An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis

PURPOSE: In an attempt to decrease the risk for reactivation of life-threatening invasive aspergillosis (IA) during subsequent myelosuppression in patients with previously diagnosed IA who were receiving antileukemic treatment, we evaluated the role of intensive antifungal therapy with amphotericin B and 5-fluorocytosine administered prophylactically throughout the antileukemic regimen and induced granulocytopenia to prevent IA reactivation without compromising the intensive chemotherapy. PATIENTS and METHODS: During a 30-month period, 10 patients with acute myelogenous leukemia and primary IA developing during initial antileukemia induction therapy and severe granulocytopenia (less than 100/mm3) underwent 14 subsequent courses of intensive marrow aplasia-producing chemotherapy during early complete remission or at leukemia relapse. All patients had evidence of ongoing IA healing by lung computerized tomography (CT) prior to reinstitution of intensive chemotherapy. Nine patients receiving 13 chemotherapy courses also received aggressive prophylactic anti-IA therapy with amphotericin B (1.0 mg/kg/day) and 5-fluorocytosine beginning at least 48 hours prior to antileukemia therapy institution and continued until the time of granulocyte recovery. RESULTS: All nine patients receiving aggressive antifungal therapy survived without clinical evidence of IA reactivation. Transient radiographic evidence of IA reactivation during granulocytopenia was detected by lung CT during two of the 13 chemotherapy courses. In contrast, the patient who did not receive anti-IA prophylaxis had both clinical and radiographic evidence of IA reactivation during severe granulocytopenia and died. Anti-IA prophylaxis was achieved without irreversible nephrotoxicity, prolonged marrow suppression, alteration of antileukemia treatment, or negative impact on clinical outcome relative to acute leukemia. CONCLUSION: This approach of antifungal prophylaxis in adults with acute leukemia and documented primary IA occurring during initial induction chemotherapy has been successful in preventing clinically significant IA reactivation during subsequent granulocytopenic courses, and allows for administration of additional intensive antileukemia therapy.     

Candida and Aspergillus infections in immunocompromised patients: an overview

Infection is a major cause of morbidity and mortality in granulocytopenic patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia in patients with cancer, the risk of disseminated fungal infection has increased. Although Candida and Aspergillus species are known to be the most common fungal pathogens responsible for disseminated infection, diagnosis of such infection may be difficult. The use of empiric amphotericin B for presumed disseminated candida infection may reduce morbidity caused by this fungal pathogen; moreover, amphotericin B remains the agent of choice for established candida infection, although fluconazole shows promise. The addition of flucytosine may enhance the efficacy of amphotericin B against Candida. Aspergillus infection is more difficult to treat. Early recognition of invasive aspergillosis and use of high-dose amphotericin B (1.0-1.5 mg/[kg.d]) alone or in combination with flucytosine may reduce associated mortality. More active, less toxic antifungal agents are needed to improve the efficacy of treatment and prophylaxis of disseminated fungal infection.     

Invasive pulmonary aspergillosis in patients with neoplastic diseases

Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in granulocytopenic patients. The purpose of this article is to review the current understanding of the microbiology, hospital epidemiology, clinical manifestations, diagnosis, prevention, and treatment of invasive pulmonary aspergillosis. Aspergillus conidia (spores) are inhaled from environmental sources into the paranasal sinuses and lower respiratory tract. Persistent fever, pulmonary infiltrates, and pleuritic pain in granulocytopenic patients receiving antibacterial antibiotics is a common manifestation of invasive pulmonary aspergillosis. Computerized tomographic scans of the chest often reveal characteristic peripheral nodules that also may progress to characteristic cavitary lesions. Hemoptysis may develop due either to hemorrhagic infarction during granulocytopenia or to the rupture of mycotic aneurysms during recovery from granulocytopenia. Aspergillus organisms may extend locally from the lung to involve other thoracic structures, including the heart and chest wall, and may disseminate to extrapulmonary sites, such as the brain, where focal neurological deficits ensue. Early diagnosis of invasive pulmonary aspergillosis may be difficult. Isolation of Aspergillus organisms from respiratory secretions of a persistently febrile granulocytopenic patient is usually indicative of invasive pulmonary aspergillosis and should not be dismissed as a contaminant or saprophyte. Amphotericin B is the treatment of choice; however, high dosages (1.0 to 1.5 mg/kg/day) are often necessary. Aspergillosis may develop in granulocytopenic patients who are already receiving empirical amphotericin B in lower doses (0.5 to 0.6 mg/kg/day). It is hoped that further investigation directed toward an understanding of pathogenesis, improving diagnostic methodology, and developing new therapeutic and preventive strategies will improve the outcome of this life-threatening infection.     

Intranasal amphotericin B reduces the frequency of invasive aspergillosis in neutropenic patients

PURPOSE: To retrospectively study the prophylaxis of invasive aspergillosis in neutropenic patients and to relate the frequency of this fungal disease to any causal or modifying factors that could be identified. PATIENTS AND METHODS: Between 1977 and 1988, 130 patients underwent 158 intensive treatment episodes to control acute leukemia, lymphoma, and aplastic anemia, and the frequency of complicating aspergillus infection was determined. RESULTS: Proven invasive aspergillus infections occurred in 22 cases, 12 of which were fatal. Invasive aspergillosis was suspected in a further 16 cases and all these patients recovered with amphotericin B treatment. Colonization by Aspergillus in the absence of clinically significant infection was seen in 31 treatment episodes. Invasive aspergillosis involved mainly the upper and lower respiratory tract and skin. Control of the infection was closely related to the control of the underlying disease, with subsequent return of normal marrow function and resolution of neutropenia. The incidence of aspergillus infection has decreased dramatically since 1985, most probably due to the introduction of intranasal amphotericin B. This occurred despite the persistence of aspergillus spores in the hematology ward air during the 1986 to 1988 period. CONCLUSION: Intranasal aerosolized amphotericin B may protect against invasive aspergillosis, even when neutropenic patients are cared for in conventional wards without HEPA filtration.     

Empiric therapy with amphotericin B in febrile granulocytopenic patients

The early diagnosis of invasive fungal infection in granulocytopenic patients remains unreliable. Granulocytopenic patients who are persistently or recurrently febrile despite therapy with appropriate antibacterial agents are at high risk for the development of such infection. Two randomized clinical trials demonstrated that the empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients decreased the frequency, morbidity, and mortality of invasive fungal infection; these effects were especially marked in profoundly granulocytopenic patients who were not receiving antifungal prophylaxis. Current studies continue to indicate that prompt empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients ensures earlier treatment of deep mycoses. The roles of newer antifungal triazole compounds and of liposomal and lipid complexes of amphotericin B in empiric antifungal therapy must be investigated further in thoughtfully designed, randomized clinical trials.     

Invasive pulmonary aspergillosis: identification of risk factors

Aspergillosis is the second most frequent fungal infection after candidiasis in teaching hospitals. Clinical manifestations of pulmonary aspergillosis range from asymptomatic colonization to disseminated disease. The aim of this study was to identify the risk factors associated with invasive pulmonary aspergillosis, in patients with positive pulmonary isolation of Aspergillus species. A review was undertaken of all clinical records with pulmonary isolation of Aspergillus species at Reina Sofia University Hospital from January 1995 to December 1998. Data collected were: age, gender, history of smoking, past medical history, such as chronic pulmonary disease, immunosuppression, granulocytopenia in the past 6 months and during the last admission, history of surgery including within the last year of the study period, number of hospital admissions and clinical evidence of invasive pulmonary aspergillosis. To investigate all the possible risk factors for invasive pulmonary aspergillosis, a multivariable logistic regression model was used. 132 patients with positive pulmonary isolation were identified, of which 42.4% had clinical evidence of invasive pulmonary aspergillosis. The independent factors significantly associated with invasive pulmonary aspergillosis were: granulocytopenia in the past 6 months, immunosuppression in the last admission and the number of hospital admissions within the past year. Patients with a history of granulocytopenia in the past 6 months and immunosuppression in the last admission are the high-risk group for invasive pulmonary aspergillosis. However, invasive pulmonary aspergillosis can also occur in mild granulocytopenic or even immunocompetent patients.     

Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation

The management of invasive aspergillosis in patients with hematological malignancies remains controversial. A major problem is how to manage patients who had invasive aspergillosis during remission induction and consolidation therapy and then undergo SCT. Indeed in these patients the mortality rate related to invasive aspergillosis recurrence remains unacceptably high. We report two cases of patients who underwent remission induction for AML, developed invasive aspergillosis during antifungal prophylaxis with itraconazole, failed amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voriconazole prophylaxis without reactivation of invasive aspergillosis.     

Aspergillus species colonization and invasive disease in patients with AIDS.

Invasive aspergillosis is an uncommon infectious complication in patients with AIDS. Of the 972 patients with AIDS who were observed at our institution over a 10-year period, Aspergillus species were isolated from the respiratory sites of 45 patients before death. Invasive aspergillosis was documented at autopsy in four of these patients and was strongly suspected in an additional patient on whom an autopsy was not performed. A fifth case was documented at autopsy (no antemortem respiratory sample was obtained from this patient). Traditional risk factors for the development of invasive disease (neutropenia, hematologic malignancy, and/or corticosteroid use) were present in all of our patients with invasive aspergillosis. A review of the literature revealed reports of an additional 13 cases of invasive aspergillosis in patients with AIDS. Therapy with amphotericin B should be considered for neutropenic patients with AIDS who have pneumonia of uncertain etiology and from whom Aspergillus species have been isolated from a respiratory specimen.     

Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing multiple courses of intensive chemotherapy

The records of 40 consecutive patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) were reviewed to determine the risk of recurrent fungal pneumonia during multiple episodes of chemotherapy-induced granulocytopenia. Fungal pneumonias were diagnosed as proven or probable using defined pathologic, microbiologic, radiologic, and clinical criteria. Sixteen patients died without a complete remission; of these, all 11 who underwent autopsy were found to have invasive fungal pneumonia. The 24 patients who achieved a complete remission received one to nine (median, four) additional courses of intensive chemotherapy for remission consolidation and/or relapse, and experienced 132 episodes of severe granulocytopenia. Seven patients never had a pulmonary infection despite 34 granulocytopenic episodes. However, fungal pneumonia complicated 32 (33 percent) of 98 granulocytopenic episodes in the other 17 patients. Fifteen of the patients who achieved a complete remission had at least one episode of fungal pneumonia; 12 received further chemotherapy, and nine (75 percent) of these had a subsequent fungal pneumonia. In all, 17 (52 percent) of 33 subsequent granulocytopenic episodes experienced by patients with a prior fungal pneumonia were complicated by another fungal pneumonia. All four patients with a probable fungal pneumonia diagnosed antemortem who subsequently underwent autopsy were found to have invasive fungal disease. It would appear that patients with ANLL who have had one episode of fungal pneumonia are at high risk for recurrence during subsequent episodes of granulocytopenia. Empiric or even prophylactic amphotericin B therapy may be warranted for such patients.     

Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group

A review of representative cases of invasive aspergillosis was conducted to describe current treatment practices and outcomes. Eighty-nine physicians experienced with aspergillosis completed case forms on 595 patients with proven or probable invasive aspergillosis diagnosed using modifications of the Mycoses Study Group criteria. Pulmonary disease was present in 56%, with disseminated infection in 19%. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but patients had a variety of underlying conditions including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%). Overall, high antifungal failure rates occurred (36%), and complete antifungal responses were noted in only 27%. Treatment practices revealed that amphotericin B alone (187 patients) was used in most severely immunosuppressed patients while itraconazole alone (58 patients) or sequential amphotericin B followed by itraconazole (93 patients) was used in patients who were less immunosuppressed than patients receiving amphotericin B alone. Response rate for patients receiving amphotericin B alone was poor, with complete responses noted in only 25% and death due to or with aspergillosis in 65%. In contrast, patients receiving itraconazole alone or following amphotericin B had death due to or with Aspergillus in 26% and 36%, respectively. These results confirm that mortality from invasive aspergillosis in severely immunosuppressed patients remains high even with standard amphotericin B. Improved responses were seen in the less immunosuppressed patients receiving sequential amphotericin B followed by itraconazole and those receiving itraconazole alone. New approaches and new therapies are needed to improve the outcome of invasive aspergillosis in high-risk patients.     

Invasive aspergillosis in patients with AIDS.

Invasive aspergillosis is a rare complication of AIDS. We discuss the cases of 18 patients with AIDS and invasive aspergillosis who were identified at our institution and 19 patients who are described in the literature. Twenty-one patients were either homosexual or bisexual, eight were intravenous drug users, three were hemophiliacs, two attributed their disease to a heterosexual contact, and one was a transfusion recipient; risk factors for AIDS were unknown for two patients. Twenty-eight of the 37 patients had pulmonary aspergillosis; for 18 of these 28, the lung was the sole site of disease. Aspergillosis involved the brain in 12 cases, the heart in five cases, and the kidney, sinuses, or skin in six other cases. Eleven patients had multiple sites of disease, and eight patients had extrapulmonary disease alone. Possible risk factors for aspergillosis included leukopenia (7 patients, of whom 5 were also neutropenic) and use of corticosteroids (8 patients), alcohol (6 patients), broad-spectrum antibiotics (5 patients), and antineoplastic agents (4 patients); 14 patients had no identifiable risk. Death was the usual outcome, despite treatment of patients with amphotericin B. In cases of AIDS and invasive aspergillosis, early diagnosis may lead to improved outcome.     

Zygomycosis in the 1990s in a tertiary-care cancer center.

Twenty-four patients with cancer met predetermined criteria for a diagnosis of zygomycosis over a 10-year period at our institution. All had hematologic malignancy, and most had either neutropenia or steroid use as a risk factor. Pulmonary involvement mimicking invasive aspergillosis was the most common presentation, and dissemination was seen in 58% of patients on whom autopsies were performed. Three-fourths of the patients with pulmonary zygomycosis had pathogenic microorganisms other than zygomycetes isolated from respiratory specimens. The sensitivity of cultures in detecting zygomycetes from respiratory specimens was low. A culture positive for zygomycetes was typically a preterminal finding in the fatal, acute cases. Two-thirds of the patients died. Favorable outcome seemed to correlate with lack of pulmonary involvement, surgical debridement, neutrophil recovery, and a cumulative total amphotericin B dose of 2000 mg. Therapy with high-dose amphotericin B, combined with aggressive surgery and immune reconstitution, offers the best chance for survival of cancer patients with zygomycosis.     

The role of fluconazole in the early treatment and prophylaxis of experimental invasive aspergillosis

The efficacy of fluconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with fluconazole at 60 or 120 mg/kg/day was begun 24 h after lethal challenge and compared to that with amphotericin B at 1.5 mg/kg/day. Fluconazole reduced mortality compared with that in untreated controls and at 120 mg/kg/day reduced the tissue burden of A. fumigatus 10- to 100-fold in liver, kidney, and lung. However, amphotericin B was more effective in sterilizing tissues. Both fluconazole and amphotericin B dramatically decreased or eliminated circulating aspergillus antigen. Prophylaxis with fluconazole, begun 48 h before sublethal challenge, sterilized liver and kidney tissues and significantly reduced the tissue burden in lung. Early treatment with fluconazole reduced mortality and reduced antigenemia but did not sterilize tissues. Fluconazole prophylaxis at these doses prevented dissemination of invasive aspergillosis. Fluconazole was shown to have activity in the early treatment and prophylaxis of experimental invasive aspergillosis.     

Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters

Between September 1993 and December 1993, during extensive hospital construction and indoor renovation, a nosocomial outbreak of invasive pulmonary aspergillosis occurred in acute leukemia patients treated in a regular ward that has only natural ventilation. The observed infection rate was 50%. Chemoprophylaxis with intravenous continuous low-dose amphotericin B was then instituted as a preventive measure. During the next 18 months invasive pulmonary aspergillosis developed in 43% of acute leukemia patients. After that period a new hematology ward was opened with an air filtration system through high-efficiency particulate air filtration (HEPA) filters, and a bone marrow transplantation program was started on the hematology service. During the following three years, none of the acute leukemia or bone marrow transplantation patients who were hospitalized exclusively in the hematology ward developed invasive pulmonary aspergillosis, although 29% of acute leukemia patients who were housed in a regular ward, because of shortage of space in the new facility, still contracted invasive pulmonary aspergillosis. Overall, 31 patients were diagnosed with invasive pulmonary aspergillosis during almost five years: 74% of patients recovered from invasive pulmonary aspergillosis, and 42% are long-term survivors; 26% of patients died of resistant leukemia with aspergillosis, but no one died of invasive pulmonary aspergillosis alone. In conclusion, during an on-going construction period, an extremely high incidence rate of invasive pulmonary aspergillosis in acute leukemia patients undergoing intensive chemotherapy was observed. Institution of low-dose intravenous amphotericin B prophylaxis marginally reduced the incidence rate of invasive pulmonary aspergillosis. Keeping patients in a special ward with air filtration through a HEPA system eliminated invasive pulmonary aspergillosis completely. Among patients who developed invasive pulmonary aspergillosis, early diagnosis and treatment are probably the explanation for the favorable outcome.     

Amphotericin B with and without itraconazole for invasive aspergillosis: A three-year retrospective study.

BACKGROUND: Treatment of invasive aspergillosis is frequently unsuccessful, so innovations in therapy are needed. Clinical studies demonstrate that itraconazole may be an effective alternative to amphotericin B. Itraconazole also has been combined with amphotericin B in animal models of aspergillosis, but this regimen produced antagonistic effects. OBJECTIVES: To determine the role of itraconazole in the adjunctive treatment of invasive aspergillosis. METHODS: A review was conducted of all patients with definite or probable aspergillosis from January 1995 to December 1997 who were treated with conventional amphotericin B alone or in combination with itraconazole. RESULTS: Of 21 patients, 10 received amphotericin B and 11 received the combination. The two groups of patients were comparable clinically at baseline (including similar mean APACHE III scores). Both groups received similar doses and days of amphotericin B treatment. Of the patients who received combination therapy, nine (82%) were cured or improved, and of those who received only amphotericin B, five (50%) were cured or improved. CONCLUSIONS: This study demonstrates that itraconazole and amphotericin B given together are not clinically antagonistic and that the promise of combination therapy for aspergillosis should be evaluated further in a randomized clinical trial.     

Low incidence of candidaemia among neutropenic patients treated for haematological diseases

Candida colonization and haematogenous infection were studied retrospectively in 277 patients with haematological diseases by reviewing the microbiological reports of fungal surveillance and blood cultures over a 4-year period. Most patients (83%) were colonized by Candida and in the majority (68%) the same Candida species was isolated from at least 2 body sites. However, candidaemia was diagnosed in only 3 patients. During the same period invasive aspergillosis was diagnosed in 7 patients. Possible causes for the low incidence of candidaemia were fluconazole prophylaxis, empirical amphotericin B and strict indication for antibacterial therapy.     

Aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in neutropenic cancer patients

To determine the value of aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis (IPA), we initiated a prospective randomized multicenter trial. The scheduled intent-to-treat interim analysis included 115 patients (30%) with prolonged neutropenia after chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia/high-grade non-Hodgkin's lymphoma, or solid tumors undergoing autologous stem cell transplantation. Sixty-five patients had been randomized to receive prophylactic aerosol amphotericin B inhalations at a dose of 10 mg twice daily (group A); for the remaining 50 patients no aerosol amphotericin B prophylaxis was used (group B). No serious side effects from amphotericin B inhalations occurred, but coughing (54%), bad taste (51%), and nausea (37%) caused early cessation of aerosol amphotericin B prophylaxis in 23% (15/65) of courses. In group A, the incidence of proven, probable, or possible IPA was 5% (3/65) as compared with 12% (6/50) in group B (p>0.05). Microbiologically documented bacterial pneumonias were observed in 5/65 (8%) patients in group A and in 1/50 (2%) patients in group B (p>0.05). Thus, no reduction in incidence of IPA from use of prophylactic aerosol amphotericin B inhalations was found in this interim analysis. As there were no serious side effects from aerosol amphotericin B prophylaxis, accrual in the study will continue for a total of 380 patients.     

Prophylaxis of invasive aspergillosis with voriconazole or caspofungin during building work in patients with acute leukemia

Background

Invasive aspergillosis is a common life-threatening infection in patients with acute leukemia. The presence of building work near to hospital wards in which these patients are cared for is an important risk factor for the development of invasive aspergillosis. This study assessed the impact of voriconazole or caspofungin prophylaxis in patients undergoing induction chemotherapy for acute leukemia in a hematology unit exposed to building work.

Design and Methods

This retrospective cohort study was carried out between June 2003 and January 2006 during which building work exposed patients to a persistently increased risk of invasive aspergillosis. This study compared the cumulative incidence of invasive aspergillosis in patients who did or did not receive primary antifungal prophylaxis. The diagnosis of invasive aspergillosis was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria.

Results

Two-hundred and fifty-seven patients (213 with acute myeloid leukemia, 44 with acute lymphocytic leukemia) were included. The mean age of the patients was 54 years and the mean duration of their neutropenia was 21 days. Eighty-eight received antifungal prophylaxis, most with voriconazole (n=74). The characteristics of the patients who did or did not receive prophylaxis were similar except that pulmonary antecedents (chronic bronchopulmonary disorders or active tobacco use) were more frequent in the prophylaxis group. Invasive aspergillosis was diagnosed in 21 patients (12%) in the non-prophylaxis group and four (4.5%) in the prophylaxis group (P=0.04). Pulmonary antecedents, neutropenia at diagnosis and acute myeloid leukemia with high-risk cytogenetics were positively correlated with invasive aspergillosis, whereas primary prophylaxis was negatively correlated. Survival was similar in both groups. No case of zygomycosis was observed. The 3-month mortality rate was 28% in patients with invasive aspergillosis.

Conclusions

This study suggests that antifungal prophylaxis with voriconazole could be useful in acute leukemia patients undergoing first remission-induction chemotherapy in settings in which there is a high-risk of invasive aspergillosis.     

Low incidence of invasive aspergillosis in allogeneic stem cell transplant recipients receiving amphotericin B inhalation prophylaxis

A. Nihtinen, V.‐J. Anttila, T. Ruutu, E. Juvonen, L. Volin. Low incidence of invasive aspergillosis in allogeneic stem cell transplant recipients receiving amphotericin B inhalation prophylaxis.
Transpl Infect Dis 2011. All rights reserved Abstract: In this retrospective study we evaluated the impact of amphotericin B (AmB) deoxycholate inhalation prophylaxis on invasive aspergillosis (IA) in 611 allogeneic stem cell transplant (alloSCT) recipients and their tolerance of the inhalations. The inhalations were not used in 1996–2000 (Period I). In 2001–2005 (Period II) all patients with acute graft‐versus‐host disease treated with high‐dose methylprednisolone used the inhalation prophylaxis with a dose of 25 mg daily. No systemic antifungal prophylaxis was routinely used during the study period. IA was detected in 17 (13 proven, 4 probable) out of 257 (6.6%) patients transplanted in Period I and in 9 (6 proven, 3 probable) out of 354 (2.5%) patients transplanted in Period II (P=0.007). The median time to the diagnosis of IA was 95 days and 155 days post transplant in the 2 periods (P=0.225). The mortality of the patients with IA was 94.1% and 66.6% in Period I and Period II. The median duration of AmB inhalation prophylaxis was 84 days. Breakthrough IA was detected in 1 of the 111 (1%) patients during the prophylaxis. No discontinuation of prophylaxis due to side effects was recorded. Overall, with a median follow‐up of 3.5 and 4.6 years, 42.4% and 59% of the patients were alive in Period I and Period II, respectively (P=0.001). In conclusion, the incidence of IA fell during the AmB inhalation prophylaxis, and the inhalations were well tolerated. Mortality of patients with IA was high. The overall survival of patients was significantly higher in Period II, indicating the advances made in SCT therapy over the 10‐year period.     

Approaching the controversies in antibacterial management of cancer patients

The principles for management of infectious complications in cancer patients are continuing to evolve. The critical element includes the prompt institution of broad-spectrum antibiotic(s) empirically when granulocytopenic patients become febrile and continuation and modification of the regimen in patients with persistent fever and granulocytopenia. The view is presented that antibiotics provide systemic prophylaxis as well as therapy in persistently granulocytopenic patients and that they should be continued until all signs of infection have cleared or the granulocyte count has recovered. Such aggressive therapy, supplemented by continued evaluation and monitoring of the patient, can significantly reduce infection-relation morbidity and mortality.