bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of clavulanic acid on the activities of ten beta-lactam agents against members of the Bacteroides fragilis group
Authors: Lamothe F , Auger F , Lacroix J M
Published: June 2012

Clavulanic acid reduced the MICs of amoxicillin, carbencillin , cefamandole, cefotaxime, ceftazidime, ceftizoxime, cephalothin, and penicillin G, but not of cefoxitin or moxalactam, against 77 isolates of the Bacteroides fragilis group, all rapidly beta-lactamase positive by the nitrocefin slide test. It had no effect on the susceptibilities of eight Bacteroides distasonis strains that were slowly beta-lactamase positive (18 h of incubation).
In vitro activity of apalcillin compared with those of piperacillin and carbenicillin against 6,797 bacterial isolates from four separate medical centers
Authors: Barry A L , Jones R N , Ayers L W , Gavan T L , Gerlach E H , Sommers H M
Published: June 2012

Quantitative susceptibility tests were performed in four separate medical centers, in which apalcillin was compared with piperacillin and carbenicillin. Data from tests of 6,797 isolates confirmed that apalcillin and piperacillin had nearly identical spectra of activity but that apalcillin was significantly more active against Pseudomonas aeruginosa (MIC required to inhibit 90% of strains, 2.0 versus 64 micrograms/ml) and Acinetobacter calcoaceticus subsp. anitratus (MIC required to inhibit 90% of strains, 2.0 versus 16 micrograms/ml). Against 166 anaerobic bacterial isolates, apalcillin demonstrated in vitro activity.
Inability of purified Pseudomonas aeruginosa exopolysaccharide to bind selected antibiotics
Authors: Tannenbaum C S , Hastie A T , Higgins M L , Kueppers F , Weinbaum G
Published: June 2012

It has been proposed that the exopolysaccharide (alginate) of mucoid Pseudomonas aeruginosa strains which infect cystic fibrosis patients might bind and hence protect this pathogen from antibiotics. To test this hypothesis, we employed equilibrium dialysis to measure the binding between several antibiotics and purified Pseudomonas alginate. Binding was calculated from the residual concentrations of antibiotics in free solution by a biological assay. The detectable binding of antibiotics to alginate was consistent with expectations; the positively charged antibiotics steptomycin and tobramycin, bound to the polyanion (0.047 and 0.024 mumol/mg of alginate, respectively), whereas the neutral species, clindamycin and penicillin, bound negligibly or not at all (0.0011 and 0 mumol/mg of alginate, respectively). When these experiments were performed in the presence of physiological concentrations of saline, none of the antibiotics bound to the polysaccharide. Since the binding observed was abrogated by salt concentrations typical of the tracheobronchial secretions of cystic fibrosis patients, the data suggest that tight binding of antibiotics to the exopolysaccharide of a mucoid P. aeruginosa strain does not provide increased antibiotic resistance.
Antimicrobial activity of SK&F 88070, an expanded-spectrum cephalosporin with high and prolonged levels in blood
Authors: Grappel S F , Phillips L , Dunn G L , Jakas D R , Pitkin D , Actor P
Published: June 2012

SK&F 88070 (7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3- [[[1-(2-sulfaminoethyl)-1H-tetrazol-5-yl]thio] methyl]-3-cephem-4-carboxylic acid) is a new parenteral cephalosporin with an expanded-spectrum profile of antibacterial activity, including activity against Pseudomonas aeruginosa, and with high and prolonged levels in sera of experimental animals. The activity of SK&F 88070 was compared with those of cefotaxime and other cephalosporins against more than 500 clinical isolates in vitro by microtiter twofold dilution tests in Mueller-Hinton broth. SK&F 88070 was extremely potent against all of the members of the family Enterobacteriaceae that were tested, including beta-lactamase-producing strains. Its activity against P. aeruginosa was comparable to those of cefotaxime, ceftizoxime, and moxalactam. SK&F 88070 was less potent than cefotaxime or ceftizoxime against Staphylococcus species but was comparable to moxalactam. It had in vivo activity against the same Bacteroides strains as did cefotaxime, although it was less potent. Both SK&F 88070 and cefotaxime had less activity when tested with high inoculum levels of most of the rarer gram-negative bacteria. There was a greater decrease in the activity of SK&F 88070 than of cefotaxime in the presence of human serum, reflecting the higher degree of binding of SK&F 88070 to serum proteins. SK&F 88070 had peak levels and half-lives in serum much greater than those of cefotaxime in experimental animals after parenteral administration. In mouse protection studies, SK&F 88070 was more effective than cefotaxime against gram-negative bacteria but less effective than cefotaxime against Staphylococcus aureus.
Susceptibility of gram-negative bacteria to polymyxin B nonapeptide
Authors: Viljanen P , Vaara M
Published: June 2012

Subinhibitory concentrations of polymyxin B nonapeptide sensitized all 21 polymyxin-susceptible gram-negative bacterial strains studied to hydrophobic antibiotics such as fusidic acid, novobiocin, and erythromycin. The susceptibility increases were usually 30- to 300-fold. The strains included representatives of Escherichia coli with different O- and K-antigens, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter agglomerans, Salmonella typhimurium, Acinetobacter calcoaceticus, Pseudomonas aeruginosa, and Pseudomonas maltophilia. In contrast, polymyxin-resistant strains (Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, and Serratia marcescens) were resistant to the action of polymyxin B nonapeptide.
In vitro evaluation of HR810, a new wide-spectrum aminothiazolyl alpha-methoxyimino cephalosporin
Authors: Jones R N , Thornsberry C , Barry A L
Published: June 2012

HR810 (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new, cyclical-pyridinium cephalosporin that appeared superior to numerous comparison drugs against 658 strains of aerobic and facultative anaerobic bacteria. Seventeen Enterobacteriaceae spp. were tested by broth microdilution methods, and the 50% MICs (MIC50S) and 90% MICs (MIC90s) were 0.03 to 0.12 and 0.03 to 2.0 micrograms/ml, respectively. Only one strain had an MIC greater than 8.0 micrograms/ml (99.6% is considered susceptible). HR810 inhibited 98% of Pseudomonas aeruginosa isolates at less than or equal to 16 micrograms/ml, and the MIC90 for Acinetobacter spp. was 4.0 micrograms/ml. It was also very active against Pseudomonas spp. and Staphylococcus aureus (MIC90, 0.5 micrograms/ml) but marginally active against methicillin-resistant staphylococcal strains (MIC90, 16 micrograms/ml) and enterococcus (MIC90, 32 micrograms/ml). Non-enterococcal streptococci had MIC50s ranging from 0.008 micrograms/ml for Streptococcus pyogenes to 0.12 micrograms/ml for pneumococci. All MICs of HR810 against Haemophilus and Neisseria spp. were less than or equal to 0.03 micrograms/ml (MIC50, 0.002 to 0.008 micrograms/ml). HR810 poorly inhibited beta-lactamases and was very stable against 11 tested beta-lactamases of plasmid (TEM, OXA, SHV-1, and PSE) and chromosomal (K1, K14, P99) types.
Strains of varicella-zoster virus resistant to 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil
Authors: Sakuma T
Published: June 2012

Strains of varicella-zoster virus resistant to 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) were isolated from varicella-zoster virus-infected Vero cells which were pulse-treated with 5-iododeoxyuridine or 5-bromodeoxyuridine or both and then treated with BV-araU. These BV-araU-resistant strains (BV-araUr) could not be isolated from varicella-zoster virus-infected cells treated with BV-araU alone and had reduced viral thymidine kinase activity. Two of five BV-araUr strains were also resistant to 5-iododeoxyuridine and 5-bromodeoxyuridine, whereas other BV-araUr strains were relatively susceptible to these drugs. All clones from the BV-araUr strain were susceptible to 1-beta-D-arabinofuranosylcytosine and phosphonoacetic acid, but 7 of 10 clones from the BV-araUr strain were resistant to 1-beta-D-arabinofuranosyladenine. The possible mechanisms of induction of BV-araU resistance are discussed.
Purification and characterization of aminoglycoside-modifying enzymes from Staphylococcus aureus and Staphylococcus epidermidis
Authors: Ubukata K , Yamashita N , Gotoh A , Konno M
Published: June 2012

Several strains of Staphylococcus aureus and Staphylococcus epidermidis, exhibiting characteristic resistance patterns to aminoglycoside antibiotics, were examined. The aminoglycoside-modifying enzymes from these strains were purified by DEAE-Sephadex A-50 chromatography, affinity chromatography, and Sephadex G-100 gel filtration. Three enzymes, a 3'-phosphotransferase III (molecular weight, 31,000; pI 4.1), a bifunctional enzyme having 6'-acetyltransferase and 2"-phosphotransferase (molecular weight, 56,000; pI 4.1) activity, and a 4'4"-adenylytransferase (molecular weight, 34,000; pI 4.7), were isolated from crude extracts of the resistant strains. Aminoglycoside-modifying enzymes with identical enzymatic properties derived from S. aureus and S. epidermidis were also immunologically identical.
Effect of decreased renal function on the pharmacokinetics of ceftazidime
Authors: Ackerman B H , Ross J , Tofte R W , Rotschafer J C
Published: June 2012

The pharmacokinetics of ceftazidime after a 1-g bolus dose were studied in 11 subjects, with creatinine clearances ranging from 113 to 6 ml/min. Concentrations of ceftazidime in serum were determined by microbiological assay. These data were fitted to a two-compartment open model, and pharmacokinetic parameters were calculated. Correlation of ceftazidime clearance with creatinine clearance was excellent (r = 0.99).
Antimicrobial spectrum of Win 49375
Authors: Jacobus N V , Tally F P , Barza M
Published: June 2012

Win 49375 had excellent activity against members of the family Enterobacteriaceae and staphylococcal species. Its activity against Pseudomonas aeruginosa was equal to that of gentamicin. Win 49375 had moderate activity against clostridia but little against Bacteroides fragilis. The drug showed a marked inoculum effect at 10(8) CFU/ml and a slight decrease in potency at pH 5.
New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A
Authors: Mack D G , McLeod R
Published: June 2012

An in vitro method by which reagents, cells, and Toxoplasma gondii trophozoites are conserved (micromethod) was developed to quantitate the effect of antimicrobial agents on T. gondii. Sulfadoxine alone had no effect on T. gondii in vitro when evaluated with a macromethod, the new micromethod, or visual inspection of Giemsa-stained preparations. Sulfadoxine combined with pyrimethamine inhibited T. gondii more than did pyrimethamine alone, but the combination of sulfadoxine plus pyrimethamine was slightly less active than was the combination of sulfadiazine plus pyrimethamine. Neither clindamycin nor metronidazole, alone or in combination with sulfadiazine or pyrimethamine and sulfadiazine, had any effect on intracellular T. gondii. Brief exposure (10 min before and during challenge) to clindamycin had no effect on extracellular T. gondii when clindamycin was studied alone or with sulfadiazine or pyrimethamine plus sulfadiazine. Cyclosporin A inhibited T. gondii replication at concentrations of ca. greater than or equal to 2 micrograms/ml.
Duodeno-pancreatic secretions enhance bactericidal activity of antimicrobial drugs
Authors: Mett H , Gyr K , Zak O , Vosbeck K
Published: June 2012

We have studied the action of various antimicrobial agents in microbiological media and in human duodeno-pancreatic secretions. In the latter medium, clioquinol exhibited a rapid bactericidal effect on both growing and stationary bacteria at concentrations near its MIC. However, it was merely bacteriostatic in microbiological media, even at high concentrations. Phanquinone, chlorquinaldol, and, to a lesser extent, also chloramphenicol and trimethoprim likewise displayed enhanced bactericidal activity in duodeno-pancreatic secretions, but various other antibacterial agents did not. These findings suggest that duodeno-pancreatic secretions contain a factor augmenting the antibacterial activity of a number of drugs.
Effects of topical applications of phosphonoacetate on colonization of mouse trigeminal ganglia with herpes simplex virus type 1
Authors: Klein R J , Friedman-Kien A E , Kaley L , Brady E
Published: June 2012

The effects of topical application of phosphonoacetic acid on the colonization of mouse trigeminal ganglia by herpes simplex virus type 1 were examined. The results showed that the extent of colonization of ganglia by virus is related to the time elapsed between virus inoculation and application of this agent. In most cases, treatment started up to 12 h after inoculation prevented invasion of ganglia by virus. When started up to 24 h after inoculation, treatment reduced and stabilized the amount of virus detectable in trigeminal ganglia during the acute phase of the ganglionic infection. Treatments started 24 h after virus inoculation had little influence on total virus accumulations in trigeminal ganglia. The data also indicate that virus titers in specimens of inoculated and treated skin sites are less affected by topical phosphonoacetic acid treatment than virus titers in ganglia. The experiments may represent a model system for testing effects of other antiviral compounds on colonization of ganglia by virus and may provide some clues regarding the pathogenic mechanism of herpes simplex virus infections.
Empirical antibacterial therapy in febrile, granulocytopenic bone marrow transplant patients
Authors: Peterson P K , McGlave P , Ramsay N K , Rhame F , Goldman A I , Kersey J
Published: June 2012

Fifty febrile, granulocytopenic allogeneic bone marrow transplant patients receiving prophylactic trimethoprim-sulfamethoxazole were randomized to one of two empirical antibiotic regimens to determine whether a shortened course of empirical therapy was beneficial. Of the 50 patients, 25 received empirical tobramycin and ticarcillin for only 3 days, and 25 were maintained on empirical tobramycin and ticarcillin until they were afebrile and no longer granulocytopenic. Although the incidence of bacterial infections in the two groups was not statistically significantly different, almost twice as many bacterial infections were observed in the group that received the short course of empirical therapy. Furthermore, because of the high incidence of bacterial infection and clinical concerns about occult bacterial sepsis, within 2 weeks of the randomization the overall use of parenteral antibacterial agents was similar in both groups. The incidence of invasive fungal disease and the use of amphotericin B therapy were similar in both groups. The results of this study suggest that little clinical benefit is likely to be seen in bone marrow transplant patients treated with short-course empirical tobramycin and ticarcillin, despite the administration of prophylactic trimethoprim-sulfamethoxazole, and emphasize the need for new strategies to prevent infections with gram-positive and trimethoprim-sulfamethoxazole-resistant gram-negative bacteria in these patients.
Antimicrobial susceptibilities of 1,292 isolates of the Bacteroides fragilis group in the United States: comparison of 1981 with 1982
Authors: Cuchural G J , Tally F P , Jacobus N V , Gorbach S L , Aldridge K , Cleary T , Finegold S M , Hill G , Iannini P , O'Keefe J P
Published: June 2012

A susceptibility survey of 537 strains of the Bacteroides fragilis group from eight centers in the United States was continued at the Tufts New England Medical Center in 1982. The results were compared with those of 755 organisms analyzed in 1981. Nine antimicrobial agents were tested by an agar dilution method. The respective percentages of resistance for 1981 and 1982 were as follows (%): cefoxitin, 8 and 10; moxalactam, 22 and 12; cefotaxime, 54 and 48; cefoperazone, 57 and 54; piperacillin, 12 and 7; clindamycin, 6 and 3; metronidazole, 0 and 0; chloramphenicol, 0 and 0; and tetracycline, 63 and 59. Regional differences in resistance rates were found. Declines in resistance to moxalactam, piperacillin, and clindamycin were noted at the participating hospitals. An outbreak of cefoxitin resistance was noted at the Tufts New England Medical Center, where the rate increased from 14 to 30%. The various species of the B. fragilis group had differing patterns of resistance; B. fragilis was the most susceptible species. Significant cross resistance among the beta-lactam agents was found. These data indicate the need to determine the susceptibility patterns of the B. fragilis group organisms within each hospital.
Single-dose pharmacokinetics of aztreonam in pediatric patients
Authors: Stutman H R , Marks M I , Swabb E A
Published: June 2012

Single intravenous doses (30 mg/kg) of aztreonam, a novel monobactam antibiotic, were administered to 29 children from 2 days to 11 years old. Serum, urine, and, when possible, cerebrospinal fluid samples were analyzed by high-pressure liquid chromatography and microbiological methods. The concentration of aztreonam in serum 15 min after drug administration was approximately 100 micrograms/ml in all age groups. The elimination half-life varied inversely, and the clearance from serum varied directly, with age. Aztreonam pharmacokinetics in 2- to 12-year-olds were similar to those in adults. The concentration in urine was high and prolonged, with potentially therapeutic concentrations still present 12 to 24 h after infusion in all age groups. Penetration into cerebrospinal fluid averaged 17.3% in children with inflamed meninges. Standard clinical and laboratory measurements revealed no untoward reactions. The 30-mg/kg dose of aztreonam produced potentially therapeutic concentrations in serum, urine, and cerebrospinal fluid. A dosage schedule of every 6 to 8 h in older children and every 8 to 12 h in neonates is suggested for multiple-dose clinical trials.
Lipopolysaccharide changes in impermeability-type aminoglycoside resistance in Pseudomonas aeruginosa
Authors: Bryan L E , O'Hara K , Wong S
Published: June 2012

Clinical isolates of Pseudomonas aeruginosa were examined for the basis of impermeability-type aminoglycoside resistance. Two apparently related burn isolate strains with high-level (strain 8803) and low-level (strain 13934) gentamicin resistance each had a plasmid. Transformation of the plasmid from either strain to P. aeruginosa PAO503 resulted in low-level gentamicin resistance. No mechanism for this resistance could be determined. Low-level gentamicin and streptomycin resistance from strain 8803 (but not 13934) was transduced with phage E79.tv2 to PAO503 without transfer of plasmid DNA. Transductants like strain 8803 showed absence or reduction of the lipopolysaccharide (LPS) "ladder" pattern of PAO503, had a change in chemical composition of LPS, and, like strain 8803, had a reduced capability to accumulate streptomycin. Comparison of the resistant clinical isolates 8803 and P10 with the apparently related but less-resistant strains 13934 and P10R, respectively, showed the latter strains had LPS ladder patterns and the former strains did not. Strain 8803 had normal outer membrane protein profiles, electron transport components, and transmembrane electrical potential relative to PAO503 and has been previously shown to have no detectable gentamicin-modifying enzymes and normal protein synthesis. We conclude that low-level impermeability-type aminoglycoside resistance in P. aeruginosa results from conversion of smooth LPS to superficial or deeper rough LPS phenotypes. High-level resistance apparently results from a plasmid-specified, but as yet unknown, mechanism combined with the preceding change in LPS structure.
In vitro bactericidal synergy of gentamicin combined with penicillin G, vancomycin, or cefotaxime against group G streptococci
Authors: Lam K , Bayer A S
Published: June 2012

The in vitro bactericidal interactions of penicillin G, cefotaxime, or vancomycin in combination with gentamicin were compared against 20 group G streptococci by the timed kill curve method. Synergy was noted at the following frequencies: penicillin plus gentamicin, 80%; cefotaxime plus gentamicin, 85%; vancomycin plus gentamicin, 90%. There was no bactericidal antagonism observed.
Analysis of pH and buffer effects on flucytosine activity in broth dilution susceptibility testing of Candida albicans in two synthetic media
Authors: Calhoun D L , Galgiani J N
Published: June 2012

We examined the influences of different pH levels and three different buffers on flucytosine activity against 12 isolates of Candida albicans in two synthetic media, yeast nitrogen base (YNB) and synthetic amino acid medium-fungal (SAAMF), using broth dilution techniques and measuring the endpoints of visual MICs and turbidimetric 50% inhibitory concentrations. The two media were originally prepared as follows: YNB, unbuffered, pH 5.6; SAAMF, buffered with morpholinepropanesulfonic acid-Tris, pH 7.4; the resultant geometric mean MIC and 50% inhibitory concentration of 5-FC were 78- and 32-fold higher, respectively, in SAAMF. Raising the pH of YNB or lowering the pH of SAAMF had virtually no effect on these differences in MIC and 50% inhibitory concentration in the two media. In contrast, virtually all of the discrepancy appeared to be due to morpholinepropanesulfonic acid-Tris, which exerted concentration-dependent inhibition of flucytosine activity not evident when N-2-hydroxyethylpiperazine-N'-ethanesulfonic acid or phosphate buffer systems were substituted. In other turbidimetric studies, growth was slowed more than 50% in YNB as the pH was raised to 7.4, regardless of which buffer was used. Based on our studies, we recommend modifying the composition of SAAMF by substituting a nonantagonistic buffer if any buffer is to be used with SAAMF in the testing of flucytosine. With this modification, SAAMF warrants further study as a generally applicable medium for fungal-susceptibility testing.
Early synergistic interactions between amikacin and six beta-lactam antibiotics against multiply resistant members of the family Enterobacteriaceae
Authors: Glew R H , Pavuk R A
Published: June 2012

An in vitro comparison of the early synergistic interaction between amikacin and each of six beta-lactam antibiotics was made by using time-kill curves against 48 multiply resistant members of the family Enterobacteriaceae. Overall, these six combinations demonstrated early synergism (greater than or equal to 2 logs of increased kill after 7 h of incubation) against the 48 strains on 74% (range, 67 to 85%) of occasions; cefotaxime-amikacin and piperacillin-amikacin were the most efficacious combinations. Antagonism was not observed with any of the combinations against any of the 48 Enterobacteriaceae strains tested.
Wide-spectrum antibiotic activity of bovine granulocyte polypeptides
Authors: Savoini A , Marzari R , Dolzani L , Serranò D , Graziosi G , Gennaro R , Romeo D
Published: June 2012

The antibiotic activity of a polypeptide fraction purified from bovine granulocyte granules was tested against Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, Bacillus subtilis, Bacillus stearothermophilus, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, Streptococcus pyogenes, and clinical isolates of Staphylococcus and Enterobacter spp. All of these bacterial species were susceptible to the antibiotic polypeptide(s), with MICs ranging from 3 to 100 micrograms of protein per ml. The antimicrobial activity was resistant to boiling and abolished by proteinase treatment. Saccharomyces cerevisiae and human fibroblasts grew normally in the presence of 100 and 50 micrograms of antibiotic polypeptide(s) per ml, respectively. [3H]thymidine incorporation into bacterial, but not fibroblast, DNA was efficiently and promptly inhibited by the antimicrobial polypeptide preparation. This suggests that its main target is a component of the system, which catalyzes and regulates the biosynthesis of bacterial DNA.
Metabolism of [14C]Cefmenoxime in normal subjects after intramuscular administration
Authors: Machinist J M , Bopp B A , Quinn D
Published: June 2012

The metabolism of cefmenoxime (SCE-1365) was studied in four healthy male volunteers after intramuscular administration of a single 500-mg dose of the 14C-labeled drug. Plasma levels of total radioactivity and cefmenoxime peaked at 0.5 and 1.0 h, corresponding to 16.5 micrograms eq/ml and 15.8 micrograms/ml, respectively. Thereafter, parent drug levels declined rapidly, with a terminal elimination half-life of ca. 1.5 h. No significant differences were noted between total radioactivity and parent drug levels up to 2 h after drug administration. After 3 h, low but persistent levels of radioactivity were significantly greater than parent drug levels, indicating metabolism or degradation of cefmenoxime. The terminal elimination half-life of total radioactivity was estimated to be ca. 40 h. The radioactive plasma metabolite(s) remaining at the end of the 5-day study represented only 1% of the administered dose. Urinary excretion was the major route of elimination of cefmenoxime, accounting for ca. 86% of the dose in 12 h. Analysis of cefmenoxime in urine by total radioactivity, high-pressure liquid chromatography, and a microbiological assay showed that 80 to 92% of the excreted dose was parent drug. Radioactivity was also excreted into the feces via the bile and represented ca. 11% of the dose after 5 days. Although extensive degradation of cefmenoxime was found in fecal samples, it was proposed that this may be due to the metabolic activity of the intestinal flora rather than in vivo biotransformation in the liver. This study supports the concept that cefmenoxime undergoes minimal metabolism in humans and is excreted largely as unchanged drug.
Evidence for two distinct mechanisms of resistance to polymyxin B in Pseudomonas aeruginosa
Authors: Moore R A , Chan L , Hancock R E
Published: June 2012

Pseudomonas aeruginosa H181 and H185 are resistant to initial exposure to polymyxin B and continue to grow in its presence. Growth of the strains in the presence of 50 U of polymyxin B per ml was characterized by a doubling time of 120 min, whereas the doubling time in the absence of polymyxin was 60 min. Growth for two generations in the presence of polymyxin caused a 23 to 31% increase in lipopolysaccharide content. In addition, a marked increase in susceptibility to the detergents sodium deoxycholate, Triton X-100, and sodium dodecyl sulfate was observed. The resistant mutants had a small but significant reduction in their levels of dodecanoic acid as compared with the parent strain; however, this was the only consistent alteration observed in levels of fatty acids or readily extractable lipids. Polymyxin was fluorescently labeled by coupling to 1-dimethylaminonaphthalene-5-sulfonyl chloride (dansyl chloride). Growth of strains H181 and H185 in the presence of dansylated polymyxin resulted in a stable association between the fluorescent antibiotic and the outer membrane. We postulate that these alterations are part of an adaptive response by the strains to the presence of polymyxin in the growth medium and reflect a resistance mechanism distinct from the mechanism affording polymyxin B resistance when these strains are initially exposed to the antibiotic.
Pharmacokinetics of ceftazidime in newborn infants
Authors: McCracken G H , Threlkeld N , Thomas M L
Published: June 2012

Doses of 50 mg of ceftazidime per kg were administered intravenously to 29 newborn infants every 8 or 12 h for 3 to 5 days. Mean peak concentrations in plasma ranged from 102 to 124 micrograms/ml. Mean elimination half-life values ranged from 2.9 to 6.7 h and varied inversely with gestational age and plasma clearances. Peak and trough plasma bactericidal titers against an Escherichia coli and a group B streptococcus strain were at least 1:16 and 1:32, respectively.
Therapeutic trial and pharmacokinetics of sulbactam for uncomplicated gonorrhea in men
Authors: Caine V A , Foulds G , Handsfield H H
Published: June 2012

The efficacy of intramuscular sulbactam for uncomplicated gonorrhea was assessed in 20 men infected with beta-lactamase-negative Neisseria gonorrhoeae. Ten subjects received 2.0 g of sulbactam given in a single intramuscular dose with 1.0 g of probenecid orally; 4 of 10 urethral infections persisted, as did one rectal infection. Ten subjects were treated with 0.5 g of intramuscular sulbactam given twice, 4 h apart; 3 of 10 urethral infections and 2 of 2 rectal infections persisted. The geometric mean MIC of sulbactam for 20 pretreatment isolates of N. gonorrhoeae was 1.37 microgram/ml (range, 0.25 to 8.0 micrograms/ml). Serum levels of sulbactam, determined for nine subjects in the two treatment groups, fell below the MIC of some gonococci after less than 6 h with both regimens. In the regimens studied, sulbactam alone is not suitable as therapy for uncomplicated gonorrhea. determined for nine subjects in the two treatment groups, fell below the MIC of some gonococci after less than 6 h with both regimens. In the regimens studied, sulbactam alone is not suitable as therapy for uncomplicated gonorrhea.
Role of Bacteroides bivius beta-lactamase in beta-lactam susceptibility
Authors: Lacroix J M , Lamothe F , Malouin F
Published: June 2012

The susceptibility of 46 clinical isolates of Bacteroides bivius to amoxicillin, cefotaxime, cefoxitin, ceftizoxime, cephaloridine, cephalothin, moxalactam, penicillin G, amoxicillin plus clavulanic acid in a ratio of 2:1, carbenicillin, cefamandole, and ceftazidime was determined by an agar dilution technique. For the first eight agents susceptibility testing was also done with the addition of clavulanic acid (0.75 microgram/ml). For all agents, beta-lactamase-positive strains (35, using a nitrocefin slide test) were inhibited at higher concentrations than beta-lactamase-negative strains. Clavulanic acid reduced the susceptibility of the beta-lactamase-positive strains to the level of the beta-lactamase-negative strains to all agents. We prepared crude extracts of beta-lactamase from six strains. Activity against nitrocefin was directly related to their susceptibilities. The beta-lactamase had a mixed-substrate profile, hydrolyzing both penicillins and cephalosporins. Our results suggest a slow inactivation of cefoxitin, ceftizoxime, and moxalactam by the beta-lactamase. Clavulanic acid and cefoxitin inhibited the enzyme, whereas p-hydroxymercuribenzoate and cloxacillin did not. Thus, there was a clear relationship between beta-lactamase activity and susceptibility to beta-lactams, including cefoxitin and third-generation cephalosporins. The substrate and inhibition profiles of the B. bivius beta-lactamase were different from those of enzymes found in the "B. fragilis group."
Penetration of aztreonam into cerebrospinal fluid of patients with and without inflamed meninges
Authors: Duma R J , Berry A J , Smith S M , Baggett J W , Swabb E A , Platt T B
Published: June 2012

Aztreonam was administered as a single, 2-g intravenous dose to 25 patients with noninflamed meninges and to 9 patients with inflamed meninges. It was well tolerated and was detected in the cerebrospinal fluid at the initial sampling period at 1 h after the end of infusion. Aztreonam levels in the cerebrospinal fluid of patients with inflamed meninges were four times higher than those recorded for the same time period in patients with noninflamed meninges. Aztreonam concentrations in cerebrospinal fluid in the presence of normal and inflamed meninges exceeded the inhibitory and bactericidal concentrations for most gram-negative bacteria. Thus, a multiple-dose treatment regimen with 2-g intravenous doses every 6 h appears to be appropriate for clinical trials of aztreonam for the treatment of gram-negative bacillary meningitis which is caused by susceptible organisms.
Development of topical treatment for cutaneous leishmaniasis caused by Leishmania major in experimental animals
Authors: El-On J , Jacobs G P , Witztum E , Greenblatt C L
Published: June 2012

Topical treatment, with drug-containing ointments, of cutaneous leishmaniasis caused by Leishmania major in BALB/c mice was studied. Twenty chemotherapeutic agents having potential or established antileishmanial activity were formulated in different ointment and cream bases. Only 15% paromomycin sulfate with 12% methylbenzethonium chloride, 12% benzethonium chloride, 12% cetalkonium chloride, or 12% dimethyl sulfoxide, all incorporated in white soft paraffin (United Kingdom patent application no. 2117237A), were completely effective. Topical treatment twice daily for 6 or more days caused total elimination of the parasites and healing of the lesion in all treated mice. All the other antileishmanial compounds, including sodium stibogluconate, pentamidine, amphotericin B, emetine hydrochloride, metronidazole, co-trimoxazole, allopurinol, and rifampin, either showed a slight effect on the parasites or were highly toxic to the animal host at the concentrations tested.
Changes in the pharmacokinetics of ciprofloxacin and fecal flora during administration of a 7-day course to human volunteers
Authors: Brumfitt W , Franklin I , Grady D , Hamilton-Miller J M , Iliffe A
Published: June 2012

Twelve male subjects, aged 19 to 40 years, shown to be healthy by examination and laboratory tests, took 500 mg of ciprofloxacin every 12 h for 7 days. After the first and the last dose, blood and urine samples were taken and drug concentrations were determined by bioassay. There was a significant buildup in mean concentrations in serum from day 1 to day 7; mean peak levels (attained after 1 to 2 h) were 1.9 and 2.8 micrograms/ml, respectively. The terminal half-life was 3.5 to 4 h. About 40% of the drug was excreted into the urine during the 12-h period after dosing; minimum mean concentrations in urine were 105 micrograms/ml on day 1 and 174 micrograms/ml on day 7. Considerable amounts of ciprofloxacin were found in the feces on day 7 (185 to 2,220 micrograms/g). Marked changes in the aerobic part of the fecal flora were observed as a result of taking ciprofloxacin: coliforms were absent on day 7, and concentrations of streptococci and staphylococci were significantly reduced. There was no overgrowth by yeasts. One week later the fecal flora had returned to a state similar to that found before treatment. Anaerobes were little affected quantitatively but acquired resistance to ciprofloxacin. Side effects were mild and transient.
Kinetics of the interaction of monophosphates of the antiviral nucleosides 2'-fluoro-1-beta-D-arabinofuranosylpyrimidine and (E)-5-(2-bromovinyl)-2'-deoxyuridine with thymidylate kinases from Vero cells and herpes simplex virus types 1 and 2
Authors: Chen M S , Amico L A , Speelman D J
Published: June 2012

The affinities of the monophosphates of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil and its 5-methyl analog for cellular thymidylate kinase were two or more orders of magnitude greater than for the thymidine-thymidylate kinases from herpes simplex virus types 1 and 2. In contrast, the monophosphate of (E)-5-(2-bromovinyl)-2'-deoxyuridine was found to have a higher affinity for the viral enzymes than for the cellular enzyme.
Amifloxacin activity against well-defined gentamicin-resistant, gram-negative bacteria
Authors: John J F , Twitty J A
Published: June 2012

Amifloxacin (WIN 49375) activity against a well-defined group of gentamicin-resistant gram-negative bacilli was compared with the activity of 11 other antimicrobial agents. For all strains, amifloxacin and norfloxacin were the most active agents, followed by cefotaxime and moxalactam. For Acinetobacter sp. only amifloxacin had an achievable MIC for 90% of the strains. Amifloxacin joins other newly developed DNA gyrase inhibitors as potentially useful agents for infections due to aminoglycoside-resistant gram-negative bacilli.
Induction of amphotericin B-specific antibodies for use in immunoassays
Authors: Little J R , Little K D , Plut E , Koldin M , Kobayashi G S
Published: June 2012

High-titered antisera specific for amphotericin B (AmB) were induced by immunization with a protein conjugate of the D-lysyl AmB methyl ester. These polyclonal anti-AmB antibodies reacted preferentially with AmB or the AmB methyl ester and discriminated sharply between nystatin and AmB. A solid-phase radioimmunoassay was developed with radioiodinated immunoglobulin G fractions derived from the anti-AmB antisera. This assay was capable of detecting AmB in the sera in the same concentration range that is regularly achieved during AmB treatment of systemic fungal infections. This study demonstrated the feasibility of immunoassays in measuring the concentration of AmB in blood and tissue fluids.
Intra- and extracellular susceptibility of Mycobacterium avium-intracellulare complex to aminoglycoside antibiotics
Authors: Nozawa R T , Kato H , Yokota T
Published: June 2012

We developed a rapid, quantitative culture method to estimate the replication of Mycobacterium avium-intracellulare complex (MAIC) in human peripheral blood mononuclear cells. Mononuclear cells were plated in a 96-well tray, infected with clinically isolated strains of MAIC in the presence of autologous plasma, and further cultivated for 1 to 2 weeks in a tissue culture medium. No MAIC cells proliferated extracellularly, since human plasma inhibited extracellular growth of the mycobacteria. The mononuclear cells were lysed through a brief treatment with alkali, and surviving intracellular mycobacteria were diluted and plated with tissue culture medium in a 96-well tray. Mycobacterial colonies were counted under a microscope after a 5-day incubation. The number of viable MAIC cells continuously increased, reaching 10 times the number of inoculated cells in a week. Thus, mononuclear phagocytes were the permissive site for the replication of MAIC. Intra- and extracellular susceptibilities of seven MAIC strains to four aminoglycoside antibiotics were then studied. The mycobacteria were most susceptible in vitro to dibekacin (MICs, 3.13 to 12.5 micrograms/ml). Dibekacin at 12.5 micrograms/ml was bacteriostatic to five of seven strains in the monocytes. Also, intracellular replication of the other two strains was greatly suppressed by that concentration of dibekacin.
Cefmenoxime pharmacokinetics in healthy volunteers and subjects with renal insufficiency and on hemodialysis
Authors: Gambertoglio J G , Alexander D P , Barriere S L
Published: June 2012

The pharmacokinetics of cefmenoxime were characterized in five healthy volunteers and in 15 subjects with various degrees of renal insufficiency after a single 10-mg/kg, 5-min intravenous infusion. Five of these subjects were studied both on hemodialysis and during an interdialytic period. Plasma, urine and dialysate were assayed for cefmenoxime by a specific high-pressure liquid chromatographic assay. Peak plasma concentrations of cefmenoxime were ca. 94 micrograms/ml after completion of the infusion. The mean plasma and renal clearances in the healthy volunteers were 281 +/- 66 and 228 +/- 52 ml/min, respectively. Plasma clearance declined in patients with renal insufficiency and correlated significantly with creatine clearance. The mean apparent volume of distribution at steady state in the healthy volunteers was 0.23 liters/kg and was not found to be significantly different in subjects with renal insufficiency. The mean cumulative 24-h urinary recovery of cefmenoxime in healthy volunteers was 81% of the administered dose and decreased with reduced renal function. Cefmenoxine dosage should be reduced in proportion to the decline in creatinine clearance. A simple nomogram for dose selection is provided.
Single-drug versus combination empirical therapy for gram-negative bacillary infections in febrile cancer patients with and without granulocytopenia
Authors: Piccart M , Klastersky J , Meunier F , Lagast H , Van Laethem Y , Weerts D
Published: June 2012

Empirical therapy with cefoperazone was compared with cefoperazone plus amikacin in granulocytopenic and nongranulocytopenic febrile patients. In nonneutropenic patients the overall response rate to cefoperazone was 88%; 10 of 12 gram-negative bacteremic patients were cured. Cefoperazone plus amikacin resulted in an 88% overall response rate and cured 14 of 15 patients with bacteremia. In neutropenic patients the overall response rate was 77% with cefoperazone alone and 73% with cefoperazone plus amikacin; the cure rates for gram-negative bacteremias were 8 of 11 and 6 of 12 patients, respectively. Our findings support the concept of single-drug empirical therapy with cefoperazone in febrile cancer patients, whether granulocytopenic or not, especially when gram-negative bacteremias are predominantly caused by Escherichia coli or Klebsiella species. The issue of Pseudomonas spp. and other more resistant pathogens needs further assessment with a larger number of patients.
In vitro activity and human pharmacokinetics of teicoplanin
Authors: Verbist L , Tjandramaga B , Hendrickx B , Van Hecken A , Van Melle P , Verbesselt R , Verhaegen J , De Schepper P J
Published: June 2012

The in vitro activity of teicoplanin, a new antibiotic related to vancomycin, was determined against 456 gram-positive cocci. The activity of teicoplanin in comparison with that of vancomycin was similar against staphylococci but 4 to 40 times higher against enterococci and beta-hemolytic and viridans streptococci. The single-dose pharmacokinetics of teicoplanin were studied in six healthy volunteers after administration of 3 and 6 mg/kg intravenously and of 3 mg/kg intramuscularly. The kinetic parameters after both intravenous doses were very similar. The curves for concentration in plasma for the 3- and 6-mg/kg intravenous doses showed a triexponential decline with elimination half-lives of 47.3 and 44.1 h, respectively. The percentages of the doses recovered in urine (0 to 102 h) were 43.2 and 44.1%, respectively. The areas under the plasma curves were dose related: 256.5 and 520.9 micrograms/h per ml, respectively. The bioavailability of teicoplanin after injection of 3 mg/kg intramuscularly was 90%, and the peak level was 7.1 micrograms/ml. The mean levels in plasma 24 h after the 3-mg/kg doses were 2.1 and 2.3 micrograms/ml, respectively, and the mean level in plasma 24 h after the 6-mg/kg intravenous dose was 4.2 micrograms/ml.
Teicoplanin, a new antibiotic from Actinoplanes teichomyceticus nov. sp
Authors: Somma S , Gastaldo L , Corti A
Published: June 2012

Teicoplanin, a new glycopeptide antibiotic belonging to the same family as vancomycin, inhibits cell wall synthesis in Bacillus subtilis; the inhibition is accompanied by an intracellular accumulation of UDP-N-acetyl-muramyl-pentapeptide. A cell-free system from Bacillus stearothermophilus, capable of synthesizing peptidoglycan, is 50% inhibited by teicoplanin at 40 micrograms/ml and 100% inhibited at 100 micrograms/ml; suppression of peptidoglycan synthesis is accompanied by parallel accumulation of the lipid intermediate. Teicoplanin binds to cell walls and forms a complex with N,N'-diacetyl-L-lysyl-D-alanyl-D-alanine. The association constant of this complex is 2.56 X 10(6) liters mol-1, calculated by spectrophotometric titration. The mechanism of action of teicoplanin is discussed in comparison with those of other inhibitors of cell wall biosynthesis, namely, vancomycin, ristocetin, and gardimycin.
In vitro antimicrobial susceptibility of a Mycobacterium sp. isolated from patients with Crohn's disease
Authors: Chiodini R J , Van Kruiningen H J , Thayer W R , Coutu J A , Merkal R S
Published: June 2012

The in vitro susceptibility of three strains of an unclassified Mycobacterium sp., isolated from three patients with Crohn's disease, to 23 antimicrobial agents was determined by a modified broth dilution method with 7H9 broth containing oleic acid-albumin-dextrose-catalase, Tween 80, and mycobactin J. All three strains were susceptible to streptomycin, viomycin, rifampin, clofazimine, cefazolin, amikacin, and kanamycin and resistant to p-aminosalicylic acid, cycloserine, 2-thiophenecarboxylic acid hydrazide, trimethoprim, diaminodiphenylsulfone, sulfamethoxazole, sulfadimethoxine, polymyxin B, metronidazole, neomycin, and carbenicillin. Variable results between strains were encountered with ethambutol, ethionamide, capreomycin, amoxicillin, and cephalothin.
In vitro inhibition of Giardia lamblia and Trichomonas vaginalis growth by bithionol, dichlorophene, and hexachlorophene
Authors: Takeuchi T , Kobayashi S , Tanabe M , Fujiwara T
Published: June 2012

Bithionol, dichlorophene, and hexachlorophene, which are used in treating some helminthic infections, killed trophozoites of Giardia lamblia and Trichomonas vaginalis in modified BI-S-33 and Asami media, respectively. Virtually all G. lamblia and T. vaginalis cells were killed within 24 h with a 0.42 mM concentration of these compounds, except that 0.93 mM dichlorophene was required for sterilizing T. vaginalis in the same period. In modified BI-S-33 and Asami media from which bovine and human sera were omitted, respectively, the inhibitory actions of the compounds against in vitro growth of these protozoa were significantly enhanced. Trophozoites of G. lamblia and T. vaginalis could be killed in shorter than 10 min with 0.074 mM dichlorophene and 0.0025 mM hexachlorophene, respectively, in serum-free media. G. lamblia, which was incubated in the complete medium containing dichlorophene, showed a characteristic swelling of the ventral side which led to disruption of the parasite, whereas bithionol caused a thin crack in the cytoplasm of T. vaginalis incubated in Asami medium. The crack appeared to enlarge and result in vacuolization of T. vaginalis. These observations suggest that bithionol, dichlorophene, and hexachlorophene merit further evaluation to ascertain whether they are useful for treatment of giardiasis and trichomoniasis.
Penetration and clearance of cefoperazone and moxalactam in pleural fluid
Authors: Yamada H , Iwanaga T , Nakanishi H , Yamaguchi M , Iida K
Published: June 2012

The penetration of cefoperazone and moxalactam into pleural fluid was studied in 11 patients after intravenous infusion of 2-g doses of these agents. Clearance of these agents from pleural fluid was studied in seven patients after instillation of 1-g doses into the pleural space. The concentrations in pleural fluid after intravenous infusion of 2-g doses reached a peak of 7 to 25 micrograms/ml for cefoperazone and 9 to 35 micrograms/ml for moxalactam at 4 to 6 h after administration. These levels exceeded reported MICs for most susceptible organisms. The elimination half-life of both agents was about two to five times longer in pleural fluid than in serum. These prolonged elimination rates of both agents might be of great advantage for killing bacteria in the pleural space.