Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia.

BACKGROUND: In view of the recent trend toward monotherapy in the treatment of bacterial infection, we evaluate the clinical efficacy and safety of cefepime vs. ceftazidime for the empiric treatment of febrile episodes in neutropenic pediatric cancer patients. METHODS: In a single site, open label study, 104 neutropenic pediatric cancer patients [96% with absolute neutrophil count (ANC) of <500 neutrophils/mm3] with a median age of 6 years were randomized (1:1) to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose every 8 h; < or = 6 g/day) for empiric treatment of fever (temperature >38.0 degrees C occurring at least twice in 24 h, or single >38.5 degrees C). Febrile episodes were classified as either microbiologically or clinically documented infection or fever of unknown origin. Therapy continued until the ANC was > or = 1,000 neutrophils/mm3 or there was an increasing ANC in low risk patients (maximum duration of treatment, 8 weeks). The primary efficacy endpoints assessed were clinical and microbiologic response to assigned drug therapy. Secondary outcome measures were rate of early discontinuation of study drug and use of concomitant antibiotic therapy to modify initial study drug regimen. RESULTS: Of 68 patients who could be evaluated for efficacy, 74% (26 of 35) of cefepime-treated patients and 70% (23 of 33) of ceftazidime-treated patients responded to treatment. The small number of study patients precluded statistical analysis of results. In a modified intent-to-treat analysis, 59% of the patients treated with cefepime and 47% of ceftazidime-treated patients responded to therapy. Cefepime patients developed fewer new infections than ceftazidime patients (9% vs. 21%, respectively) and early discontinuation of study drug therapy occurred slightly more often in the ceftazidime group. Further, the use of concomitant systemic antimicrobial therapy (mostly vancomycin) occurred less often in the cefepime-treated patients, as compared with the ceftazidime group [35% [17 of 49] vs. 44% (24 of 55), respectively]. No deaths or serious adverse events were considered to be related to study therapy. The most frequent adverse event was rash that was moderate in severity, and it occurred equally in both groups. CONCLUSION: Cefepime appears to be safe and effective compared with ceftazidime for initial empiric therapy of febrile episodes in neutropenic pediatric cancer patients.

Use of amphotericin B colloidal dispersion in children.

PURPOSE: To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. PATIENTS AND METHODS: Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. RESULTS: In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. CONCLUSIONS: ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.

High-dose trimetrexate and minimal-dose leucovorin: a case for selective protection?

Our objective was to find the minimum dose of leucovorin (LV; 5-formyltetrahydrofolate) needed to potentially provide selective protection of normal tissue in patients with tumors resistant to methotrexate (MTX) by virtue of transport during prolonged therapy with high-dose trimetrexate (TMTX). Based upon the known daily requirement for folate, that tumors are often resistant to methotrexate via a transport-based mechanism, and that large doses of trimetrexate can be given with large doses of leucovorin for the treatment of patients with Pneumocystis carinii, a protocol was designed to find the minimum LV dose required to allow the administration of large doses of TMTX. Patients were treated in 28-day cycles consisting of 14 consecutive days of oral TMTX (45 mg/m2 every 12 h), followed by 14 days of rest. The dose of concurrent LV was started at 5 mg/m2 twice daily. Cohorts of patients received successive half doses of LV so long as three consecutive patients had less than or equal to grade 3 toxicity. Ten patients received 29 courses of therapy. The most common toxicities encountered were thrombocytopenia (38%), mucositis (14%), and neutropenia (10%). At a LV dose of 2.5 mg/m2, toxicities were consistently limited to less than or equal to grade 3 and only one episode of grade 4 hematological toxicity. Although there was marked interpatient variability, the minimally effective LV dose for selective protection seems to be 2.5 mg/m2. If tumors are resistant to methotrexate because of decreased transport of drug (and also folate), then the same pharmacological principle used to develop TMTX/LV for the treatment of P. carinii may be applied to treatment of some patients with cancer.

Immune recovery in children with malignancy after cessation of chemotherapy.

PURPOSE: To study longitudinally the extent and recovery of cellular and humoral immune alterations in children with cancer after completion of their therapy. PATIENTS AND METHODS: Using standard immune assays, cellular and humoral immunity was measured in 43 infants and children with cancer at completion of therapy and every 3 months thereafter for 1 year. There were 17 patients with acute lymphoblastic leukemia, 9 with Hodgkin disease, and 17 with solid nonhematopoietic tumors. All children had received standard childhood immunizations before diagnosis of cancer. Immune assays performed included circulating lymphocyte subpopulations, in vitro antigen-induced responses, and total concentrations of serum immunoglobulin G (IgG), IgM, IgA, and IgG subclasses, and specific antibodies against diphtheria, tetanus, pertussis, and poliovirus types I, II, and III. RESULTS: At completion of therapy, the majority of patients had low circulating lymphocyte subpopulations and antigen-induced responses. Serum antibody concentrations were low in up to 89% of patients regardless of the underlying malignancy. Although improvement occurred during the year of follow-up, 35 of 43 (81%) patients continued to exhibit one or more immune abnormalities 9 to 12 months after cessation of chemotherapy. Younger patients had more persistent alterations. Other risk factors studied (including gender, duration of therapy, and underlying malignancy) did not correlate with the severity of the immune defects. With the exception of poliovirus antibodies, specific antibody titers against common childhood vaccine antigens were deficient at completion of therapy and 9 to 12 months later in a substantial proportion of patients. CONCLUSION: Children with malignancy have persistent specific and nonspecific immune alterations 9 to 12 months after cessation of chemotherapy. The clinical implications of these in vitro observations are unclear and require further evaluation.

Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms' tumor.

PURPOSE: We evaluated the in vitro hemodialysis ratio and subsequent toxicity and pharmacokinetics of ifosfamide in an anephric patient with Wilms' tumor. METHODS: An in vitro model was used to determine the extraction ratio of ifosfamide by dialysis. The toxicity and plasma concentrations of ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were then determined over 24 h after a single 1.6 g/m2 dose of ifosfamide. Plasma concentrations were also measured before and after ten dialysis sessions during four courses of ifosfamide therapy. RESULTS: The in vitro hemodialysis model showed that ifosfamide was cleared with an extraction ratio of 86.7+/-0.5% and remained constant even at low concentrations of drug. The mean decrease in vivo following hemodialysis for ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were 86.9%, 77.2%, and 36.2%, respectively. The pharmacokinetic parameters for ifosfamide using model-independent methods were calculated: Vd = 0.23 l/kg, t1/2 = 4.8 h, and ClT = 3.30 l/h per m2. Ifosfamide-associated neurotoxicity was noted within hours of drug administration and improved rapidly following hemodialysis. CONCLUSIONS: The results of our study suggest that the pharmacokinetics of parent ifosfamide may not be substantially altered in patients with renal failure. Hemodialysis was shown to remove ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide from the blood stream. Hemodialysis was also shown to reverse ifosfamide-related neurotoxicity.

Early discharge of low-risk febrile neutropenic children and adolescents with cancer.

During the past decade, a relatively lower-risk patient population of febrile neutropenic children with cancer (over one-half of all these patients) has been identified. These patients can be safely discharged from the hospital before their absolute neutrophil count (ANC) exceeds 500/mm3. To evaluate the practice of early discharge of these patients, 580 consecutive episodes of chemotherapy-induced febrile neutropenia in 253 children and adolescents with cancer between June 1992 and May 1995 were reviewed. Three hundred thirty episodes ended in discharge before the patient's ANC was > 500/mm3. Patients were characterized as being at relatively lower risk if they had sterile blood cultures, were afebrile for > 24 hours, appeared well, and were thought to have evidence of marrow recovery. Of the 330 episodes, only 21 (6%) were associated with admission for recurrent fever during the subsequent 7 days. In retrospect, in only six of these 21 cases of readmission (or 2% of 330 episodes) was there evidence of bone marrow recovery, and none of the blood cultures were positive during the subsequent hospitalization. All patients who met low-risk criteria fared well during their second hospitalization. This early discharge strategy was safe and resulted in substantial cost savings.

Safety of early hospital discharge of selected febrile children and adolescents with cancer with prolonged neutropenia.

PROBLEM: The safety of early hospital discharge (i.e., before the absolute neutrophil count [ANC] exceeds 500 cell/mm3) of febrile neutropenic children and adolescents with cancer who had experienced prolonged neutropenia (i.e., for more than 7 days) following admission has not been studied. METHOD OF STUDY: Three hundred and thirty nine consecutive admissions of children and adolescents with cancer for management of febrile neutropenia were reviewed. Early discharge criteria included absence of fever for 24 hours prior to discharge, sterile blood cultures for 24 hours, evidence of bone marrow recovery defined as a sustained increase in platelet count and ANC or absolute phagocyte count (APC), and control of local infection if present. Children hospitalized with febrile neutropenia who remained neutropenic for more than 7 days were analyzed to assess their outcomes following discharge it they had met criteria for early hospital discharge. RESULTS: Thirty-three patients in whom neutropenia had persisted for more than 7 days were discharged before attaining an ANC greater than 500/mm3 when they met the early discharge criteria. Only two children (6%) required readmission for recurrent fever, a rate which was not different from that of patients discharged after a more transient episode of neutropenia (2 of 33 vs. 3 of 121, P = 0.3). Both patients who were readmitted had a source of local infection which worsened despite oral antibiotics. Both patients appeared clinically well at the time of readmission and had sterile cultures during their second hospitalization with resolution of local infection. CONCLUSION: This study confirms that low-risk criteria used to select children with cancer for discharge before complete resolution of neutropenia can be safely applied to those patients whose neutropenia lasted more than 7 days following admission.

A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia.

Febrile neutropenic children with cancer were eligible for outpatient management with intravenous ceftriaxone therapy if they displayed selected low-risk criteria. Nineteen children were enrolled. All patients had sterile blood cultures, and only one of them was hospitalized because of persistent fever. This pilot study suggests that selected children with febrile neutropenia might be successfully managed without hospitalization.

The changing epidemiology of bacteremia in neutropenic children with cancer.

Gram-positive bacteria have been the predominant organisms causing bacteremia in febrile neutropenic cancer patients during the past decade. Recently we have noted an increase in Gram-negative bacteremia in children and adolescents with cancer. Therefore we retrospectively reviewed 153 episodes of bacteremia during a 6-year period to investigate changes in the etiology of bacteremia in pediatric oncology patients. In the early 3-year period (January, 1988, to December, 1990) Gram-positive organisms comprised 73 (74%) of the 99 isolates, and Staphylococcus epidermidis was the most common isolate. In the later 3-year period (January, 1991, to December, 1993) Gram-negative organisms were seen with greater frequency and represented 50% of isolates (P = 0.004). Pseudomonas aeruginosa was the most commonly isolated organism during this period (22% of all isolates). We speculate that the recent utilization of more intensive chemotherapy regimens has caused an alteration in the epidemiology of bacteremia in children and adolescents with cancer which could influence the initial empiric antibiotic regimens and the outcome of such infections.