Combined meropenem and linezolid as a systemic treatment for postoperative endophthalmitis

PURPOSE The aim of this study was to evaluate the antibiotic treatment of postoperative endophthalmitis with combined systemic meropenem and linezolid. METHODS A retrospective analysis of endophthalmitis treated with systemic meropenem and linezolid compared to conventional systemic antibiotics by evaluation of outcome and adverse effects was carried out. RESULTS 26 patients with unilateral postoperative endophthalmitis with a systemic combination regimen of meropenem (2 g TID, mean duration of treatment 5.5 days) and linezolid (600 mg BID, mean duration of treatment 8.9 days) (group 1, mean follow-up time 140 days) were included in this study and compared to 45 postoperative endophthalmitis patients treated with conventional systemic antibiotics (group 2; mean follow-up time 320 days). In group 1, 69.2 % of eyes additionally received intravitreal amikacin and vancomycin (vs. 24.4 % in group 2; p < 0.001), in 92.3 % pars plana vitrectomy was performed (vs. 68.9 % in group 2, p = 0.047). Mean best corrected visual acuity improved from a baseline of 1.76 logMar for group 1 and 1.83 logMar for group 2 to 0.91 logMar (p = 0.0001) and 0.90 logMar (p < 0.0001), respectively, at the end of the follow-up, revealing no significant differences between the two groups at any time point (p > 0.05). Ocular complications were observed in 34.6 % of eyes in group 1 (vs. 37.8 % in group 2; p > 0.05). Adverse drug effects occurred significantly more frequently in group 1 (26.9 % vs. 4.4 % p = 0.02). CONCLUSION In spite of the reported better penetration through the blood-ocular barrier and the broader antibacterial spectrum of meropenem and linezolid, no benefit in outcome was found in the present study. In contrast, adverse effects and costs of the combination regimen were significantly higher.

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.

The complex clinical picture of side effects to biologicals

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named alpha, beta, gamma, delta, and epsilon, reflecting overstimulation (high cytokine values, type alpha), hypersensitivity (type beta), immune deviation (including immunodeficiency, type gamma), cross-reactivity (type delta), and nonimmune mediated side effects (type epsilon). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs.

Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study

Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care.

Barriers to front propagation in ordered and disordered vortex flows

We present experiments on reactive front propagation in a two-dimensional (2D) vortex chain flow (both time-independent and time-periodic) and a 2D spatially disordered (time-independent) vortex-dominated flow. The flows are generated using magnetohydrodynamic forcing techniques, and the fronts are produced using the excitable, ferroin-catalyzed Belousov-Zhabotinsky chemical reaction. In both of these flows, front propagation is dominated by the presence of burning invariant manifolds (BIMs) that act as barriers, similar to invariant manifolds that dominate the transport of passive impurities. Convergence of the fronts onto these BIMs is shown experimentally for all of the flows studied. The BIMs are also shown to collapse onto the invariant manifolds for passive transport in the limit of large flow velocities. For the disordered flow, the measured BIMs are compared to those predicted using a measured velocity field and a three-dimensional set of ordinary differential equations that describe the dynamics of front propagation in advection-reaction-diffusion systems.

Communication barriers in counselling foreign-language patients in public pharmacies: threats to patient safety?

Foreign-language (FL) patients are at increased risk for adverse drug events. Evidence regarding communication barriers and the safety of pharmaceutical care of FL patients in European countries is scarce despite large migrant populations.

Calcium waves driven by "sensitization" wave-fronts

OBJECTIVE: Cellular Ca(2+) waves are understood as reaction-diffusion systems sustained by Ca(2+)-induced Ca(2+) release (CICR) from Ca(2+) stores. Given the recently discovered sensitization of Ca(2+) release channels (ryanodine receptors; RyRs) of the sarcoplasmic reticulum (SR) by luminal SR Ca(2+), waves could also be driven by RyR sensitization, mediated by SR overloading via Ca(2+) pump (SERCA), acting in tandem with CICR. METHODS: Confocal imaging of the Ca(2+) indicator fluo-3 was combined with UV-flash photolysis of caged compounds and the whole-cell configuration of the patch clamp technique to carry out these experiments in isolated guinea pig ventricular cardiomyocytes. RESULTS: Upon sudden slowing of the SERCA in cardiomyocytes with a photoreleased inhibitor, waves indeed decelerated immediately. No secondary changes of Ca(2+) signaling or SR Ca(2+) content due to SERCA inhibition were observed in the short time-frame of these experiments. CONCLUSIONS: Our findings are consistent with Ca(2+) loading resulting in a zone of RyR 'sensitization' traveling within the SR, but inconsistent with CICR as the predominant mechanism driving the Ca(2+) waves. This alternative mode of RyR activation is essential to fully conceptualize cardiac arrhythmias triggered by spontaneous Ca(2+) release.

Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response

BACKGROUND Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. OBJECTIVE Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. METHODS Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naïve HLA-B*58:01(+) and HLA-B*58:01(-) individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and (51) Cr release assay. RESULTS Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status. CONCLUSIONS AND CLINICAL RELEVANCE This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele.

Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth.

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.

Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.

Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia advance online publication, 13 March 2015; doi:10.1038/leu.2015.36.

Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C

INTRODUCTION: Chronic hepatitis C infection is a global disease with 160 million people infected worldwide. Until recently, therapy was characterized by long duration, suboptimal success rates and significant adverse drug reactions. The development of direct-acting antivirals initiated a dramatic change in the treatment of hepatitis C. AREAS COVERED: This review covers the development of the novel NS5A inhibitor ombitasvir (ABT-267) and its clinical evaluation in Phase I to III trials as monotherapy and in combination with the NS3/4A inhibitor ABT-450/r and the non-nucleoside NS5B inhibitor dasabuvir (ABT-333) ± ribavirin. EXPERT OPINION: Ombitasvir (ABT-267) is a potent inhibitor of the hepatitis C virus protein NS5A, has favorable pharmacokinetic characteristics and is active in the picomolar range against genotype 1 - 6. In patients with genotype 1 and 4, 12-week combination treatment with ombitasvir, dasabuvir and ABT-450/r plus ribavirin was highly effective and resulted in 12-week sustained virological response rates higher than 95% in treatment-naöve and treatment-experienced patients. In liver transplant recipients with genotype 1 hepatitis C, success rates in the same range can be expected after 24 weeks of treatment according to preliminary trial results. Genotype 1a patients with compensated cirrhosis who were prior nonresponders benefit from a treatment duration of 24 weeks.

Can geriatric approaches support the care of old patients in emergency departments? A review from a Swiss ED

In the coming decades, old patients will account for an increasing proportion of emergency department (ED) visits. During or after their stay in the ED, they more frequently suffer adverse outcomes than younger patients. There is evidence that specific age-centred approaches improve the outcomes. We therefore reviewed specific conditions needing particular attention in older ED patients, such as cognitive disorders and delirium, impaired mobility and falls, as well as problems related to the activities of daily living, disability, poly-pharmacy, adverse drug effects, co-morbidity and atypical presentation. We also propose steps to further improve the quality of care in older ED patients by using appropriate age-centred management.

Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons.

BACKGROUND The European AIDS Clinical Society (EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. GUIDELINE HIGHLIGHTS The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment (START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (PrEP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug-drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus (HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. CONCLUSIONS The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview.

Costs and quality of medication reconciliation practice in primary care clinics

Medication reconciliation, with the aim to resolve medication discrepancy, is one of the Joint Commission patient safety goals. Medication errors and adverse drug events that could result from medication discrepancy affect a large population. At least 1.5 million adverse drug events and $3.5 billion of financial burden yearly associated with medication errors could be prevented by interventions such as medication reconciliation. This research was conducted to answer the following research questions: (1a) What are the frequency range and type of measures used to report outpatient medication discrepancy? (1b) Which effective and efficient strategies for medication reconciliation in the outpatient setting have been reported? (2) What are the costs associated with medication reconciliation practice in primary care clinics? (3) What is the quality of medication reconciliation practice in primary care clinics? (4) Is medication reconciliation practice in primary care clinics cost-effective from the clinic perspective? Study designs used to answer these questions included a systematic review, cost analysis, quality assessments, and cost-effectiveness analysis. Data sources were published articles in the medical literature and data from a prospective workflow study, which included 150 patients and 1,238 medications. The systematic review confirmed that the prevalence of medication discrepancy was high in ambulatory care and higher in primary care settings. Effective strategies for medication reconciliation included the use of pharmacists, letters, a standardized practice approach, and partnership between providers and patients. Our cost analysis showed that costs associated with medication reconciliation practice were not substantially different between primary care clinics using or not using electronic medical records (EMR) ($0.95 per patient per medication in EMR clinics vs. $0.96 per patient per medication in non-EMR clinics, p=0.78). Even though medication reconciliation was frequently practiced (97-98%), the quality of such practice was poor (0-33% of process completeness measured by concordance of medication numbers and 29-33% of accuracy measured by concordance of medication names) and negatively (though not significantly) associated with medication regimen complexity. The incremental cost-effectiveness ratios for concordance of medication number per patient per medication and concordance of medication names per patient per medication were both 0.08, favoring EMR. Future studies including potential cost-savings from medication features of the EMR and potential benefits to minimize severity of harm to patients from medication discrepancy are warranted. ^

Predictors of HIV-1 slow progression among vertically infected children in Botswana

HIV-1 infected children display a highly variable rate of progression to AIDS. Data about reasons underlying the variable progression to AIDS among vertically-infected children is sparse, and the few studies that have examined this important question have almost exclusively been done in the developed world. This is despite the fact that Sub-Saharan Africa is home to over 90% of all HIV infected children around the world.^ The main objective of this study was to examine predictors of HIV-1 slow progression among vertically infected children in Botswana, using a case control design. Cases (slow progressors) and controls (rapid progressors) were drawn from medical records of HIV-1 infected children being followed up for routine care and treatment at the BBCCCOE between February 2003 and February 2011. Univariate and Multivariate Logistic Regression Analyses were performed to identify independent predictors of slow disease progression and control for confounding respectively. ^ The study population comprised of 152 cases and 201 controls with ages ranging from 6 months to 16 years at baseline. Low baseline HIV-1 RNA viral load was the strongest independent predictor of slow progression (adjusted OR = 5.52, 95% CI = 2.75-11.07; P <0.001). Other independent predictors of slow disease progression identified were: lack of history of PMTCT with single dose Nevirapine plus Zidovudine (adjusted OR = 4.45, 95% CI = 1.45-13.69; P = 0.009) and maternal vital status (alive) (adjusted OR = 2.46, 95% CI = 1.51-4.01; P < 0.00 ).^ The results of this study may help clinicians and policy-makers in resource-limited settings to identify, at baseline, which children are at highest risk of rapid progression to AIDS and thus prioritize them for immediate intervention with HAART and other measures that would mitigate disease progression. At the same time HAART may be delayed among children who are at lower risk of disease progression. This would enable the highly affected, yet impoverished, Sub-Saharan African countries to use their scarce resources more efficiently which may in turn ensure that their National Antiretroviral Therapy Programs become more sustainable. Delaying HAART among the low-risk children would also lower the occurrence of adverse drug reactions associated with antiretroviral drugs exposure.^ Keywords. Slow Progressors, Rapid Progressors, HIV-1, Predictors, Children, Vertical Transmission, Sub-Saharan Africa^