Mara Poulakos

Doripenem: a new carbapenem antibiotic.

PURPOSE The chemistry, pharmacology, antimicrobial activity, pharmacokinetics, pharmacodynamics, efficacy and safety in humans, and formulary considerations of doripenem are reviewed. SUMMARY Doripenem, a member of the β-lactam class of antibiotics, is the newest addition to the carbapenems. It exhibits concentration-independent bactericidal activity against gram-positive bacteria; enteric and nonenteric gram-negative bacteria, including extended-spectrum β-lactamase-producing strains; and anaerobic pathogens. Doripenem was found to be noninferior to meropenem in the treatment of complicated intraabdominal infections and noninferior to levofloxacin in the treatment of complicated urinary tract infections including pyelonephritis and was granted marketing approval by the Food and Drug Administration for these two indications. Doripenem was also found to be noninferior to imipenem in the treatment of ventilator-associated pneumonia and noninferior to piperacillin-tazobactam in the treatment of hospital-acquired pneumonia. It has a favorable safety profile, with gastrointestinal complaints and headache being the most common adverse effects and allergic reactions the most serious adverse effects. Doripenem has a relatively low potential to induce seizures. The only known clinically relevant drug interaction is that coadministration with valproic acid may result in reductions of valproic acid serum concentrations. As with most renally eliminated antibiotics, the dose of doripenem should be adjusted according to kidney function. CONCLUSION Doripenem is an injectable carbapenem antibiotic with a spectrum of activity comparable to that of imipenem and meropenem. Its safety is similar to that of other carbapenems.

Edoxaban: A direct oral anticoagulant

PURPOSE The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, and place in therapy of edoxaban for prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and treatment of venous thromboembolism (VTE) are reviewed. SUMMARY Although warfarin has been an established therapy for stroke prevention in AF and VTE, the need for agents with less monitoring requirements, fewer food and drug interactions, and a lower risk of major bleeding led to the development of direct oral anticoagulants (DOACs). Current DOACs work by either directly blocking thrombin (dabigatran) or inhibiting factor Xa (apixaban, edoxaban, and rivaroxaban). Edoxaban is the newest DOAC and only the second Food and Drug Administration-approved anticoagulant for once-daily administration. Unlike apixaban and rivaroxaban, edoxaban does not interact with the cytochrome P-450 system. The results of the ENGAGE AF-TIMI 48 and Hokusai-VTE trials demonstrated edoxabans noninferiority to warfarin. However, the adverse-effect profile of edoxaban may limit the drugs use in clinical practice; in clinical trials, patients with AF who had a creatinine clearance of ≥95 mL/min had a higher rate of strokes with the use of edoxaban versus warfarin. CONCLUSION A review of the literature showed that edoxaban, the most recently approved DOAC, is noninferior to warfarin for management of VTE (after parenteral anticoagulant therapy) and for stroke risk reduction in many patients with nonvalvular AF.

Efinaconazole and Tavaborole: Emerging Antifungal Alternatives for the Topical Treatment of Onychomycosis.

Purpose: The purpose of this article is to review the safety, efficacy, and role of efinaconazole and tavaborole in the treatment of onychomycosis. Summary: Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, and nondermatophyte fungi. Distal and lateral subungual onychomycosis (DLSO) accounts for the majority of the cases. These infections cause structural damage to the nail which makes treatment difficult. Both oral and topical agents exist for the treatment of onychomycosis. Oral medications have generally been more effective, yet adverse effects and drug interactions limit their use in some patients. Food and Drug Administration (FDA)-approved agents in the United States for oral therapies include terbinafine, itraconazole, and griseofulvin. The only topical product available up to recently was ciclopirox. Conclusion: This article will review efinaconazole and tavaborole, 2 new topical antifungal agents released in 2014.

Mepolizumab for the treatment of severe eosinophilic asthma

Purpose Published data on the pharmacology, pharmacokinetics and pharmacodynamics, and clinical efficacy and safety of the interleukin‐5 antagonist mepolizumab are reviewed. Summary Asthma of the eosinophilic phenotype is characterized by persistent eosinophilic airway inflammation promoted primarily by T‐helper type 2 cytokines, the key regulator of eosinophils. Patients with severe eosinophilic asthma are burdened by the need to administer high doses of corticosteroids to help manage their symptoms. In November 2015, mepolizumab (Nucala, GlaxoSmithKline) gained U.S. marketing approval for use as an add‐on maintenance treatment for severe eosinophilic asthma in patients 12 years of age or older, making it the first personalized targeted therapy for this population. Efficacy results from clinical trials provided evidence of the corticosteroid‐sparing effects of mepolizumab and its ability to reduce both blood and sputum eosinophil counts. Safety data from several Phase II or III studies involving a total of more than 1,300 patients indicated that mepolizumab was generally well tolerated, and types and rates of adverse events in mepolizumab recipients were comparable to those reported with placebo use; the only mepolizumab‐associated serious adverse drug events were asthma exacerbations in 2 patients. The recommended dosage of mepolizumab is 100 mg administrated via subcutaneous injection every 4 weeks. Conclusion Mepolizumab is a safe and efficacious novel add‐on therapy for a small subgroup of patients with severe eosinophilic asthma whose asthma is not adequately controlled by standard regimens for asthma treatment.

Probable Linezolid-Induced Thrombocytopenia in a Patient With Vancomycin-Resistant Enterococci

Purpose: A probable case of linezolid-induced thrombocytopenia is reported. Summary: A 74-year-old Caucasian male with renal dysfunction was diagnosed with diverticulosis. Patient was prescribed linezolid 600 mg orally twice daily for vancomycin-resistant enterococci abdominal infection that developed secondary to colon resection. Upon initiation of linezolid, platelet count dropped from 248 000 cells/mm3 on day 1 to 97 000 cells/mm3 on day 5 of treatment. Linezolid was discontinued and platelet counts improved to pretreatment levels. Application of the Naranjo probability scale indicated a probable association of linezolid therapy and thrombocytopenia. Clinicians should be aware that linezolid has this hematologic side effect and that patients with renal dysfunction are at increased risk. Monitoring platelet count more than once weekly should be advisable in these patients. Conclusion: A 74-year-old Caucasian male with renal dysfunction developed a probable case of linezolid-induced thrombocytopenia after receiving the drug for 5 days for treatment of vancomycin-resistant enterococci abdominal infection.

Early Vancomycin Concentrations and the Applications of a Pharmacokinetic Extrapolation Method to Recognize Sub-Therapeutic Outcomes

Vancomycin trough concentrations should be measured within 30 min of the next dose, but studies have shown that troughs are often measured too early, producing erroneous results that could lead to dosing errors. The purpose of this study was to identify the frequency of early trough measurements and to evaluate whether pharmacokinetically extrapolating mistimed concentrations may locate sub-therapeutic concentrations. Vancomycin troughs were retrospectively reviewed. For troughs ≥10 mg/L and measured >0.5 h early, the true trough was estimated using pharmacokinetic extrapolation methods to identify sub-therapeutic outcomes. Differences ≥2 mg/L between the measured and estimated true trough level was considered to have potential clinical significance. Of 143 troughs evaluated, 62 (43%) were measured too early and 48 of those troughs were ≥10 mg/L. 25% of those 48 troughs were sub-therapeutic. The potential for a difference ≥2 mg/L between the measured and estimated true trough was found to be greatest when the measured trough was ≥10 mg/L, the patient’s creatinine clearance (CrCl) was ≥60 mL/min, and the timing error was ≥2 h. To increase the therapeutic utility of early vancomycin trough concentrations, estimated true troughs can be determined by extrapolating measured values based on the time difference and CrCl.

Vedolizumab A New Opponent in the Battle Against Crohn’s Disease and Ulcerative Colitis

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal (GI) tract that encompass Crohns disease (CD) and ulcerative colitis (UC). In these disease states, epithelial damage of the intestinal mucosa is evident due to increased lymphocyte trafficking to the area, which affects the normal intestinal barrier function. Currently available pharmacotherapy can be limited in terms of efficacy and associated toxicities. Newer agents have emerged, including the monoclonal antibody natalizumab, which antagonizes integrin, an important component within the inflammation cascade. Natalizumab works by modulating both the GI and brain biologic responses and as a result there is risk of the opportunistic infection known as progressive multifocal leukoencephalopathy (PML), putting patients at risk for severe disability and death. Vedolizumab, another integrin inhibitor, is selective for modulating the gut biologic response but not the brain, consequently decreasing the risk for PML. To generate information regarding the role of vedolizumab in the treatment of IBD, a literature search was conducted, yielding 7 phase I to III clinical trials. This article serves as a summary of efficacy, safety, and other relevant information from clinical studies to explore the role of vedolizumab in the treatment of CD and UC.

Posaconazole: An Update of Its Clinical Use

Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against Aspergillus fumigatus, Blastomyces dermatitidis, selected Candida species, Crytopcoccus neoformans, and Trichosporon. PCZ also has fungistatic activities against Candida, Coccidioides, selected Fusarium spp., Histoplasma, Scedosporium and Zygomycetes. In addition, combining the drug with caspofungin or amphotericin B results in a synergistic interaction against A. fumigatus, C. glabrata and C. neoformans. The absorption of PCZ suspension is enhanced when given with food, nutritional supplements, and carbonated beverages. Oral administration of PCZ in divided doses also increases its bioavailability. PCZ has a large volume of distribution and is highly protein bound (>95%). The main elimination route of PCZ is fecal. PCZ is an inhibitor of the CYP3A4 enzyme; therefore, monitoring for drug-drug interactions is warranted with other CYP3A4 substrates/inhibitors/inducers. The most common adverse effects include headache, fatigue, nausea, vomiting and elevated hepatic enzymes. PCZ, with its unique antifungal activities, expands the azole class of antifungal agents. Because of its limit in formulation, PCZ oral suspension is recommended in immunocompromised patients with functional gastrointestinaltracts who fail conventional antifungal therapies or who are suspected to have a breakthrough fungal infection. However, a delayed-release tablet formulation and intravenous (IV) injection became available in 2014, expanding the use of PCZ in other patient populations, including individuals who are unable to take oral formulations.