hr-810 and Escherichia-coli-Infections

Antibiotics not only support to alleviate the infections but also facilitate to avert the multiplication of microbes. Due to the irrational use of antibiotics, the resistance of antibiotics has been augmented which results may increase in morbidity and mortality with the span of time. World renowned regulatory bodies like Food and Drug Administration (FDA), Center of Disease Control and Prevention (CDC), and World Health Organization (WHO) vigorously advocate the surveillance of the resistance of antibiotics. During the present study by Kirby-Bauer disk diffusion method 141 clinical isolates of Staphylococcus aureus (n=47, 33.34%), Escherichia coli (n=54, 38.3%), Proteus species (n=26, 18.4%), and Klebsiella pneumoniae (n=14, 9.92%) are evaluated against cefepime and cefpirome which comes of fourth generation cephalosporin. It has been found that cefpirome has better bactericidal activity than cefepime against E. coli and K. pneumoniae while cefepime has been possessed better antibacterial activity against S. aureus and Proteus species which were isolated from respiratory tract infections, blood stream infection, intra-abdominal and urinary tract infections, and skin and soft tissue infections. K. pneumoniae, E. coli, Proteus species, and S. aureus were 34.8%, 26.3%, 11.3%, and 37.7% resistance against cefepime respectively. S. aureus, E. coli, K. pneumoniae, Proteus species has shown 41.4%, 21.7%, 17.6%, and 8.9% resistance against cefpirome correspondingly.

Topics: Anti-Bacterial Agents; Bacteremia; Cefepime; Cefpirome; Cephalosporins; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; In Vitro Techniques; Intraabdominal Infections; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pakistan; Proteus; Proteus Infections; Respiratory Tract Infections; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus aureus; Urinary Tract Infections

Two clinical isolates of Escherichia coli, EC18 and EC21, were non-susceptible (MICs 4-16 mg/L) to cefpirome and cefepime, with marked synergy with clavulanate, yet were susceptible to cefotaxime and ceftazidime (MICs ≤ 1 mg/L). EC19, from the same patient as EC21, was susceptible to all four cephalosporins. We sought to characterize the molecular basis of resistance in isolates EC18 and EC21.. PFGE was used to study the genetic relationships of the isolates, and MICs were determined. β-Lactamases were characterized by PCR, isoelectric focusing (IEF), construction of genomic libraries and sequencing. A double mutant of E. coli J53 was constructed, lacking OmpC and OmpF porins. Plasmids from clinical isolates were transformed into E. coli J53 and J53ΔompCF. Outer membrane proteins (OMPs) were analysed by SDS-PAGE and OmpA by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. Expression of omp and bla genes was analysed by RT-PCR.. Isolates EC19 and EC21 had identical PFGE profiles, whereas EC18 was distinct. PCR and IEF confirmed β-lactamases with pIs of 5.4 (TEM-1) in EC18 and 7.4 (OXA-1) in both EC19 and EC21. EC18 had bla(TEM-1b) with the strong promoter P5 and lacked OmpC and OmpF. RT-PCR showed stronger expression of bla(OXA-1) in EC21 versus EC19, along with diminished expression of OmpC, though with increased OmpF. Plasmids extracted from EC18 and EC21 conferred increased MICs of cefpirome and cefepime, although susceptibility to cefotaxime and ceftazidime was retained.. The 'cefpiromase' or 'cefepimase' ESBL phenotype of the clinical isolates non-susceptible to cefpirome and cefepime resulted from high expression of TEM-1 or OXA-1 β-lactamases combined with loss of porins.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; beta-Lactamases; Cefepime; Cefpirome; Cephalosporins; Clavulanic Acid; DNA; DNA, Recombinant; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enzyme Inhibitors; Escherichia coli; Escherichia coli Infections; Isoelectric Focusing; Microbial Sensitivity Tests; Plasmids; Porins; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transformation, Bacterial

Two clinical strains of Escherichia coli (2138) and Enterobacter cloacae (7506) isolated from the same patient in France and showing resistance to extended-spectrum cephalosporins and low susceptibility to imipenem were investigated. Both strains harbored the plasmid-contained bla(TEM-1) and bla(KPC-2) genes. bla(KLUC-2), encoding a mutant of the chromosomal beta-lactamase of Kluyvera cryocrescens, was also identified at a plasmid location in E. cloacae 7506, suggesting the ISEcp1-assisted escape of bla(KLUC) from the chromosome. Determination of the KPC-2 structure at 1.6 A revealed that the binding site was occupied by the C-terminal (C-ter) residues coming from a symmetric KPC-2 monomer, with the ultimate C-ter Glu interacting with Ser130, Lys234, Thr235, and Thr237 in the active site. This mode of binding can be paralleled to the inhibition of the TEM-1 beta-lactamase by the inhibitory protein BLIP. Determination of the 1.23-A structure of a KPC-2 mutant in which the five C-ter residues were deleted revealed that the catalytic site was filled by a citrate molecule. Structure analysis and docking simulations with cefotaxime and imipenem provided further insights into the molecular basis of the extremely broad spectrum of KPC-2, which behaves as a cefotaximase with significant activity against carbapenems. In particular, residues 104, 105, 132, and 167 draw a binding cavity capable of accommodating both the aminothiazole moiety of cefotaxime and the 6 alpha-hydroxyethyl group of imipenem, with the binding of the former drug being also favored by a significant degree of freedom at the level of the loop at positions 96 to 105 and by an enlargement of the binding site at the end of strand beta 3.

Topics: Aged; Base Sequence; beta-Lactam Resistance; beta-Lactamases; beta-Lactams; Catalytic Domain; Cephalosporin Resistance; Crystallography, X-Ray; DNA Primers; DNA, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; France; Genes, Bacterial; Humans; Imipenem; Kinetics; Male; Models, Molecular; Mutation

In a rabbit Escherichia coli meningitis model, endotoxin liberation and concentrations of leukocytes, tumor necrosis factor (TNF), and lactate were compared after a single intravenous dose of cefotaxime, cefpirome, meropenem, chloramphenicol, or gentamicin. These antibiotics caused a 2- to 10-fold increase in cerebrospinal fluid concentrations of free (filterable) endotoxin within 2 h of starting treatment. By contrast, free endotoxin concentrations increased almost 100-fold in untreated animals 4 h later as bacteria continued to multiply. An initial enhancement of inflammation in the central nervous system occurred in all treatment groups compared with untreated controls. No significant differences were observed between treatment groups except for lower TNF concentrations in chloramphenicol-treated animals. Antibiotic therapy in E. coli meningitis, irrespective of the agent used, may result in an increase in free endotoxin and enhancement of inflammation, but the amount of endotoxin liberated is considerably smaller than that shed by untreated bacteria.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Cefpirome; Cephalosporins; Chloramphenicol; Endotoxins; Escherichia coli Infections; Gentamicins; Inflammation; Male; Meningitis, Bacterial; Meropenem; Rabbits; Thienamycins

Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad spectrum of gram-negative and gram-positive organisms. The pharmacokinetics and bacteriological efficacy of cefpirome administered as a single intravenous dose were assessed in rabbits with experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. The mean penetrations into the cerebrospinal fluid (CSF) in relation to the amount of drug in serum of animals infected with H. influenzae and E. coli were 25 and 54%, respectively. The median CSF bactericidal titers were 1:128 against both organisms at 1 h of uninfected animals, the mean penetration was 4.5%. There was a significant reduction in the concentrations of bacteria in CSFs of both groups of animals treated with cefpirome compared with that in untreated groups. Mortality was also significantly lower in treated animals than it was in untreated animals. Intravenous administration of dexamethasone before the cefpirome dose did not compromise penetration, bactericidal titers, or antibacterial activity of cefpirome in CSF.

Topics: Animals; Cefpirome; Cephalosporins; Colony Count, Microbial; Escherichia coli; Escherichia coli Infections; Haemophilus influenzae; Male; Meningitis, Haemophilus; Microbial Sensitivity Tests; Rabbits

In systemic and local infections, the therapeutic efficacy of cefpirome was compared to that of imipenem and cefotaxime. Murine septicemia induced with methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains responded well to cefpirome and imipenem therapy, the ED50 values ranged from 0.8 to 28.40 mg/kg and 0.5 to 15.58 mg/kg, respectively. The carbapenem also displayed high efficacy against Enterococci and was more potent than cefpirome. Cefotaxime, however, exhibited lower activity or proved to be inactive against these strains. With ED50 values of 0.03 to 31.33 mg/kg, cefpirome was the most active of the three antibiotics in protecting mice challenged with Enterobacteriaceae. The corresponding ED50 values of imipenem and cefotaxime ranged from 0.72 to 70.95 mg/kg and 0.06 to 66.30 mg/kg, respectively. Despite distinctly lower in vitro activity against the infecting organism, cefpirome showed efficacy similar to imipenem in the treatment of subcutaneous S. aureus abscesses in mice. It was more effective than imipenem and cefotaxime against experimental Klebsiella pneumonia in mice and the Escherichia coli infected granuloma pouch in rats.

Topics: Abscess; Animals; Bacterial Infections; Cefotaxime; Cefpirome; Cephalosporins; Enterobacteriaceae Infections; Escherichia coli Infections; Female; Granuloma; Imipenem; Male; Mice; Mice, Hairless; Mice, Inbred C3H; Pneumonia; Rats; Rats, Inbred Strains; Sepsis; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections