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Fenbendazole controls in vitro growth, virulence potential and animal infection in the Cryptococcus model [Experimental Therapeutics]

The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.




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Imipenem population pharmacokinetics: therapeutic drug monitoring data collected in critically ill patients with or without extracorporeal membrane oxygenation [Pharmacology]

Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens.




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Repurposing the antiamoebic drug diiodohydroxyquinoline for treatment of Clostridioides difficile infections [Experimental Therapeutics]

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at the concentrations of 0.5 μg/mL and 2 μg/mL, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3-log10 within six hours. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.




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Development of probiotic formulations for oral candidiasis prevention: Gellan gum as a carrier to deliver Lactobacillus paracasei 28.4 [Experimental Therapeutics]

Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and there is a necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeting local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food-additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1%). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic/gellan formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacteria-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic/gellan formulations provided a release of L. paracasei cells over 24 hours that was sufficient to inhibit the growth of C. albicans with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic/gellan formulations also had inhibitory activity against Candida spp. biofilms by reducing the number of Candida spp. cells (p < 0.0001), decreasing the total biomass (p = 0.0003), and impairing hyphae formation (p = 0.0002), compared to the control group which received no treatment. Interestingly, probiotic formulation of 1% w/v gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log of CFU/mL after 10 days. This formulation inhibited the C. albicans growth (p < 0.0001), prevented the development of candidiasis lesions (p = 0.0013), and suppressed inflammation (p = 0.0006) when compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis.




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The Added Value of Longitudinal Imaging for Preclinical In vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis [Experimental Therapeutics]

Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly relies on survival studies or post-mortem analyses in large groups of animals, but these techniques only provide information on specific organs of interest at predefined time points. In this proof-of-concept study, we validated the use of non-invasive preclinical imaging to obtain longitudinal information on the therapeutic efficacy of amphotericin B or fluconazole monotherapy in meningoencephalitis and cryptococcoma mouse models. Bioluminescence imaging (BLI) enabled the rapid in vitro and in vivo evaluation of drug efficacy while complementary high-resolution anatomical information obtained by magnetic resonance imaging (MRI) of the brain allowed a precise assessment of the extent of infection and lesion growth rates. We demonstrated a good correlation between both imaging readouts and the fungal burden in various organs. Moreover, we identified potential pitfalls associated with the interpretation of therapeutic efficacy based solely on post-mortem studies, demonstrating the added value of this non-invasive dual imaging approach compared to standard mortality curves or fungal load endpoints. This novel preclinical imaging platform provides insights in the dynamic aspects of the therapeutic response and facilitates a more efficient and accurate translation of promising antifungal compounds from bench to bedside.




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Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants With Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis) [Clinical Therapeutics]

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This Phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (N = 22) were confined to the clinic at baseline, received oral gepotidacin 1,500 mg twice daily for 5 days (on-therapy; Days 1 to 5), and returned to the clinic for test-of-cure (Days 10 to 13) and follow-up (Day 28±3). Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 hours postdose. Steady state was attained by Day 3. Urinary exposure over the dosing interval increased from 3,742 μg.h/ml (Day 1) to 5,973 μg.h/ml (Day 4), with trough concentrations of 322 to 352 μg/ml from Day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥105 CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <103 CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up, respectively. Plasma area under the free-drug concentration-time curve over 24 hours at steady state divided by the MIC (fAUC0-24/MIC) and urine AUC0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (NCT03568942)




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Therapeutic efficacy of a mixed formulation of conventional and PEGylated liposomes containing meglumine antimoniate, combined with allopurinol, in dogs naturally infected with Leishmania infantum [Experimental Therapeutics]

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.




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Epidemiological study on prevalence, serovar diversity, multi-drug resistance and CTX-M-type extended-spectrum {beta}-lactamases of Salmonella spp. from patients with diarrhea, food of animal origin, and pets in several provinces of China [Epidemiology an

A total of 2,283 Salmonella spp. isolates were recovered from 18,334 samples including patients with diarrhea, food of animal origin and pets across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistant to ≥ 1 antimicrobial and 56.4% were multi-drug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), 200 of which were CTX-M-type that were mostly detected from chicken meat and turtle fecal. Overall, eight blaCTX-M genes were identified, with blaCTX-M-65, blaCTX-M-123, blaCTX-M-14, blaCTX-M-79, and blaCTX-M-130 being the most prevalent. Totally, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (and S80I), whilst the PMQR-encoding genes oqxA/B, qepA, and qnrB/S were detected in almost all isolates. Of the fifteen sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in the number of isolates. Our study revealed considerable serovars diversity, high prevalence of co-occurrence of MDR determinants, including CTX-M-type ESBLs, QRDRs mutations and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDRs mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in the health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M Salmonella spp. isolates.




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Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Patients Infected with Influenza at High Risk of Influenza Complications [Clinical Therapeutics]

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor, baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11846 plasma concentration data items from 1827 subjects including 2341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications.

Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing < 80 kg and 80 mg for patients weighing ≥ 80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients.

The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.




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Thioridazine is an efflux pump inhibitor in Mycobacterium avium complex but of limited clinical relevance [Susceptibility]

Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore thioridazine's efficacy against M. avium using minimum inhibitory concentrations (MICs), time-kill combination assays, ex vivo macrophage infection assays and efflux assays. Thioridazine is bactericidal against M. avium, inhibits intracellular growth at 2x MIC and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations, make it unlikely to add efficacy to MAC-PD therapy.




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Anidulafungin and Micafungin concentrations in Cerebrospinal Fluid and in Cerebral Cortex [Pharmacology]

Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01-0.66 μg/ml) and micafungin levels (<0.01-0.16 μg/ml) were lower than the simultaneous plasma concentrations (0.77-5.07 μg/ml and 1.21-8.70 μg/ml, respectively). In cerebral cortex, anidulafungin and micafungin levels were 0.21-2.34 μg/g and 0.18-2.88 μg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.




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Effect of the Lysin, Exebacase, on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus (MRSA) Endocarditis as Determined by Echocardiography [Pharmacology]

Background: MRSA pose significant therapeutic challenges, related to their: frequency in clinical infections; innate virulence properties; and propensity for multi-antibiotic resistance. MRSA are among the most common causes of endovascular infections, including infective endocarditis (IE).

Objective: To employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE.

Study Design: TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (vs daptomycin alone). Primary intravegetation outcomes were: maximum size; weights at sacrifice; and MRSA counts at infection baseline vs after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment Day 1).

Results: A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase + daptomycin vs the daptomycin-alone therapy groups (p = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower vs daptomycin-alone (p < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (p = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower vs untreated controls (p<0.0001) and the daptomycin-alone group (p<0.0001).

Conclusion: This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size and weight. Moreover, TTE appears to be an efficient non-invasive tool to assess therapeutic efficacies in experimental MRSA IE.




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Impact of vanA-positive Enterococcus faecium exhibiting diverse susceptibility phenotypes to glycopeptides on 30-day mortality of patients with a bloodstream infection [Epidemiology and Surveillance]

Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.

Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.

Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).

Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.




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Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulate in vivo susceptibility to artemisinin and chloroquine in Plasmodium berghei. [Mechanisms of Resistance]

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.




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Combination Therapy Using Benznidazole and Aspirin During the Acute Phase of Experimental Chagas Disease Prevents Cardiovascular Dysfunction and Decreases Typical Cardiac Lesions in the Chronic Phase [Clinical Therapeutics]

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA4 receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.




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The emergence of fexA in mediating resistance to florfenicols in Campylobacter [Mechanisms of Resistance]

Florfenicol belongs to a class of phenicol antimicrobials widely used as feed additives and for the treatment of respiratory infections. In recent years, increasing resistance to florfenicol has been reported in Campylobacter spp., the leading foodborne enteric pathogen causing diarrheal diseases worldwide. Here, we reported the identification of fexA, a novel mobile florfenicol resistance gene in Campylobacter. Of the 100 Campylobacter jejuni strains isolated from poultry in Zhejiang, China, nine of them were shown to be fexA positive, and their whole genome sequences were further determined by integration of Illumina short-read and MinION long-read sequencing. The fexA gene was found in the plasmid of one strain and chromosomes of eight strains, and its location was verified by S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting. Based on comparative analysis, the fexA gene was located within a region with the tet(L)-fexA-catA-tet(O) gene arrangement, demonstrated to be successfully transferrable among C. jejuni strains. Functional cloning indicated that acquisition of the single fexA gene significantly increased resistance to florfenicol, whereas its inactivation resulted in increased susceptibility to florfenicol in Campylobacter. Taken together, these results indicated that the emerging fexA resistance is horizontally transferable, which might greatly facilitate the adaptation of Campylobacter in food producing environments where florfenicols are frequently used.




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Optimal dose or optimal exposure? Consideration for linezolid in tuberculosis treatment [Letters]

Exploring different ways of minimising linezolid toxicity without compromising efficacy is a major quest in the treatment of drug resistant tuberculosis (TB)....




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Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs [Susceptibility]

Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here we extended this study and included isolates with acquired fluconazole resistance.

Isolates (n=835) were identified using CHROMagar, MALDI-TOF and, when needed, ITS-sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole and voriconazole. Manogepix wildtype-upper-limit (WT-UL) values were established following EUCAST-principles for ECOFF setting allowing wildtype/non-wildtype classification. Drug-specific MIC correlations were investigated using Pearson's correlation.

Manogepix modal MICs were low (range 0.004-0.06 mg/L against 16/20 included species). Exceptions were C. krusei and C. inconspicua, and to a lesser extent C. kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot-spot alterations (n=17). Adopting the WT-UL established for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis, 14/724 (1.9%) isolates were non-wildtype for manogepix. Twelve of these (85.7%) were also non-wildtype for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis (Pearson r=0.401-0.575), but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r=0.519 for manogepix versus micafungin).

Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1-4 two-fold-dilution increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.




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Reply to Kim et al., "Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment" [Author Reply]

We thank Kim and colleagues for their interest in our study....




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Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages. [Susceptibility]

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.




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Google's Advanced Protection Expands to Phone-Only Users

Google has made it easier to join the company's Advanced Protection Program, which is designed to stop the most sophisticated hackers from breaking into your Gmail account. Before you needed two security keys to enroll. Now you just need a smartphone.




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Fin24.com | JSE erases earlier gains as global economy exhibits more strain

The local bourse had managed to open firmer following a rally in Asian stocks in earlier trading.




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Fin24.com | Markets wrap | Firmer close in Asia lifts JSE All-Share Index

On the currency market, the rand traded softer against the greenback as it slipped to a session low of R18.77/$.




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Breastfeeding Initiation, Duration, and Supplementation Among Mexican-Origin Women in Texas

BACKGROUND:

Mexican-origin women breastfeed at similar rates as white women in the United States, yet they usually breastfeed for less time. In our study, we seek to identify differences in Mexican-origin women’s breastfeeding intentions, initiation, continuation, and supplementation across nativity and country-of-education groups.

METHODS:

The data are from a prospective cohort study of postpartum women ages 18 to 44 recruited from 8 Texas hospitals. We included 1235 Mexican-origin women who were born and educated in either Texas or Mexico. Women were interviewed at delivery and at 3, 6, 12, 18, and 24 months post partum. Breastfeeding intentions and initiation were reported at baseline, continuation was collected at each interview, and weeks until supplementation was assessed for both solids and formula. Women were classified into 3 categories: born and educated in Mexico, born and educated in the United States, and born in Mexico and educated in the United States.

RESULTS:

Breastfeeding initiation and continuation varied by nativity and country of birth, although all women reported similar breastfeeding intentions. Women born and educated in Mexico initiated and continued breastfeeding in higher proportions than women born and educated in the United States. Mexican-born and US-educated women formed an intermediate group. Early supplementation with formula and solid foods was similar across groups, and early supplementation with formula negatively impacted duration across all groups.

CONCLUSIONS:

Nativity and country of education are important predictors of breastfeeding and should be assessed in pediatric and postpartum settings to tailor breastfeeding support. Support is especially warranted among US-born women, and additional educational interventions should be developed to forestall early supplementation with formula across all acculturation groups.




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Costs and Use for Children With Medical Complexity in a Care Management Program

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

DESIGN AND METHODS:

We conducted a prospective cohort analysis of a population of 4530 CMC enrolled in a learning collaborative designed to improve care for CMC ages 0 to 21 years identified using 3M Clinical Risk Group categories 5b through 9. The primary outcome was total per-member per-year standardized spending; secondary outcomes included inpatient and emergency department (ED) spending and use. We used a 1:1 propensity score match to compare enrolled patients to eligible nonenrolled patients and statistical process control methods to analyze spending and usage rates.

RESULTS:

Comparison with the matched group showed a 4.6% (95% confidence interval [CI]: 1.9%–7.3%) decrease in total per-member per-year spending (P < .001), a 7.7% (95% CI: 1.2%–13.5%) decrease in inpatient spending (P = .04), and an 11.6% (95% CI: 3.9%–18.4%) decrease in ED spending (P = .04). Statistical process control analysis showed a decrease in hospitalization rate and ED visits.

CONCLUSIONS:

CMC enrolled in a learning collaborative showed significant decreases in total spending and a significant decrease in the number of hospitalizations and ED visits. Additional research is needed to determine more specific causal factors for the results and if these results are sustainable over time and replicable in other settings.




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HIV Testing Among Adolescents With Acute Sexually Transmitted Infections

BACKGROUND AND OBJECTIVES:

Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.

METHODS:

Retrospective study of STI episodes (gonorrhea, Chlamydia, trichomoniasis, or syphilis) of adolescents between 13 and 24 years old from July 2014 to December 2017 in 2 urban primary care clinics. We performed mixed effects logistic regression modeling to identify patient and health care factors associated with HIV testing within 90 days of STI diagnosis.

RESULTS:

The 1313 participants contributed 1816 acute STI episodes. Mean age at STI diagnosis was 17.2 years (SD = 1.7), 75% of episodes occurred in females, and 97% occurred in African Americans. Only half (55%) of acute STI episodes had a completed HIV test. In the adjusted model, female sex, previous STIs, uninsured status, and confidential sexual health encounters were associated with decreased odds of HIV testing. Patients enrolled in primary care at the clinics, compared with those receiving sexual health care alone, and those with multipathogen STI diagnoses were more likely to have HIV testing.

CONCLUSIONS:

HIV testing rates among adolescents with acute STIs are suboptimal. Patient and health care factors were found to be associated with receipt of testing and should be considered in clinical practice.




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Transgender Youth Experiences and Perspectives Related to HIV Preventive Services

BACKGROUND:

In the United States, transgender youth are at especially high risk for HIV infection. Literature regarding HIV prevention strategies for this vulnerable, often-hidden population is scant. Before effective, population-based HIV prevention strategies may be adequately developed, it is necessary to first enhance the contextual understanding of transgender youth HIV risk and experiences with HIV preventive services.

METHODS:

Two 3-day, online, asynchronous focus groups were conducted with transgender youth from across the United States to better understand participant HIV risk and experiences with HIV preventive services. Participants were recruited by using online advertisements posted via youth organizations. Qualitative data were analyzed by using content analysis.

RESULTS:

A total of 30 transgender youth participated. The average age was 18.6 years, and youth reported a wide range of gender identities (eg, 27% were transgender male, 17% were transgender female, and 27% used ≥1 term) and sexual orientations. Four themes emerged: (1) barriers to self-efficacy in sexual decision-making; (2) safety concerns, fear, and other challenges in forming romantic and/or sexual relationships; (3) need for support and education; and (4) desire for affirmative and culturally competent experiences and interactions (eg, home, school, and health care).

CONCLUSIONS:

Youth discussed experiences and perspectives related to their gender identities, sexual health education, and HIV preventive services. Findings should inform intervention development to improve support and/or services, including the following: (1) increasing provider knowledge and skills to provide gender-affirming care, (2) addressing barriers to services (eg, accessibility and affordability as well as stigma and discrimination), and (3) expanding sexual health education to be inclusive of all gender identities, sexual orientations, and definitions of sex and sexual activity.




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Whistle GO Explore

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Unexpected love and respect

Rosario, Argentina :: Church members from a vulnerable community learn about human trafficking and experience care and respect.




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An architect explores using his passion in missions

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Fin24.com | 3 'practicalities' to consider before investing in property in Africa – expert

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Fin24.com | Here's what SA financial experts would do with R10 000 in 2020

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Fin24.com | Coronavirus and retirement savings: 5 things experts want you to think about

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Futsal entering an exciting era

The UEFA Futsal EURO is being enhanced, and will soon be joined by two new futsal competitions – the UEFA Women's Futsal EURO and the UEFA European Under-19 Futsal Championship.




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Unexpected love and respect

Rosario, Argentina :: Church members from a vulnerable community learn about human trafficking and experience care and respect.




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An architect explores using his passion in missions

For years, Gustavo, an architect from Central America, felt drawn to working in the Arabian Peninsula. Then, on a short-term trip, he saw what it could be like to use his profession overseas.




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Ordinary woman, extraordinary journey

God uses Janet to reach people through one-on-one encounters at a bookshop in a closed country.




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Legal clinic at Happy Valley LaunchBox expands scope in response to pandemic

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Mechanical Engineering department draws from existing success in online teaching

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Western Digital Launches 5 WD Black External Gaming Drives

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How to Handle IEPs During the Coronavirus Crisis? Some Expert Advice

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Autism Amid Uncertainty: Expert Advice for Parents and Teachers

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