Gepotidacin: a novel, oral, 'first-in-class' triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea.

The ongoing spread of antimicrobial resistance has made the treatment of uncomplicated urinary tract infections (UTIs) and urogenital gonorrhoea increasingly difficult. New oral treatment options are urgently needed. Gepotidacin (previously GSK2140944) is a novel, bactericidal, oral, 'first-in-class' triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Mutations in both enzymes would likely be necessary for resistance to occur, thus raising hopes that the drug will be able to maintain long-term effectiveness. Data from Phase II clinical trials of gepotidacin in UTIs and urogenital gonorrhoea appear promising, and Phase III trials are underway. In this review we summarize the development of gepotidacin and discuss its potential role in clinical practice. If approved, gepotidacin will be the first new oral antibiotic for UTIs in more than 20 years.

Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation provide an update on potential drug-drug interactions between anti-infectives and immunosuppressants, which are most notable with calcineurin and mTOR inhibitors. Drug-drug interactions may occur through pharmacokinetic mechanisms leading to altered drug concentrations of either the anti-infective or immunosuppressive drug, or by pharmacodynamic interactions increasing or decreasing the efficacy or toxicity of the medications. Many of the significant pharmacokinetic interactions occur through inhibition or induction of the cytochrome 3A4 system by anti-infective agents leading to increased or decreased immunosuppressive agent levels, respectively. The membrane transporter P-glycoprotein is also often involved in drug interactions. Since the last iteration of these guidelines, multiple new hepatitis C virus direct-acting antivirals have become available for use in SOT recipients. Of these agents, some are substrates of cytochrome and drug transporter systems, while others inhibit these systems and may affect immunosuppressive agents. Due to the high risk for drug-drug interactions in the solid organ transplant population, practitioners must be aware of potential interactions and be vigilant in monitoring and adjusting drug dosing when appropriate.

An update on the association of vitamin D deficiency with common infectious diseases.

Vitamin D plays an important role in modulating the immune response to infections. Deficiency of vitamin D is a common condition, affecting both the general population and patients in health care facilities. Over the last decade, an increasing body of evidence has shown an association between vitamin D deficiency and an increased risk for acquiring several infectious diseases, as well as poorer outcomes in vitamin D deficient patients with infections. This review details recent developments in understanding the role of vitamin D in immunity, the antibacterial actions of vitamin D, the association between vitamin D deficiency and common infections (like sepsis, pneumonia, influenza, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus type-1 (HIV), and hepatitis C virus (HCV)), potential therapeutic implications for vitamin D replacement, and future research directions.

Evaluation of infections in the lung transplant patient.

PURPOSE OF REVIEW: Infections in lung transplant recipients (LTRs) are a serious complication that is associated with high mortality. Early and accurate diagnosis is critical in the management of these infections in order to achieve improved outcomes. This review focuses on studies published in the last 2 years related to the evaluation and management of infections following lung transplantation. RECENT FINDINGS: Valganciclovir is well tolerated and effective for long-term cytomegalovirus prophylaxis. Recently published guidelines recommend that foscarnet be added to ganciclovir for patients with life-threatening or sight-threatening disease while waiting for genotypic assay results because of ganciclovir-resistant strains. Mycobacterium abscessus has emerged as a significant pathogen in LTRs and should be eradicated in potential recipients before transplantation is performed. Preoperative Aspergillus colonization appears to not increase the risk of death after transplant. Azithromycin is protective against the development of bronchiolitis obliterans syndrome (BOS) and reduces mortality in LTRs. Eradication of Staphylococcus aureus in patients colonized prior to surgery can decrease postoperative surgical site infections from it by 80%. RNA interference therapy improves the symptoms of BOS in LTRs but does not have a direct antiviral effect. SUMMARY: Although life-saving for most recipients, lung transplantation can be complicated by serious postoperative infections. Additional prospective studies are needed to better elucidate the role of molecular testing in the diagnosis of infections, to determine whether eradication of S. aureus colonization improves outcomes in LTRs, and to further evaluate the role of RNA interference therapy for infections in LTRs.

Update on cytomegalovirus infections of the gastrointestinal system in solid organ transplant recipients.

Cytomegalovirus (CMV) infection of the gastrointestinal tract is the most common manifestation of tissue-invasive CMV disease, and is a significant cause of morbidity and mortality in the solid organ transplantation (SOT) recipient. In addition to the direct effects of the infection, its indirect effects on allograft function, risk for other opportunistic infections, and mortality are significant in this population. The most common clinical syndromes are esophagitis, colitis, and hepatitis; however, infection can occur anywhere in the gastrointestinal tract. Diagnosis is usually by histopathology or viral culture of tissue specimens; molecular assays also often have a role. Antivirals are the cornerstone of therapy for gastrointestinal tract CMV disease and complications such as recurrent infection and antiviral resistance are not uncommon. Prevention with antiviral prophylaxis or preemptive therapy is important. This review summarizes recent data regarding the clinical manifestations, diagnosis, treatment, and prevention of gastrointestinal tract CMV infection in the SOT population.

Diagnosis and management of community-acquired pneumonia in adults.

Community-acquired pneumonia is diagnosed by clinical features (e.g., cough, fever, pleuritic chest pain) and by lung imaging, usually an infiltrate seen on chest radiography. Initial evaluation should determine the need for hospitalization versus outpatient management using validated mortality or severity prediction scores. Selected diagnostic laboratory testing, such as sputum and blood cultures, is indicated for inpatients with severe illness but is rarely useful for outpatients. Initial outpatient therapy should include a macrolide or doxycycline. For outpatients with comorbidities or who have used antibiotics within the previous three months, a respiratory fluoroquinolone (levofloxacin, gemifloxacin, or moxifloxacin), or an oral beta-lactam antibiotic plus a macrolide should be used. Inpatients not admitted to an intensive care unit should receive a respiratory fluoroquinolone, or a beta-lactam antibiotic plus a macrolide. Patients with severe community-acquired pneumonia or who are admitted to the intensive care unit should be treated with a beta-lactam antibiotic, plus azithromycin or a respiratory fluoroquinolone. Those with risk factors for Pseudomonas should be treated with a beta-lactam antibiotic (piperacillin/tazobactam, imipenem/cilastatin, meropenem, doripenem, or cefepime), plus an aminoglycoside and azithromycin or an antipseudomonal fluoroquinolone (levofloxacin or ciprofloxacin). Those with risk factors for methicillin-resistant Staphylococcus aureus should be given vancomycin or linezolid. Hospitalized patients may be switched from intravenous to oral antibiotics after they have clinical improvement and are able to tolerate oral medications, typically in the first three days. Adherence to the Infectious Diseases Society of America/American Thoracic Society guidelines for the management of community-acquired pneumonia has been shown to improve patient outcomes. Physicians should promote pneumococcal and influenza vaccination as a means to prevent community-acquired pneumonia and pneumococcal bacteremia.

Histoplasma capsulatum prosthetic valve endocarditis with negative fungal blood cultures and negative histoplasma antigen assay in an immunocompetent patient.

We report a case of Histoplasma capsulatum endocarditis in which Histoplasma antigen assay and fungal blood cultures were negative. The diagnosis was made by microscopic examination and culture of the excised valve. Histoplasma capsulatum should be considered in the differential diagnosis of culture-negative endocarditis in regions where it is endemic and in travelers.

Mold Infections in Solid Organ Transplant Recipients.

Mold infections carry a substantial clinical and economic burden in solid organ transplant (SOT) recipients with a high overall mortality of near 30%. The most important pathogens include Aspergillus, the Zygomycetes, Fusarium, Scedosporium/Pseudallescheria, and the dematiaceous (dark) molds. Risk factors for the infections vary by transplant type but include degree of immune suppression and loss of skin or mucosal integrity. Correct diagnosis usually requires histopathology and/or culture. Management often requires a multidisciplinary team approach with combined antifungal and surgical therapies. This article reviews the epidemiology, risk factors, microbiology, diagnostic, and treatment approach to mold infections in SOT recipients.

Differences in Clinical Manifestations of Acute and Early HIV-1 Infection between HIV-1 Subtypes in African Women.

Little is known about the differences in clinical manifestations between women with various HIV-1 subtypes during acute (AI) and early (EI) HIV infection. In a longitudinal cohort study, clinical signs and symptoms among Uganda and Zimbabwe women with AI and EI were compared with HIV-negative controls; symptoms were assessed quarterly for 15 to 24 months. Early HIV infection was defined as the first visit during which a woman tested HIV antibody positive. Women who were HIV negative serologically but DNA polymerase chain reaction positive were considered AI. In all, 26 women were classified AI and 192 EI, with 654 HIV-negative controls. Primary HIV infection (AI and EI) was associated with unexplained fever (P <.01), weight loss (P <.01), fatigue (P <.01), inguinal adenopathy (P <.01), and cervical friability (P =.01). More women with subtype C infection had unexplained fever, fatigue, and abnormal vaginal discharge compared to subtype A or D infection. Inguinal adenopathy occurred less often in women with subtype A infection than those with subtype C or D infection.

Serum procalcitonin in the diagnosis and management of intra-abdominal infections.

The biomarker procalcitonin (PCT) has been used to diagnose and monitor a number of clinically significant infections. Serum levels of PCT are often increased in the presence of bacterial and fungal infections but not viral infections or noninfectious inflammation. Intra-abdominal infections (IAIs) are serious conditions that pose difficult challenges to physicians and the healthcare system. Researchers have evaluated PCT in the management of IAIs, both for diagnosis and for guiding antibiotic therapy. The studies have produced mixed results, leading to controversy on the utility of PCT in IAIs. PCT appears to be most useful in diagnosing postoperative infections and necrotizing pancreatitis. This review aims to summarize these data, explore the pathophysiology of PCT in sepsis from IAIs, discuss the strengths and weaknesses of PCT monitoring in IAIs, and provide guidance for the interpretation of PCT levels.

An evidence-based review of linezolid for the treatment of methicillin-resistant Staphylococcus aureus (MRSA): place in therapy.

Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated and hospital-associated strains, is a major cause of human morbidity and mortality. Treatment options have become limited due to the emergence of MRSA strains with decreased sensitivity to vancomycin, which has long been the first-line therapy for serious infections. This has prompted the search for novel antibiotics that are efficacious against MRSA. Linezolid, an oxazolidinone class of antibiotic, was approved by the Food and Drug Administration in 2000 for treatment of MRSA infections. Since then, there have been a multitude of clinical trials and research studies evaluating the effectiveness of linezolid against serious infections, including pneumonia (both community- and hospital-acquired), skin and soft-tissue infections such as diabetic foot ulcers, endocarditis, osteomyelitis, prosthetic devices, and others. The primary aim of this review is to provide an up-to-date evaluation of the clinical evidence for using linezolid to treat MRSA infections, with a focus on recently published studies, including those on nosocomial pneumonia. Other objectives are to analyze the cost-effectiveness of linezolid compared to other agents, and to review the pharmokinetics and pharmacodynamics of linezolid, emphasizing the most current concepts.

Immune response to CMV in solid organ transplant recipients: current concepts and future directions.

Despite advances in immunosuppression and antiviral therapy, CMV continues to be a significant opportunistic pathogen adversely affecting the outcome of solid organ transplantation (SOT) recipients. While a significant proportion of CMV disease is caused by reactivation of latent virus, the risk is highest among CMV donor+ and recipient- SOT patients. CMV is responsible for both direct (e.g., pneumonitis, colitis) and indirect (e.g., rejection, atherosclerosis) morbidity and mortality. Healthy CMV-seropositive individuals have a high frequency of CMV-specific CD4(+) and CD8(+) T cells that provide immune protection by limiting CMV reactivation and replication. Changes to the innate and adaptive immune system from immunosuppressive therapy following SOT contribute to CMV disease pathogenesis. CMV disease after SOT is associated with poorer outcomes, thus novel strategies to prevent it are an area of active research. In this article, we review the current state of knowledge on the immune response to CMV following SOT.

The role of vitamin D deficiency in sepsis and potential therapeutic implications.

Recent studies have shown that vitamin D has important functions besides bone and calcium homeostasis. Cells of the innate and adaptive immune system express vitamin D receptors and respond to stimulation by 1, 25-dihydroxyvitamin D. Patients with sepsis have a high mortality rate as well as a high prevalence of vitamin D deficiency. In addition, septic patients have decreased vitamin D binding protein levels which further exacerbates vitamin D deficiency. Therapy with vitamin D in animal models of sepsis improves blood coagulation parameters in disseminated intravascular coagulation and modulates levels of systemic inflammatory cytokines including TNF-α and IL-6. Vitamin D can enhance the induction of the antimicrobial peptides cathelicidin and ß-defensin which are found on mucosal and epithelial surfaces and act as the body's first line of defense against viral and bacterial pathogens. Vitamin D is potentially an attractive therapeutic agent for sepsis given its low cost and low risk of toxicity and side effects. Further prospective, randomized, controlled clinical trials of adjunctive vitamin D therapy in patients who are deficient are needed in the management of human sepsis syndrome.