SWOT and Root Cause Analyses of Antimicrobial Resistance to Oral Antimicrobial Treatment of Cystitis.

Nearly 150 million cases of urinary tract infections (UTIs) are reported each year, of which uncomplicated cystitis triggers > 25% of outpatient prescriptions of oral antimicrobial treatment (OAT). OAT aids immune cells infiltrating the urothelium in eliminating uropathogens capable of invading the urothelium and surviving hyperosmotic urine. This self-evident adaptability of uropathogens and the short interval between the introduction of Penicillin and the first report of antimicrobial resistance (AMR) implicate AMR as an evolutionary conserved heritable trait of mutant strains selected by the Darwinian principle to survive environmental threats through exponential proliferation. Therefore, AMR can only be countered by antimicrobial stewardship (AMS) following the principle of the five Ds-drug, dose, duration, drug route, and de-escalation. While convenient to administer, the onset of the minimum inhibitory concentration (MIC) for OAT in urine leaves a window of opportunity for uropathogens to survive the first contact with an antimicrobial and arm their descendant colonies with AMR for surviving subsequent higher urine antimicrobial levels. Meanwhile, the initial dose of intravesical antimicrobial treatment (IAT) may be well above the MIC. Therefore, the widespread clinical use of OAT for cystitis warrants an analysis of the strengths, weaknesses, opportunity, and threats (SWOTs) and a root cause analysis of the AMR associated with OAT and IAT.

Unnatural Amino Acid-Based Ionic Liquid Enables Oral Treatment of Nonsense Mutation Disease in Mice.

This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation's unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation.

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives.

Bacteremia and endocarditis are two clinical syndromes that, for decades, were managed exclusively with parenteral antimicrobials, irrespective of a given patient's clinical condition, causative pathogen, or its antibiotic susceptibility profile. This clinical approach, however, was based on low-quality data and outdated expert opinions. When a patient's condition has improved, gastrointestinal absorption is not compromised, and an oral antibiotic regimen reaching adequate serum concentrations is available, a switch to oral antibacterials can be applied. Although available evidence has reduced the timing of the oral switch in bacteremia to three days/until clinical improvement, there are only scarce data regarding less than 10-day intravenous antibiotic therapy in endocarditis. Many standard or studied oral antimicrobial dosages are smaller than the approved doses for parenteral administration, which is a risk factor for treatment failure; in addition, the gastrointestinal barrier may affect drug bioavailability, especially when the causative pathogen has a minimum inhibitory concentration that is close to the susceptibility breakpoint. A considerable number of patients infected by such near-breakpoint strains may not be potential candidates for oral step-down therapy to non-highly bioavailable antibiotics like beta-lactams; different breakpoints should be determined for this setting. This review will focus on summarizing findings about pathogen-specific tailoring of oral step-down therapy for bacteremia and endocarditis, but will also present laboratory and clinical data about antibiotics such as beta-lactams, linezolid, and fosfomycin that should be studied more in order to elucidate their role and optimal dosage in this context.

Comparative Analysis of Oral Ondansetron, Metoclopramide, and Domperidone for Managing Vomiting in Children With Acute Gastroenteritis.

Background Acute gastroenteritis (AGE) is a major health concern in pediatric populations because of its associated vomiting, which worsens dehydration and the severity of illness. Objective The purpose of the research was to compare the relative effectiveness of oral ondansetron in treating AGE in children's vomiting when compared to oral domperidone and oral metoclopramide. Methodology A clinical investigation involving 120 pediatric patients diagnosed with AGE was conducted in Pakistan from November 2022 to April 2023 using a single-blind randomized design and convenience sampling. The participants received oral suspensions of ondansetron, metoclopramide, and domperidone, with doses of 0.15 mg/kg, 0.1-0.2 mg/kg, and 0.5 mg/kg, respectively, adjusted according to their body weight. The outcome in different groups was analyzed using the Statistical Package for the Social Sciences (SPSS) (version 20.0; IBM SPSS Statistics for Windows, Armonk, NY). Results At six hours, vomiting cessation rates were 80.0% for ondansetron (n=32), 72.5% for domperidone (n=29), and 67.5% for metoclopramide (n=27; p=0.29). By 24 hours, ondansetron exhibited significantly higher efficacy (92.5%; n=37) compared to domperidone (82.5%; n=33) and metoclopramide (77.5%; n=31; p=0.03). Adverse effects were minimal and comparable across groups. Conclusion Oral ondansetron demonstrated superior efficacy in managing AGE-related vomiting in children within 24 hours compared to metoclopramide and domperidone.

Clinical implementation of partial oral treatment in infective endocarditis: the Danish POETry study.

BACKGROUND AND AIMS: In the Partial Oral Treatment of Endocarditis (POET) trial, stabilized patients with left-sided infective endocarditis (IE) were randomized to oral step-down antibiotic therapy (PO) or conventional continued intravenous antibiotic treatment (IV), showing non-inferiority after 6 months. In this study, the first guideline-driven clinical implementation of the oral step-down POET regimen was examined. METHODS: Patients with IE, caused by Staphylococcus aureus, Enterococcus faecalis, Streptococcus spp. or coagulase-negative staphylococci diagnosed between May 2019 and December 2020 were possible candidates for initiation of oral step-down antibiotic therapy, at the discretion of the treating physician. The composite primary outcome in patients finalizing antibiotic treatment consisted of embolic events, unplanned cardiac surgery, relapse of bacteraemia and all-cause mortality within 6 months. RESULTS: A total of 562 patients [median age 74 years (IQR, interquartile range, 65-80), 70% males] with IE were possible candidates; PO was given to 240 (43%) patients and IV to 322 (57%) patients. More patients in the IV group had IE caused by S. aureus, or had an intra-cardiac abscess, or a pacemaker and more were surgically treated. The primary outcome occurred in 30 (13%) patients in the PO group and in 59 (18%) patients in the IV group (P = .051); in the PO group, 20 (8%) patients died vs. 46 (14%) patients in the IV group (P = .024). PO-treated patients had a shorter median length of stay [PO 24 days (IQR 17-36) vs. IV 43 days (IQR 32-51), P < .001]. CONCLUSIONS: After clinical implementation of the POET regimen almost half of the possible candidates with IE received oral step-down antibiotic therapy. Patients in the IV group had more serious risk factors for negative outcomes. At 6-month follow-up, there was a numerically but not statistically significant difference towards a lower incidence of the primary outcome, a lower incidence of all-cause mortality and a reduced length of stay in the PO group. Due to the observational design of the study, the lower mortality may to some extent reflect selection bias and unmeasured confounding. Clinical implementation of PO regimens seemed feasible and safe.

Effect of Oral High Molecular Weight Hyaluronic Acid (HMWHA), Alpha Lipoic Acid (ALA), Magnesium, Vitamin B6 and Vitamin D Supplementation in Pregnant Women: A Retrospective Observational Pilot Study.

Background-Pregnancy represents a nutritional challenge, since macro- and micronutrients intake can affect mother' health and influence negative outcomes. The aim of this retrospective pilot study is to evidence whether the oral supplementation with high molecular weight hyaluronic acid (HMWHA), in association with alpha lipoic acid (ALA), magnesium, vitamin B6 and vitamin D, in pregnant women, could reduce adverse effects, such as PTB, pelvic pain, contraction and hospitalization. Methods-Data were collected from n = 200 women treated daily with oral supplements of 200 mg HMWHA, 100 mg ALA, 450 mg magnesium, 2.6 mg vitamin B6 and 50 mcg vitamin D (treatment group) and from n = 50 women taking with oral supplements of 400 mg magnesium (control group). In both groups, supplementation started from the 7th gestational week until delivery. Results-Oral treatment with HMWHA, in association with ALA, magnesium, vitamin B6 and vitamin D in pregnant women, significantly reduced adverse events, such as PTB (p < 0.01), pelvic pain and contractions (p < 0.0001), miscarriages (p < 0.05) and admission to ER/hospitalization (p < 0.0001) compared with the control group. Conclusions-Despite HMWHA having been poorly used as a food supplement in pregnant women, our results open a reassuring scenario regarding its oral administration during pregnancy.

An Open-Label, Uncontrolled, Single-Arm Clinical Trial of Tofacitinib, an Oral JAK1 and JAK3 Kinase Inhibitor, in Chinese Patients with Keloid.

BACKGROUND: The keloid treatment is still a thorny and complicated clinical problem, especially in multiple keloids induced by wound, severe burn, ethnic background or cultural behaviors, or unexplained skin healing. Mainstream treatments have limited efficacy in treating multiple keloids. As no oral treatment with painlessness and convenience is available, oral treatment strategies should be formulated. OBJECTIVES: This study aimed to investigate the efficacy and therapeutic mechanism of oral tofacitinib in keloid patients. METHODS: We recruited the 7 patients with keloid scars and prescribed 5 mg of tofacitinib twice a day orally with a maximum follow-up of 12 weeks. The Patient and Observer Scar Assessment Scale (POSAS), the Vancouver scar scale (VSS), ANTERA 3D camera, and the DUB Skin Scanner 75 were used to assess the characteristics of the lesion. Immunohistochemistry was performed to evaluate collagen synthesis, proliferation, and relative molecular pathways. Moreover, the effects of tofacitinib were assessed on keloid fibroblast in vitro. RESULTS: After 12 weeks of oral tofacitinib, significant improvement in POSAS, VSS, and Dermatology Life Quality Index (DLQI) scores was observed (p < 0.05). The volume, lesion height, and dermis thickness of the keloid decreased (p < 0.05). Moreover, significant decreases in the expression of collagen I, Ki67, p-STAT 3, and p-SMAD2 were observed after 12 weeks of administration. In vitro experiments suggested that tofacitinib treatment inhibits fibroblast proliferation and collagen I synthesis via suppression of STAT3 and SMAD2 pathway. CONCLUSION: Tofacitinib, a new candidate oral drug for keloid, could reduce keloid lesion volume by inhibiting collagen synthesis and inhibiting fibroblast proliferation, and alleviate itch and pain to obtain a better life quality.

All-oral low-dose chemotherapy TEPIP is effective and well-tolerated in patients with peripheral T-cell lymphoma.

Purpose: Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. Methods: In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Results: The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. Conclusion: TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

Exploring preferences of different modes of administration of hypomethylating agent treatments among patients with acute myeloid leukemia.

Introduction: About half of patients with Acute Myeloid Leukemia (AML) are not eligible for Standard Induction Chemotherapy (SIC). Hypomethylating Agents (HMAs) intravenously (IV) or subcutaneously (SC) in a clinical setting are typically offered as an alternative. However, injectable HMAs may be burdensome for patients given the frequent hospital visits and side effects. This study explored patient treatment preferences for different modes of administration (MOA) and the relative importance of treatment-related characteristics that influence treatment decisions. Methods: Semi-structured 1:1 interviews were conducted with 21 adult patients with AML in Germany, the United Kingdom, and Spain, who are not eligible for SIC, had experience with HMAs or were scheduled to be treated with HMAs. After discussing their experience of living with AML and its treatments, patients were presented with hypothetical treatment scenarios to explore their preferences, and a ranking exercise to assess the relative importance of treatment characteristics that influence their treatment-decisions for AML. Results: Most patients reported an overall preference for oral administration over parenteral routes (71%), mostly due to convenience. Those preferring IV or SC routes (24%) reasoned with faster speed of action and onsite monitoring. When presented with a hypothetical situation of a patient having to choose between two AML treatments that were identical except for their MOA, the majority preferred the oral route (76%). Regarding treatment characteristics that influence treatment decisions, patients most frequently reported efficacy (86%) and side effects (62%) as important, followed by mode of administration (29%), daily life impacts (24%) and location of treatment (hospital versus home) (14%). However, only efficacy and side effects were rated as number one deciding factors (67% and 19%, respectively). Patients most frequently rated dosing regimen (33%) as least important. Conclusion: The insights gained from this study may help support patients with AML who are receiving HMA treatment instead of SIC. A potential oral HMA with similar efficacy and tolerability profiles to injectable HMAs could influence treatment decisions. Furthermore, an oral HMA treatment might decrease the burden of parenteral therapies and improve patients' overall quality of life. However, the extent of influence MOA has on treatment decisions requires further investigation.

Detecting representative characteristics of different genders using intraoral photographs: a deep learning model with interpretation of gradient-weighted class activation mapping.

BACKGROUND: Sexual dimorphism is obvious not only in the overall architecture of human body, but also in intraoral details. Many studies have found a correlation between gender and morphometric features of teeth, such as mesio-distal diameter, buccal-lingual diameter and height. However, it's still difficult to detect gender through the observation of intraoral photographs, with accuracy around 50%. The purpose of this study was to explore the possibility of automatically telling gender from intraoral photographs by deep neural network, and to provide a novel angle for individual oral treatment. METHODS: A deep learning model based on R-net was proposed, using the largest dataset (10,000 intraoral images) to support the automatic detection of gender. In order to reverse analyze the classification basis of neural network, Gradient-weighted Class Activation Mapping (Grad-CAM) was used in the second step, exploring anatomical factors associated with gender recognizability. The simulated modification of images based on features suggested was then conducted to verify the importance of characteristics between two genders. Precision (specificity), recall (sensitivity) and receiver operating characteristic (ROC) curves were used to evaluate the performance of our network. Chi-square test was used to evaluate intergroup difference. A value of p < 0.05 was considered statistically significant. RESULTS: The deep learning model showed a strong ability to learn features from intraoral images compared with human experts, with an accuracy of 86.5% and 82.5% in uncropped image data group and cropped image data group respectively. Compared with hard tissue exposed in the mouth, gender difference in areas covered by soft tissue was easier to identify, and more significant in mandibular region than in maxillary region. For photographs with simulated removal of lips and basal bone along with overlapping gingiva, mandibular anterior teeth had similar importance for sex determination as maxillary anterior teeth. CONCLUSIONS: Deep learning method could detect gender from intraoral photographs with high efficiency and accuracy. With assistance of Grad-CAM, the classification basis of neural network was deciphered, which provided a more precise entry point for individualization of prosthodontic, periodontal and orthodontic treatments.

Antimicrobial susceptibility of bacterial uropathogens in a South African regional hospital.

Background: Urinary tract infections are common bacterial infections affecting millions worldwide. Although treatment options for urinary tract infections are well established, with ciprofloxacin long considered one of the antibiotics of choice, increasing antibiotic resistance may delay the initiation of appropriate therapy. While this increase in antimicrobial resistance has been demonstrated in multiple studies around the world, there is a dearth of information from developing countries. Objective: This study aimed to describe the antimicrobial susceptibility patterns of commonly isolated bacterial uropathogens in a South African hospital. Methods: Antimicrobial susceptibility data of isolates obtained from urine specimens at the RK Khan Hospital, a regional hospital in KwaZulu-Natal, South Africa, between January 2018 and December 2020 were retrieved from the hospital's laboratory information system and analysed to determine the differences in resistance rates between the most frequently isolated bacterial uropathogens. Results: Of the 3048 bacterial urinary pathogens isolated between 2018 and 2020, Escherichia coli (1603; 53%) was the most common, followed by Klebsiella spp. (437; 14%). Both E. coli and Klebsiella spp. showed high rates of resistance to amoxicillin/clavulanic acid (29.8% and 42.3%) and ciprofloxacin (37.7% and 30.4%). Nitrofurantoin resistance was low among E. coli (6.2%) but high among Klebsiella spp. (61.3%). Conclusion: E. coli and Klebsiella spp. in this study were highly resistant to amoxicillin/clavulanic acid and ciprofloxacin, two of the frequently prescribed oral treatment options. What this study adds: This study highlights the importance of regular local antimicrobial resistance surveillance to inform appropriate empiric therapy.

Apigenin is a promising molecule for treatment of visceral leishmaniasis.

Current treatment for visceral leishmaniasis is based on drugs such as pentavalent antimony and amphotericin B. However, this treatment remains mostly ineffective and expensive, resulting in several side effects and generating resistance. Apigenin, a flavonoid present in fruits and vegetables, has demonstrated several biological functions. In the present study, we observed a concentration-dependent inhibition of the L. infantum promastigote in the presence of apigenin, exhibiting an IC50 value of 29.9 µM. Its effect was also evaluated in L. infantum-infected murine peritoneal macrophages, presenting an C50 value against intracellular amastigotes of 2.3 µM and a selectivity index of 34.3. In a murine model of visceral leishmaniasis, the in vivo effect of apigenin was measured using short-term and long-term treatment schemes. Treatment with apigenin demonstrated 99.7% and 94% reductions in the liver parasite load in the short-term and long-term treatment schemes, respectively. Furthermore, no alterations in serological and hematological parameters were observed. Taken together, these results suggest that apigenin is a potential candidate for visceral leishmaniasis chemotherapy by oral administration.

Antimicrobial treatment of patients with a periprosthetic joint infection: basic principles.

The antibiotic treatment of periprosthetic joint infections (PJI) is complicated by the presence of biofilm produced by bacteria on the abiotic surface of the implant. Bacteria within the deeper layers of the biofilm become metabolically less active, resulting in antibiotic tolerance due to several mechanisms. This review describes the basic principles of antibiotic treatment in PJI in relation to the behavior of bacteria within the biofilm. The concept of biofilm-active antibiotics will be explained from an in vitro as well as in vivo perspective. Evidence from clinical studies on biofilm-active antibiotics in PJI will be highlighted, mainly focusing on the role of rifampicin for Gram-positive microorganisms and fluoroquinolones for Gram-negative microorganisms. The optimal treatment duration will be discussed as the timing of switching to oral antibiotic therapy.

Analysis of 2'-hydroxyflavanone (2HF) in mouse whole blood by HPLC-MS/MS for the determination of pharmacokinetic parameters.

Given the lack of investments, structure, and difficulty of metabolite isolation, promising natural product studies do not progress to preclinical studies, such as pharmacokinetics. 2'-Hydroxyflavanone (2HF) is a flavonoid that has shown promising results in different types of cancer and leishmaniasis. For accurate quantification of 2HF in BALB/c mouse blood, a validated HPLC-MS/MS method was developed. Chromatographic analysis was performed using C18 (5µm, 150 mm × 4.6 mm). The mobile phase consisted of water containing 0.1% formic acid, acetonitrile, and methanol (35/52/13 v/v/v) at a flow rate and total running time of 0.8 mL/min and 5.50 min, respectively, with an injection volume of 20 µL. 2HF was detected by electrospray ionization in negative mode (ESI-) using multiple reaction monitoring (MRM). The validated bioanalytical method showed satisfactory selectivity without significant interference for the 2HF and IS. In addition, the concentration range between 1 and 250 ng/mL showed good linearity (r = 0.9969). The method showed satisfactory results for the matrix effect. Precision and accuracy intervals varied between 1.89% and 6.76% and 95.27% and 100.77%, respectively, fitting the criteria. No degradation of 2HF in the biological matrix was observed since stability under freezing and thawing conditions, short duration, postprocessing, and long duration showed deviations less than 15%. Once validated, the method was successfully applied in a 2HF oral pharmacokinetic study with mouse blood, and the pharmacokinetic parameters were determined. 2HF demonstrated a Cmax of 185.86 ng/mL, a Tmax of 5 min, and a half-life (T1/2) of 97.52 min.

A 68-Year-Old Man with Multiple Comorbidities Presents with a Weeping Wound of the Left Lower Extremity: A Case Report.

In cases of cellulitis, identification of a specific pathogen is often not possible on clinical grounds, and in our institution the recommended practice for empiric treatment of skin infections is to cover for the usual pathogens, such as Staphylococcus aureus and Streptococcus pyogenes. This article describes the management of a 68-year-old man in whom the choice of appropriate antibiotic treatment for suspected cellulitis was complicated by many factors, including several known risk factors for recurrent cellulitis, multiple comorbid conditions, and the patient's wish to leave hospital as soon as possible. Given this patient's clinical syndrome, coverage for methicillin-resistant S. aureus was part of the treatment decision, and to enable a prompt discharge, an effective oral treatment was needed for him to take at home. These and other considerations that guided the selection of omadacycline as appropriate antibiotic therapy for this patient are discussed.

Effectiveness of school-based strategies to prevent tooth decay in Filipino children: A cluster-randomized trial.

OBJECTIVES: Evidence for affordable and pragmatic programmes to address the burden of untreated tooth decay in children in low- and middle-income settings is limited. This study aimed to (1) assess the effect of a government-run, school-based daily group toothbrushing programme compared to standard school-based oral health education on the incidence of dental caries and odontogenic infections in Filipino children over a period of 3 years; and (2) assess the additional preventive effect of on-demand oral urgent treatment (OUT) and weekly fluoride gel application. METHODS: A cluster-randomized trial was conducted in Camiguin, Philippines. Schools in three regions were randomly assigned to one of three intervention groups: The Essential Health Care Programme (EHCP), which includes daily toothbrushing with fluoride toothpaste; EHCP plus twice-yearly access to on-demand urgent oral treatment (EHCP + OUT) and EHCP plus weekly application of high-concentrated fluoride gel (EHCP + Fluoride). Schools in a nearby province with a similar child population were selected as external concurrent control group. Clinical oral examinations were performed by calibrated dentists from a random sample of 682 seven-year-old students who were examined at baseline and over the following 3 years. Outcome variables were the number of decayed primary teeth, the number of decayed, missing and filled permanent teeth (DMFT) and surfaces (DMFS), and the number of permanent teeth with pulpal involvement, ulcerations, fistula or abscess (PUFA). Data were analysed using multilevel mixed-effects negative binomial regression. RESULTS: Three years after implementation, increments in dental caries and odontogenic infections in permanent teeth did not significantly differ between the EHCP and control group, yet the incidence of DMFT was lower by 22% in children receiving EHCP. Compared to controls, children receiving EHCP + Fluoride had a significantly lower increment of DMFT, DMFS and PUFA by 40%, 40% and 47%, respectively. Children receiving EHCP + OUT had lower incidence rates of DMFT and DMFS than control children by 23% and 28%, respectively. A lower incidence rate was also found for PUFA, but the effect was not statistically significant. CONCLUSIONS: Findings suggest that the weekly application of fluoride gel and urgent oral treatment, in addition to daily school-based toothbrushing with fluoride toothpaste, are realistic and effective strategies to lower the burden of dental caries in Filipino children. Implementation challenges may explain why no substantial caries-preventive benefits were demonstrated for school-based toothbrushing only. Intervention compliance should be considered in future programme implementation and evaluation research.

Preferences for Anaemia Treatment Attributes among Patients with Non-Dialysis-Dependent Chronic Kidney Disease.

INTRODUCTION: Information about patient preferences for the treatment of anaemia associated with chronic kidney disease (CKD) is scarce. Hence, our aim was to examine how patients with non-dialysis-dependent CKD valued attributes of alternative hypothetical anaemia treatments. METHODS: A discrete choice experiment (DCE) was conducted in adult patients who reported a clinical diagnosis of CKD-related anaemia. Treatment attributes included mode and frequency of administration, need for iron supplementation, risk of gastrointestinal side effects, risk of major cardiovascular events and impact on energy levels (as defined by the vitality section of the SF-6D health index). Logit models were used to analyse patients' preferences. RESULTS: The DCE was completed by 200 patients in four countries. Patients preferred an oral mode of administration. Patients were willing to tolerate a 5.1% (95% CI 2.0-8.3%) increase in the risk of a major cardiovascular event and an 11.7% (95% CI 5.0-18.5%) increase in the risk of gastrointestinal side effects to switch from an at-home subcutaneous injection administered once every 2 weeks to an at-home oral pill administered three times a week. Patients were willing to tolerate a 20.3% (95% CI 15.0-25.6%) increase in the risk of gastrointestinal side effects and an 8.9% (95% CI 6.1-11.7%) increase in the risk of a major cardiovascular event to transition from 'Sometimes having a lot of energy' to 'Always having a lot of energy'. CONCLUSIONS: Patients with non-dialysis-dependent CKD-related anaemia demonstrated clear treatment preferences and were willing to accept increased gastrointestinal or cardiovascular risks in exchange for more energy or an oral treatment.

A new oral self-emulsifying drug delivery system improves the antileishmania efficacy of fexinidazole in vivo.

The aim of this study was to develop, characterize and evaluate the in vivo oral efficacy of self-emulsifying drug delivery systems (SEDDS) containing fexinidazole (FEX) in the experimental treatment of visceral leishmaniasis (VL). The developed FEX-SEDDS formulation presented as a clear, yellowish liquid, with absence of precipitate. The droplet size, polydispersion index and zeta potential after dilution in water (1:200) was of 91 ± 3 nm, 0.242 ± 0.005 and -16.7 ± 0.2, respectively. In the simulated gastric and intestinal media, the FEX-SEDDS had a size of 97 ± 1 and 106 ± 9 nm, respectively. The FEX retention in droplet after SEDDS dilution in simulated gastrointestinal media was almost 100 %. Antileishmanial efficacy studies showed that FEX-SEDDS was the only treatment able to significantly (p < 0.05) reduce the parasite burden in the liver and spleen of animals experimentally infected with Leishmania infantum. Our intestinal permeability data suggest that FEX-SEDDS showed no evidence of injury to the intestinal mucosa. These findings suggest that FEX-SEDDS can be a promising oral alternative for the treatment of VL caused by L. infantum.

MIC Discrepancies between Parenteral and Oral Anti-Staphylococcal Beta-Lactams among MSSA.

INTRODUCTION: Recent evidence has shown that oral antibiotic therapy is not inferior to IV antibiotic therapy in the treatment of complicated Staphylococcus aureus infections. Therefore, oral antibiotic therapy is now frequently prescribed in clinical practice due to cost benefit, ease of administration, decreased complication rate, and lack of need for IV access. In vitro susceptibility testing for ß-lactam oral antibiotics is not routinely performed as the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI) recommend using oxacillin and cefoxitin as surrogate markers. Hence, oral antibiotic susceptibilities for cephalexin and dicloxacillin are not reported and implied based on oxacillin and cefoxitin. The objective of the current study was to determine whether susceptibilities among S. aureus isolates are predictable when comparing commonly used IV and oral beta-lactams. METHODS: Cefazolin, cephalexin, dicloxacillin, and oxacillin broth microdilution minimum inhibitory concentrations (MICs) were determined for 100 clinical isolates of methicillin-sensitive S. aureus by broth microdilution following CLSI guidelines. RESULTS: Among these isolates, median MICs for cephalexin were eight-fold higher than cefazolin MICs and median MICs for dicloxacillin were four-fold less than oxacillin MICs. Ten percent of more strains studied had a major or very major error in its susceptibility reporting when cephalexin was compared to its surrogate marker oxacillin. DISCUSSIONS/CONCLUSIONS: The variations in MICs observed compounded with the dosing and pharmacokinetic differences of oral versus IV ß-lactam suggests that establishing breakpoints for oral ß-lactam antibiotics is necessary to ensure adequate therapy is selected for the treatment of complex S. aureus infections.