Assessment Of Spanlastic Vesicles Of Zolmitriptan For Treating Migraine In Rats.

OBJECTIVE: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%). MATERIALS AND METHODS: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally. RESULTS: We found decreased Tmax, increased Cmax, AUC0-6, AUC0-∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan. CONCLUSION: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.

Cost-Effectiveness of Reclassifying Triptans in Australia: Application of an Economic Evaluation Approach to Regulatory Decisions.

BACKGROUND: Migraine is a common, chronic, disabling headache disorder. Triptans, used as an acute treatment for migraine, are available via prescription in Australia. An Australian Therapeutic Goods Administration (TGA) committee rejected reclassifying sumatriptan and zolmitriptan from prescription medicine to pharmacist-only between 2005 and 2009, largely on the basis of concerns about patient risk. Nevertheless, pharmacist-only triptans may reduce migraine duration and free up healthcare resources. OBJECTIVES: To estimate the cost-effectiveness of reclassifying triptans from prescription-only to pharmacist-only in Australia. METHODS: The study design included decision-analytic modeling combining data from various sources. Behavior before and after reclassification was estimated using medical practitioner and patient surveys and also administrative data. Health outcomes included migraine frequency and duration as well as adverse events (AEs) discussed by the TGA committee. Efficacy and AEs were estimated using randomized controlled trials and observational studies. RESULTS: Reclassifying triptans will reduce migraine duration but increase AEs. This will result in 337 quality-adjusted life-years gained at an increased cost of A$5.9 million over 10 years for all Australian adults older than 15 years (19.6 million). The incremental cost-effectiveness ratio was estimated to be A$17 412/quality-adjusted life-year gained. CONCLUSIONS: The incremental cost-effectiveness ratio is likely to be considered cost-effective by Australian decision makers. Serotonin syndrome, a key concern of the TGA committee, had little impact on the results. Further research is needed regarding pharmacist-only triptan use by migraineurs currently using over-the-counter medicines and by nonmigraineurs, the efficacy of triptans, and the risk of cardiovascular and cerebrovascular AEs and chronic headaches with triptans.

Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis.

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (Cmax), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter (P = 0.005); time to Cmax (Tmax) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half-life (t1/2), 9.1 ± 3.6 versus 8.9 ± 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma Cmax and delayed Tmax values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

Evaluation of the treatment of methicillin-resistant Staphylococcus aureus bacteremia.

BACKGROUND: Bloodstream infections are a leading cause of death in the United States. Methicillin-resistant Staphylococcus aureus (MRSA) encompasses >50% of all S aureus strains in infected hospitalized patients and increases mortality, length of stay and healthcare costs. The objective of this study was to evaluate the treatment of MRSA bacteremia with daptomycin, linezolid and vancomycin. METHODS: Patients with MRSA bacteremia between June 2008 and November 2010 were reviewed retrospectively. A microbiology laboratory report identified patients with ≥ 1 positive MRSA blood culture. Patients ≥ 18 years receiving daptomycin, linezolid or vancomycin for ≥ 7 consecutive days were included. Polymicrobial blood cultures and patients treated concomitantly with >1 anti-MRSA agent were excluded. RESULTS: Of 122 patients included, 53 received daptomycin, 15 received linezolid and 54 received vancomycin. Clinical and microbiologic cure rates were similar between daptomycin, linezolid and vancomycin (58.5% versus 60% versus 61.1%; 93.6% versus 100% versus 90%, respectively). Thirteen patients (daptomycin 4/24 versus linezolid 1/9 versus vancomycin 8/49, P = 0.5960) had recurrence while 12 patients had re-infection (daptomycin 5/42 versus linezolid 0/9 versus vancomycin 7/49, P = 0.4755). Treatment failure occurred in 11 patients treated with daptomycin, 4 with linezolid and 9 with vancomycin (P = 0.662). Compared with daptomycin and vancomycin, linezolid-treated patients had higher mortality (P = 0.0186). CONCLUSIONS: No difference in clinical or microbiologic cure rates was observed between groups. Daptomycin and vancomycin appear equally efficacious for MRSA bacteremia, whereas linezolid therapy was associated with higher mortality.

Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation.

OBJECTIVES: To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. METHODS: We performed a retrospective study of patients whose plasma C(min) and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a C(min) of 2-7 mg/L and/or an estimated AUC24 of 160-300 mg · h/L. Patients were divided into two subgroups (Group 1, 2-11 years; Group 2, 12-18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥ 80 or ≥ 100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. RESULTS: A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in C(min) (adjusted R(2) of 0.692). Simulations showed a PTA of ≥ 90% with the current dosing regimens in both groups only for pathogens with an MIC ≤ 1 mg/L. CONCLUSIONS: Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC >1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure.

Modeling economic implications of alternative treatment strategies for acute bacterial skin and skin structure infections.

OBJECTIVE: The economic implications from the US Medicare perspective of adopting alternative treatment strategies for acute bacterial skin and skin structure infections (ABSSSIs) are substantial. The objective of this study is to describe a modeling framework that explores the impact of decisions related to both the location of care and switching to different antibiotics at discharge. METHODS: A discrete event simulation (DES) was developed to model the treatment pathway of each patient through various locations (emergency department [ED], inpatient, and outpatient) and the treatments prescribed (empiric antibiotic, switching to a different antibiotic at discharge, or a second antibiotic). Costs are reported in 2012 USD. RESULTS: The mean number of days on antibiotic in a cohort assigned to a full course of vancomycin was 11.2 days, with 64% of the treatment course being administered in the outpatient setting. Mean total costs per patient were $8671, with inpatient care accounting for 58% of the costs accrued. The majority of outpatient costs were associated with parenteral administration rather than drug acquisition or monitoring. Scenarios modifying the treatment pathway to increase the proportion of patients receiving the first dose in the ED, and then managing them in the outpatient setting or prescribing an oral antibiotic at discharge to avoid the cost associated with administering parenteral therapy, therefore have a major impact and lower the typical cost per patient by 11-20%. Since vancomycin is commonly used as empiric therapy in clinical practice, based on these analyses, a shift in treatment practice could result in substantial savings from the Medicare perspective. CONCLUSIONS: The choice of antibiotic and location of care influence the costs and resource use associated with the management of ABSSSIs. The DES framework presented here can provide insight into the potential economic implications of decisions that modify the treatment pathway.

Antibiotic treatment patterns across Europe in patients with complicated skin and soft-tissue infections due to meticillin-resistant Staphylococcus aureus: a plea for implementation of early switch and early discharge criteria.

This retrospective observational medical chart review aimed to describe country-specific variations across Europe in real-world meticillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) treatment patterns, antibiotic stewardship activity, and potential opportunities for early switch (ES) from intravenous (i.v.) to oral formulations and early discharge (ED) from hospital using standardised data collection and criteria and economic implications of these opportunities. Patients were randomly sampled from 12 countries (Austria, Czech Republic, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Slovakia, Spain and the UK), aged ≥18 years, with documented MRSA cSSTI, hospitalised between 1 July 2010 and 30 June 2011, discharged alive by 31 July 2011. Of 1502 patients, 1468 received MRSA-targeted therapy. Intravenous-to-oral switch rates ranged from 2.0% to 20.2%, i.v. length of therapy from 10.1 to 18.6 days and hospital length of stay (LoS) from 15.2 to 25.0 days across Europe. Of 341 sites, 82.9% had antibiotic steering committees, 23.7% had i.v.-to-oral switch antibiotic protocols and 12.9% had ED protocols for MRSA cSSTI. ES and ED eligibility ranged from 12.0% (Slovakia) to 56.3% (Greece) and from 10% (Slovakia) to 48.2% (Portugal), respectively. Potential cost savings per ED-eligible patient ranged from €414 (Slovakia) to €2703 (France). MRSA cSSTI treatment patterns varied widely across countries, but further reductions in i.v. therapy, hospital LoS and associated costs could be realised. These data provide insight into clinical practice patterns across diverse European healthcare systems and identify potential opportunities for local clinicians and policy-makers to improve clinical care and cost-effectiveness of this therapeutic area.

European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant hospital-acquired infections worldwide and remains a public health priority in Europe. Nosocomial pneumonia (NP) involving MRSA often affects patients in intensive care units with substantial morbidity, mortality and associated costs. A guideline-based approach to empirical treatment with an antibacterial agent active against MRSA can improve the outcome of patients with MRSA NP, including those with ventilator-associated pneumonia. New methods may allow more rapid or sensitive diagnosis of NP or microbiological confirmation in patients with MRSA NP, allowing early de-escalation of treatment once the pathogen is known. In Europe, available antibacterial agents for the treatment of MRSA NP include the glycopeptides (vancomycin and teicoplanin) and linezolid (available as an intravenous or oral treatment). Vancomycin has remained a standard of care in many European hospitals; however, there is evidence that it may be a suboptimal therapeutic option in critically ill patients with NP because of concerns about its limited intrapulmonary penetration, increased nephrotoxicity with higher doses, as well as the emergence of resistant strains that may result in increased clinical failure. Linezolid has demonstrated high penetration into the epithelial lining fluid of patients with ventilator-associated pneumonia and shown statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in a phase IV, randomized, controlled study. This review focuses on the disease burden and clinical management of MRSA NP, and the use of linezolid after more than 10 years of clinical experience.

Comparative cost-effectiveness of alternative empiric antimicrobial treatment options for suspected enterococcal bacteremia.

OBJECTIVES: Enterococcus species are the fourth leading cause of bacteremia. Resistance rates are rising and delays in appropriate initial antimicrobial therapy have been associated with increased mortality. Empiric treatment of patients with suspected enterococcal bacteremia varies and significant cost differences exist between alternatives. The objective of this study was to determine the cost-effectiveness of various empiric treatments for patients with suspected enterococcal bacteremia. METHODS: A decision-analytic model was constructed from the hospital perspective to assess the cost-effectiveness of alternative empiric treatment options for enterococcal bacteremia, including antimicrobials active against vancomycin-resistant enterococcus (VRE). The model was populated from available literature sources and included resistance patterns, associated mortality with early versus delayed effective treatment, and the cost of treatment. Univariate sensitivity analyses tested the robustness of the model to determine the degree to which model uncertainties influenced outcomes. We also undertook a probabilistic sensitivity analysis varying parameters in 10,000 Monte Carlo simulations. MAIN RESULTS: The incremental cost-effectiveness ratio was $791 and $749/quality-adjusted-life-year utilizing empiric daptomycin and linezolid, respectively. The model also predicted an incremental cost/life saved of $11,703 by utilizing empiric daptomycin and $11,084 with linezolid utilization. Ampicillin was dominated (i.e., less effective and associated with increased costs) by both VRE-active agents and vancomycin. A probabilistic Monte Carlo sensitivity analysis showed that an agent with VRE activity had a 100% chance of being cost-effective at traditionally used willingness-to-pay thresholds. The decision-analytic model was sensitive to variations in E. faecium mortality and short-term postdischarge survival rates. CONCLUSION: Results of our model showed that empiric utilization of an antimicrobial with activity against VRE may be a cost-effective option for the treatment of suspected enterococcal bacteremia when compared with vancomycin or ß-lactam therapy.

Out-of-pocket costs and prescription reversals with oral linezolid.

OBJECTIVE: To determine the relationship between benefit design, out-of-pocket costs, and prescription reversals, and the impact of reversals on rehospitalizations and total healthcare costs among Medicare members prescribed oral linezolid. STUDY DESIGN: Medicare members from a national health plan prescribed oral linezolid posthospitalization for skin and soft tissue infection (SSTI) or pneumonia were followed retrospectively. METHODS: Members were identified by an oral linezolid prescription between June 1, 2007, and April 30, 2011, where the index event was a prescription fill or reversal less than 2 days before or 10 days after discharge. Associations between out-of-pocket costs and reversal, and between reversal and rehospitalization 30 days postindex, were compared for prescription fills versus reversals. A generalized linear model calculated adjusted total healthcare costs per member controlling for age, sex, geographic region, and clinical characteristics. RESULTS: Reversal rates rose progressively from 2% for members with out-of-pocket costs of $0 to 27% for members with out-of-pocket costs higher than $100 (P < .0001). Infection-related rehospitalizations were 23% versus 9% for members with a prescription reversal versus a fill (P < .0001). While postdischarge prescription drug costs were $1228.78 lower (P <.0001), adjusted mean medical costs were $2061.69 higher (P = .0033) and total healthcare costs were $1280.93 higher (P = .0349) for reversal versus fill members. CONCLUSIONS: Higher out-of-pocket costs were associated with higher rates of reversal, and reversals were associated with higher rates of rehospitalization and adjusted total healthcare costs among Medicare members prescribed oral linezolid posthospitalization for SSTI or pneumonia.

A practical guide to community-acquired MRSA.

As the number of CA-MRSA skin and soft tissue infections continues to grow, it's important to know which patients are at greatest risk and which evidence-based treatment protocols to turn to when needed.

Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in surgical wounds.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infection after surgery is usually rare, but incidence can be up to 33% in certain types of surgery. Postoperative MRSA infection can occur as surgical site infections (SSI), chest infections, or bloodstream infections (bacteraemia). The incidence of MRSA SSIs varies from 1% to 33% depending upon the type of surgery performed and the carrier status of the individuals concerned. The optimal antibiotic regimen for the treatment of MRSA in surgical wounds is not known. OBJECTIVES: To compare the benefits and harms of various antibiotic treatments in people with established surgical site infections (SSIs) caused by MRSA . SEARCH METHODS: In February 2013 we searched the following databases: The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE); NHS Economic Evaluation Database; Health Technology Assessment (HTA) Database; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) comparing one antibiotic regimen with another antibiotic regimen for the treatment of SSIs due to MRSA. All RCTs irrespective of language, publication status, publication year, or sample size were included in the analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently decided on inclusion and exclusion of trials, and extracted data. We planned to calculate the risk ratio (RR) with 95% confidence intervals (CI) for comparing the binary outcomes between the groups and mean difference (MD) with 95% CI for comparing the continuous outcomes. We planned to perform the meta-analysis using both a fixed-effect and a random-effects model. We performed intention-to-treat analysis whenever possible. MAIN RESULTS: We included one trial involving 59 people hospitalised because of MRSA SSIs. Thirty participants were randomised to linezolid (600 mg either intravenously or orally every 12 hours for seven to 14 days) and 29 to vancomycin (1 g intravenously every 12 hours for seven to 14 days). The type of surgical procedures that were performed were not reported. The trial reported one outcome, which was the eradication of MRSA. The proportion of people in whom MRSA was eradicated was statistically significantly higher in the linezolid group than in the vancomycin group (RR 1.80; 95% CI 1.20 to 2.68). AUTHORS' CONCLUSIONS: There is currently no evidence to recommend any specific antibiotic in the treatment of MRSA SSIs. Linezolid is superior to vancomycin in the eradication of MRSA SSIs on the basis of evidence from one small trial that was at high risk of bias, but the overall clinical implications of using linezolid instead of vancomycin are not known. Further well-designed randomised clinical trials are necessary in this area.

Evaluating the impact of a pharmacist's absence from an antimicrobial stewardship team.

PURPOSE: Results of a study to determine the impact of a clinical pharmacist's temporary absence from a hospital's antimicrobial stewardship team are presented. METHODS: A retrospective chart review was conducted to compare the appropriateness of the use of selected antimicrobial medications with and without regular pharmacist involvement on the hospital's antimicrobial stewardship team. The charts of two samples of patients were evaluated: (1) 119 patients who had received prolonged (≥72 hours) imipenem-cilastatin, linezolid, or micafungin therapy over a three-month period during which a clinical pharmacist routinely provided interventions to help ensure the drugs were used according to institutional guidelines and (2) 111 patients treated with one of the three drugs during a three-month period when the clinical pharmacist did not serve on the stewardship team. RESULTS: Relative to the period of active pharmacist involvement in antimicrobial stewardship, rates of inappropriate use of imipenem-cilastatin, linezolid, and micafungin during the pharmacist's absence were deemed to have increased by 27, 39, and 35 percentage points, respectively, with corresponding increases in the average duration of therapy of 0.7, 4.0, and 3.2 days; in addition, the number of cases of Clostridium difficile infection increased more than threefold (from 8 to 25) during the pharmacist's absence. CONCLUSION: The temporary absence of a pharmacist from the antimicrobial stewardship team was associated with increased rates of inappropriate use of restricted antimicrobial agents and consequent increases in average durations of therapy.

Cost-effectiveness of linezolid in methicillin-resistant Staphylococcus aureus skin and skin structure infections.

Linezolid is a novel oxazolidinone antibacterial agent with a broad clinical application, especially in methicillin-resistant Staphylococcus aureus skin and soft-tissue infections and skin and skin-structure infections. Pharmacoeconomic advantages include decreased hospital duration, reduction in intravenous antibiotic use and early discharge opportunities that contribute to an overall reduction in healthcare resources. Linezolid's oral formulation has a pharmacokinetic profile that is similar to its intravenous formulation, which creates opportunities for early discharge not available to comparators like vancomycin and daptomycin. Both vancomycin and daptomycin require intravenous therapy, which compounds the resources required in treating methicillin-resistant S. aureus skin and soft tissue/skin and skin structure infections. Pharmacoeconomic studies have demonstrated an overall reduction in total direct costs to the payer in favor of linezolid over its comparators. Its overall reduction in healthcare utilization makes it an appropriate alternative to the standard therapy, vancomycin.

Pharmacotherapy for methicillin-resistant Staphylococcus aureus nosocomial pneumonia.

OBJECTIVE: To review the evidence for pharmacologic agents available in the treatment of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. DATA SOURCES: A search of PubMed (1975-July 2012) was conducted using a combination of the terms methicillin-resistant Staphylococcus aureus, pneumonia, nosocomial, vancomycin, linezolid, telavancin, ceftaroline, tigecycline, and quinupristin/dalfopristin. STUDY SELECTION AND DATA EXTRACTION: Randomized comparative clinical trials, meta-analyses, and review articles published in English were included. A manual review of the bibliographies of available literature was conducted and all relevant information was included. Observational and in vitro studies were incorporated as indicated. DATA SYNTHESIS: Pharmacotherapy for the treatment of nosocomial MRSA pneumonia is limited. Vancomycin has been the treatment of choice for several years. Linezolid has demonstrated similar efficacy to vancomycin in randomized clinical trials and recent data have suggested that it may be superior in some cases, although there are limitations to this conclusion. Telavancin has also demonstrated similar clinical efficacy to vancomycin; however, the drug is not commercially available in the US. Other agents with MRSA activity include ceftaroline, clindamycin, quinupristin/dalfopristin, and tigecycline, although the evidence for their use in nosocomial pneumonia is limited. CONCLUSIONS: Based on the currently available evidence and cost-effectiveness, vancomycin should continue to be the drug of choice for most patients with nosocomial MRSA pneumonia. Linezolid is a reasonable alternative for patients with treatment failure while receiving vancomycin, isolates with vancomycin minimum inhibitory concentrations over 2 µg/mL, allergic reactions, or vancomycin-induced nephrotoxicity.

Treatment of methicillin-resistant Staphylococcus aureus infections with a minimal inhibitory concentration of 2 µg/mL to vancomycin: old (trimethoprim/sulfamethoxazole) versus new (daptomycin or linezolid) agents.

BACKGROUND: Guidelines recommend that agents other than vancomycin be considered for some types of infection due to methicillin-resistant Staphylococcus aureus (MRSA) when the minimum inhibitory concentration (MIC) to vancomycin is 2 µg/mL or more. Alternative therapeutic options include daptomycin and linezolid, 2 relatively new and expensive drugs, and trimethoprim/sulfamethoxazole (TMP/SMX), an old and inexpensive agent. OBJECTIVE: To compare the clinical efficacy and potential cost savings associated with use of TMP/SMX compared to linezolid and daptomycin. METHODS: A retrospective study was conducted at Detroit Medical Center. For calendar year 2009, unique adults (age >18 years) with infections due to MRSA with an MIC to vancomycin of 2 µg/mL were included if they received 2 or more doses of TMP/SMX and/or daptomycin and/or linezolid. Data were abstracted from patient charts and pharmacy records. RESULTS: There were 328 patients included in the study cohort: 143 received TMP/SMX alone, 89 received daptomycin alone, 75 received linezolid alone, and 21 patients received a combination of 2 or more of these agents. In univariate analysis, patients who received TMP/SMX alone had significantly better outcomes, including in-hospital (p = 0.003) and 90-day mortality (p < 0.001) compared to patients treated with daptomycin or linezolid. Patients receiving TMP/SMX were also younger (p < 0.001), had fewer comorbid conditions (p < 0.001), had less severe acute severity of illness (p < 0.001), and received appropriate therapy more rapidly (p = 0.001). In multivariate models the association between TMP/SMX treatment and mortality was no longer significant. Antimicrobial cost savings associated with using TMP/SMX averaged $2067.40 per patient. CONCLUSIONS: TMP/SMX monotherapy compared favorably to linezolid and daptomycin in terms of treatment efficacy and mortality. Use of TMP/SMX instead of linezolid or daptomycin could potentially significantly reduce antibiotic costs. TMP/SMX should be considered for the treatment of MRSA infection with MIC of 2 µg/mL to vancomycin.

Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children.

BACKGROUND: Treatment options for drug-resistant tuberculosis (DR-TB) are limited. Linezolid has been successfully used to treat DR-TB in adults, but there are few case reports of its use in children for TB. The reported rate of adverse events in adults is high. METHODS: We conducted a retrospective review of children with DR-TB treated with linezolid-containing regimens from February 2007 to March 2012 at two South African hospitals. RESULTS: Seven children (three human immunodeficiency virus [HIV] infected) received a linezolid-containing regimen. All had culture-confirmed DR-TB; five had previously failed second-line anti-tuberculosis treatment. Four children were cured and three were still receiving anti-tuberculosis treatment, but had culture converted. None of the non-HIV-infected children experienced adverse events while receiving linezolid. Three HIV-infected children had adverse events, one of which was life-threatening; linezolid was permanently discontinued in this case. Adverse events included lactic acidosis (n = 1), pancreatitis (n = 2), peripheral neuropathy (n = 1) and asymptomatic bone marrow hypoplasia (n = 1). CONCLUSION: Linezolid-containing regimens can be effective in treating children with DR-TB even after failing second-line treatment. Adverse events should be monitored, especially in combination with medications that have similar adverse effects. Linezolid remains costly, and a reduced dosage and duration may result in fewer adverse events and lower cost.

Tangier disease: epidemiology, pathophysiology, and management.

Tangier disease is one of the most severe forms of familial high-density lipoprotein (HDL) deficiency. Since its discovery it has been diagnosed in about 100 patients and is characterized by severe plasma deficiency or absence of HDL, apolipoprotein A-I (apoA-I, the major HDL apolipoprotein) and by accumulation of cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma cholesterol (below 150 mg/dL), and normal or high plasma triglycerides. Tangier disease is caused by mutations in the 'ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the membrane transporter ABCA1. This transporter plays a key role in the first step of reverse cholesterol transport, through which the efflux of free cholesterol from peripheral cells is transferred to lipid-poor apoA-I. The Tangier disease clinical phenotype is inherited as an autosomal recessive trait, the biochemical phenotype is inherited as an autosomal co-dominant trait. Nearly all the children affected by Tangier disease were identified on the basis of large, yellow-orange tonsils, while half of the adult patients affected by Tangier disease came to medical attention because of symptoms of neuropathy. Diagnosis in the remaining subjects was related to the clinical features of hepatomegaly, splenomegaly, premature myocardial infarction (about 30% of Tangier disease cases) or stroke, thrombocytopenia, anemia, gastrointestinal disorders, corneal opacities, hypocholesterolemia, low HDL cholesterol, or following a familial screening of Tangier patients. To date there is no specific treatment for Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients. The possible and more realistic therapeutic strategy should be designed to obtain a selective increase of mature HDL concentration to restore cholesterol efflux. Recently designed drugs like the cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib and reconstituted forms of HDL could be considered until the development of gene therapy.

[Pharmacoeconomic assessment of daptomycin as first-line therapy for bacteraemia and complicated skin and skin structure infections caused by gram-positive pathogens in Spain]. / Evaluación farmacoeconómica de daptomicina como terapia de primera línea en el tratamiento de bacteriemia e infecciones complicadas de piel y tejidos blandos causadas por microorganismos grampositivos en España.

OBJECTIVE: To assess the efficiency of daptomycin as firstline therapy (D) versus daptomycin as salvage therapy after vancomycin (V→D ) or linezolid (L→D) failure in gram-positive bacteraemia and complicated skin and skin-structure infections (cSSTIs). METHODS: Cost-effectiveness analysis of 161 bacteraemia and 84 cSSTIs patients comparing the above mentioned therapeutic alternatives was performed using the data from 27 Spanish hospitals involved in the EUCORE study. Direct medical costs were considered. Patients were observed from the first antibiotic dose for infection until either the end of daptomycin therapy or exitus. A multivariate Monte Carlo probabilistic sensitivity analysis was applied for costs (lognormal distribution) and effectiveness (normal distribution). RESULTS: In terms of effectiveness there were no statistical differences between groups but referring total costs per patient, there were significant differences. Sensitivity analysis confirmed that D dominates over L→D between 44.2%-62.1% of simulations in bacteraemia and between 48.2%-67.5% in cSSTIs. In comparison to V→D, D dominance was detected in 29.2%-33.2% of simulations in bacteraemia and between 48.2%-59.3% in cSSTIs. CONCLUSIONS: Daptomycin as first-line therapy dominates over daptomycin as salvage therapy after linezolid failure both in bacteraemia and cSSTIs. Comparing daptomycin as first-line therapy with its use after vancomycin failure, in cSSTIs the former is dominant. In bacteremia daptomycin as first line therapy is as effective as daptomycin as salvage therapy after vancomycin failure and implies lower costs.