The attempt by Congo and Rwanda to end the deadly conflict in eastern Congo by a secret presidential deal and military force is failing and must be changed fundamentally by the Kinshasa government and the international community.

Despite three agreements between the rebels and the government, peace is still elusive in eastern Democratic Republic of Congo. The Kivus need regional dialogue and a clear, fair repatriation plan, argues Thierry Vircoulon at the International Crisis Group.

A la veille de l’entrée en vigueur le 15 avril de l’obligation de rendre publique l’origine des minerais pour les grandes compagnies basées aux Etats-Unis, ICG a effectué une mission au Nord Kivu afin d’évaluer les différentes stratégies de lutte contre les minerais des conflits et leur impact sur le terrain.

As legislation requiring large U.S. companies to disclose the origins of the minerals they use is meant to come into force this year, Crisis Group sent a mission to North Kivu to assess the different strategies used to fight conflict minerals and their impact in the field.

The technical preparations for the presidential and legislative elections scheduled on 28 November and the beginning of the electoral campaign in the East of Congo have generated suspicion that risks developing into a crisis of confidence in the whole electoral process.

Die Zentralafrikanische Republik trägt einen nüchternen, doch gerade in jüngster Zeit allzu treffenden Namen. Denn sie scheint tatsächlich zum Zentrum oder zumindest zum Ballungsraum all der vielfältigen Probleme geworden zu sein, unter denen der Kontinent seit langem leidet und von denen sich aber mittlerweile viele afrikanische Länder befreien können. Da sind die Konflikte um den Abbau wertvoller Ressourcen, besonders von Diamanten. Aus einer kleinen Elite ist eine Reihe unfähiger politischer Führer hervorgegangen. Es mehren sich Konflikte zwischen nomadischen Stämmen und der sesshaften Bevölkerung, was Ursachen auch im Klimawandel hat, und zu neuen Konkurrenzen zwischen den beiden Bevölkerungsteilen führt. Aus Rivalitäten zwischen ethnischen Gemeinschaften erwuchsen blutige Kämpfe und neue Feindschaften: die altbekannte, berüchtigte Kombination von historischen Altlasten und politischem Opportunismus schuf Konflikte auf der Grundlage religiöser Gruppenzugehörigkeit, wie jetzt zwischen Christen und Muslimen. Die schwierige Lage hat dem Land international eine erhöhte, aber nicht immer nützliche Aufmerksamkeit verschafft: des Nachbarlands Tschad, der Zentralafrikanischen Wirtschaftsgemeinschaft, von der Afrikanischen Union und von den Vereinten Nationen. Außerdem von multilateralen und Nicht­regierungs­organisationen, von der ehemaligen Kolonialmacht Frankreich und von weiteren internationalen Akteuren wie den Vereinigten Staaten, Südafrika, der Europäischen Union und unlängst auch von Deutschland. In kürzester Zeit ist die Zentralafrikanische Republik zu trauriger Berühmtheit gelangt. Doch so stark die Aufmerksamkeit auch gestiegen ist, so viel Wissen ist über dieses Land nachzuholen – Wissen, das man braucht, um vernünftig zu handeln. Mein Kollege Thibaud Lesueur und ich haben in den vergangenen drei Jahren viele Monate in der Zen­tralafrikanischen Republik verbracht. Wir konnten vor Ort beobachten, wie der Staat erst allmählich, dann rasant auseinanderfiel. Wir verfolgten, wie ein französisches Expeditionskorps, die Operation Sangaris, den afrikanischen Truppen zu Hilfe kam, um noch eine Spur von Ordnung vor dem drohenden Chaos zu retten, wie es nur eine gut ausgestattete Berufsarmee kann. Wir sahen, wie aus der einst stabilen Bevölkerung eine Generation plündernder Krieger hervorging. Und wir erlebten, wie aus Bangui, der Hauptstadt am Ubangi Fluss mit 750 000 Einwohnern, ein Schauplatz von Lynchjustiz wurde, was 90 Prozent der muslimischen Bevölkerung in die Flucht trieb. Ein Opfer dieser Selbstjustiz wurde auch Jean-Emmanuel Ndjaroua, ein Mitglied des nationalen Übergangsrats. Er machte im Februar den verhängnisvollen Fehler, öffentlich zu Toleranz und Frieden aufzurufen, und wurde auf offener Straße erschossen. Die große Herausforderung besteht nun darin zu verhindern, dass aus Tausenden viele Zehntausende Tote werden. Noch besteht Hoffnung, dass ein solches Blutvergießen vermieden werden kann. Die neue Regierung unter Präsidentin Catherine Samba-Panza hat Potenzial, und die von der Zentralafrikanischen Wirtschaftsgemeinschaft zügig entsandten – aber zu schwachen – Truppen hat man durch eine hoffentlich zielgerichtetere Mission unter Führung der ­Afrikanischen Union ersetzt. Unter der Federführung Frankreichs hat der UN-Sicherheitsrat am 10. April eine Resolution zum Einsatz einer neuen UN-Friedensmission beschlossen. Diese sieht vor, dass die Truppen der Afrikanischen Union im September 2014 unter das Kommando der Vereinten Nationen gestellt werden und die Zahl der internationalen Friedenssoldaten nahezu verdoppelt wird. Die Europäische Union hat derweil für Mai die Stationierung einer „Überbrückungsmission“ angekündigt. Diese Einsatzverpflichtungen sind mehr als bloße Versprechen, aber sie bleiben dennoch hinter dem zurück, was man als entschiedenes Handeln bezeichnen würde. Was also ist zu tun? Vertrauen zwischen den Religionen Es ist entscheidend, zwischen den Bevölkerungsteilen wieder Vertrauen aufzubauen. Der Imam, der Erzbischof und Vertreter der anderen christlichen Kirchen in Bangui arbeiten bereits eng zusammen, aber ihre Anstrengungen sind bisher auf die Hauptstadt begrenzt – aus der fast alle Muslime geflohen sind. Ein interkonfessioneller Dialog und eine Versöhnungskampagne müssen an der Basis beginnen und mithilfe der Übergangsregierung und ihrer internationalen Unterstützer auf die Provinzen ausgeweitet werden. Die Bausteine dafür existieren bereits – im Westen des Landes beispielsweise sind die verbliebenen muslimischen Flüchtlinge mehrheitlich bei christlichen Missionen untergekommen. Erinnern wir uns: Religiöse Gruppenzugehörigkeiten sind noch nicht lange eine Konfliktursache in der Zentralafrikanischen Republik. Zwei frühere Präsidenten, Bokassa und Patassé, konvertierten zum Islam, und diverse ethnische Gruppen setzen sich aus Christen und Muslimen zusammen. Bis heute sind im vorwiegend muslimischen nordöstlichen Distrikt, in dem sich auch viele aus Bangui vertriebene Krieger aufhalten, die Christen des Saraa-Stammes (zu dem auch viele Muslime gehören) nicht angegriffen worden, und auch nicht das zahlenmäßig große christliche Volk der Banda in Bria. In Bangui entstand als Reaktion auf die Morde eine Nichtregierungsorganisation, Les Frères Centrafricains, die über Aufkleber an Taxis zur Versöhnung aufrief. Junge Christen taten sich zusammen, um gemeinsam Moscheen vor Angriffen zu beschützen. Ankurbelung der Wirtschaft Die Wirtschaft des Landes muss neu belebt werden. Die wichtigsten Exportgüter des Landes sind Holz und Diamanten – und der Handel mit diesen Gütern setzt Sicherheit voraus. Von den fünf privaten Firmen, die bislang die Holzindustrie dominierten, arbeiten nur noch zwei. Ein Angestellter vor Ort erzählte uns, wie sein Betrieb zuerst Anfang 2013 von der Präsidentengarde durchsucht wurde, daraufhin von den muslimisch dominierten Séléka-Rebellen und schließlich von der prochristlichen Anti-Balaka-Bewegung, und wie alle von ihnen Fahrzeuge stahlen. Der Diamantenhandel ist ebenfalls in eine schwere Schieflage geraten, denn die Händler waren fast ausschließlich Muslime. Mit Beginn des Gegenaufstands der Anti-Balaka-Milizen flohen sie aus den Städten, ihre Geschäfte wurden geplündert. Auf lange Sicht muss der Staat seine Kontrolle über die Diamantenfelder wiederherstellen und für die Sicherheit der Händler sowie die Transparenz der Handelswege sorgen. Dazu müssen Zivilbeamte und Polizei eingesetzt werden. Zum jetzigen Zeitpunkt können allein Friedenstruppen dafür sorgen, dass der Handel wieder sicher aufgenommen werden kann. Der bedeutendste nicht exportorientierte Wirtschaftszweig des Landes ist die landwirtschaftliche Selbstversorgung. Auch sie leidet unter der problematischen Sicherheitslage, besonders dort, wo Nomaden und Farmer in Konkurrenz um Land aufeinandertreffen. Die Wanderungen der nomadischen Hirten aus dem Tschad im Norden in die Zentralafrikanische Republik müssen dringend unter eine von allen Seiten ausgehandelte Regelung gestellt werden, von der Art, wie sie in Niger und Tschad bereits erfolgreich ist. In den größeren Städten des Landes muss indessen Arbeit für die ­dortigen Kämpfer geschaffen werden. In der Hauptstadt Bangui herrscht Gewalt. Dort wird neben einer verbesserten Sicherheitslage dringend mehr Beschäftigung für die Jugendlichen gebraucht, damit diese eine Alternative zu den Milizen finden, die ihnen bisher „Arbeit“ verschafft haben. Die Hauptstadt und weitere Landesteile leiden unter infrastrukturellen Problemen, die durch beschäftigungsintensive Maßnahmen zu lösen wären, für die ungelernte und angelernte Arbeitskräfte eingesetzt werden können. Sicherheit Um die Sicherheit im Land wiederherzustellen, muss die Afrikanische Union mit den Vereinten Nationen zusammenarbeiten. Die neue UN-­Resolution will aus den 6000 AU-Soldaten UN-Blauhelme machen, aber Streit um Zuständigkeiten könnte die Umsetzung erschweren. Auch Frankreich und die Europäische Union müssen eine Grundlage zur Zusammenarbeit finden. Hier wird vermutlich Deutschland eine Schlüsselrolle spielen. Die deutsche Koalitionsregierung hat den Versuch gestartet, die deutsch-französische ­Zusammenarbeit neu zu beleben, gerade auf außenpolitischem Gebiet. Im April sprach Bundeskanzlerin Angela Merkel von Frankreich und Deutschland als „Motor“ der Beziehungen zwischen der EU und Afrika, und Frankreichs Staatspräsident François Hollande unterstrich die „besondere Freundschaft“ beider Länder. Deutschland hat sich in bisher nicht gekannter Weise verpflichtet, in Mali und der Zentralafrikanischen Republik militärische Hilfen bereitzustellen – dies soll jeweils in enger Abstimmung mit Frankreich geschehen. Hinzu kommt eine bedeutsame entwicklungspolitische Unterstützung. Diese französisch-deutsche Führung hat aus einem vagen Plan ein handfestes Unternehmen gemacht; mittlerweile haben sich Estland, Finnland, Frankreich, Deutschland, Italien, Lettland, Litauen, Luxemburg, Polen, Portugal, Schweden, Spanien, Großbritannien sowie Georgien zur Mission bekannt. Der Großteil der Truppen wird von Estland, Frankreich, Georgien, Polen und Spanien gestellt. Deutschland legt seinen Schwerpunkt auf den strategischen Lufttransport, Großbritannien kümmert sich um logistische Fragen und Italien um die Technik. Selbst wenn die EU-Überbrückungsmission Realität wird und sich die Beziehungen zur Afrikanischen Union verbessern, wird es für den ­Sicherheitsrat der Vereinten Nationen und die UN-Organisationen sehr schwierig werden, erfolgreich eine Blauhelmtruppe in der Zentralafrikanischen Republik zu etablieren. Die Vereinten Nationen müssen die Frage beantworten, welche ihrer Mitgliedstaaten die Truppen stellen. Dabei sollten sie Tschad außen vor lassen. Das Land ist schon zu sehr in die Angelegenheiten der Zentralafrikanischen Republik verstrickt und hat seine Friedensmission Anfang April aufgekündigt, nachdem tschadische Soldaten beschuldigt wurden, für den Tod von Zivilisten verantwortlich zu sein. Die Befehlsgewalt über die Truppen wird zwar formal im September von der AU auf die UN übergehen. Aber praktisch wird die UN-Mission wahrscheinlich nicht vor Ende des Jahres in vollem Umfang anlaufen. Dabei erfordert die Entwaffnung der Milizen schnelles Handeln: Die verbliebene muslimische Bevölkerung in Bangui hat sich in der PK5 genannten muslimischen Enklave bewaffnet, und auch die Anti-Balaka-Milizen haben bisher keine Probleme, in der Hauptstadt an Waffen zu kommen – obwohl Tausende französische und afrikanische Friedenssoldaten durch die Straßen der Hauptstadt patrouillieren. Der muslimische Bürgermeister von Banguis drittem Bezirk, zu dem auch PK5 gehört, sagte im März: „Wenn wir PK5 verlassen, um in ein benachbartes Gebiet zu gehen, werden wir noch am gleichen Tag getötet.“ Die Franzosen verpassten im Dezember und Januar die Gelegenheit zur weitgehenden Entwaffnung der Séléka-Truppen, als diese noch in vier Lagern festgehalten wurden. Eine UN-Mission wird es mit der Entwaffnung nicht leichter haben als die Franzosen. Der Plan der Vereinten Nationen sieht vor, dass zuerst Soldaten stationiert werden, dann eine funktionierende Polizei aufgebaut wird, und dann ein Justizsystem. Die größten Schwachstellen sind die Soldaten und Geld: Von beiden gibt es viel zu wenig. Ein strategischer Fahrplan Die Übergangsregierung der Zentralafrikanischen Republik wie auch die internationale Gemeinschaft brauchen dringend einen Plan. Auf nationaler Ebene hatte es Ende vergangenen Jahres einen gegeben – einen mangelhaften, aber immerhin etwas. Die neue Regierung unter Catherine Samba-Panza ist die dritte Regierung innerhalb eines Jahres, aber sie ist vielversprechend. Die meisten wichtigen Ministerien sind mit Technokraten statt mit Parteigenossen besetzt. Präsidentin Samba-Panza hat bereits zu Beginn ihrer Amtszeit die Bedeutung von Justiz und Versöhnung betont. In einem Gespräch im April mit Crisis-Group-Präsidentin Louise Arbour bestätigte sie dies und unterstrich, dass ihr Land auf die Hilfe ausländischer Richter angewiesen sei, um ein effektives Justizsystem aufzubauen. All dies gibt Anlass zur Hoffnung. Was man jedoch für die erweiterte internationale Intervention braucht, sind eine kohärente Führung, strategisches Denken sowie einen gemeinsamen Stabilisierungsplan, der es der Übergangsregierung ermöglicht, mittel- und langfristige Prioritäten zu setzen. Die internationale Kontaktgruppe sowie der jüngste Bericht des UN-Generalsekretärs betonen zu Recht, wie wichtig es ist, die Sicherheit im Land wiederherzustellen, die staatlichen Dienste zu reaktivieren und Wahlen vorzubereiten. Aber sie gehen nicht auf die tieferliegenden Probleme ein, insbesondere nicht auf den wirtschaftlichen Niedergang, der die Hauptursache für den Staatszerfall ist. Jemand – beispielsweise die EU oder Mitglieder der internationalen Kontaktgruppe – sollte dafür sorgen, dass die bisherigen Entwicklungs- und Aufbauprogramme überprüft werden. Eine solche Überprüfung ist aus zwei Gründen wichtig: erstens um zu verstehen, was bei der Reform des Sicherheitssektors, bei der Entwaffnung und Demobilisierung von Kämpfern sowie den Reintegrationsmaßnahmen schiefgelaufen ist. Und zweitens, um eine Stabilisierungsstrategie zu entwerfen, die die Wirtschaft in den Mittelpunkt stellt und das bietet, was zurzeit fehlt: neue Ideen für alte Probleme sowie eine langfristige Roadmap für die nationalen und internationalen Akteure. Auf diese Weise hätte man eine Grundlage für die angedachte Geberkonferenz im späteren Jahresverlauf und es wäre einfacher, eine sinnvolle Aufgabenverteilung unter den internationalen Akteuren zu verabreden. Ein solcher Rahmen ist unverzichtbar, um der neuen Regierung ein Fundament für ihre Herkulesaufgabe zu geben, nämlich aus dem Land wieder einen funktionierenden Staat zu machen und die Wirtschaft wieder aufzubauen, die Grundlage eines jeden zukunftsfähigen Staates. Bei dieser Überprüfung sollte man keine Zeit verlieren. Denn wie schon in der Vergangenheit könnte das ­Interesse der in­ternationalen Gemeinschaft an der Zentralafrikanischen Republik wieder schwinden. Gerade dies war in der Vergangenheit ein Hauptgrund dafür, dass sich die Probleme des Landes so häufig wiederholten. Geschieht das nicht, könnte es passieren, dass die geplante Überbrückungsmission schon in einem Jahr nur noch eine vage Erinnerung ist, dass der Fall Zentralafrikanische Republik Frankreich aufgebürdet wird, dass die afrikanischen Staaten gerade genug Mittel haben, um einzuschreiten, aber zu wenig, um irgendetwas langfristig zu stabilisieren, und dass die Übergangsregierung dann nur noch damit beschäftigt ist, die Fassade eines Staates aufrechtzuerhalten.

The U.S. Education Department says the states need more evidence to use the popular admissions test to measure high school achievement.

The U.S. tests its students more than most nations, but is the deluge of data providing the information schools need?

Continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes including the pfdhps A581G and A613S/T mutations was high at delivery among post-SP treatment isolates (18.2%) compared to those of first-antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP); 6.1%; p = 0.03). Regarding the pfk13 marker gene, two non-synonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast-Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance on additional mutations associated with increased SP resistance as well as emergence of resistance against artemesinin derivatives.

β-lactam resistance in Staphylococcus aureus limits treatment options. Stp1 and Stk1, a serine-threonine phosphatase and kinase respectively, mediate serine-threonine kinase (STK) signaling. Loss of function point mutations in stp1 were detected among laboratory passaged, β-lactam resistant S. aureus strains lacking mecA and blaZ, the major determinants of β-lactam resistance in the bacteria. Loss of Stp1 function facilitates β-lactam resistance of the bacteria.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US-FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), β-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC_50/90, 0.5/1 mg/L; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [lsqb]MRSA[rsqb]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [lsqb]ESBL[rsqb]-phenotype). A total of 74.4% of P. aeruginosa, 100% of β-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/L. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium. Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016–2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for the potential ABSSSI indication.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in the virology, epidemiology and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing towards the development of treatment for COVID-19. Recent studies have revealed many attractive threptic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.

Objectives: Carbapenemase-producing Enterobacterales and specifically KPC-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp) is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than if caused by carbapenem-susceptible isolates.

Study design and methods: This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent Intensive Care Unit in a university hospital (> 40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression).

Results. We analyze 69 cases of K. pneumoniae VAP of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/mL). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [lsqb]HR[rsqb] 1.25; 95% CI: 0.46–3.41). Adequate targeted therapy (HR 0.03; 95% CI: <0.01–0.23) was associated with all-cause mortality.

Conclussion. Assuming the limitations due to the available sample size, the prognosis of VAP caused by KPC-Kp is similar to VAPs caused by carbapenem-susceptible K. pneumoniae when appropriate treatment is used.

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.

KBP-7072 is a semi-synthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens including multidrug resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (IV) administration of single and multiple doses were investigated in animal models including during fed and fasted states and also evaluated the protein binding and excretion characteristics. In Sprague-Dawley (SD) rats, Beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after administration of single oral and IV and multiple oral doses. Oral bioavailability ranged from 12% to 32%. Mean T_max ranged from 0.5 to 4 hours, and mean half-life ranged from approximately 6 to 11 hours. Administration of oral doses in the fed state resulted in a marked reduction in C_max and AUC compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5 mg/kg oral dose of KBP-7072 in SD rats, cumulative excretion in feces was 64% and in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single and multiple ascending dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once daily oral and IV administration in clinical studies.

Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually for the last few years. Although studies on mechanisms of polymyxin are expanding, system-wide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapt to colistin (polymyxin E) pressure, we carried out proteomic analysis of Klebsiella pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in Klebsiella pneumoniae involving several pathways, including (i) gluconeogenesis and TCA cycle; (ii) arginine biosynthesis; (iii) porphyrin and chlorophyll metabolism; and (iv) enterobactin biosynthesis. Interestingly, decreased abundance of class A β-lactamases including TEM, SHV-11, SHV-4 were observed in cells treated with colistin. Moreover, we also present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant Klebsiella pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of Klebsiella pneumoniae ATCC BAA 2146, showed missense mutation in crrB. The crrB mutant Ci, which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose (L-Ara4N) and palmitoylation, showed striking increases of CrrAB, PmrAB, PhoPQ, ArnBCADT and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediate colistin resistance, which may further offer valuable information to manage polymyxin resistance.

Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.

Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing area under the concentration time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime 100 mg/kg q8h i.v. had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam half-maximal effect was induced with enmetazobactam 4.71 mg/kg q8h i.v. The dose fractionation study suggest both fT>threshold and fAUC:MIC are potentially relevant PD indices. The AUC_ELF:AUC_plasma for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT>MIC of ≥20% and enmetazobactam fT>2 mg/L of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

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.

The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was followed to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen's proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches.

The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3^rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.

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 bla_CTX-M genes were identified, with bla_CTX-M-65, bla_CTX-M-123, bla_CTX-M-14, bla_CTX-M-79, and bla_CTX-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.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicentre trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90ms mean QTc-prolongation per 100ng/mL increase in piperaquine concentration. The effect of piperaquine on absolute QTc-interval estimated a mean maximum QTc-interval of 456ms (EC₅₀=209ng/mL). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98-2.46% risk of having QTc-prolongation > 60ms in all treatment settings. Although piperaquine administration resulted in QTc-prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern.

Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate.

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.

One of the reasons for the lengthy tuberculosis (TB) treatment is the difficult to treat non-multiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our pre-clinical drug development pipeline. In most available dormancy models it takes a long time to create a dormant state and it is difficult to identify and quantify this non-multiplying condition.

The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes non-multiplying after 10 days of streptomycin starvation, but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetic model to assess the difference in the activity of isoniazid, rifampicin, moxifloxacin and bedaquiline against log-phase growth compared to the non-multiplying M. tuberculosis subpopulation by CFU counting including a novel AUC-based approach as well as time-to-positivity (TTP) measurements.

We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampicin and high dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value as it identifies a specific mycobacterial subpopulation that is non-culturable on solid media.

In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

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.

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 (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 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 (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem 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.

Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects.

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.

According to a recent forensic analysis, a WhatsApp account from the Saudi Crown Prince Mohammed bin Salman allegedly sent government-bought spyware to Bezos' phone in May 2018, two UN human rights experts said on Wednesday.

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In number 10 in our countdown, I tried to offer a few thoughts to funders as they embraced new agendas and looked to avoid repeating yesterday's missteps.

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.

Rachel Hooker, who will graduate May 9 with a 3.99 GPA in supply chain and information systems, has been selected as the Smeal College of Business’ spring 2020 supply chain and information systems student marshal.

MASC has successfully designed and delivered critical equipment and supplies needed to protect health care workers and patients during the COVID-19 pandemic.

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.

Lehigh Valley's Practical Nursing Program has moved to the Shadow Health Digital Clinical Experience so students can continue clinical rotations through virtual simulations.

Although complications caused by the coronavirus pandemic have temporarily halted the Fulbright Specialist Program, Nichola D. Gutgold looks forward to officially joining the Roster after the U.S. Department of State determines that projects can resume.

SIM-swap fraud complaints seem to be on the rise with a growing number of victims coming forward to share their dreadful experiences. Vodacom offers some helpful tips.

This list looks at seven top South African products disrupting the traditional way of doing finance.