Penicillin-resistant Streptococcus Research Articles

Comparative in vitro potency and kill curve activity of tedizolid and linezolid against Gram-positive bacteria isolated from Chinese hospitalized patients in 2013–2016

We compared the kill-curve activity of tedizolid and linezolid at clinically relevant (total or free plasma, lung) concentrations against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP) isolated from Chinese patients. Tedizolid had greater in vitro potency than linezolid against staphylococci, streptococci and enterococci species (tedizolid minimum inhibitory concentration (MIC) range: ≤ 0.016–0.5 µg/mL; linezolid MIC range: 0.25–2 µg/mL). In kill-curve experiments, growth of MRSA was inhibited at tedizolid concentration of 0.6 µg/mL (i.e. 4.8 × MIC; MIC = 0.125 µg/mL) and linezolid concentration of 2 µg/mL (2× MIC; MIC = 1 µg/mL). Against PRSP, tedizolid at a concentration of 0.25 µg/mL (representing its MIC) was bacteriostatic, but exerted a bactericidal effect at higher concentrations. Results were similar for linezolid, however, even at 21 µg/mL, a small proportion of organisms survived beyond 24 h. The results demonstrated the potency of tedizolid against clinical strains of Gram-positive pathogens supporting its use as a suitable alternative to linezolid in Chinese patients.

In vitro activities of Eravacycline against 336 isolates collected from 2012 to 2016 from 11 teaching hospitals in China

BackgroundIn China multidrug-resistant bacteria pose a considerable threat to public health. Antimicrobial resistance has weakened the effectiveness of many medicines widely used today. Thus, discovering new antibacterial drugs is paramount in the effort to treat emerging drug-resistant bacteria.MethodsEravacycline, tigecycline and other clinical routine antibiotics were tested by reference broth micro-dilution method against 336 different strains collected from 11 teaching hospitals in China between 2012 and 2016. These isolates included Enterobacteriaceae, non-fermentative, Staphylococcus spp., Enterococcus, and a number of fastidious organisms. The strains involved in this study possess the most important drug resistance characteristics currently known in China. Drug resistant bacteria such as those producing extended spectrum β-lactamases (ESBL) and carbapenemases (KPC-2 and NDM-1), and those exhibiting colistin resistance (mcr-1) and tigecycline were included in this study. Additionally, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), β-lactamase positive Haemophilus influenzae, and penicillin resistant Streptococcus pneumoniae (PRSP) were also included.ResultsEravacycline exhibited good efficacy against all the strains tested, especially for organisms with ESBLs, carbapenemases, and mcr-1 gene compared with tigecycline and other antibiotics tested. The MIC values of eravacycline against carbapenemase producing Enterobacteriaceae and OXA-23-producing A. baumannii were much lower than the MIC values of other antibiotics. MRSA, VRE, β-lactamase positive Haemophilus influenza, and PRSP were sensitive to eravacycline in every strain tested. Furthermore, in most strains tested, the MICs of eravacycline were two to four-fold lower than the MICs of tigecycline.ConclusionsEravacycline has shown potent antibacterial activity against common and clinically important antibiotic-resistant pathogens. The MIC distribution of eravacycline was generally lower than that of tigecycline which demonstrates that this new drug is potentially more effective than the existing medications.

Activity of ceftaroline against pathogens associated with community-acquired pneumonia collected as part of the AWARE surveillance program, 2015–2016

We report Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) program data for ceftaroline and comparators against isolates collected from identified lower respiratory tract sources in 2015 and 2016. MICs and susceptibility were determined using CLSI broth microdilution methodology and EUCAST breakpoints. Ceftaroline susceptibility among penicillin-resistant Streptococcus pneumoniae (MIC≥4 mg/L [nonmeningitis breakpoint]) ranged from 77.4% (Asia, 72/93) to 100% (Oceania, 16/16; Latin America, 15/15). Among MRSA, ceftaroline susceptibility ranged from 72.3% (Asia, 553/765) to 100% (Oceania, 39/39). Among β-lactamase–positive Haemophilus influenzae, ceftaroline susceptibility ranged from 69.2% (Asia, 36/52) to 100% (Oceania, 19/19). Susceptibility to ceftaroline against non–ESBL-producing Klebsiella pneumoniae was between 91.4% (Europe, 659/721) and 100% (Oceania, 55/55) and for Escherichia coli between 85.7% (Africa/Middle East, 42/49) and 92.1% (Oceania, 35/38). Ceftaroline is not active against ESBL producers. In this study, susceptibility to ceftaroline was high among the S. pneumoniae, Staphylococcus aureus, β-lactamase–negative H. influenzae, and ESBL-negative K. pneumoniae and E. coli collected.

Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development

Since the start of the 21st century, antibiotic drug discovery and development from natural products has experienced a certain renaissance. Currently, basic scientific research in chemistry and biology of natural products has finally borne fruit for natural product-derived antibiotics drug discovery. A batch of new antibiotic scaffolds were approved for commercial use, including oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003), and mutilins (retapamulin, 2007). Here, we reviewed the thiazolyl peptides (thiopeptides), an ever-expanding family of antibiotics produced by Gram-positive bacteria that have attracted the interest of many research groups thanks to their novel chemical structures and outstanding biological profiles. All members of this family of natural products share their central azole substituted nitrogen-containing six-membered ring and are classified into different series. Most of the thiopeptides show nanomolar potencies for a variety of Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonia (PRSP). They also show other interesting properties such as antiplasmodial and anticancer activities. The chemistry and biology of thiopeptides has gathered the attention of many research groups, who have carried out many efforts towards the study of their structure, biological function, and biosynthetic origin. Here we reviewed a total of 119 natural thiopeptides discovered during the last 50 years. Moreover, we summarized biological profiles, mechanisms of action, and biosynthesis of these thiopeptides.

Antimicrobial susceptibility among gram-positive and gram-negative blood-borne pathogens collected between 2012-2016 as part of the Tigecycline Evaluation and Surveillance Trial

BackgroundAntimicrobial activity of tigecycline and comparator agents was assessedin vitroagainst 27857 isolates source from blood samples collected between 2012 and 2016 as part of the Tigecycline Evaluation and Surveillance Trial (TEST).MethodsThe broth microdilution methods was used to determine minimum inhibitory concentrations (MIC) of blood-borne isolates according to guildlines of the Clinical and Laboratory Standards Institute (CLSI). Antimicrobial susceptibility breakpoints from CLSI guidelines were used as standards to determine susceptibility against comparator agents, whereas tigecycline breakpoints were provided by the US Food and Drug Administration (FDA).ResultsMore than 91% Enterobacteriaceae isolates, belonging to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacaeandSerratia marcescens, were susceptible to amikacin, meropenem, and tigecycline. Meropenem resistance was observed in 8% ofK.pneumoniae isolates worldwide. Extended-spectrum β-lactamase (ESBL) was produced in 15.9 and 20.9%E.coli and K.pneumoniaeisolates, respectively. MIC90 of tigecycline against Acinetobacter baumannii was 2 μg/ml. The highest proportion of susceptible A.baumanniiisolates was 70.8% for minocycline. Among P.aeruginose isolates worldwide, 71.1–94.9% were susceptible to six antibiotics. Almost all Staphylococcus aureusisolates were susceptible to linezolid(100%), vancomycin(100%), and tigecycline (99.9%). The proportion of methicillin-resistant S.aureus (MRSA) was 33.0% among S.aureusisolates worldwide; it was highest in Asia with 46.6%, followed by North America and Latin America with 37.7 and 34.2%, respectively. Vancomycin-resistant (VR) isolates represented 1.4% ofEnterococcus faecalis (VR.E.faecalis) and 27.6% of Enterococcus faecium(VR.E.faecium). Highest percentages of VR.E.faeciumwere found in North America and Latin America, with 61.6 and 58.1% of the isolates, respectively. Production of penicillin-resistant Streptococcus pneumoniae(PRSP) represented 9.0% of S. pneumoniae isolates worldwide; the PRSP proportion was 25.8% in Asia, 13.0% in Africa, and 11.8% in Latin America.ConclusionsIn our study, tigecycline was the only antibiotic that was active against over 90% of all major blood-borne pathogens. A global comparison revealed that antimicrobial resistance was higher in Africa, Asia and Latin America than in Europe and North America.

BIOINFORMATION SEARCH AND ANALYSIS OF STRUCTURES OF CRISPR/CAS SYSTEMS IN PHAGE STAPHYLOCOCUS AUREUS GENOME AND ESTIMATION OF PROFILES OF PHAGE DETECTED THROUGH CRISPR-CASSETTE BACTERIA

The emergence of resistance among the most important bacterial pathogens is generally recognized as one of the major public health problems. The most important of these organisms are penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci and methicillin- and vancomycin-resistant Staphylococcus aureus. These antibiotic resistance in common pathogens have made antimicrobial therapy of many infections. Scientists need to look for new ways of treating bacterial infections in the work, using the developed algorithm from the methods of search software in the genomic structure of Staphylococcus aureus subsp. aureus ST228, the CRISPR/Cas locus and the division structures of its CRISPR cassette. The results of the bacteriophage search through the decoded spacer sequences of CRISPR-cassettes of this strain were also obtained using the developed algorithm of the software methods of bioinformatics. It was determined that the CRISPR/Cas system of strain of ST228 of S. aureus was of type IIIA. It is shown that cas-genes are in the immediate vicinity of CRISPR cassettes. The spacer structures in the detected CRISPR cassette are the Staphylococcus, Mycobacterium, Streptococcus, Bacillus, Gordonia, Arthrobacter, Streptomyces. The implementation of the algorithm of program methods for locating CRISPR/Cas-loci can be applied to many other decoded bacterial genomes to return bacteriophage therapy.

Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens.

Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.

New cephalosporins

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.

Diversity of Mosaic pbp2x Families in Penicillin-Resistant Streptococcus pneumoniae from Iran and Romania.

ABSTRACTPenicillin-resistant Streptococcus pneumoniae strains are found at high rates in Romania and Iran. The mosaic structure of PBP2x was investigated in 9 strains from Iran and in 15 strains from Romania to understand their evolutionary history. Mutations potentially important for β-lactam resistance were identified by comparison of the PBP2x sequences with the sequence of the related PBP2x of reference penicillin-sensitive S. mitis strains. Two main PBP2x mosaic gene families were recognized. Eight Iranian strains expressed PBP2x variants in group 1, which had a mosaic block highly related to PBP2x of the Spain23F-1 clone, which is widespread among international penicillin-resistant S. pneumoniae clones. A second unique PBP2x group was observed in Romanian strains; furthermore, three PBP2x single mosaic variants were found. Sequence blocks of penicillin-sensitive strain S. mitis 658 were common among PBP2x variants from strains from both countries. Each PBP2x group contained specific signature mutations within the transpeptidase domain, documenting the existence of distinct mutational pathways for the development of penicillin resistance.

Antimicrobial resistance in Africa: a systematic review

BackgroundAntimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed to understand and describe the current status of AMR in Africa in relation to common causes of infections and drugs recommended in WHO treatment guidelines.MethodsPubMed, EMBASE and other relevant databases were searched for recent articles (2013–2016) in accordance with the PRISMA guidelines. Article retrieval and screening were done using a structured search string and strict inclusion/exclusion criteria. Median and interquartile ranges of percent resistance were calculated for each antibiotic-bacterium combination.ResultsAMR data was not available for 42.6% of the countries in the African continent. A total of 144 articles were included in the final analysis. 13 Gram negative and 5 Gram positive bacteria were tested against 37 different antibiotics. Penicillin resistance in Streptococcus pneumoniae was reported in 14/144studies (median resistance (MR): 26.7%). Further 18/53 (34.0%) of Haemophilus influenza isolates were resistant to amoxicillin. MR of Escherichia coli to amoxicillin, trimethoprim and gentamicin was 88.1%, 80.7% and 29.8% respectively. Ciprofloxacin resistance in Salmonella Typhi was rare. No documented ceftriaxone resistance in Neisseria gonorrhoeae was reported, while the MR for quinolone was 37.5%. Carbapenem resistance was common in Acinetobacter spp. and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae.ConclusionOur review highlights three important findings. First, recent AMR data is not available for more than 40% of the countries. Second, the level of resistance to commonly prescribed antibiotics was significant. Third, the quality of microbiological data is of serious concern. Our findings underline that to conserve our current arsenal of antibiotics it is imperative to address the gaps in AMR diagnostic standardization and reporting and use available information to optimize treatment guidelines.

New Aspects of the Interplay between Penicillin Binding Proteins, murM, and the Two-Component System CiaRH of Penicillin-Resistant Streptococcus pneumoniae Serotype 19A Isolates from Hungary.

ABSTRACTThe Streptococcus pneumoniae clone Hungary19A-6 expresses unusually high levels of β-lactam resistance, which is in part due to mutations in the MurM gene, encoding a transferase involved in the synthesis of branched peptidoglycan. Moreover, it contains the allele ciaH232, encoding the histidine kinase CiaH (M. Müller, P. Marx, R. Hakenbeck, and R. Brückner, Microbiology 157:3104–3112, 2011, https://doi.org/10.1099/mic.0.053157-0). High-level penicillin resistance primarily requires the presence of low-affinity (mosaic) penicillin binding protein (PBP) genes, as, for example, in strain Hu17, a closely related member of the Hungary19A-6 lineage. Interestingly, strain Hu15 is β-lactam sensitive due to the absence of mosaic PBPs. This unique situation prompted us to investigate the development of cefotaxime resistance in transformation experiments with genes known to play a role in this phenotype, pbp2x, pbp1a, murM, and ciaH, and penicillin-sensitive recipient strains R6 and Hu15. Characterization of phenotypes, peptidoglycan composition, and CiaR-mediated gene expression revealed several novel aspects of penicillin resistance. The murM gene of strain Hu17 (murMHu17), which is highly similar to murM of Streptococcus mitis, induced morphological changes which were partly reversed by ciaH232. murMHu17 conferred cefotaxime resistance only in the presence of the pbp2x of strain Hu17 (pbp2xHu17). The ciaH232 allele contributed to a remarkable increase in cefotaxime resistance in combination with pbp2xHu17 and pbp1a of strain Hu17 (pbp1aHu17), accompanied by higher levels of expression of CiaR-regulated genes, documenting that ciaH232 responds to PBP1aHu17-mediated changes in cell wall synthesis. Most importantly, the proportion of branched peptides relative to the proportion of linear muropeptides increased in cells containing mosaic PBPs, suggesting an altered enzymatic activity of these proteins.

Current Clinical Trials on the Use of Ceftaroline in the Pediatric Population.

The rate of antibiotic resistance in children continues to rise requiring the use of new antibiotics. Ceftaroline fosamil, a newer-generation cephalosporin, was recently approved for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in children aged >2months. Ceftaroline provides coverage against staphylococcal and streptococcal infections, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. Pediatric dosing differs from adult dosing, but it maintains a similar pharmacokinetic profile and offers similar efficacy in terms of time above the minimum inhibitory concentration as compared to the adult population. The clinical safety and efficacy of this antibiotic has been assessed in three pediatric clinical trials that led to its approval by the US Food and Drug Administration, and each trial is described within this review. This article will also discuss the ongoing trials assessing the possibility of expanding the indications of this antibiotic to late-onset sepsis, meningitis and osteomyelitis in the pediatric population.

Emergence of quinolone-resistant strains in Streptococcus pneumoniae isolated from paediatric patients since the approval of oral fluoroquinolones in Japan.

Tosufloxacin (TFLX) is a fluoroquinolone antimicrobial agent. TFLX granules for children were initially released in Japan in 2010 to treat otitis media and pneumonia caused by drug-resistant bacteria, e.g. penicillin-resistant Streptococcus pneumoniae and beta-lactamase-negative, ampicillin-resistant Haemophilus influenzae. The evolution of bacterial resistance since TFLX approval is not known. To clarify the influence of quinolones administered to children since their approval, we examined the resistance mechanism of TFLX-resistant S.pneumoniae isolated from paediatric patients as well as patient clinical characteristics. TFLX-resistant strains (MIC≥2mg/L) were detected among clinical isolates of S.pneumoniae derived from children (≤15 years old) between 2010 and 2014. These strains were characterised based on quinolone resistance-determining regions (QRDRs), i.e. gyrA, gyrB, parC, and parE. In addition, the antimicrobial susceptibility, serotype, and multilocus sequence type of strains were determined, pulsed-field gel electrophoresis was performed, and patient clinical characteristics based on medical records were assessed for cases with underling TFLX-resistant strains. Among 1168 S.pneumoniae isolates, two TFLX-resistant strains were detected from respiratory specimens obtained from paediatric patients with frequent exposure to TFLX. Both strains had mutations in the QRDRs of gyrA and parC. One case exhibited gradual changes in the QRDR during the clinical course. This is the first study of quinolone-resistant S.pneumoniae isolated from children, including clinical data, in Japan. These data may help prevent increases in infections of quinolone-resistant S.pneumoniae in children; specifically, the results emphasise the importance of administering fluoroquinolones only in appropriate cases.

Espectro antimicrobiano de dalbavancina. Mecanismo de acción y actividad in vitro frente a microorganismos Gram positivos

Because of the increase in bacterial resistance, there is a need for new antimicrobial agents. Dalbavancin is a semisynthetic glycopeptide that inhibits the late stages of bacterial cell wall synthesis in the same way as vancomycin, but in addition, its lipophilic side chain anchors dalbavancin to the cellular membrane and allows enhanced activity compared with that of vancomycin. Dalbavancin possesses a broad spectrum of in vitro activity against Gram-positive aerobic and anaerobic microorganisms, being 4-8 times more potent than vancomycin. The spectrum of dalbavancin includes staphylococci, enterococci, streptococci, and anaerobic Gram-positive cocci and bacilli. It is active against different species of multiresistant microorganisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant viridans streptococci and Streptococcus pneumoniae. Although it shows in vitro activity against Enterococcus spp., it is inactive against isolates expressing the VanA phenotype of vancomycin resistance. It also shows slow bactericidal activity against S. aureus, coagulase-negative staphylococci, and Streptococcus pyogenes. In general, the MIC90 (minimum inhibitory concentration 90%) against the majority of the microorganisms is 0.06mg/L and, more than 98% of the isolates that have been tested are inhibited at concentrations of ≤ 0.12mg/L. Dalbavancin is an interesting addition to the therapeutic armamentarium for the treatment of infections caused by Gram-positive microorganisms, including multidrug-resistant isolates.

Detection of pbp2b Gene and Antimicrobial Susceptibility Pattern of Streptococcus Pneumoniae Isolates in Tehran Hospitals, Iran

Background: Streptococcus pneumoniae is the major cause associated with otitis, sinusitis, bronchitis, and pneumonia, as well as an outstanding cause of meningitis, bacteremia, and many other infections. Throughout the world, an increase in antibiotic resistance S.pneumoniae has become a serious problem in the recent years in many different countries. Penicillin resistance in S. pneumoniae cause of altered on the penicillin target position, the penicillin-binding proteins (PBPs). Objectives: In the present study, we describe the prevalence and antimicrobial susceptibility pattern and identification of the pbp2b gene of S. pneumoniae isolates at specimens of several general hospitals in Tehran, the capital of Iran. Methods: A total of 73 S. pneumoniae were obtained from various clinical specimens from hospitals in Tehran from September 2012 to July 2015. Antibiotic susceptibility of isolates was determined by the broth microdilution method. The genes pbp2b in penicillin-resistant streptococcus pneumoniae (PRSP) were detected using polymerase chain reaction (PCR). Results: In total, 73 isolates were collected and diagnosed as S. pneumoniae. Isolates were susceptible to ofloxacin 95.9%, vancomycin 93%, penicillin 78%, trimethoprim-sulfamethoxazole 61.6%, ceftriaxone 53.5%, meropenem 52%, cefotaxime 46.5%, and erythromycin 8.2%. Of the 15 PRSP isolates, the pbp2b gene was identified in 12 (80%). In 1 penicillin-intermediate S. pneumoniae isolate the pbp2b was detected. Conclusions: These results in comparison with same studies in other parts of the world showed us an increase in resistant S. pneumoniae isolates to conventional drugs in the treatment of the acute infections caused by this bacteria. In the present study, PRSP possess the pbp2b gene were the most frequently found, which means they have a high level of resistance of S. pneumoniae. For decreasing the mortality and morbidity of patients, it is suggested to determine the antibiotic susceptibility pattern of the isolates in each hospital for doing necessary medical interventions.

Longitudinal surveillance on antibiogram of important Gram-positive pathogens in Southern China, 2001 to 2015.

A longitudinal surveillance aimed to investigate the antibiogram of three genus of important Gram-positive pathogens in Southern China during 2001-2015. A total of 3849 Staphylococcus, Enterococcus and Streptococcus strains were isolated from Southern China during 2001-2015. Bacteria identification was performed by colony morphology, Gram staining, the API commercial kit and the Vitek 2 automated system. Antimicrobial susceptibility testing was determined by disk diffusion method and MIC method. As sampling site was concerned, 51.4% of Staphylococcus strains were isolated from sputum, whereas urinary tract remained the dominant infection site among Enterococcus and Streptococcus. According to the antimicrobial susceptibility, three genus of important Gram-positive pathogens showed high resistance against erythromycin, tetracycline, ciprofloxacin and clindamycin. Resistance rates to penicillins (penicillin, oxacillin, ampicillin) were high as well, with the exception of E.faecalis and Streptococcus. Overall, resistance rates against methicillin (oxacillin) were 63.2% in S.aureus and 76.2% in coagulase-negative Staphylococcus (CNS), along with continuous increases during the study. VRSA and vancomycin-resistant coagulase-negative Staphylococcus only appeared in 2011-2015. Sight decline was obtained for the vancomycin resistance of E.faecalis, while vancomycin-resistant E.faecium only appeared in 2011-2015, with its intermediate rate decreasing. Significant decrease in penicillin-resistant Streptococcus pneumonia (PRSP) was observed during studied period. Glycopeptide antibiotic remained highly effective to Staphylococcus, Enterococcus and Streptococcus (resistance rates <5%). Despite decline obtained for some antibiotic agents resistance during 2001-2015, antimicrobial resistance among Gram-positive pathogens still remained high in Southern China. This study may aid in the guidance for appropriate therapeutic strategy of infections caused by nosocomial pathogens.

Clinical features and outcomes of invasive pneumococcal disease in pediatric intensive care unit

Objective To investigate the clinical features of invasive pneumococcal disease(IPD) in pediatric intensive care unit(PICU) and to analyze outcomes, so as to provide evidence for early and reasonable diagnosis and treatment as well as to improvement of prognosis. Methods A retrospective study was conducted at a research center for IPD in PICU in Beijing Children's Hospital from January 2013 to April 2016.Clinical data of children with IPD were collected and analyzed.All specimens were for bacteria culture, isolation, strain identification and drug sensitivity test. At the same time, the quellung test was used to identify serotypes of the streptococcus pneumoniae. Results A total of 30 children meeting inclusion criteria were included, 19 male and 11 female.The median age was 1.5 years (range 3 months to 7.5 years). The Pediatric Critical Illness Scores (PCIS) were 72 (64, 82) scores.There were 13 cases whose Glasgow Coma Scores (GCS) were below 15 scores.The 28-day mortality rate was 36.7% (11/30 cases). Among death cases, there were 7 cases of purulent meningitis, 3 cases of septicemia and 1 case of purulent pleurisy.The onset age, peripheral blood leucocytes count, PCIS and GCS of death group were significantly lower than those of survival group (all P<0.05). The mortality rate of children complicated with septic shock was significantly higher than that of children without septic shock [75.0%(6/8 cases) vs 22.7%(5/22 cases), P<0.05]. The most common serotypes were 19F and 19A.The coverage rate of pneumococcal conjugate vaccine 13 was 96.7%.The percentage of penicillin nonsusceptible streptococcus pneumoniae was 73.3%, and the percentage of penicillin resistant streptococcus pneumoniae was 53.3%, and multi-drug resistant was 90%. Conclusions The mortality rate of IPD in PICU is high, and the main serotypes were 19F and 19A. Most patients of death group were less than 2 years old.Peripheral blood white blood cell count, PCIS and GCS were significantly reduced, and more complicated with septic shock.Vaccination of pneumococcal conjugate vaccine 13 for children less than 2 years old may reduce the incidence of IPD. Key words: Pediatric intensive care unit; Invasive pneumococcal disease; Clinical feature; Outcome

Novel broad-spectrum and long-acting parenteral cephalosporins having an acyl cyanamide moiety at the C-3 terminal: Synthesis and structure-activity relationships

A series of novel 7β-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]-cephalosporins having pyridinium-linked acyl cyanamide at the C-3 position were prepared and their antibacterial activities and pharmacokinetics profiles were evaluated. Most of the compounds exhibited potent antibacterial activities against penicillin-resistant Streptococcus pneumoniae (PRSP) and β-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR). Introduction of a propenyl group between the cephalospoin core and the side chains at the C-3 position improved the pharmacokinetics profile. Among these compounds, 7β-[2-(2-aminothiazole-4-yl)-2-(Z)- (alkoxyimino)acetamido]-3-(pyridin-1-ium-1-yl)prop-1-en-1-yl)cephalosporins (32j) showed well-balanced antibacterial activity against S. pneumoniae and H. influenzae which included resistant strains and also other Gram-positive or Gram-negative pathogens. Furthermore, 32j showed a long half-life comparable to that of Ceftriaxone in mice and monkeys.

Identification of novel aminopiperidine derivatives for antibacterial activity against Gram-positive bacteria

We have previously reported amidopiperidine derivatives as a novel peptide deformylase (PDF) inhibitor and evaluated its antibacterial activity against Gram-positive bacteria, but poor pharmacokinetic profiles have resulted in low efficacy in in vivo mouse models. In order to overcome these weaknesses, we newly synthesized aminopiperidine derivatives with remarkable antimicrobial properties and oral bioavailability, and also identified their in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP).

Important Mutations Contributing to High-Level Penicillin Resistance in Taiwan19F-14, Taiwan23F-15, and Spain23F-1 of Streptococcus pneumoniae Isolated from Taiwan.

Penicillin-resistant Streptococcus pneumoniae is a serious concern worldwide. In this study, we analyzed the cause of β-lactam resistance in pandemic multidrug-resistant clones. A total of 41 penicillin-nonsusceptible clinical isolates were collected from 1996 to 2012. Sero- and molecular typing confirmed that these isolates were clonal types of Taiwan19F-14, Taiwan23F-15, and Spain23F-1. Sero-switching was found in four isolates. All isolates were multidrug resistant. Sequencing analysis of the penicillin binding proteins (PBPs) was performed on PBP1a, 2b, and 2x, and a large number of mutations were identified in comparing to clinical penicillin-susceptible isolates and the recipient strain R6 used for homologous recombination. The T451A substitution was the key amino acid in PBP2b that contributed to penicillin resistance. T338A in PBP2x played a role in resistance and reached the highest level of resistance when combined with other mutations in PBP2x. High-level penicillin resistance could not be obtained without the combination of mutations in PBP1a with PBP2b and 2x. The amino acid substitutions in PBP1a, 2b, and 2x were the crucial factors for β-lactam resistance.