达托霉素用于治疗粒细胞缺乏症患者革兰阳性菌感染

多中心回顾性观察研究评价达托霉素治疗粒细胞减少症患者革兰阳性菌感染的临床疗效。     

达托霉素在中性粒细胞减少伴发热成人肿瘤患者中的药动学

达托霉素为第一个环脂肽类抗菌药,体外对万古霉素耐药肠球菌、甲氧西林耐药葡萄球菌及糖肽类耐药金葡菌等革兰阳性菌具有杀菌活性。作者报道了在29例中性粒细胞减少伴发热成人肿瘤患者中进行达托霉素的药动学研究结果。给予29例中性粒细胞减少伴发热肿瘤患者单剂30min内静脉滴注达托霉素6mg／kg,并分别留取用药前及用药结束后0、0．5、1、2、4、8、12和24h血样。     

Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections.

Ten patients were treated with conventional dosing (CD) and continuous-infusion (CI) vancomycin therapy in this prospective, randomized, crossover study. Patients were randomized to receive either CD or CI therapy for 2 consecutive days and then crossed over to receive the opposite regimen for 2 days. CD therapy consisted of 1 g of vancomycin every 12 h. CI therapy consisted of a 500-mg loading dose followed by 2 g infused over 24 h. Ten serum samples were obtained on the second day of each therapy for pharmacokinetic and pharmacodynamic analyses. Two clinical isolates of Staphylococcus aureus, one methicillin sensitive (MSSA 1199) and one methicillin resistant (MRSA 494), were chosen for pharmacodynamic evaluation of both regimens. The patient demographics (means +/- standard deviations [SD]) were as follows: sex, six males, four females; age, 36 +/- 11 years; and serum creatinine, 0.72 +/- 0.18 mg/dl. Mean pharmacokinetic parameters +/- SD for CD therapy were as follows: elimination rate constant, 0.16 +/- 0.07 h-1; half-life, 5.6 +/- 3.5 h; volume of distribution, 33.7 +/- 25 liters, 0.5 +/- 0.2 liters/kg; maximum concentration in serum, 53.4 +/- 19.3 micrograms/ml; and minimum concentration, 8.4 +/- 5.9 micrograms/ml. The steady-state concentration for CI was 20.2 +/- 11.1 micrograms/ml. Overall, both regimens resulted in the MIC being exceeded 100% of the time. The mean CD trough serum bactericidal titer (SBT) was 1:8, and the average CI SBTs were 1:16 for both isolates. Even though there was no statistically significant difference between CD trough and CI SBTs, the CI SBTs remained > 1:8 for 100% of the time versus 60% of the time for CD therapy. During CI therapy, 20 and 40% of the patients maintained SBTs of > 1:32 throughout the dosing interval for MSSA 1199 and MRSA 494, respectively. During CD therapy, however, only 10% of patients maintained SBTs of > 1:32 during the entire dosing interval for both isolates. The mean areas under the bactericidal titer-time curve (AUBC24s) +/- SD for MSSA 1199 were 528 +/- 263 for CD therapy and 547 +/- 390 for CI therapy. The mean AUBC24s +/- SD against MRSA 494 were 531 +/- 247 for CD and 548 +/- 293 for CI therapy. Similar to the AUBC24, the mean area under the concentration-time curve for a 24-h dosing interval divided by the MIC (AUC/MIC24) ratios +/- SD were 550.0 +/- 265.7 for CD and 552.6 +/- 373.4 for CI therapy, respectively. No statistically significant differences were found between any of the pharmacodynamic parameters for CD and CI therapy. In addition, no adverse effects with either CD or CI therapy were observed during the study. We conclude that CI and CD vancomycin therapy demonstrated equivalent pharmacodynamic activities. Although CI therapy was more likely to result in SBTs that remained above 1:8 for the entire regimen, the clinical impact of this result is unknown. Serum drug concentration variability was observed with both treatment regimens but to a lesser extent with CI administration. CI administration of vancomycin should be further evaluated to determine the clinical utility of this method of administration.     

Diagnosing fungal infections in neutropenic patients

Fungal infections are among the most serious complications in neutropenic patients. A major problem that has compromised management of fungal infections is healthcare professionals' inability to recognize the infections when they occur. No adequate diagnostic tools exist to detect many of the fungal infections. Early diagnosis of disseminated candidiasis is a challenge because only 35%-50% of neutropenic patients have positive blood cultures (Bodey, 1997), and radiologic tests have low specificity in that patient population. For example, a routine chest x-ray can be negative, yet a computed tomography (CT) scan of the chest can be positive for pneumonia the next day. Therefore, fungal infections often are advanced before diagnostic confirmation; thus, overall outcomes are poor. A great effort has been invested in developing serologic tests to detect circulating antigens of fungi.     

Daptomycin dose-effect relationship against resistant gram-positive organisms

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.     

Peroperative teicoplanin for prevention of gram-positive infections in neutropenic patients with indwelling central venous catheters: a randomized, controlled study

 A prospective, randomized, open study comparing two doses of teicoplanin with no therapy administered at the time of insertion of a central venous catheter was performed in patients with hematological malignancies and in patients scheduled to undergo allogeneic or autologous stem cell transplantation. The study was designed as a group sequential study. At predetermined intervals statistical analysis was performed for the main efficacy variable, which was the number of days to treatment failure. Sixty-five patients were randomized. Three patients were judged to be not evaluable. Baseline characteristics were identical in the two groups. No differences were found in overall infections, bacteremias, gram-positive infections, or local infections between the teicoplanin and control groups. Teicoplanin given at the time of insertion of central venous catheters did not reduce the risk of bacteremias or other line-associated infections.     

Empirical therapy for bacterial infections in neutropenic patients

Infection in neutropenic patients remains a continuing challenge as the modalities of cancer treatment evolve and new pathogens appear. Although the concept of empirical therapy remains valid, there is a need for adaptation of our therapeutic approaches to new clinical and microbiological evidence.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

Addition of teicoplanin or vancomycin for the treatment of documented bacteremia due to gram-positive cocci in neutropenic patients with hematological malignancies: microbiological, clinical and economic evaluation

A prospective, randomized, double-blind trial was conducted on 124 febrile patients with hematological malignancies to compare teicoplanin with vancomycin as an addition to the initial empiric amikacin-ceftazidime regimen after documented bacteremia due to gram-positive cocci. At enrollment, patients in both groups were comparable with respect to age, sex, underlying hematologic disorders and duration of neutropenia. Rates of therapeutic success were 55/63 (87.3%) in the teicoplanin group and 56/61 (91.8%) in the vancomycin group (p = 0.560). The mean duration of treatment was similar, being 12.2 and 11.4 days, respectively (p = 0.216). Patients treated with teicoplanin remained febrile for slightly longer than those treated with vancomycin (4.9 vs. 4.0 days) (p = 0.013). Thirteen patients experienced an adverse drug reaction, but without any significant difference in the two arms. Isolated staphylococci showed a progressive and significant decrease in susceptibility to both glycopeptides during the 8 study years. The economic analysis performed showed that the addition of vancomycin is cost-saving.     

Management of infections in critically ill neutropenic cancer patients

Because of improving antineoplastic treatment options with increasing cure rates, prolonging survival, and improving quality of life, the reluctance to admit patients with malignant disease to an intensive care unit is not justified; thus, the number of patients with malignancies treated in intensive care units rises. The use of more aggressive anticancer regimens leads to an increase of attendant infections, which are the most frequent and often life-threatening complications in cancer patients. A multidisciplinary practical approach to evaluation and treatment is needed to optimize treatment results and to meet the various diagnostic and therapeutic challenges in this subset of patients on an intensive care unit.     

利奈唑胺治疗恶性血液病患者粒细胞减少期并发革兰阳性菌感染的疗效观察

目的评价恶性血液病患者化疗后中性粒细胞减少期并发革兰阳性菌感染利奈唑胺治疗的疗效和安全性。方法28例化疗后中性粒细胞减少的恶性血液病患者,在明确诊断并发革兰阳性菌感染后,给予利奈唑胺注射液治疗。同时观察用药前后疗效和不良反应。结果患者经利奈唑胺治疗,痊愈50%(14/28),显效28.3%(8/28),进步7.1%(2/28),无效14.2%(4/28),临床有效率78.6%。细菌清除率78.6%(21/28)。药物相关不良反应发生率为14.2%(4/28),其中临床不良反应2例(7.1%,2/28),主要为胃纳减退等胃肠道反应,实验室检测异常2例(7.1%,2/28),表现为一过性血小板减少。结论利奈唑胺是治疗恶性血液病患者中性粒细胞减少期并发革兰阳性菌感染的良好选择,患者耐受性好。     

Emerging gram-positive bacterial infections

Over the last several decades, a number of previously known or newly described species of gram-positive bacteria have emerged as important human pathogens, particularly in industrialized countries. These microbes have demonstrated an impressive ability to produce an array of striking infectious diseases never before seen or only infrequently encountered in the past. Despite aggressive therapeutic intervention, many of these conditions portend significant morbidity and mortality. Diseases caused by members of the Staphylococcus and Streptococcus genera have figured prominently in this regard, with Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes, and other beta-hemolytic streptococci being regarded as the most important species. This review focuses on the clinical and microbiologic aspects of key emerging infections caused by this group of microorganisms.     

Defining invasive fungal infections in neutropenic or stem cell transplant patients

Consistent definition of invasive fungal infection is important for managing individual patients, for conducting clinical trials and for evaluating diagnostic tests. However, a recent systematic review of the literature found that at least 25 adverbs have been used to categorize infections and when the criteria in these papers were applied to a single database of patients with fungal infections, there was little agreement. This is the consequence of the varying sensitivity and specificity of different clinical features and investigations in different patient groups and an inconsistency in their application. This review examines the clinical presentation of invasive fungal infections in neutropenic patients and those receiving stem cell transplants, as well as the performance of currently available investigations, in order to consider their value as invasive fungal infection criteria. The recent publication of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions has provided an international standard for the performance of clinical research in this group of patients. The definitions committee has now been reconvened to consider some of the criticisms of the original criteria and these are likely to evolve further in the future.     

White blood cell transfusions for control of infections in neutropenic patients

Four hundred and fifty-four leukocyte transfusions from unrelated donors with chronic myelogenous leukemia were given to 128 patients during 179 febrile episodes with a median circulating granulocyte count prior to leukocyte transfusions of 80/cm. Forty-nine per cent of the serious and life-threatening infections responded to a combination of granulocyte transfusions and appropriate antibiotic therapy. Minor complications occurred in approximately 25 per cent of patients and more severe toxicity was seen in only 2 per cent. No deaths were attributed to leukocyte transfusions.     

Comparison of fluconazole with oral polyenes in the prevention of fungal infections in neutropenic patients

The goal of this prospective randomized single-center study was the comparison of safety and efficacy of high-dose oral/intravenous fluconazole (400 mg daily) (group A) with oral nystatin plus miconazole inhalations (group B) in the prevention of fungal infections on a hemato-oncological isolation Ward. Of 157 patients admitted to the isolation ward during the study period only 90 (57%) were eligible for randomization; 22 (14%) had a fungal infection at admission. Of the 90 randomized patients, 89 were evaluable, 43 in group A and 46 in group B. The age, sex, diagnosis, planned therapy and risk factors for fungal infections at admission as well as the duration of neutropenia were in the same proportions in both groups. Oral thrush and mucocutaneous candidiasis were prevented in all patients of both groups, and 29 patients (32%: 17 in group A, 12 in group B) were discharged after successful prophylaxis (NS). Empiric amphotericin B was given according to predetermined criteria to 45 patients (51%: 23 group A, 22 group B; NS). Fluconazole significantly delayed the time before the start of intravenous amphotericin B. It was begun after a median of 10 days (0–45 days, range) of neutropenia below 0.5x10⁹ granulocytes/l in group A and 7.5 days (0–26, range) in group B (P<0.05). The duration of successful prophylaxis was significantly longer in group A (26 days median) than in group B (21 days, median) (P<0.05). Systemic fungal infection was documented in 3 patients (1 group A, 2 group B; NS). Colonisation with Candida persisted for more than 14 days or occurred de novo after admission in 1 patient in group A and in 7 patients in group B (NS). Oral nystatin had to be discontinued because of oral intolerance in 3 patients and fluconazol had to be stopped because of increased liver values in one patient. Compliance was worse (P<0.01) in group B; 82% of the planned dose was given in group B compared to 99% in group A. Both regimens successfully prevented oral fungal complications. Fluconazole was better tolerated and delayed the need for empiric amphotericin B. Neither approach cancelled the need for the empiric use of amphotericin B nor prevented fungal infections or colonization. Systemic fungal infections occur probably independently of oral or mucocutaneous candidiasis.