Characteristics of initial compared with subsequent bacterial infections among hospitalised haemato-oncological patients

Surveys of bacterial infections among neutropenic cancer patients frequently report pooled antibiotic susceptibility data. Management guidelines address initial antibiotic regimens for febrile neutropenia. In this study, rates of bacterial infection and antibiotic susceptibilities among initial and subsequent or breakthrough episodes of fever were analysed. Prospective surveillance of fever of unknown origin (FUO), clinically documented infection and microbiologically documented infection (MDI) was conducted in the haemato-oncology and haematopoietic stem cell transplantation wards in a single cancer centre in Israel. Subsequent infections were defined as those developing during or after broad-spectrum antibiotic treatment. A total of 567 febrile episodes were documented among 271 patients. Bacterial MDIs were documented in 104/162 (64%) initial febrile episodes and 75/405 (19%) subsequent episodes and Gram-negative bacteria predominated (64% and 71%, respectively). Escherichia coli was the most common species isolated. Higher antibiotic susceptibilities were observed for initial compared with subsequent MDIs for Gram-negative bacteria [ceftazidime 80% vs. 45%, piperacillin/tazobactam (TZP) 86% vs. 40% and meropenem 95% vs.76%] and Gram-positive bacteria. TZP monotherapy was the most commonly used antibiotic and its susceptibility decreased to 22.2% following its use. Appropriate empirical antibiotic treatment was administered in 71/97 (73%) initial and 40/74 (54%) subsequent episodes (P=0.009) and was significantly associated with mortality (adjusted odds ratio=0.4, 95% confidence interval 0.18-0.87). We conclude that previous antibiotic exposure significantly impacts antibiotic susceptibility and that pooled reporting of all infections can be misleading. Treatment guidelines should address the antibiotic treatment of breakthrough fever.     

Oral voriconazole for empiric antifungal treatment in patients with uncomplicated febrile neutropenia

STUDY OBJECTIVE: To determine the success rate and toxicity profile of oral voriconazole when used as empiric antifungal therapy in patients with uncomplicated persistent neutropenic fever. DESIGN: Retrospective medical record review. SETTING: University hospital. PATIENTS: Twenty-seven patients who received oral voriconazole as empiric antifungal treatment during 31 episodes of persistent neutropenic fever between August 1, 2003, and April 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data were collected on patient demographics, diagnosis, cancer treatment plan, voriconazole regimen, dates of voriconazole treatment, other antibiotics administered during the episode of fever, and adverse events. Patient survival data from at least 3 months of follow-up were also collected. Treatment success, which was defined as survival to the resolution of fever without a need to change antibiotics and without new fungal infections, was also determined. Median duration of therapy was 11 days (range 2-54 days). No patient discontinued the drug because of toxicity. The success rate was 55% (95% confidence interval [CI] 36-73%). For all patients, 90-day survival from the start of voriconazole treatment was 81% (95% CI 63-93%). Neither treatment success nor 90-day survival rates differed significantly when they were compared by the route used for loading doses or by the presence of a possible invasive fungal infection at the start of voriconazole therapy. CONCLUSION: Oral voriconazole appears to be a safe empiric antifungal treatment with an encouraging rate of activity for patients with neutropenia and uncomplicated persistent fever. Further research, including randomized controlled trials comparing the efficacy of intravenous versus oral voriconazole, is needed.     

Comparison of meropenem with amikacin plus ceftazidime in the empirical treatment of febrile neutropenia: a prospective randomised multicentre trial in patients without previous prophylactic antibiotics. Meropenem Study Group of Turkey

Eighty three patients with neutropenia and cancer were randomised to receive either 1 g meropenem tds or amikacin 15 mg/kg single dose daily plus ceftazidime 2 g tds. No prophylactic antibiotics were allowed before entry to the trial. Seventy seven patients were available for analysis. Infection was microbiologically or clinically documented in 53 episodes (69%). The overall success rate without adjustment was 49% in monotherapy, 37.5% in the combination group. These rates were increased to 65% and 56%, respectively when secondary infection episodes requiring a different class of chemotherapy were taken into account. Median duration for defervescence was 3 days in successfully treated patients in both groups. Only minor reversible side effects were noted in both treatment arms. Meropenem monotherapy seemed as effective and safe as amikacin plus ceftazidime for the empirical treatment of neutropenic cancer patients with fever.     

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections

BACKGROUND: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. DESIGN: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. RESULTS: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. CONCLUSION: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.     

Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections.

STUDY OBJECTIVE: To understand the relationship between dosage and therapeutic response of amphotericin B lipid complex (ABLC) by analyzing underlying diseases, types of infections, and therapeutic outcomes with different dosages as second-line antifungal therapy. DESIGN: Retrospective analysis of low-dose (initial dose < or = 3 mg/kg) ABLC from three open-label, clinical, second-line treatment studies. SETTING: Centers in the United States (204), Canada (3), Australia (1), Mexico (1), and The Netherlands (1). PATIENTS: Five hundred fifty-one patients (5 enrolled twice) with invasive fungal infections, of whom 289 failed and 267 were intolerant to conventional antifungal therapy. INTERVENTIONS: Patients were to receive the recommended dosage of ABLC 5 mg/kg/day, with dosage reduction for markedly increased serum creatinine. The duration of treatment was 4 weeks; therapy could be extended if the investigator considered additional treatment necessary. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients (13%) received ABLC 3 mg/kg/day (low dosage) instead of the protocol-recommended 5 mg/kg/day Response was 65% and 56%, respectively. Logistic regression analysis revealed that the following patients are most likely to start therapy at the lower dosage: those with candidiasis and other yeast infections, patients with nephrotoxicity due to prior amphotericin B, and those with underlying conditions other than hematologic malignancy. CONCLUSION: These results suggest that ABLC 3 mg/kg/day may be effective in treating patients with candidiasis who do not have hematologic malignancy.     

Lipid-based amphotericin B: a review of the last 10 years of use

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.     

Increasing-dose gemcitabine plus low-dose cisplatin in metastatic non-small cell lung cancer

Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. CHEMOTHERAPY: cisplatin 50 mg/m2 on day 1, gemcitabine starting at 1400 mg/m on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2 because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2 days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.     

Empiric antibiotic protocols for cancer patients with neutropenia: a single–center study of treatment efficacy and mortality in patients with bacteremia

Background

There are several empiric antibiotic treatment options for febrile neutropenia, yet there is no universally-accepted initial protocol. We aimed to assess the performance of a protocol (piperacillin, gentamicin and cefazolin) introduced over 40 years ago and compare its coverage against bacteria isolated from blood of neutropenic patients with that of various commonly used antibiotic treatment protocols.

Prospective audit of the effectiveness of hydrocortisone premedication on drug delivery reactions following amphotericin B lipid complex

ABSTRACT

Objective: Amphotericin B lipid complex (ABLC), a lipid-based formulation of amphotericin B, is an effective treatment for fungal infections, but is associated with mild to moderate drug delivery reactions (DDRs), such as fever, rigors and chills, in some patients. Although clinical studies have indicated that premedication with hydrocortisone may reduce the incidence of DDRs, there are currently limited confirmatory data from clinical practice. The aim of the audit was to assess prospectively a hydrocortisone premedication strategy with ABLC to reduce the rate of DDRs.

Methods: Over an 18-month period, all cancer patients treated with ABLC at The Royal Shrewsbury Hospital were audited prospectively. Each patient received 100?mg of intravenous hydrocortisone 15–30 minutes prior to each ABLC infusion. The primary outcome was to determine the DDR rate per cycle of ABLC.

Results: A total of 275 cycles of ABLC (mean dosage 930.6?mg) were administered during the course of the study period, and 16.0% were associated with DDRs. The majority of reactions occurred following the first infusion of a cycle (15.3%; subsequent infusions: 2.9%). The most common DDRs were rigor (15.3%) and fever (12.7%). There was no significant difference in the DDR rate (17.2 vs. 15.5%) or types of reactions between ABLC-naïve and previously treated patients. The dosage of ABLC administered had no effect on the DDR rate. Female gender, being neutropenic and younger age were found to be predictive of having a DDR.

Conclusions: The audit demonstrates that premedication with hydrocortisone results in a low incidence of DDRs following ABLC. The main limitation of this study is the lack of a randomised control group.     

Cefoperazone/sulbactam versus cefoperazone plus mezlocillin: empiric therapy for febrile, neutropenic bone marrow transplant patients

We conducted a prospective, randomized trial in 132 patients undergoing bone marrow transplantation comparing cefoperazone in combination with sulbactam (S), N = 66, vs. cefoperazone plus mezlocillin (CM), N = 66, as empiric antibiotic therapy for fever and neutropenia. Overall duration of neutropenia was 3-55 (median, 13) days. Forty-one patients had positive initial cultures (S = 22 and CM = 19). Twelve of these 41 patients responded to initial study antibacterial agent treatment (S = 6 and CM = 6). Twenty-nine of 41 patients were withdrawn from study because of clinical deterioration, continued fever, or persistently positive cultures (S = 16 and CM = 13). Of the 90 patients who had culture-negative fever (S = 44 and CM = 46), 44 subjects responded with or without the addition of amphotericin B (S = 21 and CM = 23). Thirty-seven of 90 patients were withdrawn from study due to continued fever or clinical deterioration (S = 17 and CM = 20). Nine patients were withdrawn as a result of rash or diarrhea (S = 6 and CM = 3). We conclude that in patients undergoing bone marrow transplantation, there was no difference in efficacy between cefoperazone/sulbactam and the combination of cefoperazone plus mezlocillin in the empiric treatment of the febrile neutropenic patient. Since the majority of initial infections were due to gram positive bacteria, consideration should be given to broadening initial empiric antibacterial agent therapy with drugs that possess potent activity against these organisms.     

Current research in empirical therapy for febrile neutropenia in cancer patients: what should be necessary and what is going on

Introduction: Fever is an important complication in neutropenic patients and standard of care calls for empirical broad-spectrum antibiotics, followed by ‘empirical' antifungal therapy in persisting fever. Emergence of infections due to resistant bacteria, especially Gram-negatives, and usefulness of empirical antifungal therapy represent the major concerns in this field.

Areas covered: Clinical trials registered in 5 international databases were referred for randomized clinical trials (RCTs) of empirical antibacterial therapy or empirical antifungal therapy in neutropenic cancer patients. The majority of RCTs compared antibiotics without major differences in the spectrum of activity, especially in the wake of the present epidemiology with an increase of infections and mortality due to resistant Gram-negatives; oral therapy and home care were analyzed in 3 RCTs. As regards empirical antifungal therapy, 1 ongoing study is comparing ‘standard' empirical treatment vs diagnostic-driven approach.

Expert opinion: In an era of increasing antibiotic resistance the comparison of different strategies more than that of different drugs will probably represent the future in studies in this field. The next future will tell us if a diagnostic-driven approach is safe for fungal infections, or if we should continue to treat them only on the basis of the persistence of febrile neutropenia.     

Epirubicin/docetaxel regimen in progressive breast cancer-a phase II study

The purpose of this investigation was to evaluate the efficacy and toxicity of 6 months' treatment with the combination of epirubicin and docetaxel in metastatic breast cancer. Thirty-eight women (mean age 51 years, range 35-72) with metastatic breast cancer were treated with a regimen of epirubicin 75 mg/m and docetaxel 75 mg/m every 3 weeks, given 4 times if progression was seen upon evaluation after 4 courses or 8 times in responding/stable patients. The patients received 285 cycles of combination treatment and two treatments with docetaxel or epirubicin alone. When neutropenia with fever was observed, further cycles were given with dose reduction. The median cumulative docetaxel dose was 462 mg/m (range 199-600) and that of epirubicin 476 mg/m (range 199-740). The overall response rate was 54% (95% CI 37-71), with a median duration of response of 14.8 months (95% CI 8.8-27.8). Median time to progression was 12 months, median survival 26 months. Neutropenia below 0.5 x 10 /l occurred following 113 (39%) of the total of 285 cycles given; 21 patients (55%) were hospitalized for febrile neutropenia. We conclude that dose tailoring is required in treatment with an epirubicin and docetaxel regimen to avoid grade 3/4 adverse effects in a significant number of patients treated for metastatic breast cancer.     

美罗培南治疗血液肿瘤伴发热及中性粒细胞减少患儿的疗效分析

目的初步探讨美罗培南对血液系统肿瘤伴发热及中性粒细胞减少患儿的疗效及安全性。方法收集2012年7月至2013年10月湖南省儿童医院住院的血液系统肿瘤伴中性粒细胞减少及初次发热经美罗培南治疗患儿的病例资料,分析美罗培南的疗效及安全性。并根据不同肿瘤类别、中性粒细胞绝对数减少程度分组比较。结果共55例纳入研究,微生物学检测确诊及临床确诊感染的病例分别为22例(40.0%)、24例(43.6%)、未知感染源者9例(16.4%)。实体瘤患儿的发热性中性粒细胞减少(FN)持续时间及住院时间较白血病患儿短(P<0.05),治疗有效率差异无统计学意义;ANC≥0.2×109·L-1组的FN持续时间及住院时间较ANC<0.2×109·L-1组患儿短(P<0.05),治疗有效率高于后者;未出现不良反应、总有效率89.1%(49/55)。结论应用美罗培南治疗血液系统肿瘤伴发热及FN患儿安全有效,可作为临床医师初期经验性抗菌药物选用的药物。     

Safe and effective outpatient treatment of adults with chemotherapy-induced neutropenic fever.

PURPOSE: The safe and effective outpatient treatment of adults with chemotherapy- induced neutropenic fever is reviewed. SUMMARY: Chemotherapy-induced neutropenic fever is a potentially life-threatening circumstance in high-risk patients. The standard of care for neutropenic fever is inpatient treatment with i.v. broad-spectrum antibiotics. Within the past 5-10 years, there has been growing interest in oral therapy and outpatient treatment for carefully selected low-risk patients. Outpatient treatment has the potential to avoid patient exposure to multidrug-resistant organisms found in the hospital, provide a more comfortable environment for the patient and his or her family, and achieve significant cost savings. Two risk-assessment tools have been developed to identify patients with a low risk of developing complications from neutropenic fever. A limited number of clinical trials have been conducted to evaluate outpatient treatment of low-risk patients. The evidence from well-designed randomized controlled trials comparing the safety and efficacy of outpatient therapy with standard therapy is not extensive. However, some centers have reported successful outpatient therapy in low-risk patients with febrile neutropenia. The greatest amount of evidence for outpatient treatment of neutropenic fever is available for the combination regimen of ciprofloxacin plus amoxicillin-clavulanate. Clinical practice guidelines are available to guide patient evaluation, antibiotic selection, monitoring, and follow-up. CONCLUSION: The accepted standard for treatment of neutropenic fever remains inpatient therapy with i.v. broad-spectrum antibiotics. However, some centers have had success treating selected low-risk patients with neutropenic fever as outpatients.     

Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: A prospective cohort

ObjectivesAntibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy.MethodsBased on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017.ResultsAntibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24–30). Antibiotics were started at day 9 (IQR 5–13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7–16) vs. 19 days (IQR 15–23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3–7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2–8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia.ConclusionsDiscontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing.     

A phase II study of induction chemotherapy followed by concurrent chemoradiotherapy in elderly patients with locally advanced non-small-cell lung cancer

The optimal management of unresectable locally advanced non-small-cell lung cancer in older patients has not been defined to date. The present phase II study was planned to evaluate the activity and safety of platinum-based induction chemotherapy followed by concurrent chemoradiotherapy in elderly patients with locally advanced non-small-cell lung cancer. Patients received two cycles of paclitaxel (175 mg/m) and carboplatin (area under the curve: 5) day 1, every 3 weeks. Chemoradiotherapy (thoracic radiation therapy) was initiated on day 42 and consisted of 1.8 Gy daily, five times per week over 5 weeks (45.0 Gy target dose) followed by 10 2.0 Gy daily fractions. Concomitant chemotherapy was weekly paclitaxel 50 mg/mq followed by weekly carboplatin at an area under the curve of 2. The eligibility for patients: age 70 or older and histologically documented untreated non-small-cell lung cancer, locally advanced, unresectable, stage III A N2 bulky or III B. Thirty consecutive patients were enrolled onto the study. The median age was 73 (range 70-76). According to the intention-to-treat analysis, 1 month after the end of combined chemoradiotherapy, we observed complete and partial responses in one and 19 of the 30 patients, respectively, for an overall response rate of 66% (95% confidence interval, 45-76%). Median progression-free survival was 8.7 months (95% confidence interval, 3.4-37.8) and median survival was 15 months (95% confidence interval, 4.2-52.1). During the treatment, 12 patients (40.0%) experienced grade 3-4 neutropenia, two patients neutropenic fever, and three patients grade 3 anaemia and grade 3 thrombocytopenia, respectively. Grade 3 oesophagitis, during concomitant radiotherapy, was observed in six patients (20.0%). No treatment-related mortality was reported. The investigated sequential approach including induction chemotherapy followed by concurrent chemoradiotherapy appears safe and seems a reasonable chance for the treatment of locally advanced non-small-cell lung cancer in the elderly population.     

Institutional experience with voriconazole compared with liposomal amphotericin B as empiric therapy for febrile neutropenia

STUDY OBJECTIVE: To assess the effectiveness, safety, and cost of empiric treatment of febrile neutropenia before and after implementing an algorithm in which voriconazole was substituted for liposomal amphotericin B (L-AmB). DESIGN: Retrospective cohort analysis. SETTING: An 850-bed tertiary care hospital, which is also a referral site for patients with acute leukemia. PATIENTS: Fifty-five adult patients who started empiric antifungal therapy for febrile neutropenia between January 1, 2002, and December 31, 2003, encompassing 58 treatment episodes (defined as a hospitalization during which empiric antifungal therapy was administered). MEASUREMENTS AND MAIN RESULTS: Medical charts, including patients' pharmacy and laboratory data, were reviewed. Twenty-six and 32 episodes of L-AmB and voriconazole use, respectively, were identified. No significant differences between the L-AmB and voriconazole groups were noted at baseline. Rates of fever resolution (54% vs 59%, p=0.791) and breakthrough invasive fungal infections (11% vs 12%, p>0.999) were similar for the L-AmB and voriconazole episodes. Premature drug discontinuation due to the prescriber's perceived lack of efficacy occurred most frequently in the voriconazole group (25% vs 8%, p=0.160). Survival was significantly higher in the voriconazole than in the L-AmB group (100% vs 77%, p=0.006). Adverse effects that were significantly more common in the L-AmB group than in the voriconazole group were elevated serum creatinine levels (27% vs 3%, p=0.017) and electrolyte disturbances (19% vs 0%, p=0.014). Adverse effects reported more frequently in the voriconazole group than in the L-AmB group were visual disturbances (9% vs 0%, p=0.245) and elevated hepatic enzyme levels (9% vs 8%, p>0.999). Mean drug expenditures/episode for initial empiric antifungal therapy were lower for voriconazole than for L-AmB ($1593 vs $4144, or $153 vs $380/day). CONCLUSION: Our institution's algorithm incorporating voriconazole into the empiric management of febrile neutropenia was associated with effectiveness outcomes comparable to those observed with L-AmB as well as a lower frequency of adverse effects and overall expenditures for antifungal drugs.     

Pharmacokinetics of amphotericin B lipid complex in critically ill patients on continuous veno-venous haemofiltration

Pharmacokinetics of amphotericin B lipid complex (ABLC) was determined in two critically ill patients requiring continuous veno-venous haemofiltration (CVVH) because of acute renal failure. ABLC was administered at a mean daily dose of 4.94 mg/kg for suspected invasive mycosis. Mean C(max) was 0.56 microg/ml, the mean AUC(0-24 h) was 7.46 mgh/l, V(ss) 9.13 l/kg, and t(1/2) was 13.21 h. The haemofilter clearance accounted about 20% of the total ABLC clearance. In one patient sampling was repeated after CVVH had been discontinued. The concentration-time profiles were very similar on and off haemofiltration. Data on our two patients suggest, that pharmacokinetics of ABLC is not significantly affected by CVVH and that ABLC can be administered at the standard doses during CVVH.     

Gemcitabine plus dose-escalated epirubicin in advanced breast cancer: results of a phase I study

Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.