Progress in fighting systemic fungal infections in haematological neoplasia. Presented as an invited lecture at the 9th International Symposium. Supportive Care ...
Support Care Cancer (1998) 6 : 31–38 Q Springer-Verlag 1998
Ben E. De Pauw Jacques F.G.M. Meis
Presented as an invited lecture at the 9th International Symposium Supportive Care in Cancer, St. Gallen, Switzerland, 26 February–1 March 1997
B.E. De Pauw, M.D., Ph.D. (Y) Department of Haematology, University Hospital St. Radboud, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands Tel.: (31) 24–36 13 666 Fax: (31) 24–25 42 080 J.F.G.M. Meis, M.D., Ph.D. Department of Medical Mycology, University Hospital St. Radboud, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands
REVIEW ARTICLE
Progress in fighting systemic fungal infections in haematological neoplasia
Abstract Considering the limited data available, there is clearly a need for thorough, well-designed clinical research on the epidemiology, diagnosis, treatment and prevention of invasive fungal infection in patients who are treated for cancer. Our knowledge has increased, but the information obtained so far is patchy and not generally applicable, as it is influenced by local problems and circumstances. New diagnostic tools have become available, but they are still insufficient in many cases. Until the value of the presently available chemoprophylaxis has been established beyond doubt, the strategy should be one of wait-and-see for patients with a low or moderate risk of developing infection. In bone marrow transplant recipients fluconazole has shown favourable results in eliminating yeast infections, but in patients at high risk of mould infections early initiation of intravenous treatment with amphotericin B at a therapeutic dose remains the best approach. The question of the optimal time point to start em-
Introduction Bacteria are usually the initial cause of a fever during a chemotherapy-induced neutropenic episode, but broadspectrum antibiotics have eliminated early death due to gram-negative rods, thereby putting the patient at risk for subsequent other infectious complications. Yeasts
pirical antifungal treatment remains and has even been extended by the dispute about what antifungal drugs should be used for this purpose. Amphotericin B is still the drug of choice for the treatment of disseminated fungal infection, but its lipid formulations seem to offer a safer, though far more expensive, alternative. Headto-head comparisons between the different formulations are required before a final conclusion on their respective efficacies and toxicities can be drawn, and it is questionable whether a higher dose will produce better results. Fluconazole appears very useful against the majority of Candida infections, whereas itraconazole is effective against both yeast and moulds, providing that adequate resorption can be ensured. The results of the first clinical trial of voriconazole in pulmonary aspergillosis have proved very promising. Key words Neutropenia 7 Fungal infection 7 Amphotericin B 7 Fluconazole 7 Itraconazole
and moulds now rank amongst the ten most frequently isolated pathogens, and approximately 7% of all febrile episodes can be attributed definitely to these micro-organisms. Moreover, virtually every major medical centre will be confronted with an increased incidence of invasive fungal infections as a result of the intensification of antitumour treatment with protracted neutrope-
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nia and serious mucosal damage. This is witnessed by the higher incidence of invasive fungal infections in bone marrow transplant recipients than in patients who have received conventional cytoreductive chemotherapy [32].
Prevalent fungal pathogens and clinical manifestations Candida species are the leading pathogens in invasive fungal infections in neutropenic patients. Candida species invade the body through a disruption in the integument, such as chemotherapy- or irradiation-induced mucosal lesions and indwelling venous catheters [28]. Disseminated candidosis may emanate from a central venous catheter, but mainly originates from the alimentary tract. Disturbance of the commensal flora after a course of broad-spectrum antibiotics, impaired quality and quantity of the saliva, and presumably altered epithelial binding sites for micro-organisms contribute to a microbial shift with increased numbers of yeast cells in the gastrointestinal tract [22]. Candida infection is usually preceded by colonisation, but in about 50% of cases with candidaemia surveillance cultures had been negative [43]. The diagnosis of oropharyngeal candidosis is often made when classic beige plaques are seen on physical examination. However, clinically it is impossible to distinguish between Candida-like lesions and bacterial or herpes simplex virus infections; the diagnosis has to be confirmed by microscopy or culture. Candidaemia can be associated with a sepsis syndrome accompanied by myalgia and ocular and skin lesions, but it also may be an atypical manifestation of a clinically occult deep tissue infection without sepsis-like symptoms. Whilst acute disseminated candidosis can appear in a matter of hours, the chronic form of the infection develops over several months. Typically, the initial signs and symptoms of chronic disseminated candidosis are non-specific, the most common presentation being persistent fever despite empirical broad-spectrum antibiotics and a gradual clinical deterioration accompanied by progressive debilitation and dysfunction of the organs involved. After neutrophil recovery, lesions become apparent in major organs, manifesting as multiple pulmonary infiltrates, cutaneous nodules or liver disturbances that may be attributed to other causes, including concomitant drugs and bacterial infection. Moulds from the genus Aspergillus are the second most common fungal pathogens, A. fumigatus being the predominant strain. They are usually endogenous organisms, but the risk of infection is also dependent on the patients’ exposure to exogenous concentrations of potential pathogens. Mould infections are virtually always acquired by inhalation of spores into the airways with subsequent localisation in the sinuses and bron-
chial tree. This may have occurred during earlier life or during the actual treatment episode [13]. Aspergilli have a propensity for invading the blood vessels, causing local thrombosis and haemorrhage, and surrounding tissues such as ribs, muscles, pericardium and pleura. When a new infiltrate appears and progresses, particularly in conjunction with fever and chest pain, a fungal pneumonia caused by Aspergillus fumigatus is the leading diagnostic consideration. This explains the relatively frequent treatment failures of antibacterials in this category of infection. Disseminated aspergillosis, which may extend to the brain, is a relatively rare and distinctively preterminal event without characteristic signs or symptoms.
Diagnostic possibilities Owing to limitations in diagnostic tools only 20–30% of all invasive fungal infections can be firmly established during a patient’s life [6]. Greater awareness and attempts to improve detection have helped to increase recognition, but the majority of fungal infections are still only diagnosed at autopsy. Patients did not receive any antifungal therapy in as many as 30% of cases of invasive fungal infections found post mortem, indicating that the diagnostic tools for detecting disseminated fungal infection are still largely insufficient. The yield of cultures from blood and sputum is low; cultures tend to become positive when the infection has already reached its fatal stage. In most cases it is impossible to perform a diagnostic biopsy because of concomitant thrombocytopenia. Besides, even if tissue specimens are obtained they rarely yield growth, but this is a critical prerequisite to correct identification of the offending fungus. The histological differentiation of Aspergillus species from Fusarium, Acremonium scopulariopsis, Trichoderma, Blastoschizomyces species and Pseudallescheria boydii is particularly difficult, as these fungi may induce similar clinical features and exhibit similar filamentous development in the host tissue. Immunoperoxidase staining with specific monoclonal antibodies appears to be helpful in the histopathological confirmation of Aspergillus infection [48]. Because of the chemotherapy, antibodies are produced at a level that is insufficient to allow detection. Unfortunately, commercially available latex agglutination tests to detect the polysaccharide Aspergillus antigen galactomannan have a rather low sensitivity in the early stage of invasive aspergillosis. They may be helpful if serum levels are monitored at regular intervals throughout the risk episode, but ELISA sandwich techniques have shown a better sensitivity [46]. Molecular diagnostic techniques such as a polymerase chain reaction to detect Aspergillus DNA fragments may provide a solution to this problem, since they are suited for the
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detection of minute amounts of DNA [47], but the specificity of the present probes is not optimal. Detection of metabolites from the fungal metabolism, such as mannose, enolase, mannitol and arabinitol, seem to offer other options, but they are found in varying amounts and appear to be aspecific. Post-mortem histology and cultures are very reliable, but unfortunately, they only increase the knowledge on the pathophysiology of invasive fungal infections. In the majority of cases the clinician has to rely upon clinical skills and imaging techniques. If after 48– 72 h of empirical antibacterial treatment the clinical condition of a persistently neutropenic patient has not stabilised, a definitive diagnosis should be sought by means of sequential chest X-rays, abdominal ultrasound, high-resolution CT scans, bronchoalveolar lavage, and, for instance, isotope scanning with indium111-labelled human immunoglobulin [36].
Prevention Adequate hand washing by visitors, nurses, doctors and other personnel is of paramount importance in the prevention of all kinds of infection, and neglect of this makes a nonsense of all other, more sophisticated, means of achieving optimal hygiene [9]. Gastric antacids should only be prescribed on very strict indication, because a low pH offers protection against colonisation of the small and large intestine by Candida species. Unnecessary antibacterials and corticosteroids should be avoided, and notorious sources of spores have to be eliminated. Environments with a high concentration of spores should be protected by means of HEPA filtration; for centres with a high incidence of invasive aspergillosis this constitutes probably the most efficient measure to reduce the number of nosocomial Aspergillus infections in immunocompromised patients. The intact mucosal barrier constitutes a dependable defence mechanism against fungi, as is corroborated by the beneficial effects of antivirals that curtail the mucosal damage resulting from herpes simplex virus infection. Prophylactic use of oral antifungals has reached great popularity amongst the antifungal strategies during the last decade. In many instances, however, soothing the physician’s conscience seems to be the primary incentive rather than rational evidence on efficacy. Randomised trials with sufficient statistical power on this subject are still rare, and historical controls are absolutely inadequate for the assessment of efficacy of an antifungal chemoprophylactic regimen, since the risk of infection varies considerably with time owing to changing antitumour therapy or other local circumstances such as building reconstructions. It is also often overlooked that the centres with a high incidence of invasive fungal infections are those most interested in de-
veloping new prophylactic strategies [25, 34]. Therefore, results obtained in studies with historical controls may look more impressive than they actually are, since any observed decrease in the incidence of mycosis is likely to be exaggerated. The results obtained with the oral polyenes and the older imidazoles in the prevention of disseminated mycoses are at least unimpressive. Moreover, they are invariably associated with a limited patient compliance, which inevitably jeopardises possibly beneficial effects. The newer triazoles are better tolerated and appear more efficacious. In several prospective, double blind, placebo-controlled, multicentre studies of patients undergoing bone marrow transplantation, prophylaxis with fluconazole at a dose of 400 mg once daily was shown to be effective in preventing superficial and disseminated candidosis [20, 45]. However, the picture was already less clear when fluconazole was tested for prophylaxis in adults during remission induction therapy for acute leukaemia [30, 55]. Results from studies in which a lower dose of fluconazole was used do suggest that half the dose may suffice in the majority of cases [1, 17]. Fluconazole was well tolerated at all dosage levels and free of serious adverse events apart from the tendency to select resistant Candida species[53–55]. Patients with proven colonisation seem to constitute the chief target group for this intervention [21, 22]. Regardless of the dose, fluconazole offers no protection against infections by Aspergillus species and other moulds, which continue to be a major constraint in treatment-induced neutropenia. Itraconazole has clinically worthwhile activity against Aspergillus and promising results have been reported [39], but in a prospective, double-blind randomised study in leukaemic patients itraconazole at a level of 400 mg daily neither reduced the incidence of documented and presumed Aspergillus infections nor influenced the perceived need for treatment with intravenous amphotericin B [51]. This may be due to inadequate serum levels in a substantial number of these patients with severe mucositis [7]. At the present time, a new formulation of itraconazole suspended in cyclodextrin solution, which appears to be better absorbed, is being investigated [31, 40], but the first reported results are not encouraging. Amphotericin B sprays and inhalations [11, 24, 25] as well as reduced intravenous doses of 0.1 to 0.25 mg kg –1 day –1 or 0.5 mg/kg 3 days a week [37, 42] have been tested for prophylactic treatment, principally in bone marrow transplant recipients, in an endeavour to reduce the drug’s toxicity while retaining its excellent antifungal activity. Promising results and excellent tolerance encouraged a prospective randomised study which, unfortunately, showed that the aerosol offered no statistically significant advantage with respect to the number of documented infections or overall survival [5].
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Although lack of data would justify watchful waiting, it seems not unreasonable to give patients who are at high risk of developing a life-threatening invasive fungal infection the benefit of the doubt by treating them prophylactically or pre-emptively with an antifungal drug or regimen, preferably as part of a randomised study. These risk groups include, but are not limited to, patients who are heavily colonised by Candida species, patients with long-standing mucosal lesions who are being treated with broad-spectrum antibacterials, patients with a history of an invasive fungal infection during a previous neutropenic episode, and adult recipients of an allogeneic bone marrow transplant who are seropositive for cytomegalovirus and suffer from graft-versushost disease [32]. Nebulised amphotericin B in combination with fluconazole seems to be a theoretically attractive option for prophylaxis in patients without a history of a previous systemic fungal infection. Therapeutic doses of intravenous amphotericin B seem to be required to protect patients with previous aspergillosis against recrudescence during later cycles of intensive chemotherapy [26]. Provided that adequate serum levels can be achieved, itraconazole is an alternative option to protect the patient during the time between consecutive neutropenic episodes [12, 33].
Treatment of documented and presumed invasive fungal infections
start empirical antifungal therapy after only 3 days of fever unresponsive to broad-spectrum antibacterials without there being any evidence in the literature that this might be beneficial. Until recently it was assumed that amphotericin B was the only option for empirical treatment. Now there is evidence that in patients with persisting unexplained fever adequate results can also be obtained with fluconazole [8, 50]. These findings are remarkable and make a reappraisal of the principle of empirical antifungal therapy necessary, because it was presumed for a long time that empirical antifungals were aimed at protection against early stages of mould infections. Presently, there is a marked divergence between Europe and North America in the perceived need for intravenous amphotericin B, mainly reflecting differences in the attitude of physicians towards empirical administration of this compound. The well-known side effects of parenteral amphotericin B underscore the therapeutic dilemma: too long a delay while awaiting laboratory or clinical confirmation will result in high failure rates, but starting early on the grounds of persistent fever alone can lead to over-treatment. It must be emphasised that patients who are at high risk of an invasive fungal infection might profit from a very early institution of systemic antifungals. This pertains essentially the same patients who are the principal candidates for antifungal prophylaxis. In fact, treating this category of patients constitutes a pre-emptive rather than an empiric or prophylactic approach.
Empirical antifungal therapy Even with the most modern and sophisticated diagnostic tools, it is rarely possible to identify deep-seated fungal infection at an early stage of the disease. By the time clinicians are confronted with infection it is usually advanced and therefore difficult to cure. The fatal outcome of a culturally and/or histologically proven invasive fungal infection may well exceed 90%, particularly in cases with persisting neutropenia and unremitting underlying disease. Therefore, most febrile neutropenic patients will receive systemic antifungal therapy in the case of unexplained fever continuing for 4–6 days in spite of adequate broad-spectrum antibacterial treatment. This is based on studies by Pizzo et al. at the National Cancer Institute [38] and by the Antimicrobial Study Group of the European Organisation for Research on Treatment of Cancer (EORTC) [19]. These investigators showed that ultimately, i.e. at the end of neutropenia, a systemic fungal infection was present in 63% and 9% of patients who did not receive empirical intravenous amphotericin B, in contrast to an incidence of invasive fungal infections of 23% and 2%, respectively, in patients who were given amphotericin B. Moreover, fear of a possible confrontation with disseminated fungal disease has prompted some centres to
Antifungal drugs Amphotericin B, considered the gold standard by many, forms complexes with steroids such as ergosterol in the fungal cell membrane. Binding to its human counterpart cholesterol, however, accounts for the drug’s notorious toxicity. Many procedures have been suggested to mitigate the resulting chills, fever, malaise, headache, nausea and/or diarrhoea, but there is no proof that any are helpful. Nephrotoxicity, which is reversible to some degree, is variable from patient to patient and may be ameliorated by making certain that the patient is eunatraemic. Considering its broad spectrum of activity amphotericin B remains the first choice against invasive fungal infections, in spite of its side effects. There is no agreement on the therapeutic dose of amphotericin B desoxycholate; in most centres a starting dose of 1.0–1.5 mg kg –1 day –1 i.v. in a 1- to 4-h infusion is used, whereas in patients with impaired kidney function and in those receiving other possibly nephrotoxic drugs concomitantly, 0.7 mg kg –1 day –1 is recommended. If the serum creatinine exceeds 250 mmol/l (or 2! baseline in children), treatment should be interrupted for 1 or 2 days to allow for recovery of the kid-
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ney function. Thereafter amphotericin B has to be reinstituted at a dose of 0.5 mg kg –1 day –1 with daily dose increases up to the maximally tolerated level with monitoring of the serum creatinine level. During the last 10 years there has been tremendous interest in alternative modalities for administration of amphotericin B and in the search for new classes of antifungal agents. This research has yielded liposomal formulations of amphotericin B and nystatin, and such promising agents as echinocandins, pneumocandins, pradimidicin, terbenafine and the newer azoles, including fluconazole, itraconazole, and voriconazole. Liposomal formulations of amphotericin B seem to offer a safer alternative to the standard desoxycholate preparation. The various new lipid formulations of amphotericin B – amphotericin B lipid complex (Abelcet), amphotericin B colloidal dispersion (Amphocil), liposomal amphotericin B (Ambisome) – have been used with some success in many open and small randomised studies during the last 5 years. Because individual pharmacological and chemical properties of these preparations are different, each lipid formulation of amphotericin B should be evaluated separately. Data from several studies on individual compounds are available [3, 35, 41, 52] and are summarised in Tables 1 and 2, but head-to-head comparisons between the different formulations are required before a final conclusion on their respective efficacies and toxicities can be drawn. They are all undoubtedly better tolerated than conventional amphotericin B and allow for prescription of higher daily doses. However, it is questionable whether a higher dose will produce superior results. A recent trial by the EORTC’s Invasive Fungal Infection Group [18] showed that a dose of 1 mg kg –1 day –1 of Ambisome was as effective as 4 mg kg –1 day –1 in treating invasive aspergillosis (see Table 3). A high price is another major drawback of lipidbased amphotericin B; particularly if high dosages are being used it may consume an unwarranted amount of a hospital’s medication budget [23]. Intralipid with amphotericin B was suggested by French investigators as a cheaper alternative to the comercially available lipid formulations [10]. At a dosage of 1.2 mg kg –1 day –1, this mixture appeared to be effective against candidaemia in neutropenic patients, but it has to be emphasised that clinical experience is limited and that there are sincere doubts about the safety [44]. More than a decade ago ketoconazole seemed to be promising in the treatment of yeast infections, but its liver toxicity and unreliable absorption tempered the initial enthusiasm. Fluconazole is a far better option for the immunocompromised host. It is safe, and both its oral and its intravenous formulation have good bioavailability. Absorption is not dependent on the presence of gastric acid, but interactions with cytochrome P450associated drugs have been observed. It must be emphasised that fluconazole provides no coverage against
Table 1 Comparison of efficacy and safety of empirically administered antifungal drugs Survival
Nephrotoxicity
Other side effects
Fungizone 0.5–1.0 mg kg P1 day P1
60%
65%
30%
Ambisome 1.0–5.0 mg kg P1 day P1
58%
15%
5%
Amphocil 6.0 mg kg P1 day P1
57%
15%
20%
Abelcet 5.0 mg kg P1 day P1
78%
25%
5%
Fluconazole 400 mg day P1
80%
0%
3%
Table 2 Comparison of antifungal drugs in proven and probable Aspergillus infections Number
Response rate
Fungizone Ambisome Amphocil Abelcet Itraconazole Voriconazole
`1000 147 32 72 64 141
a
45% 59% 35% a 60% 50% 58%
Fungizone treatment failures only
Table 3 Ambisome 1 mg kg P1 day P1 vs 4 mg kg P1 day P1 for pulmonary aspergillosis (np119)
Definitely documented infections Days on treatment Total dose given (mg) Response rate Death due to fungal infection Renal toxicity
1 mg kg P1 day P1
4 mg kg P1 day P1
31% 20 1260 68% 33% 3%
23% 19 4020 49% 28% 9%
Aspergillus species. Itraconazole offers an alternative to fluconazole [14]; this drug is active in vitro against most Candida and Aspergillus species, but the drug’s unreliable absorption makes this compound less suitable for therapy in critical circumstances. Other concerns about itraconazole include the possible induction or inhibition of hepatic enzymes by itraconazole, interaction with cyclosporin, and a propensity to increase intracellular levels of cytotoxic drugs, such as vincristine and anthracyclines, which might enhance their effects. The first phase II study on the new azole voriconazole in 141 patients has been completed recently, and the results in the treatment of pulmonary aspergillosis are encouraging, with response rates in probable and prov-
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en cases of more than 60% and 40%, respectively (see also Table 2). Notably, the survival of more than 50% of allogeneic bone marrow transplant recipients with pulmonary aspergillosis was an encouraging finding. Anaissie et al. found an original way of using haematopoietic growth factors to improve the prognosis of patients with a therapy-refractory documented invasive fungal infection. He pretreated healthy donors with growth factors and harvested by leukapheresis unequalled high numbers of white cells that could successfully be given to patients. So far, the results of rather small therapeutic trials have been disappointing, but granulocyte-macrophage colony-stimulating factor certainly deserves further study in view of its potency to stimulate and activate the mononuclear-phagocytic system. The role of interleukins and interferons in the treatment of invasive fungal infections is still uncertain, but results in animal studies warrant reasonable hope for the near future. Candida infections Disseminated candidosis, including candidaemia, is frequently rapidly fatal without early therapy with antifungal drugs that have systemic activity. Amphotericin B with or without 5-flucytosine is considered the standard therapy; 50–70% of patients will respond to this regimen, which is toxic and inconvenient and requires intravenous administration of drugs. Patients with a probable or proven invasive infection by Candida may have a favourable outcome if they are treated with a daily dose of fluconazole of 800 mg or higher. Response rates are similar to those achieved with amphotericin B [4, 15, 49]. Besides, the opportunity to manage chronic disseminated candidosis in an outpatient setting is both convenient and less expensive for patients who require prolonged treatment [2, 15, 27]. Superinfections by Aspergillus species may emerge when fluconazole is given alone in patients with documented or presumed invasive Candida infections during neutropenia [2, 15]. Combination with amphotericin B may solve this problem, but the feasibility of such a combination has not been proven. Given these limitations of the antifungal agents and the lack of clinical trials with sufficient power to allow firm conclusions, it is not surprising that there is no consensus on the optimal management of severe Candida infections in immunocompromised hosts. During a meeting at the Harbor/UCLA Research and Education Institute [16], 21 investigators with expertise in this field all agreed that every candidaemic patient should be treated with a systemically active antifungal agent. However, even after ample discussions they failed to reach consensus on the treatment of choice for the different situations that may occur. For empirical therapy
and for the management of candidaemia, candiduria, candidal peritonitis, chronic disseminated candidosis and endophthalmitis, the individual expert had to make a selection from several pregiven therapeutic options. In less critically ill patients the tendency to favour fluconazole in a dosage of 400–800 mg daily was obvious, unless a patient had been pretreated with another azole or if a non-albicans strain was isolated. Intravenous amphotericin B with or without 5-flucytosine served as a frequently chosen alternative. A substantial minority, however, selected combinations of fluconazole with amphotericin B or 5-flucytosine in spite of the wellrecognised paucity of data on the possible efficacy. At first sight such a behaviour of experienced clinicians might be surprising, but in fact it emphasises the magnitude of the problem. In the absence of adequate clinical trials physicians will feel the need to apply theoretically attractive alternatives as long as treatment results are unsatisfactory. Despite the agreement on the need of early catheter removal, legitimate controversy remains in the treatment of candidaemia associated with a central venous catheter. Removal of a central venous catheter appears appropriate when a patient fails to respond antifungal therapy within 96 h or when candidaemia persists for more than 48 h while the patient is receiving appropriate intravenous antifungal therapy [29]. It is generally recognised that fluconazole or itraconazole are not of substantial value in the treatment of a proven or presumed invasive fungal infection, if they have been used as prophylactic agents in an adequate dosage, as it must be assumed that the offending pathogen is resistant to these drugs.
Mould infections Whereas the response rate of patients with persisting unexplained fever to systemically active antifungals is about 80% if neutropenia resolves, the successful outcome of documented invasive fungal infection may, even under optimal circumstances, not exceed 20%. This figure is influenced by the state of the underlying disease and possible recovery of the granulocytes. In case of a documented Aspergillus infection a minimal total dose of 2 g of amphotericin B is recommended, whereas in other cases the drug must at least be continued until neutropenia has resolved and all signs and symptoms of the infection have dissolved. In the less critically ill patient itraconazole may be an alternative, especially when amphotericin B is not well tolerated or is difficult to administer [12, 14], but the aforementioned unreliable absorption makes this compound less suitable for therapeutic purposes in severely ill neutropenic patients. For this target group one of the lipid preparations might be a suitable alternative.
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