may lead to false-positive BG assays. The role of BG is unclear in thermally injured patients who frequently require extensive gauze coverage; therefore, we prospectively evaluated BG levels in burn-injured patients. Serum BG levels were measured in 18 burn patients immediately before application of the first dressing and 12 h after. Patients were stratified by extent of total body surface area (TBSA) requiring gauze coverage: <20%, 20-39%, 40-60% and >60%. BG levels were obtained from patients with non-burn trauma as controls. BG results were positive (>80 pg ml⁻¹) in 9/18 (50%) patients at baseline and in 8/18 (44%) 12 h after application of the first dressing. BG levels were positive in 1/5 (20%) of patients with <20% TBSA requiring gauze and in 10/13 (77%) with ≥ 20% (P < 0.05). None of the control patients had positive BG at any time point and none of the patients had candidemia at baseline. Mean serum BG levels decreased (19.44 pg ml⁻¹) after gauze placement. False-positive serum BG elevations are common in this patient population. Positivity correlates with extent of TBSA injured, but is not impacted by the gauze itself.
Mycoses 07/2011; 55(3):224-7. · 2.25 Impact Factor
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ABSTRACT: High-level mupirocin resistance (H-Mu(r)) in S. aureus is associated with the mupA gene. The mupA Evigene test rapidly identifies this gene. This study assessed the performance of mupA Evigene compared to that of susceptibility disk testing. mupA Evigene detected H-Mu(r) in 6/179 S. aureus isolates, and the results were concordant with those of susceptibility disk testing.
Journal of clinical microbiology 08/2010; 48(8):2953-4. · 4.16 Impact Factor
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ABSTRACT: Invasive fungal infections are major causes of morbidity and mortality in critically ill patients. Foremost among these is invasive candidiasis. In recent years, invasive aspergillosis (IA) and zygomycosis have emerged as major problems in susceptible, critically ill patients. Risk factors for invasive fungal infections, including disrupted anatomic barriers, suppressed antifungal host responses, and exposure to potentially opportunistic fungi are common in critically ill patients. The expanded antifungal armamentarium and advent of rapid diagnostic techniques are altering the approach to invasive fungal infections in the intensive care unit (ICU). Herein, we review recent developments in the field of antifungal host defenses, the changing epidemiology of fungal infections in the ICU, the pharmacology of antifungal agents of importance to critically ill patients, and the evolving approaches to therapy in this setting.
Journal of Intensive Care Medicine 12/2009; 25(2):78-92.
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Vasilios Pyrgos,
Diane Mickiene,
Tin Sein,
Margaret Cotton,
Andrea Fransesconi,
Isaac Mizrahi,
Martha Donoghue,
Nikkida Bundrant,
Su-Young Kim,
Matthew Hardwick, Shmuel Shoham,
Thomas J Walsh
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ABSTRACT: Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P < or = 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P < or = 0.04). TNF-alpha and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P < or = 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-alpha decreased tight-junction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1beta, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-alpha and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.
Antimicrobial Agents and Chemotherapy 12/2009; 54(3):1305-10. · 4.84 Impact Factor
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ABSTRACT: Pneumocystis pneumonia (PCP) is a life-threatening infection in immunocompromised children with quantitative and qualitative defects in T lymphocytes. At risk are children with lymphoid malignancies, HIV infection, corticosteroid therapy, transplantation and primary immunodeficiency states. Diagnosis is established through direct examination or polymerase chain reaction (PCR) from respiratory secretions. Trimethoprim-sulphamethoxazole is used for initial therapy in most patients, while pentamidine, atovaquone, clindamycin plus primaquine, and dapsone plus trimethoprim are alternatives. Prophylaxis of high-risk patients reduces but does not eliminate the risk of PCP. Improved understanding of the pathogenesis of PCP is important for future advances against this life-threatening infection.
Paediatric Respiratory Reviews 12/2009; 10(4):192-8. · 2.77 Impact Factor
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ABSTRACT: Lipid formulations of amphotericin B are increasingly used in lieu of deoxycholate amphotericin B for primary treatment of zygomycosis, but little is known about the efficacy of the former antifungal in treating this fungal disease. We therefore undertook an analysis of a case series of all patients with zygomycosis who received L-AMB for primary antifungal therapy in five major mid-Atlantic medical centers. Among the categories of variables studied were demographics, methods of diagnosis, microbiology, sites of infection, global responses, and survival. The median patient age was 44 years and 71% were male. Immunosuppressive hematological disorders (54%) were the most common underlying condition. Pulmonary disease constituted 50% of infections, sinus infection 29%, and cutaneous disease 18%. Members of the genus Rhizopus were the most common recovered agents. Success as defined by complete or partial positive response was noted in 32% of the cases. Concomitant surgery was performed in 46% of the cases, with similar response rates (31%). Overall survival was 39%. L-AMB was effective as primary therapy in only some patients in this cohort of highly immunocompromised individuals with invasive zygomycosis underscoring the importance of host response and the need for further advances for treatment of this lethal infection.
Medical mycology: official publication of the International Society for Human and Animal Mycology 10/2009; 48(3):511-7. · 2.13 Impact Factor
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ABSTRACT: Cardiac assist devices have emerged as an increasingly important option for circulatory support in patients with advanced congestive heart failure. Infection has been the leading cause of death with use of ventricular assist devices for the past 25 years, and continues to be a major cause of morbidity and mortality in this population. Infections may involve the internal (blood-containing) components, or occur on the external device surfaces. The pump pocket and the percutaneous driveline are particularly vulnerable. In this article we review the pathogenesis, epidemiology, clinical course, and approaches for treatment and prevention of cardiac assist device infections.
Current Infectious Disease Reports 08/2009; 11(4):268-73.
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ABSTRACT: We created a clinical prediction rule to identify patients at risk of invasive candidiasis (IC) in the intensive care unit (ICU) (Eur J Clin Microbiol Infect Dis 2007; 26:271). The rule applies to <10% of patients in ICUs. We sought to create a more inclusive rule for clinical trials. Retrospective review of patients admitted to ICU ≥ 4 days, collecting risk factors and outcomes. Variations of the rule based on introduction of mechanical ventilation and risk factors were assessed. We reviewed 597 patients with a mean APACHE II score of 14.4, mean ICU stay of 12.5 days and mean ventilation time of 10.7 days. A variation of the rule requiring mechanical ventilation AND central venous catheter AND broad spectrum antibiotics on days 1-3 AND an additional risk factor applied to 18% of patients, maintaining the incidence of IC at 10%. Modification of our original rule resulted in a more inclusive rule for studies.
Mycoses 08/2009; 54(1):46-51. · 2.25 Impact Factor
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New England Journal of Medicine 03/2009; 360(6):634; author reply 635-6. · 53.30 Impact Factor
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Thomas J Walsh,
Vidmantas Petraitis,
Ruta Petraitiene,
Jeffrey Solomon,
John D Bacher,
Lora Greene,
Margaret Cotton,
Andreas Groll,
Emmanuel Roilides,
Nilo Avila,
Vasilios Pyrgos, Shmuel Shoham
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ABSTRACT: Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are caused by organism-mediated tissue injury, vascular invasion, and hemorrhagic infarction. Ultrafast computed tomography (UFCT) scanning reproducibly measures these lesions in experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. The pulmonary lesion score from UFCT scanning is a useful outcome variable for measuring differences in efficacy of antifungal compounds alone and in combination, as well as the virulence of different strains and species of Aspergillus. Several studies demonstrate that the course of pulmonary lesions treated with amphotericin B, lipid formulations of amphotericin B, triazoles, echinocandins, and combination therapy measured by serial UFCT scans correlate with those measured by survival, histopathological resolution of lesions, microbiological clearance of Aspergillus fumigatus, and resolution of galactomannan index. We further developed a multidimensional volumetric imaging (MDVI) method for analysis of the volume of pulmonary infiltrates over time in response to antifungal therapy. Volumetric data by MDVI correlate with UFCT pulmonary lesion scores and validated biological endpoints. A recent pilot clinical study demonstrated the applicability of MDVI to human pulmonary fungal infections. MDVI also improves objectivity of radiological assessment of therapeutic response to antifungal therapy and merits more extensive evaluation in patients with invasive aspergillosis, as well as other fungal and bacterial pneumonias.
Medical mycology: official publication of the International Society for Human and Animal Mycology 03/2009; 47 Suppl 1:S138-45. · 2.13 Impact Factor
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ABSTRACT: Candidemia is a major cause of morbidity and mortality in patients undergoing hemodialysis but it has not been well defined in this patient population. We performed a retrospective case-control study to characterize the epidemiology, microbiology, and outcomes of hemodialysis-associated candidemia. All cases of candidemia at our institution were evaluated from 1 January 2000 until 1 September 2004. For each case, two non-candidemic dialysis patients served as controls. Among 350 cases of candidemia, 78 (22%) occurred in adult hemodialysis patients. Cases and controls were similar with respect to age, corticosteroid, antibiotics use, prevalence of diabetes mellitus, liver cirrhosis, surgical procedures, and cancer. Multivariate analysis found total parenteral nutrition (TPN) (19.5% vs. 1.3%; P<0.0001) and dialysis through a vascular catheter (74% vs. 46.8%; P=0.0001) to be independently associated with candidemia. Non-C.albicans Candida spp. particularly C. glabrata and C. krusei were more common in hemodialysis recipients than in candidemic patients not receiving hemodialysis (31% vs. 17% p = 0.009). In-hospital mortality was significantly elevated for candidemic vs. non-candidemic hemodialysis recipients (51.9% vs. 7.8%; P<0.0001). Candidemia in hemodialysis recipients is frequently caused by non-C. albicansCandida species, is associated with TPN and dialysis via a vascular catheter (vs. shunt or fistula) and carries a high mortality rate.
Medical mycology: official publication of the International Society for Human and Animal Mycology 10/2008; 47(5):463-7. · 2.13 Impact Factor
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ABSTRACT: Fluorescence in situ hybridization using peptide nucleic acid probes (PNA-FISH) differentiates Staphylococcus aureus from other Gram-positive-cocci in clusters (GPCC). 101/202 patients with GPCC+ blood cultures were randomly assigned to clinician-notification of PNA FISH results. Notification was associated with reduced mortality (8% vs.17%, p = 0.05), further antibiotic use (median -2.5 days, p = 0.01), and trended toward reduced hospital stay and charges.
Therapeutics and Clinical Risk Management 07/2008; 4(3):637-40.
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ABSTRACT: Zygomycosis has emerged as an increasingly common infection in immunocompromised patients. Although the majority of these cases are community acquired, hospital outbreaks have been described, linked to the use of contaminated products. Risk factors for development of zygomycosis include uncontrolled diabetes mellitus, neutropenia, use of immunosuppressive medications, and iron overload states. Recent studies have shown the central role of iron in the pathogenesis of zygomycosis and the effect of disease states such as ketoacidosis and hyperglycemia on the availability of iron to the Zygomycetes. These organisms most commonly infect the sinuses, lungs, central nervous system, and skin and soft tissues. Diagnosis often involves invasive procedures, including deep tissue biopsy, because radiological studies are not specific for this disease, and other less invasive diagnostic modalities have not yet been proven to be sensitive or specific. Treatment may require a combined medical and surgical approach in these frequently frail patients; yet, even with such aggressive measures the mortality of zygomycosis remains high.
Seminars in Respiratory and Critical Care Medicine 05/2008; 29(2):111-20. · 2.43 Impact Factor
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ABSTRACT: Caspofungin was the first echinocandin to be licensed for the treatment of invasive fungal infections. Caspofungin has in vitro and in vivo activity against Candida spp. and Aspergillus spp., which constitute the majority of medically important opportunistic fungal pathogens. Caspofungin inhibits the synthesis of the 1,3-beta-glucan, with resultant osmotic instability and lysis. The pharmacology of caspofungin is relatively complex. Trafficking of drug into tissues is an important determinant of the shape of the concentration-time relationship. Caspofungin has demonstrated efficacy in experimental models of invasive candidiasis and aspergillosis, which reflect its activity in the treatment of oropharyngeal, esophageal and disseminated candidiasis, as well as salvage therapy for patients with invasive aspergillosis.
Expert Opinion on Drug Metabolism & Toxicology 04/2007; 3(2):263-74. · 3.12 Impact Factor
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ABSTRACT: During the period 1998-2004, candidemia developed in 7 of 117 ventricular assist device recipients at our hospital, and the associated mortality rate was 71%. Five cases of candidemia were due to Candida parapsilosis, and 2 were due to Candida albicans. Three of the 7 patients with ventricular assist device-associated Candida bloodstream infections were cured, and the device was retained in 2 of the 3 patients.
Clinical Infectious Diseases 02/2007; 44(2):e9-12. · 9.15 Impact Factor
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Elias J Anaissie,
Brahm H Segal,
John R Graybill,
Carola Arndt,
John R Perfect,
Michael Kleinberg,
Peter Pappas,
Danny Benjamin,
Robert Rubin,
Judith A Aberg, [......],
Paul VerWeij,
Claudio Viscoli,
Maria Anna Viviani,
Randall C Walker,
Joseph L Wheat,
Joseph Wiley,
Peter Williamson,
John R Wingard,
Victor L Yu,
Theoklis Zaoutis
Clinical Infectious Diseases 11/2006; 43(8):1031-9. · 9.15 Impact Factor
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ABSTRACT: We report a case of a 52-year-old man with post-surgical meningitis due to a multi-drug resistant Acinetobacter baumannii. Despite therapy with intravenous amikacin and imipenem the meningitis progressed. Upon institution of combination therapy with amikacin by the intravenous and intrathecal (IT) routes, and intravenous colistin the patient experienced successful clinical and microbiological outcomes.
The Journal of infection 01/2006; 51(5):e249-51. · 4.13 Impact Factor
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ABSTRACT: During the past two decades, invasive fungal infections have emerged as a major threat to immunocompromised hosts. Patients with neoplastic diseases are at significant risk for such infections as a result of their underlying illness and its therapy. Aspergillus, Candida, Cryptococcus and emerging pathogens, such as the zygomycetes, dark walled fungi, Trichosporon and Fusarium, are largely opportunists, causing infection when host defences are breached. The immune response varies with respect to the fungal species and morphotype encountered. The risk for particular infections differs, depending upon which aspect of immunity is impaired. This article reviews the current understanding of the role and relative importance of innate and adaptive immunity to common and emerging fungal pathogens. An understanding of the host response to these organisms is important in decisions regarding use of currently available antifungal therapies and in the design of new therapeutic modalities.
British Journal of Haematology 07/2005; 129(5):569-82. · 4.94 Impact Factor
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ABSTRACT: Meningitis due to Cryptococcus neoformans may be associated with elevated intracranial pressure (ICP), but management of this complication is often overlooked. We retrospectively analyzed 39 consecutive patients with cases of culture-proven, community-acquired meningitis and ascertained adherence to Infectious Diseases Society of America (IDSA) practice guidelines for management of cryptococcal meningitis. Of these 39 patients, 26 (67%) had infection due to C. neoformans. Cerebrospinal fluid opening pressure had been measured for 13 (50%) of these 26 patients, and major deviations from the guidelines with respect to ICP management were observed in the care of 14 (54%). Seven (50%) of these 14 patients developed neuropathies during therapy, compared with 1 of the 5 patients whose care had minor or no deviations from the guidelines (P=.024). Major departures from the IDSA guidelines for management of ICP due to C. neoformans meningitis are common and can be associated with neurological injury during therapy.
Clinical Infectious Diseases 03/2005; 40(3):477-9. · 9.15 Impact Factor
