Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts.
ABSTRACT Invasive fungal infection (IFI) is a leading cause of infection-related mortality among patients with cancer and prolonged neutropenia and among allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Invasive candidiasis was the principal IFI in the period predating fluconazole prophylaxis, whereas today, invasive aspergillosis and other mold infections cause the majority of deaths from fungal infection in this patient population. The changing epidemiology of IFI, in addition to advances made in antifungal therapeutics and early diagnosis of IFI, warrant a reevaluation of earlier strategies aimed at prevention and early treatment of IFI that were developed several years ago. Here, we propose that persistent neutropenic fever is nonspecific for an IFI and should not be used as the sole criterion for empirical modification in the antifungal regimen in a patient receiving mold-active prophylaxis. We explore the potential benefits and gaps in knowledge associated with employing chest CT scans and laboratory markers as diagnostic adjuncts for IFI. Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies.
Article: Diagnostic challenges and recent advances in the early management of invasive fungal infections.[show abstract] [hide abstract]
ABSTRACT: During the past 20 yr, the population of immunocompromized patients at risk of developing invasive fungal infections (IFIs) has increased, and there has been a shift in fungal epidemiology, with more infections caused by non-Aspergillus molds and yeasts, which are often resistant to one or more antifungal drugs. Traditional diagnostic methods, such as culture and the histopathology of infected tissue, often fail to detect IFIs until the later stages. Furthermore, invasive diagnostic methods to obtain tissue may be contraindicated in severely ill patients; even when tissue is available, the morphology of several filamentous fungi is identical, or the cultures may fail to grow the pathogen. Recently developed non-invasive diagnostic techniques, such as tests for serum markers and polymerase chain reaction assays, may allow for earlier and more accurate diagnoses - crucial in the effort to reduce morbidity and the risk of mortality. This article reviews current approaches to diagnosis and treatment, focusing on how an early and accurate diagnosis can guide treatment and improve outcomes. Strategies for improving the management of IFIs also are discussed.European Journal Of Haematology 11/2009; 84(4):281-90. · 2.61 Impact Factor
Article: Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients.[show abstract] [hide abstract]
ABSTRACT: The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.Antimicrobial Agents and Chemotherapy 10/2010; 54(10):4143-9. · 4.84 Impact Factor
Article: Galactomannan-guided preemptive vs. empirical antifungals in the persistently febrile neutropenic patient: a prospective randomized study.[show abstract] [hide abstract]
ABSTRACT: Patients with neutropenic fever after 4-7 days of broad-spectrum antibiotics are given antifungals empirically. This strategy may lead to over-treatment. Patients with hematological malignancies undergoing intensive chemotherapy or hematopoietic stem cell transplantation were randomized to two arms. Patients in the 'preemptive' arm had regular galactomannan (GM) assays, and received caspofungin, amphotericin or voriconazole (CAV) for persistent febrile neutropenia if they had two positive GM results, or a positive GM result and a computed tomography (CT) of the thorax suggestive of invasive pulmonary aspergillosis (IPA). Patients in the 'empirical' arm received CAV in accordance with established guidelines. Of 27 episodes in the preemptive arm, two cases of IPA were picked up by monitoring. In six episodes, CAV was started despite persistently negative GM readings. One additional patient received CAV for a false-positive GM. Of 25 episodes in the empirical arm, CAV was started empirically in 10, one of whom had CT features of IPA. By intent-to-treat and evaluable-episode analyses, respectively, the preemptive approach saved 11% and 14% of patients from empirical antifungals. Twelve-week survival was 85.2% in the preemptive arm and 84% in the empirical arm. A preemptive approach may reduce empirical antifungal use without compromising survival in persistently febrile neutropenic patients.International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 03/2011; 15(5):e350-6. · 2.17 Impact Factor