Antimicrobial resistance is one of the critical public health issues in the world. There is an urgent need to develop effective broad-spectrum antibiotics to treat the infection of multi-drug resistant Gram-negative bacilli. Cefiderocol, developed by the Shionogi Inc. in Japan, is a new type of iron carrier cephalosporin antibiotics, which overcomes the drug resistance of Gram-negative bacilli due to the down-regulation of outer membrane pore protein and the up-regulation of efflux pump, and has good stability to serine- and metallo-carbapenemases. This drug has a broad spectrum and strong antibacterial activity against carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. Cefiderocol can be used to treat complex urinary tract infections (including pyelonephritis), hospital-acquired pneumonia, and ventilator-associated pneumonia. By summarizing the chemical structure, antibacterial mechanism, in vitro antibacterial activity, pharmacokinetics, pharmacodynamics, and clinical treatment of cefiderocol, this review shows the application potential of cefiderocol as a new iron carrier cephalosporin in the treatment of multi-drug resistant Gram-negative bacilli infections.
Cephalosporins/therapeutic use* ; Gram-Negative Bacteria ; Microbial Sensitivity Tests ; Siderophores/pharmacology*

No abstract available.
Anti-Bacterial Agents/*pharmacology ; Azabicyclo Compounds/*pharmacology ; Bacterial Proteins/genetics ; Ceftazidime/*pharmacology ; Cephalosporins/*pharmacology ; DNA, Bacterial/genetics/metabolism ; Drug Resistance, Bacterial/*drug effects ; Gram-Negative Bacteria/drug effects/*isolation & purification ; Humans ; Microbial Sensitivity Tests ; Penicillanic Acid/*analogs & derivatives/pharmacology ; Pseudomonas aeruginosa/drug effects/isolation & purification ; Real-Time Polymerase Chain Reaction

BACKGROUNDAcinetobacter baumannii has emerged as an important pathogen causing a variety of infections. Using data from the China Surveillance of Antimicrobial Resistance Program conducted biennially, we investigated the secular changes in the resistance of 2917 isolates of A. baumannii from 2004 to 2014 to differ antimicrobial agents.

METHODSPathogen samples were collected from 17 to 20 hospitals located in the eastern, central, and western regions of China. Minimum inhibitory concentrations (MICs) were determined by a 2-fold agar dilution method, and antimicrobial susceptibility was established using the 2014 Clinical Laboratory Standards Institute-approved breakpoints. Isolates not susceptible to all the tested aminoglycosides, fluoroquinolones, β-lactams, β-lactam/β-lactam inhibitors and carbapenems were defined as extensively drug resistant.

RESULTSThe rates of nonsusceptibility to common antimicrobial agents remained high (>65%) over the years with some fluctuations to certain agents. The prevalence of imipenem-resistant A. baumannii (IRAB) increased from 13.3% in 2004 to 70.5% in 2014 and that of extensively drug-resistant A. baumannii (XDRAB) increased from 11.1% in 2004 to 60.4% in 2014. The activity of tigecycline was stable with MIC90 ≤4 mg/L against A. baumannii from 2009 to 2014. Susceptibility to colistin remained high (97.0%) from 2009 to 2014. The prevalence of XDRAB increased in all the three surveillance regions over the years and was significantly higher in Intensive Care Unit (ICU) wards than non-ICU wards.

CONCLUSIONSThis longitudinal multicenter surveillance program revealed the nationwide emergence of A. baumannii in China and showed a significant increase in prevalence from 2004 to 2014. High levels of bacterial resistance were detected among samples collected from clinical settings in China, with IRAB and XDRAB being especially prevalent. This study will help to guide empirical therapy and identify at-risk groups requiring more intense interventional infection control measures, while also helping to focus surveillance efforts.

Acinetobacter baumannii ; drug effects ; Amikacin ; pharmacology ; Anti-Infective Agents ; pharmacology ; Cefoperazone ; pharmacology ; Ceftazidime ; pharmacology ; Cephalosporins ; pharmacology ; China ; Colistin ; pharmacology ; Drug Resistance, Multiple, Bacterial ; Humans ; Imipenem ; pharmacology ; Levofloxacin ; pharmacology ; Microbial Sensitivity Tests ; Minocycline ; pharmacology ; Penicillanic Acid ; analogs & derivatives ; pharmacology ; Piperacillin ; pharmacology ; Sulbactam ; pharmacology

INTRODUCTIONIncreasing resistance in Escherichia coli and Klebsiella pneumoniae to firstline antibiotics makes therapeutic options for urinary tract infections (UTIs) challenging. This study investigated the in vitro efficacies of 6 antibiotics against multidrug resistant (MDR) uropathogens.

MATERIALS AND METHODSMinimum inhibitory concentrations to ceftibuten, cefpodoxime, fosfomycin, mecillinam, temocillin, and trimethoprim were determined against 155 MDR-isolates of E. coli and K. pneumoniae. The presence of extended-spectrum beta-lactamases (ESBL) and plasmid-borne AmpC enzymes was determined by phenotypic testing with genotyping performed by multiplex polymerase chain reaction.

RESULTSTemocillin demonstrated highest susceptibility rates for both E. coli (95%) and K. pneumoniae (95%) when breakpoints for uncomplicated UTIs were applied; however, temocillin susceptibility was substantially lower when "systemic infection" breakpoints were used. Fosfomycin demonstrated the best in vitro efficacy of the orally available agents, with 78% and 69% of E. coli and K. pneumoniae isolates susceptible, respectively. The next most effective antibiotics were ceftibuten (45%) and mecillinam (32%). ESBL and ampC genes were present in 47 (30%) and 59 (38%) isolates.

CONCLUSIONThis study demonstrated few oral therapeutic options for MDR-uropathogens, with fosfomycin demonstrating the best in vitro activity.

Amdinocillin ; pharmacology ; Anti-Bacterial Agents ; pharmacology ; Bacterial Proteins ; genetics ; Ceftizoxime ; analogs & derivatives ; pharmacology ; Cephalosporins ; pharmacology ; Drug Resistance, Multiple, Bacterial ; genetics ; Escherichia coli ; drug effects ; genetics ; Escherichia coli Infections ; microbiology ; Fosfomycin ; pharmacology ; Genotype ; Humans ; In Vitro Techniques ; Klebsiella Infections ; microbiology ; Klebsiella pneumoniae ; drug effects ; genetics ; Microbial Sensitivity Tests ; Multiplex Polymerase Chain Reaction ; Penicillins ; pharmacology ; Singapore ; Trimethoprim ; pharmacology ; Urinary Tract Infections ; microbiology ; beta-Lactamases ; genetics

BACKGROUNDOver the last decade, Clostridium difficile infection (CDI) has emerged as a significant nosocomial infection, yet little has been reported from China. This study aimed to characterize the clinical and microbiological features of CDI from a hospital in Shanghai.

METHODSPatients with CDI seen between December 2010 and March 2013 were included in this study, of which clinical data were retrospectively collected. The microbiological features of corresponding isolates were analyzed including genotype by multi-locus sequence typing (MLST), antimicrobial susceptibility, toxin production, sporulation capacity, biofilm formation, and motility.

RESULTSNinety-four cases of CDI were included during this study period, 12 of whom were severe cases. By reviewing the clinical data, all patients were treated empirically with proton pump inhibitor or antibiotics or both, and they were distributed widely across various wards, most frequently to the digestive ward (28/94, 29.79%). Comparing the severe with mild cases, no significant differences were found in the basic epidemiological data or the microbiological features. Among the 94 isolates, 31 were toxin A-negative toxin B-positive all genotyped as ST37. They generated fewer toxins and spores, as well as similar amounts of biofilm and motility percentages, but exhibited highest drug resistance to cephalosporins, quinolones, macrolide-lincosamide and streptogramin (MLSB), and tetracycline.

CONCLUSIONSNo specific clinical genotype or microbiological features were found in severe cases; antimicrobial resistance could be the primary reason for epidemic strains leading to the dissemination and persistence of CDI.

Anti-Bacterial Agents ; pharmacology ; Biofilms ; drug effects ; Cephalosporins ; pharmacology ; China ; Clostridium difficile ; drug effects ; genetics ; isolation & purification ; Genotype ; Multilocus Sequence Typing ; methods ; Quinolones ; pharmacology ; Tertiary Healthcare ; statistics & numerical data ; Tetracycline ; pharmacology

OBJECTIVETo investigate the mechanism of drug resistance of carbapenems-resistant Acinetobacter baumannii (CRAB) in burn patients and the antimicrobial activity of a combination of drugs against this bacteria in vitro.

METHODSA total of 135 strains of Acinetobacter baumannii (AB) from wound excretion, sputum, and venous catheter wall of patients hospitalized in our department from January 2011 to July 2013 were collected individually. Drug resistance of 135 strains of AB to 12 antibiotics commonly-used in clinic was detected using K-B paper diffusion method. Among the CRAB strains, double-disk synergy test was used to screen metallo-β-lactamase (MBL)-producing strains, and the drug resistance rates between MBL-producing strains and non-MBL-producing strains were compared. Minimal inhibitory concentration (MIC), 50% MIC (MIC50), and 90% MIC (MIC90) of cefoperazone/sulbactam, imipenem, cefepime, ampicillin/sulbactam, and amikacin used alone against MBL-producing CRAB were determined by broth microdilution method. MIC, MIC50, and MIC90 of amikacin respectively combined with imipenem, cefoperazone/sulbactam, cefepime, or ampicillin/sulbactam against MBL-producing CRAB were determined by checkerboard method with diluted agar. Fractional inhibitory concentration (FIC) index was calculated to determine the antibacterial effect of each combination of two antibiotics. Synergy with FIC lower than or equal to 0.5, or additivity with FIC higher than 0.5 and lower than or equal to 1.0 was regarded as effective, and indifference with FIC higher than 1.0 and lower than or equal to 2.0 or antagonism with FIC higher than 2.0 was regarded as ineffective. The effective rate was calculated. Data were processed with Chi-square test.

RESULTSThe resistant rates of the 135 strains of AB to imipenem, meropenem, and ceftazidime were high, and those of piperacillin/tazobactam and ampicillin/sulbactam were low. A total of 120 strains of CRAB was screened, accounting for 88.89%, among which the MBL-producing strains accounted for 78.33% (94/120). The resistant rates of MBL-producing strains to piperacillin/tazobactam, imipenem, meropenem, piperacillin, and cefepime were respectively 59.5%, 87.2%, 93.5%, 87.0%, 86.0%, and they were significantly higher than those of non-MBL-producing strains (respectively 43.0%, 81.3%, 87.5%, 78.4%, 64.0%, with χ(2) values from 4.571 to 8.260, P < 0.05 or P < 0.01). Among the inhibition concentrations of each of the 5 antibiotics used alone against MBL-producing strains, MIC, MIC50, and MIC90 of ampicillin/sulbactam were the lowest, respectively 4.00, 16, 64 µg/mL, while those of cefepime were high, respectively 32.00, 128, 512 µg/mL. MIC, MIC50, and MIC90 of amikacin combined with each of the other 4 antibiotics were decreased from 50.00% to 98.44% as compared with that of single administration of each antibiotic. Among the 94 strains of MBL-producing CRAB, the synergic, additive, indifferent, and antagonistic effects were respectively observed in 40, 33, 6, and 15 strains applied with combination of amikacin and ampicillin/sulbactam; 42, 30, 5, 17 strains applied with combination of amikacin and cefoperazone/sulbactam; 38, 15, 19, 22 strains applied with combination of amikacin and cefepime; 34, 2, 37, 21 strains applied with combination of amikacin and imipenem, among which the antibacterial effective rates decreased successively, respectively 77.7%, 76.6%, 56.4%, and 38.3%. The former two rates were respectively significantly higher than the latter two rates (with χ(2) values from 8.618 to 29.889, P values below 0.01).

CONCLUSIONSProduction of MBL is the main mechanism of resistance of the CRAB isolated from burn patients hospitalized in our department against carbapenems in about 3 years. The antibacterial effects of amikacin combined with each of the former-mentioned 4 agents are better than those of each of the five antibiotics used singly, and the effects are particularly obvious when combining amikacin with compound agent containing enzyme inhibitors.

Acinetobacter Infections ; drug therapy ; microbiology ; Acinetobacter baumannii ; drug effects ; isolation & purification ; Ampicillin ; pharmacology ; Anti-Bacterial Agents ; pharmacology ; Carbapenems ; pharmacology ; Cephalosporins ; pharmacology ; Drug Resistance ; Humans ; In Vitro Techniques ; Microbial Sensitivity Tests ; Penicillanic Acid ; analogs & derivatives ; pharmacology ; Pharmaceutical Preparations ; Piperacillin ; pharmacology ; Sulbactam ; pharmacology ; Thienamycins ; pharmacology ; beta-Lactamase Inhibitors ; pharmacology

OBJECTIVEGroup A β-hemolytic streptococcus (GAS) or Streptococcus pyogenes may be encountered in diverse clinical situations in children. A rising incidence of invasive group A streptococcus (IGAS) infections has been noted in children in the past three decades. The aim of this study was to summarize the clinical characteristics and antimicrobial resistance of IGAS in children, and to raise the level of diagnosis and treatment of this infection.

METHODThe clinical data from 19 cases of IGAS younger than 14 years old seen from January 2004 to December 2011 treated in the authors' hospital were analyzed. IGAS infections are defined as the isolation of GAS from a normally sterile site in patients.

RESULTThe 19 cases were identified as IGAS infections, among whom 15 were male and 4 were female, and the ratio of them was 3.75. The age ranged from 1 day to 14 years, with a median age of 4 years. The course of disease was 4 h-10 days. The average length of stay was 12.2 days. In 13 cases the episodes of the infection occurred in winter and spring. In 18 cases the infection was community-acquired. Overall, 10 cases had neck or foot dorsum abscess, four cases had purulent peritonitis, and 3 cases were diagnosed as streptococcal toxic shock syndrome (STSS) complicated with empyema, pyopneumothorax occurred in 1 case and neonatal septicemia in another. Three cases had an underlying disease, including 2 cases wounded in a car accident and 1 case of congenital esophageal atresia and tracheoesophageal fistula. Before the isolation of GAS, 5 cases had stayed in ICUs, the length of ICU stay was 1-32 days, 4 cases had received intubation and mechanical ventilation, the ventilation time was 8 h-24 days, 2 cases had received major surgery; 5 cases had other pathogen coinfection, including 4 cases of abdominal pus at the same time and Escherichia coli was isolated, and 1 case had parainfluenza virus type I coinfection. Peripheral blood leucocyte increased in 18 cases, one case dropped off. The C-reactive protein (CRP) levels increased in all patients, including 16 cases who had 14-160 mg/L, 3 cases had levels higher than 160 mg/L. Twenty strains of GAS were isolated from 19 cases' sterile sites, of them 10 strains were isolated from abscess, 4 strains were isolated from blood and another 4 from ascites. Two strains were from the same patient at different times of pleural effusion. All 20 strains displayed a full susceptibility to cefazolin, levofloxacin and vancomycin, and the rates of resistance to both cefotaxime and penicillin were 10.0%. The rates of resistance to erythromycin and clindamycin were 55.0% and 70.0% respectively. Among the patients 3 cases were cured, 14 cases improved, and 2 cases died, of whom 1 case died of STSS secondary to multiple organ dysfunction, 1 case died of basic disease secondary to multiple organ dysfunction.

CONCLUSIONSkin and soft tissues were the most common IGAS infection sites in children, and IGAS infection also can lead to serious STSS and even can be life threatening. Penicillin and cephalosporin are still sensitive for children IGAS infections.

Abscess ; drug therapy ; epidemiology ; microbiology ; Adolescent ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Cephalosporins ; therapeutic use ; Child ; Child, Preschool ; Clindamycin ; therapeutic use ; Community-Acquired Infections ; drug therapy ; epidemiology ; microbiology ; Drug Resistance, Bacterial ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Microbial Sensitivity Tests ; Retrospective Studies ; Soft Tissue Infections ; drug therapy ; epidemiology ; microbiology ; Streptococcal Infections ; drug therapy ; epidemiology ; microbiology ; Streptococcus pyogenes ; drug effects ; isolation & purification

INTRODUCTIONCeftaroline is a fifth-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that was recently launched in Singapore. It received approval from the United States (US) Food Drug Administration (FDA) and European Commission for the treatment of adult patients with community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSTI). This study aimed to review current published data and determine its clinical role, particularly in the local setting.

MATERIALS AND METHODSA literature review on published articles in English on ceftaroline, focusing in particular on clinical trials and other clinical reports. Susceptibility testing was also performed on a limited sample of local MRSA and Streptococcus pneumoniae isolates.

RESULTSCeftaroline has an extensive spectrum of activity, including coverage of MRSA and multidrug-resistant S. pneumoniae. However, it has limited activity against non-fermenting Gram-negative bacteria and is susceptible to hydrolysis by extended spectrum beta-lactamases. It is only available for intravenous delivery, with a reconstituted stability of just 6 hours, rendering it unavailable for use for outpatient antibiotic therapy. Clinical trials demonstrate non-inferiority compared to first-line comparators in the treatment of CAP and cSSTI. Published case reports/series suggest a potential greater role in the treatment of MRSA bacteremia and endocarditis. No resistance was found among local archived MRSA and S. pneumoniae isolates.

CONCLUSIONWe believe ceftaroline will occupy primarily niche roles for culture-directed treatment of various infections--in particular those caused by MRSA--until further clinical trial data become available. A variety of factors render it less useful or appealing for empirical treatment of CAP or healthcare-associated infections.

Cephalosporins ; pharmacology ; therapeutic use ; Humans ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; Singapore ; Staphylococcal Infections ; drug therapy

OBJECTIVETo analyze the distribution of Enterobacteriaceae isolated from West China Hospital, investigate the antibiotic resistance profile of Enterobacteriaceae with decreased susceptibility to carbapenems and explore the molecular mechanism.

METHODSForty-five Enterobacteriaceae strains resistant or with reduced susceptibility to carbapenems were isolated from patients in West China Hospital. The antimicrobial susceptibility and carbapenemase-producing phenotypes of the bacteria were examined and specific PCR were performed to determine the molecular mechanism.

RESULTSOf the 45 isolates, 17, 21 and 36 were resistant or intermediate strains to imipenem, meropenem and ertapenem, respectively. The majority of these isolates showed resistance to cephalosporins. The modified Hodge test resulted in the highest positivity rate (77.8%), followed by EDTA disc test (57.8%) and PBA disc test (22.2%). BlaTEM, blaSHV and blaCTX-M were detected in 60.0%, 53.3% and 15.6% of these strains with reduced susceptibility. The rate of strains carrying 2 or more genes was 44.4%, and the detection rate of blaIMP was 48.9%. BlaKPC was identified in 4 (8.9%) high-level resistant strains and confirmed to locate on the plasmid.

CONCLUSIONProduction of carbapenemase contributes to reduced susceptibility of carbapenems in Enterobacteriaceae. The presence of blaKPC, MBL and ESBL, and their possible combinations can be the main factor contributing to carbapenem resistance or reduced susceptibility in Enterobacteriaceae. The KPC-2 carbapenemase gene located on the plasmids we found in this study can cause potential horizontal transmission across strains.

Anti-Bacterial Agents ; pharmacology ; Bacterial Proteins ; genetics ; metabolism ; Carbapenems ; pharmacology ; Cephalosporins ; pharmacology ; Enterobacteriaceae ; drug effects ; enzymology ; genetics ; Gene Amplification ; Imipenem ; pharmacology ; Microbial Sensitivity Tests ; Polymerase Chain Reaction ; Thienamycins ; pharmacology ; beta-Lactam Resistance ; beta-Lactamases ; genetics ; metabolism ; beta-Lactams ; pharmacology

To produce TEM-116 extended-spectrum beta-lactamase (ESBL) from recombinant bacteria in a cost-effective way, we purified and renatured the recombinant TEM-116 ESBL from the inclusion bodies by Ni(2+)-NTA affinity and gel filtration chromatography through subcloning the bla(TEM-116) into expression vector pET28a(+), transforming into Escherichia coli BL21(DE3) and inducing with IPTG. We characterized the purified protein that had the molecular weight of 30 kDa and specific activity of 476 IU/mg. The recombinant TEM-116 ESBL showed higher efficiency in eliminating penicillin and cephalosporin in vitro and in vivo. Specifically, the recombinant TEM-116 ESBL could eliminate 7000 mg penicillin G (PG) when used at 10.0 IU in 1 L fermentation medium. When used at 320.0 IU, it could also degrade a mix of PG, ampicillin and cefazolin each at 200 mg in 1 L of urine. In milk, 1.0-2.5 IU of the recombinant enzyme could remove 80 U/L of PG. The recombinant enzyme was fully active at the temperature ranged from 4 degrees C to 37 degrees C. Furthermore, the recombinant enzyme used at 2.0x10(4)-2.3x10(4) IU/(kg bw) (body weight) eliminated 8.0x10(4)-9.1x10(4) microg/(kg bw) PG in mouse models in vivo. The recombinant TEM-116 ESBL has the potential as a tool enzyme in food and environmental protection to eliminate harmful residues of antibiotics.
Animals ; Cephalosporins ; antagonists & inhibitors ; Escherichia coli ; genetics ; metabolism ; Genetic Vectors ; genetics ; Mice ; Penicillins ; antagonists & inhibitors ; Recombinant Proteins ; biosynthesis ; genetics ; isolation & purification ; pharmacology ; beta-Lactamases ; biosynthesis ; genetics ; isolation & purification