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Pre-exposure prophylaxis (PrEP) is a promising intervention to prevent HIV acquisition, with benefits both to the individual and to population-level health. PrEP is an opportunity to complement ongoing public health efforts to eliminate HIV. For women, PrEP can also serve as a gateway to access sexual and reproductive health (SRH) services. Clinical efficacy of PrEP was initially reported in women using a 1% tenofovir vaginal gel in 2010, followed by an efficacy trial of oral PrEP using TDF/FTC in men who have sex with men (MSM). Since then, further trials have reported efficacy in oral PrEP containing tenofovir in women and heterosexual men, while the subsequent trials for women using tenofovir gel reported no efficacy, stemming from difficulties in achieving adequate adherence. In an effort to offer women additional choices to oral PrEP, alternative modalities are being tested in clinical research, including long-acting injectable formulations and intra-vaginal rings. In 2015, a meta-analysis of clinic trials and open-label extension studies led to the World Health Organization (WHO) strongly recommending the provision of oral PrEP containing tenofovir for any person at substantial risk of HIV infection, irrespective of gender or population group. Currently, PrEP services for women around the world, including those who are either pregnant or breastfeeding, remain limited. Outside sub-Saharan Africa, most PrEP programmes are focused on MSM. South Africa, Kenya, and the USA have the greatest utilization of oral PrEP by women. Yet, since 2012, of the estimated > 300,000 people globally who have initiated PrEP, a minority are women. In this narrative review, we examine the most recent literature on clinical and implementation PrEP research among women. We highlight the high burden of disease related to common sexually transmitted infections (STIs) in women, and the opportunity to integrate PrEP and other HIV prevention services, STI case management, and family planning services, as part of a more robust package of SRH services. Raising awareness on PrEP amongst women and their healthcare providers, minimizing gaps in access, and ensuring adherence and persistence of PrEP during periods of risk are critical issues if PrEP can have a meaningful impact on reducing HIV incidence in women globally. [ABSTRACT FROM AUTHOR]

The diagnosis and management of hematologic malignancy during pregnancy is a significant challenge. This is due to both medical and ethical considerations regarding when and how to treat this special sub-group of patients. Recurring uncertainties remain around appropriate imaging techniques, timing and dosage of chemotherapy, and timing of delivery. In this article we examine and summarize current literature in this field to assist physicians in their understanding and management of this patient group. Special attention has been given to diagnostic and staging procedures, risks associated with chemotherapy at different stages of gestation, and chemotherapy-dose adaption during pregnancy. In addition, recommended guidelines for management of lymphoma, leukemia, and planning delivery are discussed. A multidisciplinary team approach is critical for patient care, as is shared decision making with the patient and family. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) guidelines and strategies suggest escalating treatment, mainly depending on the severity of airflow obstruction. However, some de-escalation of therapy in COPD would be appropriate, although we still do not know when we should switch, step-up or step-down treatments in our patients. Unfortunately, trials comparing different strategies of step-up and step-down treatment (e.g. treatment initiation with one single agent and then further step-up if symptoms are not controlled versus initial use of double or triple therapy, possibly with lower doses of the individual components, or the role of N-acetylcysteine in combination therapy for a step-down approach) are still lacking. In general, there is a large and often inappropriate use of the inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combination. However, the withdrawal of the ICS in COPD patients at low risk of exacerbation can be safe, provided that patients are under regular treatment with long-acting bronchodilators. Maximising the treatment in patients with a degree of clinical instability by including an ICS in the therapeutic regimen is useful to control the disease, but may not be needed during periods of clinical stability. In patients with severe but stable COPD, the withdrawal of the ICS from triple therapy [LABA + long-acting muscarinic antagonist (LAMA) + ICS] is possible, but not when the patient has been hospitalised for an acute exacerbation of COPD. We must still establish how long we should wait before withdrawing the ICS. It is still unclear whether the same is true when only the LABA or the LAMA is withdrawn while continuing treatment with the other bronchodilator and the ICS. In any case, we strongly believe that it is always better to avoid a therapeutic step-up progression when it is not needed rather than being forced subsequently into a step-down approach in which the outcome is always unpredictable. [ABSTRACT FROM AUTHOR]

Radiation-induced hemorrhagic cystitis (HC) is a complication of pelvic radiotherapy, mainly for prostate and uterine cancers. In the acute phase, patients feel urinary urgency and bladder pain. This phase is reversible after radiotherapy. In the chronic stage, an irritative syndrome is coupled with hematuria during the 2-10 years following radiotherapy. Cystoscopy shows white and frosted mucosa with telangiectasia. The incidence is estimated at 5 % or less. It is suggested that the radiation oncologist reviews the dosimetry plan to validate that the lesions coincide with significant radiation exposure confirming diagnosis of radiation-induced HC. The treatment for HC is first symptomatic, with bladder lavage, clot evacuation, coagulation via cystoscopy and blood transfusions if necessary. Subsequently, hyaluronic acid bladder instillation can be done with little toxicity. Hyperbaric oxygen therapy delivers pure oxygen to patients in a pressurized cabin, promoting angio-neogenesis and lowering hypoxia to the irradiated tissues. The clinical response rate is estimated to be around 80 %. Nevertheless, this approach is limited by the low availability, and length of treatment. While surgery remains an effective treatment for HC, it is the last option because of the high morbidity and mortality risks. Prospective studies need to be conducted to identify and evaluate new interventions, particularly for HC. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings. [ABSTRACT FROM AUTHOR]

Clopidogrel is a cornerstone of dual antiplatelet therapy. Hypersensitivity reactions potentially limit the use of this treatment and present a significant clinical challenge. The authors have developed recommendations for the management of clopidogrel hypersensitivity with consideration for the etiology, pathophysiology, and critical evaluation of potential management strategies. The clopidogrel hypersensitivity reaction is complex in mechanism and presents generally around day 5 of treatment. Generalized reactions are most common, but the reaction may also be localized or systemic. Screening patients for hypersensitivity is not always possible because the type IV delayed reaction is not detected reliably by conventional skin prick, intradermal challenge, or patch testing. Proposed strategies for management of clopidogrel hypersensitivity include treatment of the reaction with corticosteroids, clopidogrel desensitization, substituting an alternative P2Y12 inhibitor, or clopidogrel avoidance. The safety, efficacy, and cost of each potential strategy must be considered when managing a patient with clopidogrel hypersensitivity. [ABSTRACT FROM AUTHOR]

In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing-remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6-month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing-remitting disease. It is also becoming increasingly clear that therapies effective in relapsing-remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes. [ABSTRACT FROM AUTHOR]

Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR. [ABSTRACT FROM AUTHOR]

Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed. [ABSTRACT FROM AUTHOR]

Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A (HbA) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes. [ABSTRACT FROM AUTHOR]

Despite their transfusion-independence, non-transfusion-dependent thalassemia (NTDT) patients experience a variety of serious clinical complications that require prompt and comprehensive management. Transfusion therapy may still be an important part of management of this disease, in cases of acute stress, to support growth and development in childhood, or to prevent clinical morbidities stemming from ineffective erythropoiesis or hemolytic anemia. Although splenectomy is associated with improvements in hemoglobin levels, it leads to several short- and long-term adverse events, warranting caution in application of this intervention. Fetal hemoglobin induction therapy has been evaluated in non-randomized studies, with benefits extending beyond hematologic improvements to lowering morbidity risk. Effective and safe iron chelation therapy is now available for NTDT patients in whom iron overload develops, irrespective of transfusions, due to increased intestinal absorption, ultimately leading to clinically high iron burden levels and subsequent morbidity. Optimal management of NTDT patients requires a holistic approach targeting all hallmarks of the disease to ensure favorable patient outcomes. [ABSTRACT FROM AUTHOR]

This article addresses the emergence of echinocandin resistance among Candida species, mechanisms of resistance, factors that promote resistance and confounding issues surrounding standard susceptibility testing. Fungal infections remain a significant cause of global morbidity and mortality, especially among patients with underlying immunosupression. Antifungal therapy is a critical component of patient management for acute and chronic diseases. Yet, therapeutic choices are limited due to only a few drug classes available to treat systemic disease. Moreover, the problem is exacerbated by the emergence of antifungal resistance, which has resulted in difficult to manage multidrug resistant strains. Echinocandin drugs are now the preferred choice to treat a range of candidiasis. These drugs target and inhibit the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a key cell wall polymer. Therapeutic failures involving acquisition of resistance among susceptible organisms like Candida albicans is largely a rare event. However, in recent years, there is an alarming trend of increased resistance among strains of Candida glabrata, which in many cases are also resistant to azole drugs. Echinocandin resistance is always acquired during therapy and the mechanism of resistance is well established to involve amino acid changes in 'hot-spot' regions of the Fks subunits carrying the catalytic portion of glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values. A range of drug responses, from complete to partial refractory response, is observed depending on the nature of the amino acid substitution, and clinical responses are recapitulated in pharmacodynamic models of infection. The cellular processes promoting the formation of resistant Fks strains involve complex stress response pathways, which yield a variety of adaptive compensatory genetic responses. Stress-adapted cells become drug tolerant and can form stable drug resistant FKS mutations with continued drug exposure. A major concern for resistance detection is that classical broth microdilution techniques show significant variability among clinical microbiology laboratories for certain echinocandin drugs and Candida species. The consequence is that susceptible strains are misclassified according to established clinical breakpoints, and this has led to confusion in the field. Clinical factors that appear to promote echinocandin resistance include the expanding use of antifungal agents for empiric therapy and prophylaxis. Furthermore, host reservoirs such as biofilms in the gastrointestinal tract or intra-abdominal infections can seed development of resistant organisms during therapy. A fundamental understanding of the primary molecular resistance mechanism, along with cellular and clinical factors that promote resistance emergence, is critical to develop better diagnostic tools and therapeutic strategies to overcome and prevent echinocandin resistance. [ABSTRACT FROM AUTHOR]

Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage. [ABSTRACT FROM AUTHOR]

The value of combination therapy with inhaled corticosteroids and long-acting β-agonists (ICS/LABA) is well recognized in the management of asthma and chronic obstructive pulmonary disease (COPD). Despite differences in the pharmacological properties between two well-established ICS/LABA products (budesonide/formoterol and fluticasone/salmeterol), data from randomized clinical trials (RCTs) and meta-analyses suggest that these two products perform similarly under RCT conditions. In contrast, a few recently reported real-world comparative effectiveness studies have suggested that there are substantial differences between ICS/LABA combination treatments in terms of clinical and healthcare outcomes in patients with asthma or COPD. The purpose of this article is to provide a brief review of the benefits, as well as the limitations, of comparative effectiveness research (CER) in the therapeutic area of asthma and COPD. We conducted a structured literature review of the current CER studies on ICS/LABA combinations in asthma and COPD. These articles were then used to illustrate the unique challenges of CER studies, providing a summary of study results and limitations. We focus particularly on difficult biases and confounding factors that may be introduced before, during, and after the initiation of therapy. Beyond being a review of these two ICS/LABA combination treatments, this article is intended to help those who wish to assess the quality of CER published projects in asthma and COPD, or guide investigators who wish to design new CER studies for chronic respiratory disease treatments. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a very prevalent disease that affects children as well as adults. The disease has a severe impact on quality of life for the patients and their families. The skin in atopic dermatitis patients is a site of both a severe inflammatory reaction dominated by lymphocytes and decreased skin barrier function. The treatment of the disease is mainly aimed at reducing the inflammation in the skin and/or restoring the skin barrier function. However, most of the treatments used today singularly aim at reducing the inflammation in the skin. Depending on the severity of the disease, the anti-inflammatory treatment may be topical or systemic, but basic treatment, no matter the severity, should always be emollients. In addition, new studies have shown good effects of psychosocial interventions, such as eczema schools, for patients and their families. This review covers the latest trends in the treatment of atopic dermatitis. [ABSTRACT FROM AUTHOR]

Exenatide, administered subcutaneously twice daily (Byetta), is a synthetic version of the natural peptide exendin-4, which is a glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic). Exenatide binds to the GLP-1 receptor with the same affinity as GLP-1, but has a much longer half-life, since it is not degraded by the enzyme dipeptidyl peptidase-4. Exenatide twice daily enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, slows gastric emptying and reduces caloric intake. In well-designed clinical trials, adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16-52 weeks significantly and dose-dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs (OADs) and/or basal insulin. The improvements in glycaemic control and reductions in body weight were stably maintained during long-term therapy (up to 3.5 years). The efficacy of adjunctive exenatide twice daily was generally similar to that of basal, prandial or biphasic insulin, sulfonylureas, rosiglitazone and lixisenatide, and less than that of liraglutide, taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin. Exenatide twice daily was generally well tolerated; mild to moderate nausea and vomiting, which decreased with time on therapy, were the most common adverse events. In patients not receiving concomitant sulfonylureas or insulin, the incidence of hypoglycaemia was low; when it did occur, it was generally mild in severity. Thus, adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and/or basal insulin. [ABSTRACT FROM AUTHOR]

Anemia and iron deficiency anemia are very common in inflammatory bowel disease (IBD). In most cases, anemia is a consequence of mixed pathogenesis; inflammation and iron deficiency being the most important factors. Iron status should be evaluated carefully, as ferritin is unreliable in the presence of inflammation. It is always necessary to control disease activity; however, supplementation is usually required to fully correct iron deficiencies. Oral iron, intravenous iron, erythropoietin, and blood transfusions can be used in different clinical scenarios. Oral iron may be used in mild cases if the disease has no clinical activity. Intravenous iron should be preferred where oral iron is poorly tolerated or where it has failed in moderate to severe anemia, and in combination with erythropoietin. Iron sucrose is very safe and effective, but not very convenient, as the total needed dose must be divided into several infusions. Ferric carboxymaltose is much more convenient, and has been shown to be more effective than iron sucrose in a large randomized trial. Iron isomaltose shows theoretical promise, but very limited data are available from IBD populations. Blood transfusion can be necessary, especially in acute life-threatening situations, but the trigger for indication should be in the low range. With the correct use of available resources, anemia and iron deficiency should be well controlled in practically all IBD patients. [ABSTRACT FROM AUTHOR]

Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease. [ABSTRACT FROM AUTHOR]

Potent combination antiretroviral therapy (ART) has resulted in dramatic improvements in AIDS-associated morbidity and mortality. Although combination ART has resulted in a significant reduction in HIV-associated dementia, the most severe of the HIV-associated neurocognitive disorders (HAND), the overall prevalence of HAND among this population is estimated at 40 %. It has been recognized that the central nervous system (CNS) serves as a reservoir for HIV, and neuronal damage begins at the time of acute infection and persists due to chronic infection of microglial and perivascular macrophages. Although combination ART has resulted in virologic control in the plasma compartment, virologic breakthrough can potentially ensue within the CNS compartment due to limited ART drug exposure. The purpose of this review is to discuss the definition, clinical spectrum, and risk factors associated with HAND, review the pathogenesis of HAND, and address the pharmacologic challenges associated with ART drug exposure in the CNS compartment. [ABSTRACT FROM AUTHOR]

Although the incidence of HIV-associated cryptococcosis has decreased in developed countries since the introduction of antiretroviral therapy, this disease continues to cause significant morbidity and mortality in sub-Saharan Africa among patients with AIDS. Important strides have been made in an attempt to decrease the burden of disease, particularly the development of the lateral flow assay cryptococcal antigen (LFA CrAg) as a diagnostic tool in resource-limited settings, coupled with the introduction of pre-emptive treatment with fluconazole for HIV-positive patients at risk for cryptococcosis with a positive LFA CrAg. Among solid organ transplant recipients, recent prospective studies have identified cryptococcosis as the third most common invasive fungal infection, and progress is being made toward earlier diagnosis and more effective therapy. Finally, the Cryptococcus gattii outbreak in British Columbia, Canada and the US Pacific Northwest is providing important new insights into the emergence of this pathogen in geographic areas previously considered low risk for acquisition of infection. Understanding the similarities and differences among C. gattii and C. neoformans infections will provide critical insights into the behavior of these organisms in the human host. Both pathogens affect immunocompetent and immunosuppressed hosts, causing pulmonary, central nervous system and widely disseminated infections. Treatment recommendations in the future will necessarily take into account the site of infection, clinical severity of the infection, Cryptococcus species, host immune status and economic resources. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a serotonin 5-HT receptor antagonist, dexamethasone and a neurokinin 1 (NK) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT receptor antagonist with a different half-life, a different binding capacity and a different mechanism of action than the first-generation 5-HT receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first and only agent clinically available in the NK receptor antagonist drug class has been used effectively as an additive agent to the 5-HT receptor antagonists and dexamethasone to control CINV. Rolapitant and netupitant are other NK receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a US-FDA approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as a very effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. [ABSTRACT FROM AUTHOR]

Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan. [ABSTRACT FROM AUTHOR]

The global burden of erectile dysfunction (ED) is increasing. It is estimated that 8-19% of men in Europe have ED and that by 2025 the prevalence of ED worldwide will reach 322 million. The gold standard therapy for ED is an oral phosphodiesterase type 5 (PDE5) inhibitor, but they are not suitable for everyone; approximately 25% of patients do not respond to this therapy and it is contraindicated in others, e.g. those with vascular disease. When PDE5 inhibitors are not suitable, available options include intraurethral and intracavernosal alprostadil--a synthetic vasodilator chemically identical to the naturally occurring prostaglandin E1 indicated for the treatment of ED. Intraurethral alprostadil is delivered by the Medicated System for Erection (MUSE)--a single-use pellet containing alprostadil suspended in polyethylene glycol administered using an applicator. It is recommended that intraurethral alprostadil be initiated at a dose of 500 µ, as it has a higher efficacy than the 250 µg dose, with minimal differences with regard to adverse events. Data from key clinical studies of intraurethral alprostadil show that it has a fast onset of effect and a good safety profile, with no occurrences of priapism, fibrosis (as seen with intracavernosal injection) or the typical systemic effects observed with oral ED pharmacological treatments. Intraurethral alprostadil has been associated with high patient preference, acceptance rates and quality of life versus intracavernosal injection due to its ease of administration. Evidence has shown that combination treatment with sildenafil may be a possible efficient alternative when single oral or local treatment has failed. Intraurethral alprostadil can be administered in all patients irrespective of ED origin and should be the first option in patients with ED for whom therapy with PDE5 inhibitors has failed or is contraindicated. [ABSTRACT FROM AUTHOR]

Behcet's syndrome (BS) is a vasculitis, seen more commonly around the Mediterranean and the Far East, and manifests with oral and genital ulcerations, skin lesions, uveitis, and vascular, central nervous system and gastrointestinal involvement. Its natural history of getting less severe over time, more severe disease in males and lack of specific diagnostic testing separates it from other commonly seen conditions in rheumatology. Most of the serious manifestations respond well to immunosuppression, and these are the mainstays of treatment for BS. BS is more prevalent in regions along the Silk Road, from the Mediterranean to the Far East. The genetic risk factor most strongly associated with BS is the human leukocyte antigen (HLA)-B5I allele. While genetic factors seem to play a role in the development of certain features of BS, there is general consensus that as yet unidentified environmental stimuli are necessary for initiation of disease. Proposed exogenous triggers include both bacterial and viral infections, which may then lead to dysregulation of the immune system, ultimately leading to the phenotypic expression of disease. The clinical manifestations of BS are protean in nature. While most patients develop mucocutaneous and genital ulcers along with eye disease, other patients may also present with arthritis, frank vasculitis, thrombophlebitis and CNS disease. Interestingly, the manifestations of this illness vary considerably based on gender and ethnicity. As the phenotypic expression among patients with BS is quite heterogeneous, pharmacological therapy is variable and dependent upon the severity of the disease as well as organ involvement. Treatment for BS overlaps considerably with therapies for other autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and the vasculitides. Pharmacological agents utilized for treatment of BS include corticosteroids, colchicine, azathioprine, and tumour necrosis factor (TNF)-α inhibitors, among others. In this article, we review the salient clinical studies for each drug class along with important side effects as well as drug toxicity monitoring. Management of the patient with BS is complex and often times requires a multidisciplinary approach. We discuss strategies to assess and stratify patients based on clinical manifestations and disease severity. A summary of drug toxicities as they relate to the aforementioned pharmacological agents, as well as guidelines regarding vaccinations in this patient population, are offered. Finally, we conclude with treatment strategies for the common manifestations of BS along with a discussion of the management of thrombotic disease in these patients. [ABSTRACT FROM AUTHOR]

The generalized term 'peripheral vascular disease' (PVD) may be used to refer to vascular disorders in any non-coronary arterial bed. The more specific term 'peripheral arterial disease' (PAD) is used to refer to a more specific process, atherosclerotic disease of the lower extremities. PAD is common. Conservative estimates suggest more than 8 million Americans may be affected by PAD. Since atherosclerosis is a systemic process, PAD should be identified as a coronary heart disease risk equivalent. However, PAD remains an under-diagnosed and under-recognized risk for cardiovascular morbidity and mortality. PAD symptoms may range from non-specific ambulatory leg complaints, to typical symptoms of intermittent claudication to critical limb ischaemia with rest pain, gangrene or ulceration. These symptoms directly impact quality of life and may affect functional capacity. There are two therapeutic goals for patients with PAD: first, to reduce the risk of cardiovascular events and second, to manage the lower extremity symptoms. This manuscript reviews the medical management of patients with PAD, briefly discussing the goals of cardiovascular risk factor modification and then focusing on pharmacological management strategies for patients with intermittent claudication and critical limb ischaemia. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of potentially life-threatening complications that occur after solid organ and bone marrow transplantation. Risk factors for acquiring PTLD are type of organ transplanted, age, intensity of immunosuppression, viral infections such as Epstein-Barr virus (EBV) and time after transplantation. Due to a dearth of well designed prospective trials, treatment for PTLD is often empirical, with reduction in immunosuppression accepted as the first step. Rituximab, a monoclonal antibody directed against the CD20 antigen of immature B cells, is often used as monotherapy after reduction in immunosuppression, although this is associated with a high risk of relapse if patients have at least one of the following risk factors: age greater than 60 years, elevated lactate dehydrogenase levels and Eastern Cooperative Oncology Group Score between 2 and 4. For such patients, rituximab should be considered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), particularly if high-grade PTLD is present. Although widely prescribed, the use of ganciclovir for PTLD remains controversial as EBV-transformed cells lack the thymidine kinase necessary for ganciclovir activation. Newer antivirals that combine ganciclovir with activators of cellular thymidine kinase have shown promising results in pre-clinical studies. In the absence of controlled trials, surgery may be indicated for localized disease and radiotherapy for patients with impending spinal cord compression or disease localized to the central nervous system or orbit. Future interventions may include adoptive immunotherapy, intravenous immunoglobulin, mammalian target of rapamycin inhibitors, monoclonal antibodies to interleukin-6 and galectin-1, and even EBV vaccination. Although several trials are in progress, it is necessary to wait for the long-term outcome of these studies on risk of PTLD relapse. [ABSTRACT FROM AUTHOR]

Delirium is commonly observed in critically ill patients and is associated with negative outcomes. The pathophysiology of delirium is not completely understood. However, alterations to neurotransmitters, especially acetylcholine and dopamine, inflammatory pathways and an aberrant stress response are proposed mechanisms leading to intensive care unit (ICU) delirium. Detection of delirium using a validated delirium assessment tool makes early treatment possible, which may improve prognosis. Patients at high risk of delirium, especially those with cognitive decline and advanced age, should be identified in the first 24 hours of admission to the ICU. Whether these high-risk patients benefit from haloperidol prophylaxis deserves further study. The effectiveness of a multicomponent, non-pharmacological approach is shown in non-ICU patients, which provides proof of concept for use in the ICU. The few studies on this approach in ICU patients suggest that the burden of ICU delirium may be reduced by early mobility, increased daylight exposure and the use of earplugs. In addition, the combined use of sedation, ventilation, delirium and physical therapy protocols can reduce the frequency and severity of adverse outcomes and should become part of routine practice in the ICU, as should avoidance of deliriogenic medication such as anticholinergic drugs and benzodiazepines. Once delirium develops, symptomatic treatment with antipsychotics is recommended, with haloperidol being the drug of first choice. However, there is limited evidence on the safety and effectiveness of antipsychotics in ICU delirium. [ABSTRACT FROM AUTHOR]

Disease stabilization after first-line chemotherapy, also known as induction chemotherapy, is defined, according to the Response Evaluation Criteria in Solid Tumours (RECIST), as having neither sufficient shrinkage to qualify as a partial response (PR) nor sufficient increase to qualify as progressive disease (PD). In oncology, stable disease (SD) has often been viewed as an equivocal result and is therefore of unclear clinical value. In SD patients with advanced non-small cell lung cancer (NSCLC) who have already received four cycles of first-line chemotherapy with platinum agents plus a third-generation agent (gemcitabine, vinorelbine, docetaxel or paclitaxel) or pemetrexed, the continuation of the original treatment is not recommended according to the American Society of Clinical Oncology (ASCO) guidelines. The ASCO guidelines recommend maintenance with bevacizumab or cetuximab, as tolerated until progression, only for platinum-based chemotherapy combined with bevacizumab or cetuximab. Several trials and a meta-analysis have, however, suggested a role for maintenance treatment in patients without progression after induction chemotherapy. The National Comprehensive Cancer Network guidelines recently suggested that maintenance therapy may be considered after four to six cycles of induction platinum doublets for patients with tumour responses or SD, and recommended first-line treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutated patients to continue until PD. More recently, two randomized clinical trials that compared pemetrexed or erlotinib with a placebo demonstrated a better overall survival in favour of maintenance therapy. In subgroup analyses for both trials, patients with SD after first-line induction chemotherapy had pronounced survival benefits when erlotinib or pemetrexed maintenance therapy was given, although this result was not achieved in patients with a complete response or PR after induction chemotherapy. The management of patients with SD after first-line chemotherapy is an important issue because only a minority of patients with advanced NSCLC experience tumour shrinkage after standard platinum-based chemotherapy. Many more patients experience either SD or PD. The notion that the prognosis of SD patients varies greatly due to the complexity of SD should, however, be taken into careful consideration for the treatment decision. Therefore, suggestions for the further classification of SD are urgently needed to enable the use of an alternative therapy at an early time. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute systemic vasculitis affecting young children and is rising in incidence worldwide. It is most common in children <5 years of age, males and those of Asian ethnicity. It is an important cause of acquired heart disease in children. Standard treatment with high-dose aspirin (acetylsalicylic acid; ASA) and intravenous immune globulin (IVIG) has been shown to decrease the rate of coronary artery aneurysm development. Anti- coagulation has an important place in the management of KD, although guidance based on evidence is lacking. Treatment of refractory KD is an area under intense study and may include IVIG, corticosteroids and/or tumour necrosis factor (TNF)-oc inhibitors among immunosuppressive agents. Acute complications of KD iinclude myocarditis/KD shock syndrom and macrophage activation syndrome, which necessitate appropriate awareness in order ot initiate proper management. [ABSTRACT FROM AUTHOR]

Metastatic prostate cancer remains a considerable therapeutic challenge; however, advances in clinical research have resulted in five new treatments in the last 2 years. The immunotherapy sipuleucel-T, the cytotoxic cabazitaxel, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope al- pharadin and the anti-androgen MDV3100 have all been shown to improve overall survival in randomized phase III studies for patients with metastatic castration-resistant prostate cancer. The therapeutic strategies of targeting androgen-receptor signalling and other key intracellular pathways involved in tumour progression and treatment resistance are yielding promising results. Agents such as the dual vascular endothelial growth factor receptor/ MET inhibitor cabozantinib, the clusterin inhibitor custirsen and the Src inhibitor dasatinib have shown encouraging results in phase II studies. Novel immunotherapeutics such as prostate-specific membrane antigen-directed therapy and the anti-cytotoxic T lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under investigation. Optimal methods of treatment selection, combination and sequencing have yet to be determined. [ABSTRACT FROM AUTHOR]

Etravirine (Intelence®) is an orally administered next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). It is approved for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and are harbouring HIV-1 strains resistant to other antiretroviral (ARV) agents. In the US, etravirine must be used in combination with other ARV agents; in the EU, it must be used in combination with other ARV agents that include a boosted HIV-1 protease inhibitor. Etravirine shows good activity in vitro against most wild-type strains of HIV-1, as well as against several strains resistant to available NNRTIs. Furthermore, etravirine appears to present a higher barrier than first-generation NNRTIs against the development of drug resistance. Whereas the presence of a single mutation is sufficient to affect the virological response to efavirenz or nevirapine, the resistance profile of etravirine is more complex and a prediction of virological response may be calculated using a weighted genotypic score. Importantly, the most prevalent NNRTI-associated mutation, K103N, alone does not affect the etravirine response. In two identically designed randomized clinical trials, the addition of etravirine to an optimized background therapy (OBT) regimen improved virological responses to a greater extent than placebo plus OBT following 24 weeks' treatment in highly treatment-experienced adult patients with HIV-1 infection who had evidence of viral replication (HIV-1 RNA levels of >5000 copies/mL at baseline). Furthermore, pre-planned pooled analyses of the trials at 48 and 96 weeks showed that etravirine plus OBT provided durable virological suppression. Consistently higher virological response rates were observed for recipients of etravirine plus OBT than placebo plus OBT in a pre-specified subgroup analysis of baseline viral loads, CD4+ cell counts, HIV-1 subtype or the composition of background ARV therapy. Greater improvements from baseline in immunological outcomes were also observed for recipients of etravirine plus OBT compared with those receiving placebo plus OBT over the 96-week treatment period of the trials. When used as part of an OBT regimen in trials of up to 96 weeks duration, etravirine was well tolerated with an overall tolerabilty profile similar to that of placebo. The only treatment-emergent adverse event that occurred with a higher frequency for recipients of etravirine compared with placebo plus OBT was rash. In highly treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of etravirine to an OBT regimen provides an effective and well tolerated treatment that leads to improvements in both virological and immunological outcomes. [ABSTRACT FROM AUTHOR]

Critically ill patients admitted to the intensive care unit (ICU) are frequently treated with antimicrobials. The appropriate and judicious use of antimicrobial treatment in the ICU setting is a constant clinical challenge for healthcare staff due to the appearance and spread of new multiresistant pathogens and the need to update knowledge of factors involved in the selection of multiresistance and in the patient's clinical response. In order to optimize the efficacy of empirical antibacterial treatments and to reduce the selection of multiresistant pathogens, different strategies have been advocated, including de-escalation therapy and pre-emptive therapy as well as measurement of pharmacokinetic and phar-macodynamic (pK/pD) parameters for proper dosing adjustment. Although the theoretical arguments of all these strategies are very attractive, evidence of their effectiveness is scarce. The identification of the concentration-dependent and time-dependent activity pattern of antimicrobials allow the classification of drugs into three groups, each group with its own pK/pD characteristics, which are the basis for the identification of new forms of administration of antimicrobials to optimize their efficacy (single dose, loading dose, continuous infusion) and to decrease toxicity. The appearance of new multiresistant pathogens, such as imipenem-resistant Pseudomonas aeruginosa and/or Acinetobacter baumannii, carbapenem-resistant Gram-negative bacteria harbouring carbapenemases, and vancomycin-resistant Enterococcus spp., has determined the use of new antibacterials, the reintroduction of other drugs that have been removed in the past due to toxicity or the use of combinations with in vitro synergy. Finally, pharmacoeconomic aspects should be considered for the choice of appropriate antimicrobials in the care of critically ill patients. [ABSTRACT FROM AUTHOR]

The incidence of squamous cell carcinoma of the head and neck (SCCHN) is on the rise in the US despite a drop in cigarette smoking rates. Much of this rise is due to the increasing incidence of SCCHN attributable to human papillomavirus (HPV). HPV-related SCCHN has a high cure rate, which contributes to the stable death rates despite the increased incidence. Up to half of patients with SCCHN will develop recurrence. For these patients, the first clinical decision is whether the recurrence is potentially treatable for cure, or is incurable. For those deemed potentially curable, surgical or radiation- based therapies, or both, are undertaken. For those who have incurable recurrences, the goals are palliation and possibly prolongation of life--average survivals are in the range of 6-12 months depending on the type of recurrence and other factors. Several chemotherapy drugs are active in SCCHN, most notably the platinum compounds, taxanes, fluorouracil (5-FU), methotrexate and cetuximab. Approximately 10-25% of patients will respond to treatment with one of these drugs. The response rate is higher for combinations such as a platinum plus a taxane, a platinum plus 5-FU, a combination of the three, or one of more of these drugs plus cetuximab. Combination chemotherapy has not been shown to prolong survival over single-agent therapy, with the exception of the addition of cetuximab to a platinum and 5-FU combination. A number of orally bioavailable tyrosine kinase inhibitors have been tested or are undergoing trials in SCCHN. None of these has as yet been shown to be more effective than the currently available drugs. For patients with recurrences who are undergoing active therapy, and especially for those for whom further Therapy is no longer appropriate or is declined, strict attention is necessary to palliation of pain, oral and airway issues, and to nutrition, speech, and social and psychological issues. [ABSTRACT FROM AUTHOR]

The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients. [ABSTRACT FROM AUTHOR]

Although ovarian cancer is often a chemosensitive malignancy, patients who are resistant to platinum-based chemotherapy represent a therapeutic challenge. Currently, the only drugs that are US FDA approved to treat this subset of patients are paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan. The response rates with these agents is in the 10-15% range and overall survival is around 12 months. Other drugs that have shown some activity in platinum-resistant ovarian cancer include the taxane analogues, oral etoposide, pemetrexed and bevacizumab. Unfortunately, randomized phase III trials of second-line chemotherapy in patients with platinum- resistant ovarian cancer have not shown an advantage over existing therapy with respect to progression-free survival or overall survival. The only trial that has reported a significant progression-free survival advantage over standard therapy is a randomized phase II trial of PLD with or without EC145, a folate-linked vinca alkaloid. Final survival results of this trial are pending. [ABSTRACT FROM AUTHOR]

Globally, tuberculosis (TB) and HIV interact in deadly synergy. The high burden of TB among HIV-infected individuals underlies the importance of TB diagnosis, treatment and prevention for clinicians involved in HIV care. Despite expanding access to antiretroviral therapy (ART) to treat HIV infection in resource-limited settings, many individuals in need of therapy initiate ART too late and have already developed clinically significant TB by the time they present for care. Many co-infected individuals are in need of concurrent ART and anti-TB therapy, which dramatically improves survival, but also raises several management challenges, including drug interactions, shared drug toxicities and TB immune reconstitution inflammatory syndrome (IRIS). Due to the survival benefits of promptly initiating ART among all HIV-infected individuals, including those with TB, it is recommended that co-infected individuals receive treatment for both diseases, regardless of CD4+ cell count. We review current screening and treatment strategies for TB and HIV co-infection. Recent findings and ongoing studies will assist clinicians in managing the prevention and treatment of TB and HIV co-infection, which remains a major global health challenge. [ABSTRACT FROM AUTHOR]

Colorectal cancer remains one of the most common causes of cancer death in the US, with approximately a quarter of patients presenting with meta- static disease at the time of diagnosis. Recent advances over the past 2 decades have increased the repertoire of chemotherapeutic agents for this disease and extended median overall survival to more than 20 months. An increasing body of evidence also supports the addition of targeted agents. those directed towards vascular endothelial growth factor and epidermal growth factor receptors, to expand treatment options for patients with mc- tastatic disease. Ongoing trials are exploring the optimal combinations of these drugs as well as promising new investigational agents that take advantage of the genetic aberrations that drive tumour biology. This review aims to summarize the pertinent data on available cytotoxic and biological agents used to extend survival in metastatic colorectal cancer patients and provide a modern approach to treatment strategies while acknowledging the areas of controversy on which future clinical trials should be based. [ABSTRACT FROM AUTHOR]

Drug-resistant tuberculosis (DR-TB) is an emerging global health threat as treatment involves complex multiple drug regimens, which are longer and more toxic than standard therapy and yet have worse outcomes. In the presence of resistance to one or more first-line drugs, an alternative regimen should be designed. A major problem is the almost complete lack of published evidence regarding the optimal drug combinations and duration of treatment for the different types of DR-TB. Current principles, some of which are based on expert opinion, are that at least three new anti-TB agents should be added to a failing regimen and four agents when multidrug resistance is suspected. All first-line oral anti-TB agents to which the M y co- bacterium tuberculosis strains are susceptible should be used, plus one fluor- oquinolone. In addition, one injectable anti-TB agent and one or more second-line oral anti-TB agents should be added to the regimen until the target number of drugs is reached. The duration of treatment depends on the type of drug resistance, the type and number of drugs used in the regimen, and the extent of the disease. All forms of DR-TB should receive daily, not intermittent, therapy and all doses should be directly observed. Because of the high rate of adverse drug effects, careful monitoring and appropriate management of these adverse reactions are important to achieve successful treatment. Supportive measures, such as adequate nutrition along with emotional and social supports, are an important part of the treatment. Careful consideration is required when dealing with pregnant or lactating women and HIV co-infected patients, as well as in treatment of extrapulmonary DR-TB. [ABSTRACT FROM AUTHOR]

Clostridium difficile infection (CDI) is an increasing problem in hospitalized patients. Recurrences of disease, despite the recommended treatments with metronidazole or vancomycin, are frequently seen and pose major problems for the clinical management of patients with CDI. Evidence for efficient clinical cure and low recurrence rates with primary use of alternative antibacterial treatment, such as fidaxomicin and rifaximin, is growing and these treatment strategies need further exploration. The use of probiotics (e.g. Saccharomyces boulardii) may be considered, as well as combination therapy with vancomycin. Other promising therapies are the use of (monoclonal) antibodies and faecal transplantation, the efficacy of which has been suggested in smaller studies. Large studies evaluating faecal transplantation and other microbial products are underway. This article focuses on recurrent CDI and the possibilities for treatment and reduction of recurrence rates. Furthermore, general concepts of CDI and the primary treatment strategies are discussed. In summary, recurrent CDI remains a challenging clinical entity for which more treatment options will be forthcoming in the next few years. [ABSTRACT FROM AUTHOR]

Histamine dihydrochloride (Ceplene®) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer cells. When administered in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and natural killer cells by IL-2, resulting in the killing of tumour cells of various cancers, including acute myeloid leukaemia (AML). In a 3-year, randomized, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than recipients of no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were grade 1 or 2 of the National Cancer Institute Common Toxicity Criteria. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients, histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission. [ABSTRACT FROM AUTHOR]

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR- activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies. EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Treat-to-target in spondyloarthritis: implications for clinical trial designs" published in a 2014 issue is presented.

A letter to the editor is presented in response the article ‘‘Treat-to-target in spondyloarthritis: implications for clinical trial designs" by J. C. Wei published in a 2014 issue of the periodical.