Granulocyte transfusion therapy in abdominal organ transplant recipients

Background: Patients with neutropenia are at increased risk for infections. Granulocyte transfusions (GT) have had mixed success in treatment of neutropenic infections in adult patients with hematologic malignancy. This study examined the outcomes of GT therapy in neutropenic solid organ transplant recipients, a novel population for this therapy. Methods: We performed a retrospective examination of the transfusion and medical records of all 14 solid organ‐transplant recipients without hematologic malignancy who experienced neutropenia and received GT therapy from 2004 to 2006. Results: Twelve patients received GT therapy for an active infection and two patients for infection prophylaxis. The mean absolute neutrophil count (ANC) one day increment per GT in these patients was 526/μl (median 215/μl). The mean ANC one day increment per dose of 10¹⁰ granulocytes was 246/μl (median 86/μl). Of the 12 infected patients, four patients (33%) showed a clinical response to GT with improvement or resolution of the infection, 7 (58%) patients had no clinical response and one additional patient had a clinical response to a course of GT but died during a second GT course. Neither patient receiving GT for prophylaxis developed an infection. Conclusions: We observed temporal increases in ANC to levels above 1,000/μl in 15/18 (83.3%) courses of GT. We observed a clinical response to infection in 5/12 (42%) patients, the remaining infected patients had no clinical response. Our results suggest that GT therapy in neutropenic solid organ transplant recipients can boost peripheral blood neutrophil counts. Additional studies areneeded to document an independent clinical benefit for GT in this patient population. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Increment of hematopoietic progenitor cell count as an indicator of efficient autologs stem cell harvest in patients with multiple myeloma

We previously showed that hematopoietic progenitor cell (HPC) count is a useful surrogate for the timing of autologs stem cell collection (ASCC). We investigated the role of HPC count increment in predicting the time for optimal ASCC in patients with multiple myeloma (MM). Between May 2002 and January 2011, 138 patients with MM who underwent ASCC after mobilization with cyclophosphamide (4 g/m²) and granulocyte‐colony stimulating factor at Asan Medical Center. HPC monitoring was started on the 10th day of cyclophosphamide administration and ASCC was performed when HPC count reached at least 10/mm³. Velocity of HPC increment (/mm³/day) was calculated as HPC count on the first day of ASCC/number of days from cyclophosphamide infusion to the first day of ASCC. A total of 422 leukapheresis were performed in 136 patients (median per patient: 3; range: 2–8). Of these patients, 131 (94.9%) successfully achieved optimal ASCC (≥5 × 106 CD34+ cells/kg). The median velocity of HPC increment was 2.17/mm³/day (range: 0.07–144.2/mm³/day). The mean ± standard error numbers of apheresis procedures in patients with velocity of HPC increment ≤2.0/mm³/day and >2.0/mm³/day were 3.43 ± 0.17 and 2.70 ± 0.11, respectively, and their median times to optimal ASCC were 15 and 13 days, respectively, with a hazard ratio of 0.47 (95% confidence interval, 0.32–0.68; P < 0.001) on multivariate analysis. Therefore, a slower increase of HPC of ≤2.0/mm³/day is associated with larger number of apheresis procedures for optimal ASCC. J. Clin. Apheresis 27:229–234, 2012. © 2012 Wiley Periodicals, Inc.     

Prognosis of infections in elderly patients with haematological diseases

The goal of work was to evaluate epidemiological features and prognostic factors of infections in elderly patients affected by haematological neoplasms. From 1 May 1989 to 30 April 1994 we observed 765 infectious episodes in 416 patients: 554 in patients younger than 65, 211 in patients aged over 65. No difference in rate of combined- or single-agent antibiotic therapy was present, nor in the rate of patients receiving growth factors. The outcome has been classified as positive, death from infections or death from causes other than infection (NID). When all deaths are considered, younger patients had a lower rate of death (120/554, 22%) than the elderly (59/211, 28%)P=0.069 (Fisher's exact test). When NID are excluded 77/511 (15%) younger patients and 34/186 (18%) elderly patients diedP=0.34. A significantly higher rate of younger patients had an absolute neutrophil count (ANC) lower than 500/mm³ at the onset: younger patients 322/554 (58%), the elderly 79/211 (38%)P<0.00001. When only neutropenic (ANC < 500/mm³) patients are considered, the difference in outcome between the two groups is more evident: positive outcome was achieved by 251/322 younger (78%) and by 49/79 elderly patients (62%)P=0.004; when NID were excluded, positive outcome was achieved by 251/306 younger (82%) and by 49/68 elderly patients (72%)P=0.066. Taking into account a higher rate of NID, it is possible to achieve an outcome for infection in the elderly that is not significantly different from that in younger patients, when less severe neutropenia is induced. However, among neutropenic patients, the prognosis for infections become poorer in elderly patients. This must be evaluated when aggressive chemotherapy for these patients is being designed.     

Engraftment after autologous hematopoietic stem cell transplantation in patients mobilized with Plerixafor: A retrospective,multicenter study of a large series of patients

Plerixafor (PLX) appears to effectively enhance hematopoietic stem-cell mobilization prior to autologous hematopoietic stem cell transplantation (auto-HCT). However, the quality of engraftment following auto-HCT has been little explored. Here, engraftment following auto-HCT was assessed in patients mobilized with PLX through a retrospective, multicenter study of 285 consecutive patients. Information on early and 100-day post-transplant engraftment was gathered from the 245 patients that underwent auto-HCT. The median number of PLX days to reach the stem cell collection goal (≥2 × 10⁶ CD34⁺ cells/kg) was 1 (range 1–4) and the median PLX administration time before apheresis was 11 h (range 1–18). The median number of apheresis sessions to achieve the collection goal was 2 (range 1–5) and the mean number of CD34⁺ cells collected was 2.95 × 10⁶/kg (range 0–30.5). PLX administration was safe, with only 2 mild and transient gastrointestinal adverse events reported. The median time to achieve an absolute neutrophil count (ANC) >500/μL was 11 days (range 3–31) and the median time to platelet recovery >20 × 10³/μL was 13 days (range 5–69). At 100 days after auto-HCT, the platelet count was 137 × 10⁹/L (range 7–340), the ANC was 2.3 × 10⁹/L (range 0.1–13.0), and the hemoglobin concentration was 123 g/L (range 79–165). PLX use allowed auto-HCT to be performed in a high percentage of poorly mobilized patients, resulting in optimal medium-term engraftment in the majority of patients in whom mobilization failed, in this case mainly due to suboptimal peripheral blood CD34⁺ cell concentration on day +4 or low CD34⁺ cell yield on apheresis.     

Probable vancomycin-induced neutropenia

OBJECTIVE: To report a case of vancomycin-induced neutropenia and provide a review of the literature. CASE SUMMARY: A 64-year-old white man was treated with intravenous vancomycin 1.5 g/day for finger osteomyelitis. He developed neutropenia after 21 days of vancomycin therapy. The absolute neutrophil count reached a nadir of 418 cells/mm(3) during vancomycin use and returned to normal 7 days after its discontinuation. The eosinophil count was also elevated during the neutropenic episode and probably related to vancomycin. Based on the Naranjo probability scale, the reaction was probably related to vancomycin use. DISCUSSION: Articles describing cases of vancomycin-induced neutropenia were identified. All patients developed neutropenia as a result of vancomycin therapy >/=12 days. Neutrophil counts generally increased following discontinuation of vancomycin. One article reported successful resolution of neutropenia and infection by switching the patient's therapy to the structurally related antibiotic agent teicoplanin. Other patients were continued on vancomycin therapy, and neutropenia was treated with moderate to good success with filgrastim. Rechallenge was not generally attempted. The mechanism of neutropenia caused by vancomycin is unclear, but appears to be immune-mediated. CONCLUSIONS: Vancomycin therapy should not be prolonged unless absolutely necessary, and therapy should be reserved for patients with clear indications for the drug, such as infections due to gram-positive organisms resistant to other therapies. Patients should have periodic assessment of white blood cell and neutrophil counts with consideration to discontinue vancomycin if neutropenia develops.     

Itraconazole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients.

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 x 10(9) cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 x 10(9) cells/L for >14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment.     

Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients

Between July 1993 and September 1996, 107 consecutive febrile episodes in 83 neutropenic cancer patients with a median age of 41 years were randomized to treatment either with piperacillin/tazobactam 4.5 g every 8 h i.v. or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day. In the case of fever >38° C 48 h after initiation of the antibiotic therapy, vancomycin 500 mg every 6 h i.v. was added. The study population was at serious risk of a poor outcome, since 67% of the patients had leukemia or lymphoma, 19% of the febrile events occurred after autologous bone marrow or blood stem cell transplantation, the median total duration of neutropenia was 16 days, and the median neutrophil count at study inclusion was 0.09 × 10⁹/l. The two patient groups were comparable in terms of risk factors. Bacteremia was found in 37%, other microscopically documented infections in 16%, and clinically documented infections in 26% of the febrile episodes. Most (96) febrile episodes were evaluable for response. No significant difference was found between piperacillin/ tazobactam and ceftazidime plus amikacin in terms of success rate (81% versus 83%), empirical addition of vancomycin (42% versus 38%), median time to fever defervescence (3.3 versus 2.9 days) or median duration of antibiotic therapy (7.2 versus 7.4 days). No patient died from the infection. Both antibiotic regimens were well tolerated, the study treatment being stopped only in 1 patient because of toxicity (cutaneous allergy to piperacillin/tazobactam). On the basis of the 107 febrile events encountered, we conclude that piperacillin/tazobactam is a safe and effective monotherapy. To define the definitive value of piperacillin/ tazobactam as a monotherapy for febrile neutropenic patients a large randomized trial is warranted.     

Utilization study of filgrastim (Neutromax) during autologous haematopoietic precursor transplantation for myeloma and lymphoma patients

To describe utilization of a biosimilar product containing filgrastim (Neutromax^®), data of 414 myeloma or lymphoma patients subjected to autologous SCT between 1998 and 2007 were analyzed. Filgrastim was used for mobilization of progenitors (5 days at 300 μg/day) and for the recovery of neutropenia after transplantation (100 μg/day, since day +5). In 2003, the excipient mannitol was replaced by sorbitol. A mean dose of 9.47 × 10⁶ CD34⁺ cells/kg was infused; 100 neutrophils/mm³ required 5-day treatment; 500 neutrophils/mm³, 6 days and 1000 neutrophils/mm³, 7 days. Neutromax^® effect in SCT is similar to reports with other brands. No difference was found between formulations.     

Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Phase II study

Febrile neutropenia (FN) remains a potentially life-threatening complication of anticancer chemotherapy. Bacterial translocation via intestinal mucosa is a significant mechanism of FN development. Competitive inhibition of bowel colonization by pathogenic microorganisms by lactic acid bacteria could be a useful prevention of FN. The aim of the study was the prevention of FN by probiotic strain Enterococcus faecium M-74 enriched with selenium in leukemic patients. Fourteen (six males/eight females) patients with myelogenous leukemia treated by induction or consolidation chemotherapy were included in the study. Patients received prophylaxis with E. faecium M-74 during one cycle of chemotherapy. The daily dose was 36×10⁹ CFU tid. Prophylaxis started between day –2 and day +2 of chemotherapy and continued until the absolute neutrophile count (ANC) was >1,000/l. All patients experienced febrile neutropenia. During 231 days of severe neutropenia, 30 febrile episodes occurred. No any febrile episode or infection provoked by the strain tested was noticed. Tolerance of therapy was excellent without significant adverse effects. Our results demonstrate the safety of the probiotic strain E. faecium M-74 enriched with selenium in leukemic patients with severe neutropenia. However, its administration was not effective in the prevention of febrile neutropenia, but this does not preclude the protective effect of other probiotic strains.     

Mobilization of peripheral blood stem cells in high-risk breast cancer patients using G-CSF after standard dose docetaxel

Chemotherapy, in addition to recombinant growth factors, has been effective in mobilizing stem cells. Unfortunately, the use of chemotherapy for this purpose has resulted in profound myelosuppression and increased morbidity. Docetaxel, the single most active agent in the treatment of advanced breast cancer, was evaluated for its potential to mobilize stem cells when given at conventional doses followed by granulocyte colony-stimulating factor (G-CSF). Sixteen high-risk breast cancer patients were mobilized with a regimen consisting of docetaxel (100 mg/m2) followed by daily G-CSF (10 microg/kg), beginning 72 h after the docetaxel, and continuing until completion of the apheresis. The median white blood cell count (WBC) nadir was 1,000/microl (range 500 to 4000/microl ) occurring a median of 6 days (range 4 to 9 days) after the docetaxel. No patient experienced a neutropenic febrile episode due to the mobilization regimen. The median time interval for initiating the apheresis was 8 days (range 6 to 11 days) following the docetaxel. The median number of apheresis was 2 (range 1 to 3) in each patient. Stem cell recovery as measured by the CD34 cell count x 10(6)/kg was a median of 5.2 (range 1.4 to 15.1). A significant correlation was found between CFU-GM, BFU-E, and CFU-GEMM/kg and CD34 cells/kg (r = 0.891, 0.945, and 0.749, respectively, p < 0.001). When our results were compared to a matched cohort receiving G-CSF alone, the docetaxel group demonstrated a superior CD34 cells/kg yield (p = <0.001). Following myeloablative chemotherapy consisting of thiotepa and cyclophosphamide with or without carboplatinum, the hematopoetic recovery determined by an absolute neutrophil count (ANC) of greater than 500/microl and an unsupported platelet count of > or =20,000/microl for 48 h, was a median of 10 days (range 9 to 14 days) and 10 days (range 8 to 30 days), respectively. The results demonstrate that conventional dose docetaxel, combined with G-CSF, is an effective mobilization regimen with minimal toxicity in high-risk breast cancer patients.     

Prophylactic antibiotics eliminate bacteremia and allow safe outpatient management following high-dose chemotherapy and autologous stem cell rescue

This study examines the effectiveness of prophylactic ciprofloxacin and rifampin following high-dose chemotherapy and autologous stem cell rescue (HDC/ASCR). Specific endpoints included the incidence of fever, clinically documented infection, bacteremia, and readmission rates from an outpatient bone marrow transplant setting following infection or fever. A group of 97 patients receiving 134 cycles of HDC/ASCR were studied. Patients were given ciprofloxacin 750 mg p.o. twice daily and rifampin 300 mg p.o. twice daily beginning on the day of stem cell reinfusion (24-48 h after completion of high-dose chemotherapy). Most patients were either discharged to an outpatient setting following completion of their chemotherapy or received all of their chemotherapy in an outpatient setting. Febrile neutropenia was treated with empirical antibiotics in an outpatient setting unless it was complicated by hypotension, renal failure, severe mucositis or other problems. The median duration of neutropenia (absolute neutrophil count below 500/mm³) was 7 days. Neutropenic fever occurred in 62% of patients but clinically documented bacterial infection occurred in only 2 (1.5%) patients during their neutropenic period. No bacteremia was noted. Readmission to the hospital following fever or infection occurred in 26% of patients maintained in the outpatient setting. There were no deaths from a bacterial infection in this study although 1 patient (0.7%) died from aspergillosis. Prophylactic ciprofloxacin and rifampin is a well-tolerated and highly effective combination that effectively decreases the risk of both gram-positive and gram-negative bacterial infection following HDC/ASCR. It facilitates outpatient management of myelosuppressed patients receiving autologous stem cell rescue.Presented in part as an invited lecture at the 7th International Symposium: Supportive Care in Cancer, Luxembourg, 20–23 September 1995     

伊曲康唑联合重组人粒细胞集落刺激因子治疗中性粒细胞减少的血液病患者侵袭性真菌感染的疗效及安全性评价

目的 评价伊曲康唑联合重组人粒细胞集落刺激因子（rhG-CSF）治疗中性粒细胞减少的血液病患者合并侵袭性真菌感染的临床疗效及安全性.方法 回顾性分析2007年1月至2011年12月收治的103例血液病合并真菌感染的患者,治疗期间72例患者出现粒细胞缺乏,其中44例患者应用伊曲康唑联合rhG-CSF治疗（治疗组）,28例患者单独应用伊曲康唑治疗（对照组）.结果 治疗组患者有效率为72.73％,对照组为46.43％（P＜0.05）;中性粒细胞≤500/mm3且≥100/mm3的患者抗真菌治疗有效率明显高于中性粒细胞≤100/mm3的患者（P＜0.05）;粒缺持续时间≤10 d的抗真菌治疗有效率明显低于粒缺持续时间＜10 d的患者（P ＜0.05）;72例患者中确诊9例、临床诊断33例、拟诊30例;确诊组有效率低于临床诊断与拟诊组（P＜0.05）,抢先性治疗组（87.50％）和经验性治疗组（64.00％）的有效率均明显高于目标性治疗组（34.78％）,差异有统计学意义（P均＜0.05）.结论 伊曲康唑联合rhG-CSF治疗中性粒细胞减少的血液病患者真菌感染是有效安全的;中性粒细胞减少的程度和时间是影响真菌治疗效果的重要因素.     

Efficacy and safety of lipegfilgrastim compared with placebo in patients with non-small cell lung cancer receiving chemotherapy: post hoc analysis of elderly versus younger patients

Purpose

Lipegfilgrastim, a glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF), reduces neutropenia duration and febrile neutropenia (FN) incidence in patients with cancer receiving myelosuppressive chemotherapy. A phase 3 trial of lipegfilgrastim was conducted in patients with advanced non-small cell lung cancer (NSCLC) receiving cisplatin/etoposide (which produces mild-to-moderate myelosuppression). Because patients aged >65 years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (>65 years) versus younger participants in this trial.

Methods

Patients were randomized 2:1 to receive a once-per-cycle single subcutaneous injection of lipegfilgrastim 6 mg or placebo, with up to 4 cycles of every-3-week cisplatin (day 1) and etoposide (days 1–3). The primary end point was FN incidence during cycle 1. Outcomes were compared across treatment groups and by age groups (≤65 and >65 years).

Results

For patients aged ≤65 years, FN incidence during cycle 1 was similar in the lipegfilgrastim and placebo groups (3.0 vs 3.2 %, respectively), whereas for elderly patients, there was a reduction in FN incidence with lipegfilgrastim (0 vs 13.3 %, respectively). In both age subgroups, lipegfilgrastim showed a propensity to reduce the incidence and duration of severe neutropenia, time to absolute neutrophil count (ANC) recovery, and depth of ANC nadir. Adverse events were generally similar between groups.

Conclusions

This analysis suggests that in patients with a higher FN risk, such as the elderly patients of this study, lipegfilgrastim reduces not only the duration of severe neutropenia but also the incidence of FN.

     

A randomized, crossover comparison of standard-dose versus low-dose lenograstim in the prophylaxis of post-chemotherapy neutropenia

The aim of this trial was to compare the severity of neutropenia, the frequency of hospital admission for fever or infection, and the use of antibiotics among patients treated with a standard dose of lenograstim (263 microg/day of Euprotin) and others treated with half of this dose (131.5 microg/day) and the cost-effectiveness of each of the two doses. In this single-center study, 44 patients with solid tumors, who were all receiving standard-dose chemotherapy regimens following previous neutropenia or were at high risk of neutropenia, were randomized to receive lenograstim at a dose of 263 microg or 131.5 microg daily in the first cycle and then crossed over to the alternate dose for the following cycle. Crossover to the alternate dose was repeated for patients who received more than two cycles. Lenograstim was administered from day +5 to day +14. The absolute neutrophil count (ANC) was assessed on days +5, +8, +12 and +15 of each cycle. Statistical analysis was performed using a general lineal model for repeated samples. In all, 120 cycles were administered, with a median of 3 cycles (range 1-6). Only 4 patients received only 1 cycle. No statistically significant difference (P=0.324) in ANC was observed between standard-dose (mean 5.3, 10.7, 8.3, 11.4 x 10(9)/l) and low-dose (5.0, 8.6, 5.4, 7.5 x 10(9)/l) treatment at days +5, +8, +12 and + 15. Neutropenia grade III-IV was more common in patients receiving the low than in those receiving the standard dose of lenograstim (20% vs 12%, respectively), but the difference did not reach statistical significance (P=0.1). The incidence of fever and frequency of hospital admission were not affected by the dose of lenograstim: 3 patients presented with fever with the standard dose (all of those were admitted to hospital) and 2 patients with the low dose (1 was admitted). ANC in both groups (standard and low doses) was independent of chemotherapy line (first versus second or more). Lenograstim at a dose of 131.5 microg/day is as effective as the standard dose in limiting the severity of neutropenia and in preventing episodes of fever and hospital admissions after chemotherapy for solid tumors. The lower dose of lenograstim is cost-effective in neutropenia prophylaxis. Starting its administration on day +5 reduces costs while maintaining efficacy.     

Resource implications of febrile neutropenia in cancer patients

 No previous study has compared countries with respect to differences in clinical practice and resource use of cancer patients with febrile neutropenic episodes (FNE). The purpose of this international, cross-sectional pilot study conducted in tertiary care centers across Europe, Brazil and Australia was to evaluate the resource use attributable to febrile neutropenia in different countries. A total of 17 centers from eight countries provided 128 patients. The leading malignant disorders were hematological malignancies (n=47), lymphomas (n=27), and breast cancer (n=26). The median length of duration of FNE was 4 days (interquartile range, 3–8). The incidence density of antimicrobial exposure was 4.691 days of antimicrobial therapy per 1,000 days of FNE. There were 23 patients who received a total of 280 days of G-CSF therapy. On average, 5 (±5.4) blood samples per patient were drawn and cultured. The most common diagnostic radiographic test was the chest X-ray, with a total of 224 such examinations performed in 82 patients. We conducted an international cross-sectional study on resource implications of febrile neutropenia in cancer patients. The records of the febrile neutropenic patients included in this study reflect clinical practice in a heterogeneous, international patient population, treated with modern supportive care and early empiric antibiotics by clinicians at different levels of expertise. Published online: 22 July 1999     

Specific MAIT cell behaviour among innate-like T lymphocytes in critically ill patients with severe infections

Purpose

In between innate and adaptive immunity, the recently identified innate-like mucosal-associated invariant T (MAIT) lymphocytes display specific reactivity to non-streptococcal bacteria. Whether they are involved in bacterial sepsis has not been investigated. We aimed to assess the number and the time course of circulating innate-like T lymphocytes (MAIT, NKT and γδ T cells) in critically ill septic and non-septic patients and to establish correlations with the further development of intensive care unit (ICU)-acquired infections.

Methods

We prospectively enrolled consecutive patients with severe sepsis and septic shock. Controls were critically ill patients with non-septic shock and age-matched healthy subjects. Circulating innate-like lymphocytes were enumerated using a flow cytometry assay at day 1, 4 and 7.

Results

One hundred and fifty six patients (113 severe bacterial infections, 36 non-infected patients and 7 patients with severe viral infections) and 26 healthy subjects were enrolled into the study. Patients with severe bacterial infections displayed an early decrease in MAIT cell count [median 1.3/mm³; interquartile range (0.4–3.2)] as compared to control healthy subjects [31.1/mm³ (12.1–45.2)], but also to non-infected critically ill patients [4.3/mm³ (1.4–13.2)] (P < 0.0001 for all comparisons). In contrast NKT and γδ T cell counts did not differ between patients groups. The multivariate analysis identified non-streptococcal bacterial infection as an independent determinant of decrease in MAIT cell count. Furthermore, the incidence of ICU-acquired infections was higher in patients with persistent MAIT cell depletion.

Conclusions

This large human study provides valuable information about MAIT cells in severe bacterial infections. The persistent depletion of MAIT cells is associated with the further development of ICU-acquired infections.     

Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm³) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.     

Daptomycin use in neutropenic patients with documented gram-positive infections

Purpose

The goal of this study was to describe the outcomes associated with daptomycin treatment of documented gram-positive infections in patients with neutropenia.

Methods

All patients with neutropenia (≤500 cells/m³) and at least one documented gram-positive culture from 2006–2009 were identified from a retrospective, multicenter, and observational registry (Cubicin® Outcome Registry and Experience (CORE®)). Investigators assessed patient outcome (cured, improved, failed, nonevaluable) at the end of daptomycin therapy. All patients were included in the safety analysis.

Results

The efficacy population had 186 patients; 159 (85 %) patients had either cure (n?=?108, 58 %) or improved (n?=?51, 27 %) as an outcome. Success rates (cure plus improved) by the lowest WBC during daptomycin were 98/116 (84 %) for ≤100 cells/m³ and 61/70 (87 %) for 101–499 cells/m³, P?=?0.6. Most patients had cancer; 135/186 (73 %) had hematological malignancy; 26/186 (14 %) had solid tumors, and 9 (5 %) had both. One hundred fifty-six (84 %) patients received other antibiotics before daptomycin treatment; 82 % vancomycin, of which 31 % failed vancomycin. The most common infections were bacteremia (78 %), skin and skin structure infections (8 %), and urinary tract infections/pyelonephritis (6 %). The most common pathogens were vancomycin-resistant Enterococcus faecium (47 %), methicillin-resistant Staphylococcus aureus (20 %), and coagulase-negative staphylococci (19 %). The median (min, max) initial daptomycin dose was 6 mg/kg (3.6, 8.3). The median (min, max) daptomycin duration of therapy was 14 days (1, 86). Possibly related adverse events occurred in 12/209 patients (6 %), and 13 patients (6 %) discontinued daptomycin due to adverse event.

Conclusions

The results suggest that daptomycin appeared useful and well tolerated in neutropenic patients, and the degree of neutropenia did not affect daptomycin success rates. Comparative clinical trials are needed to confirm these findings.     

Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia

Increasing bacterial antimicrobial resistance has prompted physicians to choose broad-spectrum antimicrobials in order to reduce the likelihood of inactive empirical therapy. However, for bacteremic patients already receiving supportive care, it is unclear whether delay of active antimicrobial therapy significantly impacts patient outcomes. We performed a retrospective cohort study of patients with monomicrobial bloodstream infections at a large urban hospital in the United States from 2001 to 2006. We assessed the impact of delay of active antimicrobial therapy on mortality by using multivariable logistic regression modeling with and without propensity score methodology. We evaluated 1,523 episodes of monomicrobial bacterial bloodstream infections at our institution. Nine hundred eighty-three bacteremic episodes (64.5%) were treated with an active antimicrobial agent within 24 h of the index blood culture; the remaining 540 episodes (35.5%) were considered to have delay of active antimicrobial therapy. In adjusted analysis, among patients in the non-intensive-care-unit setting with an absolute neutrophil count (ANC) of <100 cells/μl, delay was associated with increased mortality (odds ratio [OR], 18.0; 95% confidence interval [CI], 2.84 to 114.5; P < 0.01); among intensive-care-unit patients with an ANC of <100 cells/μl, the effect of delay on mortality was nearly significant (OR, 5.56; 95% CI, 0.85 to 36.3; P = 0.07). However, for patients who were nonneutropenic (ANC, >500 cells/μl) or had ANCs of 100 to 500 cells/μl, delay was not associated with increased mortality. While the delay of active antimicrobial therapy was not significantly associated with higher mortality for most patients in this cohort, patients with severe neutropenia appeared to be vulnerable.     

Clinical efficacy of adjunctive G-CSF on solid tumor and lymphoma patients with established febrile neutropenia

Background

The use of granulocyte colony-stimulating factor (G-CSF) as a prophylaxis against febrile neutropenia (FN) is well documented in the literature; however, the therapeutic use of G-CSF in the treatment of FN remains controversial. This study assessed the efficacy of adjunctive G-CSF in the treatment of FN by evaluating clinical outcomes.

Methods

This was a single-center, prospective cohort study conducted at the National Cancer Center in Singapore. Adult patients who had received chemotherapy and developed FN between January 2009 and January 2012 were included in the analysis. The clinical efficacy of adjunctive G-CSF was evaluated by investigating the duration of hospitalization, duration to absolute neutrophil count (ANC) recovery, duration of grade IV neutropenia, duration to fever resolution, duration of antibiotic therapy, and incidence of documented infections. A multivariate analysis was performed to identify patients who could potentially benefit from adjunctive G-CSF.

Results

Four hundred and thirty patients were analyzed. Majority manifested low-risk FN (81.2 %) based on the Multinational Association of Supportive Care in Cancer (MASCC) scoring. Compared to patients who did not receive adjunctive G-CSF, patients receiving adjunctive G-CSF had a nonsignificant reduction in the duration of hospitalization (3.5 vs. 3.7 days, p?=?0.41) and in ANC recovery time (3.4 vs. 3.5 days, p?=?0.76). Neutropenia-related mortality was lower among those who have received adjunctive G-CSF (2.4 vs. 8.4 %, p?=?0.006). Patients of Indian ethnicity and those who underwent gemcitabine-containing chemotherapy were less likely to receive adjunctive G-CSF treatment.

Conclusions

This observational study suggested that adjunctive G-CSF may confer clinical benefits among solid tumor and lymphoma patients with established febrile neutropenia. Further research should be conducted to validate the findings.