多黏菌素B治疗多重耐药病原菌：要点综述

在过去10年中，铜绿假单胞菌、鲍曼不动杆菌等革兰阴性杆菌产生对现有几乎所有抗菌药物耐药，被称作超级细菌（superbug）或泛耐药菌，已经对临床构成严重威胁。多黏菌素类等抗菌药物因此被重新应用，并成为治疗对所有其他抗菌药物均耐药的多重耐药革兰阴性杆菌感染的最后选择。由于该药的研发系在约50年前，因此其药动学、药效学数据十分有限。提高对多黏菌素B的药理特性认识、优化其临床应用极为迫切。     

Polymyxin B hemoperfusion: a mechanistic perspective

Direct hemoperfusion therapy with polymyxin B immobilized fiber cartridge (PMX-DHP) is an established strategy in the treatment of septic shock in Japan and parts of Western Europe. PMX-DHP is currently the subject of a pivotal North American randomized controlled trial (EUPHRATES) in patients with septic shock and confirmed endotoxemia, as measured by the endotoxin activity assay. The major mechanism of action of this therapy is the removal of circulating endotoxin. High affinity binding of circulating endotoxin by the PMX-DHP column may decrease circulating endotoxin levels by up to 90% after two standard treatments. Basic research has shown reductions in circulating cytokine levels and in renal tubular apoptosis. Clinical research has shown that PMX-DHP therapy results in hemodynamic improvements, improvements in oxygenation, renal function, and reductions in mortality. Further research is needed to further define additional patient populations with endotoxemia that may benefit from PMX-DHP therapy as well as to further elucidate dosing, timing, and additional information on mechanisms of action. This review will present the mechanistic rationale for this targeted strategy of endotoxin removal using PMX-DHP in endotoxemic septic patients, highlighting both the specific effects of the therapy and the evidence accumulated so far of clinical improvement following this therapy in terms of recovery of organ function.     

多黏菌素B与其他抗菌药物相比较治疗铜绿假单胞菌所致血流感染

通过一项回顾性列队研究,比较静脉使用多黏菌素B与其他抗菌药物在治疗医院获得铜绿假单胞菌所致血流感染的疗效。评估多种潜在混杂因素。本研究分析2004年1月至2009年12月,18岁以上并接受48 h以上抗菌治疗铜绿假单胞菌血流感染患者,使用多黏菌素B或其他抗菌药物的疗效及肾毒性。     

Intravenous fosfomycin for the treatment of multidrug-resistant pathogens: what is the evidence on dosing regimens?

Introduction: The intravenous (IV) formulation of fosfomycin has been re-introduced in clinical practice mainly to overcome treatment failures against multidrug-resistant (MDR) bacteria. Appropriate dosing schedules of the IV formulation have not yet been established.

Areas covered: The mechanism of action and resistance development, commercial IV formulations, pharmacokinetic/pharmacodynamic (PK/PD) properties, IV dosing regimens for the treatment of MDR infections along with efficacy and safety issues were reviewed. Data regarding specific MDR pathogens, daily doses and patients’ outcomes, gaps in the current literature, and in progress research agenda are presented.

Expert opinion: The doses of fosfomycin IV range between 12 and 24 grams/day depending on the severity of infection. The efficacy and safety of the commonly administered doses have been shown mainly in observational non-comparative trials. The optimal dose ensuring maximal efficacy with minimal toxicity along with the most appropriate co-administered antibiotic(s) need further evaluation. The pharmacokinetic/pharmacodynamic parameter associated with maximum efficacy has not yet been established, although, the ratio of the area under the concentration-time curve (AUC) for the free unbound fraction of fosfomycin versus the MIC (fAUC/MIC) may be linked to optimal treatment. RCTs and other comparative studies are underway to address gaps of knowledge in adult patients and neonates.     

The treatment of provoked vestibulodynia: a critical review

OBJECTIVE: To carry out a critical review of published studies concerning the treatment of provoked vestibulodynia. METHODS: MEDLINE, PsycINFO, and Cochrane were used to identify treatment studies published between January 1996 and December 2006. All studies published in English that dealt specifically with the treatment of provoked vestibulodynia were included in the review regardless of their methodological quality. Thirty-eight treatment studies were thus examined in the present paper. RESULTS: Since 1996, surgical treatment has received somewhat less empirical attention. Nevertheless, it still boasts the best success rates, which range from 61% to 94%. More studies have focused on medical treatments, yielding success rates varying between 13% and 67%. Behavioral treatments have been the least studied, although 35% to 83% of patients benefit from them. Despite these interesting results, only 5 of the 38 treatment studies reviewed are randomized clinical trials. Furthermore, the majority of studies have several methodological weaknesses, such as the absence of (1) control or placebo group, (2) double-blind evaluation, (3) pretreatment pain evaluation, and (4) validated measures of pain and sexual functioning. DISCUSSION: On the basis of the results of the reviewed prospective studies and the randomized clinical trials, vestibulectomy is the most efficacious treatment to date. Though some medical treatments seem little effective, others appear promising and should be investigated further, as is the case with behavioral treatments. Additional randomized clinical trials are necessary to confirm the efficacy of surgery and validate nonsurgical treatments for provoked vestibulodynia.     

Action of Polymyxin B on Bacterial Membranes: Phosphatidylglycerol- and Cardiolipin-Induced Susceptibility to Polymyxin B in Acholeplasma laidlawii B

To identify the polymyxin receptor molecules in the membranes of living microorganisms, fusion of intact Acholeplasma laidlawii B with lipid vesicles was investigated according to the procedure of Grant and McConnell (1973). The naturally polymyxin-resistant A. laidlawii B was treated with phospholipid vesicles prepared from purified phospholipids of the polymyxin-susceptible Salmonella typhimurium G30. A. laidlawii B absorbed between 15 and 45% of its own lipid content of the added tritium-labeled phospholipids without loss of viability. Association with the acidic components phosphatidylglycerol and cardiolipin produced a 10- to 30-fold increase in polymyxin susceptibility, which was not obtained with egg-phosphatidylcholine and mixed phosphatidylcholine-phosphatidylethanolamine vesicles. The polymyxin-sensitized cells bound 12 times more radioactive antibiotic than resistant cells. The phosphatidylglycerol-induced susceptibility was abolished by serum fraction V (Cohn) proteins.     

Polymyxin B versus colistin: an update

Polymyxin B and colistin (polymyxin E) are polypeptide antibiotics that were developed in the 1940s, but fell into disfavor due to their high toxicity rates. These two antibiotics were previously regarded to be largely equivalent, due to similarities in their chemical structure and spectrum of activity. In recent years, several pertinent differences, especially in terms of potency and disposition, have been revealed between polymyxin B and colistin. These differences are mainly attributed to the fact that polymyxin B is administered parenterally in its active form, while colistin is administered parenterally as an inactive pro-drug, colistimethate. In this review, we summarize the similarities and differences between polymyxin B and colistin. We also discuss the potential clinical implications of these findings, and provide our perspectives on how polymyxins should be employed to preserve their utility in this era of multi-drug resistance.     

Monotherapy for hepatitis B infection: a review of treatment options

Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.     

Static magnetic field therapy: a critical review of treatment parameters

Static magnetic field (SMF) therapy, applied via a permanent magnet attached to the skin, is used by people worldwide for self-care. Despite a lack of established SMF dosage and treatment regimens, multiple studies are conducted to evaluate SMF therapy effectiveness. Our objectives in conducting this review are to:(i) summarize SMF research conducted in humans; (ii) critically evaluate reporting quality of SMF dosages and treatment parameters and (iii) propose a set of criteria for reporting SMF treatment parameters in future clinical trials. We searched 27 electronic databases and reference lists. Only English language human studies were included. Excluded were studies of electromagnetic fields, transcranial magnetic stimulation, magnets placed on acupuncture points, animal studies, abstracts, posters and editorials. Data were extracted on clinical indication, study design and 10 essential SMF parameters. Three reviewers assessed quality of reporting and calculated a quality assessment score for each of the 10 treatment parameters. Fifty-six studies were reviewed, 42 conducted in patient populations and 14 in healthy volunteers. The SMF treatment parameters most often and most completely described were site of application, magnet support device and frequency and duration of application. Least often and least completely described were characteristics of the SMF: magnet dimensions, measured field strength and estimated distance of the magnet from the target tissue. Thirty-four (61%) of studies failed to provide enough detail about SMF dosage to permit protocol replication by other investigators. Our findings highlight the need to optimize SMF dosing parameters for individual clinical conditions before proceeding to a full-scale clinical trial.     

Antimicrobial treatment of minor soft tissue lacerations: a critical review

This article is a collective review of all the prospective clinical studies that assessed the therapeutic value of antibiotics in minor soft tissue lacerations. This review critically evaluates each study that tests the hypothesis that antibiotic treatment reduces the incidence of infection. Even though the design of each of the studies was scientifically inadequate, important factors were identified that influenced the incidence of infection. On the basis of this collective review as well as other studies, indications for antibiotic therapy of minor soft tissue lacerations have been identified. Future clinical studies must be designed to test more precisely the validity of these recommendations.     

In vitro double and triple synergistic activities of Polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii

Eight unrelated clinical Acinetobacter baumannii isolates resistant to all commonly used antibiotics were subjected to three-dimensional checkerboard microtiter plate dilution and time-kill studies at one-fourth of their MICs of polymyxin B, imipenem, and rifampin. Synergy was demonstrated with combinations of polymyxin B and imipenem, polymyxin B and rifampin, and polymyxin B, imipenem, and rifampin. Double combinations of polymyxin B and imipenem and of polymyxin B and rifampin were bactericidal for seven of eight isolates, and triple combinations were bactericidal for all isolates within 24 h. Future clinical studies using double and triple therapy with these antibacterials may provide an effective option against potentially lethal infection due to multiresistant Acinetobacter baumannii.     

Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review

OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosing of rosiglitazone, the second thiazolidinedione approved for the treatment of type 2 diabetes mellitus. METHODS: Background information for this article was obtained from searches of MEDLINE , Iowa Drug Information Service, and International Pharmaceutical Abstracts, as well as from data on file with the manufacturer of rosiglitazone. RESULTS: Rosiglitazone is indicated for use alone or in combination with metformin or sulfonylureas for the maintenance of glycemic control in patients with type 2 diabetes mellitus. Rather than stimulation of insulin secretion, rosiglitazone's primary mechanism of action is sensitization of tissues to insulin through activation of the peroxisome proliferator-activated receptor gamma and increasing expression of the glucose transporter-4 receptor. Rosiglitazone is administered orally, is absorbed almost completely, and is 99.8% bound to plasma proteins. The majority of a dose is metabolized by the cytochrome P-450 2C8 isozyme, with the inactive metabolites excreted primarily in the urine. Four to 8 mg/d of rosiglitazone given alone or in combination with metformin, sulfonylureas, or insulin has produced reductions in baseline fasting plasma glucose and glycosylated hemoglobin in studies of up to 1 year's duration. Common adverse effects (occurring in > or = 5.0% of patients) include upper respiratory tract infection, injury, and headache. Edema, weight gain, and increased low-density lipoprotein cholesterol concentrations have also been observed. It is recommended that rosiglitazone be avoided in patients with alanine aminotransferase levels >2.5 times normal. No clinically relevant drug interactions have been documented with rosiglitazone to date. The initial starting daily dose of rosiglitazone is 4 mg in single or divided doses, without regard to meals, to a maximum of 8 mg. CONCLUSIONS: No direct comparative trials of the efficacy and safety of rosiglitazone versus those of the other available thiazolidinedione, pioglitazone, have yet been performed. The role of rosiglitazone as a single agent and in combination with other antidiabetic agents remains to be clarified as additional comparative and long-term data become available.     

Comorbidity issues in the pharmacological treatment of pathological gambling: a critical review

Background

Pathological Gambling (PG) is an impulse control disorder often comorbid with other psychopathology, particularly bipolar spectrum disorders, attention deficit/hyperactivity disorder, obsessive-compulsive disorder (OCD) and substance abuse. This paper reviews the published literature on the pharmacological management of PG, highlighting how clinical and subclinical comorbid psychopathology influences the choice of pharmacological treatment.

Methods

Using Medline, the authors reviewed relevant articles published on this topic from1995 to 2005, focusing on the best-designed studies for inclusion.

Results

Much of the literature on PG-treatment presupposes different theories regarding this disorder. Data suggest the utility of differentiating the pharmacotherapy of pathological gamblers in light of their comorbid profile, specifically assessing for comorbid bipolar, ADHD, OCD, and substance abuse disorders.

Conclusion

Decisions about pharmacological treatment of PG should take into account current and previous comorbid disorders which influence treatment selection.

     

Inactivation of Endotoxin by Polymyxin B

The limulus gelation assay was utilized to investigate endotoxin inactivation by a number of antibiotics in vitro. Endotoxin activity was sharply reduced by polymyxin B and sodium colistimethate. The effect of the polymyxin was not significantly inhibited by 0.001 M calcium or 90% serum. Crude endotoxins from a variety of aerobic gram-negative bacteria, including several not previously studied, could be inactivated 1 or more logs by as little as 1 mug of polymyxin B per ml, whereas Bacteroides fragilis endotoxin was poorly detoxified. A 10,000-fold range in the relative susceptibility of different endotoxins to inactivation by polymyxin B was found. The endotoxin most susceptible to polymyxin B was derived from an organism resistant to polymyxin B by disk sensitivity testing, suggesting that the bacteriocidal and endotoxin detoxifying properties of polymyxin need not be directly related.