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The emergence of fungi as major hospital pathogens
Journal of Hospital Infection (1988) 11 (Supplement
The emergence
A), 41 l-426
of fungi as major pathogens* Gerald
hospital
P. Bodey
Section of Infectious Diseases, Department of Medical Specialties, The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston Introduction During the last 25 years, substantial progress has been made in our management of fever in the understanding optimum of the immunocompromized host. The use of empirical antibiotic regimens promptly after the onset of fever in neutropenic patients led to a major reduction in the fatality rate from infection. The introduction of a multitude of new broad-spectrum antibiotics has made it possible to treat successfully a variety of bacterial infections that had been uniformly fatal. These accomplishments have resulted in prolonged survival of patients who are highly susceptible to infection. Furthermore the successful management of bacterial infections has resulted in the use of more aggressive therapy against patients’ underlying disease processes, leading to even greater susceptibility to infection. Hence, it is not surprising that fungal infections have emerged as a major cause of morbidity and mortality in immunocompromized patients. Frequency
of fungal
infection
Accurate information with regard to frequency of fungal infections in studies do not provide immunocompromized hosts is sparse. Clinical complete information because the size of the population at risk is usually not described and, since fungal infections often remain undiagnosed, the true frequency is difficult to define. Autopsy studies are limited because many patients who die are not examined and patients who survive their infection are not included. Nevertheless, there is substantial evidence that fungal infections are increasing. Candida oesophagitis was a rare infection 30 years ago; today it is common among cancer patients. Systemic fungal infection *Based Society
on the Lowbury Lecture given held in September 1987.
Correspondence to: Gerald Holcombe, Houston, Texas 0195-6701/88/02A411+
P. Bodey, 77030.
at the First Infectious
International Diseases
16 $03.00/O
(Box
Conference
of the Hospital
47),
Anderson
M.D.
Q 1988 The Hospital
411
Infection
Hospital,
Infection
1515
Soaety
G. P. Bodey
412
nearly equals bacterial infection as a cause of death in leukaemic patients. Aspergillus and candida infections are no longer limited to those patients failing to respond to antileukaemic therapy, but are occurring increasingly among patients undergoing initial remission induction therapy. The frequency of aspergillus infections among patients receiving chronic adrenal corticosteroid therapy also appears to be increasing. Fungal infections are common among patients with indwelling vascular catheters, extensive burn wounds, extensive surgery and organ transplants. Chronic serious fungal infections such as aspergillus fungus balls in the lung, and candida hepatitis, are being diagnosed more often. New fungal pathogens are being identified, including Alternaria sp, Fusarium sp, Trichosporon beigelii and Drechslera SP.
The frequency of fungal infection in patients with acute leukaemia was examined in two studies at our institution (Table I). In both studies, patients were followed from their first admission until death or to the completion of the study period. Both the frequency of total fungal infections and major fungal infections increased substantially during the second of fungal period (Bodey et al., 1978; Anaissie et al., 1987). The distribution organisms also changed. Candida albicans was the most common fungal organism during the first period. During the second period, C. albicans caused only 41% of fungal infections whereas C. tropicalis caused 19% and Aspergillus spp. also caused 19%. A wide variety of other fungi caused occasional infections during the latter period. The frequency of fungal infections in transplant recipients is changing because many aspects of the transplantation process are in a state of continuing evolution. The introduction of cyclosporin has altered the type of infectious complications and the side-effects of their therapy. The type of surgical procedure, the nature of the donor organ and the recipient’s general health at the time of the procedure affect susceptibility to fungal infection. For example, 141 infections occurred in 10.5 patients during the first 6 months after transplantation in whom immunosuppressive therapy was cyclosporin (Dummer et al., 1983). Eleven fungal infections occurred in the 24 liver transplant recipients but no fungal infections occurred among the 64 renal transplant and 17 cardiac transplant recipients. The reported frequency of fungal infection varies from 28% to 42% in liver transplant Table
I. Distribution
of infections in leukaemic patients at MD Anderson Hospital, Study
Patients Infectious episodes Organism identified Total fungal infections Major infections Major fungal infections
Houston
period
1966-1972
1978-1982
494 1209 884 93 (11%) 859 42 (5%)
377 1137 757 150 (20%) 528 120 (23%)
Fungi
as major
hospital
pathogens
413
recipients, 2% to 30% in bone marrow transplant recipients and 10% to 35% in cardiac transplant recipients. The frequency of fungal infections among renal transplant recipients has diminished from 20% to c 5% as patient management has improved. The advent of the epidemic of acquired immunodeficiency syndrome (AIDS) has created a new population of patients susceptible to fungal infection. Thrush and oesophageal candidiasis are ubiquitous infections. Cryptococcosis has been described in about 7% of these patients in some areas of the United States (Kovacs et al., 1985). Histoplasmosis is prevalent among those who reside or have travelled in endemic areas. Aspergillosis does not appear to be a complication of this disease. Predisposing
factors
Many factors have been incriminated as predisposing to fungal infections (Table II). D efi ciencies in T cell number or function, as occur in mucocutaneous candidiasis syndromes and AIDS, predispose to superficial candida infection, but systemic infection does not occur (Kirkpatrick, 1984). Neutropenia is an important predisposing factor to aspergillosis and disseminated candidiasis, but may be less important in cryptococcosis. liz vitro, the neutrophil ingests and kills C. albicans and this is the primary defence against infection caused by these organisms (Lehrer & Cline, 1971). The frequency of autopsy-proven fungal infection in bone marrow transplant recipients correlates with the duration of neutropenia (Myers 8z Atkinson, 1983). Fungal infection was found in 21% of cases with neutropenia for one to 20 days, 41% for 21 to 40 days and 57% for more than 40 days. The importance of the neutrophil and macrophage in protecting against aspergillus infection has been delineated in mice (Schaffner & Douglas, 1982). Neutrophils protect against the hyphal form of Aspergillus fumigatus and kill mycelia in vitro. In normal but not in neutropenic mice, hyphal growth was eliminated and mycelia were eradicated. Macrophages prevented germination and killed spores in vitro and eradicated conidia, even in neutropenic mice. Cortisone directly inhibited the killing of conidia Table
II. Factors predisposing to fungal infection
Chronic debilitation, malnutrition Adrenal corticosteroid therapy Antibiotic therapy Deficient T cell number or function Deficient neutrophil number or function Hyperglycaemia, acidosis Parenteral alimentation Extensive surgery Haematological malignancy Indwelling intravascular catheter Immunosuppressive therapy
414
G. P. Bodey
by macrophages in oitro and in viva and reduced the mobilization of neutrophils. Myelosuppression alone was only important when mice were challenged by activated spores that cannot be killed by macrophages. While some antibiotics permit candida overgrowth by suppressing the normal gastrointestinal flora, most studies have failed to demonstrate that parenteral antibiotic therapy is more prevalent among patients who acquire fungal infections than other similarly compromized patients. When C. albicans are present in high concentrations in the gastrointestinal tract they can migrate across the intact endothelium by a process known as persorption. A variety of factors such as endotoxin, cancer chemotherapy and adrenal corticosteroids can interfere with the liver’s ability to prevent these organisms from entering the bloodstream (Stone et al., 1974). Candida organisms can also gain access to the bloodstream directly via intravascular catheters. While the majority of infections are caused by C. albicuns in most centres, C. tropicalis has emerged as an important pathogen, especially in catheter-related infections. Other species such as C. Krusei have also been implicated as common causes of catheter-related infections. Much is known about the epidemiology of some fungal infections such as histoplasmosis, coccidioidomycosis and cryptococcosis, but less is known of Aspergillus spp. are airborne pathogens and aspergillosis and candidiasis. epidemics of infection have been described due to construction adjacent to the hospital or contamination of air conditioning ducts. However, micro-epidemics of aspergillosis have occurred in hospitals where it has been impossible to identify a source. Cundidu spp. are ubiquitous in the environment and it is presumed that most infections arise from the patient’s endogenous flora. Sporadic reports have suggested that nosocomial strains may be transmitted from patient to patient and be responsible for infections et al., 1985). A similar situation is being recognized with (Burnie StuphyZococcus epidermidis and diphtheroids. The importance of these observations needs to be examined further and, if true, the means of transmission identified and eliminated when possible. Some important questions remain unanswered. For example, why do some patients who have multiple predisposing factors and are heavily colonized with C. albicuns never become infected? How great a risk is thrush for disseminated candidiasis? Are some new broadspectrum antibacterial regimens more likely to cause fungal superinfection in susceptible hosts than other regimens ? Are most aspergillus infections nosocomially acquired, or are some patients’ sinuses colonized chronically resulting in subsequent infection when the patient’s host defences are compromized? Why is aspergillosis increasing in frequency during remission induction therapy for acute leukaemia ? Do prophylactic antibacterial or antifungal agents really increase the risk of aspergillosis? These and other questions need to be addressed if we are to reduce the inexorable trend of increasing fungal infection.
Fungi
as major
Diagnostic
hospital
pathogens
415
considerations
A major obstacle to the successful management of many systemic fungal infections is our inability to establish the diagnosis. Often the only reliable diagnostic procedure is a tissue biopsy and that cannot be obtained because the patient is too ill or has severe thrombocytopenia. This problem is most common in patients with aspergillosis, phycomycosis and disseminated candidiasis. Since candida overgrowth is common among patients receiving antibacterial agents, positive cultures from body orifices are not generally helpful in establishing the diagnosis of systemic infection. Studies in BMT recipients and heart and lung transplant recipients indicate that Can&da spp. are frequently cultured from body orifices in the absence of infection. In one study of patients with leukaemia and BMT recipients, C. albicans was isolated from surveillance cultures of 67% of patients but caused disseminated infection in only 5% (Wingard, Merz & Saral, 1979). However, C. tropicalis was cultured from only 28% of patients but out of this group caused disseminated infection in 56%. Positive cultures from closed body spaces are usually indicative of infection. Blood cultures are an unreliable means for diagnosing disseminated candidiasis. Catheter-associated fungaemia is common, and it is often difficult to ascertain which of these patients have tissue invasion. Only 25% to 45% of patients with autopsy-proven candidiasis ever had a positive blood culture during their infection. In one series, only 18% of patients had a positive blood culture within one week of onset of their infection and 45% with positive blood cultures died before the result was known to their physicians (Maksymiuk et al., 1984). These rather dismal results have led many investigators to try to develop other means of diagnosing systemic candidiasis. Some of these approaches are listed in Table III (Kozinn & Taschdjian, 1985). Serological tests directed against detection of antibodies have not generally been useful because severely immunocompromized patients are unable to produce antibodies. One would anticipate that tests directed against detection of antigen would be more successful. Although many promising studies have been reported, these tests usually fail in those patients where they are most needed. Table
III.
Methods
attempted
Agglutinating antibodies Precipitins - gel diffusion, CIE Mannan - ELISA, RIA, latex agglutination Arabinitol- GLC Cytoplasmic antigen - ELISA Cell wall polysaccharide Mycelial antigen - CIE Mannose - GLC
- CIE
for diagnosis
of candidz’usis
416
G. P. Bodey
A different problem exists in the diagnosis of aspergillosis and phycomycosis. These organisms are seldom cultured from any site in infected patients. Indeed, the organisms may not be cultured from tissue known to be infected on histological examination. For many years, it was taught that Aspergillus spp. are common laboratory contaminants and should be ignored when isolated from patient specimens. A recent study examined patients who had Aspergillus sp. isolated from respiratory tract cultures (Yu, Muder & Poorsattar, 1986). The frequency of proven aspergillosis was 100% among those patients with acute leukaemia, 94% among neutropenic patients, 65% among patients receiving adrenal corticosteroids, but only 40% among patients receiving parenteral antibiotics. Another study has suggested that cancer patients who have Aspergillus sp. isolated from routine nasal cultures are at high risk of having aspergillosis (Aisner et al., 1979). Hence, it would seem prudent to consider positive cultures seriously when collected from susceptible patients. Unfortunately, uniformly reliable serological tests for the diagnosis of aspergillosis are not available, but the possibility of achieving that goal may be greater than in candidiasis. The diagnosis of other fungal infections such as histoplasmosis, coccidioidomycosis and cryptococcosis is usually easier to establish. These organisms can usually be isolated from appropriate culture specimens and their presence indicates disease. Serological tests are helpful, especially the test for cryptococcal antigen which can be detected in serum and cerebrospinal fluid of infected patients. Systemic
candidiasis
Disseminated candidiasis can involve any organ in the body. The major sites of origin of infection are the gastrointestinal tract and the bloodstream directly via vascular catheters. Organ distribution appears to differ depending on the site of origin. The predominant organs involved when the gastrointestinal tract is the site of origin include the liver, spleen and lungs; the predominant organs involved when a catheter is the site of origin include the kidneys, heart and lungs. Candida pneumonia due to aspiration of infected secretions occurs infrequently. More often candida pneumonia is secondary to haematogenous dissemination. Most cases of disseminated candidiasis are caused by C. albicans, but infections caused by other species are increasing in frequency. In some institutions, C. tropicalis, C. parapsilosis and C. stellatoidea infections are not uncommon (Table IV) (Hurley, 1964; Young et al., 1974; Richards et al., 1972; Meunier-Carpentier, Kiehn & Armstrong, 1981), and many of these infections are associated with intravenous catheters and infusions. Why these Candida spp. are more likely to cause infection in this setting remains to be determined. Unfortunately, most patients with candidiasis do not develop any
species
albicans tropicalis pseudotropicalis krusei parapsilosis
Multiple
C. C. C. C. C.
Patient population Total candidiasis No. speciated
El 0 3
0
Leukaemia 71 54 39 10
Bodey
IV. Distribution
i
4
5
Undefined 48 46 37
Hurley
Table
:,
1
Immunocompromised 29 29 19 8 0 0
i
Burn 53 50 41 2 0
Richards
spp. in systemic infection
Young
of Candida
9
:
Cancer 182 163 92 54 0
Maksymiuk
Meunier _____ Cancer 82 82 40 25 1 3 13 0
2
i
f z c a P) 6 &
2
&
6. c
418
G. P. Bodey Table
Y Organ
infections
Laryngitis Pyeionephritis Peritonitis Arthritis Osteomyelitis Myositis Hypersplenism
associated
with disseminated
candidiasis
Endocarditis Pneumonitis Oohthalmitis H’epatic abscesses Cerebritis Meningitis Skin nodules
characteristic signs and symptoms to suggest this infection. Often fever is the only evidence of infection and this may be suppressed if the patient is receiving adrenal corticosteroids. Three distinct groups of patient with disseminated candidiasis have been identified (Louria, Stiff & Bennett, 1962). The first group presents with the acute onset of fever, tachycardia, tachypnoea, occasionally with chills or hypotension. A second group develop intermittent fever and only feel ill when febrile. A third group consists of patients who manifest progressive deterioration of their general condition with or without fever. The presence of thrush or oesophagitis is not a reliable indicator of disseminated infection. Some patients with disseminated candidiasis have predominant involvement of a single organ. Some of these infections are listed in Table V. Aspergillosis
and phycomycosis
Aspergillus spp. and phycomycetes are primarily respiratory pathogens; consequently, the majority of infections involve either the sinuses or the lungs. In about 30% of patients, the infection disseminates throughout the body (Bodey, 1966). Aspergillus fumigatus causes most infections, although several other species, including A. $uz)us, A. niger and A. glaucus, are also pathogenic. Pulmonary infection is most frequent and usually presents as necrotizing bronchopneumonia or haemorrhagic pulmonary infarction (Young et al., 1970). The organisms have a propensity for invading blood vessels, causing thrombosis and infarction of the surrounding tissues (Baker, 1962). As a consequence, these infections may present with the classic signs and symptoms of acute pulmonary embolus, with pleuritic chest pain, fever, haemoptysis, a friction rub and a wedge-shaped infiltrate on radiographic examination. Another characteristic presentation on the chest radiographic film is single or multiple, rounded densities (Libshitz & Pagoni, 1981). As the infection progresses, the lesions cavitate, and fungus balls may fill the cavities. The rhinocerebral form of aspergillosis occurs substantially less often than pulmonary infection. It originates in the sinuses and progresses through the soft tissues, cartilage and bone, causing lesions in the palate and the nose. Occasionally, the infection progresses through the base of the skull to involve the brain. Disseminated infection may be manifested as an acute vascular event such as myocardial infarction, cerebral haemorrhage or Budd-Chiari syndrome.
Fungi
as major
Other
fungal
hospital
pathogens
419
infections
Cryptococcosis is acquired prior to hospitalization. The organism is ubiquitous in animals and in soil specimens. Infection occurs in about 8% of patients with Hodgkin’s disease, accounting for 25% of fungal infections complicating this malignancy. In one series, 7% of AIDS patients developed this infection; in some it was the initial infectious complication (Kovacs et al., 1985). Infection begins in the lung but meningitis or disseminated infection are most frequently seen in immunocompromized and may arise patients. Infection may be acute, subacute or chronic suddenly or insidiously. Prominent features of disseminated cryptococcosis include acneiform skin lesions, lymphadenitis and bone infection. Cryptococcal pneumonia may manifest itself as miliary, nodular or cavitary lesions on chest radiographic examination. Acute fulminant histoplasma pneumonia has been described in renal transplant recipients and lymphoma patients. Patients with prior exposure to histoplasmosis or coccidioidomycosis may experience recrudescence of Disseminated infection due to local infection and dissemination. Trichosporon beige&, Fusarium sp. and Alternaria sp. has occurred in recent years. Multiple organs may be involved in the process and some patients develop skin lesions. The skin lesions caused by Fusarium sp. are similar to those caused by Aspergillus spp. Antifungal
therapy
Amphotericin B remains the mainstay of antifungal therapy despite its undesirable acute and chronic side effects. Its major advantage is a broad spectrum of activity against most fungal pathogens. For many years it was believed that fungi did not develop resistance to amphotericin B, but recent evidence suggests that therapeutic failure in some cases may be due to emergence of resistance. Also disconcerting is the report of amphotericin B resistance among Candida isolates in a cancer unit where nystatin was used extensively for prophylaxis (Dick, Merz & Saral, 1980). Unfortunately, amphotericin B is not very effective for the therapy of systemic infections in immunocompromized patients although it may be quite beneficial against superficial infections. In a recent review, only 26% of cancer patients treated with amphotericin B survived their infection (Maksymiuk et al., 1984). A major prognostic factor was the patients’ neutrophil counts during the infection. No patient with persistent neutropenia (< 1000 neutrophils mmW3) survived their infection, whereas 38% of those whose neutrophil count increased to normal levels during therapy survived. The response of AIDS patients with systemic fungal infection is also unsatisfactory. For example, only about 40% of patients with cryptococcosis respond (Kovacs et al., 1985). Furthermore, many of them relapse when therapy is discontinued, hence, it is advisable to administer maintenance therapy indefinitely.
420
G. P. Bodey
A recent study helps to explain the inadequacy of the current preparation of amphotericin B (Christiansen et al., 1985). The concentration of amphotericin B was determined in tissue collected at autopsy examination from eight patients who had received total doses of 101 to 2688 mg. The highest concentrations were detected in the liver and substantial concentrations were also detected in the spleen, kidney and lung. The drug retained antifungal activity but several patients had persistent fungal infection in these organs despite tissue concentrations that should have been sufficient to kill the organisms. Presumably, the drug is bound to host cell membranes and is not available to attack the fungal cells. Despite its use for many years, much remains unknown about the optimum method of administration of amphotericin B to immunocompromized patients. Early data suggesting that low dose therapy could be effective in systemic infections have not been substantiated by subsequent experience. Some investigators have suggested that early administration of therapy has produced better therapeutic results, but they usually have failed to take into consideration changes in the patients’ host defences such as recovery from neutropenia. Would patients benefit from higher doses given more frequently, or does more aggressive therapy only cause more toxicity? Should a patient be treated to a fixed total dose or should the duration of therapy be individually determined according to response? Our experience favours the latter approach but there are little data on this subject and it deserves further study. Other antifungal agents currently available for the therapy of systemic infections include S-fluorocytosine, miconazole and ketoconazole. The spectrum of activity of S-fluorocytosine is limited to Candida spp. and Cryptococcus neoformans. It should not be used alone because organisms develop resistance to it. A major side-effect of this drug is myelosuppression which is especially undesirable in immunocompromized patients. A prospective randomized trial comparing amphotericin B alone to amphotericin B plus S-fluorocytosine for the treatment of cryptococcal meningitis indicated that the combination was superior (Bennett et al., 1979). Since the two drugs act synergistically against Cundidu spp. in witro, the combination may be more effective than either agent alone. One clinical study has supported this conclusion, especially against Cundidu tropic& infections (Horn et al., 1985). Sporadic reports also have suggested that the combination may be useful for aspergillus infections, but our experience has been discouraging. The activity of miconazole for treating fungal infections in immunocompromized patients has been debated. Early studies of systemic candida infections in cancer patients indicated a recovery rate of 37% (Jordan et al., 1979). More extensive experience at the same institution indicates a much lower recovery rate of less than 20%. Ketoconazole is only available as an oral preparation and is therefore difficult to use in acutely ill patients, especially if they have mucositis. The drug requires acidity in the
Fungi
as major
hospital
pathogens
421
stomach for absorption, hence cimetidine and antacids interfere with its absorption. Ketoconazole lacks activity against C. tropicalis and Aspergillus spp. Although it is much less toxic than amphotericin B, it can cause In a prospective hepatitis and interfere with steroid metabolism. randomized trial, ketoconazole compared favourably with amphotericin B (Fainstein et al., 1987). Neither drug was effective against disseminated infections and no patient with a C. tropicalis infection responded to ketoconazole. It is clear that new broad-spectrum agents are needed for the treatment of that are efficacious in immunocompromized systemic fungal infections, patients and that are less toxic than amphotericin B. Present avenues of exploration include the synthesis of new triazole compounds, the discovery of unique new compounds, and the development of new delivery systems. Itraconazole and fluconazole are two new triazole compounds. Itraconazole is of interest because it is purported to have activity against Aspergillus spp. The few reports of its use for this purpose do not provide convincing evidence that it represents a striking therapeutic advance. Fluconazole has a spectrum of activity similar to that of ketoconazole. However, its longer half-life permits a once daily dosage schedule and it may lack some of ketoconazole’s side-effects. LY 1210019 is a novel analogue of the polypeptide, echinocandin B (Gordee et al., 1984). Its activity against Candida spp. is comparable to that of amphotericin B but it does not appear to be active against Aspergillus spp. and phycomycetes. A potential advantage of this drug may be reduced toxicity. Other new compounds are being evaluated in the laboratory and * hopefully will soon become available for clinical investigation. Recently, liposomal preparations of amphotericin B have been investigated as an alternative to the conventional preparation. Liposomal amphotericin B is substantially less toxic in mice and is more effective in normal and neutropenic mice against experimental candidiasis (Lopez-Berestein et al., 1984). Early clinical studies with this preparation have been encouraging (Lopez-Berestein et al., 1985). Over 50% of patients that have failed to respond to with candida or aspergillus infections, conventional amphotericin B, have achieved a complete or partial response to liposomal amphotericin B. The acute toxicities of amphotericin B are B-induced nephrotoxicity has greatly ameliorated and amphotericin improved during therapy with the liposomal preparation. Other delivery systems, such as lipid emulsions and cyclodextrans are also under investigation. Empirical
antifungal
therapy
A major obstacle to the successful management of fungal infections is our inability to establish the diagnosis. This is an especially frustrating but regular occurrence in neutropenic patients in whom fever is often the only
422
G. P. Bodey
sign of infection and where the diagnosis may be suspected clinically but confirmed only at autopsy examination. As a consequence, only 17% to 30% of infected patients receive antifungal therapy. For about two decades, amphotericin B has been used empirically for the management of neutropenic patients with persistent fever unresponsive to antibacterial antibiotics. Despite this fact, only two prospective randomized studies have examined the utility of that practice. One study evaluated neutropenic patients who had fever of unknown origin for one week after cephalothin and carbenicillin receiving the combination of gentamicin, (Pizzo et al., 1972). They were then randomly assigned to continue these antibacterial antibiotics, to discontinue all antimicrobial therapy, or to B in addition to the antibacterial antibiotics. receive amphotericin Subsequent to this random assignment, 38% of the 16 patients who discontinued the combination therapy developed infection, primarily with bacterial pathogens. Likewise, 38% of the 16 patients who continued the combination therapy developed infection, but most of these were caused by fungal pathogens. Only 10% of the 18 patients who were also given amphotericin B had subsequent infection. The European Organization for Research on Treatment of Cancer (Klastersky, 1986) has conducted a similar prospective, randomized trial in patients who remained febrile after 4 days of antibacterial therapy. Patients were assigned to continue the antibacterial antibiotics with or without amphotericin B. The subsequent response rates of 60% and 37%, respectively, were significantly different, although the fatality rates were similar (17% vs. 22%). Empirical antifungal therapy is clearly indicated for some patients but, unfortunately, many patients without fungal infection suffer the toxicities of amphotericin B unnecessarily. Until better diagnostic techniques become available this situation will remain unchanged. The incidence of toxicity can be minimized by treating only those patients at greatest risk of acquiring a fungal infection. Table VI lists some of the criteria that should be used to identify patients who should receive empirical amphotericin B therapy. Table
VI.
Indications for empirical amphotericin B in neutropenic patients
Fever of 5-7 days duration, unresponsive to antibacterial antibiotics Neutropenia of > 7 days duration No other obvious cause for fever Progressive debilitation Adrenal corticosteroid therapy Fever which responds to adrenal corticosteroids Diffuse pulmonary infiltrates without significant hypoxaemia Progressive unexplained liver or renal failure
l
Miconazole
leukaemia
leukaemia
Acute
Acute
cotrimoxazole.
Clotrimazole
Cancer and transplant
CTX,
Ketoconazole
Ketoconazole
Haematological Diseases
group
Ketoconazole
Acute leukaemia: CTX group
No CTX
Ketoconazole
Transplant
Ketoconazole
Antifungal agent
Disease
Patients
16 3 11
13
32 28
42
8
12 45
11
7
2
11
0
11
0
11
0
42
24
38
32
13
19
15
57
0
18
7
0
3
16
0
62 34
11
Systemic infections (%I -~ 7
47
4
Total infections (%)
Systemic infections W)
Total infections W)
prophylaxis No prophylaxis
Antifungal
Prophylaxis
VII.
19
15
Patients
Table
Reference
Acuna, Winston &Young (1981) Owens et al. (1984)
(1984)
Estey et al. (1984) Estey et al.
Brincker (1978) Brincker (1983) Siegel et al. (1982)
-__~~
r
i% w
6 $ g m
E w
8 5)
w
2’
E
4. 3
2
424
G. P. Bodey Antifungal
prophylaxis
While topical antifungal agents such as nystatin have been used extensively for the prevention of fungal infections in susceptible populations, only a few studies have been designed to evaluate antifungal prophylaxis (Table VII). A striking observation is the disparity between the frequencies of total fungal infections and systemic fungal infections among patients who received no prophylaxis in these different studies. Considering only studies limited to patients with acute leukaemia, the frequency of total fungal infection varied from 4 to 58%. In several of these studies, antifungal prophylaxis significantly reduced the frequency of infections. For example, among cancer patients and recipients of renal transplants, the frequency of thrush was 60% in controls and 17% in those receiving clotrimazole (P
Assuming that current practices and trends continue, fungal infection will become an increasingly common complication among hospitalized patients. Until more reliable diagnostic tests are available, many fungal infections will only be suspected by the physician. As a consequence, patients will be given antifungal therapy empirically because they have failed to respond to antibacterial agents. In the absence of more effective antifungal agents, correction of the underlying deficiences in host defences will remain the mainstay of successful management of these infections. It is clear that much work remains to be done. Hopefully, these challenging problems will be addressed and substantial progress will be achieved in the next few years. Only the combined efforts of laboratory scientists and clinicians within academia and the pharmaceutical industry will bring this to pass.
Fungi
as major
hospital
pathogens
425
References Acuna, G., Winston, D. J. & Young, L. S. (1981). Ketoconazole prophylaxis of fungal infections in the eranulocvtooenic natient: A double-blind. randomized controlled trial (Abstract 852). In Program and Abstracts 2lst Interscience’ Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C., American Society of Microbiology. Aisner. I.. Murillo. I.. Schimoff. S. C. & Steere. A. C. (1979). Invasive asoergillosis in acute leukaemia: C&relation -with nose cultures and’ antibiotic use. Annals of Internal
Medicine 90, 4-9. Anaissie, E., Elting, L., Kantarjian, H., Bodey, G. P. & F reireich, E. (1987), Correlation between infection and status of underlying disease: a new look at infection in acute leukaemia (Abstract). In Program and Abstracts 27th Interscience Conference on Antimicrobial Agents and Chemotherabv. New York. American Societv of Microbioloev. Baker, R. D. (1962f Leukopenia and th&apy in leukemia as factors predisposing to fayal mycoses. American Journal of Clinical Pathology 37, 358-363. Bennett, J. E., Dismukes, W. E., Duma, R. J. et al. (1979). A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. New England Journal of Medicine 301, 126-l 3 1. Bodev. G. P. (1966). Funeal infections comolicatine acute leukemia. ‘fournal of Chronic h&eases 14, 6671787. Bodey, G. P., Rodriguez, V., Ch ang, H. Y. & Narboni, G. (1978). Fever and infection in leukemic natients. A studv of 494 consecutive oatients. Cancer 41. 161&1622. Brincker, H. (1978). Prophylactic treatment with miconazole in patients highly predisposed to fungal infection. A placebo-controlled double-blind study. Acta Medica Scandinavica 204, 123. Brincker, H. (1983). Prevention of mycosis in granulocytopenic patients with prophylactic ketoconazole treatment. Mycosen 24, 242. Burnie, J. P., Odds, F. C., Lee, W., Webster C. & Williams, J. D. (1985). Outbreak of systemic Candida albicans in intensive care unit caused by cross infection. British
Medical Journal 290, 746-748. Christiansen, K. J., Bernard, E. M., Gold, J. W. M. & Armstrong, D. (1985). Distribution and activity of amphotericin B in humans. Journal of Infectious Diseases 152,1037-1043. Dick, J. D., Merz, W. G. & Saral, R. (1980). Incidence of polyene-resistant yeasts recovered Agents and Chemotherapy 18, 158-l 63. from clinical specimens. Antimicrobial Dummer, J. S., Hardy, A., Poorsatter, A. & Ho, M. (1983). Early infections in kidney, heart and liver transplant recipients on cyclosporine. Transplantation 36, 259-267. Estey, E., Maksymiuk, A., Smith, T., Fainstein, V., Keating, M., McCredie, K. B., Freireich, E. J. & Body, G. P. (1984).. Infection prophylaxis of acute leukemia: Comparative effectiveness of trimethoprimsulfamethoxazole, ketoconazole, and trimethoprimsulfamethoxazole + ketoconazole. Archives of Internal Medicine 144, 1562-1568. Fainstein, V., Bodey, G. P., Elting, L., Maksymiuk, A., Keating, M. & McCredie, K. B. (1987). Amphotericin B or ketoconazole therapy of fungal infections in neutropenic cancer patients. Antimicrobial Agents and Chemotherapy 31, 11-l 5. Gordee, R. S., Zeckner, D. J., Ellis, L. F., Thakkar, A. L. & Howard, L. C. (1984). In vitro and in vivo anticandida activity and toxicology of LY 121019. Journal of Antibiotics 37, 1054-1065. Horn, R., Wong, B., Kiehn, T. E. & Armstrong, D. (1985). Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Reviews of Infectious Diseases 7, 646-655. Hurley, R. (1964). Acute disseminated (septicaemic) moniliasis in adults and children.
Postgraduate Medical Journal 40, 644-653. Jordan, W. M., Bodey, G. P., Rodriguez, V., Ketchel, S. J. & Henney, J. (1979). therapy for treatment of fungal infections in cancer patients. Antimicrobial
Miconazole
Agents and
Chemotherapy 16, 792-797. Kirkpatrick,
C. H.
(1984).
Host
factors in defense against fungal infections. 4D), l-12. Klastersky, J. (1986). Concept of empiric therapy with antibiotic combinations. and limits. American Journal of Medicine 80 (Suppl. SC), 2-l 2.
American
Journal of Medicine 77 (Suppl.
Indications
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Kovacs, J. A., Kovacs, A. A., Polis, M., Wright, W. C., Gill, V. J., Tuazon, C. U., Gelmann, E. P., Lane, H. C., Longfield, R., Overturf, G., Macher, A. M., Fauci, A. S., Parrillo, J. E., Bennett, J. E. & Masur, H. (1985).Cryptococcosis in the acquired immunodeficiency Annals of Internal Medicine 103, 533-538. syndrome. Kopzinn, P. J, & Taschdjian, C. L. (1985). Laboratory diagnosis of candidiasis. In Candidiasis (Bodey, G. P. & Fainstein, V., Eds) pp. 85-l 10. Raven Press, New York. Lehrer, R. L. & Cline, M. J. (1971). Leukocyte candidacidal activity and resistance to systemic candidiasis in patients with cancer. Cancer 27, 121 I-1217. Libshitz, H. I. & Pagoni, J. (1981). Aspergillosis and mucormycosis: two types of opportunistic fungal pneumonia. Radiology 140, 301-306. Lopez-Berestein, G., Hopfer, R., Mehta, R., Mehta, K., Hersh, E. M. & Juliano, R. L. (1984). Treatment of disseminated candidiasis in neutropenic mice with liposome-encapsulated amphotericin 9. Journal of Infectious Diseases 3, 278-282. Lopez-Berestein, G., Fainstein, V., Hopfer, R., Mehta, K., Sullivan, M. P., Keating, M., Rosenblum, M. G., Mehta, R., Luna, M., Hersh, E. M., Reuben, J., Juliano, R. L. & Bodey, G. P. (1985). Liposomal amphotericin B for the treatment of systemic fungal Diseases 151, infections in natients with cancer: a preliminary study._ -Yournal of- Infectious 704-710. Louria, D. B., Stiff, D. P. & Bennett, 9. (1962). Disseminated moniliasis in the adult.
Medicine 41, 307-333. Maksymiuk, A. W., Thongprasert, S., Hopfer, R., Luna, M., Fainstein, V. & Bodey, G. P. (1984). Systemic Candidiasis in cancer patients. American Journal of Medicine 77 (Suppl. 4D), 20-27. Meunier-Carpentier, F., Kiehn, T. E. & Armstrong, D. (1981). Fungemia in the immunocomnromized host. American rournal of Medicine 71. 363-370. Myers, J. D. & Atkinson, K. (1983). Infiction in”bone marrow transplantation. Clinical
Haematology
12.791-811.
Owens, N. J., Nightingale, C. H., Schweizer, R. T., Schauer, P. K., Dekker, P. T. & Quintiliani, R. (1984). Prophylaxis of oral candidiasis with clotrimazole troches. Archives of Internal Medicine 144, 290. Pizzo, P. A., Robichaud, K. J., Gill, F. A. & Witebsky, F. G. (1972). Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. American Journal of Medicine 77, 101-l 10. Richards, K. E., Pierson, C. L., Bucciarelli, L. & Feller, I. (1972). Monilia sepsis in the surgical patient. Surgical Clinics of North America 52, 1399-1406. Schaffner, A. & Douglas, H. (1982). Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. Journal of Clinical Investigation 69, 617-631. Siegel, M., Murphy, M., Counts, G. W. et al. (1982). Prophylactic ketoconazole for the prevention of fungal infection in bone marrow transplant patients (Abstract 166). In
Programs and Abstracts 22nd Interscience Conference on Antimicrobial Chemotherapy, p. 94. Washington, D.C., American Society of Microbiology.
Agents and
Stone, H. H., Kolb, L.D., Currie, C. A., Geheber, C. E. & Cuzzell, J. 2. (1974). Candida sepsis. Pathogenesis and principles of treatment. Annals of Surgery 179, 697-710. Wingard, J. R., Merz, W. G. & Saral, R. (1979). Candida tropicalis: a major pathogen in immunocompromised patients. Annals of Internal Medicine 91, 539-543. Young, R. C., Bennett, J. E., Vogel, C. L., Carbone, P. P. & DeVita, V. T. (1970). Aspergillosis. The spectrum of the disease in 98 patients. Medicine (Baltimore) 49, 147-162. Young, R. C., Bennett, J. E., Geelhoed, G. W. & Levine, A. S. (1974). Fungemia with compromised host resistance. A study of 70 cases. Annals of Internal Medicine 80, 605-612. Yu, V. L., Muder, R. R. & Poorsattar, A. (1986). Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis. American Journal of Medicine 81, 249-254.
The emergence
A), 41 l-426
of fungi as major pathogens* Gerald
hospital
P. Bodey
Section of Infectious Diseases, Department of Medical Specialties, The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston Introduction During the last 25 years, substantial progress has been made in our management of fever in the understanding optimum of the immunocompromized host. The use of empirical antibiotic regimens promptly after the onset of fever in neutropenic patients led to a major reduction in the fatality rate from infection. The introduction of a multitude of new broad-spectrum antibiotics has made it possible to treat successfully a variety of bacterial infections that had been uniformly fatal. These accomplishments have resulted in prolonged survival of patients who are highly susceptible to infection. Furthermore the successful management of bacterial infections has resulted in the use of more aggressive therapy against patients’ underlying disease processes, leading to even greater susceptibility to infection. Hence, it is not surprising that fungal infections have emerged as a major cause of morbidity and mortality in immunocompromized patients. Frequency
of fungal
infection
Accurate information with regard to frequency of fungal infections in studies do not provide immunocompromized hosts is sparse. Clinical complete information because the size of the population at risk is usually not described and, since fungal infections often remain undiagnosed, the true frequency is difficult to define. Autopsy studies are limited because many patients who die are not examined and patients who survive their infection are not included. Nevertheless, there is substantial evidence that fungal infections are increasing. Candida oesophagitis was a rare infection 30 years ago; today it is common among cancer patients. Systemic fungal infection *Based Society
on the Lowbury Lecture given held in September 1987.
Correspondence to: Gerald Holcombe, Houston, Texas 0195-6701/88/02A411+
P. Bodey, 77030.
at the First Infectious
International Diseases
16 $03.00/O
(Box
Conference
of the Hospital
47),
Anderson
M.D.
Q 1988 The Hospital
411
Infection
Hospital,
Infection
1515
Soaety
G. P. Bodey
412
nearly equals bacterial infection as a cause of death in leukaemic patients. Aspergillus and candida infections are no longer limited to those patients failing to respond to antileukaemic therapy, but are occurring increasingly among patients undergoing initial remission induction therapy. The frequency of aspergillus infections among patients receiving chronic adrenal corticosteroid therapy also appears to be increasing. Fungal infections are common among patients with indwelling vascular catheters, extensive burn wounds, extensive surgery and organ transplants. Chronic serious fungal infections such as aspergillus fungus balls in the lung, and candida hepatitis, are being diagnosed more often. New fungal pathogens are being identified, including Alternaria sp, Fusarium sp, Trichosporon beigelii and Drechslera SP.
The frequency of fungal infection in patients with acute leukaemia was examined in two studies at our institution (Table I). In both studies, patients were followed from their first admission until death or to the completion of the study period. Both the frequency of total fungal infections and major fungal infections increased substantially during the second of fungal period (Bodey et al., 1978; Anaissie et al., 1987). The distribution organisms also changed. Candida albicans was the most common fungal organism during the first period. During the second period, C. albicans caused only 41% of fungal infections whereas C. tropicalis caused 19% and Aspergillus spp. also caused 19%. A wide variety of other fungi caused occasional infections during the latter period. The frequency of fungal infections in transplant recipients is changing because many aspects of the transplantation process are in a state of continuing evolution. The introduction of cyclosporin has altered the type of infectious complications and the side-effects of their therapy. The type of surgical procedure, the nature of the donor organ and the recipient’s general health at the time of the procedure affect susceptibility to fungal infection. For example, 141 infections occurred in 10.5 patients during the first 6 months after transplantation in whom immunosuppressive therapy was cyclosporin (Dummer et al., 1983). Eleven fungal infections occurred in the 24 liver transplant recipients but no fungal infections occurred among the 64 renal transplant and 17 cardiac transplant recipients. The reported frequency of fungal infection varies from 28% to 42% in liver transplant Table
I. Distribution
of infections in leukaemic patients at MD Anderson Hospital, Study
Patients Infectious episodes Organism identified Total fungal infections Major infections Major fungal infections
Houston
period
1966-1972
1978-1982
494 1209 884 93 (11%) 859 42 (5%)
377 1137 757 150 (20%) 528 120 (23%)
Fungi
as major
hospital
pathogens
413
recipients, 2% to 30% in bone marrow transplant recipients and 10% to 35% in cardiac transplant recipients. The frequency of fungal infections among renal transplant recipients has diminished from 20% to c 5% as patient management has improved. The advent of the epidemic of acquired immunodeficiency syndrome (AIDS) has created a new population of patients susceptible to fungal infection. Thrush and oesophageal candidiasis are ubiquitous infections. Cryptococcosis has been described in about 7% of these patients in some areas of the United States (Kovacs et al., 1985). Histoplasmosis is prevalent among those who reside or have travelled in endemic areas. Aspergillosis does not appear to be a complication of this disease. Predisposing
factors
Many factors have been incriminated as predisposing to fungal infections (Table II). D efi ciencies in T cell number or function, as occur in mucocutaneous candidiasis syndromes and AIDS, predispose to superficial candida infection, but systemic infection does not occur (Kirkpatrick, 1984). Neutropenia is an important predisposing factor to aspergillosis and disseminated candidiasis, but may be less important in cryptococcosis. liz vitro, the neutrophil ingests and kills C. albicans and this is the primary defence against infection caused by these organisms (Lehrer & Cline, 1971). The frequency of autopsy-proven fungal infection in bone marrow transplant recipients correlates with the duration of neutropenia (Myers 8z Atkinson, 1983). Fungal infection was found in 21% of cases with neutropenia for one to 20 days, 41% for 21 to 40 days and 57% for more than 40 days. The importance of the neutrophil and macrophage in protecting against aspergillus infection has been delineated in mice (Schaffner & Douglas, 1982). Neutrophils protect against the hyphal form of Aspergillus fumigatus and kill mycelia in vitro. In normal but not in neutropenic mice, hyphal growth was eliminated and mycelia were eradicated. Macrophages prevented germination and killed spores in vitro and eradicated conidia, even in neutropenic mice. Cortisone directly inhibited the killing of conidia Table
II. Factors predisposing to fungal infection
Chronic debilitation, malnutrition Adrenal corticosteroid therapy Antibiotic therapy Deficient T cell number or function Deficient neutrophil number or function Hyperglycaemia, acidosis Parenteral alimentation Extensive surgery Haematological malignancy Indwelling intravascular catheter Immunosuppressive therapy
414
G. P. Bodey
by macrophages in oitro and in viva and reduced the mobilization of neutrophils. Myelosuppression alone was only important when mice were challenged by activated spores that cannot be killed by macrophages. While some antibiotics permit candida overgrowth by suppressing the normal gastrointestinal flora, most studies have failed to demonstrate that parenteral antibiotic therapy is more prevalent among patients who acquire fungal infections than other similarly compromized patients. When C. albicans are present in high concentrations in the gastrointestinal tract they can migrate across the intact endothelium by a process known as persorption. A variety of factors such as endotoxin, cancer chemotherapy and adrenal corticosteroids can interfere with the liver’s ability to prevent these organisms from entering the bloodstream (Stone et al., 1974). Candida organisms can also gain access to the bloodstream directly via intravascular catheters. While the majority of infections are caused by C. albicuns in most centres, C. tropicalis has emerged as an important pathogen, especially in catheter-related infections. Other species such as C. Krusei have also been implicated as common causes of catheter-related infections. Much is known about the epidemiology of some fungal infections such as histoplasmosis, coccidioidomycosis and cryptococcosis, but less is known of Aspergillus spp. are airborne pathogens and aspergillosis and candidiasis. epidemics of infection have been described due to construction adjacent to the hospital or contamination of air conditioning ducts. However, micro-epidemics of aspergillosis have occurred in hospitals where it has been impossible to identify a source. Cundidu spp. are ubiquitous in the environment and it is presumed that most infections arise from the patient’s endogenous flora. Sporadic reports have suggested that nosocomial strains may be transmitted from patient to patient and be responsible for infections et al., 1985). A similar situation is being recognized with (Burnie StuphyZococcus epidermidis and diphtheroids. The importance of these observations needs to be examined further and, if true, the means of transmission identified and eliminated when possible. Some important questions remain unanswered. For example, why do some patients who have multiple predisposing factors and are heavily colonized with C. albicuns never become infected? How great a risk is thrush for disseminated candidiasis? Are some new broadspectrum antibacterial regimens more likely to cause fungal superinfection in susceptible hosts than other regimens ? Are most aspergillus infections nosocomially acquired, or are some patients’ sinuses colonized chronically resulting in subsequent infection when the patient’s host defences are compromized? Why is aspergillosis increasing in frequency during remission induction therapy for acute leukaemia ? Do prophylactic antibacterial or antifungal agents really increase the risk of aspergillosis? These and other questions need to be addressed if we are to reduce the inexorable trend of increasing fungal infection.
Fungi
as major
Diagnostic
hospital
pathogens
415
considerations
A major obstacle to the successful management of many systemic fungal infections is our inability to establish the diagnosis. Often the only reliable diagnostic procedure is a tissue biopsy and that cannot be obtained because the patient is too ill or has severe thrombocytopenia. This problem is most common in patients with aspergillosis, phycomycosis and disseminated candidiasis. Since candida overgrowth is common among patients receiving antibacterial agents, positive cultures from body orifices are not generally helpful in establishing the diagnosis of systemic infection. Studies in BMT recipients and heart and lung transplant recipients indicate that Can&da spp. are frequently cultured from body orifices in the absence of infection. In one study of patients with leukaemia and BMT recipients, C. albicans was isolated from surveillance cultures of 67% of patients but caused disseminated infection in only 5% (Wingard, Merz & Saral, 1979). However, C. tropicalis was cultured from only 28% of patients but out of this group caused disseminated infection in 56%. Positive cultures from closed body spaces are usually indicative of infection. Blood cultures are an unreliable means for diagnosing disseminated candidiasis. Catheter-associated fungaemia is common, and it is often difficult to ascertain which of these patients have tissue invasion. Only 25% to 45% of patients with autopsy-proven candidiasis ever had a positive blood culture during their infection. In one series, only 18% of patients had a positive blood culture within one week of onset of their infection and 45% with positive blood cultures died before the result was known to their physicians (Maksymiuk et al., 1984). These rather dismal results have led many investigators to try to develop other means of diagnosing systemic candidiasis. Some of these approaches are listed in Table III (Kozinn & Taschdjian, 1985). Serological tests directed against detection of antibodies have not generally been useful because severely immunocompromized patients are unable to produce antibodies. One would anticipate that tests directed against detection of antigen would be more successful. Although many promising studies have been reported, these tests usually fail in those patients where they are most needed. Table
III.
Methods
attempted
Agglutinating antibodies Precipitins - gel diffusion, CIE Mannan - ELISA, RIA, latex agglutination Arabinitol- GLC Cytoplasmic antigen - ELISA Cell wall polysaccharide Mycelial antigen - CIE Mannose - GLC
- CIE
for diagnosis
of candidz’usis
416
G. P. Bodey
A different problem exists in the diagnosis of aspergillosis and phycomycosis. These organisms are seldom cultured from any site in infected patients. Indeed, the organisms may not be cultured from tissue known to be infected on histological examination. For many years, it was taught that Aspergillus spp. are common laboratory contaminants and should be ignored when isolated from patient specimens. A recent study examined patients who had Aspergillus sp. isolated from respiratory tract cultures (Yu, Muder & Poorsattar, 1986). The frequency of proven aspergillosis was 100% among those patients with acute leukaemia, 94% among neutropenic patients, 65% among patients receiving adrenal corticosteroids, but only 40% among patients receiving parenteral antibiotics. Another study has suggested that cancer patients who have Aspergillus sp. isolated from routine nasal cultures are at high risk of having aspergillosis (Aisner et al., 1979). Hence, it would seem prudent to consider positive cultures seriously when collected from susceptible patients. Unfortunately, uniformly reliable serological tests for the diagnosis of aspergillosis are not available, but the possibility of achieving that goal may be greater than in candidiasis. The diagnosis of other fungal infections such as histoplasmosis, coccidioidomycosis and cryptococcosis is usually easier to establish. These organisms can usually be isolated from appropriate culture specimens and their presence indicates disease. Serological tests are helpful, especially the test for cryptococcal antigen which can be detected in serum and cerebrospinal fluid of infected patients. Systemic
candidiasis
Disseminated candidiasis can involve any organ in the body. The major sites of origin of infection are the gastrointestinal tract and the bloodstream directly via vascular catheters. Organ distribution appears to differ depending on the site of origin. The predominant organs involved when the gastrointestinal tract is the site of origin include the liver, spleen and lungs; the predominant organs involved when a catheter is the site of origin include the kidneys, heart and lungs. Candida pneumonia due to aspiration of infected secretions occurs infrequently. More often candida pneumonia is secondary to haematogenous dissemination. Most cases of disseminated candidiasis are caused by C. albicans, but infections caused by other species are increasing in frequency. In some institutions, C. tropicalis, C. parapsilosis and C. stellatoidea infections are not uncommon (Table IV) (Hurley, 1964; Young et al., 1974; Richards et al., 1972; Meunier-Carpentier, Kiehn & Armstrong, 1981), and many of these infections are associated with intravenous catheters and infusions. Why these Candida spp. are more likely to cause infection in this setting remains to be determined. Unfortunately, most patients with candidiasis do not develop any
species
albicans tropicalis pseudotropicalis krusei parapsilosis
Multiple
C. C. C. C. C.
Patient population Total candidiasis No. speciated
El 0 3
0
Leukaemia 71 54 39 10
Bodey
IV. Distribution
i
4
5
Undefined 48 46 37
Hurley
Table
:,
1
Immunocompromised 29 29 19 8 0 0
i
Burn 53 50 41 2 0
Richards
spp. in systemic infection
Young
of Candida
9
:
Cancer 182 163 92 54 0
Maksymiuk
Meunier _____ Cancer 82 82 40 25 1 3 13 0
2
i
f z c a P) 6 &
2
&
6. c
418
G. P. Bodey Table
Y Organ
infections
Laryngitis Pyeionephritis Peritonitis Arthritis Osteomyelitis Myositis Hypersplenism
associated
with disseminated
candidiasis
Endocarditis Pneumonitis Oohthalmitis H’epatic abscesses Cerebritis Meningitis Skin nodules
characteristic signs and symptoms to suggest this infection. Often fever is the only evidence of infection and this may be suppressed if the patient is receiving adrenal corticosteroids. Three distinct groups of patient with disseminated candidiasis have been identified (Louria, Stiff & Bennett, 1962). The first group presents with the acute onset of fever, tachycardia, tachypnoea, occasionally with chills or hypotension. A second group develop intermittent fever and only feel ill when febrile. A third group consists of patients who manifest progressive deterioration of their general condition with or without fever. The presence of thrush or oesophagitis is not a reliable indicator of disseminated infection. Some patients with disseminated candidiasis have predominant involvement of a single organ. Some of these infections are listed in Table V. Aspergillosis
and phycomycosis
Aspergillus spp. and phycomycetes are primarily respiratory pathogens; consequently, the majority of infections involve either the sinuses or the lungs. In about 30% of patients, the infection disseminates throughout the body (Bodey, 1966). Aspergillus fumigatus causes most infections, although several other species, including A. $uz)us, A. niger and A. glaucus, are also pathogenic. Pulmonary infection is most frequent and usually presents as necrotizing bronchopneumonia or haemorrhagic pulmonary infarction (Young et al., 1970). The organisms have a propensity for invading blood vessels, causing thrombosis and infarction of the surrounding tissues (Baker, 1962). As a consequence, these infections may present with the classic signs and symptoms of acute pulmonary embolus, with pleuritic chest pain, fever, haemoptysis, a friction rub and a wedge-shaped infiltrate on radiographic examination. Another characteristic presentation on the chest radiographic film is single or multiple, rounded densities (Libshitz & Pagoni, 1981). As the infection progresses, the lesions cavitate, and fungus balls may fill the cavities. The rhinocerebral form of aspergillosis occurs substantially less often than pulmonary infection. It originates in the sinuses and progresses through the soft tissues, cartilage and bone, causing lesions in the palate and the nose. Occasionally, the infection progresses through the base of the skull to involve the brain. Disseminated infection may be manifested as an acute vascular event such as myocardial infarction, cerebral haemorrhage or Budd-Chiari syndrome.
Fungi
as major
Other
fungal
hospital
pathogens
419
infections
Cryptococcosis is acquired prior to hospitalization. The organism is ubiquitous in animals and in soil specimens. Infection occurs in about 8% of patients with Hodgkin’s disease, accounting for 25% of fungal infections complicating this malignancy. In one series, 7% of AIDS patients developed this infection; in some it was the initial infectious complication (Kovacs et al., 1985). Infection begins in the lung but meningitis or disseminated infection are most frequently seen in immunocompromized and may arise patients. Infection may be acute, subacute or chronic suddenly or insidiously. Prominent features of disseminated cryptococcosis include acneiform skin lesions, lymphadenitis and bone infection. Cryptococcal pneumonia may manifest itself as miliary, nodular or cavitary lesions on chest radiographic examination. Acute fulminant histoplasma pneumonia has been described in renal transplant recipients and lymphoma patients. Patients with prior exposure to histoplasmosis or coccidioidomycosis may experience recrudescence of Disseminated infection due to local infection and dissemination. Trichosporon beige&, Fusarium sp. and Alternaria sp. has occurred in recent years. Multiple organs may be involved in the process and some patients develop skin lesions. The skin lesions caused by Fusarium sp. are similar to those caused by Aspergillus spp. Antifungal
therapy
Amphotericin B remains the mainstay of antifungal therapy despite its undesirable acute and chronic side effects. Its major advantage is a broad spectrum of activity against most fungal pathogens. For many years it was believed that fungi did not develop resistance to amphotericin B, but recent evidence suggests that therapeutic failure in some cases may be due to emergence of resistance. Also disconcerting is the report of amphotericin B resistance among Candida isolates in a cancer unit where nystatin was used extensively for prophylaxis (Dick, Merz & Saral, 1980). Unfortunately, amphotericin B is not very effective for the therapy of systemic infections in immunocompromized patients although it may be quite beneficial against superficial infections. In a recent review, only 26% of cancer patients treated with amphotericin B survived their infection (Maksymiuk et al., 1984). A major prognostic factor was the patients’ neutrophil counts during the infection. No patient with persistent neutropenia (< 1000 neutrophils mmW3) survived their infection, whereas 38% of those whose neutrophil count increased to normal levels during therapy survived. The response of AIDS patients with systemic fungal infection is also unsatisfactory. For example, only about 40% of patients with cryptococcosis respond (Kovacs et al., 1985). Furthermore, many of them relapse when therapy is discontinued, hence, it is advisable to administer maintenance therapy indefinitely.
420
G. P. Bodey
A recent study helps to explain the inadequacy of the current preparation of amphotericin B (Christiansen et al., 1985). The concentration of amphotericin B was determined in tissue collected at autopsy examination from eight patients who had received total doses of 101 to 2688 mg. The highest concentrations were detected in the liver and substantial concentrations were also detected in the spleen, kidney and lung. The drug retained antifungal activity but several patients had persistent fungal infection in these organs despite tissue concentrations that should have been sufficient to kill the organisms. Presumably, the drug is bound to host cell membranes and is not available to attack the fungal cells. Despite its use for many years, much remains unknown about the optimum method of administration of amphotericin B to immunocompromized patients. Early data suggesting that low dose therapy could be effective in systemic infections have not been substantiated by subsequent experience. Some investigators have suggested that early administration of therapy has produced better therapeutic results, but they usually have failed to take into consideration changes in the patients’ host defences such as recovery from neutropenia. Would patients benefit from higher doses given more frequently, or does more aggressive therapy only cause more toxicity? Should a patient be treated to a fixed total dose or should the duration of therapy be individually determined according to response? Our experience favours the latter approach but there are little data on this subject and it deserves further study. Other antifungal agents currently available for the therapy of systemic infections include S-fluorocytosine, miconazole and ketoconazole. The spectrum of activity of S-fluorocytosine is limited to Candida spp. and Cryptococcus neoformans. It should not be used alone because organisms develop resistance to it. A major side-effect of this drug is myelosuppression which is especially undesirable in immunocompromized patients. A prospective randomized trial comparing amphotericin B alone to amphotericin B plus S-fluorocytosine for the treatment of cryptococcal meningitis indicated that the combination was superior (Bennett et al., 1979). Since the two drugs act synergistically against Cundidu spp. in witro, the combination may be more effective than either agent alone. One clinical study has supported this conclusion, especially against Cundidu tropic& infections (Horn et al., 1985). Sporadic reports also have suggested that the combination may be useful for aspergillus infections, but our experience has been discouraging. The activity of miconazole for treating fungal infections in immunocompromized patients has been debated. Early studies of systemic candida infections in cancer patients indicated a recovery rate of 37% (Jordan et al., 1979). More extensive experience at the same institution indicates a much lower recovery rate of less than 20%. Ketoconazole is only available as an oral preparation and is therefore difficult to use in acutely ill patients, especially if they have mucositis. The drug requires acidity in the
Fungi
as major
hospital
pathogens
421
stomach for absorption, hence cimetidine and antacids interfere with its absorption. Ketoconazole lacks activity against C. tropicalis and Aspergillus spp. Although it is much less toxic than amphotericin B, it can cause In a prospective hepatitis and interfere with steroid metabolism. randomized trial, ketoconazole compared favourably with amphotericin B (Fainstein et al., 1987). Neither drug was effective against disseminated infections and no patient with a C. tropicalis infection responded to ketoconazole. It is clear that new broad-spectrum agents are needed for the treatment of that are efficacious in immunocompromized systemic fungal infections, patients and that are less toxic than amphotericin B. Present avenues of exploration include the synthesis of new triazole compounds, the discovery of unique new compounds, and the development of new delivery systems. Itraconazole and fluconazole are two new triazole compounds. Itraconazole is of interest because it is purported to have activity against Aspergillus spp. The few reports of its use for this purpose do not provide convincing evidence that it represents a striking therapeutic advance. Fluconazole has a spectrum of activity similar to that of ketoconazole. However, its longer half-life permits a once daily dosage schedule and it may lack some of ketoconazole’s side-effects. LY 1210019 is a novel analogue of the polypeptide, echinocandin B (Gordee et al., 1984). Its activity against Candida spp. is comparable to that of amphotericin B but it does not appear to be active against Aspergillus spp. and phycomycetes. A potential advantage of this drug may be reduced toxicity. Other new compounds are being evaluated in the laboratory and * hopefully will soon become available for clinical investigation. Recently, liposomal preparations of amphotericin B have been investigated as an alternative to the conventional preparation. Liposomal amphotericin B is substantially less toxic in mice and is more effective in normal and neutropenic mice against experimental candidiasis (Lopez-Berestein et al., 1984). Early clinical studies with this preparation have been encouraging (Lopez-Berestein et al., 1985). Over 50% of patients that have failed to respond to with candida or aspergillus infections, conventional amphotericin B, have achieved a complete or partial response to liposomal amphotericin B. The acute toxicities of amphotericin B are B-induced nephrotoxicity has greatly ameliorated and amphotericin improved during therapy with the liposomal preparation. Other delivery systems, such as lipid emulsions and cyclodextrans are also under investigation. Empirical
antifungal
therapy
A major obstacle to the successful management of fungal infections is our inability to establish the diagnosis. This is an especially frustrating but regular occurrence in neutropenic patients in whom fever is often the only
422
G. P. Bodey
sign of infection and where the diagnosis may be suspected clinically but confirmed only at autopsy examination. As a consequence, only 17% to 30% of infected patients receive antifungal therapy. For about two decades, amphotericin B has been used empirically for the management of neutropenic patients with persistent fever unresponsive to antibacterial antibiotics. Despite this fact, only two prospective randomized studies have examined the utility of that practice. One study evaluated neutropenic patients who had fever of unknown origin for one week after cephalothin and carbenicillin receiving the combination of gentamicin, (Pizzo et al., 1972). They were then randomly assigned to continue these antibacterial antibiotics, to discontinue all antimicrobial therapy, or to B in addition to the antibacterial antibiotics. receive amphotericin Subsequent to this random assignment, 38% of the 16 patients who discontinued the combination therapy developed infection, primarily with bacterial pathogens. Likewise, 38% of the 16 patients who continued the combination therapy developed infection, but most of these were caused by fungal pathogens. Only 10% of the 18 patients who were also given amphotericin B had subsequent infection. The European Organization for Research on Treatment of Cancer (Klastersky, 1986) has conducted a similar prospective, randomized trial in patients who remained febrile after 4 days of antibacterial therapy. Patients were assigned to continue the antibacterial antibiotics with or without amphotericin B. The subsequent response rates of 60% and 37%, respectively, were significantly different, although the fatality rates were similar (17% vs. 22%). Empirical antifungal therapy is clearly indicated for some patients but, unfortunately, many patients without fungal infection suffer the toxicities of amphotericin B unnecessarily. Until better diagnostic techniques become available this situation will remain unchanged. The incidence of toxicity can be minimized by treating only those patients at greatest risk of acquiring a fungal infection. Table VI lists some of the criteria that should be used to identify patients who should receive empirical amphotericin B therapy. Table
VI.
Indications for empirical amphotericin B in neutropenic patients
Fever of 5-7 days duration, unresponsive to antibacterial antibiotics Neutropenia of > 7 days duration No other obvious cause for fever Progressive debilitation Adrenal corticosteroid therapy Fever which responds to adrenal corticosteroids Diffuse pulmonary infiltrates without significant hypoxaemia Progressive unexplained liver or renal failure
l
Miconazole
leukaemia
leukaemia
Acute
Acute
cotrimoxazole.
Clotrimazole
Cancer and transplant
CTX,
Ketoconazole
Ketoconazole
Haematological Diseases
group
Ketoconazole
Acute leukaemia: CTX group
No CTX
Ketoconazole
Transplant
Ketoconazole
Antifungal agent
Disease
Patients
16 3 11
13
32 28
42
8
12 45
11
7
2
11
0
11
0
11
0
42
24
38
32
13
19
15
57
0
18
7
0
3
16
0
62 34
11
Systemic infections (%I -~ 7
47
4
Total infections (%)
Systemic infections W)
Total infections W)
prophylaxis No prophylaxis
Antifungal
Prophylaxis
VII.
19
15
Patients
Table
Reference
Acuna, Winston &Young (1981) Owens et al. (1984)
(1984)
Estey et al. (1984) Estey et al.
Brincker (1978) Brincker (1983) Siegel et al. (1982)
-__~~
r
i% w
6 $ g m
E w
8 5)
w
2’
E
4. 3
2
424
G. P. Bodey Antifungal
prophylaxis
While topical antifungal agents such as nystatin have been used extensively for the prevention of fungal infections in susceptible populations, only a few studies have been designed to evaluate antifungal prophylaxis (Table VII). A striking observation is the disparity between the frequencies of total fungal infections and systemic fungal infections among patients who received no prophylaxis in these different studies. Considering only studies limited to patients with acute leukaemia, the frequency of total fungal infection varied from 4 to 58%. In several of these studies, antifungal prophylaxis significantly reduced the frequency of infections. For example, among cancer patients and recipients of renal transplants, the frequency of thrush was 60% in controls and 17% in those receiving clotrimazole (P
Assuming that current practices and trends continue, fungal infection will become an increasingly common complication among hospitalized patients. Until more reliable diagnostic tests are available, many fungal infections will only be suspected by the physician. As a consequence, patients will be given antifungal therapy empirically because they have failed to respond to antibacterial agents. In the absence of more effective antifungal agents, correction of the underlying deficiences in host defences will remain the mainstay of successful management of these infections. It is clear that much work remains to be done. Hopefully, these challenging problems will be addressed and substantial progress will be achieved in the next few years. Only the combined efforts of laboratory scientists and clinicians within academia and the pharmaceutical industry will bring this to pass.
Fungi
as major
hospital
pathogens
425
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