Aztreonam for febrile neutropenia in patients with beta-lactam allergy.

BACKGROUND: Beta-lactam antibiotics are the mainstay of empiric therapy for febrile neutropenia. Aztreonam may benefit certain patients because of a lack of cross-hypersensitivity to penicillins and cephalosporins. This is the first study, to our knowledge, to evaluate the efficacy of aztreonam as monotherapy for febrile neutropenia (FN). METHODS: Our study was a single-center retrospective chart review of patients ≥18 years of age receiving aztreonam for the treatment of FN. Primary outcome was treatment success of aztreonam monotherapy. Secondary analyses included need for modification to antimicrobial therapy, patients transitioned to aztreonam from another empiric regimen, and patients receiving aztreonam in combination with other antibacterial agents. RESULTS: In patients prescribed aztreonam for first fever, 11 of 27 (40.7%) patients who received aztreonam alone and 19 of 40 (47.5%) given aztreonam plus another antibiotic responded within 96 h (P = 0.62). Twenty-four (89%) patients prescribed aztreonam monotherapy were alive when FN resolved or treatment ended. Infectious mortality was low (1 patient, 3.7%). In patients prescribed aztreonam monotherapy following an adverse reaction to cefepime, 6 of 11 (54.5%) responded within 96 h of initiating aztreonam; 10 (91%) were alive when FN resolved or treatment ended. CONCLUSION: Aztreonam monotherapy may be acceptable for use in patients with a history of beta-lactam hypersensitivity or following an adverse reaction with another beta-lactam. Further studies are needed to compare efficacy of aztreonam monotherapy with other therapies for the treatment of FN.

Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis.

The term "aspergillosis" comprises several categories of infection: invasive aspergillosis; chronic necrotizing aspergillosis; aspergilloma, or fungus ball; and allergic bronchopulmonary aspergillosis. In 24 medical centers, we examined the impact of a culture positive for Aspergillus species on the diagnosis, risk factors, management, and outcome associated with these diseases. Most Aspergillus culture isolates from nonsterile body sites do not represent disease. However, for high-risk patients, such as allogeneic bone marrow transplant recipients (60%), persons with hematologic cancer (50%), and those with signs of neutropenia (60%) or malnutrition (30%), a positive culture result is associated with invasive disease. When such risk factors as human immunodeficiency virus infection (20%), solid-organ transplantation (20%), corticosteroid use (20%), or an underlying pulmonary disease (10%) are associated with a positive culture result, clinical judgment and better diagnostic tests are necessary. The management of invasive aspergillosis remains suboptimal: only 38% of patients are alive 3 months after diagnosis. Chronic necrotizing aspergillosis, aspergilloma, and allergic bronchopulmonary aspergillosis have variable management strategies and better short-term outcomes.

Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses.

Studies of invasive fungal infections have been and remain difficult to implement. Randomized clinical trials of fungal infections are especially slow and expensive to perform because it is difficult to identify eligible patients in a timely fashion, to prove the presence of the fungal infection in an unequivocal fashion, and to evaluate outcome in a convincing fashion. Because of these challenges, licensing decisions for antifungal agents have to date depended heavily on historical control comparisons and secondary advantages of the new agent. Although the availability of newer and potentially more effective agents makes these approaches less desirable, the fundamental difficulties of trials of invasive fungal infections have not changed. Therefore, there is a need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses, and this article summarizes the possible strategies in this area.

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.

Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases.

The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy. All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02). Among 162 patients with serum creatinine values > or = 2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P < or = .0003). Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis. Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection). These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy.

Nephrotoxicity of high-dose ifosfamide/carboplatin/etoposide in adults undergoing autologous stem cell transplantation.

The objective of this study was to evaluate nephrotoxicity in adult patients treated with high-dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation. We conducted a retrospective analysis of clinical and laboratory data from 131 patients with various malignancies who received treatment with escalating doses of ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation as part of a phase I/II therapeutic trial. Abnormalities in glomerular filtration were evaluated by measuring peak creatinine levels and tubular dysfunction by the lowest recorded serum levels of potassium, magnesium, and bicarbonate, at different time periods after administration of ifosfamide, carboplatin, and etoposide, and after autologous stem cell transplantation. For the entire group of 131 patients, peak creatinine levels were > 1.5 mg/dL but < 3.0 mg/dL in 37% and levels were > 3.0 mg/dL in 11% at some time during their hospital stay. At the time of discharge, creatinine levels were 1.6 mg/dL to 3.0 mg/dL in 25% of patients and were > 3 mg/dL in 5%. Immediately after high-dose therapy, peak creatinine levels were significantly higher in patients receiving higher doses of ifosfamide compared to those receiving lower doses (P < 0.00001) and those receiving intermediate doses (P < 0.005). There was a dramatic decrease in serum bicarbonate, potassium, and magnesium levels immediately after chemotherapy, and they remained significantly decreased throughout the patient's hospital stay, despite massive replacement efforts (P ranging between < 0.008 and < 0.001). This is the largest adult population study documenting the incidence and severity of ifosfamide/carboplatin/etoposide-associated acute nephrotoxicity. Renal dysfunction was dose related and reversible in the majority of patients.

Nocardiosis after bone marrow transplantation: a retrospective study.

To evaluate the spectrum of nocardiosis after marrow transplantation, we reviewed the medical records of 27 patients with nocardiosis who were treated at three centers, and we reviewed the findings of three cases reported in the literature. Nocardial involvement was defined as invasive nocardiosis (n = 25), colonization (n = 4), or contamination (n = 1). The median time to the diagnosis of nocardiosis after marrow transplantation was 210 days. Nocardia asteroides complex accounted for 96% of isolates. All 25 invasive infections occurred in allogeneic marrow recipients. Ten (40%) of 25 patients with invasive nocardiosis were receiving double-strength oral trimethoprimsulfamethoxazole twice weekly as prophylaxis for Pneumocystis carinii pneumonia. Treatment regimens for nocardiosis included sulfonamides; synergistic agents were also often added. The overall survival rate at 6 years was 34%; survival from the infection itself was 84%. Two of four nocardiosis-related deaths also involved other pathogens. The incidence of nocardiosis among allogeneic marrow recipients averaged 0.3% over 25 years. We conclude that nocardiosis is a rare infection that occurs later after marrow transplantation than other infections and that is marginally associated with increased mortality among long-term survivors of allogeneic marrow transplantation.

Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis.

To assess the efficacy and safety of amphotericin B colloidal dispersion (ABCD), 82 patients with proven or probable aspergillosis who were treated in clinical trials with ABCD were compared retrospectively with 261 patients with aspergillosis who were treated with amphotericin B at six cancer or transplant centers from January 1990 to June 1994. The groups were balanced in terms of underlying disease; ABCD recipients were younger and more likely to have preexisting renal insufficiency than were amphotericin B recipients (40.7% vs. 8.7%, respectively), and amphotericin B recipients were more likely to be neutropenic at baseline than were ABCD recipients (42.5% vs. 15.9%, respectively). Response rates (48.8%) and survival rates (50%) among ABCD-treated patients were higher than those (23.4% and 28.4%, respectively) among amphotericin B-treated patients (P < .001 for both comparisons). Renal dysfunction developed less frequently in ABCD recipients than in amphotericin B recipients (8.2% vs. 43.1%, respectively; P < .001). Multivariate analysis revealed that treatment group was the best predictor of response, mortality, and nephrotoxicity (ABCD: relative risk [RR] = 3.00, P = .002; RR = 0.35, P < .001; and RR = 0.13, P = .001; respectively). This retrospective study suggests that in the treatment of aspergillosis ABCD causes fewer nephrotoxic effects than amphotericin B and the efficacy of ABCD is at least comparable with that of amphotericin B.

Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC-IE): a novel, intensive induction chemotherapy regimen for patients with high-risk multiple myeloma.

We evaluated toxicities and responses to a novel, dose intensive and time sequenced, chemotherapy programme (DC-IE) in 45 patients with high-risk myeloma. DC-IE consisted of: dexamethasone (days 1-4); cyclophosphamide (day 5); idarubicin and etoposide (days 8-10). Complete response (CR) was achieved in four patients, six patients achieved near complete responses (nCR) and 21 patients achieved a partial remission (PR). Overall response rate was 76% (CI 56-94%) for newly diagnosed patients (n = 21) and 62% (CI 36-81%) for relapsed/refractory patients (n = 24). Toxicities were limited to myelosuppression; two patients died of sepsis during neutropenia (4%). DC-IE is active and tolerable for high-risk multiple myeloma, including patients with relapsed or refractory disease to anthracycline containing regimens.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

Identification of an amphotericin B resistant strain of Candida albicans using a rapid 3H-glucose incorporation microassay.

Using a 3H-glucose incorporation assay, antifungal sensitivity testing undertaken on an isolate of Candida albicans cultured from the blood of a bone marrow transplant patient documented resistance to amphotericin B but sensitivity to fluconazole and itraconazole. Information obtained from in vitro antifungal sensitivity testing can be used to direct in vivo antifungal therapy. Widespread application of standardized in vitro antifungal sensitivity testing is needed.

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients.

Invasive fungal infections, including disseminated candidiasis and invasive pulmonary aspergillosis, are important causes of morbidity and mortality in neutropenic patients. The recent development of fluconazole, itraconazole, lipid formulations of amphotericin B, and recombinant cytokines have expanded our therapeutic armamentarium. Clinical trials have elucidated new strategies for utilizing these compounds in the prevention and treatment of opportunistic mycoses. The population of more severely immunocompromised patients, however, continues to expand and the spectrum of drug-resistant fungi, including but not limited to Candida spp, Fusarium spp, Zygomycetes, and dematiaceous moulds, continues to evolve, thus presenting new challenges to recent therapeutic advances. Development of new antifungal chemotherapeutic agents and novel approaches for augmentation of host response will be required to meet these new mycologic challenges.

Lipid formulations of amphotericin B: recent progress and future directions.

Three lipid formulations of amphotericin B are now either marketed for clinical use or undergoing further study before they can be approved in various countries worldwide. Amphotericin B lipid complex (ABLC; Abelcet, Liposome Company, Princeton, NJ) is a concentration of ribbonlike structures of a bilayered membrane formed by combining a 7:3 molar ratio of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with amphotericin B. Amphotericin B colloidal dispersion (ABCD; Amphocii, Sequus Pharmaceuticals, Menlo Park, CA) is composed of disklike structures of cholesteryl sulfate complexed with amphotericin B. AmBisome (Nexstar, San Dimas, CA), the only true liposomal amphotericin B, consists of small unilamellar vesicles made up of a bilayer membrane of hydrogenated soy phosphatidylcholine and distearoylphosphatidylglycerol stabilized with cholesterol in a 2:0.8:1 ratio combined with amphotericin B. All of the preparations appear to be preferentially accumulated in organs of the reticuloendothelial system, as opposed to the kidney. In vivo animal models as well as current clinical experience suggest that use of these formulations results in overall improvement in the therapeutic index. Patients with life-threatening mycosis for whom therapy has failed or who are intolerant to therapy with amphotericin B deoxycholate have been successfully treated with these formulations. However, further study is warranted to help clarify the usefulness of each of the lipid formulations as first-line therapy for documented or suspected invasive fungal infections.

High-dose ifosfamide/carboplatin/etoposide: maximum tolerable doses, toxicities, and hematopoietic recovery after autologous stem cell reinfusion.

We treated 115 patients in a phase I/II dose-escalation study of ifosfamide/carboplatin/etoposide (ICE) followed by autologous stem cell rescue. Patients treated had a variety of diagnoses, including breast cancer (high-risk stage II disease with eight or more positive nodes, stage III disease, and responsive metastatic disease), non-Hodgkin's lymphoma, Hodgkin's disease, acute leukemia in first remission, and various solid tumors that were responsive to induction therapy. Patients received autologous bone marrow stem cells or peripheral blood stem cells primed by one of several methods. The maximum tolerated dose of ICE was determined to be ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2 when administered as a 6-day regimen. The dose-limiting toxicities included acute renal failure, severe central nervous system toxicity, and "leaky capillary syndrome" with hypoalbuminemia, profound fluid overload, and pulmonary insufficiency. Analysis of hematologic recovery based on stem cell source and influence of hematopoietic growth factor administration was undertaken. Hematopoietic growth factor use significantly reduced neutrophil engraftment time for patients receiving bone marrow stem cells, with evidence of earlier recovery times for patients receiving granulocyte colony-stimulating factor compared with granulocyte-macrophage colony-stimulating factor. Neutrophil recovery times varied based on the source of stem cells used, with the earliest engraftment times seen for patients receiving peripheral blood stem cells primed with cyclophosphamide and granulocyte colony-stimulating factor. Platelet recovery times were not statistically different for any of the subsets. In conclusion, the maximum tolerated dose of ICE has been defined, and the source of stem cells and the use of hematopoietic growth factors influence hematopoietic recovery.

Ifosfamide, carboplatin, and etoposide: a new regimen with a broad spectrum of activity.

PURPOSE: To conduct a phase I/II evaluation of the combination of ifosfamide, carboplatin, and etoposide (ICE) to determine toxicity and activity in a variety of refractory malignancies. PATIENTS AND METHODS: Two hundred four patients, 13 to 64 years of age, with a variety of malignancies, including refractory breast cancer and Hodgkin's and non-Hodgkin's lymphoma, were treated with two cycles of ICE, consisting of intravenous ifosfamide 2 g/m2, carboplatin 400 mg/m2, and continuous infusion etoposide 600 mg/m2 administered in divided doses over 2 days. The regimen was repeated at approximately 28-day intervals. RESULTS: One hundred ninety-one patients (94%) received two cycles at full doses and were assessable for response and toxicity. Complete and partial responses were seen in breast cancer (20%, n = 93), non-Hodgkin's lymphoma (30%, n = 37), Hodgkin's disease (60%, n = 10), melanoma (9%, n = 11), a variety of sarcomas (20%, n = 10), and other malignancies (43%, n = 30). Myelosuppression was prominent, with significant neutropenia requiring frequent hospitalization for neutropenic fever, and thrombocytopenia and anemia requiring frequent platelet and RBC transfusions. However, the overall treatment-related mortality rate was only 3%. No other moderate to severe organ toxicity was seen at a frequency of greater than 1%. CONCLUSION: This regimen is active in a variety of refractory malignancies, with significant but tolerable hematologic toxicity. The addition of hematopoietic growth factors may allow further dose escalation.

Two novel high-dose treatment regimens for metastatic breast cancer--ifosfamide, carboplatin, plus etoposide and mitoxantrone plus thiotepa: outcomes and toxicities.

This report describes the results of two phase I/II dose escalation trials for the treatment of metastatic breast cancer. Successive groups of patients with metastatic breast cancer responsive to induction therapy following standard doses of chemotherapy were treated with escalating doses of ifosfamide (6,000 to 24,000 mg/m2), carboplatin (1,200 to 2,100 mg/m2), and etoposide (1,800 to 3,000 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2. Major nonhematologic toxicity consisted of mucositis and enteritis, and the dose-limiting toxicities were central nervous system toxicity and acute renal failure. The overall treatment-related mortality rate was 4%. The event-free survival rate at 500 days for these patients was 31%. Patients with metastatic breast cancer refractory to all standard dose therapy were treated with escalating doses of mitoxantrone (45 to 105 mg/m2) and thiotepa (900 to 1,350 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as mitoxantrone 90 mg/m2 and thiotepa 1,200 mg/m2 with mucositis and enteritis as the major nonhematologic toxicities and delayed myelosuppression as the dose-limiting toxicity. Twelve percent of the patients remain event free at 500 days and the treatment-related mortality rate for this group of heavily pretreated patients was 17%. These data suggest that patients with metastatic breast cancer may benefit from high-dose therapy and that treatment-related toxicity is tolerable.

Special considerations for the patient undergoing allogeneic or autologous bone marrow transplantation.

Improvements in the diagnosis, treatment, and prevention of infectious complications of bone marrow transplantation over the past two decades have markedly reduced the morbidity and mortality of this procedure. We are now able to begin early empiric antibiotic coverage with less toxic, but equally effective, antibacterial agents. Once believed to be uniformly fatal, complications such as CMV pneumonia are now considered treatable in at least half the cases with a combination of intravenous immunoglobulin and ganciclovir. Although probably the most controversial, prophylactic therapy has improved the outcome of patients undergoing bone marrow transplantation. The appropriate setting, agents to use, dose, and dose intervals will require further study in coming years. In the introduction to this article, we attempted to outline what is known about the immunobiology of bone marrow transplantation. A clear understanding of this process helps us recognize and anticipate the infectious complications encountered in this population of patients. It may also allow clinicians to focus more on immune augmentation as a means of prevention, as has been attempted with the newly available cytokines and the use of intravenous immunoglobulin infusions. Despite improvements in diagnosis, treatment, and prevention, infectious complications remain the leading cause of morbidity and mortality in the patient undergoing bone marrow transplantation. Future studies are required in this area to build on the successes of the last two decades.