Penicillin-binding proteins (PBPs) are the target of β-lactam antibiotics (the major treatment for Streptococcus pneumoniae infections), and mutations in PBPs are considered as a primary mechanism for the development of β-lactam resistance in S. pneumoniae. This study was conducted to investigate the mutations in the PBPs of clinical S. pneumoniae isolates in Hangzhou, China, in correlation with β-lactam resistance. Results showed that 19F was the predominant serotype (7/27) and 14 of the S. pneumoniae isolates were resistant to both penicillin G and cephalosporin. Genotyping results suggested that β-lactam-resistant isolates primarily exhibited single-site mutations in both the STMK and SRNVP motifs of pbp1a in combination with double-site mutations in the STMK motif of pbp2x, which might be the primary mechanisms underlying the β-lactam resistance of the isolates in this study.
Anti-Bacterial Agents ; pharmacology ; China ; epidemiology ; Drug Resistance, Bacterial ; Humans ; Pneumococcal Infections ; epidemiology ; microbiology ; Streptococcus pneumoniae ; drug effects ; genetics ; beta-Lactams ; pharmacology

BACKGROUND: The development of new drugs or alternative therapies effective against methicillin-resistant Staphylococcus aureus (MRSA) is of great importance, and various natural anti-MRSA products are good candidates for combination therapies. We evaluated the antibacterial activities of a Phellinus baumii ethyl acetate extract (PBEAE) and its synergistic effects with beta-lactams against MRSA. METHODS: The broth microdilution method was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the PBEAE. The PBEAE synergistic effects were determined by evaluating the MICs of anti-staphylococcal antibiotic mixtures, with or without PBEAE. Anti-MRSA synergistic bactericidal effects of the PBEAE and beta-lactams were assessed by time-killing assay. An ELISA was used to determine the effect of the PBEAE on penicillin binding protein (PBP)2a production. RESULTS: The MICs and MBCs of PBEAE against MRSA were 256-512 and 1,024-2,048 microg/mL, respectively. The PBEAE significantly reduced MICs of all beta-lactams tested, including oxacillin, cefazolin, cefepime, and penicillin. However, the PBEAE had little or no effect on the activity of non-beta-lactams. Time-killing assays showed that the synergistic effects of two beta-lactams (oxacillin and cefazolin) with the PBEAE were bactericidal in nature (Deltalog10 colony forming unit/mL at 24 hr: 2.34-2.87 and 2.10-3.04, respectively). The PBEAE induced a dose-dependent decrease in PBP2a production by MRSA, suggesting that the inhibition of PBP2a production was a major synergistic mechanism between the beta-lactams and the PBEAE. CONCLUSIONS: PBEAE can enhance the efficacy of beta-lactams for combined therapy in patients infected with MRSA.
Acetates/chemistry ; Agaricales/*chemistry/metabolism ; Anti-Infective Agents/chemistry/*pharmacology ; Drug Synergism ; Enzyme-Linked Immunosorbent Assay ; Methicillin-Resistant Staphylococcus aureus/*drug effects/metabolism ; Microbial Sensitivity Tests ; Penicillin-Binding Proteins/analysis/metabolism ; Plant Extracts/chemistry/*pharmacology ; beta-Lactams/*pharmacology

OBJECTIVETo investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism.

METHODSThe multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of β-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively.

RESULTSThe 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P < 0.05 and r = -0.473, P < 0.05), while the culture medium without 17-AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of &beta;-catenin and C-MYC proteins (P < 0.05); At same time of culture, the more high of 17-AAG concentration, the more high of cell ratio in G1 phase (P < 0.05), at same concentration of 17-AAG, the more long time of culture, the more high of cell ratio in G1 phase (P < 0.05).

CONCLUSIONThe HSP90 inhibitory 17-AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/&beta;-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.

Apoptosis ; Benzoquinones ; pharmacology ; Cell Cycle ; Cell Division ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; drug effects ; Down-Regulation ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; Humans ; Lactams, Macrocyclic ; pharmacology ; Multiple Myeloma ; metabolism ; pathology ; Proto-Oncogene Proteins c-myc ; metabolism ; Wnt Signaling Pathway ; drug effects ; beta Catenin ; metabolism

Rhus chicken is a common health food in Korea and is used as an herbal medicine to cure gastrointestinal diseases such as indigestion, loose stool, and peptic ulcers. Unfortunately, systemic contact dermatitis due to the ingestion of Rhus chicken occasionally occurs and its incidence is increasing. The clinical findings of systemic contact dermatitis induced by ingesting Rhus chicken are maculopapules, erythroderma, erythema multiforme-like lesions, vesicles, wheals, purpura, and pustules. Acute generalized exanthematous pustulosis (AGEP) is an acute generalized pustular eruption characterized by rash with sterile pustules, high fever, and neutrophilia. Most cases are caused by drugs, predominantly beta-lactams and macrolide antimicrobials, viral infections, and contact hypersensitivity. Rarely, intake of Rhus chicken can cause AGEP. Herein, we describe two cases of AGEP induced by ingestion of Rhus chicken.
Acute Generalized Exanthematous Pustulosis* ; beta-Lactams ; Chickens* ; Dermatitis, Contact ; Dermatitis, Exfoliative ; Dyspepsia ; Eating* ; Erythema ; Exanthema ; Fever ; Gastrointestinal Diseases ; Food, Organic ; Herbal Medicine ; Incidence ; Korea ; Peptic Ulcer ; Purpura ; Rhus*

BACKGROUND: Fluoroquinolone resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression and/or target mutations. We designed this study to investigate the efflux pump mediated fluoroquinolone resistance and check the increasing effectiveness of fluoroquinolones in combination with an efflux pumps inhibitor among P. aeruginosa isolates from burn wounds infections. MATERIALS AND METHODS: A total of 154 consecutive strains of P. aeruginosa were recovered from separate patients hospitalized in a burn hospital, Tehran, Iran. The isolates first were studied by disk diffusion antibiogram for 11 antibiotics and then minimum inhibitory concentration (MIC) experiments were performed to detect synergy between ciprofloxacin and the efflux pump inhibitor, carbonyl cyanide-m-chlorophenyl hydrazone (CCCP). Then to elucidate the inducing of multi drug resistance due to different efflux pumps activation in Fluoroquinolone resistant isolates, synergy experiments were also performed in random ciprofloxacin resistant isolates which have overexpressed efflux pumps phenotypically, using CCCP and selected antibiotics as markers for Beta-lactams and Aminoglycosides. The isolates were also tested by polymerase chain reaction (PCR) for the presence of the MexA, MexC and MexE, which encode the efflux pumps MexAB-OprM, MexCD-OprJ and MexEF-OprN. RESULTS: Most of the isolates were resistant to 3 or more antibiotics tested. More than half of the ciprofloxacin resistant isolates exhibited synergy between ciprofloxacin and CCCP, indicating the efflux pump activity contributed to the ciprofloxacin resistance. Also increased susceptibility of random ciprofloxacin resistant isolates of P. aeruginosa to other selected antibiotics, in presence of CCCP, implied multidrug extrusion by different active efflux pump in fluoroquinolones resistant strains. All of Ciprofloxacin resistant isolates were positive for MexA, MexC and MexE genes simultaneously. CONCLUSION: In this burn hospital, where multidrug resistant P. aeruginosa isolates were prevalent, ciprofloxacin resistance and multidrug resistance due to the overexpression of fluoroquinolones mediated efflux pumps has also now emerged. Early recognition of this resistance mechanism should allow the use of alternative antibiotics and use an efflux pumps inhibitor in combination with antibiotic therapy.
Aminoglycosides ; Anti-Bacterial Agents ; beta-Lactams ; Burns ; Carbonyl Cyanide m-Chlorophenyl Hydrazone ; Ciprofloxacin ; Diffusion ; Drug Resistance ; Drug Resistance, Multiple* ; Fluoroquinolones ; Humans ; Iran ; Microbial Sensitivity Tests ; Polymerase Chain Reaction ; Pseudomonas aeruginosa* ; Wounds and Injuries

PURPOSE: To evaluate the clinical outcomes of ertapenem administered as an outpatient parenteral antibiotic therapy for intractable cystitis caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. MATERIALS AND METHODS: We retrospectively reviewed a case series of 3 years of therapeutic experience with ertapenem for intractable recurrent cystitis caused by ESBL-producing E. coli. Ertapenem 1 g/d was parenterally administered to the patients on an outpatient basis until the acquisition of symptomatic improvement and negative conversion of urine culture. Demographic and clinical characteristics of patients, antimicrobial resistance, and clinical response data were analyzed from the patients' medical records. RESULTS: During the course of this study, a total of 383 patients were diagnosed with cystitis, and 24 of them showed ESBL-producing E. coli (6.26%). The mean treatment duration of all patients was 8.5 days. The early clinical and microbiological cure rates 0 to 7 days after the end of treatment were 91.7% (22/24) and 90.9% (20/22), respectively. The late clinical and microbiological cure rates 4 to 6 weeks after the end of treatment were 72.2% (13/18) at both time points. CONCLUSIONS: Parenteral ertapenem treatment can be an effective and well-tolerated treatment option for intractable recurrent cystitis by multidrug-resistant ESBL-producing E. coli.
beta-Lactamases ; beta-Lactams ; Cystitis* ; Escherichia coli* ; Escherichia* ; Female* ; Humans ; Medical Records ; Outpatients* ; Retrospective Studies

BACKGROUNDErtapenem has been demonstrated to be highly effective for the treatment of complicated infections. The aim of this study was to compare the efficacy and safety of ertapenem with ceftriaxone.

METHODSWe searched the PubMed, EMBASE, and the Cochrane Library for published randomized controlled trials (RCTs) that compared the efficacy and safety of ertapenem with ceftriaxone for the treatment of complicated infections including community-acquired pneumonia (CAP), complicated urinary tract infections (cUTIs), and complicated intra-abdominal infections (cIAIs). Meta-analysis was performed by RevMan 5.0.

RESULTSEight RCTs, involving 2 883 patients, were included in our meta-analysis. Ertapenem was associated with similar clinical treatment success with ceftriaxone for complicated infections (1 326 patients, fixed-effect model, OR: 1.13, 95% CI: 0.75-1.71). There was no difference between the compared treatment groups with regard to the microbiological treatment success, and no difference was found with regard to the incidence of clinical and laboratory drug-related adverse events between ertapenem and ceftriaxone groups. As to local tolerability, overall, there was no difference between the compared groups; however, in the subgroup analysis, local reaction was significantly less in the ertapenem subgroup than the ceftriaxone plus ceftriaxone subgroup.

CONCLUSIONSErtapenem can be used as effectively and safely as ceftriaxone for the treatment of complicated infections. It is an appealing option for the treatment of these complicated infections.

Anti-Bacterial Agents ; therapeutic use ; Ceftriaxone ; therapeutic use ; Humans ; Intraabdominal Infections ; drug therapy ; Pneumonia ; drug therapy ; Randomized Controlled Trials as Topic ; Urinary Tract Infections ; drug therapy ; beta-Lactams ; therapeutic use

OBJECTIVES: Group B Streptococcus (GBS), a common bowel commensal, is a major cause of neonatal sepsis and an emerging cause of infection in immune-compromised adult populations. Fluoroquinolones are used to treat GBS infections in those allergic to beta-lactams, but GBS are increasingly resistant to fluoroquinolones. Fluoroquinolone resistance has been previously attributed to quinolone resistance determining regions (QRDRs) mutations. We demonstrate that some of fluoroquinolone resistance is due to efflux-mediated resistance. METHODS: We tested 20 GBS strains resistant only to norfloxacin with no mutations in the QRDRs, for the efflux phenotype using norfloxacin and ethidium bromide as substrates in the presence of the efflux inhibitor reserpine. Also tested were 68 GBS strains resistant only to norfloxacin not screened for QRDRs, and 58 GBS strains resistant to ciprofloxacin, levofloxacin or moxifloxacin. Isolates were randomly selected from 221 pregnant women (35-37 weeks of gestation) asymptomatically carrying GBS, and 838 patients with GBS infection identified in South Korea between 2006 and 2008. The VITEK II automatic system (Biomerieux, Durham, NC, USA) was used to determine fluoroquinolone resistance. RESULTS: The reserpine associated efflux phenotype was found in more than half of GBS strains resistant only to norfloxacin with no QRDR mutations, and half where QRDR mutations were unknown. No evidence of the efflux phenotype was detected in GBS strains that were resistant to moxifloxacin or levofloxacin or both. The reserpine sensitive efflux phenotype resulted in moderate increases in norfloxacin minimum inhibitory concentration (average=3.6 fold, range=>1-16 fold). CONCLUSIONS: A substantial portion of GBS strains resistant to norfloxacin have an efflux phenotype.
Adult ; beta-Lactams ; Ciprofloxacin ; Ethidium ; Female ; Fluoroquinolones ; Humans ; Korea ; Levofloxacin ; Microbial Sensitivity Tests ; Norfloxacin* ; Phenotype ; Pregnant Women ; Reserpine ; Sepsis ; Streptococcus*

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

The Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have recently revised the susceptibility interpretive criteria of oxyimino-beta-lactams and carbapenems for Enterobacteriaceae. According to the new criteria, susceptibility testing results are sufficient to detect extended-spectrum beta-lactamases (ESBLs) and carbapenemases; it is not necessary to perform ESBL or carbapenemase detection tests for therapeutic purposes. Thus, it has been recommended that these related tests be performed only for infection control. These changes in the susceptibility guidelines are supported by some clinical cases and the results of pharmacodynamic and animal studies. However, differences still exist between the breakpoints established by the CLSI and EUCAST with regard to some oxyimino-beta-lactam and carbapenem antibiotics, in particular, the breakpoints for ceftazidime and cefepime established by the CLSI are higher than those established by the EUCAST. Also, similar numbers of successful and unsuccessful cases have been reported regarding the use of cephalosporins or carbapenems in treating infections caused by low-minimal inhibitory concentration (MIC) ESBL-producers or low-MIC carbapenemase-producers. Finally, routine susceptibility test methods are not as accurate as research-purpose test methods, showing differences in MICs ranging approximately from 1 to 8 microg/mL. In conclusion, it is strategically prudent to continue to perform ESBL and carbapenemase detection tests and to avoid the use of the corresponding antimicrobial agents for the treatment of ESBL- or carbapenemase-producing bacterial infections.
Animals ; Anti-Infective Agents ; Bacterial Infections ; Bacterial Proteins ; beta-Lactamases ; beta-Lactams ; Carbapenems ; Ceftazidime ; Cephalosporins ; Enterobacteriaceae ; Infection Control ; Microbial Sensitivity Tests