John W. Hiemenz

Liposomal Amphotericin B for Empirical Therapy in Patients with Persistent Fever and Neutropenia

Background In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. Methods We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. Results The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respective...

Pneumocystis carinii Pneumonia: A Comparison Between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

invasive Aspergillosis Disease Spectrum, Treatment Practices, and Outcomes

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.

A Randomized Trial Comparing Ceftazidime Alone with Combination Antibiotic Therapy in Cancer Patients with Fever and Neutropenia

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients with Neutropenia during Cancer Chemotherapy

BACKGROUND Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment. METHODS We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved. RESULTS A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patients inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07). CONCLUSIONS In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective.

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.

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.

A randomized trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates.

Twenty-four cancer patients with diffuse interstitial pneumonitis (DIP) were randomized to undergo an open lung biopsy (OLB) within 8 hours of presentation (12 patients) or to receive empiric antimicrobial therapy (ET) with trimethoprim-sulfamethoxazole (TMP-SMX) erythromycin for a minimum of 4 days (12 patients). Patients whose condition deteriorated underwent an OLB on day 4. Eight of 12 patients (67%) having OLB survived versus 10 of 12 (83%) receiving ET (P = .64). Morbidity occurred in nine of 12 (75%) having OLB versus eight of 12 (67%) receiving ET (P = 1.0). Concurrently, there were 14 additional cancer patients with DIP who were not randomized (nine refused, three had a coagulopathy contraindicating surgery, two were excluded by primary care physicians) and who were comparable demographically to the randomized group. Two received OLB and 12 ET. Combining the randomized and nonrandomized groups, eight of 14 (57%) having an initial OLB survived versus 18 of 24 (75%) of ET-treated patients (P2 = .19). Results of the OLB were seven Pneumocystis carinii pneumonia (PCP), five nonspecific pneumonitis (NSP), one cytomegalovirus, and one lymphoma. Results of OLB led to discontinuation of antibiotics in three patients. Of the 24 ET patients, eight failed to improve by day 4 and had an OLB. Results were two NSP, two PCP, two cancer, one blastomycosis, and one Candida pneumonia. Complications were seen in 10 of 14 (72%) initial OLB patients versus 14 of 24 (58%) patients on the ET arm (P = .65). When the complication rate between patients receiving only empiric antibiotics was compared with all patients having an OLB (initially or on day 4), the difference was greater in patients undergoing OLB (37% v 72%, respectively) (P2 = .14). ET with TMP-SMX plus erythromycin and broad spectrum antibiotics in granulocytopenic patients appeared to be as successful and potentially less toxic than an OLB in this study. Although the number of patients in this study was small, these data suggest that a trial of empiric antibiotic management may be reasonable in cancer patients presenting with DIP, especially if they are nonneutropenic.

New beta-lactam antibiotics in granulocytopenic patients: New options and new questions

Infectious complications are a frequent cause of morbidity and, at many centers, the major cause of death in patients with cancer. The increased risk and severity of infectious sequelae result from profound alterations in normal host defenses that occur secondary to the underlying malignancy and the treatment thereof. During the last decade, early empiric antibiotic therapy has become standard practice in the initial management of febrile granulocytopenic patients and has contributed significantly to the improved outcome among patients undergoing cancer therapy. Although early death due to unsuspected or inadequately treated bacterial infection has been largely overcome, new problems--also with life-threatening implications--have emerged. As the use of cancer chemotherapy continues to increase, new populations of patients are being placed at increased risk of infection. Defining the host and environmental factors that contribute to this risk assumes central importance for delineating those patients who require the most intense surveillance. Changing medical practices (e.g., increased use of indwelling catheters) have contributed to the emergence of new pathogens. Recent drug developments (e.g., the third-generation cephalosporins and extended-spectrum penicillins) offer new treatment options, as well as generate controversy and confusion. For example, authorities disagree on the optimal duration and modifications in treatment that are required by cancer patients who remain granulocytopenic and who thus are at continued risk of multiple infectious episodes or superinfections. A question of current interest is whether combination therapy with synergistic agents is important in light of the development of the third-generation cephalosporins and extended-spectrum penicillins. Several of these new antibiotics have an exceedingly broad spectrum of activity that includes Pseudomonas aeruginosa, as well as Enterobacteriaceae, Serratia, Citrobacter, indole-positive Proteus, and anaerobes (including Bacteroides fragilis). However, the third-generation cephalosporins are not as active against staphylococci and streptococci as are the first-generation cephalosporins, and none is effective against enterococci. Nonetheless, these agents achieve serum levels that can be 10 to 100 times greater than the minimal inhibitory and bactericidal concentrations of gram-negative bacteria, raising the possibility that these drugs might be effective as single agents. The advantages of the third-generation cephalosporins are their minimal toxicity and long serum half-lives.(ABSTRACT TRUNCATED AT 400 WORDS)

Intensive dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell rescue: results of a Phase I/II study in breast cancer patients

We have recently treated 66 women with breast cancer with escalating doses of ifosfamide, carboplatin, and etoposide (ICE) followed by autologous stem cell rescue (ASCR). Patients received ifosfamide (6000-24,000 mg m-2), carboplatin (1200-2100 mg m-2), and etoposide (1800-3000 mg m-2) divided over 6 days with ASCR 48 h after completion of chemotherapy. Our patient population consisted of seven patients with stage II disease with eight or more positive nodes being treated in the adjuvant setting, 16 patients with a history of stage III or inflammatory breast cancer, and 43 patients with stage IV disease. Six patients were not evaluable for response due to early death from infection (three patients) and incomplete restaging (three patients). The overall response rate in patients with measurable metastatic disease was 50%. Of those patients with stage II disease, 85% remain alive and progression-free with a median follow-up of greater than one year. The two most frequent toxicities encountered were reversible elevations of liver function tests and mucositis/enteritis. The dose-limiting toxicities were central nervous system toxicity and nephrotoxicity.