targeting fungi: a challenge

SWPOSIUM ON CHEMOTHERAPY / MEUNIER

cytokine secretion, and virus spread. Over years, the immune system is destroyed, leading to progressive immunosuppression and HIV disease.

However, for reasons still not understood, in about 5% of infected people, the virus, though repli- cating, is successfully contained. Fauci et al have been studying a group of some 30 such long-term nonprogressors.4 All of these patients have been infected for at least 7 years, and some for >lO years. None are sick, none have had antiretroviral therapy, and all have normal and stable CD4+ counts.

Biopsies show that, despite persistent infection, the lymph nodes of these patients appear normal. Though their viruses were able to replicate and infect, the viral burden in their lymph nodes remain relatively low, and the patients maintained persistent, low-level viremia for 15 years without trigger- ing the vicious cycle of cytokine secretion and lym- phoid tissue destruction.

Understanding how the virus is controlled in these individuals, together with developing better antiretroviral agents, will lead to new therapeutic approaches.

Even if better antiretroviral agents are developed, will the immune system be able to regenerate its functional ability after being severely disrupted by advanced HIV disease? One way would be to transplant an immune system. This has proven to be difficult, for a number of reasons. What about

Targeting Fungi: A Challenge FRANCOISE MEUNIER, M.D., Ph.D., Brussels, Be/gum

Invasive firngal infections are more commonly identified in various categories of patients, mainly in cancer patients but also in those undergoing organ transplantation, patients in intensive care units, and those with AIDS. There is a great need to increase the awareness of practitioners who are still underestimating the morbidity and mortality relating to invasive fungal infections, and to stress the economic burden for the society and healthcare systems of invasive fungal infections. The list of fungal pathogens causing life-threatening complications has also increased recently, with the emergence of unusual fungi being more frequently identified

cytokine therapies that can expand the CD4+ cell population?

Lane and Kovacs” have shown that giving patients intermittent doses of IL-2-continuous infu- sion for 5 days, then nothing for 8 weeks-over the course of several years increased their CD4 + count baseline levels. Thus, this represents one step to- ward a more comprehensive approach to the treatment of HIV disease, and one that uses understanding of the host factors involved in pathogenesis,

From the Department of Health and Human Services, Nahonal lnstrtutes of ( Health Bethesda Maryland. , , 1

Requests for reprints should be addressed to Anthony Faucr M.D. Depart ment of Health and Human Services, Nahonal lnstltutes of Health, Building 31, Room 7A03, 31 Center Drive MSC 2520, Bethesda, Maryland 20892.2520.

REFERENCES 1. Pantaleo G, Grazrosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS. HIV Infection is active and progressive m lymphord tissue during the clinrcally latent stage of disease. Nature 1993; 362: 355-8. 2. Pantaleo G. Graziosi C, Fauci AS. The immunopathogenesis of human immunodeh crency vrrus infection. N Engl J Med 1993; 328: 327-35. 3. Krnter AL, Poli G, Fox L, Hardy E, Fauci AS. HIV replrcation rn IL-2 stimulated perrpheral blood mononuclear cells is driven In an autocrrne/paracrine manner by endogenous cytoknes. J lmmunol 1995; 154: 2448-59. 4. Pantaleo G, Memo S, Vaccarezza M, et al. Studres in subjects with long-term nonprogressrve human immunodeficrency virus Infection. N Engl J Med 1995; 332: 209-16. 5. Kovacs JA, Baseler M, Dewar RJ, et al. Increases in CD4 T lymphocytes wrth intermittent courses of rnterleukrn-2 in patrents with human rmmunodeficrency virus infection. A prelimrnary study. N Engl J Med 1995; 332: 567-75.

in such settings. Early diagnosis of invasive fungal infections is still a major challenge for the clinician at the bedside. Identification of state-of-the-art management is also a difficult task for the clinical scientists involved in the assessment of optimal strategies to prevent and to treat those invasive fungal infections, although major progress has occurred in the last 5 years with the development of new, safe, and effective antifungal agents. Empiric therapy remains a very controversial issue that should be further investigated in high- quality clinical trials. Overall, clinical research in this difficult field requires indepen- dent and objective analysis; only large multi-

6A-6OS December 29, 1995 The Amerrcan Journal of Medicine Volume 99 (suppl 6A)

center clinical trials can address these criti- cal issues and rapidly provide convincing results leading to a better prognosis of patients with invasive fungal infections. These complications still represent too often an obstacle to successful control of severe underlying diseases. Clinical research on the appropriate ways to target fungi will not only define state-of-the-art management but also identify ineffective or redundant treatments. Such an approach will make a substantial contribution to the care of the high-risk patients within the next decade and will preserve our capacity for medical excellence.

D uring the last decade, there has been a significant increase in the incidence of invasive fun-

gal infections observed among various categories of patients, including those with cancer but also those undergoing solid organ transplantation, patients with AIDS, and patients hospitalized for prolonged periods of time in intensive care units (following multiple surgery, for example). In particular, concerning the infections acquired during hospitaliza- tion, it has been shown that the rate of nosocomial fungemia has increased tremendously, and Cazdida species now represent up to 10% of the bloodstream pathogens identified in large hospitals worldwide.l~-S

These opportunistic fungal infections represent a major challenge for the patients and their families, healthcare professionals, and health authorities. There is an urgent need to increase the awareness of all involved partners still underestimating too often the morbidity and the mortality related to invasive fungal infections and to stress the economic burden for the society and healthcare systems of invasive fungal infections.

This article describes specific issues related to invasive fungal infections observed mainly in cancer patients, but these concepts are widely applica- ble to many other categories of patients at risk. Optimal management of fungdl infection remains controversial, and crucial aspects of clinical research in this field are stressed to fulfill our final objectives of preserving the capacity for medical excellence.

CURRENT ISSUES AND CONTROVERSIES: THE EXTENT OF THE PROBLEMS Epidemiology

Cancer now represents the second most common cause of mortality in the so-called developed countries. There are 2 million new cancer cases diag- nosed (and about 1 million deaths related to cancer) in the 15 European Union countries every year.

It is foreseen that the incidence of cancer will increase during the next decade only due to smoking patterns and to the aging of the population: 25% of the population will be >65 years old in 2010 and, therefore, the number of cancer patients may double in the next 20 years.

Cancer patients are immunocompromised and therefore highly susceptible to opportunistic infections. Tremendous progress in supportive care- including better control of hemorrhage and of bacterial infections, as well as more aggressive antineoplastic treatments for the underlying disease- is the major factor leading to the current higher incidence of invasive fungal infections in these patients.

Several autopsy studies have shown that the incidence of fungal infections in cancer patients is reaching 5% in patients with solid tumors, 10% for those with lymphoma, and 15-25% for patients with leukemia or these undergoing bone marrow transplantation.x-10

It must be stressed that most patients entering a hospital to be treated for such underlying diseases are often unaware of potential life-threatening fungal complications. These opportunistic infections are a catastrophe for the patients with potentially curable cancers but also represent a tremendous waste of human resources and a major burden for the society, also taking into account the increasing numbers of aggressive diagnostic and therapeutic procedures involved in the fight against cancer. It is now well recognized that invasive fungal infections are major obstacles to the adequate control of underlying diseases with good prognosis.

Diagnostic Procedures The clinical presentations of invasive fungal in-

fections are protean; various entities and syn- dromes have been described, but unfortunately the clinical signs and symptoms are not specific early in the evolution of the infection, which may remain occult during a prolonged period.

The most common pathogens encountered are Cu&ida and A.ymyillus species, particularly in neutropenic patients. However, numerous recent studies have shown an increased incidence of invasive fungal infections caused by other unusual fungi-such as Fu~~~tiwn, l’r-ichosporw~, Pseudal- 1escherG boydii, etc.-which have now been reported worldwide.“-” And it is not merely an aca- demic exercise to identify clearly the responsible fungal pathogens, as some of them are resistant to amphotericin I3 and also because there are now other treatments available.

The diagnosis of fungal infections requires com- plete identification of the pathogen by culture (e.g.,

December 29, 1995 The Amwcan Journal of Medune Volume 99 (suppl 6A) 6A-61s

in blood or in other noncontaminated sites) and his- tologic proof of invasion of deep tissue. However, 50% of patients dying with disseminated candidiasis never have a single positive blood culture pre mor- tem, and the interpretation of cultures from sites other than blood is often misleading, particularly for yeasts, False positive cultures frequently also occur in patients who are only colonized, and to establish the difference between colonization and invasion is really a major challenge for the clinicians at the bedsides of these patients.

On the other hand, identification of Aspergillus species in high-risk patients, such as neutropenic patients, is highly suggestive of invasive aspergillosis. However, once again, deep tissue involvement is required to ascertain definite diagnosis. Unfortu- nately, these patients also often have low platelet counts, which precludes biopsy of such deep tissues as the lung, the liver, the spleen, or the kidney. Def- inite proof of infection is not mandatory for the initiation of antifungal therapy, and it must be stressed that the optimal management of a patient at risk of fungal infection often requires one to take appropriate therapeutic measures in the absence of a proven infection, since invasive diagnostic procedures may be dangerous for such patients. How- ever, for the assessment of a new antifungal agent, demonstration of invasive infection is mandatory.

Numerous serodiagnostic tests have been developed and evaluated over the last 15 years.‘6-‘8 However, except for cryptococcosis, there is no reliable test to guide clinical practice, since most of these tests are still investigational. In fact, the patients who are at high risk of invasive fungal infections are severely immunocompromised and are not producing specific antibodies, at least at the point when therapeutic decisions must be made. In addition, tremendous efforts have also been developed to detect circulating antigens or metabolites early in the evolution of fungal infections, but again no commercially available test is reliable enough to promote its widespread use.

Other diagnostic procedures, including X-rays, CT scans, or MRI are in some circumstances suggestive but sometimes misleading as well; in particular, invasive aspergillosis has been demonstrated in patients with negative chest X-rays; these patients usually have very low white blood cell counts and therefore do not produce inflammatory reaction nor infiltrates.

Management of Fungal Infections The treatment of invasive fungal infections is still

too often suboptimal and toxic; the results achieved with conventional amphotericin B in patients with

documented invasive fungal infections have not been universally accepted. The outcome of these infections is still poor with an unacceptably high mortality in most circumstances, unless there is a control of the underlying disease, a recovery of adequate granulocytes counts, and a decrease of the immunosuppression. The mortality rate of patients with documented fungemia now reaches 40%, and 60-85% for those patients with aspergillosis.‘0Y21-2” Fusariosis and Trichosporinosis are almost uniformly fatal.

Further, amphotericin B has never been exten- sively investigated. The total dose needed, the duration of therapy required, and the potential role of alternate treatment (every other day) have never been defined in large convincing clinical trials.

For several decades there have been very few systemic antifungal agents available to treat patients with invasive fungal infections, and for too long, there has been a major lack of incentives to develop effective and safe antifungal drugs.

The high mortality rate of patients with documented fungal infections has led to the concept of the need for empiric management of patients at high risk in order to treat occult fungal infections.24,25 However, practical modalities for empiric antifungal management are still controversial due to the toxicity of conventional amphotericin B. The optimal drug for empiric management, the specific indications, and the appropriate time to initiate such empiric treatment are also to be further established, particularly due to the current changes in patterns of fungal pathogens encountered and the availability of new alternative antifungal agents.

There is a need to establish these appropriate strategies, taking into account that not all febrile neutropenic patients have occult invasive fungal infections. It is a dilemma for the clinician to decide whether to initiate a toxic antifungal treatment, such as amphotericin B, in patients who may not require it or whether to delay empiric antifungal therapy, which may have a very detrimental effect on the course of high-risk immunocompromised patients. The recent development of less toxic antifungal agents could allow widespread use of early empiric management.

Further, clinicians now also face a higher number of resistant pathogens, including Candida a1bican.s and such other fungal species as Candida krusei, Torulopsis glabrata, and Candida Eusitani- c~.~‘-~s There are, therefore, still numerous unre- solved clinical questions: What is the drug and dose of choice for each clinical entity? What is the optimal duration of therapy for, for example, fungemia? For invasive aspergillosis? For other mycoses?

SYMPOSIUM ON CHEMOlHEfWY / MEUNER

6A-62S December 29, 1995 The American Journal of Medicine Volume 99 (suppl6A)

Preventive ideans Due to the difficulty in diagnosing invasive fungal

infections and also due to the severity of these infections, it seems rational to prevent these complications. Candidiasis are mainly endogenous infections, whereas mold infections are often exogenous and mostly transmitted by inhalation of contami- nated air. Adequate prophylactic modalities remain controversial due to the numerous and growing number of offending fungal pathogens and the lack of simple and effective means to cover all those pathogens reliably.

This is the reason why a consensus on practical recommendations is still lacking, and one should always consider local epidemiologic factors in order to target the most likely pathogens for each unit or hospital; whereas candidiasis are the most common infections in some hospitals, epidemics of aspergillosis have been described worldwide, particularly following bone marrow transplantation in units undergoing renovation or in hospitals with construction work nearby.4*2!‘-“L

More specific measures, including isolation procedures, do not seem effective when used alone, and systemic antifungal prophylaxis seems to be required for high-risk patients facing the lack of efficacy of nonabsorbable antifungal agents, such as nystatin or oral amphotericin B, against all pathogenic fungi.

The major difficulty is to identify an antifungal agent that would be easy to administer, effective on most fungal pathogens (yeast and molds), nontoxic, and cheap-all characteristics that obviously represent a major challenge for any pharmaceutical in- dustry involved in antifungal drug development.

RECENT DEVELOPMENTS AND OPPORTUNITIES Tremendous progress has been made in the last

few years, mainly due to significant advances in molecular biology and to the development of new classes of antifungal agents or alternative modalities to administer amphotericin B.

It is now possible to evaluate local epidemiologic factors further, using new methods for typing pathogenic or other colonizing fungal strains.“2--“”

Major efforts have also recently led to the stan- dardization of in vitro susceptibility testing for fungi, with official recommendations now available allowing for better evaluation of the potential emergence of resistance to antifungal agents.“7~-“”

For a long time resistance to amphotericin B has been considered as minimal and/or rather limited to patients with hematologic malignancy.4” More recently, emergence of resistance has been estimated to be higher than initially foreseen, particularly for

fluconazole in patients with AIDS, but the correlation of outcome and susceptibility testing is still controversial.“1~4” It is now feasible to identify whether delayed complications and relapses are due to selection of initial resistant strains, to development of resistance during treatment, or to inher- ently resistant strains.

Despite the availability of standarclized methods, it is not recommended at this point to perform susceptibility testing routinely for all fungi in each microbiology laboratory; however, it may be useful to collect pathogenic strains (e.g., those isolated in blood cultures) to evaluate potential emergence of resistance further if the patient fails therapy.

Facing the widespread use of polyenes as well as the development of other alt,ernatives (such as lipid formulations) to administer amphotericin B, the definition of resistance to amphotericin B will most likely need to be adapted according to the serum levels that are achieved with some of these new formulations of amphotericin B, in order to maintain a clinical relevance of in vitro testing. Indeed, the management of invasive fungal infections has bene- fited significantly from the development of lipid formulations of amphotericin B (AmBisome, ABLC, ABCD), as well as of triazolea, including mainly fluconazole and itraconazole.

It is now recognized that not all candidemia are equal, but nevertheless it is recommended that all patients with fungemia should receive specific antifungal treatment.‘*“--45 Even patients with the so- called benign and transient phenomenon should be treated to avoid delayed complications, such as endophthalmitis or osteomyelitis, which can occur up to several years following the initial episode of fungemia. Iinfortunately, the exact incidence of these complications is underestimated due to lack of adequate follow-up for most patients; for instance, patients developing a nosocomial catheter-related fungemia following orthopedic surgery will most likely contact not the surgeon but rather the oph- thalmologist whenever endophthalmitis occurs. Whereas the overall mortality of immunocompromised patients with fungemia reached 70% in the 1970s studies performed during the 1980s show an overall mortality rate following nosocomial candidemia of 55%“‘V2”*44V”7 with an attributable mortality of c :wfh.“”

These encouraging data are mainly related to the better recognition of the severity of the prognosis of fungemia, and such increased awareness results in a higher proportion of pat.ients being treated than in the past.

Further, amphotericin B is no longer considered to be the only antifungal treatment available for

December 29, 1995 The American Journal of Medicine Volume 99 (suppl 6A) 6A-63s

these patients, and fluconazole has been shown to be an effective alternative for candida esophagitis and also for nonneutropenic patients with Candida al bicans fungemia.48,4” However, several questions remain to be investigated, including, What is the role and benefit of initiating fluconazole by the intravenous route? What is the adequate dose and duration of treatment?4”

Whether a combination of antifungal agents (fluconazole with 5fluorocytosine [5-FC], amphotericin with 5-FC or with fluconazole) is useful has never been clearly investigated except for patients with cryptococcosis.

tivation of aspergillosis. In addition, it has even been reported that these patients may undergo subsequent bone marrow transplantation. Such an approach consists in a tremendous progress due to the fact that the control of the underlying disease is crucial for the final outcome of these patients.5x*5” That such an approach is now possible is evidence of the tremendous progress made in the control of the underlying disease, which is so crucial for the final outcome of these patients.

When using an antifungal agent with predictable pharmacologic parameters (such as fluconazole), it is not useful to monitor drug concentrations, but such tests are extremely important for the evaluation of new antifungal agents that are still experi- mental or for those agents that do not benefit from such highly predictable pharmacology, which is the case with the current formulation of itraconazole.

It should also be mentioned that failure of antifungal treatment can be related to host factors and to the drugs used, and it is only the integration of all these various parameters (underlying disease, multiple organ failure, pharmacokinetics, compli- ance, sites of infection) that allows one to make a pertinent judgment on the optimal management of patients with invasive fungal infections and on the value of an antifungal agent.

The question of whether fluconazole could be administered prior to the identification of the species of Candida responsible for fungemia is to be evaluated in the context of local epidemiology; for a patient colonized with Candida krusei in various sites, it does not seem adequate to initiate fluconazole empirically due to the lack of susceptibility of this pathogen and to avoid failure or re- lapse. :B.50,51

Significant progress in the management of patients with invasive aspergillosis (one of the most life-threatening complications), has also been made in the last few years. Various lipid formulations of amphotericin B has been shown to be less toxic and safer, including in patients with renal failure sec- ondary to previous courses of conventional ampho- teriein B or other nephrotoxic drugs. These encouraging observations have been made with Am- Bisome as well as ABLC and ABCD; all these formulations allow the administration of 4-6 mg/kg of amphotericin B daily.“2-“7

Another new area of investigation is in the careful evaluation of cytokines and growth factors for the management of invasive fungal infections. These are also very difficult issues to address, due to the fact that these agents are used not only for controlling fungal infections but also for such other reasons as allowing more aggressive antineoplastic therapy. Particularly in this field, close cooperation and high standards are needed to assess the indications and cost effectiveness of “adjuvant” antifungal treatments, but their definite role for patients with documented fungal infections remains controversial pending adequate and convincing studies. 60,61

With the availability of new antifungal drugs, better strategies for empiric management are also foreseen, provided that high-quality clinical trials address the remaining controversial issues concerning optimal timing for the initiation of empiric treatment.

However, although well tolerated, it has not yet been fully assessed whether those regimens provide a significant clinical improvement of the response rate or of the overall survival of these patients. Moreover, taking into account the high cost of these new modalities to administer amphotericin B, careful evaluation of the optimal dose should be provided to clinicians and to health authorities.

Finally, several large and well controlled studies have been performed during the last few years to test the potential role of fluconazole as prophylaxis in neutropenic patients (adults and children) who are undergoing bone marrow transplantation or who have leukemia. Large studies including several hundreds of patients have indeed shown that fluconazole reduces the incidence of Candida al&- cans fungemia, but it must be stressed that fluconazole, even at a dose of 400 mg daily, does not prevent aspergillosis.

During the last few years, it has also been shown that patients who had a previous episode of inva-

The overall impact of fluconazole prophylaxis on

sive aspergillosis and who survived may pursue the empiric use of amphotericin B or on fungal

anti-neoplastic chemotherapy, provided that they death rate has not been uniformly assessed in stud-

receive adequate antifungal coverage to avoid reac- ies conducted in Europe,fie-04 or in the United states,6547 and the range of daily doses of

SYMPOSiUM ON CHEMOTHERAPY / MEUNIER

6A-64S December 29, 1995 The Amencan Journal of Medicine Volume 99 (SUPPI 6A)

SYMPOSIUM ON CHEMOTHERAPY / MEUNIER

fluconazole tested was rather large (50-400 mg). Moreover, the effect of antifungal prophylaxis on colonization rate is perhaps not an adequate end- point for such studies; the primary objective should rather be the role of antifungal prophylaxis in decreasing the incidence of proven fungal infections and fungal deaths. Further, it is a fantastic and perhaps unrealistic challenge to look for an overall decrease of mortality, due only to antifungal prophylaxis, in such high-risk patients.

only on the collaboration of patients and their medical doctors but also on statisticians, data managers, computer analysts, ethicists, economists, and quality-of-life specialists.

Overall, practical recommendations for antifungal prophylaxis should be based on an open dialogue among all involved partners-i.e., the hematologist or the oncologist, the microbiologist, and a special- ist in infectious diseases-taking into account all the risk factors, including the epidemiologic parameters. for each specific unit. Particularly for prevention of aspergillosis, the optimal approach remains to be defined, including the role of conventional amphotericin B, new lipid formulations, and other investigational agents currently being developed.“7-~”

Adequate education programs are also part of the prevention means? and it must be stressed that other measures, nonspecific to fungi-such as hand washing, personal hygiene, cooking food, diet, etc.- must also be integrated in the overall recommendations concerning prophylaxis.

Careful design of clinical trials should include appropriate definition of the various clinical entities to be investigated. For example, there is too often a great confusion in the literature about candidiasis, including systemic candidiasis, invasive candidiasis, disseminated candidiasis, deep-seated candidiasis, chronic systemic candidiasis, etc. In addition, all consecutive patients within each institution should be enrolled in the study, if eligible, and, if not, the reasons for exclusion should be annotated; adequate endpoints, optimal monitoring, and quality assur- ance measures for each clinical trial should be care- fully established. Specific guidelines have been pro- duced in the United States and in Europe on this topic, but they should be adopted and regularly re- Vised,74-7~j according to specific needs. For example, the role and indications of growth factors for patients with fungal infections must be further clari- fied. ~il.76,77

Among the major issues to be addressed when investigating antifungal treatment are effectiveness, morbidity, quality-of-life impact, and cost. High-quality clinical trials require more effective coordination of research approaches to avoid waste of resources.

FUTURE PRIORITIES AND PERSPECTIVES There is a major need to improve the quality of

clinical research in the field of invasive fungal infections, taking advantage of the recent developments and the knowledge acquired in the last few years. There will be no further progress without high quality clinical research to define state-of-the-art treatments, identify ineffective and/or redundant treatments, and support the preservation of medical excellence in daily practice. Such duties and re- sponsibilities will be fulfilled by a multidisciplinary effort and large networks of clinical scientists: only well-designed clinical trials with adequate numbers of patients will provide definite answers with convincing, reliable, and unbiased data.

Current challenges for clinical research in the field of invasive fungal infections include the decreasing opportunities to do such high-quality clinical trials. Health policy authorities should encour- age scientific thinking for clinicians with, for example, the creation of clinical research centers or units within hospitals. Only large-scale trials will detect small but medically important differences that will guarantee good medical pra&ice. Close interaction between the researchers and the practitioners is mandatory to improve the quality of medical practice not only for cancer patients t,reated in research- oriented institutions but also for all immunocompromised patients at risk of fungal infections.

Particularly in the field of invasive fungal infections, clinical research relies on teams of experts involving not only a large variety of specialists but also practitioners. Appropriate correlations between in vitro testing and predictive values for outcome will also depend on such team effort.

Such collaboration is mandatory not only within each hospital but also at the international level, because no single institution will produce enough data in a reasonable time frame. It should be emphasized that such clinical research is also dependent not

Continuous efforts should be made to gather more information about patients, since today only a fraction of available patients are entered into clinical trials (which represent ~5% of the overall population with cancer). It is a waste of resource to initiate poorly designed clinical trials in such a difficult field. It must be acknowledged as well that few eth- ics committees include statisticians, a situation that allows useless studies to be approved. Additionally, too few journals use statistical refereeing.

During the last few years, these requirements for clinical trials on fungal infect,ions have led to tre-

December 29, 1995 The American Journal of Medune Volume 99 (suppl 6A) 6A-6%

SYMPOSIUM ON CHEMOTHERAPY / MEUNIER

mendous collaborative efforts between scientists and pharmaceutical industries, to the benefit of patients and to the satisfaction of regulatory authorities and drug registration agencies.

Approaches using the advantage of high-quality multicenter clinical trials and benefiting from central facilities, insurance coverage, quality assur- ance, and statistical expertise have been under- taken in the United States by the NIAID Mycoses Study Group and in Europe by the EORTC Inva- sive Fungal Infections Cooperative Group. Such structures and activities allow us to face with confi- dence the challenges of targeting fungi and will thereby allow UP to have a significant impact on long-term survival of patients at risk of invasive fungal infections.

CONCLUSION In the face of increasing numbers of patients

dying from invasive fungal infections, appropriate research and education tools are urgently needed. Tremendous progress has been made for the control of hemorrhage and bacterial infections, including septic shock due to gram negative sepsis, but targeting fungi is now a major challenge for the medical community and for society. Current developments promoting professionalism and scientific out- put through clinical research will result in improved epidemiological knowledge, better diagnostic tools, more effective therapeutic strategies and means of prevention and thereby will preserve the capacity for medical excellence.

Only large-scale trials with key endpoints (avoid- ing ill-conceived clinical research) will provide us with practical recommendations for all patients at risk of invasive fungal infections and thereby will allow us to achieve our final objective of decreasing the morbidity and mortality related to invasive fungal infections.

I From the EORTC Central OffIce. Data Center, Brussels, Belgium.

Requests for reprints should be addressed to Francotse Meunler, M.D., Ph.D., EORTC Central Offlce. Data Center, Avenue E. Mounter, 83 Box 11, B-1200 Brussels, Belgium.

REFERENCES 1. Bross J, Talbot GH, Maiskn G, Hurwitz S, Strom BL. Risk factors for nosocomial candldemla: a casecontrol study in adults wrthout leukemia. Am J Med 1989; 87: 614-20. 2. Butler KM, Baker CJ. Candlda: an lncreaslngly important pathogen In the nursery, Pediatric Cllntcs of North America 1988; 35: 543-63. 3. Harvey RL. Myers JP. Nosocomtal fungemra In a large community teaching hospl- tal. Arch Intern Med 1987; 147: 2117-20. 4. Weber DJ, Rutala WA. Epidemiology of hospital-acquired fungal Infections. In: Dlag- nosis and Therapy of Systemic Fungal InfectIons. Holmberg K, Meyer R, eds. New York: Raven Press, 1989: 1-24.

5. Walsh TJ, Pizzo PA. Nosocomlal fungal infections. Ann Rev Mlcroblol 1988; 42: 517-47. 6. Pfaller M, Wenzel R. Impact of the changing epidemiology of fungal Infections in the 1990s. Eur J Clan Mlcroblol Infect DIS 1992; 11: 287-91. 7. Banerjee SN, Emorl TG, Culver DH, et al. Secular trends in nosocomlal primary bloodstream Infections in the United States, 1980-1989. Am J Med 1991 (Suppl 38): 86S-9s. 8. Bodey G, Bueltmann B, Duguid W, et al. Fungal Infections In cancer pabents: an International autopsy survey. Eur J Clin Mlcrobiol Infect Dis 1992; 11: 99-109. 9. Cohen J, Denning DW, Vivian1 MA, EORTC lnvaslve Fungal Infections Cooperative Group. Epidemiology of Invasive aspergillosis In European cancer centres. Eur J Clin Mlcroblol Infect DIS 1993; 12: 392-3. 10. Meyers JD. Fungal tnfecbons in bone marrow transplant patients. Seminar Oncol- ogy 1990; 17 (SuppI 6): 10-3. 11. Analssie E. Opportunisttc mycoses in the lmmunocompromised host: experi- ence at a cancer center and review. Clin Infect DIS 1992; 14 lSuppl 11: 543-553. 12. Liu KL, Herbrecht R, Bergerat JP, Koenig H, Waller J, Oberllng F. Disseminated trlchosporon capltatum tnfectlon In a patient with acute leukaemla undergoIng bone marrow transplantation. Bone Marrow Transplantation 1990; 6: 219-21. 13. Marttno P, Vendltti M, Micozzi A, et al. Blastoschlzomyces capitatus: an emerging cause of invasive fungal disease In leukemic patients. Rev Infect DIS 1990; 12: 570-82. 14. Viscoli C, Castagnola E, Moroni C, Garaventa A, Manno G, Savrok C. Infections with Fusarium sp. In two children with neuroblastoma. Eur J Clan Microblol Infect DIS 1990; 9: 773-6. 15. Walsh TJ, Melcher GP, Rlnaldi MG, et al. Trichosporon beigelii: an emerging pathogen resistant to amphoterlcln B. J Clan Mlcrobiol 1990; 28: 1616-22. 16. Bennett JE. Raptd diagnosis of candldiasls and aspergillosls. Rev Infect Dis 1987; 9: 398-402. 17. de Repentigny. Serodlagnosls of Candrdlasis, Aspergillosis, and Cryprococ- COSIS. Clin Infect Dis 1992; I4 (Suppl 11: Sll-S22. 18. Walsh TJ, Lyman CA, PIZZO PA. Laboratory diagnosis of invasive fungal Infections In patients with neoplastic diseases. In: F Meunier, ed. Invasive Fungal Infections In Cancer Patients. Bailliere’s Clinical lnfectlous Dtseases 1995; 2: 25-70. 19. Meunter F, Aoun M, Bltar N. Candldemia in lmmunocompromised patients. Clin Infect DIS 1992; 14 (Suppl 1): S120-5. 20. Wey SB, Mori M, Pfaller MA. Woolson RF, Wenzel RP. Hospital-acquired Candide- mia. The attributable mortality and excess length of stay. Arch Intern Med 1988; 148: 2642-5. 21. Aisner J, Schimpff SC, Wternlk PH. Treatment of invasive aspergillosls: relation of early diagnosis and treatment to response. Ann Intern Med 1977; 86: 539-43. 22. Fischer BS, Armstrong D, Yu B, et al. lnvaslve asperglllosis: progress In early diagnosis and treatment. Am J Med 1981; 71: 571-7. 23. Dennlng DW, Stevens DA. Antifungal and surgical treatment of invasive aspergil- 10~1s: revtew of 2121 published cases. Rev Infect Dis 1990; 12: 1147-201. 24. PIZZO PA, Robichaud KJ, GIII FA, Wttebsky F. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenla. Am J Med 1982; 72: 101-11. 25. EORTC International AntimicrobIal Therapy Cooperative Group. Empirical antifungal therapy in febrile granulocytopenlc patlents. Am J Med 1989; 86: 668-72. 26. Merz WG. Candtda lusltaniae: frequency of recovery, colonizabon, InfectIon, and amphotericin B resistance. J Ckn Microbloi 1984; 20: 1194-5. 27. Merz W, Sandford G. Isolation and charactertzatlon of a polyene reslstant variant of C. tropIcalis. J Clan Microbial 1979; 9: 677-80. 28. Merz WG, Karp JE, Schrom D, Sara1 R. Increased incidence of fungemia caused by Candida krusei. J Clin Microb 1986; 24: 581-4. 29. Walsh T, Dixon D. Nosocomlal asperglllosis: environmental, microbiology, hospl- tal epidemrology, dlagnosls and treatment. Eur J Epldemlol 1989; 5: 131-42. 30. Opal SM, Asp A4. Cannady PB, et al. Effcacy of infect/on control measures during a nosocomlal outbreak of disseminated aspergillosis associated with hospital construction. J Infect DIS 1986; 153: 634-7. 31. lwen P, Davis J, Reed E, et al. Airborne fungal spore monitoring In a prospective envrronment during hospital construction, and correlation with an outbreak of Inva- save aspergillosls. lnfec Control Hosp Epidemiol 1994; 15: 303-6. 32. Pfaller MA. Epldemiologtcal typing for mycoses. Clin Infect Dis 1992; 14 (Suppl 11: s4-SlO.

33. Matthews RC, Burnle JP. Diagnosis of systemic candidiasis by an enzymeltnked dot immunobinding assay for a clrculatlng lmmunodomlnant 47 kD antigen, J Clin Mlcrobiol 1988; 26: 459-63.

6A-66S December 29, 1995 The Amencan Journal of Medicine Volume 99 (suppl6A)

34. Glrardin H, Sarfab J, TraorC F, et al. Molecular epidemiology of nosocomial lnvaslve aspergillosis. J Ckn Micro 1994; 32: 684-90. 35. lsenberg HD, Tucci V, Cmtron F, Singer C, Weinstein G, Tyras 0. Single-source outbreak of Candida tropicalls complicating coronary bypass surgery. J Clin Micro- biol 1989; 27: 2426-8. 36. Doebbeling B, Hollis R, lsenberg H, Wenzel R, Pfaller M. Restrtcbon fragment analysis of a Candida troplcalis outbreak of sternal wound Infections. J Clan Microbial 1991; 29: 1268-70. 37. National CommIttee for Cllnical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of yeasts; proposed standard. M27-P. Natlonal CommIttee for Clinical Laboratory Standards. VIllanova, PA, 1992. 38. Rex J, Cooper C, Merz W, GalgIant J, Analssie E. Detection of Amphotericin B-resistant Candida isolates in a broth-based system. Antimicrob Agents Chemother 1995; 39: 906-g. 39. Rex J, Rmaldi M, Pfaller M. Resistance of Candlda species to fluconazole. An- hmlcrob Agents Chemother 1995; 39: l-8. 40. Dick JD, Merz WG, Sara1 R. lncldence of polyene-reststant yeasts recovered from clinlcal specimens. Antimlcrob Agents Chemother 1980; 18: 158-63. 41. Anaissle E, Karyotakls N, Hachem R, DIgnan M, Rex J, Paetznlck V. Correlabon between In vitro and in vivo activity of antifungal agents against Candlda species. J Infect DIS 1994; 170: 384-9. 42. Rex J, Pfaller M, Barry A, et al. Antifungal suscepbbllity tesbng of Isolates from a randomized multicenter trial of fluconazole versus amphoterlcin B as treatment of nonneutropenic pahents wtth candldemia. Antrmlcrob Agents Chemother 1995; 39: 40-4. 43. Edwards JE. lnvaslve candida infections. Evolution of a fungal pathogen. (Edito- rial.) N Engl J Med 1991; 324: 1060-2. 44. Lecciones J, Lee J, Navarro E, et al. Vascular catheter-assoctated fungemla in patients with cancer: analysis of 155 episodes. Clin Infect DIS 1992; 14: 875-83. 45. Meunler F. Management of Candldemia. IEditorIal.) N Engl J Med 1994; 331: 1371-2. 46. Meumer-Carpentier F, Kiehn T, Armstrong D. Fungemla in the Immuno-compromised host: changing patterns, antlgenemla, high mortakty. Am J Med 1981; 1: 363-70. 47. Komshian SV, Uwaydah AK, Sobel JD, Crane LR. Fungemla caused by Candida species and Torulopsls glabrata In the hospltakzed patient: frequency, characterls- tics, and evaluabon of factors influencing outcome. Rev Infect DIS 1989; 2: 379-90. 48. Meunier F. Fluconazole treatment of fungal mfecbons in the immunocompro- mused host. Seminars In Oncology 1990; 17: 19-23. 49. Rex J, Bennett J, Sugar A, et al. A randomized trial comparing fluconazole with amphotencin B for the treatment of Candldemia rn patients wlthout neutropenia. N Engl J Med 1994; 331: 1325-30. 50. Wmgard JR, Merz WG, Rlnaldl MG, Johnson TR, Karp JE, Sara1 R. Increase In Candlda krusei infection among pabents with bone marrow transplantation and neu- tropenra treated prophylactlcally with fluconazole. N Engl J Med 1991; 325: 1274- 7. 51. McQuillen DP, Zmgman ES, Meunter F, Levitz SM. lnvaslve infections due to Candida krusel: report of ten cases of fungemia lnciudlng three cases of endophthal- mttis. Clin Infect DIS 1992; 14: 472-8. 52. Meunier F, Prentice HG, Ringden 0. Liposomal amphoterlcln B: safety data from a phase llnll cllnical trial with ambisome. J Antimicrob Chemother 1991; 28 (Suppl B): 83-91. 53. Ringden 0, Meunier F, Tollemar J, etai. Efficacy of amphoterlcln B encapsulated in liposomes (amBlsome) In the treatment of Invasive fungal Infections In immunocompromised patients. J Antimicrob Chemother 1991; 28 (Suppl B): 73-82. 54. van Burlk J-A, Bowden R. Standard anttfungal treatment, including role of alternative modallbes to administer amphotencrn B. In: F Meunier, ed. lnvaslve fungal Infec- tions In cancer patients. Ballltere’s Clinical Infectious Diseases 1995: 2; 89-109. 55. Walsh T, Hlemenz J, Selbei N, Analssie E. Amphotencin B lkpld complex in the treatment of 288 cases of Invasive mycosis. (Abstr. M69.) In: Program and abstracts of the thirty fourth Interscience conference on anbmlcroblal agents and chemotherapy (OrlandoI. WashIngton, DC: American Society for MIcrobIology, 1994. 56. Bowden R, Cays M. Phase I study of amphoterlcin B colloidal dlsperston (ABCD)

for the treatment of Invasive fungal infection after marrow transplant. (Abstr. 56.1 Trends In invasive fungal infecbons II, September 2-4, Manchester, UK, 1993. 57. de Mane S, Janknegt R, BakkerJNoudeberg I. Clintcal use of liposomal and Ilpld- complexed amphotericin B. J Antimicrob Chemother 1994; 33: 907-16. 58. Karp JE, Burch P, Merz MG. An approach to intensive antileukemia therapy in pabents with previous invasive asperglllosls. Am J Med 1988; 85: 203-9. 59. Richard C, Romon I, Baro J, et al. lnvaslve pulmonary aspergillosis prtor to BMT in acute leukemia patients does not predict a poor outcome. Bone Marrow Transplan- tabon 1993; 12: 237-41. 60. Mayordomo J, Rlvera F, Diaz-Puente M, et al. Improving treatment of chemo therapy-induced neutropenlc fever by administration of colony-stimulating factors. J National Cancer lnstttute 1995; 87: 803-8. 61. Freifeld A, Pizzo P. Colony-stimulahng factors and neutropenia: intersecbon of data and clinlcal relevance. J National Cancer lnsbtute 1995; 87: 781-2. 62. Phllpott-Howard JN, Wade JJ, Mufti GJ, Brammer KW, Enninger G. Randomized comparison of oral fluconazole versus oral polyenes for the prevenbon of fungal InfectIon in patients at risk of neutropenia. J Antimlcrob Chemother 1993; 31: 973- 84. 63. Menlchetti F, Del Favero A, Matilno P, et al. GIMEMA Infection Program. Prevent- ing fungal infectlon In neutropenic patients with acute leukemia: fluconazole com- pared wtth oral amphoterlcin B. Ann Intern Med 1994; 120: 913-8. 64. Nmane J, Multicentre Study Group. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Eur J Mlcrobiol Infect DIS 1994; 13: 330-7. 65. Goodman JL, WInston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoIng bone marrow transplantation. N Engl J Med 1992; 326: 845-51. 66. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebe controlled, double-blind, multicenter trial. Ann Intern Med 1993; 118: 495-503. 67. Bodey GP, Anaissie E, Elting LS, Estey E, O’Brien S, Kantarjian H. Antifungal prophylaxis during remission, induction therapy for acute leukemia, fluconazole versus Intravenous amphoterictn B. Cancer 1994; 73: 2099-106. 68. Perfect JR, Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotertcin B in neutropenlc autologous bone marrow transplant reclplents. J Infect Dis 1992; 165: 891-7. 69. Perfect JR. Anbfungal prophylaxis: to prevent or not. Am J Med 1993; 94: 233- 4. 70. O’Donnell M, Schmidt G, Tegtmeter B, et ai. Predlcbon of systemic fungal Infec- tion In allogenelc marrow recipients: Impact of amphoterlcln prophylaxis in high risk patients. J Clin Oncology 1994; 12: 827-34. 71. Riley K, Pavla A. Beatty P, et al. The prophylactic use of lowdose amphotericin B In bone marrow transplant pabents. Am J Med 1994; 97: 509-14. 72. Tollemar J, Ringden 0, Andersson S, Sundberg B, Ljungman P, Sparrelid E, Tyden G. Prophylactic use of liposomal amphotencln B (AmBlsome) agamst fungal Infections: a randomized trial in bone marrow transplant recipients. Transplantahon Proceedings 1993; 25: 1495-7. 73. lmmunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patlent. J Infect Dis 1990; 161: 397-401. 74. Medoff G, Dismukes W, Pappagianis D. Diamond RK, Galks H, Drutz D. General gutdeltnes for the evaluation of new antifungal drugs for the treatment of systemic fungal infections. Clin Infect Dis 1992; 15 (Suppl 1): S274-81. 76. Meunler F for the European Working Party, Medoff G, Dlismukes WE, Pap- paglanls D, et al. General guidellnes for the evaluation of new anti-fungal drugs for the treatment of invasive fungal infecbons. In: Beam TR Jr, GIlbert DN, Kunin CM, eds. European Guidelines for the Clinical Evaluabon of Ant!-Infective Drug Products 1993. Eur J Clin Microblol Infect Dis 1993: 221-8. 76. American Society of Clinical Oncology. Recommendations for the use of hemato. poletic colony-stlmulabng factors: evidence-based, clinical practice guidelines, J Clfn Oncology 1994; 12: 2471-508. 77. Boogaerts M, Cavalli F, CortBsSunes H, et al. Granulocyte growth factors: achieving a consensus. Annals of Oncology 1995; 6: 237-44.

December 29, 1995 The American Journal of Medlclne Volume 99 (suppl 6A) 6Ad7S

targeting fungi: a challenge

Documents