Previous studies have explored combining β-lactams with siderophores to create Trojan horse molecules that can penetrate the outer membrane of Gram-negative bacteria via TonB-dependent transporter (TBDT). While the main advantage explaining their enhanced antibiotic activity is believed to be improved membrane permeability, other factors remain underexplored. This study evaluates three siderophore-β-lactam compounds: a bis-catechol siderophore linked to ampicillin or loracarbef, and a mixed bis-catechol-mono-hydroxamate siderophore linked to cefaclor. Minimal inhibitory concentrations showed that siderophore conjugation could enhance β-lactam efficacy by over 8000-fold. Comparison with unconjugated β-lactams revealed a complex interplay between β-lactamase susceptibility, competition with endogenous siderophore, membrane uptake, and binding to penicillin-binding proteins (PBPs). Enhanced PBP binding, particularly in Escherichia coli, emerged as a key factor contributing to improved bacterial inhibition by siderophore-β-lactam conjugates. Overall, the study provides insights into how siderophore conjugation enhances β-lactam activity and the therapeutic potential of the conjugates as narrow or broad-spectrum antibiotics.

An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.

Although no information is available on the use of loracarbef during breastfeeding, beta-lactam antibiotics are generally not be expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush have been reported with beta-lactams, but these effects have not been adequately evaluated. Loracarbef is acceptable in nursing mothers.

There is increasing resistance to the oral antibiotics currently recommended for the treatment of pyelonephritis, and increased healthcare costs are associated with the reliance on alternative intravenous agents. We, therefore, performed a systematic review of randomised controlled trials to determine the clinical efficacy and safety of oral antibiotics for the treatment of pyelonephritis in adults. A search of four major medical databases (MEDLINE, Embase+ Embase classic, CENTRAL and Cochrane Database for Systematic Reviews) in addition to manual reference searching of relevant reviews was conducted. Clinical cure and adverse event rates were reported, and trial quality and bias were assessed. A total of 277 studies were reviewed; five studies matched all eligibility criteria and were included. Antibiotics included were cefaclor, ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, loracarbef, norfloxacin, rufloxacin and trimethoprim-sulfamethoxazole. In included studies, the clinical success of the outpatient treatment of pyelonephritis by cefaclor, ciprofloxacin and norfloxacin at 4 to 6 weeks was comparable at between 83 to 95%. Relatively high rates of adverse events were noted in a trial of ciprofloxacin (24%) and trimethoprim-sulfamethoxazole (33%). Significant heterogeneity between all aspects of the trial designs was identified, with all studies having a potential for bias. This review demonstrates a need for high-quality clinical trials into the oral antibiotic treatment of pyelonephritis, with more consistent designs and reporting of outcomes. There are data to support further research into oral norfloxacin and cefaclor for the outpatient treatment of pyelonephritis in adults.

Two laboratory mutants of NDM-1 were generated by replacing the isoleucine at position 35 with threonine and serine residues: the NDM-1(I35T)and NDM-1(I35S)enzymes. These mutants were well characterized, and their kinetic parameters were compared with those of the NDM-1 wild type. Thekcat,Km, andkcat/Kmvalues calculated for the two mutants were slightly different from those of the wild-type enzyme. Interestingly, thekcat/Kmof NDM-1(I35S)for loracarbef was about 14-fold higher than that of NDM-1. Far-UV circular dichroism (CD) spectra of NDM-1 and NDM-1(I35T)and NDM-1(I35S)enzymes suggest local structural rearrangements in the secondary structure with a marked reduction of α-helix content in the mutants.

Chemical syntheses and biological evaluation of biscatecholate-monohydroxamate mixed ligand sideromycins utilizing the carbacephalosporin β-lactam antibiotic loracarbef and the fluoroquinolone antibiotic ciprofloxacin are described. The mixed ligand β-lactam sideromycin (1b) had remarkably selective and extremely potent antibacterial activity against the Gram-negative pathogen Acinetobacter baumannii ATCC 17961 (MIC = 0.0078 μM). The antibacterial activity of the β-lactam sideromycin was inversely related to the iron(III) concentration in the testing media and was antagonized by the presence of the competing parent siderophore. These data suggested that active transport of the mixed ligand β-lactam sideromycin across the outer cell membrane of A. baumannii via siderophore-uptake pathways was responsible for the selective and potent antibacterial activity.

Three siderophore-drug conjugates (sideromycins) were synthesized by preparation of a maleimide linked derivative of the siderophore desferrioxamine B and reacting the corresponding Ga(3+)-complex with freshly prepared thiol-containing antibiotics: loracarbef, ciprofloxacin and nadifloxacin. The conjugates and their synthetic precursors were tested against a broad panel of bacteria and were found to display Gram-positive selective, growth inhibitory activity (µM) indicating that this approach is suitable for the convergent synthesis and screening of novel sideromycins.

Clinical and Laboratory Standards Institute breakpoints for cefazolin against Enterobacteriaceae that were published in January 2010 have been revised by the Subcommittee on Antimicrobial Susceptibility Testing, based on the examination of recent data about in vitro activity, pharmacokinetic-pharmacodynamic characteristics and published clinical outcome studies. The new breakpoints, to be formally published in January 2011, have increased the minimum inhibitory concentration interpretive criteria by one 2-fold dilution, linked to an adult dosing schedule of 2 g every 8 h intravenously. Disk diffusion zone diameter correlates, shown to be impossible to define with the January 2010 interpretive criteria, have been able to be set for the new interpretive criteria. Diagnostic laboratories will continue to need to test cephalothin to predict susceptibility to the oral cephalosporins cefadroxil, cefpodoxime, cephalexin, and loracarbef.

Novel cephalosporins, penicillins, and carbacephems were synthesized by amination of catechols with amino-beta-lactams like cefadroxil, amoxicillin, ampicillin and the structurally related carbacephem loracarbef using laccase from Trametes sp. All isolated monoaminated products inhibited the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus strains and vancomycin-resistant Enterococci. Observed differences in the cytotoxicity and in vivo activity in a "Staphylococcus-infected, immune suppressed mouse" model are discussed.

This randomized open-label single-dose crossover pharmacokinetic study was carried out to assess the effect of different diets on the bioavailability of loracarbef in 24 healthy male volunteers. A single dose of loracarbef in 200-mg tablet form was administered at 5 different times: after overnight fasting, after two vegetarian (high-fat and low-fat) diets, and following two non-vegetarian (high-fat and low-fat) diets. Serial blood samples were collected up to 10 h post-dose. Serum loracarbef concentrations were determined by a validated high performance liquid chromatographic (HPLC) method. Area under curve (AUC) values were significantly affected only by non-vegetarian diets; however the time to reach maximum serum concentration (Tmax) was prolonged and the maximum serum concentration (Cmax was decreased by all types of meals. The non-vegetarian diets affected the rate of absorption of loracarbef more than the vegetarian diets. The lowest decrease in Cmax was produced by the high-fat vegetarian diet, while the maximum was produced by the low-fat non-vegetarian diet. The results of this study indicate that while the rate of loracarbef absorption is significantly decreased by all diets, the extent of absorption is only reduced significantly by the non-vegetarian diets. The rate of elimination (k(el)) was not found to be significantly decreased by any of the diets. As compared to the high-fat non-vegetarian diet, the time beyond minimum inhibitory concentration (MIC90) concentration was significantly increased by the high-fat vegetarian diet. The implications of these findings for the large Indian vegetarian population are considerable.

The present study was performed to investigate the in vitro activity of oxacillin and other antimicrobial agents against S. aureus strains obtained from nursing personnel. We tested 127 S. aureus colonizing nasal mucous and hand skin and isolated from nursing personnel of University Hospital Department of Infectious Diseases, Iaşi, during June 2005 period. Minimum inhibitory concentrations (MICs) were determined by the dilution method in Mueller-Hinton agar. Most of the S. aureus strains were susceptible to tested agents excepted erythromycin and azithromycin. Erythromycin and azithromycin resistance was observed among 29.1% respectively 22% of S. aureus strains. Vancomycin was active against all isolates. Teicoplanin was active against against all MRSA excepted one of the strain, with an reduced susceptibility. Linezolid has very good in vitro activity against staphylococci, with an MIC 90 of 2 mcg/ml and only 0.8% resistance. The MIC values range was between 0.5-2 mcg/ml. In conclusion, the usually hygienic methods (disposable gowns, hygienic hand disinfection after each patients contact, masks use when is a risk of aerosolization of MRSA) are indicate for significantly reducing of these strains.

Sixteen novel cephalosporins were synthesized by amination of 2,5-dihydroxybenzoic acid derivatives with the aminocephalosporins cefadroxil, cefalexin, cefaclor, and the structurally related carbacephem loracarbef using laccases from Trametes sp. or Myceliophthora thermophila. All products inhibited the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The products protected mice against an infection with Staphylococcus aureus lethal to the control animals. Cytotoxicity and acute toxicity of the new compounds were negligible. The results show the usefulness of laccase for the synthesis of potential new antibiotics. The biological activity of the new compounds stimulates intensified pharmacological tests.

Loracarbef is an oral synthetic beta-lactam antibiotic of the carbacephem class. The aim of this study was to compare the efficacy and safety of loracarbef 15 mg/kg versus 30 mg/kg in children with acute sinusitis. A randomized, parallel-group, clinical study was conducted. Fifty-eight children aged 5-12 years with acute sinusitis were divided into two groups, which received either loracarbef 15 mg/kg/day or 30 mg/kg/day orally, divided in two doses for 10 days. Clinical examination, anterior rhinoscopy and sinus radiographs were performed at the beginning of treatment. Clinical evaluation was repeated in a second session, 0-2 days after the final dose, and in a third session, 30 days after the beginning of the treatment. Sinus X-rays were repeated selectively in the second session and in all patients in the third session. Nineteen of 29 (65.5%) patients in the 15 mg/kg/day group and 26 of 29 (89.6%) in the 30 mg/kg/day group were characterized as completely or clinically cured at the end of the study. In conclusion, a statistically significant difference between the two treatment groups was shown with better results in the 30 mg/kg group. Despite the slight difference in adverse events between the two groups (with fewer adverse events in the 15 mg/kg group), we recommend that if loracarbef is chosen as initial therapy in acute sinusitis, a regimen of 30 mg/kg/day in two doses is followed.