Typical Bacterial Pathogens Research Articles

Enterococci may not present the pollution of most enteric pathogenic bacteria in recreational seawaters of Xinghai bathing Beach, China

Abstract Many un-developed countries select fecal indicator bacteria (FIB) based on the recommendation of the U.S. EPA, or WHO criteria. To prove its applicability in China, FIB, human markers, and 15 typical bacterial pathogens were assessed using both culture dependent and independent methods (PCR, gene chip, and quantitative PCR) in Xinghai bathing beach of China. In most cases, enterococcus can indicate the pollution phenomenon of the main pathogenic bacteria (Staphylococcus aureus, Aeromonas caviae and Streptococcus faecalis), while only correlated with human Bacteroides and Staphylococcus aureus, which all suggested that the use of enterococci may not accurately assess the risk of most enteric pathogenic bacteria. Therefore, periodic surveying of human specific Bacteroides is strongly recommended, the monitoring of the most prevalent enteric pathogen, Aeromonas caviae, and the autochthonous pathogen, Vibrio parahaemolyticus should also be taken into consideration in the routine monitoring to protect bathers health.

703. In Vitro Activity of Lefamulin Against Bacterial Pathogens Causing Community-Acquired Bacterial Pneumonia (CABP): SENTRY Surveillance 2017–2018 Results From the United States (US)

BackgroundLefamulin (LEF), a novel pleuromutilin protein synthesis inhibitor in development for use as an empiric IV and oral monotherapy for CABP, recently demonstrated safety and efficacy in two phase 3 trials in adults with CABP (PORT II–V). LEF IV or IV/oral (5–7 days; 10 days for methicillin-resistant Staphylococcus aureus [MRSA]) and LEF oral (5 days) were noninferior to MOX IV or IV/oral (7 days; 10 days for MRSA) and MOX oral (7 days) in patients with CABP caused by the most prevalent typical and atypical bacterial pathogens. This study investigated the in vitro activity of LEF and comparators against bacterial respiratory pathogens collected in the United States in 2017 and 2018.MethodsAs part of the SENTRY Surveillance Programme, isolates (n = 2299, 1/patient) were collected from 39 medical centers in the United States from patients with community-acquired respiratory tract infections (1812/2299 [78.8%]) and pneumonia in hospitalized patients (487/2299 [21.2%]). LEF and comparators were tested by broth microdilution and CLSI (2019) breakpoints were applied.ResultsLEF demonstrated potent antibacterial activity against all pathogens tested and was unaffected by resistance to other antibiotic classes (table). Streptococcus pneumoniae isolates were largely susceptible ( >80%) to most comparators; however, 45.6% and 20.4% were resistant (R) to macrolides and tetracycline, respectively. LEF exhibited a MIC50/90 of 0.12/0.25 mg/L for S. pneumoniae, including all R subsets. Among S. aureus isolates, and particularly MRSA, resistance to macrolides was high (48.5% and 81.2% R, respectively). LEF showed a MIC50/90 of 0.06/0.12 mg/L for S. aureus, including all R subsets. Haemophilus influenzae isolates were susceptible to all comparators except for ampicillin (31.4% R) and trimethoprim-sulfamethoxazole (35.3% R). LEF displayed a MIC50/90 of 0.5/2 mg/L for H. influenzae isolates. Moraxella catarrhalis isolates, which were largely β-lactamase positive (98%), were susceptible to all comparators.ConclusionLEF displayed potent in vitro activity against contemporary CABP pathogens collected in the United States. LEF activity was unaffected by resistance to other antibiotic classes, including fluoroquinolones, macrolides, β-lactams, and tetracyclines. Disclosures All authors: No reported disclosures.

Чувствительность изолятов возбудителей заболеваний свиней к антибактериальным препаратам

A retrospective review of antimicrobial susceptibility to the fluoroquinolones and potentiated sulfonamides of 120 isolates of the most typical porcine bacterial pathogens isolated from animals of different age groups from 2009 to 2019 at FGBI «ARRIAH» was carried out. According to the results, P. multocida, H. parasuis are highly susceptible to enrofloxacin, which can be used for empirical treatment of pasteurellosis and Glasser's disease. A. pleuropneumoniae and S. suis are also susceptible to enrofloxacin, so it can be recommended for the treatment of A. pleuropneumonia and streptococcosis. 50% of isolates of S. suis isolated from the brain tissues are susceptible to the potentiated sulfonamides, so this medication can be recommended for the treatment of streptococcosis only after susceptibility testing.

A comprehensive analysis of the microbial diversity in natural and engineered ecosystems based on high-throughput sequencing of 16S rRNA gene

Understanding microbial diversity across different ecosystems is important for discerning the mechanisms shaping the microbial community assembly. However, knowledge on differentiations of microbial diversity in various habitats especially engineered systems remains very limited. A comprehensive comparison of microbial diversity across natural and engineered environments, namely heavy metal polluted farm soil, forest, wastewater treatment plants (WWTPs), anaerobic digesters (ADs) and the Caspian Sea sediments, was made base on a collection of 115 samples from seven published 16S rRNA gene datasets generated by high-throughput sequencing. In each sample, 16,590 and 19,771 qualified sequences were detected, and they were classified into 615 to 3,162 operational taxonomic units (OTUs). The microbial communities in the engineered systems especially the AD showed relatively low alpha taxonomic and phylogenetic diversity. A total of 49 genera were present in more than 80% of the samples, accounting for 6.0% in population number and 25.6% in relative abundance (RA). The average abundance-weighted rRNA operon copy number of the communities from ADs and a food wastewater treatment plant (FW) was higher than that of others, suggesting that high loading rate of pollutants in ADs and FW resulted in relatively high abundance of r-strategists. Among 104 typical human bacterial pathogens (HBPs), 2 to 25 HBPs were detected in each sample, accounting for 0.05%–21.34% in RA. Mycobacterium phlei was widely present in 111 samples with an average RA of 0.12%. The number and RA of all the HBPs in each sample did not show an obvious ecosystem type related pattern. Results of detrended correspondence analysis (DCA) and cluster analysis showed that the microbial communities clustered based on habitat types. The communities of WWTPs and soil were very similar, falling into one cluster. For any two communities from the datasets, 75.6% of their beta nearest taxon index (βNTI) values were higher than +2 or lower than −2, suggesting that environmental conditions played an important role in shaping the microbial community assembly. Temperature and geographic locations were effective factors among all factors considered in this study.

Literature review and future strategies of childhood respiratory diseases in Korea

Thirty years have passed since the Korean Association of Pediatric Allergy and Respiratory Disease was founded. There have been great changes in the pattern of respiratory diseases in Korean children during the last 30 years with economic development in the country. Pneumonia remains the leading cause of childhood morbidity, despite advances in the prevention and management. The incidence and mortality of pneumonia caused by typical bacterial pathogens have been reduced. However, the predominance of Mycoplasma pneumoniae or virus-associated diseases is emerging, which suggests that novel diagnostic and therapeutic strategies are needed. Viral bronchiolitis is one of the most substantial health burdens for infants and young children worldwide. Although re spiratory syncytial virus is the most common pathogen, molecular diagnostic techniques have identified many other viruses includ ing human rhinovirus causing bronchiolitis. Bronchiectasis is a chronic respiratory condition characterized by chronic infection, air way inflammation, and progressive lung function decline. Research into the interactions between early life respiratory infections and development of bronchiectasis is imperative to halt the disease in its origin and improve adult outcomes. Acute respiratory dis tress syndrome (ARDS) is a severe, life-threatening lung disease with diffuse inflammatory lung injury leading to pulmonary edema and hypoxia. Although many modalities to treat ARDS have been studied, supportive therapies and lung protective ventilator sup port remains the mainstay. This review focuses on the current trends in research on these childhood respiratory diseases through lit erature review and aims to investigate the impact of Korean study results in this field. (Allergy Asthma Respir Dis 2018;6 Suppl 1:S66-76)

Bacterial Pathogens Associated with Community-acquired Pneumonia in Children Aged Below Five Years.

To determine the spectrum of bacterial pathogens causing community-acquired pneumonia in children below 5 years of age. Children aged below 5 years satisfying the WHO criteria for pneumonia, severe pneumonia or very severe pneumonia, and with the presence of lung infiltrates on chest X-ray were enrolled. Two respiratory samples, one for culture and the other for PCR analysis, and a blood sample for culture were collected from every child. Of the 180 samples processed, bacterial pathogens were detected in 64.4%. Streptococcus pneumoniae and Hemophilus influenzae were most frequently detected. The performance of PCR analysis and culture were identical for the typical bacterial pathogens; atypical pathogens were detected by PCR analysis only. S. pneumoniae and H. influenza were the most commonly detected organisms from respiratory secretions of children with community acquired pneumonia.

Perspectives on Yersinia pestis: A Model for Studying Zoonotic Pathogens.

Yersinia pestis is a typical zoonotic bacterial pathogen. The following reasons make this pathogen a model for studying zoonotic pathogens: (1) Its unique lifestyle makes Y. pestis an ideal model for studying host-vector-environment-pathogen interactions; (2) population diversity characters in Y. pestis render it a model species for studying monomorphic bacterial evolution; (3) the pathogenic features of bacteria provide us with good opportunities to study human immune responses; (4) typical animal and vector models of Y. pestis infection create opportunities for experimental studies on pathogenesis and evolution; and (5) repeated pandemics and local outbreaks provide us with clues about the infectious disease outbreaks that have occurred in human history.

Use of Antibiotics and Antimicrobial Resistance in Veterinary Medicine as Exemplified by the Swine Pathogen Streptococcus suis.

Use of antimicrobial agents in veterinary medicine is essential to control infectious diseases, thereby keeping animals healthy and animal products safe for the consumer. On the other hand, development and spread of antimicrobial resistance is of major concern for public health. Streptococcus (S.) suis reflects a typical bacterial pathogen in modern swine production due to its facultative pathogenic nature and wide spread in the pig population. Thus, in the present review we focus on certain current aspects and problems related to antimicrobial use and resistance in S. suis as a paradigm for a bacterial pathogen affecting swine husbandry worldwide. The review includes (i) general aspects of antimicrobial use and resistance in veterinary medicine with emphasis on swine, (ii) genetic resistance mechanisms of S. suis known to contribute to bacterial survival under antibiotic selection pressure, and (iii) possible other factors which may contribute to problems in antimicrobial therapy of S. suis infections, such as bacterial persister cell formation, biofilm production, and co-infections. The latter shows that we hardly understand the complexity of factors affecting the success of antimicrobial treatment of (porcine) infectious diseases and underlines the need for further research in this field.

A novel termini analysis theory using HTS data alone for the identification of Enterococcus phage EF4-like genome termini.

BackgroundEnterococcus faecalis and Enterococcus faecium are typical enterococcal bacterial pathogens. Antibiotic resistance means that the identification of novel E. faecalis and E. faecium phages against antibiotic-resistant Enterococcus have an important impact on public health. In this study, the E. faecalis phage IME-EF4, E. faecium phage IME-EFm1, and both their hosts were antibiotic resistant. To characterize the genome termini of these two phages, a termini analysis theory was developed to provide a wealth of terminal sequence information directly, using only high-throughput sequencing (HTS) read frequency statistics.ResultsThe complete genome sequences of phages IME-EF4 and IME-EFm1 were determined, and our termini analysis theory was used to determine the genome termini of these two phages. Results showed 9 bp 3′ protruding cohesive ends in both IME-EF4 and IME-EFm1 genomes by analyzing frequencies of HTS reads. For the positive strands of their genomes, the 9 nt 3′ protruding cohesive ends are 5′-TCATCACCG-3′ (IME-EF4) and 5′-GGGTCAGCG-3′ (IME-EFm1). Further experiments confirmed these results. These experiments included mega-primer polymerase chain reaction sequencing, terminal run-off sequencing, and adaptor ligation followed by run-off sequencing.ConclusionUsing this termini analysis theory, the termini of two newly isolated antibiotic-resistant Enterococcus phages, IME-EF4 and IME-EFm1, were identified as the byproduct of HTS. Molecular biology experiments confirmed the identification. Because it does not require time-consuming wet lab termini analysis experiments, the termini analysis theory is a fast and easy means of identifying phage DNA genome termini using HTS read frequency statistics alone. It may aid understanding of phage DNA packaging.

Ectopic Expression of a Proteinase Inhibitor I4 (MtPiI4) Gene from Medicago truncatula Confers Plant Resistance to Pseudomonas syringae pv. Tomato DC3000

Proteinase inhibitors (PIs) play an important role in plant responses to biotic and environmental stimuli, but little is known about the role of PIs in mediating plant immune responses to microbial infection. In this study, a gene named proteinase inhibitor I4 (MtPiI4) was isolated from Medicago truncatula and characterized as a serpin family gene with a typically conserved DUF716 domain. MtPiI4 was differentially expressed in seed, root, leaf, stem and flower tissues. Expression of MtPiI4 was induced by inoculation with a typical bacterial pathogen Pseudomonas syringae pv. tomato DC3000 strain (Pst DC3000). It was also up-regulated by methyl jasmonate (MeJA) treatment. To identify its function in regulating plant immunity against Pst DC3000, we constructed transgenic Arabidopsis plants over-expressing MtPiI4. Compared to wild type, 35S::MtPiI4 plants showed enhanced resistance to Pst DC3000. Expression of JA biosynthetic and responsive genes such as LOX2, PDF1.2, and VSP1 was depressed in 35S::MtPiI4 plants as compared to wild type, suggesting that the JA signaling response was attenuated in 35S::MtPiI4 plants upon Pst DC3000 exposure. Furthermore, over-expression of MtPiI4 led to up-regulation of NPR1 (nonexpressor of pathogenesis-related gene 1—a negative regulator of JA signaling) and down-regulation of MAPK4 (mitogen-activated protein kinase4—a positive regulator of JA signaling). These results indicate that MtPiI4 regulation of plant resistance to Pst DC3000 is involved in the JA signaling transduction pathway.

Detection of Pneumonia Associated Pathogens Using a Prototype Multiplexed Pneumonia Test in Hospitalized Patients with Severe Pneumonia

Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods – particularly in patients with prior antibiotic treatment – and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time.Trial RegistrationDeutsches Register Klinischer Studien (DRKS) DRKS00005684

Emerging cystic fibrosis pathogens and the microbiome

Cystic fibrosis (CF) respiratory infection is characterised by the presence of typical human bacterial pathogens such as Pseudomonas aeruginosa, Haemophilus influenzae and Staphylococcus aureus. Less typical pathogens such as Burkholderia, Stenotrophomonas, Achromobacter, Pandorea and Ralstonia have emerged as problematic infections which are largely unique to people with CF. Using molecular methods, two groups of anaerobic bacteria Prevotella species and the Streptococcus milleri group have also recently been shown to be highly prevalent in CF sputum. Collectively, the diversity of microorganisms present in respiratory specimens has been designated the CF microbiome. The challenges posed by emerging CF pathogens and a microbiome-based view of CF infection are discussed in terms of their impact on clinical outcome, diagnosis and therapy.

Nasopharyngeal Microbiota in Healthy Children and Pneumonia Patients

Our study is the first to compare the nasopharyngeal microbiota of pediatric pneumonia patients and control children by 454 pyrosequencing. A distinct microbiota was associated with different pneumonia etiologies. Viral pneumonia was associated with a high abundance of the operational taxonomic unit (OTU) corresponding to Moraxella lacunata. Patients with nonviral pneumonia showed high abundances of OTUs of three typical bacterial pathogens, Streptococcus pneumoniae complex, Haemophilus influenzae complex, and Moraxella catarrhalis. Patients classified as having no definitive etiology harbored microbiota particularly enriched in the H. influenzae complex. We did not observe a commensal taxon specifically associated with health. The microbiota of the healthy nasopharynx was more diverse and contained a wider range of less abundant taxa.

Prognostic value of severity indicators of nursing-home-acquired pneumonia versus community-acquired pneumonia in elderly patients

BackgroundThe credibility of prognostic indicators in nursing-home-acquired pneumonia (NHAP) is not clear. We previously reported a simple prognostic indicator in community-acquired pneumonia (CAP): blood urea nitrogen to serum albumin (B/A) ratio. This retrospective study investigated the prognostic value of severity indicators in NHAP versus CAP in elderly patients.MethodsPatients aged ≥65 years and hospitalized because of NHAP or CAP within the previous 3 years were enrolled. Demographics, coexisting illnesses, laboratory and microbiological findings, and severity scores (confusion, urea, respiratory rate, blood pressure, and age ≥65 [CURB-65] scale; age, dehydration, respiratory failure, orientation disturbance, and pressure [A-DROP] scale; and pneumonia severity index [PSI]) were retrieved from medical records. The primary outcome was mortality within 28 days of admission.ResultsIn total, 138 NHAP and 307 CAP patients were enrolled. Mortality was higher in NHAP (18.1%) than in CAP (4.6%) (P<0.001). Patients with NHAP were older and had lower functional status and a higher rate of do-not-resuscitate orders, heart failure, and cerebrovascular diseases. The NHAP patients more frequently had typical bacterial pathogens. Using the receiver-operating characteristics curve for predicting mortality, the area under the curve in NHAP was 0.70 for the A-DROP scale, 0.69 for the CURB-65 scale, 0.67 for the PSI class, and 0.65 for the B/A ratio. The area under the curve in CAP was 0.73 for the A-DROP scale, 0.76 for the CURB-65 scale, 0.81 for the PSI class, and 0.83 for the B/A ratio.ConclusionPatient mortality was greater in NHAP than in CAP. Patient characteristics, coexisting illnesses, and detected pathogens differed greatly between NHAP and CAP. The existing severity indicators had less prognostic value for NHAP than for CAP.

Snp-search: simple processing, manipulation and searching of SNPs from high-throughput sequencing

BackgroundA typical bacterial pathogen genome mapping project can identify thousands of single nucleotide polymorphisms (SNP). Interpreting SNP data is complex and it is difficult to conceptualise the data contained within the large flat files that are the typical output from most SNP calling algorithms. One solution to this problem is to construct a database that can be queried using simple commands so that SNP interrogation and output is both easy and comprehensible.ResultsHere we present snp-search, a tool that manages SNP data and allows for manipulation and searching of SNP data. After creation of a SNP database from a VCF file, snp-search can be used to convert the selected SNP data into FASTA sequences, construct phylogenies, look for unique SNPs, and output contextual information about each SNP. The FASTA output from snp-search is particularly useful for the generation of robust phylogenetic trees that are based on SNP differences across the conserved positions in whole genomes. Queries can be designed to answer critical genomic questions such as the association of SNPs with particular phenotypes.Conclusionssnp-search is a tool that manages SNP data and outputs useful information which can be used to test important biological hypotheses.

Medikamentöse Therapie der infektiösen Diarrhö

Diarrheal diseases are among the most common diseases worldwide. In this review the current treatment recommendations for acute (Part 1) and chronic (Part 2) infectious diarrhea are summarized and typical enteropathogens are discussed. The second part of the article describes chronic diarrhea, its related pathogens and treatment. In contrast to acute diarrhea which is mainly caused by viral and typical bacterial pathogens, chronic diarrhea has mainly non-infectious origins. Protozoal pathogens, such as Giardia lamblia and Entamoeba histolytica in particular are found and more rarely bacterial pathogens, such as Tropheryma whipplei. Opportunistic pathogens cause diarrhea in immunocompromised patients, such as in HIV patients. In these patients cytomegalovirus (CMV) colitis or infections with Cryptosporidium spp., Cyclospora cayetanensis, Isospora belli or microsporidia have to be considered. Besides targeted specific antimicrobial therapy, anti-retroviral drugs improving the underlying immunosuppression and thus the reconstitution of the adaptive immune response remain a cornerstone of the treatment in HIV-positive patients.

Etiology of Community-acquired Pneumonia in Hospitalized Children in Northern Taiwan

Pneumonia is the leading reason for hospitalization in children. The heptavalent pneumococcal conjugate vaccine was introduced in Taiwan in October 2005. There has been no comprehensive study of the etiology of childhood community-acquired pneumonia (CAP), either in the pre- or postpneumococcal conjugate vaccine era, in Taiwan. From August 2001 to July 2002, consecutive children admitted to a teaching hospital with radiologically confirmed CAP were prospectively enrolled. The following were considered indicative of infection when positive: blood or pleural effusion bacterial culture or urinary Streptococcus pneumoniae antigen test (Binax NOW), direct immunofluorescent antigen test for Chlamydia species and viruses, virus isolation and identification and viral, mycoplasmal or chlamydial serologic tests. A total of 209 children were included, and 102 children (48.8%) were male. Patients' ages ranged from 7 months to 16 years with a median of 4 years and 3 months. The combined tests identified at least 1 etiologic agent in 85.6% of all cases, including typical bacterial pathogens in 88 cases (42.1%; 86 S. pneumoniae, 1 methicillin-resistant Staphylococcus aureus and 1 Mycobacterium tuberculosis), Mycoplasma pneumoniae in 77 cases (36.8%), Chlamydia species in 24 cases (11.5%), viral etiology in 86 cases (41.1%) and mixed viral-bacterial infections in 69 cases (33%). Children with S. pneumoniae infection were significantly younger than those with Mycoplasma pneumoniae infection (P = 0.0055) or unknown etiology (P = 0.0140). S. pneumoniae, Mycoplasma pneumoniae and viruses were equally common etiologic agents of childhood CAP in Taiwan. Frequent coinfection increased the difficulty of both predicting the responsible organisms and choosing empiric antibiotics for the management of pediatric CAP.

Summary of Ceftaroline Fosamil Clinical Trial Studies and Clinical Safety

In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.

Structural and functional characterization of CATH_BRALE, the defense molecule in the ancient salmonoid, Brachymystax lenok

Thick-lipped lenok, Brachymystax lenok is one of the ancient fish species in China and northeast Asia countries. Due to the overfishing, the population of lenok has been declined significantly. Cathelicidins are innate immune effectors that possess both bactericidal activities and immunomodulatory functions. This report identifies and characterizes the salmonoid cathelicidin (CATH_BRALE) from this ancient fish. It consists of open reading frame (ORF) of 886 bp encoding the putative peptide of 199 amino acids. Sequence alignment with other representative salmonid cathelicidins displayed two distinctive features of current lenok cathelicidin: high level of arginine, resulting in high positive charge and glycine residues, which is significantly different from most acknowledged types of cathelicidins; and the six-amino-acid tandem repeated sequence of RPGGGS detected in a variable number of copies among fish cathelicidins, suggesting the existence of a genetically unstable region similar to that found in some mammalian cathelicidins. Expression of CATH_BRALE is predominantly found in gill, with lower levels in the gastrointestinal tract and spleen. The homology modeled structure of CATH_BRALE exhibits structural features of antiparallel β-sheets flanked by α-helices that are representative of small cationic cathelicidin family peptides. CATH_BRALE possesses much stronger antimicrobial activity against gram-negative bacteria than that of the human ortholog, LL-37. The growth of two typical fish bacterial pathogens, gram-negative bacterium of Aeromonas salmonicida and Aeromonas hydrophila was substantially inhibited by synthetic CATH_BRALE, with both MICs as low as 9.38 μM.

Day 4 Clinical Response of Ceftaroline Fosamil Versus Ceftriaxone for Community-Acquired Bacterial Pneumonia

In Brief Background Ceftaroline (active metabolite of ceftaroline fosamil) was efficacious in 2 phase 3 community-acquired pneumonia (CAP) trials (FOCUS 1 and 2) using clinical cure rates at the test-of-cure visit. Recent US Food and Drug Administration guidelines for design of noninferiority CAP trials recommend evaluation of clinical response at 72 to 96 hours after initiating therapy (day 4) rather than traditional test of cure. The day 4 end point may be more clinically relevant with respect to hospital discharge and oral stepdown therapy. Methods A retrospective integrated analysis of the FOCUS trials was conducted in 309 adult patients with moderate to severe CAP and at least 1 proven typical bacterial pathogen at baseline. Patients received intravenous ceftaroline fosamil (600 mg) every 12 hours or ceftriaxone (1 g) every 24 hours for 5 to 7 days. Clinical response at day 4 included normalization of signs (fever, white blood cell count, blood pressure, respiratory rate) and improvement in respiratory symptoms (cough, dyspnea, sputum production, chest pain). Results Day 4 clinical response rates were 69.5% (107/154) for ceftaroline and 59.4% (92/155) for ceftriaxone (difference 10.1%; 95% confidence interval, −0.6% to 20.6%). In individual studies, absolute treatment differences of 14.1% (FOCUS 1) and 6.8% (FOCUS 2) favoring ceftaroline were observed. Clinical response rates at day 4 associated with the most common pathogens, Streptococcus pneumoniae (ceftaroline, 54/74 [73.0%]; ceftriaxone, 42/75 [56.0%]) and Staphylococcus aureus (ceftaroline, 14/24 [58.3%]; ceftriaxone, 17/31 [54.8%]), were numerically higher for ceftaroline. Conclusions Ceftaroline appears to provide clinical benefit over ceftriaxone at day 4 for treatment of community-acquired bacterial pneumonia. Ceftaroline was previously shown noninferior to ceftriaxone in clinical cure rate at the traditional test-of-cure visit in two pivotal Phase 3CABP trials (FOCUS 1 and FOCUS 2); however, clinical response at day 4 among subjects with a proven pathogen may be a more appropriate endpoint for such FDA registration trials. In this analysis from the FOCUS trials, ceftaroline had a nurmerically higher clinical response rate than ceftriaxone at day 4 (69.5% vs. 59.4%, respectively).