Disseminated histoplasmosis in an immunosuppressed patient successfully treated with isavuconazole.

Histoplasmosis is an endemic fungal infection caused by the dimorphic fungus, Histoplasma capsulatum, which is treated with intravenous amphotericin B and oral itraconazole as first-line and second-line therapy. We report a case of a man in his early 70s treated with methotrexate and infliximab for rheumatoid arthritis who developed disseminated histoplasmosis. The patient was unable to absorb itraconazole due to intractable diarrhoea and developed a severe, anaphylactoid reaction or an immune reconstitution inflammatory syndrome when treated with liposomal amphotericin B. He was subsequently treated with isavuconazole and steroids and made a full recovery.A literature review revealed other cases of histoplasmosis which were treated with isavuconazole including both primary pulmonary and disseminated presentations. Cases of blastomycosis which were treated with isavuconazole are also reviewed including those with severe immunocompromised statuses including solid-organ transplant and tumour necrosis factor-alpha antagonist recipients. Our report describes the potential role of isavuconazole in cases of histoplasmosis where first-line and second-line therapies have failed or are contraindicated (excluding meningitis).

Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI).

Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea that is deemed a global health threat. C. difficile strain BI/NAP1/027 has contributed to the increase in the mortality, severity of CDI outbreaks and recurrence rates (rCDI). Updated CDI treatment guidelines suggest vancomycin and fidaxomicin as initial first-line therapies that have initial clinical cure rates of over 80%. Unacceptably high recurrence rates of 15-30% in patients for the first episode and 40% for the second recurrent episode are reported. Alternative treatments for rCDI include fecal microbiota transplant and a human monoclonal antibody, bezlotoxumab, that can be used in patients with high risk of rCDI. Various emerging potential therapies with narrow spectrum of activity and little systemic absorption that are in development include 1) Ibezapolstat (formerly ACX-362E), MGB-BP-3, and DS-2969b-targeting bacterial DNA replication, 2) CRS3213 (REP3123)-inhibiting toxin production and spore formation, 3) ramizol and ramoplanin-affecting bacterial cell wall, 4) LFF-571-blocking protein synthesis, 5) Alanyl-L-Glutamine (alanylglutamine)-inhibiting damage caused by C. difficile by protecting intestinal mucosa, and 6) DNV3837 (MCB3681)-prodrug consisting of an oxazolidinone-quinolone combination that converts to the active form DNV3681 that has activity in vitro against C. difficile. This review article provides an overview of these developing drugs that can have potential role in the treatment of rCDI and in lowering recurrence rates.

Investigational drug therapies currently in early-stage clinical development for the treatment of clostridioides (clostridium) difficile infection.

INTRODUCTION: Clostridioides (Clostridium) difficile Infection (CDI) is an urgent global threat causing ~500,000 infections annually in the United States of America (USA) and is associated with a 36% 30-day attributable mortality rate. Despite the availability of three therapeutic agents, CDI recurrence occurs in 20-40% of patients, with a 30-40% second recurrence rate in these patients. Consequently, there is a need for novel agents for treating CDI. AREAS COVERED: We searched MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for agents in early stages of clinical development. These drugs include ACX-362E, DS-2969b, LFF 571, RBX2660, ribaxamase, ridinilazole that have advanced to at least phase 2 and several other drugs in phase 1 development. EXPERT OPINION: The challenge for these new agents is three-fold: (1) to have a novel approach such as a different target/mechanism of action; (2) be 'significantly' better than existing agents in regard to 'sustained clinical response'; or (3) be priced at a reasonable cost when it comes to market or perhaps all three. Their utility can only be proven by clinical trials.

The times they are a-changin': new antibacterials for skin and skin structure infections.

Twenty-one agents are approved by the US Food and Drug Administration (FDA) for the therapy of skin and soft tissue infections. Of these, the five newest agents, tedizolid, telavancin, oritavancin, dalbavancin, and ceftaroline, are active against and "non-inferior" to vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Oritavancin is indicated as a single-dose intravenous regimen, while dalbavancin is a two-dose intravenous regimen given 1 week apart. Telavancin has multiple mechanisms of action. A 6-day regimen of once-daily intravenous or oral dose of tedizolid was compared with 10 days of linezolid and found to be "non-inferior" and have fewer side effects. Ceftaroline has not only MRSA activity but also activity against Escherichia coli and Klebsiella spp. We review the spectra of activity of these new agents, their clinical trials and their therapeutic efficacy, noting differences in their dosing schedules, in vitro activities and costs as potential determinants for appropriate utilization.

Clostridium difficile: improving the prevention paradigm in healthcare settings.

Clostridium difficile infection (CDI) is a major public health problem worldwide with significant morbidity and mortality that is spread by spores and fecal oral transmission. A variety of risk factors have been identified. Some risk factors such as age, are not amenable to change, while others such as antimicrobial utilization have resulted in broadly implemented antimicrobial stewardship programs. New risk factors are emerging such as proton pump inhibitor (PPI) use, irritable bowel disease (IBD) and obesity, with others yet to be determined. Prevention of spread of CDI is imperative, since therapy remains imperfect. We review established and emerging risks for CDI and offer potential preventative strategies with the use of a multidisciplinary CDI prevention bundle checklist.

Therapy of Clostridium difficile infection: perspectives on a changing paradigm.

INTRODUCTION: Clostridium difficile disease (CDI) have increased in frequency and severity over the past decade and are a leading cause of hospital acquired infections, contributing to increased hospital length of stay and costs, as well as associated increased mortality, especially amongst the elderly. Standard therapy has been associated with 20 - 30% relapse rates. Consequently, new CDI therapeutic approaches have emerged. AREAS COVERED: The role of metronidazole, vancomycin, fidaxomicin, rifaximin, nitizoxanide, tigecycline, fusidic acid, LFF-571, cardazolid, SMT 19969, CamSA and surotomycin were reviewed. EXPERT OPINION: New IDSA/SHEA guidelines are expected within the next year and may impact selection of primary therapy for CDI. Until then, metronidazole will likely remain as first line therapy because of low cost and despite its inferiority compared to vancomycin. Vancomycin will likely see increasing use, especially as generics become available. Fidaxomicin will emerge as an important therapy for relapse patients and perhaps as initial therapy for patients at greatest risk for relapse, with concomitant antibiotics, multiple comorbidities and renal insufficiency, advanced age and hypoalbuminemia. Biotherapeutics such as fecal microbiota transplantation and non-toxogenic C. difficile prevention will emerge as the preferred therapy in multiple relapse patients and the development of an oral formulation will occur within five years.