血液病房革兰阳性球菌感染病例回顾分析

本研究回顾性分析了利奈唑胺、万古霉素、替考拉宁治疗血液科革兰阳性球菌患者的疗效和安全性.选择解放军总医院2011年1月-12月细菌培养为革兰阳性球菌并使用利奈唑胺、万古霉素或替考拉宁单药治疗的血液科住院发热患者.记录用药前后各种参数包括退热时间、呼吸道症状、体征、影像学改变、血常规指标、生化常规指标、不良反应发生情况.比较利奈唑胺、万古霉素、替考拉宁3种药物的退热时间、细菌清除率、临床有效率及不良反应发生情况.三组患者分别为利奈唑胺15例,万古霉素17例,替考拉宁20例.结果表明,利奈唑胺治疗组平均退热时间（4.43 ±3.15）d,细菌清除率55.56％,临床有效率86.67％;万古霉素治疗组平均退热时间（6.83±4.67）d,细菌清除率54.54％,临床有效率76.47％;替考拉宁组平均退热时间（5.57±4.16）d,细菌清除率41.67％,临床有效率80.00％.三组组间比较无统计学差异,P＞ 0.05.利奈唑胺组中发生腹泻1例,血小板减少2例;万古霉素组中发生恶心1例,肌酐升高2例;替考拉宁组中发生血小板减少3例.5例血小板下降均与白血病患者治疗后血象下降重叠,未停药,血小板随造血功能恢复而正常,与用药无关.结论：利奈唑胺、万古霉素、替考拉宁三组药物治疗革兰阳性球菌感染疗效相当,并无统计学差异,但利奈唑胺的退热时间、细菌清除率及临床有效率有优于万古霉素和替考拉宁的趋势.     

Safety and tolerability of linezolid

Clinical trials have shown that linezolid (600 mg twice daily in adults) is safe and generally well tolerated for up to 28 days. Drug-related adverse events, which are typically mild to moderate in intensity and of limited duration, include diarrhoea, nausea and headache in adults, and diarrhoea, loose stools and vomiting in children. Clostridium difficile-related complications with linezolid are uncommon. Linezolid is a weak, reversible monoamine oxidase inhibitor: foods containing high concentrations of tyramine should be avoided, and linezolid should be used with caution in patients taking adrenergic or serotonergic agents or in those with uncontrolled hypertension. In the majority of patients, linezolid has minimal adverse effects on blood chemistry or haematology. There have been case reports of reversible thrombocytopenia, anaemia and neutropenia associated with linezolid therapy. In Phase III studies, 2.4% of patients treated with linezolid and 1.5% of patients treated with comparator drugs developed reversible thrombocytopenia (P = 0.066), but there was no evidence of an increased risk of agranulocytosis, aplastic anaemia or other irreversible blood dyscrasias. Reduced platelet counts were associated with linezolid treatment for >/=2 weeks; complete blood counts should be monitored weekly in patients receiving linezolid for more than 14 days and treatment should be discontinued if there is evidence of myelosuppression.     

Severe linezolid-induced lactic acidosis in a child with acute lymphoblastic leukemia: A case report

Linezolid is an antibiotic increasingly used for treatment of resistant Gram-positive infections, which blocks bacterial proteosythesis through direct inhibition of mitochondrial ribosomes. The most common adverse effects of linezolid include gastrointestinal symtoms, peripheral neuropathy, bone marrow depression and lactic acidosis.Here we present a rare case of a 9-year-old female, a survivor of acute lymphoblastic leukemia (ALL) and a hematopoietic stem cell transplant (HSCT), who developed life-threatening lactic acidosis with vomiting, impaired consciousness and Kussmaul breathing after 51 days of intravenous linezolid administration due to mycobacterial infection. She fully recovered after drug discontinuation and normalization of the plasma levels.We conclude that plasma lactate concentrations should be monitored closely during any linezolid treatment, particularly in patients with hepatic or renal dysfunction.     

Modeling the economic impact of linezolid versus vancomycin in confirmed nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus

Introduction

We compared the economic impacts of linezolid and vancomycin for the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA)–confirmed nosocomial pneumonia.

Methods

We used a 4-week decision tree model incorporating published data and expert opinion on clinical parameters, resource use and costs (in 2012 US dollars), such as efficacy, mortality, serious adverse events, treatment duration and length of hospital stay. The results presented are from a US payer perspective. The base case first-line treatment duration for patients with MRSA-confirmed nosocomial pneumonia was 10 days. Clinical treatment success (used for the cost-effectiveness ratio) and failure due to lack of efficacy, serious adverse events or mortality were possible clinical outcomes that could impact costs. Cost of treatment and incremental cost-effectiveness per successfully treated patient were calculated for linezolid versus vancomycin. Univariate (one-way) and probabilistic sensitivity analyses were conducted.

Results

The model allowed us to calculate the total base case inpatient costs as $46,168 (linezolid) and $46,992 (vancomycin). The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with lower costs ($824 less) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA nosocomial pneumonia). Approximately 80% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). The results of our probabilistic sensitivity analysis indicated that linezolid is the cost-effective alternative under varying willingness to pay thresholds.

Conclusion

These model results show that linezolid has a favorable incremental cost-effectiveness ratio compared to vancomycin for MRSA-confirmed nosocomial pneumonia, largely attributable to the higher clinical trial response rate of patients treated with linezolid. The higher drug acquisition cost of linezolid was offset by lower treatment failure–related costs and fewer days of hospitalization.     

利奈唑胺对老年患者血液系统的影响

目的探讨利奈唑胺对老年患者血液系统产生的不良影响,为合理用药和提高老年患者用药安全性提供参考。方法回顾性分析2011~2012年在住院期间曾使用利奈唑胺抗感染治疗的老年患者血液系统异常的发生率及特点。结果使用利奈唑胺后15.6%患者白细胞降低至正常值以下,但停药后多数可恢复。42.2%患者发生血红蛋白下降,其中不到半数患者停药后可恢复至治疗前水平,且需时间较长。78.1%患者出现血小板降低,其中42.2%降低至正常值以下,25%降至50×109/L以下,大多数患者停药2周后血小板可恢复至治疗前水平。结论老年患者使用利奈唑胺后血液系统不良反应的发生率和严重程度高于其他人群,故老年患者使用利奈唑胺过程中需密切监测血常规。     

Varying linezolid susceptibility of vancomycin-resistant Enterococcus faecium isolates during therapy: a case report

OBJECTIVES: Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by vancomycin-resistant enterococci. Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA. Patient and methods: We present clinical details and susceptibility data from multiple Enterococcus faecium strains isolated from a liver transplant patient over 13 months. MICs of linezolid, vancomycin and quinupristin/dalfopristin were determined using Etest. Molecular typing was performed by pulsed-field gel electrophoresis. Domain V of the 23S rRNA gene in the vancomycin-resistant Enterococcus faecium was amplified. Linezolid concentrations were analysed by HPLC. RESULTS: We report the emergence of resistance to linezolid in a vancomycin-resistant Enterococcus faecium during linezolid treatment. After discontinuation of the linezolid therapy, the isolate reverted to susceptibility. However, after re-administration of linezolid the vancomycin-resistant Enterococcus faecium became resistant to linezolid again. The isolates that were resistant to linezolid had a G2576T mutation in their 23S rDNA. CONCLUSION: We describe a clinical case that shows the shift of a vancomycin-resistant Enterococcus faecium from linezolid resistance to susceptibility and then back to resistance again related to linezolid therapy.     

Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis

OBJECTIVES: Although linezolid has good in vitro activity against Mycobacterium tuberculosis, its long-term use in the treatment of multidrug-resistant tuberculosis (MDR-TB) may be limited by its cost and serious adverse reactions. We therefore evaluated the efficacy and tolerability of a reduced dose of linezolid, in combination with other anti-TB drugs, in patients with intractable or extensive MDR-TB. METHODS: MDR-TB patients unresponsive to at least three cycles of treatment were treated with daily-half doses of linezolid (600 mg once per day) plus at least four companion drugs. RESULTS: As of March 2006, eight patients, all HIV-negative, had been treated with linezolid for 3-18 months. Cultures became negative in all patients in an average of 82 days. Four patients developed peripheral neuropathy, two developed optic neuropathy and one developed anaemia. Although optic neuropathy resolved after cessation of linezolid therapy, peripheral neuropathy continued. One patient completed 18 months of linezolid therapy. Two patients, who have taken linezolid for 15-17 months, are still on treatment and remain in culture conversion. Three patients stopped linezolid after 7-9 months, two because of side effects and one for economic reasons, but remain on treatment with other second-line drugs with culture conversion. Two patients died from severe respiratory failure, but both previously had shown culture conversion. CONCLUSIONS: Although daily-half doses of linezolid were effective in patients with intractable or extensive MDR-TB, this dosage regimen did not reduce long-term use-related side effects, such as peripheral and optic neuropathy.     

Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient

Linezolid was initially discovered as an antidepressant because of its effect on blocking intracellular metabolism of serotonin, norepinephrine, and other biogenic amines. As time passed, it was realized that linezolid possessed antibacterial activity, and linezolid has been developed and marketed as such. In medicine we are quick to categorize drugs into specific classes as a mechanism to recall indication and use. By classifying linezolid as an antibacterial, it is common to forget about its antidepressant roots. A case report involving linezolid with citalopram and mirtazepine in the precipitation of serotonin syndrome in a critically ill bone marrow transplant patient is described in this article.     

Chronic mandibular osteomyelitis caused by Granulicatella adiacens in an immunocompetent child

We report a pediatric case aged 10 years with Granulicatella adiacens-associated chronic mandibular osteomyelitis. The causative pathogen was uncertain because polymicrobial species were detected from the bacterial culture in bone marrow fluid. In contrast, G. adiacens was predominantly identified in the clone library analysis of the bacterial 16S rRNA gene sequence. Vancomycin to which G. adiacens was reported to be susceptible was not administrated sufficiently to this patient because of its adverse event, whereas linezolid and ciprofloxacin was alternatively effective for the treatment of chronic mandibular osteomyelitis.     

Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma

Paracetamol overdose is a common reason for presentation to the emergency department and N-acetylcysteine is frequently used in the treatment of toxic paracetamol ingestions. Adverse reactions to N-acetylcysteine are common though usually mild and easily treated. Serious reactions to N-acetylcysteine however, are rare and there have been no previous reported fatalities with its therapeutic use. This report describes the case of a 40 year old brittle asthmatic patient who died after treatment with intravenous N-acetylcysteine. Asthma is a risk factor for adverse reactions to N-acetylcysteine and special caution should be exercised in its use in brittle asthmatic patients.     

Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia

What is known and objective: Serotonin syndrome can be a rare but life‐threatening condition that is commonly the result of a drug–drug interaction causing excessive serotonin activity. The symptoms associated with serotonin syndrome can include hyperthermia, mental status changes, autonomic hyperactivity and neuromuscular abnormalities, all of which can be concealed in the critically ill patient owing to concomitant therapies. The objective of this case report is to describe a probable drug–drug interaction between buspirone and linezolid, and to highlight the potential confounding effects of hypothermia in this case. Case summary: We present a case of a 28‐year‐old man who potentially developed serotonin syndrome after coadministration of buspirone and linezolid while being therapeutically cooled for traumatic brain injury. The patient developed hyperthermia, hypertension and tachycardia when buspirone and linezolid were administered concomitantly for 2 days. Symptoms resolved within 24 h after discontinuation of both medications. What is new and conclusions: Caution should be used in patients receiving multiple serotonergic agents in addition to therapeutic hypothermia. The use of therapeutic hypothermia may mask the symptoms associated with serotonin syndrome, thus delaying the diagnosis and treatment of this potentially deadly condition. If a patient requires the combination of such medications, close monitoring for the symptoms of serotonin syndrome is warranted.     

Reversibility of blue-gray cutaneous discoloration from amiodarone

A 45-year-old man had severe blue-gray cutaneous discoloration during amiodarone therapy for atrial fibrillation. Therefore, this drug regimen was discontinued, and long-term anticoagulation and digoxin therapy were used. The patient was advised to avoid exposure of his skin to sunlight, and a bleaching agent was prescribed. After 18 months of follow-up, the blue-gray hyperpigmentation had diminished. Although photosensitivity reactions from amiodarone occur in more than 50% of patients, blue-gray cutaneous discoloration occurs in less than 10% of patients on prolonged therapy with amiodarone. The presence of high concentrations of iodine, detected by electron probe analysis, suggests that the cutaneous deposits are amiodarone itself or a metabolite. The slow rate of elimination of amiodarone and a high uptake by fat-associated tissues may explain the delayed disappearance of cutaneous photosensitivity and late resolution of the blue-gray discoloration. Our current case supports the reversibility of these adverse effects on long-term follow-up.     

Antidepressant-induced adverse reactions in a patient with hemorrhagic stroke

OBJECTIVE: To report a case of antidepressant-induced adverse drug reactions in a patient with hemorrhagic stroke. CASE SUMMARY: A 56-year-old man developed life-threatening adverse reactions after fluoxetine was added to his previously prescribed regimen of buspirone and olanzapine. One week after starting fluoxetine 60 mg/day, the patient developed syndrome of inappropriate antidiuretic hormone secretion and serotonin syndrome concurrently. The patient had experienced a hemorrhagic stroke before the adverse drug reactions occurred. DISCUSSION: A patient with a history of hemorrhagic stroke developed serious adverse drug reactions when fluoxetine was added to his drug therapy. When the combination therapy was stopped, all adverse effects gradually disappeared and laboratory abnormalities were corrected. The likelihood that the adverse reactions were caused by fluoxetine is probable according to the Naranjo probability scale. In addition, a history of stroke may be a risk factor for the development of such reactions. CONCLUSIONS: Today, patients with depression after experiencing a stroke are treated more effectively, but antidepressant-induced adverse drug reactions may be serious. A growing number of patients are treated for post-stroke depression; they require close supervision and careful dosing of antidepressants to prevent full-blown adverse reactions from occurring.     

Long-term use of tedizolid for pulmonary nocardiosis

Nocardiosis usually occurs in immunocompromised patients and causes infections in various organs, including the lungs, skin, and organs of the central nervous system. Herein, we report the case of a patient with minimal change nephrotic syndrome who had been on immunosuppressive drugs and developed pulmonary nocardiosis due to Nocardia nova complex and Pneumocystis pneumonia. For pulmonary nocardiosis, trimethoprim-sulfamethoxazole, linezolid, and clarithromycin were initiated sequentially, but were subsequently discontinued due to side effects; the treatment was completed with tedizolid. Tedizolid was used safely for 200 out of 286 days of antibiotic treatment, and clinical improvement was observed. Tedizolid is a bacteriostatic oxazolidine antibiotic that inhibits bacterial protein synthesis, the same mechanism as its predecessor, linezolid. Tedizolid is thought to cause less frequent myelosuppression than linezolid, at least for short-term use. In the future, tedizolid may be a promising alternative to linezolid in cases of nocardiosis that usually require long-term treatment.     

Acute oculogyric crisis after administration of prochlorperazine

We report a case of acute oculogyric crisis due to prochlorperazine administration in a young black woman with a concomitant viral infection. Neuroleptic medications are the most common cause of drug-induced acute dystonic reactions such as oculogyric crisis. Prochlorperazine is an antiemetic agent with a phenothiazine-type chemical structure and is known to cause dystonic reactions. Drug-induced acute dystonic reactions are most common in young adults and in men. Viral infections may also predispose patients to these adverse reactions. Caution is warranted when this drug is used in patients who have other risk factors for an acute dystonic reaction.     

Linezolid for the treatment of resistant gram-positive cocci

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faecium infections. The adverse effect profile is similar to that of comparator agents (beta-lactams, clarithrornycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazoildinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and choramphenicol, will further define the role of linezolid.     

Comparative study of the effects of pyridoxine, rifampin, and renal function on hematological adverse events induced by linezolid

Hematological disturbances that develop during linezolid treatment are a major concern when linezolid is administered for prolonged periods of time. The aim of this study was to evaluate the influences of pyridoxine, rifampin, and renal function on hematological adverse events. From January 2002 to April 2006, 52 patients received a long-term course of linezolid. Blood cell counts were monitored weekly. Thrombocytopenia was defined as a decrease to <75% of the baseline platelet count, and anemia was defined when the hemoglobin concentration decreased by > or =2 g/liter from the baseline value. Twenty-four patients received linezolid alone, and 28 patients received linezolid plus 200 mg of pyridoxine. The Kaplan-Meier survival method, followed by the log-rank test, was used to estimate the cumulative probability of adverse events, and Cox regression analysis was performed to evaluate the independent predictors of toxicity. The baseline characteristics of the patients in both groups were similar. The cumulative probability of thrombocytopenia and anemia in patients who received pyridoxine was not different from that in patients who did not receive it. Hematological adverse events were less frequent in patients taking rifampin and were more frequent in patients with renal failure. However; the Cox regression analysis showed that rifampin was the only independent predictor associated with a lower risk of thrombocytopenia (hazard ratio, 0.37; 95% confidence interval, 0.14 to 0.98; P = 0.045). In conclusion, pyridoxine did not prevent linezolid-related hematological adverse events, and the coadministration of rifampin was associated with a lower risk of thrombocytopenia.     

Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network survey

Since linezolid was licensed, rare-but-serious adverse events caused by inhibition of mitochondrial protein synthesis have been identified. These events may be more common when the drug is used longer than 28 days, which is the treatment length currently approved by the US Food and Drug Administration. The purpose of this study was to determine how often longer courses of linezolid are prescribed and the nature and relative frequency of adverse events associated with longer courses. Most of the 460 infectious diseases physician respondents had prescribed extended course linezolid (greater than 28 days) at least once, and they reported that 74% of these patients were able to complete the extended course. Hematologic toxicity was the most common adverse event. Peripheral neuropathy and serotonin syndrome (with serotonin reuptake inhibitor use) were encountered more frequently than lactic acidosis. Close monitoring for signs and symptoms of these adverse events should be considered for patients receiving long-term therapy.     

Levetiracetam for mood stabilization and maintenance of seizure control following multiple treatment failures

OBJECTIVE: To report the case of a patient who experienced adverse events in succession to antiepileptic medications being used for both antiepileptic and mood-stabilization benefit. CASE SUMMARY: A 46-year-old white woman developed hyponatremia with carbamazepine, hyperammonemia with divalproex, cognitive impairment with topiramate, and hyponatremia with oxcarbazepine. The patient was stabilized physically and psychiatrically on levetiracetam without any noted adverse events. DISCUSSION: The adverse events in this report have been associated with the medications in question. The patient's presentation is unique, as she developed adverse events in succession to antiepileptic drugs being used to treat both a seizure disorder and symptoms of mood instability. The Naranjo rankings for the reported adverse events indicated the associations were probable (carbamazepine, divalproex, oxcarbazepine) and possible (topiramate). After repeated incidences of intolerability to these drugs, levetiracetam was initiated and provided both seizure control and mood-stabilizing benefits, which eventually led to hospital discharge. CONCLUSIONS: Levetiracetam may provide mood-stabilizing qualities through a mechanism that is unique from that of other antiepileptic agents used for their mood-stabilizing properties. There are potential advantages with levetiracetam, as no specific therapeutic drug monitoring parameters need to be followed after its introduction. Additionally, this case emphasizes the importance of therapeutic drug monitoring and frequent assessments to prevent physical and psychiatric adverse reactions.     

Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid,an oxazolidinone antibiotic,in healthy volunteers

AIMS: To determine the pharmacokinetics and tolerance of oral and intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers following single- and multiple-dose administration. METHODS: In two randomized, double-blind, placebo-controlled, dose-escalating trials, subjects were exposed either to oral (375, 500 or 625 mg) or intravenous (500 or 625 mg) linezolid or placebo twice daily. Serial blood and urine samples were obtained after the first- and multiple-dose administrations for up to 18 days. Non-compartmental pharmacokinetic analyses were used to describe the disposition of linezolid. RESULTS: Plasma linezolid concentrations and area under the concentration-time curves increased proportionally with dose irrespective of the route of administration. Plasma linezolid concentrations remained above the MIC90 for susceptible target pathogens (4.0 mg/L) for the majority of the 12 h dosing interval. Mean clearance, half-life and volume of distribution were similar irrespective of dose for both the oral and intravenous routes. Linezolid was well tolerated and the frequency of drug-related adverse events was similar between the linezolid and placebo groups. CONCLUSIONS: Oral and intravenous linezolid exhibit linear pharmacokinetics, with concentrations remaining above the target MIC90 for most of the dosing interval. These results support a twice-daily schedule for linezolid and demonstrate the feasibility of converting from intravenous to oral dosing without a dose adjustment.