An Updated Economic Assessment of Moxidectin Treatment Strategies for Onchocerciasis Elimination.

BACKGROUND: Concerns that annual mass administration of ivermectin, the predominant strategy for onchocerciasis control and elimination, may not lead to elimination of parasite transmission (EoT) in all endemic areas have increased interest in alternative treatment strategies. One such strategy is moxidectin. We performed an updated economic assessment of moxidectin- relative to ivermectin-based strategies. METHODS: We investigated annual and biannual community-directed treatment with ivermectin (aCDTI, bCDTI) and moxidectin (aCDTM, bCDTM) with minimal or enhanced coverage (65% or 80% of total population taking the drug, respectively) in intervention-naive areas with 30%, 50%, or 70% microfilarial baseline prevalence (representative of hypo-, meso-, and hyperendemic areas). We compared programmatic delivery costs for the number of treatments achieving 90% probability of EoT (EoT90), calculated with the individual-based stochastic transmission model EPIONCHO-IBM. We used the costs for 40 years of program delivery when EoT90 was not reached earlier. The delivery costs do not include drug costs. RESULTS: aCDTM and bCDTM achieved EoT90 with lower programmatic delivery costs than aCDTI with 1 exception: aCDTM with minimal coverage did not achieve EoT90 in hyperendemic areas within 40 years. With minimal coverage, bCDTI delivery costs as much or more than aCDTM and bCDTM. With enhanced coverage, programmatic delivery costs for aCDTM and bCDTM were lower than for aCDTI and bCDTI. CONCLUSIONS: Moxidectin-based strategies could accelerate progress toward EoT and reduce programmatic delivery costs compared with ivermectin-based strategies. The costs of moxidectin to national programs are needed to quantify whether delivery cost reductions will translate into overall program cost reduction.

Translation elongation rate varies among organs and decreases with age.

There has been a surge of interest towards targeting protein synthesis to treat diseases and extend lifespan. Despite the progress, few options are available to assess translation in live animals, as their complexity limits the repertoire of experimental tools to monitor and manipulate processes within organs and individual cells. It this study, we developed a labeling-free method for measuring organ- and cell-type-specific translation elongation rates in vivo. It is based on time-resolved delivery of translation initiation and elongation inhibitors in live animals followed by ribosome profiling. It also reports translation initiation sites in an organ-specific manner. Using this method, we found that the elongation rates differ more than 50% among mouse organs and determined them to be 6.8, 5.0 and 4.3 amino acids per second for liver, kidney, and skeletal muscle, respectively. We further found that the elongation rate is reduced by 20% between young adulthood and mid-life. Thus, translation, a major metabolic process in cells, is tightly regulated at the level of elongation of nascent polypeptide chains.

Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population.

Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential. SIGNIFICANCE STATEMENT: Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.

The use of Cydectin® by wildlife carers to treat sarcoptic mange in free-ranging bare-nosed wombats (Vombatus ursinus).

Wombats suffer from sarcoptic mange, a mite infection that ultimately leads to their death from secondary infections. In 2017, wildlife carers were granted legal approval to treat bare-nosed wombats (Vombatus ursinus) for sarcoptic mange in the field using 4 mL of topical Cydectin® per adult wombat. However, (limited) scientific field trials suggest approved protocols are inadequate which has been supported anecdotally by wildlife carers. Elucidating carer experience is key to holistically advancing understandings of sarcoptic mange treatment. We interviewed 18 wildlife carers regarding the use of Cydectin® to treat free-ranging adult wombats infected with sarcoptic mange which uncovered 43 detailed case studies for examination. Case studies revealed that wildlife carers have used 10-200-mL doses of topical Cydectin® to treat wombats to recovery. These results suggest there is no best-fit for treating wombats in the field, due to individual differences in observed levels of sarcoptic mange severity and differences in wombat behavior. Furthermore, wildlife carers suggested pour-on Cydectin® appeared non-toxic to wombats at rates as high as 200 mL per treatment. We recommend scientific trials should be undertaken to determine the impact and efficacy of the varying treatment regimens, including low and high doses of topical Cydectin® on bare-nosed wombats. This information is required for regulating authorities, and subsequently wildlife carers, and managers, to make fully informed decisions about wombat sarcoptic mange treatment.

Miconazole induces protective autophagy in bladder cancer cells.

Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.

Targeting CD155 by rediocide-A overcomes tumour immuno-resistance to natural killer cells.

CONTEXT: Therapeutic benefits of immunotherapy are restricted by cancer immune-resistance mechanisms. Rediocide-A (Red-A), a natural product extracted from Traditional Chinese Medicine, is a promising agent to battle against cancer which acts as an immune checkpoint inhibitor. OBJECTIVE: To investigate the effect of Red-A on NK-cell tumouricidal activity. MATERIALS AND METHODS: NK cells were co-cultured with A549 or H1299 cells and treated with 10 or 100 nM Red-A for 24 h. Cells treated with 0.1% dimethyl sulphoxide (DMSO) was employed as vehicle control. NK cell-mediated cytotoxicity was detected by biophotonic cytotoxicity and impedance assay. Degranulation, granzyme B, NK cell-tumour cell conjugates and ligands profiling were detected by flow cytometry. Interferon-γ (IFN- γ) production was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Red-A increased NK cell-mediated lysis of A549 cells by 3.58-fold (21.86% vs. 78.27%) and H1299 cells by 1.26-fold (59.18% vs. 74.78%), compared to vehicle control. Granzyme B level was increased by 48.01% (A549 cells) and 53.26% (H1299 cells) after 100 nM Red-A treatment. INF-γ level was increased by 3.23-fold (A549 cells) and 6.77-fold (H1299 cells) after 100 nM Red-A treatment. Red-A treatment down-regulated the expression level of CD155 by 14.41% and 11.66% in A549 cells and H1299 cells, respectively, leading to the blockade of tumour immuno-resistance to NK cells. CONCLUSIONS: Red-A overcomes immuno-resistance of NSCLCs to NK cells by down-regulating CD155 expression, which shows the possibility of developing checkpoint inhibitors targeting TIGIT/CD155 signalling to overcome immuno-resistance of cancer cells.

BTS guideline on long-term macrolides in adults with respiratory disease: not quite a panacea.

The British Thoracic Society (BTS) guideline on the use of long-term macrolides in adults with respiratory disease has been published. It indicates where there is evidence to support the use of long-term low-dose macrolides and where there is not. It discusses the potential benefits of such therapy for patients and also describes the potential risks to individuals and wider populations. It seeks to provide a pragmatic approach for clinicians considering long-term macrolide therapy for their patients. This guideline has also acted as a learning exercise for the BTS in introducing the Grading of Recommendations Assessment, Development and Evaluation approach to guideline development, which will be used going forwards.

Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets.

BACKGROUND: Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets. RESULTS: Gamithromycin was well absorbed and fully bioavailable (87.2-101%) after intramuscular and subcutaneous administrations. The MICs of gamithromycin for 192 clinical H. parasuis isolates ranged from 0.008 to 128 mg/L and the epidemiological cutoff (ECOFF) was calculated as 1.0 mg/L. A large potentiation effect of serum on in vitro susceptibility of gamithromycin was observed for H. parasuis, with broth/serum ratios of 8.93 for MICs and 4.46 for MBCs, respectively. The postantibiotic effects were 1.5 h (1 × MIC) and 2.4 h (4 × MIC), and the postantibiotic sub-MIC effects ranged from 2.7 to 4.3 h. Gamithromycin had rapid and concentration-dependent killing against H. parasuis, and the AUC24h/MIC ratio correlated well with ex vivo efficacy (R2 = 0.97). The AUC24h/MIC targets in serum associated with bacteriostatic, bactericidal and eradication activities were 15.8, 30.3 and 41.2, respectively. The PK/PD-based population dose prediction indicated a probability of target attainment (PTA) for the current marketed dose (6 mg/kg) of 88.9% against H. parasuis. The calculated gamithromycin dose for a PTA ≥ 90% was 6.55 mg/kg. Based on Monte Carlo simulations, the PK/PD cutoff (COPD) was determined to be 0.25 mg/L. CONCLUSION: The determined cutoffs and PK/PD-based dose prediction will be of great importance in gamithromycin resistance surveillance and serve as an important step in the establishment of optimum dose regimen and clinical breakpoints.

A nationwide questionnaire survey of clinic doctors on antimicrobial stewardship in Japan.

BACKGROUND: Clinics are high prescribers of antimicrobials in Japan, but the present situation and the attitude of clinic doctors toward prescribing them remain unclear. OBJECTIVE: To investigate the present situation at clinics and clinic doctors' attitude toward antimicrobial stewardship. STUDY DESIGN: A questionnaire survey of clinic doctors. METHODS: A questionnaire targeting doctors was sent to 1500 clinics that were randomly selected from across the country. RESULTS: Among 274 respondents (response rate, 18.3%), 269 provided consent and their responses were analyzed. Awareness of the National Action Plan on Antimicrobial Resistance and the Manual of Antimicrobial Stewardship was low, but awareness of antimicrobial stewardship was high. A certain proportion of doctors prescribed antimicrobials for the common cold and acute bronchitis, and macrolides were the most commonly prescribed group of antimicrobials. Such prescription was not based solely on the doctors' knowledge but was also influenced by complex factors such as the doctor-patient relationship. CONCLUSION: Various measures such as improving doctor-patient communication and improving clinic doctors' knowledge are necessary to promote antimicrobial stewardship in the outpatient setting.

Short communication: Herd-level analysis of antimicrobial use and mortality in veal calves: Do herds with low usage face higher mortality?

The veal calf sector fears that a too-rapid and large decrease in antimicrobial use (AMU) as demanded by European authorities would increase mortality, causing economic and welfare issues. To determine whether this concern is justified, the relationship between AMU (total and different classes) and mortality in dairy-type white veal calves, managed by 2 large veal companies, was explored. A retrospective cohort study was performed on electronically collected antimicrobial consumption and mortality data from the largest Belgian veal practice during the period 2014 to 2016. Mixed linear [mortality (%) as continuous outcome] and generalized linear mixed models with binary outcome for event and trial approach were built to identify factors associated with mortality. Data consisted of 76 production cycles from 29 farms managed by 2 veal companies (1 and 2) and covering 45,001 calves. Average AMU was 30.1 ± 10.4 defined daily doses for animals per year (± standard deviation) and was higher in veal company 2 than in veal company 1 (35.9 ± 9.3 and 22.4 ± 5.7 defined daily doses for animals per year, respectively). In contrast, mean mortality was lower in veal company 2 (2.3 ± 1.4%) than in veal company 1 (4.1 ± 1.4%). Both models showed a positive association between AMU and mortality in veal company 1 and no association in veal company 2. The final linear model identified increasing herd size and the use of third- or fourth-generation cephalosporins as risk factors for mortality and the use of long-acting macrolides as a protective factor. The final logistic model identified an increased mortality risk with increased use of third- or fourth-generation cephalosporins and sulfonamides-trimethoprim and decreased mortality when using long-acting macrolides. Based on these data, at the current levels of AMU in Belgian veal calves, an increase in mortality when reducing AMU could not be evidenced. Differences in herd size and factors other than AMU likely better explain why one veal company faces almost double the mortality of another one. Abandoning the use of long-acting macrolides might have negative consequences for mortality under the current state of the industry. The most ethical way to further reduce AMU in veal calves is likely simultaneously monitoring AMU and animal welfare parameters, starting with, but not limited to, mortality.

Ophthalmic Thelazia callipaeda infections: first feline and new canine imported cases in Germany.

The first case of feline ocular Thelazia callipaeda infection and two new canine imported infections in West Germany are here described. The three animals had a history of recent travel to/from other countries. The young adult cat imported from Spain presented an intermittent unilateral ocular discharge. During in-depth ophthalmic examination, a single alive nematode was removed from the conjunctival compartment of the affected eye. Referring to the canine cases, an adult female dog originated from Kenya presented epiphora and mucous whitish-grey discharge of the right eye. During flushing of the nasolacrimal duct two small, thin and long nematodes were removed. Furthermore, a male Borzoi racing dog with regular visit to racing tracks in different countries presented ocular mucous discharge. At ophthalmologic examination, two transparent-whitish vital nematodes were removed. All nematode specimens of the three cases were morphologically identified as adult T. callipaeda parasites. The animals were treated orally with milbemycin oxime (2.0 mg/kg; cat) or milbemycin oxime/praziquantel (0.5 mg/kg and 5.0 mg/kg; dogs) twice with 1-week interval resulting in complete resolution of symptoms. The repeated introduction of patent T. callipaeda-infected animals, especially from southern and eastern endemic countries, will ease the establishment of ophthalmic thelaziosis in Northern Europe. The male fruit fly, Phortica variegata, an intermediate host of T. callipaeda, is endemic within European countries. Considering the clinical and zoonotic relevance of ophthalmic thelaziosis, enhanced disease awareness of European medical and veterinarian doctors and in-depth eye examination for proper detection of T. callipaeda are crucial for appropriate anthelmintic treatments and to limit spreading of the infection.

COVID-19: therapeutic approaches description and discussion.

COVID-19 emerged in December 2019 in China, and since then, has disrupted global public health and changed economic paradigms. In dealing with the new Coronavirus, SARS-CoV-2, the world has not faced such extreme global fragility since the "Spanish flu" pandemic in 1918. Researchers globally are dedicating efforts to the search for an effective treatment for COVID-19. Drugs already used in a clinical setting for other pathologies have been tested as a new therapeutic approach against SARS-CoV-2, setting off a frenzy over the preliminary data of different studies. This work aims to compile and discuss the data published thus far. Despite the potential effects of some antivirals and antiparasitic against COVID-19, clinical studies must confirm real effectiveness. However, non-pharmacological approaches have proven to be the most efficient strategy to date.

Bordetella bronchiseptica experimental model development in pigs and efficacy evaluation of a single intramuscular injection of gamithromycin (Zactran® for Swine) against Bordetella bronchiseptica-associated respiratory disease in experimentally infected piglets.

In the Bordetella bronchiseptica infection model development study, twenty-eight piglets were inoculated with B. bronchiseptica strain of either canine (109  CFU/ml) or swine (108 and 109  CFU/ml) origin; swine origin strain at 109  CFU/ml was chosen for the efficacy assessment study due to higher incidence and severity of gross and histopathological lesions compared with other strains. To assess efficacy of gamithromycin against B. bronchiseptica, forty piglets were experimentally inoculated on Day 0 and clinical signs were scored as per severity. Animals were then treated either with gamithromycin or saline on Day 3. The Global Clinical Scores in gamithromycin-treated group were consistently lower than the saline-treated control group from Day 4 onwards and were 0 and 40 in the gamithromycin-treated and saline-treated control groups, respectively, on Day 6. Severity and frequency of gross and histopathological observations were significantly lower in gamithromycin-treated animals compared with saline-treated controls. The efficacy of Zactran® for Swine at the label dose for the treatment of B. bronchiseptica-associated respiratory disease was demonstrated based on the faster reduction in clinical signs as early as 1 day post-gamithromycin treatment and based on the significant difference in the severity of macroscopic and microscopic lung lesions 10 days post-gamithromycin treatment.

Autophagy modulates transforming growth factor beta 1 induced epithelial to mesenchymal transition in non-small cell lung cancer cells.

Lung cancer is considered one of the most frequent causes of cancer-related death worldwide and Non-Small Cell Lung Cancer (NSCLC) accounts for 80% of all lung cancer cases. Autophagy is a cellular process responsible for the recycling of damaged organelles and protein aggregates. Transforming growth factor beta-1 (TGFß1) is involved in Epithelial to Mesenchymal Transition (EMT) and autophagy induction in different cancer models and plays an important role in the pathogenesis of NSCLC. It is not clear how autophagy can regulate EMT in NSCLC cells. In the present study, we have investigated the regulatory role of autophagy in EMT induction in NSCLC and show that TGFß1 can simultaneously induce both autophagy and EMT in the NSCL lines A549 and H1975. Upon chemical inhibition of autophagy using Bafilomycin-A1, the expression of the mesenchymal marker vimentin and N-cadherin was reduced. Immunoblotting and immunocytochemistry (ICC) showed that the mesenchymal marker vimentin was significantly downregulated upon TGFß1 treatment in ATG7 knockdown cells when compared to corresponding cells treated with scramble shRNA (negative control), while E-cadherin was unchanged. Furthermore, autophagy inhibition (Bafilomycin A1 and ATG7 knockdown) decreased two important mesenchymal functions, migration and contraction, of NSCLC cells upon TGFß1 treatment. This study identified a crucial role of autophagy as a potential positive regulator of TGFß1-induced EMT in NSCLC cells and identifies inhibitors of autophagy as promising new drugs in antagonizing the role of EMT inducers, like TGFß1, in the clinical progression of NSCLC.

Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial.

BACKGROUND: The morbidity and socioeconomic effects of onchocerciasis, a parasitic disease that is primarily endemic in sub-Saharan Africa, have motivated large morbidity and transmission control programmes. Annual community-directed ivermectin treatment has substantially reduced prevalence. Elimination requires intensified efforts, including more efficacious treatments. We compared parasitological efficacy and safety of moxidectin and ivermectin. METHODS: This double-blind, parallel group, superiority trial was done in four sites in Ghana, Liberia, and the Democratic Republic of the Congo. We enrolled participants (aged ≥12 years) with at least 10 Onchocerca volvulus microfilariae per mg skin who were not co-infected with Loa loa or lymphatic filariasis microfilaraemic. Participants were randomly allocated, stratified by sex and level of infection, to receive a single oral dose of 8 mg moxidectin or 150 µg/kg ivermectin as overencapsulated oral tablets. The primary efficacy outcome was skin microfilariae density 12 months post treatment. We used a mixed-effects model to test the hypothesis that the primary efficacy outcome in the moxidectin group was 50% or less than that in the ivermectin group. The primary efficacy analysis population were all participants who received the study drug and completed 12-month follow-up (modified intention to treat). This study is registered with ClinicalTrials.gov, number NCT00790998. FINDINGS: Between April 22, 2009, and Jan 23, 2011, we enrolled and allocated 998 participants to moxidectin and 501 participants to ivermectin. 978 received moxidectin and 494 ivermectin, of which 947 and 480 were included in primary efficacy outcome analyses. At 12 months, skin microfilarial density (microfilariae per mg of skin) was lower in the moxidectin group (adjusted geometric mean 0·6 [95% CI 0·3-1·0]) than in the ivermectin group (4·5 [3·5-5·9]; difference 3·9 [3·2-4·9], p<0·0001; treatment difference 86%). Mazzotti (ie, efficacy-related) reactions occurred in 967 (99%) of 978 moxidectin-treated participants and in 478 (97%) of 494 ivermectin-treated participants, including ocular reactions (moxidectin 113 [12%] participants and ivermectin 47 [10%] participants), laboratory reactions (788 [81%] and 415 [84%]), and clinical reactions (944 [97%] and 446 [90%]). No serious adverse events were considered to be related to treatment. INTERPRETATION: Skin microfilarial loads (ie, parasite transmission reservoir) are lower after moxidectin treatment than after ivermectin treatment. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress towards elimination. FUNDING: UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

Impact of Previous Exposure to Macrolide Antibiotics on Helicobacter pylori Infection Treatment Outcomes.

OBJECTIVES: Helicobacter pylori (H. pylori) guidelines, including the recent ACG clinical guideline, recommend avoiding clarithromycin-based triple therapy (TT-C) among patients with past macrolide exposure. Data to support this recommendation are scarce, and the impact of macrolide exposure on quadruple therapies is unclear. We aimed to determine the impact of macrolide exposure on the efficacy of H. pylori treatment in our region. METHODS: We searched the Clalit Health Services database to identify subjects aged 25-60 years who underwent the first-ever C-urea breath test between 2010 and 2015. Patients who underwent a previous H. pylori stool antigen test or gastroscopy were excluded. Pharmacy dispensation data were retrieved. RESULTS: We identified 7,842 subjects (36.1% male individuals, age: 40.3 ± 10.5 years), including 3,062 (39.0%) with previous macrolide exposure. The efficacy of TT-C was 74.3% and 82.4% among subjects with and without macrolide exposure, respectively (odds ratio (OR), 0.62; 95% confidence interval (CI), 0.55-0.70; P < 0.0001). TT success was adversely affected by exposure to clarithromycin (55.5%; OR, 0.31; 95% CI, 0.24-0.39; P < 0.0001), roxythromycin (74.4%; OR, 0.65; 95% CI, 0.58-0.74; P < 0.0001), and erythromycin (73.9%; OR, 0.72; 95% CI, 0.57-0.89; P < 0.01) but not by exposure to azithromycin. A greater time elapsed because exposure to clarithromycin and roxythromycin was associated with higher eradication (OR, 1.007; 95% CI, 1.002-1.012; P < 0.01 and OR, 1.004; 95% CI, 1.002-1.006; P < 0.0001). A higher dose of clarithromycin and roxythromycin was associated with a lower likelihood of successful eradication (OR, 0.99988; 95% CI, 0.99982-0.99996; P < 0.01 and OR, 0.99981; 95% CI, 0.99971-0.99992; P < 0.001). The efficacies of sequential and concomitant therapies were 82.7% and 81.3%, respectively, and were not significantly affected by macrolide exposure. CONCLUSIONS: TT-C is adversely affected by previous exposure to macrolide antibiotics. Sequential, concomitant, and bismuth-based treatment may be preferred in this setting.

Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis.

INTRODUCTION: Non-cystic fibrosis (CF) bronchiectasis ("bronchiectasis") is a chronic airway disease for which little data exist to inform treatment decisions. We sought to compare the risks of respiratory infections in chronic users of inhaled corticosteroids (ICSs) versus macrolide monotherapy. METHODS: We identified a cohort of US Medicare enrollees with a bronchiectasis diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 494.0 or 494.1) between 2006 and 2014, excluding CF. We defined chronic new use as the first ≥28-day prescription of ICS therapy or macrolide monotherapy. We compared the characteristics of the exposure cohorts using standardised mean differences (SMDs) and computed a propensity score (PS) to account for treatment differences. The risks of acute exacerbation, hospitalised respiratory infection, all-cause hospitalisation and mortality were compared using PS decile-adjusted Cox regression models. RESULTS: We identified 83 589 new users of ICSs and 6500 new users of macrolides from 285 043 included Medicare enrollees with bronchiectasis. The crude incidence of hospitalised respiratory infection was 12.6 (ICS therapy) and 10.3 (macrolide monotherapy) per 100 patient-years. The PS-adjusted HRs comparing ICS with macrolide new users were 1.39 (95% CI 1.23-1.57) for hospitalised respiratory infection, 1.56 (95% 1.49-1.64) for acute exacerbation and 1.09 (95% 0.95-1.25) for mortality. INTERPRETATION: Among patients with bronchiectasis, the use of ICSs was associated with an increased risk of hospitalised respiratory infections compared with macrolide monotherapy.

Cardiovascular safety of macrolide and fluoroquinolone antibiotics: An analysis of the WHO database of adverse drug reactions.

INTRODUCTION: The cardiovascular safety profile of macrolides and fluoroquinolones has been widely discussed. The aim of the present study is to provide the contribution of real-world data onto the ongoing discussion about cardiovascular toxicity of both macrolides and fluoroquinolones. METHODS: Reports of adverse drug reactions (ADRs) were retrieved from VigiBase. Macrolides and fluoroquinolones were compared with amoxicillin by using the reporting odds ratio (ROR) as a measure of disproportionality. Macrolides were then compared with fluoroquinolones. RESULTS: Overall, 6810 reports of ADRs were retrieved: 62% of them were serious and 35% concerned female. Macrolides were more frequently associated with "atrial fibrillation" (ROR = 1.26, CI 1.02-1.57) and "ventricular fibrillation" ROR = 2.60, CI 1.92-3.54) than fluoroquinolones. Antimicrobials more frequently reported for "cardiac disorder" were azithromycin (375 reports) and clarithromycin (302) for macrolides and levofloxacin (470) and moxifloxacin (391) for fluoroquinolones. CONCLUSION: Our data highlighted that macrolides and fluoroquinolones may influence cardiac rhythm and suggest caution in the prescribing of these drugs to patients with hidden cardiovascular risk factors. Although these ADRs seem to be not common, they have a notable impact in clinical practice because of the huge number of the exposed subjects.

Evaluation of new generation macrolides for the treatment and metaphylaxis of contagious bovine pleuropneumonia (CBPP) in cattle experimentally infected with Mycoplasma mycoides subspecies mycoides.

BACKGROUND: Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subspecies mycoides (Mmm) is an important disease of cattle that causes serious economic losses. With the known effectiveness of new generation macrolides, tulathromycin and gamithromycin were assessed in comparison with oxytetracycline as a positive control and saline as a negative control for effectiveness in inhibiting lung lesion development, promoting resolution, preventing spread and bacteriological clearance in susceptible local cattle breeds in two separate studies in Kenya and Zambia. Animals were monitored for clinical signs, sero-conversion as well as detailed post-mortem examination for CBPP lesions. RESULTS: Using the Hudson and Turner score for lesion type and size, tulathromycin protected 90%, gamithromycin 80%, and oxytetracycline 88% of treated animals in Kenya. In Zambia, all animals (100%) treated with macrolides were free of lung lesions, while oxytetracycline protected 77.5%. Using the mean adapted Hudson and Turner score, which includes clinical signs, post-mortem findings and serology, tulathromycin protected 82%, gamithromycin 56% and oxytetracycline 80% of the animals in Kenya whereas in Zambia, tulathromycin protected 98%, gamithromycin 94% and oxytetracycline 80%. The saline-treated groups had 93 and 92% lesions in Kenya and Zambia respectively, with Mmm recovered from 5/14 in Kenya and 10/13 animals in Zambia. Whereas the groups treated with macrolides were free from lesions in Zambia, in Kenya 5/15 tulathromycin-treated animals and 6/15 gamithromycin-treated animals showed lesions. Oxytetracycline-treated animals showed similarities with 3/14 and 4/15 showing lesions in Zambia and Kenya respectively and Mmm recovery from one animal in Kenya and six in Zambia. In both studies, lesion scores of saline-treated groups were significantly higher than those of the antibiotic treated groups (p < 0.001). In sentinel animals, CBPP lesions were detected and Mmm recovered from one and two animals mixed with the saline-treated groups in Kenya and Zambia respectively. CONCLUSIONS: This study demonstrated that tulathromycin, a mycoplasmacidal, can achieve metaphylactic protection of up to 80%, while non-recovery of Mmm from sentinels suggests macrolides effectiveness in preventing spread of Mmm. It is recommended that further studies are conducted to evaluate strategies comparing vaccination alone or combining vaccination and antibiotics to control or eradicate CBPP.

Nationwide study of outpatient oral antimicrobial utilization patterns for children in Japan (2013-2016).

BACKGROUND: Antimicrobial resistance (AMR) is a major multinational public health concern. The Japanese government set goals in its AMR action plan to reduce use of oral cephalosporins, macrolides, and quinolones by half between 2013 and 2020. We aimed to evaluate antimicrobial use in children in Japan by observing prescription patterns as an interim assessment of the national AMR action plan. METHODS: Using the national health claims database, we retrospectively analyzed all oral antimicrobials dispensed from outpatient pharmacies in Japan to children under 15 years old from 2013 to 2016 by age, prefecture, type of antimicrobial, and year. Data were presented as days of therapy (DOTs) per 1000 pediatric inhabitants per day (DOTs/PID). The χ2 test for trends was performed to evaluate annual changes in DOTs/PID overall as well as within each stratum. RESULTS: A total of 721,627,553 oral antimicrobial DOTs were identified during 2013-2016. No statistically significant changes were observed in total antimicrobial use in children (2013: 28.54 DOTs/PID; 2016: 28.70 DOTs/PID; Ptrend = 0.25) and amount of cephalosporins, macrolides, and quinolones prescribed. Prescription rates of all antimicrobials were highest among children 1-5 years old, peaking at 1 year old. Targeted antimicrobials for the AMR action plan showed similar distribution by age. CONCLUSION: The amount of antimicrobials prescribed to children in Japan is not decreasing. Overall antimicrobial prescriptions, as well as prescriptions of cephalosporins, macrolides, and quinolones, were most prevalent in children ≤5 years old. Rigorous antimicrobial stewardship interventions targeting infants and younger children are necessary.