Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Mega-Cecum: An Unrecognized Cause of Symptoms in Some Female Patients with Uro-Gynecological Symptoms and Severe Slow Transit Constipation.

BACKGROUND: A subset of female patients with severe constipation report overlapping uro-gynecological symptoms which have been attributed to visceral hypersensitivity. AIMS: To study colon morphology and motor function in female patients with medically refractory chronic constipation with or without uro-gynecological symptoms and to assess clinical outcomes following laparoscopic ileo-proctostomy. METHODS: Colon anatomy and cecal emptying time were assessed with plain films and fluoroscopy following a standardized test meal mixed with barium. Transit time was determined with radiopaque markers. IBS-QOL and urinary incontinence questionnaires were employed to assess post-colectomy clinical response. RESULTS: In 21 consecutive patients, mean colon transit time (h) was 211.1 ± 11.3, which was significantly greater than 58.9 ± 5.1 of 10 normal subjects (P < 0.001). Mega-cecum was found in 15 (Group 1) with mean cecal volume of 587 ± 27.9 cm3, significantly greater (P < 0.001) than 169.5 ± 10.4 cm3 of six without mega-cecum (Group 2). Mean cecal empting time (days) of barium-mixed feces in Group 1, 4.0 ± 0.6 was significantly greater than 1.33 ± 0.21 in Group 2 (P < 0.001). Eighteen patients (Groups 1 and 2) who had laparoscopic ileo-proctostomy experienced significantly improved quality of life (P < 0.001). In particular, Group 1 patients benefited significantly from improved uro-gynecological symptoms. CONCLUSIONS: Hitherto an unrecognized mega-cecum with markedly impaired emptying function was found in patients with severe slow transit constipation and uro-gynecological symptoms. Subtotal colectomy relieved constipation and improved significantly uro-gynecological symptoms, suggesting strongly that mega-cecum is causally related to these symptoms.

Development and application of Multiple-Locus Variable number of tandem repeat Analysis (MLVA) to subtype a collection of Listeria monocytogenes.

In this study we report the development and application of a Multiple-Locus Variable number of tandem repeat Analysis (MLVA) strategy for subtyping Listeria monocytogenes. Genome profiles of a collection of forty-five food-borne L. monocytogenes isolates were compared using MLVA. These isolates were obtained as part of an active surveillance programme of foods in the south-east region of Ireland. MLVA successfully discriminated amongst the isolates. The method was easy to perform, relatively fast and could be deployed in any molecular laboratory with basic laboratory equipment. This approach is a valuable tool, which has the capability to provide comparable results when compared with other more established typing methods, including pulsed-field gel electrophoresis (PFGE).

Comparison of Listeria monocytogenes strain types in Irish smoked salmon and other foods.

An investigation of Listeria monocytogenes in Irish retail smoked salmon products and other unrelated food products was undertaken. Serotyping and genotyping methods were applied. Twenty-six L. monocytogenes isolates cultured from ready-to-eat smoked salmon and an additional 20 L. monocytogenes isolates from various commercially available food products (other than smoked salmon) were compared. Four serotypes, 12 ribotypes, 12 amplified fragment length polymorphism (AFLP) types and 17 pulsed-field gel electrophoresis (PFGE) types were identified among the 46 isolates studied. Genotyping identified a single dominant strain that accounted for 65% of those cultured from smoked salmon and this strain was present in product obtained from three out of five of the manufacturers surveyed. When compared to the food products obtained from a variety of sources, those from smoked salmon appeared to cluster as a single group. In Irish smoked salmon this strain may have adapted, and be capable of persisting in this food product. All isolates were grouped into genetic lineages based on their EcoR1 ribotypes. The attendant risk to public health following consumption of these foods is discussed.

The epidemiology of antibiotic resistance in Campylobacter.

Antibiotic resistance, particularly with the fluoroquinolones and macrolide antibiotics, has now emerged globally with thermophilic campylobacters, including Campylobacter jejuni and C. coli, giving rise to concerns about how these organisms have acquired such resistance characteristics, as well as consequences for human and animal treatment. This review examines (i) the clinical epidemiology of antibiotic resistance in human and animal thermophilic campylobacters, (ii) an update on resistance rates globally, (iii) surveillance of antimicrobial resistance in campylobacters originating from animals, particularly poultry, (iv) the role of the environment in the acquisition and transmission of antibiotic-resistant campylobacters, as well as (v) issues of biocide resistance in campylobacters.

Mechanisms of fluoroquinolone and macrolide resistance in Campylobacter spp.

The incidence of human Campylobacter infections is increasing worldwide, as well as the proportion of isolates resistant to fluoroquinolones and/or macrolides, the drugs of choice to treat campylobacteriosis. In this review, we report recent developments in the understanding of the resistance mechanisms to fluoroquinolones and macrolides. In addition, we will discuss the recent findings on multidrug resistance in Campylobacter spp.

An investigation of the molecular mechanisms contributing to high-level erythromycin resistance in Campylobacter.

The molecular mechanisms contributing to high-level erythromycin resistance in Campylobacter jejuni and Campylobacter coli isolates were investigated. The A2075G mutation in the 23S rRNA target genes was identified in all high-level erythromycin-resistant isolates. A number of amino acid substitutions together with insertions and deletions were identified in the corresponding genes encoding L4 and L22 ribosomal proteins both of resistant and susceptible isolates. Amino acid substitutions identified in the resistant strains were located outside regions known to be altered in these proteins. The efflux pump inhibitor L-phenylalanine-L-arginine-beta-naphthylamide (PAbetaN) increased the susceptibility to erythromycin in one of four isolates displaying high-level erythromycin resistance, and reduced the minimal inhibitory concentration displayed by an erythromycin-susceptible C. coli isolate. The A2075G mutation in the 23S rRNA appeared to be the main contributor to high-level erythromycin resistance in Campylobacter. Other mutations/amino acid substitutions found in the 50S ribosomal subunit encoding proteins L4 and L22 do not appear to be linked to the high-level erythromycin-resistant phenotype. Active efflux contributes to the intrinsic resistance to erythromycin in Campylobacter and may contribute to high-level resistance in some isolates.

Characterization of a cmeABC operon in a quinolone-resistant Campylobacter coli isolate of Irish origin.

In this study, a tripartite-operon-encoding efflux system together with its regulatory gene was characterized in an Irish Campylobacter coli isolate CIT-382 showing high-level resistance to nalidixic acid and ciprofloxacin. Sequence comparisons revealed significant homology between C. coli and the cmeABC operon of Campylobacter jejuni. Conservation of functional sequence domains and motifs were noted among C. coli and similar operons in unrelated organisms. A transcriptional regulatory gene cmeR located proximal to cmeABC was also identified. C. coli CIT-382 harbored the Thr-86-Ile amino acid substitution in the gyrA gene. Accumulation studies with ethidium bromide in the presence of known efflux pump inhibitors confirmed the presence of efflux pump activity in C. coli CIT-382. The efflux pump inhibitor PAbetaN had no effect on the MICs to quinolones. Our data suggest that the gyrA gene mutation is the main contributor to the high-level nalidixic acid and ciprofloxacin resistance observed in this Irish C. coli CIT-382 isolate.

Relative contribution of target gene mutation and efflux to varying quinolone resistance in Irish Campylobacter isolates.

The contribution of target gene mutations and active efflux to varying levels of quinolone resistance in Irish Campylobacter isolates was studied. The Thr-86-Ile modification of GyrA did not correlate with the level of quinolone resistance. The efflux pump inhibitor Phe-Arg-beta-Naphthylamide (PAbetaN) had no effect on the MICs to ciprofloxacin. In contrast, a PAbetaN sensitive efflux system contributed to the low-level nalixidic acid resistance phenotype. The lack of effect of PAbetaN in high-level resistant nalidixic isolates may be attributable to mutations identified in the CmeB efflux pump of these isolates. PAbetaN may have limited diagnostic value in the assessment of the contribution of efflux pump activity to ciprofloxacin resistance in Campylobacter.

Campylobacter.

Species within the genus, Campylobacter, have emerged over the last three decades as significant clinical pathogens, particularly of human public health concern, where the majority of acute bacterial enteritis in the Western world is due to these organisms. Of particular concern are the species, C. jejuni and C. coli, which are responsible for most of these gastrointestinal-related infections. Although these organisms have already emerged as causative agents of zoonoses, several aspects of their epidemiology and pathophysiology are only beginning to emerge. Trends in increasing antibiotic resistance are beginning to emerge with oral antibiotics, which may be the drug of choice for when it is necessary to intervene chemotherapeutically. This review wishes to examine (i) emerging clinical aspects of the disease, such as Guillain Barre syndrome (GBS), (ii) the association between these organisms and poultry as a natural host, (iii) environmental aspects of Campylobacter epidemiology, (iv) the emergence of atypical campylobacters (v) emerging trends in antibiotic resistance, (vi) adoption of modern methods for the detection of campylobacters.