Biomedical subjects

R E Kessler

Publications and source records attributed to R E Kessler.

At least 37 records · Page 2Linked to original sources

PubMed1991

In vitro activities of cefepime alone and with amikacin against aminoglycoside-resistant gram-negative bacteria.

The in vitro activity of cefepime was compared with those of ceftazidime, cefotaxime, and cefpirome against aminoglycoside-resistant gram-negative bacteria. Cefepime was the most active cephalosporin, with a MIC for 90% of strains tested for all non-Pseudomonas aeruginosa species of less than or equal to 4 micrograms/ml. No cefepime resistance was encountered among members of the family Enterobacteriaceae. Of the 40 aminoglycoside-resistant P. aeruginosa isolates, 15% were resistant to cefepime, compared with 18% for ceftazidime, 30% for cefpirome, and 35% for cefotaxime. Synergism between cefepime and amikacin was observed and occurred most frequently in P. aeruginosa strains resistant to cefepime but susceptible to amikacin. In no case did cefepime and amikacin exhibit antagonism against P. aeruginosa.

Amikacin↗

PubMed1991

Inability of cephalothin testing to predict cefprozil susceptibility.

The 30-micrograms cefprozil disk and the cephalosporin class (30-micrograms cephalothin) disk were compared for their abilities to predict cefprozil susceptibility by agar disk diffusion testing. High error (5.02% major and 14.11% minor) rates were encountered with the cephalothin disk and were most frequently observed for Escherichia coli and Enterococcus faecalis. The cefprozil disks resulted in rates of 0.05% very major, 0% major, and 3.72% minor errors. Thus, the 30-micrograms cefprozil disk is more desirable for predicting cefprozil susceptibility.

Cephalosporins↗

PubMed1991

Emergence of homogeneously methicillin-resistant Staphylococcus aureus.

Forty-seven clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), collected between 1986 and 1990 from 29 institutions, were analyzed for susceptibility to various antibiotics. Twenty-six strains were homogeneously methicillin resistant (i.e., greater than or equal to 10% of the cells in these strains were able to grow on Mueller-Hinton agar containing 50 micrograms of methicillin per ml). The MICs of gentamicin, clindamycin, trimethoprimsulfamethoxazole, methicillin, and imipenem for homogeneous MRSA strains were higher than those for heterogeneously resistant strains. Both types of strains were, for the most part, susceptible to vancomycin and trimethoprim-sulfamethoxazole. Ciprofloxacin-resistant MRSA strains were not isolated prior to 1988 but made up 40% of the post-1987 strains. The level of methicillin resistance correlated well with the imipenem MIC, suggesting that susceptibility to imipenem may serve as a marker to identify and monitor the prevalence of homogeneous MRSA strains.

Culture Media↗

PubMed1990

Fluoronaphthyridines and quinolones as antibacterial agents. 2. Synthesis and structure-activity relationships of new 1-tert-butyl 7-substituted derivatives.

A number of 7-substituted-1-tert-butyl-6-fluoroquinolone-3-carboxylic acids and 7-substituted-1-tert-butyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids have been prepared and tested for antibacterial activities. Among those the 7-aminopyrrolidinyl 20b and the 7-diazabicyclo naphthyridine 18b are the most potent compounds in vitro and in vivo. Physicochemical data and acute toxicity are also discussed. Compound 18b, BMY 40062, exhibits the most favorable overall properties, considering in vitro and in vivo microbiological activity, its low toxicity, and pharmacokinetic profile, and was selected for clinical evaluation.

4-Quinolones↗

PubMed1990

Therapeutic studies of cefepime (BMY 28142) in murine meningitis and pharmacokinetics in neonatal rats.

Cefepime (BMY 28142) was compared with ceftazidime, cefotaxime, and moxalactam for efficacy in treating experimental meningitis in mice and neonatal rats. Mice were infected intracranially with Streptococcus pneumoniae, S. agalactiae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa and treated intramuscularly. Five- to eight-day-old neonatal rats were injected intracisternally with Haemophilus influenzae, S. pneumoniae, and S. agalactiae and treated intraperitoneally. Cefepime was found to be the most active compound against induced meningitis in mice infected with S. agalactiae. Cefepime was as active as cefotaxime against Staphylococcus aureus meningitis, slightly more active than cefotaxime against S. pneumoniae and E. coli, and as active as ceftazidime against K. pneumoniae and P. aeruginosa meningitis. Cefepime was found to be the most active compound against S. pneumoniae and S. agalactiae meningitis in neonatal rats. Against H. influenzae, cefepime was as active as moxalactam and cefotaxime. Ceftazidime was the least active compound. The pharmacokinetics of cefepime in neonatal rats were similar to those of ceftazidime. Both compounds penetrated well into cerebrospinal fluid and brain tissues of uninfected neonatal rats. Relative concentrations were twice as high as those of cefotaxime and moxalactam.

Animals↗

PubMed1989

In vitro and in vivo evaluations of a new broad-spectrum oral cephalosporin, BMY-28232, and its prodrug esters.

The in vitro activity of a new cephalosporin, BMY-28232 (7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[ (Z)-1- propenyl]-3-cephem-4-carboxylic acid), was compared with those of cefuroxime and BMY-28488, the 3-vinyl congener of BMY-28232, against 899 bacteria including strains resistant to newer cephalosporins. BMY-28232 displayed potent, broad-spectrum antibacterial activity with high stability to various types of beta-lactamase. Its acetoxyethyl ester (BMY-28271) and pivaloyloxymethyl ester (BMY-28257) were well absorbed after oral administration to mice and rats. Both esters were metabolized to BMY-28232 and mainly excreted in urine. Oral bioavailability of both prodrug esters (60 to 70%) was better than that of cefuroxime axetil (46%) and gave excellent therapeutic efficacy against gram-positive- and gram-negative-bacterial infections in mice. Oral 50% protective doses (in milligrams per kilogram of body weight) of 0.65 and 0.72 for Staphylococcus aureus Smith, 0.9 and 1.2 for Escherichia coli Juhl, 1.6 and 1.6 for Proteus vulgaris, and 18.9 and 14.3 for Enterobacter cloacae were obtained for BMY-28271 and BMY-28257, respectively.

Animals↗

PubMed1989

Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels.

One hundred clinical isolates resistant to ceftazidime and/or cefotaxime were examined for susceptibility to cefepime. The most frequently encountered ceftazidime-cefotaxime-resistant strains belonged to the genera Enterobacter, Pseudomonas, and Citrobacter. Among these strains, 92% were resistant to cefoperazone, 91% were resistant to cefotaxime, 84% were resistant to ceftazidime, and 6% were resistant to cefepime. Of the members of the family Enterobacteriaceae, 57% were resistant to ceftriaxone. The six strains resistant to cefepime were all Pseudomonas aeruginosa and were resistant to both cefotaxime and ceftazidime. Cefepime-resistant P. aeruginosa strains had exceptionally high levels of beta-lactamase activity, higher than the levels found in strains resistant to ceftazidime but susceptible to cefepime. The beta-lactamases from the cefepime-resistant strains were type I (Richmond-Sykes), were constitutively produced, and did not have increased affinity or hydrolytic activity for cefepime. Thus, cefepime was active against most gram-negative bacteria which have developed resistance to the broad-spectrum cephalosporins, and resistance to cefepime in P. aeruginosa appears to be associated with higher beta-lactamase levels than in cefepime-susceptible strains.

Bacterial Infections↗

PubMed1989

In vitro and in vivo antibacterial activities of BMY 40062, a new fluoronaphthyridone.

The in vitro and in vivo activities of a new naphthyridone, BMY 40062, were compared with those of ciprofloxacin and ofloxacin. BMY 40062 showed about threefold more activity than ciprofloxacin showed and four- to eightfold more activity than ofloxacin showed against staphylococci, streptococci, and enterococci. BMY 40062 showed generally twofold less activity than ciprofloxacin showed against most species of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter spp. but twofold more activity than ofloxacin showed against these organisms. BMY 40062 and ofloxacin were more active than ciprofloxacin against Bacteroides fragilis and Clostridium difficile. The antiureaplasmal and antichlamydial activities of BMY 40062 were similar to those of the tetracyclines and were 4- and 16-fold, respectively, higher than those of ciprofloxacin. The in vitro activities of BMY 40062 were influenced by pH and magnesium, although these factors appeared to affect the activity of BMY 40062 against P. aeruginosa to a lesser extent than those of ciprofloxacin and ofloxacin. BMY 40062 was found to be bactericidal, and cross-resistance with other fluoroquinolones was observed. In mouse protection tests, the efficacy of BMY 40062 reflected its in vitro potency. BMY 40062 exhibited longer half-life, higher maximum concentration in serum, greater area under the curve, and better bioavailability in mice after oral dosing than ciprofloxacin. Compared with ofloxacin, BMY 40062 had a lower maximum concentration in serum but a much longer half-life in mice. BMY 40062 was more effective than ciprofloxacin and ofloxacin in penetrating mouse macrophages and killing macrophage-associated Staphylococcus aureus.

Animals↗

PubMed1988

Frequency of in vitro resistance of Pseudomonas aeruginosa to cefepime, ceftazidime, and cefotaxime.

The selection frequencies of cefepime (BMY 28142), ceftazidime, and cefotaxime resistance among Pseudomonas aeruginosa strains were determined. Cefepime-resistant mutants were not selected by cefepime (frequency, less than 10(-11)). Ceftazidime- and cefotaxime-resistant mutants were isolated at frequencies of 10(-5) to 10(-10) and were often cross-resistant. However, cefepime resistance among ceftazidime- and cefotaxime-resistant mutants was rare. Selected mutants resistant to cefepime constitutively produced 40- to 450-fold more beta-lactamase than did the parent strain.

Cefepime↗

PubMed1988

Glucan-binding factor in saliva.

High-molecular-weight polymers of alpha-1,6-linked D-glucans are insoluble in alcohol solutions. Whole, but not parotid, saliva prevented the precipitation of D-glucans by 80% (vol/vol) ethanol, showing that the whole saliva contained a factor which complexed with the glucan to render it alcohol soluble. The glucan-binding factor was retained on a column of Sephacryl S-200 which had been preequilibrated with 80% ethanol. The factor was then eluted with water. Passive hemagglutination assays revealed that the glucan-binding factor could sensitize erythrocytes to agglutination with anti-poly(glycerolphosphate), suggesting that the active glucan-binding component with lipoteichoic acid. The glucan-solubilizing factor was resistant to heat (100 degrees C), proteases, sialidase, lysozyme, lactoperoxidase, trichloroacetic acid, and Triton X-100. When sucrose was added to saliva, a suspension of Streptococcus cricetus AHT, or a suspension of Streptococcus sanguis 10556, relatively large amounts of glucan-binding factor were released in a soluble form. In addition, penicillin G caused the release of the glucan-solubilizing component from a suspension of S. cricetus AHT. It is suggested that whole saliva contains a component, tentatively identified as lipoteichoic acid, which can complex with glucans in a relatively hydrophobic solvent. This type of complex formation may be important in the adhesion of oral streptococci to saliva-coated surfaces.

Glucans↗

PubMed1988

Quantitation of effects of subinhibitory concentrations of trimethoprim on P fimbria expression and in vitro adhesiveness of uropathogenic Escherichia coli.

The ability to adhere to and colonize urogenital mucosa is an important virulence attribute of uropathogenic Escherichia coli. This adherence, which appears to be mediated by P fimbriae, may be affected by antibiotics or other agents that affect fimbrial expression. We describe here an enzyme immunofiltration assay to quantitate fimbriation and the application of that technique to measurement of the effects of sublethal doses of trimethoprim on P fimbrial expression. Effects on P fimbriation correlated with effects on the adherence of treated bacteria to cultured T24 bladder carcinoma epithelial cells; i.e., trimethoprim treatment decreased both P fimbriation and bacterial adherence. It was possible to quantitate effects on P fimbriation when type 1 fimbriae were also present. The enzyme immunofiltration assay may be useful for studies on the role of fimbriae in the pathogenesis of bacterial infections, and it may facilitate identification of antimicrobial agents that interfere with bacterial adherence to mucosal surfaces.

Bacterial Adhesion↗

PubMed1987

BMY 28100, a new oral cephalosporin.

BMY 28100, a new oral cephalosporin with a (Z)-propenyl side chain at the 3 position and a p-hydroxyphenylglycyl substituent at the 7 position, was evaluated in comparison with cefaclor and cephalexin and, when appropriate, ampicillin and vancomycin. In vitro, BMY 28100 was more active than the reference cephalosporins against streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, Haemophilus influenzae, Propionibacterium acnes, Clostridium perfringens, and Clostridium difficile. BMY 28100 was comparable to cefaclor and more active than cephalexin against Staphylococcus saprophyticus and ampicillin-susceptible strains of Branhamella catarrhalis; but against ampicillin-resistant strains of B. catarrhalis, BMY 28100 was comparable to cephalexin and more active than cefaclor. Against Neisseria gonorrhoeae, BMY 28100 was comparable to cephalexin, but less active than cefaclor. Members of the family Enterobacteriaceae overall were equally susceptible to BMY 28100 and cefaclor but were less susceptible to cephalexin. In human serum, BMY 28100 was 45% protein bound. After an oral dose to mice, 82% of the drug was recovered in urine. The oral therapeutic efficacy of BMY 28100 in systemically infected mice reflected its activity in vitro.

Animals↗

PubMed1986

Affinity of cephalosporins for beta-lactamases as a factor in antibacterial efficacy.

Strains of Escherichia coli, Enterobacter aerogenes, and Enterobacter cloacae that were resistant to ceftazidime (MIC greater than 16 micrograms/ml) but susceptible to BMY 28142 (MIC less than 4 micrograms/ml) were found to contain higher levels of beta-lactamase activity (50- to 3,340-fold) than control strains of the corresponding species. Ceftazidime was at least as resistant as BMY 28142 to hydrolysis by these enzymes. However, the apparent Ki of BMY 28142 for each enzyme was larger (8- to greater than 20-fold) than that of ceftazidime; i.e., the affinity of these enzymes for BMY 28142 appeared to be lower than that for ceftazidime. Thus, BMY 28142 was affected less than ceftazidime by a mechanism of resistance that depends, at least in part, on the relative affinities of cephalosporins for the beta-lactamases of these species. These results indicate that the affinity between a beta-lactamase and a cephalosporin may be a distinguishing factor in the evaluation of beta-lactamase-resistant cephalosporins and suggest that affinity can play a major role in susceptibility to highly beta-lactamase-resistant cephalosporins.

Bacteria↗

PubMed1986

Identification of pheromone-induced surface proteins in Streptococcus faecalis and evidence of a role for lipoteichoic acid in formation of mating aggregates.

The conjugative transfer of the Streptococcus faecalis plasmid pAD1 is characterized by a 10,000-fold increase in frequency following sex pheromone (cAD1) induction. Before the increase in plasmid transfer, donor cells synthesize a proteinaceous adhesin that facilitates the formation of mating aggregates. Four novel surface proteins appearing after exposure of pAD1-containing cells to sex pheromone have been identified. Thirty minutes after induction, a 130-kilodalton (kDa) protein was detectable by Western blotting. A 74-kDa protein, the major species present, and a pair of bands at 153 and 157 kDa were evident 45 min after induction. Induced cells containing another conjugative S. faecalis plasmid, pPD1, gave rise to three high-molecular-weight proteins of the same size (130, 153, and 157 kDa) as those synthesized by pAD1-containing cells. These proteins cross-reacted with antisera raised against induced cells containing pAD1. However, the major protein species produced by pPD1-containing cells had a molecular weight of 78,000 and did not cross-react significantly with the corresponding band of the pAD1 system. Pheromone-induced transfer of the two plasmids, when both were present in the same cell, was independent; induction was limited to the pheromone-specified plasmid. The possibility that lipoteichoic acid might act as a receptor (binding substance) for the induced adhesin protein was also explored. Free lipoteichoic acid (isolated from S. faecalis) inhibited clumping of induced cells, apparently by acting as a competitive inhibitor of the cellular binding substance.

Bacterial Proteins↗

PubMed1985

Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum beta-lactam antibiotics.

BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.

Animals↗

PubMed1985

Pretreatment with lipoteichoic acid sensitizes target cells to antibody-dependent cellular cytotoxicity in the presence of anti-lipoteichoic acid antibodies.

This study was performed to determine whether antibody-dependent cellular cytotoxicity (ADCC) could be directed against mammalian cells sensitized with spontaneously adhering bacterial substances. 51Cr-labeled SB leukemia cells were incubated with purified S43 group A streptococcal lipoteichoic acid (LTA; 0.001 to 100 micrograms/ml). Purified leukocyte ADCC effector cells were added to the LTA-coated target cells at various effector-to-target ratios (100:1 to 12:1), followed by the addition of rabbit anti-LTA. After incubation for 4 h, target cell lysis was calculated based on the release of label into the medium. As little as 1 ng of LTA per ml was sufficient to sensitize the target cells to ADCC lysis (12%); however, concentrations above 0.1 micrograms/ml generally resulted in 60 to 80% lysis. LTA alone was not cytotoxic to these target cells. Targeting did not occur if effector cells were sensitized or if free LTA was added to the medium. Specificity was demonstrated by cold-target inhibition, which showed that anti-LTA cytotoxicity could be inhibited only by unlabeled, LTA-treated target cells but not by cold SB cells alone. The findings indicate that certain soluble bacterial components, when bound to mammalian cells in the presence of specific antibody, can target ADCC effectors to these cells. This mechanism may be an important factor in the delayed sequelae of bacterial infections.

Adolescent↗

PubMed1984

Interaction of anti-kojibiose antibody with the lipoteichoic acids from Streptococcus faecalis and Streptococcus faecium.

Antisera prepared in rabbits by immunization with p-aminophenyl beta-kojibioside conjugated to bovine serum albumin (antikojibiose sera), readily agglutinated whole cells of Streptococcus faecalis or Streptococcus faecium, and showed specific reactions with the lipoteichoic acids (LTAs) of these streptococci by passive hemagglutination, microscale enzyme-linked immunosorbent assay, and crossed immunoelectrophoresis. The interaction of the antikojibiose sera with the LTAs was inhibited best by kojibiose [alpha-D-glucopyranosyl-(1----2)-D-glucose], somewhat less by the dextran from which the kojibiose was prepared, and not measurably by maltose [alpha-D-glucopyranosyl-(1----4)-D-glucose]. The sera reacted only minimally in only the most sensitive assay (microscale enzyme-linked immunosorbent assay) with LTA from group A streptococci (this LTA contains a single kojibiosyl residue as part of the glycolipid moiety of the molecule and failed to react with the Lactobacillus fermentum LTA which is substituted with alpha-D-galactopyranosyl-(1----2)-D -glucosyl units.

Antibody Specificity↗

PubMed1983

Plasmid content of Streptococcus faecalis strain 39-5 and identification of a pheromone (cPD1)-induced surface antigen.

Streptococcus faecalis 39-5 is a haemolytic, bacteriocinogenic strain harbouring six plasmids. One of these plasmids, pPD1 (36.4 MDal) determines a bacteriocin and encodes a conjugative response to the sex pheromone cPD1 excreted by recipient (plasmid-free) strains. The pheromone response is characterized by the formation of mating aggregates of donors (responders) with recipients. Aggregation required the presence of phosphate and divalent cations and was inhibited by agents or conditions that destroy protein structure. Aggregation was postulated to be due to synthesis of a new proteinaceous molecule on the donor cell surface. Referred to as 'aggregation substance', such a material was identified and found to exhibit antigenic properties not associated with uninduced cells; it could be detected by immunoelectron microscopy. Aggregation substance could be extracted from induced cells but not uninduced cells as demonstrated by crossed immunoelectrophoresis. Antibody raised against the aggregation substance controlled by pPD1 cross-reacted with aggregation substance determined by other plasmid systems which respond to pheromones unrelated to cPD1.

Animals↗