The treatment of invasive aspergillosis

IIDNI Volume 10, Number 8, August 1991 Editor

Associate Editors

Charles W. Stratton, MD

Roger G. Finch, FRCP, MRC Path

Ruth M. Lawrence, MD

Department of Pathology Vanderbilt University Medical Center Nashville, Tennessee

Nottingham City Hospital Nottingham, United Kingdom

Veterans Administration Outpatient Clinic Sacramento, California

H. Bradford Hawley, MD

John T. Sinnott IV, MD

Wright State School of Medicine Dayton, Ohio

University of South Florida Tampa, Florida

Richard F. Jacobs, MD Arkansas Children's Hospital Little Rock, Arkansas

Uontent~,

The Treatment of Invasive Aspergillosis David W. Denning Echocardiography in the Diagnosis and Management of Infective Endocarditis R. Lee Jobe Benjamin F. Byrd COMMENTS ON CURRENT PUBLICATIONS

Elsevier 0278-2316/91/$0.00 + 2.20

The Treatment of Invasive Aspergiliosis David W. Denning, MRCP, DCH Regional Department of Infectious Diseasesand Tropical Medicine (University of Manchester), Monsall Hospital, Manchester, UK

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Invasive aspergillosis is a disease characterized by tissue invasion with aspergillus hyphae. It is distinct from other entities caused by Aspergillus such as aspergillomas that occur in preexisting pulmonary cavities and allergic bronchopulmonary aspergillosis. The incidence of invasive aspergillosis is increasing throughout the developed world, primarily as the result of both a greater number of immunocompromised patients and greater degrees of impaired immunity in those who are immunosuppressed. Various new disease entities caused by Aspergillus and host groups that develop invasive aspergillosis have been described in the last decade. These include aspergillus epiglottitis, aspergillus sternal wound infections, invasive pulmonary aspergillosis in AIDS patients, obstructing pulmonary aspergillosis (also in AIDS patients), invasive aspergillus otitis (predominantly in leukemic patients), and ulcerative aspergillus tracheobronchitis in

heart/lung or lung transplant patients. Also more frequently recognized now is an entity called "chronic necrotizing pulmonary aspergillosis," which is an indolent symptom-laden disease occurring in less severely immunocompromised individuals such as diabetics. In all studies concerning the treatment of invasive aspergillosis, early diagnosis is emphasized as being of major importance. There are several substantial problems in the rapid diagnosis of invasive aspergillosis. Serological tests for aspergillus antigen are potentially valuable, and at least one test has been validated in patients. These tests are not available, however, for most doctors caring for these patients. Definitive diagnosis requires demonstration of hyphae in tissue or positive cytology of a percutaneous aspirate of a lesion, preferably backed up by culture. Pseudallescheria boydii may have similar histological appearances to Aspergillus spp. and will not respond to amphotericin B. During 0278-2316 IDINDN 10(8) 65-72, 1991

66 Infectious Diseases Newsletter 10(8) August 1991 neutropenia, a culture of sputum, a nasal swab, or bronchoalveolar lavage (BAL) yielding Aspergillus should be regarded as highly predictive of invasive aspergillosis, especially if accompanied by unexplained fever or a pulmonary infiltrate. This statement is probably also true of allogeneic bone marrow transplant patients whether neutropenic or not. Positive BAL cultures from other transplant patients may well represent invasive aspergillosis in at least 50% of cased but has not been well studied. In no other host groups can any inference about invasive aspergiilosis be made solely on the basis of a positive respiratory tract culture.

Pulmonary Aspergillosis Amphotericin B is considerable less efficacious for invasive aspergillosis as compared, for example, with cryptococcal meningitis. In a review of the literature that analyzed 440 courses of treatment at various body sites in 379 patients, and after excluding those who failed to respond or died within the first 14 days of treatment, the over,all rate of response to amphotericin B therapy was 55%. If the data were analyzed to include all patients given any treatment, this figure probably would fall to approximately 30%. Within this broad grouping, it is clear that some host groups and some sites of disease are much more resistant to therapy than others, most notably allogeneic bone marrow transplant patients and those with cerebral aspergillosis. Some notable successes have been recorded in some recent s e r i e s I i n particular the mortality from invasive pulmonary aspergillosis occurring during neutropenia in leukemic patients has fallen over the last 15 years from approximately 80% to approximately 13% in the most recent studies. This

may reflect earlier empirical therapy or a more intensive antifungal regimen (amphotericin B 1 mg/kg/day together with oral flucytosine). There is very little data concerning any alternative in this setting. In non-neutropenic patients, particularly solid organ transplant patients, response to slightly lower doses of amphotericin is frequently seen, and there is an increasing amount of data to suggest that itraconazole is usually successful in these settings. Both drugs have drawbacks, however. The synergistic nephrotoxicity of amphotericin B and cyclosporin often results in considerable renal impairment. This effect may prevent the patient from receiving enough amphotericin B, and therapy may thus fail. ltraconazole elevates cyclosporin serum concentrations in solid organ transplant patients, an effect that may result in renal impairment if the dose of cyclosporin is not reduced by half from the day ilracomtzole is first administered. Further reductions of cyclosporin dosing may be necessary. Despite these problems, complete response to itraconazole is seen in approximately 80% of these patients. Fluconazole is not efficacious for invasive aspergillosis at currently studied doses (400 mg/day). The relatively newly described enlily invasive aspergillus tracheobronchitis (including ulcerative aspergillus tracheobronchitis in lung transplant patients) appears to respond much better to ilracon~ole than to amphotericin B.

Cerebral Aspergillosis The treatment of cerebr',.d aspergillosis is problematic regardless of the host group in which it occurs. Very few responders are recorded in the literature. The few successes that have been re-

corded have generally been in less severely immunocompromised patients and in those who received amphotericin B 1 mg/kg/day with flucytosine. Occasionally aspergillus meningitis (with no mass lesion) occurs, and flucytosine with or without arnphotericin B appears to be effective in this setting. Thus flucytosine is probably an important component of the treatment of intracranial aspergillosis. Surgical resection or percutaneous aspiration of mass lesions has "also been advocated: the role of such procedures remains uncertail~. Aspergillus Sinusitis In the nonimmunocompromised host, maxillary sinusitis can almost always be treated successfully by surgical aeration of the affecled sinus without medical therapy. Ethmoidal disease often accompanies maxillary sinusitis and should be treated surgically at the ,same lime as aeration to ensure cure" relapse is more likely if residual ethmoidal disease remains. Sphenoid sinusitis due to Aspergillus is somewhat more problematic. There is often a longer delay before diagnosis. Bone and/or mucosa are more likely to be invaded by hyphae. In this context, surgical drainage, combined with medical therapy, is essential. Oral itraconazole therapy is efficacious in the nonimmunocompromised host, but there is little data in the neutropenic or bone marrow transplant setting, It is important to delineate the disease by CT scanning in all patients with aspergillus sinusitis to ensure that there is no bone involvemenl thai would mandate medical therapy. Likewise, the excised mucosa should be carefully evaluated histologically for evidence of hyphal invasion. If hyphal invasion is found without bony involvement, medical

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67 Infectious Diseases Newsletter 10(8) August 1991 therapy should be given serious consideration. Sinusitis in the neutropenic or bone marrow transplant patient often does not confine itself merely to the sinuses and debridement has been advocated, but delayed hemorrhage following surgical exploration is a major complication in a few of those patients thus afflicted and may lead to death. Amphotericin B, at 0.7-1 mg/kg/day, is often effective, but recent data suggest that multilamellar liposomal amphotericin B may be superior to it. Relapse, which is often fatal, is very common (around 50%) in cancer patients. There is little data available on the efficacy of itraconazole in this setting, but successful prevention of relapse with itraconazole is likely.

Aspergillus Osteomyelitis Bone aspergillosis occurs most commonly in the vertebral column and should generally be managed by a combination of medical and surgical means, particularly if there is any evidence of epidural involvement. Amphoteficin B, 0.7 mg/kg/day, is frequently effective, as apparently is oral itraconazole. However, the pathology of invasive aspergillosis frequently leads to infarction and necrosis and it may be impossible to cure these patients without surgery in many instances. Lack of improvement after a 2-3 week trial of appropriate medical therapy is a clear indication for surgery. Delayed surgery, together with bone grafting, has been successful in a few cases.

Endocarditis Aspergillus endocarditis represents a most formidable challenge to the clinician. Vegetations are usually bulky but the diagnosis is difficult to make because blood cultures are almost always negative. It is most common in those who previously have had a valve replacement and are infected at surgery (probably) by airborne contamination of the wound. It also occurs infrequently in immunocompromised

patients with disseminated aspergillosis. Failure to consider the diagnosis is the most common reason for death, since valve replacement appears to be essential for successful treatment. Surgery should be combined with amphotericin B, 1 mg/kg/day, possibly with oral flucytosine given for a long period. Adequacy of resection margins as judged histologically may be a guide to the duration of therapy. Susceptibility Testing of AspergiUus spp. In vitro testing of aspergilli to antifungal agents is possible and should be done in any complicated case. Most isolates are susceptible to amphotericin B. A third of isolates of Aspergillus are susceptible to flucytosine in vitro. Occasional instances of antagonism between flucytosine and amphotericin have been seen, which, although not correlated with in vivo data, might discourage the use of flucytosine in an individual case. Antagonism of killing has been noted in vivo and in vitro between amphotericin B and ketoconazole. The vast majority (93%) of isolates are susceptible to itraconazole. The results of in vitro testing have not been correlated with in vivo outcome partly because of the profound importance of the site of disease and host group in determining outcome. Rifampin has no intrinsic activity against the Aspergilli. However, rifampin and amphotericin are frequently synergistic in vitro but the small amount of clinical data available does not appear to endorse this finding. There are problems with the use of fifampin and amphotericin for the treatment of aspergillosis in nonneutropenic patients. Rifampin is an extremely efficient inducer of the P450 enzyme system; in transplant patients this may induce the metabolism of both corticosteroids and cyclosporin and thereby lead to unexpected rejection episodes. If rifampin is used in the initial treatment regimen and the regimen subsequently fails, its use has ©1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

precluded the use of itraconazole because of the extremely profound interaction---itraconazole serum concentrations are lowered to zero---between these two agents. It is for these reasons that rifampin should be reserved for resistant cases of aspergillosis rather than used as part of empirical therapy. These comments of course apply also to patients in whom rifampin is given for other reasons, eg, the presumptive treatment of tuberculosis in immunocompromised patients.

Itraconazole The use of itraconazole for the treatment of invasive aspergillosis requires some comment. It is a drug that has an extremely long half-life, 25-40 h in normal volunteers. Without a loading dose, it take approximately 2 weeks to reach steady state serum concentrations and probably longer to reach maximum tissue concentrations. This length of time may not be inappropriate in relatively nonimmunocompromised patients, but in the context of life-threatening aspergillosis a loading dose should be given. A dose of 200 mg itraconazole t.i.d, for 4 or 5 days achieves steady state serum concentrations in 6-7 days. However, there is another problem with the use of itraconazole: the extremely variable interpatient variation. Serum concentrations of patients taking 400 mg/kg/day (which is the minimum dose that should be used for invasive aspergillosis) can vary from less than 1 to as much as 25 lag/ml (bioassay--bioassay measurements are superior to HPLC because they also measure the activity of the major bioactive metabolite). Serum concentrations tend to be lower in AIDS patients and in patients immediately following bone marrow transplantation. For these reasons, serum concentrations of itraconazole should always be measured in patients receiving therapy for invasive aspergillosis. Target serum concentrations of 5 pg/ml or above are likely to be nearly uniformly therapeutic, even in severely immunocompromised individuals;

68 Infectious Diseases Newsletter 10(8) August 1991 Table 1. Specific Treatment Recommendations for Invasive Aspergillosis as of Early 1991 Disease Site

ttost Group Neutmpenia, especially in leukemics; bone marrow transplant

AB 1 mg/kg/day with flucytosineb; consider surgical resection and/or itraconazole if no improvementc

Lung

Heart, kidney, liver transplant, and all others

AB 0.07 mg/kg/day with or without flucytosine if no improvement initially, or itraconazoleb,c

Lung (chronic necrotizing pulmonary aspergillosis) Trachea/bronchus

Corticosteroids, diabetes, etc.

Itraconazolec, or AB 0.7 mg/kg/day if no improvement

Lung, heart-lung transplant, AIDS

Itraconazolec

Brain

All groups

AB 1 mg/kg/day with flucytosineb

Sinuses

Nonimmunocompromised

Surgery only, unless bone or mucosa involvement demonstrated, then itraconazolec

Sinuses Bone Endocarditis

Neutropenia, bone marrow transplant All groups

AB 0.8-1 mg/kg/day, or liposomal AB

Lung

All groups

Treatment Recommendationsa

AB 0.7 mg/kg/day or itraconazolec and surgical debfidement AB 1 mg/kg/day, possibly with flucytosineb and valve replacement

aAB = arnphotericinB. bIt is importantto measureflucytosineserumconcentrationsto avoidtoxicity. ¢It is impoaantto measureitraconazoleserumconcentrationsto ensuretherapeuticconcentrations. lower concentrations may be efficacious in less severely immunocompromised patients.

Combination Therapy The small amount o f data presently available limits comment on combination therapy with itraconazole and amphotericin, itraconazole and flucytosine, or all three compounds together. Some failures have been reported with the combination of itraconazole and amphotericin or with all three compounds together, but those failures have been in neutropenic patients treated for very short periods. In vitro testing on a small number o f isolates found no evidence of antagonism between amphotericin and itraconazole. In view o f the negative interaction o f ketoconazole and amphotericin in fungicidal activity, caution is advised in the use o f amphotericin and itraconazole combination therapy until further data are available. Optimizing the use o f one agent or the other seems preferable to combination therapy at this time.

Lipid Complex Amphoteriein Another major development in this field is the development of lipid-complexed amphotericin or liposomal amphotericin. There are many

preparations being studied, each using different packaging fipids. Each commercially prepared preparation will have different biological properties and it is not possible to generalize from the efficacy and toxicity o f one to another. Each will have to be judged on its merits. It is already clear that Squibb and Vestar products are less toxic than amphotericin B and allow administration o f daily doses as high as 5 mg/kg. Little efficacy data

are available at the present time: however, even efficacy rates equivalent to conventional amphotericin with lower toxicity would be preferable, and the data on these new preparations is eagerly awaited. The specific recommendations given above have been compiled in a table (Fable 1) for the major sites of disease and host groups. Much less data are available for other sites of disease and other host groups, and it is

Table 2. Indications for Surgery in Invasive Aspergillosis Disease Process Essential for management

Operative Procedures

Endocarditis

Valve replacement

Endophthalmitis Hemoptysis in pulmonary disease

Vitrectomy and AmB instillation Resection of nodules

Sinusistis in normal host

Drainage and aeration of affected sinuses

Epidural abscess

Decompression of spinal cord

Bum wound aspergillosis

Radical debridement/amputation

Peritonitis

Removal of catheter

Desirable for management Osteomyelitis Extensive pleural disease Possibly helpful, but limited data Cerebral aspergillosis lnvasive external otitis ©1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

Debridement with immediate bone grafting, if appropriate Decortication

Diagnostic and therapeutic resection Debridement

69 Infectious Diseases Newsletter 10(8) August 1991 Table 3. Continuing Major Problems in the Treatment of Invasive Aspergillosis Host Group Disease Site

Problem

All patients with persistent neutropenia have died of invasive aspergillosis Recurrent aspergillosis (often fatal) during further chemotherapy or bone marrow transplantation I. High incidence of fatal relapse after initial therapy 2. Hemorrhageafter surgery

Neutropenia Leukemia, lymphoma

Any site Lung especially

Cancer, neutropenia

Sinuses

Leukemia AIIogeneicbone marrow transplant All All, especially diabetes

Lung Lung Brain Kidney

Massive unheralded pulmonaryhemorrhage as neutrophil recovery occurs Mortality exceeds 94% despite best available therapy Mortality near 100%

Chronic granulomatousdisease

Lung, bone especially Endocarditis Skin

High incidenceof relapse

All, especially after valve replacement Bums

therefore not appropriate to make specific recommendations in an article of this type for these situations; individual judgment is called for, possibly with the assistance of expert advice. Surgical T r e a t m e n t There are numerous instances in which surgical management o f invasive aspergillosis is appropriate and may be essential, eg, endocarditis and endophthalmitis. These are summarized in Table 2. It is likely that in the future better antifungal drugs will alter the present indications for surgery.

Conclusions As can be seen from this brief survey of the treatment of invasive aspergillosis, there is clearly a long way to go in improving our present treatment strate-

Medical treatment often fails; nephrectomymay cure but often bilateral disease Surgery essential for cure but diagnosis often difficult and delayed Medical therapy apparently ineffective, often requiring amputation

gies and options. The mortality remains high. Recommendations offered for treatment are in all cases based on open studies, often a summation of several case reports. No successful randomized clinical trials of invasive aspergillosis have been done. The first multicenter trial of invasive aspergillosis is presently nearing completion, having been coordinated by the NIAID Mycoses Study Group. The most problematic management issues in the treatment of invasive aspergillosis are outlined in Table 3. It will probably be many years before we have even partial solutions for these problems. Expert advice should be sought for these clinical situations because new data is accruing rapidly.

Eur J Clin Microbiol Infect Dis 8:413437, 1989. Dupont B: Itraconazole therapy in aspergillosis" Study in 49 patients. J Am Acad Dermatol 23:607-614, 1990. Denning DW, Follansbee S, Scolaro M, et at: Pulmonary aspergillosis in AIDS. N Engl J Med 324:654-662, 1991. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis. Review of 2,121 published cases. Rev Infect Dis 12:1147-1201, 1990. Viviani MA, Tortorano AM, Langer M, et al: Experience with itraconazole in cryptococcosis and aspergillosis. J Infect 18:151-165, 1989. Weber RS, Lopez-Berestein G: Treatment of invasive Aspergillus sinusitis with liposomal-amphotericin B. Laryngoscope 97:937-941, 1987.

Bibliography

Address correspondence to DavidW. Denning, Regional Deparlmentof Infectious Diseases and Tropical Medicine (Universityof Manchester), Monsall Hospital, Newton Heath, Manchester MI0 8WR, UK.

Bodey GP, Vartivarian S: Aspergillosis.

Echocardiography in the Diagnosis and Management of Infective Endocarditis R. Lee Jobe, MD, and Benjamin F. Byrd, III, MD Division of Cardiology, Vanderbilt University School of Medicine, Nashville, Tennessee

The past decade has seen an improvement in the prognosis of patients with infective endocarditis, mainly as a result of more effective antimicrobial

therapy, earlier diagnosis and detection of complications, and earlier surgical intervention in patients with complications. The diagnosis o f infec© 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

five endocarditis is usually made in the setting o f positive blood cultures and a compatible clinical picture that includes fever, a new regurgitant mur-