con Eastern Congo: Why Stabilisation Failed By feedproxy.google.com Published On :: Thu, 04 Oct 2012 09:24:00 GMT The Kivus region of eastern Congo again faces escalating violence, including by a rebel force acting as a proxy of neighbouring Rwanda. To stop the repetitive cycle of rebellion and avoid large-scale killing, donors and African mediators need to move from crisis management to conflict resolution with the right set of pressures on Kigali and Kinshasa. Full Article
con Eastern Congo: The ADF-NALU’s Lost Rebellion By feedproxy.google.com Published On :: Wed, 19 Dec 2012 10:20:00 GMT The fight against entrenched armed groups in eastern Congo such as the ADF-Nalu needs to switch from a military to an intelligence-based approach. Full Article
con Understanding Conflict in Eastern Congo (I): The Ruzizi Plain By feedproxy.google.com Published On :: Tue, 23 Jul 2013 12:43:00 GMT The Framework Agreement signed by the UN, African organisations and eleven countries and the deployment of an intervention brigade in North Kivu are positive steps, but conflicts in the Kivu region of the Democratic Republic of the Congo also require a bottom-up approach aimed at improving intercommunal relations and restoring peace at the local level. Full Article
con Imaginación para salvar República Centroafricana. Cómo actuar con rapidez y eficacia para evitar la somalización del país. By feedproxy.google.com Published On :: Sun, 24 Nov 2013 23:00:00 GMT Los conflictos en los países pequeños suelen agravarse debido a la indiferencia internacional. Sin embargo, en el caso de la República Centroafricana (RCA), el problema es ligeramente distinto. Hay una importante presencia internacional en este Estado, pero los actores principales han decidido mantenerse al margen y esperar en vez de intervenir activamente en la crisis. Full Article
con Fields of Bitterness (II): Restitution and Reconciliation in Burundi By feedproxy.google.com Published On :: Mon, 17 Feb 2014 09:35:00 GMT To avoid a revival of past ethnic tensions between Hutu and Tutsi, Burundi needs to find the right balance between land restitution and national reconciliation. Full Article
con Danger de rechute au Burundi : question foncière et consolidation de la paix By feedproxy.google.com Published On :: Wed, 19 Feb 2014 23:00:00 GMT Le Burundi est l’un des pays les plus pauvres (le taux de pauvreté atteint 67 %) et les plus petits d’Afrique (27 834 kilomètres carrés) avec l’une des plus grandes densités humaines du continent (près de 400 habitants par kilomètre carré). C’est du reste un pays profondément rural où seulement 11 % de la population réside en ville. Alors que l’accès à la terre et à la propriété est un véritable enjeu socio-économique, le Burundi fait face à de sérieux problèmes agricoles. Full Article
con The Central African Republic’s Hidden Conflict By feedproxy.google.com Published On :: Fri, 12 Dec 2014 10:42:00 GMT Full Article
con Congo: Ending the Status Quo By feedproxy.google.com Published On :: Wed, 17 Dec 2014 10:18:00 GMT A new consensus and strategy are urgently needed to tackle the numerous, brutal armed groups in eastern Congo and to save the February 2013 Peace, Security and Cooperation Framework (PSCF) in the Great Lakes region. Full Article
con Congo: Is Democratic Change Possible? By feedproxy.google.com Published On :: Tue, 05 May 2015 15:11:00 GMT With the 2016 presidential elections approaching, tension in the Democratic Republic of Congo is increasing. President Kabila is nearing the end of his second term and political manoeuvring within the government to create conditions for a third term is mobilising popular opposition, testing the country’s fragile democratisation and stability. International pressure is now vital to find a peaceful way forward. Full Article
con Burundi: How to Deconstruct Peace By feedproxy.google.com Published On :: Tue, 24 Nov 2015 08:33:00 GMT Burundi is back in the spotlight of the world’s media and the agenda of the United Nations Security Council. As recently as two years ago, the country was considered a success story in peacebuilding circles, but now the news is firmly of a negative variety. The UN is trying to prevent a new civil war in a region still haunted by the Rwandan genocide. How did success so quickly turn to failure? Full Article
con An engineered double lipid II binding motifs-containing lantibiotic displays potent and selective antimicrobial activity against E. faecium [Chemistry; Biosynthesis] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Lipid II is an essential precursor of the bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II-binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e. HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against E. faecium than nisin (1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens. Full Article
con Combination Therapy with Ibrexafungerp (formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1->3)-{beta}-D-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:36-07:00 Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA. Full Article
con Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions. Full Article
con Mutations in ArgS arginine-tRNA synthetase confer additional antibiotic-tolerance protection to ESBL-producing Burkholderia thailandensis [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Highly conserved PenI-type class A β-lactamase in pathogenic members of Burkholderia can evolve to extended-spectrum β-lactamase (ESBL), which exhibits hydrolytic activity towards third-generation cephalosporins, while losing its activity towards the original penicillin substrates. We describe three single-amino-acid-substitution mutations in the ArgS arginine-tRNA synthetase that confer extra antibiotic tolerance protection to ESBL-producing Burkholderia thailandensis. This pathway can be exploited to evade antibiotic tolerance induction in developing therapeutic measures against Burkholderia species, targeting their essential aminoacyl-tRNA synthetases. Full Article
con Towards harmonization of voriconazole CLSI and EUCAST breakpoints for Candida albicans using a validated in vitro pharmacokinetic/pharmacodynamic model [Susceptibility] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 Background. CLSI and EUCAST susceptibility breakpoints for voriconazole and C. albicans differ by one dilution (≤0.125 and ≤0.06 mg/l, respectively) whereas the epidemiological cutoff values (ECOFF/ECV) with both methodologies are the same (0.03 mg/L). We therefore determined the pharmacokinetic-pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data.Methods. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs 0.008-0.125 mg/l) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcome. Human PK were simulated and the exposure-effect relationship fAUC0-24/MIC was described for EUCAST and CLSI24/48h methods. PK/PD breakpoints were determined using the fAUC0-24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis.Results. The in vitro 24h-PD EI50 of voriconazole against C. albicans were 2.5-5 (1.5-17) fAUC/MIC. However, the 72h-PD were higher, 133 (51-347) fAUC/MIC for EUCAST and 94 (35-252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100(95-100)%, 97(72-100)%, 83(35-99)%, and 49(8-91)% and 100(97-100)%, 99(85-100)%, 91(52-100)% and 68(17-96)% for EUCAST and CLSI MICs 0.03, 0.06, 0.125, and 0.25 mg/L, respectively. Significantly, >95% PTAs were found for EUCAST/CLSI MICs ≤0.03 mg/ll. For MICs 0.06-0.125 mg/l trough levels 1-4 mg/ll would be required.Conclusion. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/L was determined for both EUCAST/CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies. Full Article
con Evaluation of the effect of contezolid (MRX-I) on the corrected QTc interval: a randomized, double-blind, placebo- and positive-controlled crossover study in healthy Chinese volunteers [Clinical Therapeutics] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections (cSSTI) caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1600 mg) dose, placebo, and oral moxifloxacin 400 mg in 4 separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time-point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (QTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for QTc were slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 hours postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 with having a lower confidence bound ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and QTcF interval with a slope of 0.227 ms per mg/L (90% CI: 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose. Full Article
con Fenbendazole controls in vitro growth, virulence potential and animal infection in the Cryptococcus model [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 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. Full Article
con A novel deletion mutation in pmrB contributes to concurrent colistin resistance in carbapenem resistant E. coli ST 405 of clinical origin [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 We report the first clinical Escherichia. coli strain EC3000 with concomitant chromosomal colistin and carbapenem resistance. A novel in-frame deletion, 6-11(RPISLR), in pmrB contributing to colistin resistance was verified using recombinant DNA techniques. Although decreased fitness compared to the wild-type (WT) strain or EC3000 revertant (chromosomal replacement of WT pmrB in EC3000), a portion of serially passaged EC3000 strains preserving colistin resistance without selective pressure raises the concern for further spread. Full Article
con 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] By aac.asm.org Published On :: 2020-04-13T08:15:31-07:00 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. Full Article
con Population pharmacokinetics of piperacillin following continuous infusion in critically ill patients: Impact of renal function on target attainment [Clinical Therapeutics] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n=196) were assessed in 78 critically ill patients following continuous infusion of piperacillin/tazobactam (ratio 8:1). The initial dose of 8, 12 or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L), and the following PK/PD targets were evaluated: 100% fT>1xMIC and 100% fT>4xMIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into non-renal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT>1xMIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT>4xMIC. Probability of target attainment for a simulated cohort of patients showed, that increasing the daily dose by 4 g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT>4xMIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a CI regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations. Full Article
con Species Distribution and Comparison between EUCAST and Gradient Concentration Strips Methods for Antifungal Susceptibility Testing of 112 Aspergillus Section Nigri Isolates [Susceptibility] By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 Aspergillus niger, the third species responsible for invasive aspergillosis has been considered as a homogeneous species until DNA-based identification uncovered many cryptic species. These species have been recently reclassified into the Aspergillus section Nigri. However little is yet known among the section Nigri about the species distribution and the antifungal susceptibility pattern of each cryptic species. A total of 112 clinical isolates collected from 5 teaching hospitals in France and phenotypically identified as A. niger were analyzed. Identification to the species level was carried out by nucleotide sequence analysis. The Minimum Inhibitory Concentrations (MICs) of itraconazole, voriconazole, posaconazole, isavuconazole and amphotericin B were determined by both the EUCAST and gradient concentration strips methods. Aspergillus tubingensis (n=51, 45.5%) and A. welwitschiae (n=50, 44.6%) were the most common species while A. niger accounted for only 6.3% (n=7). The MICs of azoles drugs were higher for A. tubingensis than for A. welwitschiae. The MIC of amphotericin B was 2 mg/L or less for all isolates. Importantly, MICs determined by EUCAST showed no correlation with those determined by gradient concentration strips methods, these latter being lower than the former (Spearman's rank correlation tests ranging - depending on the antifungal agent - from 0.01 to 0.25; p>0.4). In conclusion, A. niger should be considered as a minority species in the section Nigri. The differences in MICs between species for different azoles underline the importance of accurate identification. Significant divergences in the determination of MIC between EUCAST and gradient concentration strips methods require further investigation. Full Article
con Concurrent local delivery of diflunisal limits bone destruction but fails to improve systemic vancomycin efficacy during Staphylococcus aureus osteomyelitis [Clinical Therapeutics] By aac.asm.org Published On :: 2020-04-27T08:14:57-07:00 Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathologic bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard of care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis, and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal in vitro and in vivo. Similarly, locally-delivered diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of sub-therapeutic vancomycin. However, we also found that the resorbable polyurethane foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard of care antibiotic therapy for S. aureus osteomyelitis, but also highlight potential pitfalls encountered with local drug delivery. Full Article
con Anidulafungin and Micafungin concentrations in Cerebrospinal Fluid and in Cerebral Cortex [Pharmacology] By aac.asm.org Published On :: 2020-04-27T08:14:56-07:00 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. Full Article
con Optimal dose or optimal exposure? Consideration for linezolid in tuberculosis treatment [Letters] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Exploring different ways of minimising linezolid toxicity without compromising efficacy is a major quest in the treatment of drug resistant tuberculosis (TB).... Full Article
con Focusing the lens on the CAMERA concepts: Early combination {beta}-lactam and vancomycin therapy in methicillin-resistant Staphylococcus aureus bacteremia [Minireviews] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy. Full Article
con Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs [Susceptibility] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 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. Full Article
con Clinically relevant epithelial lining fluid concentrations of meropenem with ciprofloxacin provide synergistic killing and resistance suppression of hypermutable Pseudomonas aeruginosa in a dynamic biofilm model [Pharmacology] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MICciprofloxacin 0.25 mg/L, MICmeropenem 2 mg/L) and CW44 (MICciprofloxacin 0.5 mg/L, MICmeropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log10 CFU/mL) and biofilm (>8log10 CFU/cm2) bacteria at 120h (MICciprofloxacin up to 8 mg/L, MICmeropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log10 CFU/mL and ≤6log10 CFU/cm2 at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains. Full Article
con Reply to Kim et al., "Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment" [Author Reply] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 We thank Kim and colleagues for their interest in our study.... Full Article
con The Best Parental Control Software for 2020 By www.pcmag.com Published On :: Parenting styles run the gamut and so do the features in parental control and monitoring utilities. We've tested the top hardware- and software-based services to help you choose the right one for your family. Full Article
con Fin24.com | Gold falls as moves to reopen economies erode appetite for havens By www.fin24.com Published On :: Tue, 28 Apr 2020 11:57:28 +0200 The precious metal eased for a third day after US equities hit the highest in almost seven weeks as states including Florida took steps toward easing restrictions. Full Article
con Fin24.com | Local bourse firms as global economies gear for partial reopening By www.fin24.com Published On :: Tue, 28 Apr 2020 17:54:10 +0200 Global markets rallied on the back of optimism that most governments were gearing up to at least partially reopen their economies following lockdowns to prevent the spread of the coronavirus. Full Article
con Fin24.com | JSE erases earlier gains as global economy exhibits more strain By www.fin24.com Published On :: Thu, 30 Apr 2020 18:14:24 +0200 The local bourse had managed to open firmer following a rally in Asian stocks in earlier trading. Full Article
con Fin24.com | Markets wrap | JSE retreats as global markets fret over economic growth By www.fin24.com Published On :: Mon, 04 May 2020 18:55:42 +0200 Deep losses were recorded across most European benchmarks except the FTSE 100 which managed to trade relatively flat on the day. Full Article
con Fin24.com | Oil rises for a fifth day with output cuts easing glut concern By www.fin24.com Published On :: Tue, 05 May 2020 09:15:12 +0200 Oil was headed for the longest run of daily gains in more than nine months on signs the worst of the supply glut may be over as production cuts start to take effect. Full Article
con Fin24.com | Oil set for second weekly gain with market starting to rebalance By www.fin24.com Published On :: Fri, 08 May 2020 10:08:03 +0200 Oil headed for its first back-to-back weekly gain since February as output cuts from the biggest producers and a nascent recovery in demand began to rebalance a market awash with crude. Full Article
con Trends in Regionalization of Emergency Care for Common Pediatric Conditions By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND: For children who cannot be discharged from the emergency department, definitive care has become less frequent at most hospitals. It is uncertain whether this is true for common conditions that do not require specialty care. We sought to determine how the likelihood of definitive care has changed for 3 common pediatric conditions: asthma, croup, and gastroenteritis. METHODS: We used the Nationwide Emergency Department Sample database to study children <18 years old presenting to emergency departments in the United States from 2008 to 2016 with a primary diagnosis of asthma, croup, or gastroenteritis, excluding critically ill patients. The primary outcome was referral rate: the number of patients transferred among all patients who could not be discharged. Analyses were stratified by quartile of annual pediatric volume. We used logistic regression to determine if changes over time in demographics or comorbidities could account for referral rate changes. RESULTS: Referral rates increased for each condition in all volume quartiles. Referral rates were greatest in the lowest pediatric volume quartile. Referral rates in the lowest pediatric volume quartile increased for asthma (13.6% per year; 95% confidence interval [CI] 5.6%–22.2%), croup (14.8% per year; 95% CI 2.6%–28.3%), and gastroenteritis (16.4% per year; 95% CI 3.5%–31.0%). Changes over time in patient age, sex, comorbidities, weekend presentation, payer mix, urban-rural location of presentation, or area income did not account for these findings. CONCLUSIONS: Increasing referral rates over time suggest decreasing provision of definitive care and regionalization of inpatient care for 3 common, generally straightforward conditions. Full Article
con Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8–18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of –21 (95% confidence interval [CI]: –16 to –27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, –2 [95% CI: –13 to 6]; 10 mg melatonin, 4 [95% CI: –7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS. Full Article
con Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ~27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables. METHODS: We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule (n = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 (n = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots. RESULTS: With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities. CONCLUSIONS: In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model’s ability to predict mortality in a population of patients with prenatally diagnosed CDH. Full Article
con Continuous Albuterol With Benzalkonium in Children Hospitalized With Severe Asthma By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND AND OBJECTIVES: The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations. METHODS: We performed a retrospective cohort study comparing the clinical outcomes of patients <18 years of age receiving continuous nebulized albuterol with and without BAC. For the primary end point (duration of continuous albuterol nebulization), we compared the 2 groups with Kaplan-Meier estimate of survival curves, conducted a log-rank test of difference, and adjusted for baseline characteristics using multivariable Cox regression. A P value <.05 was considered significant. RESULTS: A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared to 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001). CONCLUSIONS: BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization. Full Article
con Seed grants jump-start 47 interdisciplinary teams to conduct COVID-19 research By news.psu.edu Published On :: Tue, 14 Apr 2020 19:29 -0400 With speed and ingenuity, more than 100 researchers across Penn State are shifting their research programs to address the COVID-19 crisis, thanks to funding from a seed grant initiative led by the Huck Institutes of the Life Sciences. In total, the initiative awarded $2.25 million to 47 teams of researchers from three campuses, 10 colleges and more than 25 departments. Full Article
con Penn State Health resumes construction to convert space to outpatient care By news.psu.edu Published On :: Mon, 20 Apr 2020 14:50 -0400 Penn State Health today resumed construction of Penn State Health Cocoa Outpatient Center, an expansion of medical services at the former CocoaPlex Center location. Full Article
con COVID-19 response at Penn State propelled by interdisciplinary connections By news.psu.edu Published On :: Tue, 21 Apr 2020 16:32 -0400 MASC has successfully designed and delivered critical equipment and supplies needed to protect health care workers and patients during the COVID-19 pandemic. Full Article
con New decontamination protocol permits reuse of N95 respirators By news.psu.edu Published On :: Wed, 22 Apr 2020 17:00 -0400 A new protocol using aerosolized hydrogen peroxide to decontaminate N95 respirators could allow them to be safely reused in hospital settings. The protocol, optimized by a team of Penn State researchers, inactivates viruses without deforming or damaging the respirator and could help hospitals overcome the current respirator shortage due to the COVID-19 pandemic. Full Article
con Fin24.com | Credit ombud rakes in millions for consumers By www.fin24.com Published On :: Sun, 26 Mar 2017 08:52:40 +0200 Are you unhappy with your credit provider? Have you been given more debt than you can afford to pay back? Help is at hand, and it’s just an SMS away. Full Article
con Fin24.com | Debit order fraud: Consumers 'frustrated' and 'annoyed' with banks By www.fin24.com Published On :: Mon, 19 Nov 2018 21:58:33 +0200 Fin24 users speak of their frustrations with banks, calling for a crackdown on debit order fraud that sees payments they didn't authorise being deducted from their bank accounts each month. Full Article
con Fin24.com | 3 'practicalities' to consider before investing in property in Africa – expert By www.fin24.com Published On :: Sun, 10 Nov 2019 16:45:17 +0200 Africa can be a challenging place to do business and property investment is not exempt from some, often unique, challenges, says a Nedbank expert. Full Article
con Maintaining community connections, one game at a time By news.psu.edu Published On :: Wed, 08 Apr 2020 14:07 -0400 Penn State Greater Allegheny student Katarina Shields wanted to help her fellow students seek creative ways to stay connected, make new friends and reduce stress during the remote learning period. The junior IST major developed “Virtual Game Night," a place to game for students attending all Penn State campuses, through the local gamer app Discord. The first event will be held April 18. Full Article
con Penn Staters stock shelves, continue to serve students at campus pantries By news.psu.edu Published On :: Tue, 07 Apr 2020 09:39 -0400 Penn Staters across the Commonwealth are embodying the “We Are” spirit by keeping campus food pantries open and shelves stocked to continue to serve students in need during the coronavirus pandemic. Full Article
con Virtual services keeping Hazleton students, campus connected during crisis By news.psu.edu Published On :: Fri, 10 Apr 2020 11:54 -0400 Penn State Hazleton’s Student Services and Engagement team is continuing to forge personal connections with students while operating under the restrictions in the virtual environment created by the COVID-19 crisis. Full Article
con A Conservative Agenda for School Board Members By feedproxy.google.com Published On :: Tue, 17 Mar 2020 00:00:00 +0000 School boards are well positioned to push back against so much of the influences of the "progressive" left on our schools and our society, write Michael J. Petrilli and Chester E. Finn Jr. Full Article School+boards