bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissemination of the novel plasmid-mediated beta-lactamase CTX-1, which confers resistance to broad-spectrum cephalosporins, and its inhibition by beta-lactamase inhibitors
Authors: Kitzis M D , Billot-Klein D , Goldstein F W , Williamson R , Tran Van Nhieu G , Carlet J , Acar J F , Gutmann L
Published: June 2012

The novel beta-lactamase CTX-1 (pI 6.3) encoded on a transferable 84-kilobase plasmid was found in six different bacterial species. It was responsible for a significant decrease in susceptibility towards most penicillins and cephalosporins, except imipenem, temocillin, and cephalosporins which have a 7-alpha-methoxy substituent. Synergy between either ampicillin, piperacillin, cefotaxime, ceftazidime, or aztreonam and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and YTR 830) was generally found for different strains harboring CTX-1. This enzyme may be related to or derived from the TEM enzyme, since an intragenic probe of the TEM-1 gene hybridized with a fragment of the plasmid carrying CTX-1.
Inhibitors of folic acid synthesis in the treatment of experimental Pneumocystis carinii pneumonia
Authors: Walzer P D , Kim C K , Foy J M , Linke M J , Cushion M T
Published: June 2012

Inhibitors of folic acid synthesis were compared alone and in different combinations in the therapy of pneumocystosis in immunosuppressed rats. Sulfonamides (sulfamethoxazole, sulfadiazine, and sulfadoxine) and sulfones (dapsone) used alone were very active against Pneumocystis carinii, as judged by histologic examination of the lungs and by organism quantitation. Improved efficacy could not be demonstrated by the addition of an inhibitor of dihydrofolate reductase to the regimen. Dihydrofolate reductase inhibitors (trimethoprim, diaveridine, and pyrimethamine) used alone were ineffective against P. carinii. All drugs were well tolerated except pyrimethamine, which caused bone marrow depression; folinic acid ameliorated this adverse reaction but did not interfere with P. carinii treatment. These data have potential clinical implications but need to be interpreted with caution and in light of other systems of P. carinii drug evaluation.
Microanalytical high-performance liquid chromatography assay for cefpirome (HR 810) in serum
Authors: Turley C P , Kearns G L , Jacobs R F
Published: June 2012

We report a microanalytical high-performance liquid chromatography method for quantitation of cefpirome (HR 810) from serum. The drug was extracted from 0.05 ml of serum with 0.2 ml of isopropanol containing beta-hydroxypropyltheophylline, the internal standard. Separations were performed on a C18 column at ambient temperature with detection at 240 nm. The mobile phase consisted of acetate buffer (0.05 M sodium acetate) containing tetrabutylammonium hydroxide and methanol (pH 5.1; 70:30, vol/vol). The method was linear to 500 micrograms of cefpirome per ml and had a sensitivity of 0.6 micrograms/ml. Analytical recovery was greater than 86%, and the between-day coefficient of variation was less than 4.2%. The stability for 1 week at 4 to 8 degrees C and for 30 days at -20 degrees C was documented. Interference with commonly used antibiotics, analgesics, methylxanthines, and anticonvulsants was not found. The small sample volume and ease of preparation make this method suitable for use in pediatric pharmacokinetic investigations of cefpirome.
Pharmacokinetics and tissue penetration of orally administered lomefloxacin
Authors: Stone J W , Andrews J M , Ashby J P , Griggs D , Wise R
Published: June 2012

The pharmacokinetics of the quinolone lomefloxacin were determined following a single 400-mg oral dose given to each of six male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were determined by a microbiological assay. Samples from two volunteers were also assayed by high-performance liquid chromatography. The mean peak level in serum, 4.7 micrograms/ml, was attained within 1 h of administration. The mean elimination half-life from serum was 7 h. Inflammatory fluid was penetrated rapidly, with a mean peak level of 3.5 micrograms/ml occurring after 2.7 h. The mean recovery of lomefloxacin from urine over 48 h was 76% of the administered dose. There was a minor peak on the high-performance liquid chromatography trace, suggesting a small amount of unidentified metabolite. This was present only in urine; no detectable metabolites were found in serum. This study suggests that either once-daily or twice-daily dosage of lomefloxacin should be sufficient to treat urinary or systemic infections, respectively, caused by susceptible pathogens.
Effect of clindamycin on neutrophil killing of gram-negative periodontal bacteria
Authors: Baker P J , Wilson M E
Published: June 2012

Periodontal diseases are infections of the tissues supporting the dentition. Recognition that relatively specific microfloras are associated with distinct clinical forms of periodontal disease has prompted the use of antimicrobial agents as adjuncts in periodontal therapy. Clindamycin is one of several antibiotics known to concentrate in bioactive form in neutrophils and to potentiate phagocyte bactericidal activity against certain bacteria. Neutrophils appear to play a key role in host defense against periodontopathic gram-negative bacteria. In the present study, we evaluated the effect of preincubation of neutrophils with therapeutically achievable concentrations of clindamycin upon subsequent in vitro bactericidal activity against three species of gram-negative periodontal bacteria, including Actinobacillus actinomycetemcomitans, Eikenella corrodens, and Capnocytophaga ochracea. In each instance, clindamycin neither enhanced nor inhibited the kinetics of bactericidal activity at low bacterium-neutrophil multiplicities. Further, this antibiotic had no demonstrable effect upon neutrophil bactericidal capacity, as assessed at bacterium-neutrophil ratios as high as 50:1. Our results indicate that clindamycin does not potentiate neutrophil bactericidal activity against the species of gram-negative periodontal organisms tested.
High-level resistance to gentamicin in clinical isolates of Streptococcus (Enterococcus) faecium
Authors: Eliopoulos G M , Wennersten C , Zighelboim-Daum S , Reiszner E , Goldmann D , Moellering R C
Published: June 2012

During a 14-month period beginning in July 1986, three distinct clinical isolates of Streptococcus (Enterococcus) faecium demonstrating high-level resistance (MIC, greater than 2,000 micrograms/ml) to gentamicin, kanamycin, tobramycin, and streptomycin were recovered from individual patients at one institution. Combinations of ampicillin with any of these agents failed to show bactericidal synergism. By filter-mating techniques, high-level gentamicin resistance could be transferred into a susceptible recipient of the same species at frequencies as high as 1 x 10(-4); transfer into Streptococcus faecalis JH2-7 occurred at lower frequencies (less than 2 x 10(-7). Aminoglycoside substrate profile analysis of clinical isolates as well as of laboratory-derived cured strains and transconjugants revealed 2"-aminoglycoside phosphotransferase and 3'-aminoglycoside phosphotransferase (III) phosphorylating enzymes, AAC-6' acetylating activity above that attributable to the intrinsic activity characteristic of S. faecium, and a streptomycin adenylylating enzyme. All three isolates carried a 51-megadalton plasmid. Curing of this plasmid or conjugative transfer into susceptible recipients was associated with the loss or acquisition of high-level gentamicin resistance, respectively. Loss of high-level gentamicin resistance was also observed when curing techniques resulted in a decrease in the size of this plasmid equivalent to a 10-megadalton deletion. Transferable, high-level resistance to gentamicin and other aminoglycosides, which was previously recognized in S. faecalis, has now emerged in clinical isolates of S. faecium, with the attendant concerns for possible spread.
Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria
Authors: Arca P , Rico M , Braña A F , Villar C J , Hardisson C , Suárez J E
Published: June 2012

Plasmid-borne resistance to fosfomycin in bacteria is due to modification of the antibiotic molecule by a glutathione S-transferase that catalyzes the formation of a covalent bond between the sulfhydryl residue of the cysteine in glutathione and the C-1 of fosfomycin. This reaction results in opening of the epoxide ring of the antibiotic to form an inactive adduct, the structure of which was confirmed by nuclear magnetic resonance. Dialyzed extracts prepared from resistant Escherichia coli strains were unable to modify fosfomycin unless exogenous glutathione was added to the reaction mixtures. Similarly, mutants defective in glutathione biosynthesis were susceptible to fosfomycin, despite harboring a resistance plasmid. Extracts of resistant but not susceptible strains could join glutathione to 1-chloro-2,4-dinitrobenzene, confirming the nature of the enzymatic activity. Adduct formation appeared to be specific for glutathione: none of the other thiols tested (cysteine, N-acetylcysteine, and dithiothreitol) could modify fosfomycin.
Antimicrobial prophylaxis for major head and neck surgery in cancer patients
Authors: Gerard M , Meunier F , Dor P , Andry G , Chantrain G , Van der Auwera P , Daneau D , Klastersky J
Published: June 2012

A total of 113 patients were randomly allocated to receive either ticarcillin plus clavulanic acid (total dose, 20.8 g) or clindamycin (total dose, 2.4 g) plus amikacin (total dose, 1 g) as perioperative antimicrobial prophylaxis for major head and neck surgery. The two groups were similar in age, prior antineoplastic treatment (surgery, chemotherapy, and radiotherapy) or tracheostomy, and the various types of surgery including radical neck dissection. The wound infection rate was 10% in the group of patients receiving clindamycin plus amikacin and 36% in the group receiving ticarcillin plus clavulanic acid (P less than 0.05). Initiation of systemic antibiotic therapy within 15 days of surgery was necessary for 20 and 45% of these patients, respectively (P less than 0.05). The distribution of microorganisms causing wound infections was comparable in both groups, except for anaerobes, which were isolated predominantly from patients who had received ticarcillin plus clavulanic acid.
Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor
Authors: Segev S , Rehavi M , Rubinstein E
Published: June 2012

Epileptic seizures and hallucinations, which are rare in patients receiving quinolones, have been observed more frequently in patients receiving both quinolones and either theophylline or nonsteroidal anti-inflammatory drugs. Inhibition of gamma-aminobutyric acid (GABA) binding to the GABA receptor, resulting in general excitation of the central nervous system, may be the underlying mechanism of these adverse phenomena. We demonstrate here that ciprofloxacin displaced a GABA-like substance (muscimol) from the GABA receptor when administered in concentrations of greater than 10(-4) M. These concentrations were lower than those needed by pefloxacin, ofloxacin, and nalidixic acid to reach a concentration that inhibits 50% of binding. The combination of ciprofloxacin and theophylline was additive in reducing the level of muscimol binding to the GABA receptor, whereas a diclofenac-ciprofloxacin combination had no effect. The concentrations of both ciprofloxacin and the other quinolones used were much higher than those observed in human serum and cerebrospinal fluid in a clinical setting; however, different human GABA receptor affinities, preexisting GABA excitation, or underlying central nervous system disease may amplify the excitatory side effects observed by the co-administration of quinolones and theophylline. Attention should be paid to the possible epileptogenic activity of the simultaneous administration of quinolones with aminophylline, nonsteroidal anti-inflammatory drugs, or other unpredictable drugs.
Outer membrane permeability in Pseudomonas cepacia: diminished porin content in a beta-lactam-resistant mutant and in resistant cystic fibrosis isolates
Authors: Aronoff S C
Published: June 2012

Since beta-lactam resistance is a feature of Pseudomonas cepacia isolates causing pulmonary infections in cystic fibrosis (CF), this study was undertaken to determine whether alterations in beta-lactam permeability mediate drug resistance in this species. A beta-lactam-susceptible non-CF isolate (strain 75-26), a resistant mutant derived from 75-26 by selection for cross-resistance to ciprofloxacin and ceftazidime, and two resistant CF isolates of P. cepacia were used. Permeability constants were calculated from the rate of nitrocefin hydrolysis in intact bacterial cells. Qualitative changes in outer membrane proteins were determined electrophoretically. The permeability constants of the mutant and the resistant CF isolates were lower than the value for the reference strain, 75-26. Whereas the lipopolysaccharide side chains were present in the test and reference strains, the resistant mutant and the CF isolates contained reduced amounts of the 36-kilodalton (kDa) outer membrane protein and failed to express the 27-kDa outer membrane protein. These observations suggest that the 27-kDa outer membrane protein may be a major porin or a major protein component of the porin complex in P. cepacia and that decreased expression of the 36-kDa outer membrane and loss of the 27-kDa porin are associated with high-level beta-lactam resistance in some CF isolates of P. cepacia.
Ipratropium bromide treatment of experimental rhinovirus infection
Authors: Gaffey M J , Hayden F G , Boyd J C , Gwaltney J M
Published: June 2012

The importance of parasympathetic-cholinergic mechanisms in the production of common cold symptoms is not clear. The quaternary ammonium anticholinergic antagonist ipratropium bromide was intranasally administered under double-blind, randomized, placebo-controlled conditions to assess its tolerance and efficacy in reducing nasal hypersecretion in adult volunteers with experimental rhinovirus colds. Ipratropium was sprayed intranasally three times daily (80 micrograms per treatment) for 5 days beginning 24 h after intranasal inoculation of rhinovirus type 39. Clinical colds occurred in 50% of 30 infected ipratropium recipients and in 76% of 33 infected placebo recipients (P = 0.04). The nasal mucus weights tended to be lower for ipratropium-treated persons (mean +/- standard deviation, 14.7 +/- 15.1 g/5 days) than for placebo-treated recipients (24.7 +/- 28.0 g/5 days; P = 0.076). Whereas total nasal symptom scores were similar between the two groups, the rhinorrhea score analyzed for each day of treatment showed nonsignificant trends favoring the ipratropium group over the last 4 days of treatment. Ipratropium was generally well tolerated. The results suggest that cholinergic mechanisms are at least partially responsible for nasal mucus production in rhinovirus colds but that the effect of anticholinergic compounds alone is insufficient to be of practical use in treatment, although they may have value as components of multi-ingredient preparations.
Antibacterial action of 2-bromo-2-nitropropane-1,3-diol (bronopol)
Authors: Shepherd J A , Waigh R D , Gilbert P
Published: June 2012

Patterns of growth inhibition of Escherichia coli in the presence of 2-bromo-2-nitropropane-1,3-diol (bronopol) indicate a period of biocide-induced bacteriostasis followed by growth at an inhibited rate. The length of the bacteriostatic period, but not the subsequent growth inhibition, was reduced by the addition of excess cysteine. Patterns of growth inhibition were unaffected by catalase or superoxide dismutase. The bactericidal concentrations (100 to 500 micrograms/ml) were considerably in excess of the MIC (13 micrograms/ml) and generally produced first-order reductions in viability. Bactericidal activity was considerably reduced by anoxic conditions and by the presence of catalase or superoxide dismutase. Results indicate that there are two distinct reactions between bronopol and thiols. Under aerobic conditions, bronopol catalytically oxidizes thiol-containing materials such as cysteine, with atmospheric oxygen as the final oxidant. By-products of this reaction are active oxygen species such as superoxide and peroxide, which are directly responsible for the bactericidal activity of the compound and for the reduced growth rate after the bacteriostatic period. The latter effect probably results from the oxidation of intracellular thiols such as glutathione and cysteine. Catalytic oxidation of thiols in the presence of excess thiol leads to the creation of an anoxic state. Under these conditions, the slower reaction with thiols, which consumes bronopol, predominates. Consumption of bronopol by its reaction with thiols, without the involvement of oxygen, leads to the eventual removal of bronopol from treated suspensions and the resumption of growth.
Use of microdilution to assess in vitro antiamoebic activities of Brucea javanica fruits, Simarouba amara stem, and a number of quassinoids
Authors: Wright C W , O'Neill M J , Phillipson J D , Warhurst D C
Published: June 2012

A microdilution technique for the assessment of in vitro activity against Entamoeba histolytica was devised and validated with metronidazole. The test was used to detect the antiamoebic activities of plant extracts prepared from the traditional remedies Brucea javanica fruits and Simarouba amara stems. The activity was associated with quassinoid-containing fractions. The 50% inhibitory concentrations for some quassinoids against amoebae were determined by using the microdilution method. These concentrations ranged from 0.019 micrograms.ml-1 for bruceantin, the most active quassinoid, to greater than 5 micrograms.ml-1 for glaucarubol, the least active compound tested. These results are discussed with reference to the known activities of these compounds against Plasmodium falciparum. Overall, the activities of the quassinoids against both protozoa are similar. The microdilution technique will be useful in the search for novel antiamoebic drugs.
Effects of clindamycin and metronidazole on the intestinal colonization and translocation of enterococci in mice
Authors: Wells C L , Jechorek R P , Maddaus M A , Simmons R L
Published: June 2012

The intestinal colonization and translocation of enterococci was studied in mice treated intramuscularly with metronidazole or clindamycin, with or without oral streptomycin. Treatment with metronidazole resulted in selective elimination of strictly anaerobic cecal bacteria, with a 100-fold increase in the numbers of aerobic and facultative gram-negative bacilli and a 10,000-fold increase in the numbers of aerobic and facultative gram-positive species. Clindamycin had a similar effect on the cecal flora except that the numbers of aerobic and facultative gram-positive bacteria decreased at least 10-fold. The predominating gram-positive species in the cecal flora or metronidazole-treated mice was an enterococcus, but this organism could not be recovered from the ceca of clindamycin-treated mice. Translocating bacteria (primarily gram-negative enteric bacteria) were recovered from the mesenteric lymph nodes of the majority of mice given metronidazole or clindamycin. Gram-positive bacteria were not recovered from the mesenteric lymph nodes of 20 clindamycin-treated mice, whereas 26% of 19 metronidazole-treated mice had translocating enterococci. With addition of streptomycin to the metronidazole and clindamycin regimens, mice treated with metronidazole-streptomycin became colonized predominantly with an enterococcus, and this was the only translocating species recovered from 13% of 23 mice; however, enterococci could not be detected in the ceca of clindamycin-streptomycin-treated mice, and Bacillus spp. were recovered from the mesenteric lymph nodes of 8% of 24 mice, reflecting the composition of the cecal flora. The apparent elimination of enterococci from the ceca of clindamycin and clindamycin-streptomycin-treated mice was inconsistent with the observation that the average (n=6) peak levels of clindamycin in blood and ceca were 25 and 21 microgram/ml, respectively, whereas the in vitro MIC was 128 microgram/ml. However, this apparent in vivo activity of clindamycin against enterococci was not evident in mice given 10(9) oral enterococci; the concentrations of cecal enterococci in both clindamycin-streptomycin- and metronidazole-streptomycin-treated mice were 10(10) to 10(11) enterococci per g, with translocating enterococci recovered from approximately half of these antibiotic-treated mice. Thus antibiotic therapy with metronidazole, clindamycin, metronidazole-streptomycin, and clindamycin-streptomycin resulted in a wide variation in the cecal population levels and translocation frequencies of enterococci. This variation appeared to be related to the discrepancy between the in vivo and in vitro activities of clindamycin against enterococci.
Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo
Authors: Goldfarb J , Crenshaw D , O'Horo J , Lemon E , Blumer J L
Published: June 2012

The safety and efficacy of a new topical antiinfective agent, mupirocin, was compared with that of oral erythromycin ethylsuccinate in the treatment of impetigo in children. Sixty-two children aged 5 months to 13 years with impetigo were assigned to be treated with either mupirocin in three daily applications or erythromycin ethylsuccinate (40 mg/kg of body weight per day divided into four doses) according to a randomized treatment schedule. On the initial visit, exudate or cleansed infected sites or both were cultured and therapy was begun. All patients were treated for 8 days. Patients were seen again on days 4 to 5 of therapy, at the end of therapy, and 7 days after the end of therapy. Sites of infection were comparable between the groups, as were bacteriologic responses. At the first visit, 24 of 30 children in the mupirocin group and 14 of 32 children in the erythromycin group were cured or had at least a 75% reduction in size of the lesions. At the end of the study, all 29 of the children in the mupirocin group who came to follow-up, compared with 27 of 29 in the erythromycin group, were cured. Side effects were few. Five children in the erythromycin group developed mild diarrhea. Thus, mupirocin appears to be safe and effective in treating impetigo in children. Our data show a trend toward more rapid clinical response with mupirocin than with erythromycin.
Occurrence of the Campylobacter resistance gene tetO in Enterococcus and Streptococcus spp
Authors: Zilhao R , Papadopoulou B , Courvalin P
Published: June 2012

The distribution of nucleotide sequences related to tetK, tetL, tetM, and tetO was studied by dot blot hybridization in 178 strains of Streptococcus and Enterococcus spp. that were resistant to tetracycline. The tetO gene, which is responsible for tetracycline resistance in Campylobacter spp., was detected in six Streptococcus strains and two Enterococcus strains, in which it was borne by similar plasmids. This observation confirms our previous proposal that tetO originated in gram-positive cocci. tetM, the most prevalent resistance gene, was present alone in 109 strains and associated with tetL in 33 strains in which the two genes contributed cooperatively to high-level tetracycline resistance. tetL was present alone in five Enterococcus strains, and tetK was detected in a single Streptococcus strain. The existence of 22 strains that did not hybridize to the probes suggest that tetracycline resistance in streptococci and enterococci involves additional gene classes as well.
High frequency of antimicrobial resistance in human fecal flora
Authors: Levy S B , Marshall B , Schluederberg S , Rowse D , Davis J
Published: June 2012

The frequency of resistance to seven different antimicrobial agents was examined in the aerobic gram-negative gut flora of over 600 individuals from hospitals, from laboratories where antibiotics were used, and from urban and rural communities. In a majority (62.5%) of fecal samples from people without a recent history of taking antibiotics, 10% or more of the total organisms were resistant to at least one of the antibiotics. In about 40% of the samples, resistance to more than one drug was present at this level. More than one-third of the samples contained resistant organisms comprising 50% or more of the total flora examined. Organisms with coresistance to multiple drugs were found frequently. Individuals taking antibiotics produced more samples with a higher proportion (greater than 50%) of resistant bacteria, and these samples also had a significantly greater number of different resistance determinants. This extensive study revealed a high prevalence of resistant bacteria in the gut flora of ambulatory and hospitalized individuals whether or not they were taking antibiotics.
(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication
Authors: Snoeck R , Sakuma T , De Clercq E , Rosenberg I , Holy A
Published: June 2012

From a series of phosphonylmethoxyalkylpurine and -pyrimidine derivatives, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] emerged as a particularly potent and selective inhibitor of the replication of human cytomegalovirus (CMV). Its potency against CMV was similar to that of the structurally related adenine derivative (S)-HPMPA but higher than that of the reference compounds phosphonoformate and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). The minimum concentrations of phosphonoformate, DHPG, (S)-HPMPA, and (S)-HPMPC required to inhibit CMV plaque formation by 50% were 15, 0.7, 0.1, and 0.07 microgram/ml, respectively. The selectivity indices of phosphonoformate, DHPG, (S)-HPMPA, and (S)-HPMPC, as determined by the ratio of the 50% inhibitory concentration for cell growth to the 50% inhibitory concentration for plaque formation for CMV (AD-169 strain), were 14, 150, 200 and 1,500, respectively. Corresponding values for the CMV Davis strain were 20, 200, 100, and 1,000, respectively. (S)-HPMPC was inhibitory to CMV plaque formation even when added to the cells at 24 or 48 h postinfection. When (S)-HPMPC was added immediately postinfection, a 24- or 48-h incubation time sufficed to obtain a marked inhibitory effect on CMV replication. Such limited incubation time was insufficient for DHPG to achieve any protection against CMV.
Disposition of ceftazidime in surgical patients with intra-abdominal infection
Authors: Heim-Duthoy K L , Bubrick M P , Cocchetto D M , Matzke G R
Published: June 2012

The disposition of ceftazidime was assessed in 11 surgical patients with suspected intra-abdominal infection. All patients had normal hepatic function, and creatinine clearances ranged from 43 to 186 ml/min. Patients received 2 g of ceftazidime intravenously every 8 h. Trough and peak concentrations in serum were measured on day 2, and trough and postdose concentrations in serum were determined on 10 samples collected during a dosage interval between days 3 and 6 of therapy. Ceftazidime peak and trough concentrations in serum at steady state determined by high-performance liquid chromatography were 257.4 +/- 122.0 (mean +/- standard deviation) and 13.1 +/- 20.6 mg/liter. The serum-concentration-versus-time profile was multiexponential. The elimination half-life, steady-state volume of distribution, and total body clearance were 2.52 +/- 1.39 h, 0.31 +/- 0.12 liter/kg, and 0.11 +/- 0.05 liter/h per kg, respectively. Total predicted body clearance significantly correlated with the measured values (r = 0.868; P = 0.001). The disposition of ceftazidime is dependent on creatinine clearance and is not significantly altered by surgery or acute infectious processes.
Production and isolation of reuterin, a growth inhibitor produced by Lactobacillus reuteri
Authors: Talarico T L , Casas I A , Chung T C , Dobrogosz W J
Published: June 2012

Lactobacillus reuteri is a prominent member of the Lactobacillus population in the gastrointestinal ecosystem of humans, poultry, swine, and other animals. Reuterin is a newly discovered, broad-spectrum antimicrobial substance produced by this species during fermentation of glycerol. In this report, we describe procedures for (i) producing reuterin in sufficient amounts to isolate from a fermentation mixture and (ii) isolating this substance by high-performance liquid chromatography. By using uniformly labeled [14C]glycerol, reuterin was identified as a product of glycerol fermentation associated with the production of beta-hydroxypropionic acid and trimethylene glycol.
Miconazole and amphotericin B alter polymorphonuclear leukocyte functions and membrane fluidity in similar fashions
Authors: Yasui K , Masuda M , Matsuoka T , Yamazaki M , Komiyama A , Akabane T , Murata K
Published: June 2012

The influence of miconazole on polymorphonuclear leukocytes (PMN) was investigated and compared with that of amphotericin B (AmB). Human PMN were preincubated in vitro with miconazole or AmB at therapeutically attainable concentrations in plasma, and their chemotactic functions were assessed with the synthetic chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP). Changes in membrane fluidity of PMN were examined by an excimer-forming lipid technique. Adherence of PMN was measured by a nylon fiber column method. Miconazole and AmB pretreatment irreversibly depressed PMN random migration and chemotaxis under agarose but did not influence superoxide anion production. Both miconazole and AmB increased PMN adherence. Miconazole and AmB lowered the binding affinity of FMLP receptors on PMN and decreased the membrane fluidity in a similar manner. These results demonstrate that miconazole and AmB alter selected in vitro membrane properties of human PMN.
Norfloxacin binds to human fecal material
Authors: Edlund C , Lindqvist L , Nord C E
Published: June 2012

Earlier studies have reported very high (120 to 2,700 mg/kg) concentrations of norfloxacin in feces after therapeutic doses. MICs for fecal microorganisms are with few exceptions far below these levels. Nevertheless, clinical investigations show that the main part of the aerobic gram-positive and the anaerobic microflora remains unaffected after norfloxacin administration. In this study, the binding of [14C]norfloxacin to fecal material was analyzed. The binding of a group of nonlabeled quinolones to feces and the interactions between Enterococcus faecium, Bacteroides fragilis, and norfloxacin were also investigated. The results showed that norfloxacin has the ability to bind to feces. The specific binding was reversible, saturated after 90 min of incubation at 37 degrees C, and increased linearly with fecal concentration. Scatchard plots and nonlinear regression computer analyses revealed two different binding classes. The primary specific binding had a dissociation constant (KD) of 1.0 microM and a maximal binding capacity (Bmax) of 0.12 mumol/g of feces. The KD and Bmax of the secondary, more unspecific binding were 450 microM and 11.8 mumol/g of feces, respectively. The binding of unlabeled ciprofloxacin, enoxacin, ofloxacin, pefloxacin, and norfloxacin to feces was comparable to that of [14C]norfloxacin. The results of norfloxacin binding to suspensions of B. fragilis suggested that the main part of the binding is to the bacterial fraction of feces. In the presence of 8.0 g (dry weight) of B. fragilis per liter, the MBC of norfloxacin for E. faecium increased from 8 to 256 micrograms/ml. The finding of the present study indicated that binding of norfloxacin to feces may explain the paradox of high fecal concentrations of norfloxacin versus the actual effect on the normal gastrointestinal microflora.
Cilofungin (LY121019) inhibits Candida albicans (1-3)-beta-D-glucan synthase activity
Authors: Taft C S , Stark T , Selitrennikoff C P
Published: June 2012

Cilofungin (LY121019) inhibited Candida albicans growth and activity of (1-3)-beta-glucan synthase, for which it was a noncompetitive inhibitor with a Ki-app of 2.5 microM. Cilofungin had no effect on chitin synthase activity. Based on these and other data, it seems likely that cilofungin inhibits fungal growth by inhibiting (1-3)-beta-glucan synthase activity.
Characterization of resistance phenotype and cephalosporin activity in oxacillin-resistant Staphylococcus aureus
Authors: Mateos-Mora M , Knapp C C , Washington J A
Published: June 2012

Forty isolates of methicillin-resistant Staphylococcus aureus were tested versus oxacillin at 30 and 35 degrees C with and without 2% NaCl supplementation of Mueller-Hinton broth and classified as having resistance that was low (MIC, less than or equal to 16 micrograms/ml) or high (MIC, greater than or equal to 32 micrograms/ml) and temperature or NaCl dependent. Only three isolates had low-grade resistance at both 30 and 35 degrees C; for two isolates the MICs at 35 degrees C were greater than or equal to 4 X the MICs at 30 degrees C. NaCl usually increased the MICs two- to fourfold. Efficiency of plating studies were performed on strains selected for their level of oxacillin resistance and according to temperature-related difference in MICs. Most strains appeared to represent the heterogeneous resistance phenotype. Cefamandole MICs were little affected by temperature but increased with NaCl. With three exceptions, cefamandole MCBs were less than or equal to 4 X MICs. For only six isolates were cefuroxime MICs less than or equal to 16 micrograms/ml. Four strains that were susceptible to both cefuroxime and cefamandole were selected for time-killing curve studies at inocula of 10(7) CFU/ml. At 8 X MIC, cefuroxime failed to reduce the concentration of any strain by greater than or equal to 3 X log10 CFU/ml. Killing of greater than or equal to 3 X log10 CFU/ml was achieved by cefamandole at 4X and 8 X MIC in one strain, at 8 X MIC only in two strains, and by neither 4 X nor 8 X MIC in one strain. Within therapeutically attainable blood levels, cefuroxime is essentially inactive and cefamandole is variably bactericidal against oxacillin-resistant s. aureus.
Mutation of Salmonella paratyphi A conferring cross-resistance to several groups of antibiotics by decreased permeability and loss of invasiveness
Authors: Gutmann L , Billot-Klein D , Williamson R , Goldstein F W , Mounier J , Acar J F , Collatz E
Published: June 2012

A spontaneous one-step mutant of Salmonella paratyphi A selected on ampicillin showed cross-resistance to all beta-lactam antibiotics except imipenem and to aminoglycosides, chloramphenicol, tetracycline, trimethoprim, and quinolones. It also grew as small colonies. Examination of the cell envelope of the mutant showed a quantitative decrease in three major outer membrane proteins of 40.6, 39.6 (presumably porins), and 24 kilodaltons and quantitative as well as qualitative modifications in the ladder pattern of lipopolysaccharide. Direct evidence for decreased permeability in the mutant included reduced uptake of [3H]glucose and norfloxacin, reduced accessibility of aztreonam and benzylpenicillin to penicillin-binding proteins in whole cells, and decreased diffusion of lactose and cephaloridine into proteoliposomes that were reconstituted with outer membrane proteins from the mutant. There was also loss of invasiveness of the mutant into HeLa cells. We assume that a pleiotropic mutation was responsible for multiple alterations in the outer membrane components of the resistant mutant of S. paratyphi A.
Development of beta-lactam resistance and increased quinolone MICs during therapy of experimental Pseudomonas aeruginosa endocarditis
Authors: Bayer A S , Hirano L , Yih J
Published: June 2012

The in vivo efficacies of pefloxacin, a new fluoroquinolone, and amikacin-ceftazidime were compared in 50 rabbits with experimental aortic endocarditis caused by Pseudomonas aeruginosa. Animals were randomly chosen to receive 4 or 10 days of no therapy (controls), pefloxacin (40 mg/kg [body weight] per day, intramuscularly [i.m.]), or amikacin (30 or 80 mg/kg per day, i.m.)-ceftazidime (150 mg/kg per day, i.m.). Pefloxacin and both amikacin regimens significantly reduced vegetation bacterial densities compared with controls at days 4 and 10 of treatment (P less than 0.0005). By day 10 of therapy, between 33 and 40% of vegetations from amikacin-ceftazidime recipients contained ceftazidime-resistant bacteria (MICs, greater than 25 micrograms/ml); nitrocefin agar overlay confirmed that these ceftazidime-resistant variants were constitutive overproducers of beta-lactamase. At therapy days 4 and 10, approximately 30% of vegetations sampled from pefloxacin recipients contained bacteria for which pefloxacin MICs were four- to eightfold higher than the MIC for the parental strain used to initially induce endocarditis (MIC, 0.19 microgram/ml). These variants also exhibited increases in ciprofloxacin and ticarcillin MICs, as well as pleotropic resistance to chloramphenicol (but not to amikacin, ceftazidime, or tetracycline). Amikacin-ceftazidime, as well as pefloxacin, was effective in this model of aortic pseudomonal endocarditis. However, in vivo development of ceftazidime resistance and step-ups in pefloxacin MICs among intravegetation isolates were associated with inability to completely eradicate P. aeruginosa from aortic vegetations.
Amikacin pharmacokinetics during continuous ambulatory peritoneal dialysis
Authors: Smeltzer B D , Schwartzman M S , Bertino J S
Published: June 2012

The pharmacokinetics of amikacin were investigated in five stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Each patient was studied after the administration of 7.5 mg of amikacin per kg by both the intravenous (i.v.) and intraperitoneal (i.p.) route, allowing a 1-month washout period between doses. No differences in amikacin half-life, volume of distribution, total body clearance, or time-averaged peritoneal clearance were noted between the two routes of administration. After a 5-h dwell period, bioavailability as calculated by the area under the curve for i.p. amikacin was 53 +/- 14.0%. Amikacin pharmacokinetics parallel those of other aminoglycosides in CAPD patients when the drug is administered either i.v. or i.p. Single loading doses of amikacin administered i.v. to uninfected CAPD patients provided therapeutic serum and dialysate levels for many aerobic gram-negative organisms for up to 72 h. Because of the variability of absorption of i.p. administered amikacin, single i.p. doses are not recommended.
Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses
Authors: Bernareggi A , Danese A , Cavenaghi L
Published: June 2012

A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%.
Activity of a combination of three cinchona bark alkaloids against Plasmodium falciparum in vitro
Authors: Druilhe P , Brandicourt O , Chongsuphajaisiddhi T , Berthe J
Published: June 2012

In vitro studies with quinine, quinidine, cinchonine, and cinchonidine showed that despite a similarity of chemical structure, the effectiveness of these cinchona bark alkaloids against several culture lines of Plasmodium falciparum varied widely. Depending on the strain tested, quinidine and cinchonine were 1 to 10 and 1 to 5 times, respectively, more active than quinine. A combination made of equal parts of quinine, quinidine, and cinchonine was found to have several interesting features; it had activity similar to that of quinine against quinine-susceptible strains but was found to be 2 to 10 times more effective against strains resistant to quinine and had a more consistent effect than any of the alkaloids used singly. The potentiation was found to depend mainly on the presence of cinchonine in the mixtures studied. Synergism was also confirmed in a study of 25 P. falciparum strains isolated from Thai patients. Combinations of cinchona bark alkaloids could thus be of interest in areas where P. falciparum is becoming less susceptible to quinine.
In vitro activity of LY146032 alone and in combination with other antibiotics against gram-positive bacteria
Authors: Debbia E , Pesce A , Schito G C
Published: June 2012

The antibacterial activity of LY146032 alone and in combination with other drugs was assayed against gram-positive isolates. Synergism was found when LY146032 was combined with netilmicin, amikacin, imipenem, and fosfomycin by both checkerboard and time-kill tests. Indifference predominated when LY146032 was combined with teicoplanin, vancomycin, and rifampin. Under no circumstances and with no combinations was an antagonistic effect detected.
Antibacterial activities of fluorovinyl- and chlorovinylglycine and several derived dipeptides
Authors: Patchett A A , Taub D , Weissberger B , Valiant M E , Gadebusch H , Thornberry N A , Bull H G
Published: June 2012

The in vitro antibacterial activities of several halovinylglycine compounds and their L-norvalyl peptide derivatives are presented. The most potent of them, L-norvalyl-L-chlorovinylglycine, displayed good activity against gram-positive organisms, including methicillin-resistant Staphylococcus species. Chlorovinylglycine is an efficient inhibitor of alanine racemase, but the antibacterial activity of L-norvalyl-L-chlorovinylglycine may involve other physiological targets as well.
In vitro antimicrobial activity of tigemonam, a new orally administered monobactam
Authors: Fuchs P C , Jones R N , Barry A L
Published: June 2012

At five geographically separate medical centers, over 6,000 clinical bacterial isolates were tested for their susceptibility to tigemonam by the broth microdilution method. The antimicrobial spectrum of tigemonam was similar to that of aztreonam, but with two differences. Aztreonam was more active against Pseudomonas spp., and tigemonam was more active against some streptococci. Tigemonam was highly resistant to hydrolysis by the eight beta-lactamase enzymes tested. A significant (greater than a fourfold increase in the MICs of tigemonam) inoculum effect occurred when 3 of 13 isolates were tested with inocula of 5 X 10(5) and 1 X 10(7) CFU/ml. Tigemonam was bactericidal for all but 1 of the 13 isolates. Of the four quality-control strains recommended by the National Committee for Clinical Laboratory Standards, only Escherichia coli ATCC 25922 provided on-scale results. The proposed MIC quality-control range of tigemonam for E. coli ATCC 25922 is 0.13 to 0.5 micrograms/ml.
Oligonucleotide probes (TEM-1, OXA-1) versus isoelectric focusing in beta-lactamase characterization of 114 resistant strains
Authors: Ouellette M , Paul G C , Philippon A M , Roy P H
Published: June 2012

Oligonucleotide probes specific for detection of the TEM-1 and OXA-1 beta-lactamase genes were compared with isoelectric focusing in 114 gram-negative beta-lactamase-producing strains representing at least 16 species. Correlations of 96 and 100% with isoelectric points were found for the TEM-1 and OXA-1 probes, respectively.
Randomized comparative study of 0.5 and 1 g of cefodizime (HR 221) versus 1 g of cefotaxime for acute uncomplicated urogenital gonorrhea
Authors: van der Willigen A H , Wagenvoort J H , Schalla W O , Knapp J S , Boot J M , Heeres-Weststrate P L , Michel M F , van Klingeren B , Stolz E
Published: June 2012

Uncomplicated urogenital and concomitant oropharyngeal gonorrhea in 424 male and female patients was treated in a randomized comparative study with 0.5 g of cefodizime (89 men and 54 women), 1 g of cefodizime (87 men and 52 women), or 1 g of cefotaxime (86 men and 56 women). The cure rates were 100% for men and women in the group given 0.5 g of cefodizime, 100% for men and women in the group given 1 g of cefodizime, and 99% for men and 100% for women in the group given 1 g of cefotaxime. The MICs of cefodizime and cefotaxime for the isolate of Neisseria gonorrhoeae ranged from 0.004 to 0.06 micrograms/ml. Chlamydia trachomatis was isolated before treatment in 15% and after treatment in 13% of all patients. Side effects, such as nausea, diarrhea, abdominal pain, genital candidiasis, and pain at the site of injection, developed in 4% of the patients given cefodizime. Side effects, such as vertigo, genital candidiasis, fatigability, and diarrhea, developed in 4% of the patients treated with cefotaxime. In both groups of patients, the side effects were mild and transient. Cefodizime and cefotaxime are safe and effective agents in the treatment of uncomplicated urogenital gonorrhea.
Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807)
Authors: Jones R N , Barry A L
Published: June 2012

Compound U-76,253A (R-3746), the active metabolite sodium salt of the prodrug ester U-76,252 (CS-807), was demonstrated to be active against members of the family Enterobacteriaceae with 82 and 85% of strains inhibited by less than or equal to 2.0 and less than or equal to 4.0 micrograms/ml, respectively. In addition, U-76,253A inhibited all strains of Branhamella catarrhalis, Haemophilus influenzae, pathogenic Neisseria spp., oxacillin-susceptible Staphylococcus aureus, beta-hemolytic streptococci, and pneumococci at less than or equal to 4.0 micrograms/ml. Pseudomonas spp., Acinetobacter spp., enterococci, and oxacillin-resistant staphylococci were resistant to U-76,253A. This U-76,253A antimicrobial activity and spectrum was generally superior to that of comparison orally administered cephems (cefaclor, cefuroxime, and cefixime) and the amoxicillin-clavulanic acid combination. Tests with beta-lactamase-producing isolates indicated that U-76,253A was bactericidal and that its MICs were only influenced by high inoculum concentrations (10(7) CFU/ml) against type Ia and IVc enzyme-producing strains. Preliminary disk diffusion interpretive zone criteria were calculated for 10- and 30-micrograms U-76,253A disks and several possible susceptible MIC breakpoints. The absolute interpretive agreement between MICs and zone diameters ranged from 87.8 to 95.6%. Final selection of interpretive criteria awaits further U-76,252 pharmacokinetic information.
In vitro and in vivo activities of sedecamycin against Treponema hyodysenteriae
Authors: Hayashi T , Suenaga I , Narukawa N , Yamazaki T
Published: June 2012

Sedecamycin (lankacidin A), one of the lankacidin-group antibiotics, showed potent activity against Treponema hyodysenteriae. The MICs of sedecamycin against 79 field isolates of T. hyodysenteriae ranged from 0.78 to 12.5 micrograms/ml, the MIC for 90% of the strains tested (MIC90) being 3.13 micrograms/ml. The protective and therapeutic effects of sedecamycin were compared with those of carbadox, tiamulin, and lincomycin against experimental infection with T. hyodysenteriae in mice. The protective effect of sedecamycin was similar to that of carbadox, two times more potent than that of tiamulin, and three times greater than that of lincomycin. In the therapeutic test, sedecamycin showed activity similar to that of carbadox and was two times more active than both tiamulin and lincomycin. At doses of 10 mg or more of sedecamycin per kg, the recurrence of shedding of T. hyodysenteriae into the feces of mice was not detected for at least 8 weeks postmedication.