Biomedical subjects
Graeme Forrest
Publications and source records attributed to Graeme Forrest.
Clinical research in the lay press: irresponsible journalism raises a huge dose of doubt.
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Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.
BACKGROUND: : The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. METHODS: : Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. RESULTS: : Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. CONCLUSIONS: : Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.
Late-onset invasive aspergillosis in organ transplant recipients in the current era.
We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.
Gastrointestinal infections in immunocompromised hosts.
PURPOSE OF REVIEW: Gastrointestinal infections in the immunocompromised host continue to have significant morbidity and mortality throughout the world. They all have similar exposures to viruses, bacteria and parasites and respond to these infections in a similar way. This review will summarize the latest reports on the epidemiology, diagnosis and treatment of known and emerging infections over the last 12 months. RECENT FINDINGS: Highly active antiretroviral therapy has reduced esophageal opportunistic infections in HIV patients compared to patients who are not taking this therapy. Esophageal candidiasis responds to escalating doses of micafungin as effectively as fluconazole. HIV-infected patients with untreated Mycobacterium avium-complex diarrhea are associated with a wasting syndrome that disrupts the somatostatin axis. Polymerase chain reaction testing has improved diagnosis of microsporidial infections. Cytomegalovirus polymerase chain reaction of tissue may improve the diagnosis of cytomegalovirus disease of the gastrointestinal tract in organ-transplant recipients. The treatment of hypogammaglobulinemia in transplant recipients with recurrent cytomegalovirus gastrointestinal disease may resolve their symptoms. Community viruses are an emerging threat to transplant recipients and may affect drug levels. Lastly, anti-tumor necrosis factor alpha therapy in the treatment of inflammatory conditions may cause Listeria monocytogenes to disseminate. SUMMARY: Immunocompromised hosts remain at risk for severe gastrointestinal and even disseminated infections. Management includes an early rapid diagnosis with rapid restoration of the immune system and appropriate anti-infective therapy. With the immunocompromised population rapidly increasing, prevention of these infections remains the greatest challenge.
Role of antifungal susceptibility testing in patient management.
PURPOSE OF REVIEW: The review focuses on the evolving role of antifungal susceptibility testing in the clinical management of patients with invasive fungal infections. It will clarify how to clinically interpret available susceptibility testing methods. RECENT FINDINGS: Fluconazole susceptibility testing for yeasts has now shown a relationship between fluconazole resistance and therapeutic failure. Of increasing concern are the reported cases of fluconazole cross-resistance to the newer triazoles. The correlation between amphotericin B and echinocandin susceptibility testing for yeasts, resistance, and outcomes is unknown. Although there are reports of clinical failures with echinocandins, resistance is uncommon and susceptibility testing is unhelpful. There are standardized methods of testing for the triazoles and amphotericin B against molds; however, resistance has not been correlated with outcomes due to host and laboratory factors. Knowing the intrinsic resistance of molds to particular antifungals is of greater importance. Posaconazole is a potent new antifungal agent against many difficult-to-treat molds including fusariosis and zygomycosis. SUMMARY: Antifungal susceptibility testing of yeasts can assist in treating patients with prior antifungal exposure in determining resistance or cross-resistance. Mold susceptibility testing is of limited clinical benefit, while posconazole is an exciting new agent for treating difficult invasive fungal infections.
West nile virus meningoencephalitis and acute flaccid paralysis after infliximab treatment.
West Nile virus (WNV) can cause severe central nervous system (CNS) illnesses including meningoencephalitis (MNE) and acute flaccid paralysis (AFP). Risk factors include advanced age, immunosuppression, cancer, and diabetes. In vitro studies show that tumor necrosis factor (TNF) has anti-WNV activity and is protective against WNV infection. Anti-TNF-a monoclonal antibodies may increase susceptibility to WNV by inhibiting an adequate TNF-a response, leading to prolonged viremia, viral penetration into the CNS, and fulminant WNV-CNS disease. We describe a fatal case of WNV with MNE and AFP after infliximab therapy. During WNV outbreaks, clinicians should encourage patients receiving anti-TNF-a drugs to take appropriate preventive measures because of the risk of severe WNV-CNS disease.
Prevalence of Candida dubliniensis fungemia at a large teaching hospital.
Six cases of Candida dubliniensis fungemia were identified during an 8-month period in hospitalized patients with various conditions, including human immunodeficiency virus infection. Peptide nucleic acid fluorescent in situ hybridization analysis was used as a rapid and reliable test for differentiating C. dubliniensis from Candida albicans, making it feasible to determine the prevalence of C. dubliniensis fungemia.
A liver transplant recipient with an infected explanted liver.
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Failure of interferon alpha-2b in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis.
WNV infection can cause meningoencephalitis (MNE) and acute flaccid paralysis (AFP). Both syndromes are associated with high morbidity and mortality. Interferon alpha-2b (IFN-alpha-2b) inhibits WNV replication in vitro. To date, 5 patients with WNV-CNS disease have recovered neurologic function with IFN-alpha-2b. We report the first failure of IFN-alpha-2b in the treatment of WNV-MNE-AFP.
A man with fever, headache, and confusion.
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Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome.
BACKGROUND: Unique characteristics, impact of therapy with antifungal agents, and outcome of infections with Scedosporium species were assessed in transplant recipients. METHODS: The patients comprised a total of 80 transplant recipients with Scedosporium infections, including 13 patients from our institutions (University of Pittsburgh Medical Center [Pittsburgh, PA], University of Maryland [Baltimore], Duke University Medical Center [Durham, NC], Emory University [Atlanta, GA], and Hospital Gregorio Maranon [Madrid, Spain]) and 67 reported in the literature. The transplant recipients were compared with 190 non-transplant recipients with scedosporiosis who were described in the literature. RESULTS: Overall, 69% of the infections in hematopoietic stem cell transplant (HSCT) recipients and 53% of the infections in organ transplant recipients were disseminated. HSCT recipients, compared with organ transplant recipients, were more likely to have infections caused by Scedosporium prolificans (P=.045), to have an earlier onset of infection (P=.007), to be neutropenic (P<.0001), and to have fungemia (P=.04). Time elapsed from transplantation to Scedosporium infection in transplant recipients has increased in recent years (P=.002). The mortality rate among transplant recipients with scedosporiosis was 58%. In a logistic regression model using amphotericin B as comparison treatment, voriconazole was associated with a trend towards better survival (odds ratio [OR], 10.40; P=.08). Presence of disseminated infection (OR, 0.20; P=.03) predicted lower survival, and receipt of adjunctive surgery as treatment (OR, 5.52; P=.02) independently predicted a better survival in this model. CONCLUSIONS: Scedosporium infections in transplant recipients were associated with a high rate of dissemination and a poor outcome overall. The use of newer triazole agents warrants consideration as a therapeutic modality for these infections.
Gastrointestinal infections in immunocompromised hosts.
PURPOSE OF REVIEW: Patients with immunocompromised states are increasing in the world not only because of HIV infection but also as a result of better therapies in solid organ transplantation, stem cell transplantation, and leukemia. All these patients are at similar risk of gastrointestinal infections, and the subsequent morbidity and mortality from these infections makes it important to recognize the net state of immunosuppression of each person infected. RECENT FINDINGS: This review evaluates emerging pathogens, new diagnostic tools and guidelines, and the latest therapies published in the last 12 months in HIV and solid organ transplantation. The echinocandins provide a new therapy for Candida esophagitis, whereas Mycobacterium avium complex therapy may be discontinued with immune reconstitution in patients with HIV. The emergence of antimicrobial-resistant bacteria and viruses is a new threat to managing these infections, especially in poorer countries. Also, several community viruses such as adenovirus were shown to cause significant morbidity to immunocompromised patients. Lastly, the interaction among immunosuppressive medications, diarrhea, and rejection makes an important argument for evaluating patients for infection before adjusting medications. SUMMARY: The immunocompromised host is rapidly increasing in the world, resulting in exposures to new pathogenic organisms that cause gastrointestinal infections. New diagnostic tests and better antimicrobial therapy are improving outcomes in patients with access to health care. Unfortunately, these challenges are increasing daily with the development of multidrug-resistant bacteria and viruses that do not respond to standard therapies. The most important factor in overcoming these infections is restoration of the immune system, either by using antiretroviral therapy or decreasing immunosuppression.
Photo quiz. A 40-year-old man with chronic elbow swelling after minor trauma.
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