Christopher McCoy

Thalidomide: a review of approved and investigational uses.

BACKGROUND Thalidomide is best known as a major teratogen that caused birth defects in up to 12,000 children in the 1960s. More recently, this agent has been approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL) through a restricted-use program. Its immunomodulatory, anti-inflammatory, and antiangiogenic properties are currently under study in a number of clinical conditions. OBJECTIVE This article reviews the pharmacology of thalidomide; its approved and off-label uses in dermatologic, oncologic, and gastrointestinal conditions; and adverse events associated with its use. METHODS Relevant articles were identified through searches of MEDLINE (1966-June 2002), International Pharmaceutical Abstracts (1970-June 2002), and EMBASE (1990-June 2002). Search terms included but were not limited to thalidomide, pharmacokinetics, pharmacology, therapeutic use, and teratogenicity, as well as terms for specific disease states and adverse events. Further publications were identified from the reference lists of the reviewed articles. Abstracts of recent symposia were obtained from the American Society of Clinical Oncology Web site. RESULTS Thalidomide is thought to exert its therapeutic effect through the modulation of cytokines, particularly tumor necrosis factor-alpha. In addition to its approved indication for ENL, thalidomide has been studied in various other conditions, including graft-versus-host disease, discoid lupus erythematosus, sarcoidosis, relapsed/refractory multiple myeloma, Waldenstroms macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia, myelofibrosis with myeloid metaplasia, renal cell carcinoma, malignant gliomas, prostate cancer, Kaposis sarcoma, colorectal carcinoma, oral aphthous ulcers, Behçets disease, Crohns disease, and HIV/AIDS-associated wasting. Adverse events most frequently associated with its use include somnolence, constipation, rash, peripheral neuropathy, and thromboembolism. CONCLUSIONS Use of thalidomide is limited by toxicity, limited efficacy data, and restricted access. Evidence of its efficacy in conditions other than ENL awaits the results of controlled clinical trials.

Peginterferon alfa-2a: A review of approved and investigational uses

BACKGROUND In October 2002, the US Food and Drug Administration approved peginterferon alfa-2a for the management of chronic hepatitis C virus (HCV) infection. The addition of polyethylene glycol (PEG) moiety to the interferon (IFN) molecule results in a product with altered pharmacokinetic properties. OBJECTIVE The aim of this article is to review the pharmacology, medications interactions, adverse events (AEs), and approved or investigational uses of PEG-IFN alfa-2a for viral hepatitis and oncologic conditions. METHODS Relevant articles were identified through searches of MEDLINE (1980-July 2003) and EMBASE (1980-July 2003). Search terms included, but were not limited to, peginterferon alfa-2a, pharmacokinetics, pharmacology, pharmacodynamics, and therapeutic use, as well as terms for specific disease states and AEs. Further publications were identified from citations of resulting papers. RESULTS Pegylation of IFN alfa-2a results in major changes in the pharmacokinetics of the product. Absorption is prolonged and serum concentrations are sustained over the dosing regimen. PEG-IFN alfa-2a has been shown to be more effective with or without ribavirin (RBV), in the management of treatment-naive patients with chronic HCV infection, than unmodified IFN alfa-2a with or without RBV. Results in other disease states are still preliminary. AEs are similar, in incidence and severity, to those occurring with unmodified IFN. They include earlier hematologic symptoms and fewer influenza-like symptoms. Drug-drug interactions are the same as those occurring with the unmodified IFN product. CONCLUSIONS The pharmacokinetic profile of IFN alfa-2a is improved by pegylation, which enables less frequent administration and results in improved efficacy with a similar side-effect profile. Combination of PEG-IFN alfa-2a with RBV is associated with a greater chance of achieving a sustained virologic response in treatment-naive patients with chronic HCV, compared with unmodified IFN alfa-2a/RBV combinations. Documentation of efficacy in other conditions awaits results of controlled clinical trials.

Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients.

Clinicians caring for patients infected with the human immunodeficiency virus (HIV) and diagnosed with psychiatric comorbidities must be aware of potential drug‐drug interactions, particularly with protease inhibitor‐based antiretroviral therapy. Although possible interactions can be predicted based on a drugs pharmacokinetic parameters, the clinical significance is often unknown. We describe two patients who experienced serious quetiapine adverse effects potentially mediated through an interaction with ritonavir‐boosted atazanavir. The first patient was a 57‐year‐old man with HIV and bipolar disease who developed rapid and severe weight gain when quetiapine was added to a stable atazanavir‐ritonavir‐based antiretroviral regimen. After the patient discontinued both quetiapine and ritonavir, his weight returned to its baseline value. The second patient was a 32‐year‐old woman with HIV, anxiety disorder, and a history of intravenous drug abuse who developed increased sedation and mental confusion when an atazanavir‐ritonavir‐based antiretroviral regimen was added to her stable antianxiety drug regimen, which included quetiapine. Her symptoms resolved promptly after discontinuation of the quetiapine. Use of the Naranjo adverse drug reaction probability scale indicated that the adverse effects experienced by the two patients were possibly related and probably related, respectively, to an interaction between quetiapine and atazanavir‐ritonavir. Quetiapine is primarily metabolized by cytochrome P450 (CYP) 3A4, and ritonavir is a potent inhibitor of CYP3A4. Thus, it is reasonable to theorize that quetiapine concentrations will increase when these drugs are used concurrently, which would be the likely cause of the toxicities in these two patients. To our knowledge, these are the first published reports of a clinically significant interaction between atazanavir‐ritonavir and quetiapine. Clinicians should be aware of the potential for this interaction, and extreme caution should be used when prescribing quetiapine and other atypical antipsychotic agents in HIV‐positive patients who are receiving antiretroviral therapy.

Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe sepsis

BACKGROUND The search for a life-preserving drug to treat sepsis has increased understanding of the pathogenesis of the process but produced little in the way of successful treatments. The prospective, randomized, double-blind, placebo-controlled, Phase III, multicenter Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial suggested that drotrecogin alfa--recombinant human activated protein C--significantly improved 28-day mortality rates in acute sepsis (P = 0.005). OBJECTIVES The goals of this drug review were to summarize the recent findings regarding the pathogenesis of sepsis and septic shock, as well as the results of select immunomodulator drug trials, and to offer a comprehensive review of the mechanism of action, pharmacokinetic profile, efficacy and safety profile, and pharmacoeconomics of drotrecogin alfa. METHODS The English-language literature was searched using the EMBASE and MEDLINE databases. In EMBASE, the subject headings drotrecogin, activated protein C, and sepsis were used to search publications from 1980 through September 2002. In MEDLINE, the MeSH heading protein C and subject heading sepsis were used to search publications from 1966 through September 2002. Published abstracts of recent meetings and proceedings of the US Food and Drug Administration were also reviewed. RESULTS Drotrecogin alfa mimics the endogenous protein depleted during acute sepsis. Its activity as an antithrombotic, anti-inflammatory, and profibrinolytic agent appears to diminish the negative outcomes of acute sepsis, notably mortality at 28 days. The results of the PROWESS trial support this finding. A bleeding risk was noted during Phase II and III trials despite efforts to exclude those patients at high risk of bleeding. CONCLUSIONS Drotrecogin alfa is the first adjunctive agent for the treatment of sepsis to display clinically and statistically significant effects on mortality rates at 28 days. Many questions remain regarding which patients are ideal candidates for treatment. New research and treatment guidelines are necessary to address these questions.

Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates

Fosfomycin is recommended as first-line treatment for acute uncomplicated cystitis in women. It has demonstrated in vitro activity against a variety of pathogens; however, a paucity of data are available from the USA. We determined the susceptibility of a collection of urine isolates to fosfomycin and compared multiple methods of susceptibility testing. Consecutive non-duplicate Enterobacteriaceae, enterococci and Pseudomonas aeruginosa isolates were collected from the clinical microbiology laboratory between August 2013 and January 2014. Isolates represented hospitalised or emergency department patients with monomicrobial bacteriuria. Fosfomycin MICs were determined in duplicate, on separate days, by Etest and disk diffusion and results were compared with agar dilution. Nitrofurantoin and ciprofloxacin were used as comparators. MIC results were categorised using Clinical and Laboratory Standards Institute interpretive criteria for Escherichia coli and Enterococcus faecalis. Correlation between the three testing methods was evaluated. Overall susceptibility to fosfomycin was 94.4%, 93.5% and 87.9% by agar dilution, disk diffusion and Etest, respectively. Five fosfomycin-resistant isolates were identified, including two Morganella morganii, one P. aeruginosa, one Proteus mirabilis and one Enterobacter aerogenes. Across all organisms, rates of essential agreement, categorical agreement, minor errors, major errors and very major errors for Etest/disk diffusion compared with agar dilution were 77.3%/NA, 89.5/93.8%, 7.1/5.0%, 3.6/1.3% and 0/0%, respectively. Fosfomycin displayed fairly consistent activity against a majority of isolates collected when using the susceptibility breakpoint of 64 μg/mL. MICs for E. coli were particularly low (≤2 μg/mL). These data lend support to current guidelines that recommend fosfomycin as empirical first-line therapy for uncomplicated UTI.

Susceptibility of Multidrug-Resistant Gram-Negative Urine Isolates to Oral Antibiotics

ABSTRACT Increasing resistance among Gram-negative uropathogens limits treatment options, and susceptibility data for multidrug-resistant isolates are limited. We assessed the activity of five oral agents against 91 multidrug-resistant Gram-negative urine isolates that were collected from emergency department/hospitalized patients. Fosfomycin and nitrofurantoin were most active (>75% susceptibility). Susceptibilities to sulfamethoxazole-trimethoprim, ciprofloxacin, and ampicillin were ≤40%; empirical use of these agents likely provides inadequate coverage in areas with a high prevalence of multidrug-resistant uropathogens.

Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes

Background: Bacterial resistance among uropathogens is on the rise and has led to a decreased effectiveness of oral therapies. Fosfomycin tromethamine (fosfomycin) is indicated for uncomplicated urinary tract infections (UTIs) and displays in vitro activity against multidrug-resistant (MDR) isolates; however, clinical data assessing fosfomycin for the treatment of complicated or MDR UTIs are limited. Methods: We conducted a retrospective evaluation of patients who received ≥1 dose of fosfomycin between January 2009 and September 2015 for treatment of a UTI. Patients were included if they had a positive urine culture and documented signs/symptoms of a UTI. Results: Fifty-seven patients were included; 44 (77.2%) had complicated UTIs, 36 (63.2%) had MDR UTIs, and a total of 23 (40.4%) patients had a UTI that was both complicated and MDR. The majority of patients were female (66.7%) and elderly (median age, 79 years). Overall, the most common pathogens isolated were Escherichia coli (n = 28), Enterococcus spp. (n = 22), and Pseudomonas aeruginosa (n = 8). Twenty-eight patients (49.1%) were clinically evaluable; the preponderance achieved clinical success (96.4%). Fifteen out of 20 (75%) patients with repeat urine cultures had a microbiological cure. Conclusions: This retrospective study adds to the limited literature exploring alternative therapies for complicated and MDR UTIs with results providing additional evidence that fosfomycin may be an effective oral option.

In vitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa

The in vitro activity of apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32μg/ml for A. baumannii and 16/32μg/ml for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiological cutoff value of 64μg/ml. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256μg/ml for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, respectively, and the MIC50/MIC90 were ≥8/256μg/ml for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, respectively. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clinical study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chemistry exploration.

Bezlotoxumab: Could This be the Answer for Clostridium difficile Recurrence?

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B. Data Sources: A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials—MODIFY I (n = 1452) and MODIFY II (n = 1203)—demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%). Conclusions: In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

Clinical pathway for moderate to severe acute bacterial skin and skin structure infections from a US perspective: a roundtable discussion

ABSTRACT This article was written with the aim to establish a consensus clinical pathway for long-acting lipoglycopeptide antibiotics such as oritavancin (Orbactiv®) and dalbavancin (Dalvance®) for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Seven infectious diseases pharmacy specialists from a variety of facilities across the United States (US) participated in a roundtable discussion to consider the use of newer single-dose long-acting lipoglycopeptides, and integrate them into clinical pathways for ABSSSI. They identified two ways of treating with these drugs: first, to facilitate discharge from the hospital by switching from initial therapy (e.g., with intravenous (IV) vancomycin) and second, to avoid hospital admission altogether, since the product can be administered in several outpatient settings of care including the emergency department (ED), observation unit (OU) or outpatient infusion center. The participants used existing literature on classification and treatment of ABSSSI and their experience in the clinical setting as bases for their discussion and came to a consensus on the considerations for patient inclusion and exclusion as well as a pathway for outpatient treatment with long-acting lipoglycopeptides. As a result of the discussion, we concluded that the current treatment paradigm for ABSSSI is ripe for re-evaluation and reconfiguration in order to more closely align with the changing healthcare landscape. Hospital stakeholders are constantly searching for new strategies that can improve quality of care while simultaneously reducing overall expenses. The availability of single-dose long-acting lipoglycopeptides is an opportunity to opt for lower-cost outpatient treatment of appropriate ABSSSI patients. This article proposes the inclusion and exclusion considerations, along with a consensus treatment pathway, that could provide a solid foundation for facilities to construct and adapt their own effective clinical pathways for ABSSSI.