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MEDICAL FRONTIERS - 4th Advances Against Aspergillosis Conference

Rome, Italy / February 4-6, 2010

Aspergillus species are extremely prevalent in the environment and although many individuals will be extensively exposed to Aspergillus spores, they will at worst be colonized and infection will not develop. There are, however, certain clinical situations in which patients are more susceptible to invasive infection. Immunocompromised patients—e.g. transplant recipients on immunosuppressive regimens and oncology patients after hematopoietic stem cell transplantation or during chemotherapy—are clearly at greater risk. However, other conditions such as HIV/ AIDS, chronic obstruction pulmonary disease and use of steroids or anti-tumour necrosis factor- alpha agents also increase the risk of invasive aspergillosis (IA) (Maschmeyer et al. Drugs 2007;67(11):1567- 601). Physicians often confront diagnostic signs and symptoms that vary widely according to the underlying condition.

Diagnostic Challenges

Aspergillosis infection is confirmed by a positive culture of a sample taken from the suspected site of infection. However, cultures take time and many clinicians believe that early and aggressive treatment is important. In patients with impaired inflammatory response, often radiologic indicators such as the characteristic “halo” sign may not be present. Likewise, the poor condition of the patient may hide tell-tale signs of infection in standard laboratory tests. As a result, investigators have become increasingly interested in specific molecular methods for detecting infection early.

One approach is to monitor levels of galactomannan, a constituent of the cell wall of Aspergillus species, although care is needed in interpretation as many factors can influence the performance of the assay (Mennink- Kersten et al. Lancet Infect Dis 2004;4(6):349-57).

It has also been suggested that serial galactomannan measurements may be used to monitor the effectiveness of treatment, although there is some concern that treatment may act as a confounding factor in the assay and produce paradoxical effects. For example, the echinocandins, which work by inhibiting glucan synthesis in the cell wall, may actually produce a spike in concentration because of reduced galactomannan binding to the cell wall, even if they are inhibiting fungal growth. A number of studies have, however, shown a correlation between galactomannan levels and outcome, such as one study of 56 neutropenic and non-neutropenic patients with stem cell transplantation (Woods et al. Cancer 2007;110(4):830-4). Survival was significantly greater in patients whose levels of galactomannan normalized (Figure 1). “Serial measurements of galactomannan can be useful,” concluded Dr. Thomas Patterson, University of Texas, San Antonio, “but they should be interpreted with other clinical indicators of outcome.”

Figure 1. Survival of Hematological Patients with IA According to Galactomannan Status

Radiolabelled antifungal agents are currently under investigation as a means to detect fungal infection. Antifungal agents are good candidates for radiolabelling as they preferentially seek out fungal cells and have a low affinity for mammalian cells. Labelled fluconazole appears to be useful for detection of Candida infections, and natural antifungal peptides have been used to detect Aspergillus infection in animal models, although radiolabelling of antifungals such as voriconazole active against Aspergillus has not been undertaken.

Finally, a novel approach is to look for volatile markers of Aspergillus in exhaled air. After collection, samples are submitted to mass spectrometry to look for the distinctive signature of 2-pentylfuran, chosen because it is fairly specific to Aspergillus. Contamination from 2-pentylfuran present in the environment is an issue that needs to be addressed. However, “The presence of 2-pentylfuran does not indicate whether invasive infection is present or whether the patient is merely colonized,” explained Dr. Stephen Chambers, Christchurch School of Medicine and Health Sciences, New Zealand. Clearly, the technique would be complementary, intended as support to other clinical or radiological tests.

Issues with Epidemiological IA Studies

In recent years, several studies have attempted to clarify questions about the epidemiology of IA. These can be broadly classed as single-centre or multicentre studies, or health surveillance registries, each with their advantages and disadvantages. Single-centre studies can, for example, allow for follow-up of individual patients to monitor outcomes. “Unfortunately the number of patients included in such studies will necessarily be small and although diagnostic criteria will be uniform, providing homogeneous data, it is debatable whether results can be generalized to other hospitals with different therapeutic practices,” remarked Dr. Dionissios Neofytos, Thomas Jefferson University, Philadelphia, Pennsylvania.

Health-surveillance databases provide the opportunity to study very large patient populations, but the coding applied (ICD-9) lacks sensitivity. A compromise undertaken recently has been the use of prospective multicentre studies. The TRANSNET was a consortium of 23 transplant centres, which collected data from solid organ transplant recipients between 2001 and 2006 and the Prospective Antifungal Therapy (PATH) Alliance, which collected data on all types of patients at US medical centres between 2004 and 2008. In general, the findings were in reasonable agreement with previous epidemiological studies. A. fumigatus remained the predominant species isolated, although of note were presence of other Aspergillus species and other instances when the species were not determined. This may have a bearing on clinical practice in the future.

Treatment Options and Current Guidelines

According to the current Infectious Diseases Society of America (IDSA) guidelines, voriconazole is the preferred agent in proven aspergillosis infections. This is because comparative trials have supported the use of voriconazole when the infective agent is known (albeit using deoxycholate amphotericin B as a comparator because the liposomal formulation was not available) (Herbrecht et al. N Engl J Med 2002;347(6):408-15). Subsequent non-randomized studies have further supported use of voriconazole, such as an Italian registry of voriconazole, liposomal amphotericin B and caspofungin in 140 acute myeloid leukemia patients (Pagano et al. Haematologica 2009 Oct 22 [Epub ahead of print]). The failure rate was lower among patients treated w
e 1).

Table 1.

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In contrast, the liposomal formulation of amphotericin B is indicated as empirical therapy in persistently febrile neutropenic patients. There is a risk that the pathogen might be Zygomycota, against which voriconazole is not active. Dr. Livio Pagano, Catholic University of the Sacred Heart, Rome, Italy, indicated, “In our patients treated empirically, zygomycosis accounts for approximately 1 in 22 of fungal infections, and for this reason, we adhere to the guidelines.” In these patients, though rather than choice of antifungal agent, “What is most important in these patients is [for them] to recover from neutropenia,” stressed Dr. Pagano, as persistent neutropenia was the strongest predictor of mortality in the Italian registry.

Drug Resistance in Aspergillus

One drawback of any azole is that metabolism occurs in the liver by CYP3A4. There is therefore a risk of drug-drug interactions with concomitant agents such as calcineurin inhibitors in transplant patients that are also metabolized via this route. If we add to this an inherent variability in the pharmacokinetics of azoles, particularly when administered orally, there is a risk that serum concentrations are either too high or too low in these patients.

If azole dosing is too low (serum concentration <0.5 mg/L in the case of voriconazole), then there is a risk that the pathogen may develop resistance. Indeed, azole resistance is a growing concern and some centres have reported an increase in resistance over the last decade, although epidemiological data on resistance are hard to collect and interpret given that susceptibility testing is not routinely performed in many centres. As highlighted by Dr. Susan Howard, Regional Mycology Laboratory, University of Manchester, UK, “Some patients might be infected by strains already resistant to azoles, and there is also the question of cross-resistance among azoles.” Some data suggest that even very short exposure to azoles may be sufficient to generate resistance. In addition, patterns of resistance may change over time. For these reasons, in chronically-treated patients, Dr. Howard emphasized the importance of regular susceptibility testing to detect resistance.

Voriconazole is considered a relatively safe and welltolerated agent, yet if serum levels are too high, there is a risk of liver toxicity and neuropathy. Because of the possibility of drug-drug interactions, levels of immunosuppressants in transplant patients may increase, thereby actually increasing the risk of opportunistic infection.

Therapeutic Drug Monitoring

Given the narrow therapeutic window for voriconazole and the difficulties associated with attaining stable serum levels within the target therapeutic range, there is a case for therapeutic drug monitoring. The case is particularly strong when the patient is also receiving other drugs that act on CYP3A4, such as calcineurin inhibitors. An advantage of the azoles is that they are available orally, but oral administration adds to the pharmacokinetic variability of these drugs. Fortunately, the techniques for measuring serum azole levels are relatively straightforward and as Éliane Billaud, PhD, Hôpital Européen Georges Pompidou, Paris, France, remarked, “Therapeutic drug monitoring is not that expensive compared to the cost of treatment and certainly not compared to the cost to the patient of inappropriate drug failure.”

Combination Therapy in Critically Ill Patients

Throughout medicine, combination of two or more different agents with different mechanisms of action is commonplace. In the case of anti-infectives, combination therapies against HIV infection, for example, are the norm. Clinicians have sought to determine whether such a strategy could be applicable in IA, particularly in patients in the intensive care unit. According to Dr. Raoul Herbrecht, Department of Oncology-Hematology, Hôpital Hautepierre, Strasbourg, France, “These are particularly ill patients, who may have renal failure and require hemofiltration or respiratory failure, requiring intubation and mechanical ventilation.” Mortality among such patients with proven aspergillosis reported in different studies has ranged from 77% to 100%. “Combination therapy is therefore an attractive concept, but it can be dangerous. We might expect antimicrobial synergy, complementary pharmacokinetics, reduced acquired resistances, increased response rate and survival, accelerated response to therapy, but also increased toxicity and a major increase in cost,” he told delegates. Yet Dr. Herbrecht also suggested that in his opinion, current monotherapy regimens are often not optimized, citing studies that show a correlation between azole levels and outcome (Walsh et al. Clin Infect Dis 2007;44(1):2-12), an observation further supporting the need for therapeutic drug monitoring.

Although currently not recommended in the IDSA guidelines, combination therapy is used in clinical practice, particularly in critically ill patients or in a salvage setting, as illustrated by one survey of liver transplant recipients (Table 2). This use in clinical practice has allowed some studies to be performed, but often the numbers are low and a historical control is often used as a comparator group (Marr et al. Clin Infect Dis 2004;39(6):797-802).

At present, there is a lack of high-level clinical evidence to support combination therapy. To that end, a randomized study is currently ongoing to compare voriconazole as monotherapy with a combination of voriconazole and the echinocandin anidulafungin. The target for enrolment is 405 hematological patients with proven, probable or possible IA, and the primary end point is survival at week 6 of therapy. “This study should give us some current information on what is the best way to optimize therapy with currently available agents while we develop new molecular approaches (which target cell signalling or stress response)” concluded Dr. William Steinbach, Associate Professor, Department of Mole
robiology, Duke University, Durham, North Carolina.

Table 2.

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Summary

IA is a challenging problem and mortality remains high. The mainstay therapy for proven infection is voriconazole, which is generally considered to be the best option. Even in patients receiving calcineurin inhibitors, where drug-drug interactions are expected, careful therapeutic drug monitoring can help overcome the unpredictable pharmacokinetics of the agent. In seriously ill patients, combination therapy could in theory be beneficial, although hard clinical data to support such a strategy are not yet available.