bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic effect of the triazole Bay R 3783 in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis
Authors: Pappagianis D , Zimmer B L , Theodoropoulos G , Plempel M , Hector R F
Published: June 2012

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.
Pharmacokinetics of cephem antibiotics in exudate of pelvic retroperitoneal space after radical hysterectomy and pelvic lymphadenectomy
Authors: Ito K , Hayasaki M , Tamaya T
Published: June 2012

Many cephalosporin antibiotics have recently been invented and attempts have been made to use them clinically. The choice of which of these drugs should be used has been difficult in gynecology. The efficacies of these drugs depend on their antibacterial spectra, potencies, and concentrations in tissues. This study was designed to investigate the pharmacokinetics of various cephem antibiotics in the exudate of the retroperitoneal space that is formed after radical hysterectomy and pelvic lymphadenectomy. These cephem antibiotics were cefoxitin, cefotiam, cefotetan, cefpiramide, cefminox, cefotaxime, ceftizoxime, cefoperazone, cefmenoxime, cefbuperazone, ceftazidime, cefpimizole, flomoxef, and cefuzonam. The maximum concentrations after administration of a 1-g dose in the exudate of the pelvic retroperitoneal space were 37.9 micrograms/ml with cefminox, 30.3 micrograms/ml with cefpimizole, 21.6 micrograms/ml with flomoxef, 21.5 micrograms/ml with ceftazidime, and 17.6 micrograms/ml with cefbuperazone, which were relatively high. When selecting antibiotics for prophylactic use against infections in the retroperitoneal space after radical hysterectomy and pelvic lymphadenectomy, on the basis of drug transfer, flomoxef, cefminox, cefbuperazone, ceftazidime, and cefpimizole were considered to be the drugs of first choice at a dose of 1 g.
Clinical pharmacology of imipenem and cilastatin in premature infants during the first week of life
Authors: Reed M D , Kliegman R M , Yamashita T S , Myers C M , Blumer J L
Published: June 2012

The first-dose and multidose pharmacokinetics of imipenem and cilastatin were evaluated in 41 premature infants during their first week of life. Premature infants (gestational age, less than or equal to 37 weeks) were assigned to receive 10-, 15-, 20-, or 25-mg/kg doses of imipenem-cilastatin (1:1) as a single- or multiple-dose regimen. A total of 39 infants received a single dose, whereas 18 infants received multiple doses. No differences were observed in pharmacokinetic parameter estimates for either agent relative to the dose administered or infant body weight; thus, the data were pooled. Elimination half-life, steady-state volume of distribution, and body clearance averaged 2.5 h, 0.5 liter/kg, and 2.5 ml/min per kg, respectively, for imipenem and 9.1 h, 0.4 liter/kg, and 0.5 ml/min per kg, respectively, for cilastatin. Similar values for these parameter estimates were observed after multidose administration, although substantial accumulation of cilastatin in serum was observed. A total of 21% of the imipenem and 43% of the cilastatin were excreted unchanged in the urine over a 12-h collection period. Corresponding renal clearances averaged 0.4 and 0.2 ml/min per kg for imipenem and cilastatin, respectively. Substantial differences were observed in the route by which imipenem was cleared from the body compared with data from adult volunteers. These data suggest that infants should receive an imipenem dose of 20 mg/kg administered every 12 h for the treatment of bacterial infections outside the central nervous system.
Uptake of antibiotics by human polymorphonuclear leukocyte cytoplasts
Authors: Hand W L , King-Thompson N L
Published: June 2012

Enucleated human polymorphonuclear leukocytes (PMN cytoplasts), which have no nuclei and only a few granules, retain many of the functions of intact neutrophils. To better define the mechanisms and intracellular sites of antimicrobial agent accumulation in human neutrophils, we studied the antibiotic uptake process in PMN cytoplasts. Entry of eight radiolabeled antibiotics into PMN cytoplasts was determined by means of a velocity gradient centrifugation technique. Uptakes of these antibiotics by cytoplasts were compared with our findings in intact PMN. Penicillin entered both intact PMN and cytoplasts poorly. Metronidazole achieved a concentration in cytoplasts (and PMN) equal to or somewhat less than the extracellular concentration. Chloramphenicol, a lipid-soluble drug, and trimethoprim were concentrated three- to fourfold by cytoplasts. An unusual finding was that trimethroprim, unlike other tested antibiotics, was accumulated by cytoplasts more readily at 25 degrees C than at 37 degrees C. After an initial rapid association with cytoplasts, cell-associated imipenem declined progressively with time. Clindamycin and two macrolide antibiotics (roxithromycin, erythromycin) were concentrated 7- to 14-fold by cytoplasts. This indicates that cytoplasmic granules are not essential for accumulation of these drugs. Adenosine inhibited cytoplast uptake of clindamycin, which enters intact phagocytic cells by the membrane nucleoside transport system. Roxithromycin uptake by cytoplasts was inhibited by phagocytosis, which may reduce the number of cell membrane sites available for the transport of macrolides. These studies have added to our understanding of uptake mechanisms for antibiotics which are highly concentrated in phagocytes.
Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration
Authors: Barbhaiya R H , Shukla U A , Gleason C R , Shyu W C , Wilber R B , Pittman K A
Published: June 2012

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.
Lipoteichoic acid as a new target for activity of antibiotics: mode of action of daptomycin (LY146032)
Authors: Canepari P , Boaretti M , Lleó M M , Satta G
Published: June 2012

Daptomycin at the MIC allowed the cell mass increase of enterococcal strains and Bacillus subtilis to continue for 2 to 3 h at rates comparable to those of the controls. During this time the cell shape of the former changed to a rod configuration and that of the latter changed to long rods. In these bacteria, in which cell mass continued to increase, the MIC of daptomycin inhibited peptidoglycan synthesis by no more than 20% after 20 min of incubation and by roughly 50% after 2 h of incubation. Other macromolecules, such as DNA, RNA, and proteins, were only slightly affected. In contrast, incorporation of [14C]acetate into lipids was reduced by about 50% in the various strains after 20 min of treatment with daptomycin at the MIC. When the effect of the major lipid-containing polymers on synthesis was evaluated in detail, it was found that under conditions in which peptidoglycan and the other macromolecules mentioned above were inhibited only slightly (20%) and total lipid synthesis was inhibited by 50%, synthesis of teichoic and lipoteichoic acid was inhibited by 50 and 93%, respectively. Daptomycin was not found to enter the cytoplasm of either bacterial or mammalian cells. It bound, in the presence of calcium ions only, to whole bacterial cells, cell walls (both those that contained and those that did not contain membranes), and isolated membranes of bacterial and mammalian cells. Washing with EDTA removed daptomycin from all cells mentioned above and cell fractions except the bacterial membrane. It is concluded that lipoteichoic acid is most likely the primary target of daptomycin.
Mobilization of the gentamicin resistance gene in Enterococcus faecalis
Authors: Hodel-Christian S L , Murray B E
Published: June 2012

Enterococcus faecalis plasmid pBEM10 (a conjugative plasmid encoding beta-lactamase production and gentamicin resistance [Gmr]) was made transfer deficient by using Tn917. Relocation of the Gmr determinant into two sites on pCF10 was observed. Restriction analysis revealed insertion of a common 2.5-kilobase-pair HindIII and a 3.9-kilobase-pair HaeIII fragment encoding Gmr, suggesting that this determinant resides on a transposon similar to Tn4001.
Specific inhibitors of herpes simplex virus thymidine kinase diminish reactivation of latent virus from explanted murine ganglia
Authors: Leib D A , Ruffner K L , Hildebrand C , Schaffer P A , Wright G E , Coen D M
Published: June 2012

Two specific inhibitors of herpes simplex virus thymidine kinase, N2-phenyl-2'-deoxyguanosine and N2-(m-trifluoromethylphenyl)guanine, were tested for their ability to inhibit the reactivation of virus from explant cultures of latently infected murine trigeminal ganglia. Both compounds significantly diminished the frequency of reactivation compared with that of untreated controls.
Intracellular activity of tosufloxacin (T-3262) against Salmonella enteritidis and ability to penetrate into tissue culture cells of human origin
Authors: Noumi T , Nishida N , Minami S , Watanabe Y , Yasuda T
Published: June 2012

The intracellular antimicrobial activity of tosulfoxacin was tested against Salmonella enteritidis C-32 by using human lung fibroid WI-38 cells and was compared with those of ofloxacin and norfloxacin. The intracellular antimicrobial activities of these drugs were evaluated by determining the numbers of viable organisms remaining within cells after treatment with various drug concentrations. At 0.2 and 0.78 microgram/ml, tosufloxacin suppressed intracellular multiplication of S. enteritidis C-32 more effectively than ofloxacin and norfloxacin did. The ability of tosufloxacin to penetrate into WI-38 cells was also determined by the velocity gradient method. The ratio of the intracellular concentration to the extracellular concentration of tosufloxacin was 1.7- and 2.6-fold higher than those of ofloxacin and norfloxacin, respectively. The results indicate that the potent intracellular bactericidal activity of tosufloxacin may be due not only to its high in vitro activity but also to its ability to penetrate into cells at a high level.
Penetration of ampicillin and sulbactam in the lower airways during respiratory infections
Authors: Valcke Y J , Rosseel M T , Pauwels R A , Bogaert M G , Van der Straeten M E
Published: June 2012

We studied the penetration of ampicillin-sulbactam in the alveolar lining fluid (ALF) of eight patients after intravenous administration of 2,000 mg of ampicillin and 1,000 mg of sulbactam three times daily over 30 min. Bronchoalveolar lavage was performed on day 3, 30 min after the end of the morning drug administration. The mean penetration ratios (i.e., the ratios of the concentrations in ALF versus those in serum) were 53% (standard error, 12%) and 61% (standard error 31%) for ampicillin and sulbactam, respectively. The concentration ratio of ampicillin versus sulbactam in serum was not significantly different from that in ALF. From a pharmacokinetic point of view, ampicillin-sulbactam is a good choice for treatment of infectious exacerbation of chronic obstructive pulmonary disease and community-acquired bacterial pneumonia, since the concentrations of both drugs in ALF exceed the MICs for the respiratory pathogens responsible.
Different modes of vancomycin and D-alanyl-D-alanine peptidase binding to cell wall peptide and a possible role for the vancomycin resistance protein
Authors: Knox J R , Pratt R F
Published: June 2012

A comparison was made of the binding modes of the bacterial cell wall precursor L-lysyl-D-alanyl-D-alanine to the glycopeptide antibiotic vancomycin and to the D-alanyl-D-alanine-cleaving peptidase of Streptomyces sp. strain R61, a model for cell wall-synthesizing enzymes whose X-ray three-dimensional structure is established. In each of the two pairings (vancomycin with peptide and DD-peptidase with peptide), polypeptide backbones were antiparallel, and the antibiotic or enzyme enveloped the peptide substrate from opposite sides. Hydrogen-bonding groups on the substrate which are involved with the DD-peptidase were shown to be different from the ones reported from nuclear magnetic resonance studies to be involved with vancomycin. Because of steric hindrance, the binding of either molecule to the substrate prevents the binding of the other molecule. Binding to the substrate by a D-alanyl-D-alanine-recognizing protein in a manner similar to that used by the DD-peptidase could explain recent observations of vancomycin resistance, in which a new membrane-associated protein has been detected.
Risk factors for fecal colonization with trimethoprim-resistant and multiresistant Escherichia coli among children in day-care centers in Houston, Texas
Authors: Reves R R , Fong M , Pickering L K , Bartlett A , Alvarez M , Murray B E
Published: June 2012

In a previous study, we found fecal colonization with multiresistant Escherichia coli exhibiting high-level trimethoprim resistance in 19% of diapered children attending six day-care centers in Houston, Tex. To examine the potential risk factors associated with this finding, we conducted cross-sectional studies among 203 children attending 12 day-care centers, 51 children attending a well-child clinic (controls), and 64 medical students. The prevalence of fecal colonization with trimethoprim-resistant E. coli among children attending day-care centers (30%) was higher (P less than 0.001) than among control children (6%) or medical students (8%). The prevalence of colonization among the children attending the 12 centers ranged from 0 to 59% and was correlated with the number of diapered children enrolled (r = 0.73; P less than 0.01). In a case control study among the day-care center children, significant risk factors were an age of less than 12 months and attendance at a center with an enrollment of over 40 diapered children (odds ratios of 2.2 and 3.5, respectively); ethnicity, duration of attendance, and prior antibiotic administration were not associated with colonization. Plasmid analysis of 60 of the day-care center strains revealed 22 profiles, each of which was unique to a given day-care center. Transmission and carriage of trimethoprim-resistant strains for as long as 6 months was documented in one center studied on three occasions. Given the documented transmission of enteric pathogens among diapered children attending day-care centers and their spread into family members, it is likely that day-care centers are an important community reservoir of plasmid-associated antibiotic-resistant E. coli.
In situ enzyme-linked immunosorbent assay to quantitate in vitro development of Eimeria tenella
Authors: Olson J A
Published: June 2012

An in situ enzyme-linked immunosorbent assay was developed to measure in vitro development of Eimeria tenella. The assay used a polyclonal, anti-merozoite serum produced by immunization with culture-derived, chromatographically purified merozoites. Although this antiserum cross-reacted with sporozoite-infected cultures (by indirect immunofluorescence and in situ enzyme-linked immunosorbent assay), it clearly distinguished the increase in antigen synthesized throughout intracellular growth. The assay can be used for high-throughput, anticoccidial drug screening, for which it gives quantitative results that are comparable to the published radiometric [( 3H]uracil incorporation) endpoint.
Nucleotide sequence of SHV-2 beta-lactamase gene
Authors: Garbarg-Chenon A , Godard V , Labia R , Nicolas J C
Published: June 2012

The nucleotide sequence of plasmid-mediated beta-lactamase SHV-2 from Salmonella typhimurium (SHV-2pHT1) was determined. The gene was very similar to chromosomally encoded beta-lactamase LEN-1 of Klebsiella pneumoniae. Compared with the sequence of the Escherichia coli SHV-2 enzyme (SHV-2E.coli) obtained by protein sequencing, the deduced amino acid sequence of SHV-2pHT1 differed by three amino acid substitutions.
Pharmacokinetics of enoxacin and its oxometabolite following intravenous administration to patients with different degrees of renal impairment
Authors: Van der Auwera P , Stolear J C , George B , Dudley M N
Published: June 2012

Enoxacin is a fluorinated quinolone with potential clinical use in the treatment of serious infections. Twenty-three patients (age, 19 to 87 years) with different degrees of renal function, including a group undergoing chronic hemodialysis, received enoxacin (400 mg) by intravenous infusion (1 h). Blood samples were collected before infusion; at the end of infusion; and at 5, 10, 20, 30, 45, 60, 90, and 120 min and 3, 4, 6, 12, 18, 24, 48, and 72 h after infusion. Enoxacin and oxoenoxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters (mean +/- standard deviation) were calculated by using a noncompartmental PK model according to creatinine clearances (in milliliters per minute). Total clearance of enoxacin decreased from 4.95 +/- 1.16 ml/min per kg in the group with normal creatinine clearance to 0.76 +/- 0.21 ml/min per kg in the patients with severe renal failure (creatinine clearance, less than 15 ml/min), whereas the elimination half-life increased from 4.5 +/- 1.0 to 20 +/- 5 h, respectively. The elimination of oxoenoxacin (the main metabolite of enoxacin) in urine was markedly decreased when creatinine clearance was less than 15 ml/min. Hemodialysis removed an insignificant amount of enoxacin and oxoenoxacin. These data indicate that as creatinine clearance falls below 30 ml/min, the daily enoxacin dose should be reduced by half. During prolonged administration of enoxacin to patients with creatinine clearances of less than 30 ml/min, the accumulation of oxoenoxacin might lead to unexpected side effects.
Novel beta-lactamase from Capnocytophaga sp
Authors: Foweraker J E , Hawkey P M , Heritage J , Van Landuyt H W
Published: June 2012

A novel beta-lactamase activity which confers resistance to expanded-spectrum cephalosporins and penicillins has been found in strain IC 5/21 of Capnocytophaga spp. Enzyme activity migrated at a molecular size of 38,000 daltons and at an isoelectric point of 3.6, with a minor band at 4.1. Kinetic studies suggested that it belonged to Richmond and Sykes beta-lactamase class 1c. Isoelectric focusing could be achieved only if a nonionic detergent was added to the gel, suggesting the presence of a hydrophobic enzyme akin to a membrane-bound beta-lactamase of gram-positive bacteria. The location of the gene coding for this beta-lactamase is not yet known.
Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses
Authors: North T W , Cronn R C , Remington K M , Tandberg R T
Published: June 2012

The sensitivities of reverse transcriptases (RTs) from feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV) were directly compared. The two enzymes had similar sensitivities to three analogs of dTTP, namely, 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2',3'-dideoxy-2',3'-didehydrothymidine 5'-triphosphate. Each of these analogs demonstrated competitive inhibition of both enzymes. Ki values for inhibition of FIV RT by these three inhibitors were 3.3, 6.7, and 1.8 nM, respectively; Ki values for inhibition of the HIV enzyme were 6.5, 5.9, and 8.3 nM, respectively. Ratios of the Ki for the inhibitor to the Km for the substrate were also determined for each inhibitor, and no differences between the two enzymes greater than threefold were observed. Inhibition constants for 3'-amino-3'-deoxythymidine 5'-triphosphate and 3'-fluoro-3'-deoxythymidine 5'-triphosphate were determined for FIV RT, and these were similar to published values for HIV RT. The activities of three dideoxynucleoside 5'-triphosphates against FIV RT were determined; ddGTP was slightly more potent than ddTTP, whereas both were much more effective than ddCTP. The activity of a noncompetitive inhibitor, phosphonoformate, was also examined with the FIV enzyme; it was much more active with poly(rA)-oligo(dT) as the template-primer than with poly(rC)-oligo(dG) or poly(rI)-oligo(dC).
Meropenem pharmacokinetics and penetration into an inflammatory exudate
Authors: Wise R , Logan M , Cooper M , Ashby J P , Andrews J M
Published: June 2012

The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h, with the concentration in plasma declining from a mean of 23.6 micrograms/ml at 1 h to 0.7 micrograms/ml at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum, 0.75 h), and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.
In vitro response to bactericidal activity of cell wall-active antibiotics does not support the general opinion that enterococci are naturally tolerant to these antibiotics
Authors: Fontana R , Grossato A , Ligozzi M , Tonin E A
Published: June 2012

The incidence of tolerance and paradoxical response to bactericidal activity of penicillin was investigated in 50 clinical isolates of Enterococcus faecalis. Of the isolates tested, 86% exhibited the paradoxical phenomenon whereby there were more survivors at high than at low concentrations above the MIC. Low penicillin concentrations caused decreases equal to or higher than 99.9% in 11 strains, from 99.9 to 99.5% in 23 strains, and lower than 99.5% in 9 strains. Of the total strains, 14% were killed to the same extent by all concentrations above the MIC. The bactericidal activities of other beta-lactams (ampicillin and piperacillin) and other cell wall inhibitors (vancomycin and daptomycin) were also tested against some of these strains. In general, beta-lactams exhibited the best bactericidal activity at 2 x MIC. Piperacillin was the most active, as at 2 x MIC it reduced the original inoculum by 99.9% or more in most of the strains. No concentration of vancomycin above the MIC caused 99.9% killing of the strains, whereas daptomycin was bactericidal at 8 x MIC in most cases. Paradoxical response to bactericidal activity of beta-lactams was abolished by incubation of the inoculum with 2 x MIC before exposure to higher antibiotic concentrations. These findings suggest that enterococci are not always tolerant to cell wall-active antibiotics and that accurate in vitro bactericidal tests may be useful for the choice of appropriate therapy for infections caused by these microorganisms.
Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers
Authors: Tam Y K , Kneer J , Dubach U C , Stoeckel K
Published: June 2012

Cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 16 male subjects (age, 23.4 +/- 1.7 years; weight, 73.9 +/- 7.0 kg) 1 h before (BE), with (WI), and 1 h after (AF) a standard breakfast. The time to peak concentration of cefetamet in plasma (Tmax) was increased from 3.25 +/- 1.44 h in the BE group to 4.31 +/- 1.54 and 4.13 +/- 1.54 h in the WI and AF groups, respectively (P less than 0.05). The maximum cefetamet concentration in plasma (Cmax) and the area under the plasma cefetamet concentration-time profiles (AUC) in the BE, WI, and AF groups were 5.50 +/- 1.06, 5.47 +/- 1.4, and 6.57 +/- 0.93 micrograms/ml and 38.2 +/- 10.1, 35.7 +/- 11.9, and 42.8 +/- 6.8 micrograms.h/ml, respectively. The Cmax and AUC values were not different between the BE and WI groups (P greater than 0.05). However, differences in these values were found between the WI and AF groups (P less than 0.05). The effect of fluid volume intake on cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 12 male subjects (age, 23.8 +/- 2.3 years; weight, 74.9 +/- 9.0 kg) under fasted and WI conditions. Increasing fluid volume intake from 250 to 450 ml under the fasted condition had no effect on the absorption of the prodrug (Tmax, 2.50 +/- 0.52 versus 2.83 +/- 0.94 h; Cmax, 4.89 +/- 1.04 versus 4.84 +/- 0.89 micrograms/ml; AUC, 29.6 +/- 5.1 versus 30.7 +/- 7.1 micrograms.h/ml; P greater than 0.05. Thus, independent of fluid volume intake, cefetamet pivoxil absorption is enhanced when it is given within 1 h of a meal, and it is recommended that the prodrug should be taken during this period of increased bioavailability.
Cloning and sequencing of the class B beta-lactamase gene (ccrA) from Bacteroides fragilis TAL3636
Authors: Rasmussen B A , Gluzman Y , Tally F P
Published: June 2012

Bacteroides fragilis TAL3636 produces a class B, Zn2(+)-requiring beta-lactamase. The gene, ccrA, was cloned and expressed in Escherichia coli. The gene was sequenced and shown to share greater than 33% identity with the metalloenzyme from Bacillus cereus 569/H.
Blockage of cell wall receptors for yeast killer toxin KT28 with antimannoprotein antibodies
Authors: Schmitt M J , Radler F
Published: June 2012

Binding of yeast killer toxin KT28 to its primary cell wall receptor was specifically blocked with polyclonal antimannoprotein antibodies which masked all toxin-binding sites on the surface of sensitive yeast cells. By indirect immunofluorescence, it was shown that KT28 binds to the cell wall mannoprotein and that the toxin resistance of mannoprotein mutants (mnn) of Saccharomyces cerevisiae was due to a lack of killer toxin-binding sites within the yeast cell wall. Structural analysis of acetylated mannoprotein from KT28-resistant mutant strains identified the outer mannotriose side chains as the actual killer toxin-binding domains.
Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillin-resistant Staphylococcus aureus and in vitro killing studies of clinical isolates
Authors: Arathoon E G , Hamilton J R , Hench C E , Stevens D A
Published: June 2012

Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial infection problem. Colonization appears to be more common than invasive disease is. Eradication of colonization or the carrier state could limit the spread of MRSA, thus reducing the potential for mortality and morbidity in other patients. The detection of patients with MRSA infection in a rehabilitation ward led to a study of the combination of novobiocin-rifampin in vivo and in vitro. We found that 300 mg of rifampin plus 500 mg of novobiocin orally twice daily for 5 days, in 18 courses of treatment given to 12 patients, resulted in the clearing of MRSA in 79% of the evaluable courses and 81% of the evaluable sites. A second course cleared MRSA from one of the patients with a treatment failure. Side effects were not noted. All 18 pretherapy isolates were susceptible to either drug in vitro, but 1 of 2 posttherapy isolates was rifampin resistant. Timed-kill studies demonstrated that the rate of killing was the same with either drug alone or both drugs together. Pretherapy isolates from treatment successes or failure were killed at the same rate by the drug combination. However, with the rifampin-resistant isolate killing ceased after 48 h. Results of this study suggest that previously untreated patients are likely to have isolates that are susceptible to the combination of drugs and that the combination is commonly effective in eradicating MRSA carriage. Since the regimen is orally administered, and thus convenient, in conjunction with other measures it has the promise of reducing the spread of MRSA in hospitals.
Enhanced activity of combination of tobramycin and piperacillin for eradication of sessile biofilm cells of Pseudomonas aeruginosa
Authors: Anwar H , Costerton J W
Published: June 2012

An in vitro chemostat system in which Pseudomonas aeruginosa can be cultivated at a slow growth rate and under iron limitation conditions was used to study the susceptibilities of sessile bacteria of mucoid and nonmucoid P. aeruginosa strains to tobramycin and piperacillin. Planktonic cells of both mucoid and nonmucoid P. aeruginosa strains were susceptible to tobramycin and piperacillin. None of the cells was found to be viable after 2 h of exposure to 200 micrograms of piperacillin plus 10 micrograms of tobramycin per ml. Young sessile bacteria were slightly more resistant to piperacillin or tobramycin than the planktonic cells were. However, eradication of young sessile bacteria could be achieved with a combination of piperacillin and tobramycin. None of these young biofilm bacteria were found to be viable after a 2-h exposure to 200 micrograms of piperacillin plus 10 micrograms of tobramycin per ml. Old sessile bacteria were very resistant to these antibiotics. Eradication of old sessile bacteria could not be achieved with either tobramycin (200 micrograms/ml) or piperacillin (200 micrograms/ml) alone. Combination of higher concentrations of tobramycin with piperacillin resulted in an enhancement of killing of the old sessile bacteria. Exposure of old sessile bacteria to 200 micrograms of piperacillin plus 100 micrograms of tobramycin per ml resulted in the reduction of the viable count to approximately 0.02%. The data suggest that the eradication of biofilm-associated infections is best carried out as early as possible. Enhanced activities against the sessile bacteria were achieved when higher concentrations of aminoglycosides were combined with beta-lactam antibiotics.
Presence of an additional penicillin-binding protein in methicillin-resistant Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus simulans with a low affinity for methicillin, cephalothin, and cefamandole
Authors: Pierre J , Williamson R , Bornet M , Gutmann L
Published: June 2012

The presence of an additional penicillin-binding protein (PBP) was demonstrated in methicillin-resistant strains of Staphylococcus epidermidis, S. haemolyticus, S. hominis, and S. simulans. In these four species, the apparent molecular mass of this protein was analogous to that of PBP 2' of methicillin-resistant S. aureus SR 1550-9. It exhibited a low affinity for methicillin, cephalothin, and cefamandole; and its synthesis was methicillin inducible. Peptide mapping of this PBP from the four species yielded identical results that were analogous to those obtained with S. aureus SR 1550-9. These results suggest that this protein is similar to, if not the same as, PBP 2' of S. aureus and that it is involved in methicillin resistance in the four species studied.
Nucleotide sequence and phylogeny of SHV-2 beta-lactamase
Authors: Huletsky A , Couture F , Levesque R C
Published: June 2012

We determined the nucleotide sequence of the blaSHV-2(pBP60-1) gene from Klebsiella ozaenae which confers resistance to broad-spectrum cephalosporins. The structural gene encodes a polypeptide product of 286 amino acids, and the estimated molecular weight of the mature protein is 28,900. Amino acid sequence comparison of the SHV-2pBP60-1 enzyme with all known class A beta-lactamases and homology studies showed that the residues were highly conserved. Furthermore, SHV-2pBP60-1 was clearly related to SHV-1, LEN-1, and OHIO-1. The SHV-2pBP60-1 enzyme differed from SHV-1 isolated from Klebsiella pneumoniae by seven amino acid substitutions. One of these substitutions, the Gly----Ser substitution at position 234, is probably a key region for the novel activity of cefotaxime hydrolysis. A phylogenetic tree was constructed by using all class A beta-lactamases of known sequences by a progressive alignment method. The data suggested that the beta-lactamases of gram-positive Streptomyces, Staphylococcus, and Bacillus species appeared early in evolution, followed by the PSE and CARB enzymes of Pseudomonas species and, more recently, by the SHV-type and TEM-type enzymes found in enteric bacteria. Larger evolutionary distances separated clusters of the gram-positive beta-lactamases than separated clusters of the gram-negative enzymes. Results of this phylogenetic study suggested that extended-spectrum enzymes are recent derivatives that are selected by the use of new cephalosporins.
In vitro antibacterial activity of faeriefungin, a new broad-spectrum polyene macrolide antibiotic
Authors: Mulks M H , Nair M G , Putnam A R
Published: June 2012

The in vitro activity of faeriefungin, a new pentaene macrolide lactone antibiotic produced by Streptomyces griseus var. autotrophicus, against 263 clinical bacterial isolates was examined. In contrast to the related fungicidal antibiotics nystatin and amphotericin B, which show no activity against bacteria, faeriefungin showed bactericidal activity against all species of gram-positive bacteria examined. MICs for these species ranged from 8 to 64 micrograms/ml, and the MIC for 90% of the isolates tested was 32 micrograms/ml. Isolates of some fastidious gram-negative species, including Neisseria gonorrhoeae, N. meningitidis, and Haemophilus influenzae, were slightly susceptible to faeriefungin, with MICs ranging from 16 to 128 micrograms/ml, but all members of the families Enterobacteriaceae and Pseudomonadaceae, with the exception of Pseudomonas cepacia, were completely resistant to faeriefungin at the concentrations tested. Faeriefungin is also active against fungi, nematodes, and mosquito larvae. The mode of action of faeriefungin against both bacteria and fungi is under investigation.
Erythromycin and azithromycin transport into Haemophilus influenzae ATCC 19418 under conditions of depressed proton motive force (delta mu H)
Authors: Capobianco J O , Goldman R C
Published: June 2012

The effect of collapsing the electrochemical proton gradient (delta mu H) on [3H]erythromycin and [14C]azithromycin transport in Haemophilus influenzae ATCC 19418 was studied. The proton gradient and membrane potential were determined from the distribution of [2-14C]dimethadione and rubidium-86, respectively. delta mu H was reduced from 124 to 3 mV in EDTA-valinomycin-treated cells at 22 degrees C with 150 mM KCl and 0.1 mM carbonyl cyanide m-chlorophenylhydrazone. During the collapse of delta mu H, macrolide uptake increased. Erythromycin efflux studies strongly suggested that this increase was not due to an energy-dependent efflux pump but was likely due to increased outer membrane permeability. These data indicated that macrolide entry was not a delta mu H-driven active transport process but rather a passive diffusion process.
Failure of trimethoprim-sulfamethoxazole therapy in experimental enterococcal endocarditis
Authors: Grayson M L , Thauvin-Eliopoulos C , Eliopoulos G M , Yao J D , DeAngelis D V , Walton L , Woolley J L , Moellering R C
Published: June 2012

To assess the potential efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) against serious enterococcal infections, we used a rat enterococcal endocarditis model comparing TMP-SMX therapy (500 mg of TMP plus 2,500 mg of SMX per kg of body weight per day given every 8 h by intragastric gavage) with intravenous ampicillin therapy (1,000 mg/kg per day). Despite concentrations of active drug in serum well in excess of the MIC and MBC, the mean residual vegetation bacterial titer in TMP-SMX-treated rats was similar to that in untreated controls (8.4 +/- 1.1 versus 8.6 +/- 1.3 log10 CFU/g) and significantly higher than that in the ampicillin-treated group (3.6 +/- 1.5 log10 CFU/g; P less than or equal to 0.001). This demonstrates discordance between in vitro activity and in vivo efficacy of TMP-SMX in serious enterococcal infection.
Chloramphenicol concentrations in sera of patients with typhoid fever being treated with oral or intravenous preparation
Authors: Ti T I , Monteiro E H , Lam S , Lee H S
Published: June 2012

Serum chloramphenicol and chloramphenicol succinate concentrations in patients given equivalent doses of chloramphenicol base either intravenously or orally for typhoid fever were measured by high-performance liquid chromatography. The mean serum chloramphenicol concentrations were significantly lower in the 11 patients treated with intravenous chloramphenicol succinate than in the 15 patients treated with oral chloramphenicol capsules.
Genetic basis of tetracycline resistance in Moraxella (Branhamella) catarrhalis
Authors: Roberts M C , Brown B A , Steingrube V A , Wallace R J
Published: June 2012

Two-high-level-tetracycline-resistance Moraxella (Branhamella) catarrhalis strains were shown to carry DNA sequences which hybridized with the Tet B probe. The determinant appeared to be located in the chromosome and was nontransferable.
Deferoxamine and eflornithine (DL-alpha-difluoromethylornithine) in a rat model of Pneumocystis carinii pneumonia
Authors: Clarkson A B , Sarić M , Grady R W
Published: June 2012

The iron chelator deferoxamine and the polyamine biosynthesis inhibitor eflornithine (DL-alpha-difluoromethylornithine) were examined for anti-Pneumocystis carinii activity in the rat model of P. carinii pneumonia. The activity of deferoxamine at 250, 500, and 1,000 mg/kg given intraperitoneally provides evidence that iron chelation is a promising novel approach to P. carinii chemotherapy. Results with eflornithine at 2, 3, and 4% in drinking water confirm and extend previously reported activity in the rat model.
Transferable Tet M in
Fusobacterium nucleatum
Authors: Roberts Marilyn C. , Lansciardi Jobie
Published: June 2012

Two tetracycline-resistant
Fusobacterium nucleatum
strains were able to transfer, by conjugation, tetracycline resistance and the Tet M determinant to recipient
F
.
nucleatum, Peptostreptococcus anaerobius
, and
Enterococcus faecalis
strains at a frequency of 10
−1
to 10
−8
.
In vitro detection of enterococcal vancomycin resistance
Authors: Sahm D F , Olsen L
Published: June 2012

By using agar dilution as the standard method, we determined the ability of broth microdilution, disk diffusion, and an automated system (AMS Vitek) to detect three different levels of vancomycin resistance among six enterococcal isolates. Enterococcus gallinarum AIB-38 and AIB-39 exhibited low-level resistance (MIC, 16 to 32 micrograms/ml) that was detected only by agar and broth dilution methods. E. faecalis V583, E. faecium AIB-42, and E. faecalis AIB-41 showed moderately high-level resistance (MIC, 128 to 256 micrograms/ml) that was detected by dilution methods but not by disk diffusion unless prolonged incubation or an inoculum 10-fold greater than the standard was used. Similarly, this level of resistance was detected by AMS Vitek only when an inoculum 10-fold larger than recommended was used. The high resistance demonstrated by E. faecium AIB-40 (MIC, 2,048 micrograms/ml) was readily detected by all methods studied. Variation in the ability of different methods to detect vancomycin resistance among enterococci complicates monitoring the incidence of these organisms and could result in very major susceptibility reporting errors.
In vitro activity of BAY v 3522, a new cephalosporin for oral administration
Authors: Hodges T L , Eliopoulos G M , Klimm K , Moellering R C
Published: June 2012

The activity of BAY v 3522 was tested against over 500 clinical bacterial isolates and compared with the activities of ampicillin, amoxicillin-clavulanate, cefaclor, cefixime, cefuroxime, cephalexin, and/or ciprofloxacin, erythromycin, and metronidazole. BAY v 3522 activity against staphylococci and streptococci equaled or exceeded those of the other agents. BAY v 3522 exhibited no significant advantage over cefaclor, cefuroxime, or cephalexin against gram-negative bacilli.
In vitro activity of BAY v 3522, a new oral cephalosporin
Authors: Fass R J
Published: June 2012

The in vitro activity of BAY v 3522 was compared with the activities of cephalexin, cefaclor, cefuroxime, cefixime, and amoxicillin-clavulanate. MICs (in micrograms/ml) of BAY v 3522 were as follows: Staphylococcus spp. (except for oxacillin-resistant strains), 0.13 to 1; Streptococcus spp. (except for some viridans group streptococci), less than or equal to 0.015 to 0.25; Enterococcus faecalis, 2 to 8; other enterococci, 0.5 to greater than 32; beta-lactamase-negative Haemophilus influenzae and Branhamella catarrhalis, 0.13 to 1; beta-lactamase-positive H. influenzae and B. catarrhalis, 0.5 to 4; Pasteurella multocida, 0.06 to 0.25; and members of the family Enterobacteriaceae, 0.5 to greater than 32. Among the cephalosporins, BAY v 3522 was the most active against gram-positive cocci and cefixime was the most active against gram-negative bacilli; BAY v 3522 was similar in activity to amoxicillin-clavulanate against most species.
Impact of dosage schedule on the efficacy of gentamicin, tobramycin, or amikacin in an experimental model of Serratia marcescens endocarditis: in vitro-in vivo correlation
Authors: Potel G , Caillon J , Fantin B , Raza J , Le Gallou F , Lepage J Y , Le Conte P , Bugnon D , Baron D , Drugeon H
Published: June 2012

Aminoglycosides are usually considered to be concentration-dependent antibiotics and to have similar pharmacodynamic and pharmacokinetic properties. To verify the equivalent activity of the aminoglycosides on a susceptible strain, we tested the killing rate of three aminoglycosides (gentamicin, tobramycin, and amikacin) on one strain of Serratia marcescens both in vitro and in vivo by using a rabbit model of left-ventricle endocarditis. Despite, similar MICs, the time-kill curve of gentamicin was consistently better than those of amikacin and tobramycin, whatever the concentration of each antibiotic used (1, 2, 4, 8, 16, or 32 mg/liter), after a 5-h incubation. The in vivo bacterial reduction in the vegetations was measured 24 h after administration of an intravenous 48-mg/kg bolus of each antibiotic or at the end of a 24-h continuous intravenous infusion of the same dose. Gentamicin was significantly more effective when administered as a bolus than when administered as a continuous infusion (2.8 +/- 0.2 versus 6.4 +/- 1.5 log10 CFU/g of vegetation, respectively; P less than 0.01), whereas amikacin was more effective as a continuous infusion than as a bolus injection (3.6 +/- 2.0 versus 7.5 +/- 1.3 log10 CFU/g of vegetation, respectively; P less than 0.01). Tobramycin was not very effective, whatever the dosage tested (approximately 6.5 to 7 log10 CFU/g). These results suggest that concentration-dependent bactericidal activities, both in vitro and in vivo, may vary greatly among aminoglycosides despite similar MICs.
Killing of intracellular Mycobacterium tuberculosis by receptor-mediated drug delivery
Authors: Majumdar S , Basu S K
Published: June 2012

p-Aminosalicylic acid (PAS) conjugated to maleylated bovine serum albumin (MBSA) was taken up efficiently through high-affinity MBSA-binding sites on macrophages. Binding of the radiolabeled conjugate to cultured mouse peritoneal macrophages at 4 degrees C was competed for by MBSA but not by PAS. At 37 degrees C, the radiolabeled conjugate was rapidly degraded by the macrophages, leading to release of acid-soluble degradation products in the medium. The drug conjugate was nearly 100 times as effective as free PAS in killing the intracellular mycobacteria in mouse peritoneal macrophages infected in culture with Mycobacterium tuberculosis. The killing of intracellular mycobacteria mediated by the drug conjugate was effectively prevented by simultaneous addition of excess MBSA (100 micrograms/ml) or chloroquine (3 microM) to the medium, whereas these agents did not affect the microbicidal action of free PAS. These results suggest that (i) uptake of the PAS-MBSA conjugate was mediated by cell surface receptors on macrophages which recognize MBSA and (ii) lysosomal hydrolysis of the internalized conjugate resulted in intracellular release of a pharmacologically active form of the drug, which led to selective killing of the M. tuberculosis harbored by mouse macrophages infected in culture. This receptor-mediated modality of delivering drugs to macrophages could contribute to greater therapeutic efficacy and minimization of toxic side effects in the management of tuberculosis and other intracellular mycobacterial infections.
Transferable imipenem resistance in Pseudomonas aeruginosa
Authors: Watanabe M , Iyobe S , Inoue M , Mitsuhashi S
Published: June 2012

We isolated an imipenem-resistant strain, GN17203, of Pseudomonas aeruginosa. The strain produced a beta-lactamase that hydrolyzed imipenem. The beta-lactamase was encoded by a 31-MDa plasmid, pMS350, which belongs to incompatibility group P-9. The plasmic conferred resistance to beta-lactams, gentamicin, and sulfonamide and was transferable by conjugation to P. aeruginosa but not to Escherichia coli. The molecular weight of the purified enzyme was estimated to be 28,000, and the isoelectric point was 9.0. The enzyme showed a broad substrate profile, hydrolyzing imipenem, oxyiminocephalosporins, 7-methoxycephalosporins, and penicillins. The enzyme activity was inhibited by EDTA, iodine, p-chloromercuribenzoate, CuSO4, and HgCl2 but not by clavulanic acid or sulbactam.