Antimicrobial and Antibiofilm Activities of the Fungal Metabolites Isolated from the Marine Endophytes Epicoccum nigrum M13 and Alternaria alternata 13A.

Epicotripeptin (1), a new cyclic tripeptide along with four known cyclic dipeptides (2-5) and one acetamide derivative (6) were isolated from seagrass-associated endophytic fungus Epicoccum nigrum M13 recovered from the Red Sea. Additionally, two new compounds, cyclodidepsipeptide phragamide A (7) and trioxobutanamide derivative phragamide B (8), together with eight known compounds (9-16), were isolated from plant-derived endophyte Alternaria alternata 13A collected from a saline lake of Wadi El Natrun depression in the Sahara Desert. The structures of the isolated compounds were determined based on the 1D and 2D NMR spectroscopic data, HRESIMS data, and a comparison with the reported literature. The absolute configurations of 1 and 7 were established by advanced Marfey's and Mosher's ester analyses. The antimicrobial screening indicated that seven of the tested compounds exhibited considerable (MIC range of 2.5-5 µg/mL) to moderate (10-20 µg/mL) antibacterial effect against the tested Gram-positive strains and moderate to weak (10-30 µg/mL) antibacterial effect against Gram-negative strains. Most of the compounds exhibited weak or no activity against the tested Gram-negative strains. On the other hand, four of the tested compounds showed considerable antibiofilm effects against biofilm forming Gram-positive and Gram-negative strains.

Prevalence and Molecular Characterization of Extended Spectrum ß-Lactamase, Plasmid-Mediated Quinolone Resistance, and Carbapenemase-Producing Gram-Negative Bacilli in Burkina Faso.

The spreading of carbapenemase-producing gram-negative bacilli (GNB) must be considered as an "urgent" threat. The aim of this study was to determine the prevalence of extended spectrum ß-lactamase (ESBL), plasmid-mediated quinolone resistance (PMQR), and carbapenemase-producing GNB and to characterize the supporting genes in GNB specimens isolated from patients and healthy volunteers in Burkina Faso. From April to June 2016, carbapenemase-producing GNB screening was performed in 1,230 consecutive clinical specimens, and 158 fecal samples from inpatients and healthy volunteers without digestive pathology at Souro Sanou University Hospital, Bobo Dioulasso. Strains were identified by matrix-assisted laser desorption ionization-time of flight and antimicrobial susceptibility was tested with the disk diffusion method on Müller-Hinton agar. The presence of carbapenemase, ESBL, and PMQR genes was assessed by multiplex PCR. The molecular epidemiological study was performed using multilocus sequence typing analysis. From the 1,230 clinical samples, 443 GNB strains were isolated among which 4 (0.9%) were carbapenemase-producing isolates (Escherichia coli, n = 1; Acinetobacter baumannii, n = 3). Among the 158 fecal samples tested for carbapenemase-producing Enterobacteriaceae carriage, 13 (8.2%) were carbapenemase-producing isolates (E. coli, n = 4; Klebsiella pneumoniae, n = 6; A. baumannii, n = 2; Acinetobacter nosocomialis, n = 1; Acinetobacter bereziniae, n = 1). The strains from the two groups were resistant to broad-spectrum cephalosporins (100% for both), gentamicin (100% and 64.3%), levofloxacin (100% and 85.7%), and to amikacin (0% and 7.1%). The carbapenemase-encoding genes blaNDM-1, blaOxa-58, blaOxa-181, and blaVIM-2 were detected in clinical and in fecal samples. The majority (10/11) of the enterobacterial strains carried also blaCTX-M-15. The majority of the strains belonged to ST692 for E. coli, to ST147 for K. pneumoniae and to ST2 for A. baumannii. This study confirms the presence of carbapenemase-producing GNB in samples from patients and healthy volunteers. More effective active surveillance activities are needed.

In Vitro Activity of Plazomicin Compared to Amikacin, Gentamicin, and Tobramycin against Multidrug-Resistant Aerobic Gram-Negative Bacilli.

The worldwide spread of multidrug-resistant Enterobacterales is a serious threat to public health. Here, we compared the MICs of plazomicin, amikacin, gentamicin, and tobramycin against 303 multinational multidrug-resistant Gram-negative bacilli. We followed Clinical and Laboratory Standards Institute (CLSI) guidelines and applied CLSI breakpoints as well as those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for amikacin, gentamicin, and tobramycin and of the U.S. Food and Drug Administration for plazomicin. Overall, the highest percentage of susceptible isolates (80.2%) was demonstrated for plazomicin, which had the lowest MIC50 (1 µg/ml) of the aminoglycosides studied. Of the 42 isolates resistant to plazomicin, 34 had MICs of ≥128 µg/ml, with 33 of the 34 having MICs of >128 µg/ml for amikacin, gentamicin, and tobramycin. Among the 42 blaNDM-positive isolates, 35.7% were plazomicin susceptible, with the percentage of isolates susceptible to amikacin being 38.1% or 35.7% when applying the CLSI or EUCAST breakpoint, respectively. The 20 blaOXA-48-like-positive isolates showed 50.0% susceptibility to plazomicin. Among 35 isolates with blaCTX-M as their only characterized resistance mechanism, 68.6% were plazomicin susceptible, while the percentage susceptible to amikacin was 74.3% or 62.9% when applying the CLSI or EUCAST breakpoint, respectively. Among the 117 blaKPC-positive isolates, 94.9% were susceptible to plazomicin, whereas when the CLSI and EUCAST breakpoints were applied, 43.6% and 25.6%, respectively, were susceptible to amikacin; 56.4% and 44.4%, respectively, were susceptible to gentamicin; and 5.1% and 4.3%, respectively, were susceptible to tobramycin.

Sarecycline: a narrow spectrum tetracycline for the treatment of moderate-to-severe acne vulgaris.

Sarecycline is a novel, narrow-spectrum, once-daily tetracycline-derived oral antibiotic that is FDA-approved in the US to be taken with or without food for moderate-to-severe acne vulgaris for ages 9 years of age and older. Sarecycline possesses anti-inflammatory properties and potent activity against Gram-positive bacteria, including activity against multiple strains of Cutibacterium acnes, while exhibiting minimal activity against enteric aerobic Gram-negative bacteria. Unlike many acne studies, sarecycline was investigated for chest and back acne. Significant reduction in inflammatory lesions was seen at week 12 at 1.5 mg/kg/day of sarecycline, with statistically significant improvement seen as early as week 3. No reports of phototoxicity, dizziness, pseudotumor cerebri or lupus but 1.2% nausea and 1.2% vaginal candidiasis was reported in the pivotal Phase III studies.

Synthesis and Structure-Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens.

Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gram-negative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the AuI complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.

Norfloxacin salts of carboxylic acids curtail planktonic and biofilm mode of growth in ESKAPE pathogens.

AIMS: To enhance the antimicrobial and antibiofilm activity of norfloxacin against the planktonic and biofilm mode of growth in ESKAPE pathogens using chemically modified norfloxacin salts. METHODS AND RESULTS: Antimicrobial testing, synergy testing and time-kill curve analysis were performed to evaluate antibacterial effect of norfloxacin carboxylic acid salts against ESKAPE pathogens. In vivo efficacy to reduce bacterial bioburden was evaluated in zebrafish infection model. Crystal violet assay and live-dead staining were performed to discern antibiofilm effect. Membrane permeability, integrity and molecular docking studies were carried out to ascertain the mechanism of action. The carboxylic acid salts, relative to parent molecule norfloxacin, displayed two- to fourfold reduction in minimum inhibitory concentration against Staphylococcus aureus and Pseudomonas aeruginosa, in addition to displaying potent bacteriostatic effect against certain members of ESKAPE pathogens. In vivo treatments revealed that norfloxacin tartrate (SRIN2) reduced MRSA bioburden by greater than 1 log fold relative to parent molecule in the muscle tissue. In silico docking with gyrA of S. aureus showed increased affinity of SRIN2 towards DNA gyrase. The enhanced antibacterial effect of norfloxacin salts could be partially accounted by altered membrane permeability in S. aureus and perturbed membrane integrity in P. aeruginosa. Antibiofilm studies revealed that SRIN2 (norfloxacin tartrate) and SRIN3 (norfloxacin benzoate) exerted potent antibiofilm effect particularly against Gram-negative ESKAPE pathogens. The impaired colonization of both S. aureus and P. aeruginosa due to improved norfloxacin salts was further supported by live-dead imaging. CONCLUSION: Norfloxacin carboxylic acid salts can act as potential alternatives in terms of drug resensitization and reuse. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study shows that carboxylic acid salts of norfloxacin could be effectively employed to treat both planktonic- and biofilm-based infections caused by select members of ESKAPE pathogens.

Nuevas cefalosporinas / New cephalosporins

Resumen La resistencia bacteriana se ha incrementado en América Latina y el mundo, por lo que se requiere investigación y creación de nuevos antimicrobianos capaces de erradicar a los microorganismos resistentes. Se realizó una revisión acerca de nuevas cefalosporinas y sus combinaciones con un inhibidor de β-lactamasas, recopilando información de espectro, farmacocinética, farmacodinamia y estudios clínicos de las indicaciones actuales para ceftarolina, ceftazidima/avibactam y ceftolozano/tazobactam. La primera, con actividad frente a Staphylococcus aureus y Staphylococcus coagulasa negativa sensibles y resistentes a meticilina, y contra Streptococcus pneumoniae resistente a penicilina; por lo tanto, aprobada para uso en neumonía bacteriana adquirida en comunidad e infecciones bacterianas de piel y tejidos blandos. Entre las nuevas combinaciones, ceftazidima, una cefalosporina de tercera generación con actividad anti-pseudomonas, asociada a avibactam, un inhibidor de β-lactamasas, ha demostrado efectividad en el tratamiento de infecciones abdominales e infecciones urinarias complicadas. Por último, la combinación ceftolozano y el conocido tazobactam presenta acción comparable a la combinación de ceftazidima y avibactam por su actividad contra bacilos gramnegativos y, en combinación con metronidazol no presenta inferioridad a meropenem en infecciones intra-abdominales. Se presentan los estudios clínicos y las potenciales indicaciones y escenarios de uso de estas cefalosporinas.

Bacterial resistance has increased in Latin America and the world, making research and creation of new antimicrobials capable of eradicating resistant microorganisms essential. A review of new cephalosporins and their combinations with a beta-lactamase inhibitor was conducted, collecting data on the spectrum, pharmacokinetic and pharmacodynamic profile and clinical studies of the current indications for ceftaroline, and the combinations ceftazidime with avibactam and ceftolozane with tazobactam. The first one has activity against methicillin-resistant Staphylococcus aureus and coagulase negative Staphylococcus (SCoN) and against penicillin-resistant Streptococcus pneumoniae, therefore approved for use in community-acquired pneumonia and acute bacterial skin and skin structure infections. Among the new combinations, ceftazidime, a third generation cephalosporin with antipseudomonal activity, associated with avibactam, a betalactamase inhibitor, has been shown to be effective in the treatment of abdominal infections and complicated urinary infections. Finally, the combination of ceftolozane with tazobactam has comparable action to ceftazidime with avibactam due to its activity against Gram negative rods, and in combination with metronidazole they do not present inferiority to meropenem in intra-abdominal infections. The clinical studies are presented, as well as the potential indications and clinical scenarios for their use of this cephalosporins.

Sepsis neonatal tardía nosocomial en una unidad de terapia intensiva: agentes etiológicos y localización más frecuente / Late onset neonatal sepsis in an intensive care neonatal unit: etiological agents and most frequent location

Resumen Introducción: La sepsis neonatal nosocomial (SNN) es una entidad frecuente en las unidades de cuidados intensivos, donde causa una gran morbimortalidad. La ubicación más frecuente es bacteriemia, seguido de neumonía asociada a ventilador mecánico y vía urinaria. Objetivo: Conocer la etiología y localización más frecuente de la infección en el SNN. Población, Material y Métodos: Estudio retrospectivo, de prevalencias de enero a diciembre de 2015, realizado en la Unidad de Cuidados Intensivos Neonatal de un hospital de alta complejidad. Fueron incluidos todos los neonatos. Resultados: Se incluyeron 70 pacientes, se analizaron 88 episodios de SNN. La localización más frecuente fue sangre 40% de los casos, seguido de orina y aspirado traqueal en 25% respectivamente. Los microorganismos más frecuentemente aislados fueron Staphylococcus de diferentes tipos, seguido de Acinetobacter baumannii multi-resistente. La afectación del SNC fue de 32%. La mortalidad fue de 34%, elevándose a 50% ante un segundo episodio de SNN. La terapia empírica de elección fue vancomicina y carbapenem, ajustándose a antibiograma. Conclusiones: La infección más frecuente fue la bacteremia, principalmente por Staphylococcus resistentes a meticilina. La afectación del SNC fue elevada, lo mismo que la mortalidad.

Introduction: Nosocomial neonatal sepsis (NNS) is a frequent entity in intensive care units, causing great morbidity and mortality. The most frequent site is blood, followed by lungs and urine. Objective: To know the etiology and most frequent localization of infection in the NNS. Population, Material and Methods: Cross sectional study, from January to December 2015, performed in a teaching hospital. All newborns infants were included. Results: 70 patients were included, 88 episodes of NNS were analyzed. The most frequent localization was bacteremia in 40% of cases, followed by urinary tract infection and VAP in 25% respectively. The bacteria most frequently isolated were staphylococci of different types, followed by multiresistant Acinetobacter. The CNS involvement was 32%. Mortality was 34%, rising up to 50% with a second episode of NNS. The empirical therapy of choice was vancomycin and carbapenem, adjusting to antibiogram. Conclusions: The most frequent infection was bacteremia, mainly by staphylococci resistant to methicillin. CNS involvement was elevated, as well as mortality.

Epidemiología de las infecciones urinarias asociadas a catéter y no asociadas a catéter en un hospital universitario de tercer nivel / Nosocomial urinary tract infection: an analysis beyond urinary catheterization

Resumen Introducción: Las infecciones urinarias asociadas a la atención de la salud (ITU-AAS) representan un importante problema sanitario, siendo poco conocidas sus características cuando no están asociadas a cateterización urinaria u ocurren fuera de unidades de cuidados intensivos (UCI). Objetivos: Determinar las características de los pacientes con ITU-AAS, etiología y susceptibilidad antimicrobiana de las mismas, tanto asociadas a catéter (ITU-C) como no asociadas a catéter (ITU-noC), en UCI y en sala general. Materiales y Métodos: Se realizó un estudio analítico retrospectivo de corte transversal entre 2009 y 2013 en un hospital universitario de tercer nivel. Se identificaron todos los episodios de ITU-AAS, diferenciándolas en ITU-C e ITU-noC. Resultados: Se incluyeron 253 episodios de ITU-AAS, siendo más frecuentes las ITU-C (60,9%) respecto a ITU-noC. Un 37,4% de ITU-noC y 59,7% de ITU-C ocurrieron en UCI. Los microorganismos aislados más frecuentemente fueron Escherichia coli, Klebsiella pneumoniae y Enterococcus sp. El 19% de los bacilos gramnegativos fueron productores de β-lactamasa de espectro extendido, siendo su frecuencia similar en ambos grupos. Conclusión: Las co-morbilidades de los pacientes con ITU-AAS, los agentes etiológicos responsables y sus correspondientes espectros de sensibilidad, fueron similares en los grupos de ITU-C e ITU-noC, tanto en sala general como en UCI.

Introduction: Nosocomially acquired urinary tract infections (NAUTI) represent an important public health issue, but its characteristics when they are not catheter associated (CA-UTI) or when they take place outside intensive care units (ICU) are poorly understood. Objectives: To determine the patients' characteristics, etiology and antimicrobial susceptibility of NAUTI, both CA-UTI and no CA-UTI, in general ward and ICU. Methods: We conducted a retrospective analytic cross-sectional study, between 2009 and 2013, in a third level universitary hospital. All NAUTI episodes were identified, classifying them as CA-UTI and no CA-UTI. Results: We included 253 episodes of NAUTI, being CA-UTI (60,9%) more frequent than no CA-UTI. A 37,4% of no CA-UTI and 59,7% of CA-UTI were identified in ICU. The most frequently isolated microorganisms were Escherichia coli, Klebsiella pneumoniae and Enterococcus sp. A 19% of extended spectrum betalactamase producing gram negative bacilli were found, without differences between groups. Conclusion: Patients's comorbidities, microorganisms associated to NAUTI and its antimicrobial susceptibility were similar in CA-UTI and no CA-UTI, as in general ward and ICU.

Antimycobacterial and antimalarial activities of endophytic fungi associated with the ancient and narrowly endemic neotropical plant Vellozia gigantea from Brazil

BACKGROUND Endophytic fungi, present mainly in the Ascomycota and Basidiomycota phyla, are associated with different plants and represent important producers of bioactive natural products. Brazil has a rich biodiversity of plant species, including those reported as being endemic. Among the endemic Brazilian plant species, Vellozia gigantea (Velloziaceae) is threatened by extinction and is a promising target to recover endophytic fungi. OBJECTIVE The present study focused on bioprospecting of bioactive compounds of the endophytic fungi associated with V. gigantea, an endemic, ancient, and endangered plant species that occurs only in the rupestrian grasslands of Brazil. METHODS The capability of 285 fungal isolates to produce antimicrobial and antimalarial activities was examined. Fungi were grown at solid-state fermentation to recover their crude extracts in dichloromethane. Bioactive extracts were analysed by chromatographic fractionation and NMR and displayed compounds with antimicrobial, antimycobacterial, and antimalarial activities. FINDINGS Five fungi produced antimicrobial and antimalarial compounds. Extracts of Diaporthe miriciae showed antifungal, antibacterial, and antimalarial activities; Trichoderma effusum displayed selective antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare; and three Penicillium species showed antibacterial activity. D. miriciae extract contained highly functionalised secondary metabolites, yielding the compound epoxycytochalasin H with high antimalarial activity against the chloroquine-resistant strain of Plasmodium falciparum, with an IC50 approximately 3.5-fold lower than that with chloroquine. MAIN CONCLUSION Our results indicate that V. gigantea may represent a microhabitat repository hotspot of potential fungi producers of bioactive compounds and suggest that endophytic fungal communities might be an important biological component contributing to the fitness of the plants living in the rupestrian grassland.

Evaluación de test rápidos y diseño de una estrategia para la detección y caracterización de carbapenemasas en cepas de bacilos gramnegativos / Test evaluation and strategy proposal to detect and to characterize carbapenemase-producing gram negative bacilli

Resumen Introducción: La detección de bacilos gramnegativos productores de carbapenemasas es compleja, existiendo actualmente varios test disponibles. La confirmación mediante la caracterización molecular de la enzima no está disponible en todos los laboratorios del país. Objetivo: Plantear una estrategia rápida, eficiente y sencilla para la detección y confirmación de carbapenemasas en cepas de bacilos gramnegativos. Material y Métodos: Se utilizaron 39 aislados productores y ocho no productores de carbapenemasas para evaluar los test fenotípicos Carba NP, CarbAcineto NP, Blue-Carba y validar el test molecular Xpert® Carba-R directo de la colonia en comparación con RPC convencional. Resultados: La sensibilidad para Carba NP, CarbAcineto NP y Blue-Carba fue de 79,5; 87,2 y 84,6%, respectivamente; mientras que la especificidad fue de 100; 100 y 87,5%, respectivamente. La concordancia entre RPC convencional y Xpert® Carba-R fue de 100%. El límite de detección para Xpert® Carba-R fue diferente según el tipo de carbapenemasa: 40,8 ufc/reacción par KPC y NDM y 30,6 ufc/reacción para VIM. Discusión: En aislados con susceptibilidad disminuida a carbapenémicos se propone realizar un tamizaje con CarbAcineto NP, para luego caracterizar la carbapenemasa con Xpert® Carba-R y adoptar las medidas de contención específica: para cada caso.

Introduction: The detection of carbapenemase-producing gram negative bacilli is complicated, because there are available multiple options of test. The confirmation of the enzyme by molecular characterization is not available in all laboratories in our country. Objective: To propose a fast, efficient and simple strategy to detect and confirm CPB. Materials and Methods: 39 CPB isolates and 8 non-producing were used to evaluate the phenotypic test Carba NP, CarbAcineto NP and Blue-Carba, validating the test Xpert® Carba-R, to be used directly with bacterial colonies with conventional PCR. Results: The sensitivity of Carba NP, CarbAcineto NP and Blue-Carba was 79,5; 87,2 y 84,6%, respectively; and specificity was 79.5; 87.2 and 84.6%, respectively. The limit of detection of Xpert® Carba-R was different for each carbapenemasa: 40.8 ufc/reaction to KPC and NDM and 30.6 ufc/reaction to VIM. Discussion: On isolates with decreased susceptibility to carbapenems we propose to use as screening the test CarbAcineto NP, follow by Xpert®Carba-R to characterize the carbapenemase and adopt specific infection control measures.

Molecular ß-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets.

The correlation of the clinical efficacy of ceftazidime-avibactam (plus metronidazole) with that of meropenem was evaluated in subjects infected with Gram-negative isolates having characterized ß-lactam resistance mechanisms from the complicated intra-abdominal infection (cIAI) phase 3 clinical trials. Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC values of ≥2 µg/ml and Pseudomonas aeruginosa isolates with ceftazidime MIC values of ≥16 µg/ml were characterized for extended-spectrum-ß-lactamase (ESBL) content. Enterobacteriaceae and P. aeruginosa isolates with imipenem and meropenem MIC values of ≥2 and ≥8 µg/ml, respectively, were tested for carbapenemase genes. The primary efficacy endpoint was clinical cure at test of cure (TOC) among the members of the microbiologically modified intention-to-treat (mMITT) population. A total of 14.5% (56/387) and 18.8% (74/394) of patients in the ceftazidime-avibactam and meropenem arms had isolates that met the MIC screening criteria at the baseline visit, respectively. CTX-M variants alone (29.7%; 41/138) or in combination with OXA-1/30 (35.5%; 49/138), most commonly, blaCTX-M group 1 variants (79/90; 87.8%), represented the ß-lactamases most frequently observed among Enterobacteriaceae isolates. Among the patients infected with pathogens that did not meet the screening criteria, 82.2% showed clinical cure in the ceftazidime-avibactam group versus 85.9% in the meropenem group. Among patients infected with any pathogens that met the MIC screening criteria, clinical cure rates at TOC were 87.5% and 86.5% for the ceftazidime-avibactam and meropenem groups, respectively. Ceftazidime-avibactam had clinical cure rates of 92.5% to 90.5% among patients infected with ESBL- and/or carbapenemase-producing Enterobacteriaceae strains at the baseline visit, while meropenem showed rates of 84.9% to 85.4%. The ceftazidime-avibactam and meropenem groups had cure rates of 75.0% and 86.7%, respectively, among patients having any pathogens producing AmpC enzymes. The efficacy of ceftazidime-avibactam was similar to that of meropenem for treatment of cIAI caused by ESBL-producing organisms. (This study has been registered at ClinicalTrials.gov under registration no. NCT01499290 and NCT01500239.).

Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections.

Omadacycline is a first-in-class aminomethylcycline antibiotic that circumvents common tetracycline resistance mechanisms. In vitro omadacycline has potent activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus, penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus spp. It is also active against common Gram-negative aerobes, some anaerobes and atypical bacteria including Legionella spp. and Chlamydia spp. Ongoing Phase III clinical trials with omadacycline are investigating once daily doses of 100 mg intravenously followed by once-daily doses of 300 mg orally for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This paper provides an overview of the microbiology, nonclinical evaluations, clinical pharmacology and initial clinical experience with omadacycline.

Ceftazidime-Avibactam Activity against Aerobic Gram Negative Organisms Isolated from Intra-Abdominal Infections in United States Hospitals, 2012-2014.

BACKGROUND: Ceftazidime-avibactam is ceftazidime combined with the novel non-ß-lactam ß-lactamase inhibitor avibactam, which inhibits Ambler class A (e.g., extended-spectrum ß-lactamase [ESBL] and KPC), class C, and some class D enzymes. We evaluated the activity of ceftazidime-avibactam against aerobic gram negative bacteria causing intra-abdominal infections (IAI). METHODS: A total of 1,540 isolates were collected, one each from patient, with IAI in 57 United States hospitals in 2012-2014. Susceptibility testing was performed by reference broth microdilution methods, and Enterobacteriaceae isolates with an ESBL phenotype were evaluated by a microarray-based assay for the presence of genes encoding the CTX-M, TEM, SHV, KPC, NDM, and transferable AmpC enzymes. RESULTS: All Escherichia coli isolates were susceptible to ceftazidime-avibactam, whereas the susceptibility rates for meropenem, piperacillin-tazobactam, and gentamicin were 99.8%, 93.6%, and 85.5%, respectively. Among Klebsiella pneumoniae isolates, the highest ceftazidime-avibactam minimum inhibitory concentration (MIC) value was only 2 mcg/mL (MIC50/90 0.12/0.25 mcg/mL; 100% susceptible), whereas susceptibility rates to meropenem and gentamicin were 94.5% and 91.9%, respectively. The ESBL-phenotype rates among E. coli and K. pneumoniae were 15.8% and 13.3%, respectively. Overall, only one Enterobacteriaceae isolate (Enterobacter cloacae) was not susceptible to ceftazidime-avibactam and had negative results for all ß-lactamases tested. Against Pseudomonas aeruginosa, ceftazidime-avibactam (MIC50/90 2/4 mcg/mL; 97.1% susceptible) and amikacin (MIC50/90 2/8 mcg/mL; 99.0% susceptible) were the most active compounds, and ceftazidime-avibactam retained activity against many meropenem-non-susceptible (88.6% susceptible) and piperacillin-tazobactam-non-susceptible (82.9% susceptible) strains. CONCLUSION: Ceftazidime-avibactam coverage (98.7% inhibited at ≤8 mcg/mL) of intra-abdominal infection pathogens was greater than that observed for meropenem (95.7% susceptible) and piperacillin-tazobactam (88.4% susceptible).

Treatment options for extended-spectrum beta-lactamase (ESBL) and AmpC-producing bacteria.

INTRODUCTION: Extended spectrum ß-lactamases (ESBL) and AmpC ß-lactamases are increasing causes of resistance in many Gram-negative pathogens of common infections. This has led to a growing utilization of broad spectrum antibiotics, most predominately the carbapenem agents. As the prevalence of ESBL and AmpC-producing isolates and carbapenem resistance has increased, interest in effective alternatives for the management of these infections has also developed. AREAS COVERED: This article summarizes clinical literature evaluating the utility of carbapenem-sparing regimens for the treatment of ESBL and AmpC-producing Enterobacteriaceae, mainly ß-lactam-ß-lactamase inhibitor combinations and cefepime (FEP). EXPERT OPINION: Based on available data, the use of piperacillin-tazobactam (PTZ) and FEP in the treatment of ESBL-producing Enterobacteriaceae cannot be widely recommended. However, certain infections and patient characteristics may support for effective use of these alternative agents. In the treatment of infections caused by AmpC-producing Enterobacteriaceae, FEP has been shown to be a clinically useful carbapenem-sparing alternative. Carbapenems and FEP share many structurally similar characteristics in regards to susceptibility to AmpC ß-lactamases, which further create confidence in the use FEP in these situations. Patient and infection specific characteristics should be used to employ FEP optimally.

Antioxidant, antibacterial, and anti-inflammatory activities of standardized brazilin-rich Caesalpinia sappan extract.

CONTEXT: Brazilin is a major active principle of Caesalpinia sappan L. (Leguminosae or Fabaceae). For industry aspects, brazilin-rich extract (BRE) has been prepared and standardized to contain 39% w/w brazilin. BRE may have more advantages than brazilin in term of a lower-cost production process. OBJECTIVES: To investigate the antioxidant, antibacterial, and anti-inflammatory activities of BRE. MATERIAL AND METHODS: BRE was prepared by a simple one-step purification of the crude ethanol extract of C. sappan heartwood (CSE) using a Diaion® HP-20 column. The antioxidant activities were determined using three methods, including DPPH radical scavenging, reducing power, and ß-carotene bleaching assays, at concentration ranges of 1-10, 10-100, and 10-100 µg/mL, respectively. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BRE (15.6-1000 µg/mL) against Gram-positive and Gram-negative bacteria were determined by the broth microdilution method. Anti-inflammatory activity of BRE (0.1-5 µg/mL) was evaluated as anti-denaturation activity using bovine serum albumin as a substrate. RESULTS AND DISCUSSION: On the basis of ß-carotene bleaching assay, BRE showed antioxidant activity with an EC50 value of 60.5 µg/mL, which was almost equal to that of pure brazilin (52.1 µg/mL). Gram-positive bacteria were more sensitive to all tested samples than Gram-negative bacteria. BRE possessed higher antibacterial activities than CSE, but lower than brazilin. MIC/MBC values of 62.5-125/125 and 250-500/250-500 µg/mL were obtained for BRE against Gram-positive and Gram-negative bacteria, respectively. A low concentration (0.1 µg/mL) of brazilin, BRE, and CSE showed anti-inflammatory activity by inhibiting protein denaturation up to 46.8, 54.1, and 61.9%, respectively.

New polyphenols from a deep sea Spiromastix sp. Fungus, and their antibacterial activities.

Eleven new polyphenols namely spiromastols A-K (1-11) were isolated from the fermentation broth of a deep sea-derived fungus Spiromastix sp. MCCC 3A00308. Their structures were determined by extensive NMR data and mass spectroscopic analysis in association with chemical conversion. The structures are classified as diphenyl ethers, diphenyl esters and isocoumarin derivatives, while the n-propyl group in the analogues is rarely found in natural products. Compounds 1-3 exhibited potent inhibitory effects against a panel of bacterial strains, including Xanthomanes vesicatoria, Pseudomonas lachrymans, Agrobacterium tumefaciens, Ralstonia solanacearum, Bacillus thuringensis, Staphylococcus aureus and Bacillus subtilis, with minimal inhibitory concentration (MIC) values ranging from 0.25 to 4 µg/mL. The structure-activity relationships are discussed, while the polychlorinated analogues 1-3 are assumed to be a promising structural model for further development as antibacterial agents.

Biological activities and DNA interactions of Amanita ovoidea.

CONTEXT: Amanita ovoidea (Bull.) Link (Amanitaceae) is a well-known species due to its pleasant aroma and flavor since ancient times in the worldwide. This species is also known in Turkey and people consume it extensively. OBJECTIVE: To evaluate medicinal importance of A. ovoidea for human health, to explain the effect of mushroom extracts on bacterial DNA, and to find preventive role on bacterial disease. MATERIALS AND METHODS: Chloroform, acetone, and methanol extracts of A. ovoidea were tested for the antimicrobial activities against four Gram-positive bacteria, five Gram-negative bacteria, and yeast using a micro-dilution method. In addition, DNA binding, DNA cleavage activity, and restriction enzyme digestion of the methanol extract of A. ovoidea were examined at different concentrations (40.000-78.125 µg/mL). RESULTS: The highest minimum inhibitory concentration (MIC) value observed against the test micro-organisms was with the chloroform extract (MIC 19.5 µg/mL concentration) against Candida albicans. Other highest antimicrobial effects observed against the test micro-organisms were with the methanol extracts against Bacillus subtilis, Staphylococcus aureus, Listeria monocytogenes, Streptococcus pyogenes, Candida albicans, Klebsiella pneumoniae, Proteus vulgaris, and Salmonella enteritidis (MICs, 78 µg/mL concentrations). All concentrations reduced the mobility of plasmid DNA. BamHI and HindIII targeted specially to supercoils and cut them. Amanita ovoidea extract prevented cutting with HindIII by binding especially to the AA region in open circular DNA. DISCUSSION AND CONCLUSION: Present results demonstrated that A. ovoidea has excellent antimicrobial and antifungal activities by its DNA interaction activity on pBR322.

Epidemiology and antimicrobial susceptibility of Gram-negative aerobic bacteria causing intra-abdominal infections during 2010-2011.

The study for monitoring antimicrobial resistance trends (SMART) surveillance program monitors the epidemiology and trends in antibiotic resistance of intra-abdominal pathogens to currently used therapies. The current report describes such trends during 2010-2011. A total of 25,746 Gram-negative clinical isolates from intra-abdominal infections were collected and classified as hospital-associated (HA) if the hospital length of stay (LOS) at the time of specimen collection was ≥48 hours, community-associated (CA) if LOS at the time of specimen collection was <48 hours, or unknown (no designation given by participating centre). A total of 92 different species were collected of which the most common was Escherichia coli: 39% of all isolates in North America to 55% in Africa. Klebsiella pneumoniae was the second most common pathogen: 11% of all isolates from Europe to 19% of all isolates from Asia. Isolates were from multiple intra-abdominal sources of which 32% were peritoneal fluid, 20% were intra-abdominal abscesses, and 16.5% were gall bladder infections. Isolates were further classified as HA (55% of all isolates), CA (39% of all isolates), or unknown (6% of all isolates). The most active antibiotics tested were imipenem, ertapenem, amikacin, and piperacillin-tazobactam. Resistance rates to all other antibiotics tested were high. Considering the current data set and high-level resistance of intra-abdominal pathogens to various antibiotics, further monitoring of the epidemiology of intra-abdominal infections and their susceptibility to antibiotics through SMART is warranted.