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PRIORITY PRESS - 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Boston, Massachusetts / September 12-15, 2010

Despite the introduction of newer azole antifungal agents that have demonstrated unprecedented efficacy against invasive aspergillosis (IA) and other challenging pathogens, fungal infections remain a major source of hospital morbidity and mortality in immunocompromised patients. Efforts to accelerate therapy or treat high-risk patients prophylactically are appealing strategies to reduce the toll of fungal infections. However, algorithms for this purpose have proven insufficiently sensitive, complex and impractical for routine application for many populations.

“The problem is that any method that has clinical value, as opposed to research value, will have to be practical, generalizable and reasonably sensitive or it will not be used,” observed Dr. Yoav Golan, Division of Infectious Diseases, Tufts-New England Medical Center, Boston, Massachusetts. He was among several experts who concluded that the number-needed-to-treat (NNT), i.e. the number of patients who are treated to prevent one fulminant infection, must be in the range of 10 to 20 to achieve an acceptable cost efficacy. In patient groups with a low incidence of IA, even if rates of a fatal outcome are substantial, this has been difficult to achieve.

The first-line therapy for IA in major guidelines, such as those issued by the Infectious Diseases Society of America (IDSA), is voriconazole. Although deoxycholate amphotericin B (D-AMB) is also indicated for primary treatment, voriconazole was not only superiour in a key multicentre controlled trial but the data from that trial was used to predict greater cost efficacy. For patients at high risk of IA—such as patients who develop graft vs. host disease after hematopoietic stem-cell transplant (HSCT) or those with acute myelogenous leukemia or myelodysplastic syndrome who become neutropenic—IDSA guidelines recommend prophylaxis with posaconazole, an oral agent specifically studied in prevention but less well studied in proven invasive infections where intravenous (i.v.) therapy is often essential.

The Importance of Treating Early

This issue of how to increase early administration of the first-line agent is important because although voriconazole is efficacious against invasive fungal infections (IFIs), particularly aspergillosis, mortality rates remain unacceptably high in at-risk populations. Traditionally, treatment of IFI has been stratified by proven, probable or possible infection, but the high risk of major complications including death in advanced infection has led to efforts to shift a greater proportion of patients to earlier treatment, according to Dr. Thierry Calandra, Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. He, echoing other experts, indicated that prophylactic and pre-emptive strategies may be critical weapons in the effort to reduce complications.

“The problem is that we still have very little data demonstrating that prophylaxis yields significant improvements in outcome in many high-risk populations where this approach might be considered,” Dr. Calandra told delegates. He noted that pre-emptive therapy with broad-spectrum antifungal agents, such as newer azoles, might make sense in populations with relatively high rates of IA, such as those in an intensive care unit (ICU), but this cannot be assumed even with the most effective agents, particularly in the context of reasonable cost efficacy.

Cost is the major consideration because the safety of early use of newer azoles does not appear to be an obstacle to prophylactic or pre-emptive therapy. In a multicentre phase III study of 147 hospitalized cancer patients with febrile neutropenia persisting for 96 hours who were randomized to immediate or deferred voriconazole, the lower rate of proven or probable IFI in the immediate group failed to reach statistical significance (15.9% vs. 25.7%, P=0.4), but voriconazole treatment was found to be safe. According to the senior author of the study, Dr. Georg Maschmeyer, Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany, the safety of voriconazole in a population of compromised patients encourages the development of screening methodology to find the sub-group that can achieve greater survival if treated earlier.

Screening and Therapeutic Drug Monitoring

Such screening programs, which are likely to be derived from some combination of risk factors that provide a reproducible predictive value for IFIs, need not be confined to traditional at-risk populations, such as those in an ICU or who are otherwise immunocompromised. Increasing attention has been devoted to factors that define risk in the non-traditional host, such as patients with chronic obstructive pulmonary disease or diabetes. In a study looking specifically at this population, one of the most common risk factors for IFI was chronic steroid use.

“IFIs due to aspergillosis are increasingly common in patients who have not been traditionally considered to be at risk,” observed Dr. Jose A. Vazquez, Division of Infectious Diseases, Henry Ford Health Systems, Detroit, Michigan. Author of a study that sought for common characteristics in a population of 36 non-traditional patients who developed proven or probable IA at his institution, Dr. Vazquez reported that steroid use was common to 69% of patients. The next most common shared risk factor was another immunosuppressive agent. Consistent with guidelines, voriconazole was the most common primary antifungal therapy used in this population, but a mortality rate of 25% at 90 days suggests that strategies for earlier initiation of therapy are needed.

While more rapid diagnosis of fungal infection with computed tomography (CT) scanning or non-culture based screening of the aspergillosis antigen with galactomannan enzyme immunoassay (EIA) may be part of the strategy to accelerate the time to treatment, simply verifying adequate drug levels may also play a role in improved outcomes. In life-threatening IA, several centres are looking at therapeutic drug monitoring (TDM) for ensuring that plasma concentrations remain in the range of optimal antifungal activity. This may be valid for any antifungal agent, but there has been particular attention paid to therapies employed for IA. A study with voriconazole was among those that have generated evidence that TDM is an important clinical tool.

“Of the 70 TDMs performed in our series, 20 (28.7%) were outside the range of reference,” reported Dr. Isabel Ruiz Camps, Division of Infectious Diseases, Hospital Vall d’Hebron, Barcelona, Spain. Increases of 17% to 50% in the dose were required to restore the antifungal therapy to the therapeutic range, suggesting that at least some patients may have been in danger of inadequate treatment in the absence of TDM.

Dr. Ruiz Camps remarked, “Voriconazole is the first-choice treatment for IA and it also constitutes an alternative for other IFIs, but our data suggests that individualization of drug dose is required to ensure efficacy.”

Currently available oral antifungals, such as posaconazole, may provide an adequate threshold for prophylaxis, but one of the challenges going forward is to better define the boundaries between pre-emptive and empirical therapy. While Dr. Calandra identified pre-emptive treatment as an intervention when infection is “possible” while empirical is for infection that is “probable,” better methods of predicting infection may blur these distinctions. This is critical for treatment selection. For probable infections that include IA as a likely pathogen, a therapy with proven activity against IA is prudent. For prophylaxis, agents without proven activity against IA may still be adequate for preventing this or other invasive infections simply by inhibiting growth.

Summary

The guidelines clearly define a first-line agent for IA based on controlled trials, but infection control for this pathogen is expected to be increasingly directed to earlier treatment, which may increasingly stress pre-emptive treatment in tightly defined high-risk groups. Currently, the application of prophylactic and pre-emptive therapy remains uncertain except in relatively small subsets of very high-risk patients, but the persistent mortality and morbidity attributed to delayed therapy have focused efforts to expand strategies for earlier treatment whether through more rapid diagnosis, more rigorous identification of high-risk groups, more efficacious courses of therapy through TDM or, most likely, a combination of these approaches.