bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro lysis of the bloodstream forms of Trypanosoma brucei gambiense by stearylamine-bearing liposomes
Authors: Tachibana H , Yoshihara E , Kaneda Y , Nakae T
Published: June 2012

Cytolytic activity of liposomes consisting of stearylamine and phosphatidylcholine (SA/PC-liposomes) was examined in vitro against the bloodstream forms of Trypanosoma brucei gambiense. More than 99% of the cells (2 X 10(6)/ml) were killed within 30 min by treatment with 15 mol% SA/PC-liposomes (100 microM total lipids). As few as 1.2 X 10(12) liposomes per ml (equivalent to 2 nM liposome) showed trypanocidal activity. Fluorescence microscopy of cells treated with the dansylated SA/PC-liposomes suggested that the liposomes bound to and accumulated on the cell surface, eventually damaging the plasma membrane. SA/PC-liposomes showed no significant hemolysis when incubated with human and mouse erythrocytes under conditions that killed greater than 99.9% of the T. b. gambiense trypomastigotes. Human leukocytes were also shown to be less susceptible to SA/PC-liposomes than T. b. gambiense. These results may point to a new direction in strategy for therapy of African trypanosomiasis.
Mutation in a locus linked to penB-nmp causes suppression of the Mtr phenotype of Neisseria gonorrhoeae
Authors: Shinners E N , Catlin B W
Published: June 2012

The chromosomal locus mtr, which encodes low-level resistance to multiple antibacterial agents in Neisseria gonorrhoeae, is subject to phenotypic suppression by env mutations that increase the permeability of the envelope. We have identified a new locus, mom (for modifier of Mtr), which is located on the chromosome very close to penB and nmp, loci known to be linked to each other and to spc. Phenotypic suppression of Mtr was recognized by reductions of resistance to benzylpenicillin and also to oxacillin and the hydrophobic agents novobiocin and erythromycin. The resistance to each of these antibiotics returned to the Mtr levels in mom+ transformants isolated by selection for increased resistance to either novobiocin or erythromycin; the accompanying change of the outer membrane protein I seroreactions confirmed the proximity of nmp and mom. Thus, some mutant gonococci display wild-type antibiotic susceptibilities but can express multiple resistance following a mom+ mutation that releases the suppressed Mtr phenotype.
Hepatobiliary kinetics and excretion of ciprofloxacin
Authors: Parry M F , Smego D A , Digiovanni M A
Published: June 2012

The biliary excretion and metabolism of ciprofloxacin was studied in 25 hospitalized patients: 19 undergoing routine cholecystectomy and 6 with indwelling biliary drainage catheters. An intravenous dose of 200 mg of ciprofloxacin given 2.5 to 3.0 h prior to cholecystectomy resulted in concentrations in common duct bile, gallbladder bile, and gallbladder wall of 5.69 +/- 4.8, 5.43 +/- 3.34, and 2.52 +/- 1.30 micrograms/g, respectively, all at least fourfold greater than simultaneous concentrations in serum. Ciprofloxacin concentrations in common duct bile exceeded peak concentrations in serum in all but two patients with common duct obstruction. Multiple preoperative doses of ciprofloxacin prior to cholecystectomy increased concentrations in gallbladder bile by eightfold. Six patients with indwelling biliary drainage catheters also received 200 mg of ciprofloxacin intravenously. Less than 1% of the administered dose was excreted in bile as unchanged ciprofloxacin, and there was extensive metabolism. However, peak ciprofloxacin concentrations of 2.83 +/- 0.76 micrograms/ml in serum produced peak concentrations of 10.69 +/- 5.30 micrograms/ml in bile within 1.5 h after infusion and maintained concentrations of at least 0.5 microgram/ml in common duct bile for over 12 h in all patients. It appears that ciprofloxacin concentrations in bile will exceed the MICs for most susceptible biliary pathogens for a period of at least 12 h after a 200-mg intravenous dose.
Association between early inhibition of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12
Authors: Chow R T , Dougherty T J , Fraimow H S , Bellin E Y , Miller M H
Published: June 2012

Quinolone antimicrobial agents are known to interact with DNA gyrase, but the mechanism by which bacterial cell death occurs is not fully understood. In order to determine whether there is a correlation between quinolone-induced inhibition of early (i.e., 10 to 15 min) DNA synthesis and potency (MICs and MBCs), we measured the rate of DNA synthesis in log-phase Escherichia coli K-12 by using [3H]thymidine incorporation. Three quinolones (ciprofloxacin, norfloxacin, and difloxacin) were selected based on their decreasing activity against reference strain KL16. All three quinolones caused an early 50% inhibition of DNA synthesis which was proportional to MICs and MBCs (r greater than 0.99). Furthermore, 50% inhibition of DNA synthesis and MICs were nearly identical for mutant strains with an altered quinolone target (gyrA) or with decreased [nfxB(ompF)] or increased (acrA) permeability. There were significant differences (P less than 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains. The comparison of the three mutants with the wild-type strain permitted an in vivo examination of the effects of alterations of the drug target or entry on the activity determined by DNA synthesis inhibition and MICs.
Inhibition of varicella-zoster virus-induced DNA polymerase by a new guanosine analog, 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine triphosphate
Authors: Abele G , Eriksson B , Harmenberg J , Wahren B
Published: June 2012

The triphosphates of the antiherpesvirus acyclic guanosine analogs 9-[4-hydroxy-2(hydroxymethyl)butyl] guanine (2HM-HBG), 9-(2-hydroxyethoxymethyl)guanine (acyclovir [ACV]), and 9-(3,4-dihydroxybutyl)guanine (buciclovir) were examined for their effects on partially purified varicella-zoster virus (VZV) DNA polymerase as well as cellular DNA polymerase alpha. The triphosphate of 2HM-HBG competitively inhibited the incorporation of dGMP into DNA catalyzed by the VZV DNA polymerase. 2HM-HBG-triphosphate (2HM-HBG-TP) had a higher affinity for the dGTP-binding site on the VZV DNA polymerase than did dGTP; apparent Km and Ki values of dGTP and 2HM-HBG-TP were 0.64 and 0.034 microM, respectively. ACV-triphosphate (ACV-TP) was found to be the most potent inhibitor of VZV DNA polymerase. ACV-TP had a 14 and 464 times better direct inhibitory effect than 2HM-HBG-TP and buciclovir-triphosphate, respectively. The cellular (human embryonic lung fibroblast) DNA polymerase alpha inhibition was related to viral polymerase inhibition as efficacy ratios: 2HM-HBG-TP had a ratio of more than 1,000, which appeared to be similar to that of ACV-TP.
New class of antifungal agents: jasplakinolide, a cyclodepsipeptide from the marine sponge, Jaspis species
Authors: Scott V R , Boehme R , Matthews T R
Published: June 2012

Jasplakinolide is a cyclodepsipeptide which represents a new class of antifungal agents with potent activity against Candida albicans. Jasplakinolide is fungicidal against C. albicans with both a MIC and a minimum lethal concentration of 25 micrograms/ml in a broth dilution assay. This activity compares to that of the imidazole miconazole nitrate, which had a MIC of 6.2 micrograms/ml and a minimum lethal concentration of 50 micrograms/ml in the same assay. Topical administration of 2% jasplakinolide cream against a murine vaginal C. albicans infection was equivalent in efficacy to administration of miconazole nitrate at 2%. Subcutaneous administration of jasplakinolide was not effective against a systemic murine C. albicans infection.
Tn4201, a beta-lactamase transposon in Staphylococcus aureus
Authors: Weber D A , Goering R V
Published: June 2012

We report the preliminary characterization of a 6.7-kilobase transposon, Tn4201, encoding resistance to penicillin associated with the conjugative plasmid pCRG1600 in Staphylococcus aureus. Tn4201 is capable of inverting in orientation (frequently observed in derivatives of pCRG1600) and is expressed equally well in either orientation. The element is also capable of movement to alternative plasmid and chromosomal sites. Tn4201 exhibits rec-independent transposition in an apparent site-specific manner and may play an important role in the resistance of staphylococci to beta-lactam compounds.
Effectiveness of nanoparticle-bound ampicillin in the treatment of Listeria monocytogenes infection in athymic nude mice
Authors: Youssef M , Fattal E , Alonso M J , Roblot-Treupel L , Sauzières J , Tancrède C , Omnès A , Couvreur P , Andremont A
Published: June 2012

The effectiveness of nanoparticle-bound ampicillin was tested in the treatment of experimental Listeria monocytogenes infection in congenitally athymic nude mice. Nanoparticles of polyisohexylcyanoacrylate (PIHCA) 187 +/- 13 nm in diameter were bound to ampicillin at an ampicillin/PIHCA ratio of 0.2:1. The proportion of ampicillin bound was 90% +/- 3%. After adsorption onto nanoparticles, the therapeutic activity of ampicillin increased dramatically over that in the free state. Thus, 2.4 mg of nanoparticle-bound ampicillin (three doses of 0.8 mg each) had a greater therapeutic effect than 48 mg of free ampicillin (three doses of 16 mg each). These results might provide an incentive for further development of intracellular targeting of antibiotics on biodegradable polymeric carriers.
Molecular cloning and genetic analysis of a chloramphenicol acetyltransferase determinant from Clostridium difficile
Authors: Wren B W , Mullany P , Clayton C , Tabaqchali S
Published: June 2012

A gene bank from a clinical isolate of Clostridium difficile expressing high chloramphenicol acetyltransferase activity was constructed by cloning Sau3A-cleaved clostridial DNA fragments into the plasmid vector pUC13. Among 1,020 clones tested, 11 were resistant to chloramphenicol; 1 of these, with an insert size of 1.9 kilobases (pPPM9), was studied further. The clone pPPM9 was mapped using a variety of restriction enzymes, and a 0.27-kilobase EcoRV-TaqI restriction fragment was shown to be within the chloramphenicol resistance (Cmr) gene by using transposon (Tn1000) mutagenesis. The 0.27-kilobase fragment and the 1.9-kilobase insert were radiolabeled and used as DNA probes in hybridization studies. Southern blot analysis with the gene probes against chromosomal DNA from Cmr strains of C. difficile obtained from five distinct geographical locations revealed that at least two copies of the same chloramphenicol acetyltransferase gene were present for each strain. Hybridization of the gene probes against Cmr strains of Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella edwardsii, Escherichia coli, and to four other clostridial species revealed no homology even under conditions of low stringency.
Pharmacokinetics of teicoplanin in pediatric patients
Authors: Terragna A , Ferrea G , Loy A , Danese A , Bernareggi A , Cavenaghi L , Rosina R
Published: June 2012

The pharmacokinetics of teicoplanin have been studied in 13 pediatric male patients from 2 to 12 years of age. Patients were given a single 3-mg/kg intravenous dose of teicoplanin for prophylaxis. Blood and urine samples were collected for 8 days after administration, and teicoplanin levels were determined by microbiological assay. Pharmacokinetic parameters were estimated from a three-compartment open pharmacokinetic model and from a noncompartmental analysis. Levels in plasma 1 h after the administration averaged 14.8 mg/liter. The half-lives of the two distribution phases were 1.3 and 9.7 h. The half-life of the terminal phase averaged 57.9 h, with similar estimates obtained from the noncompartmental analysis and from data from urine. The volume of distribution of the central compartment was 0.15 liter/kg, whereas the volume of distribution at steady state and during the elimination phase were 0.80 and 1.25 liters/kg. The total teicoplanin clearance averaged 14.8 ml/h per kg, with renal clearance accounting for about 60% of the total. The average cumulative recovery of teicoplanin in urine over 8 days was 59% of the dose, similar to the value obtained in adult volunteers. There was no significant linear correlation between elimination half-life and age. Preliminary data after repeated administration support the reliability of the model used and the validity of the mean estimated parameters. There were no local or systemic adverse reactions to teicoplanin.
Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections
Authors: Bergeron M G , Mendelson J , Harding G K , Mandell L , Fong I W , Rachlis A , Chan R , Biron S , Feld R , Segal N B
Published: June 2012

In a prospective, randomized, multicenter study, the efficacy and safety of cefoperazone and the combination ampicillin-tobramycin as initial therapy for patients with severe acute biliary tract infections were compared. Of 77 patients initially entered in the study, definite severe biliary tract infection was confirmed in 67. Sixty-four patients completed treatment. At the end of treatment, 35 of 36 (97%) patients given cefoperazone and 23 of 28 (82%) given ampicillin-tobramycin were cured of their infection (P = 0.07). Pathogens were recovered from the bile in 32 patients; microbiological cures were observed in 18 of 19 (94%) patients receiving cefoperazone and 8 of 13 (62%) receiving ampicillin-tobramycin (P = 0.03). Thirteen patients had septicemia. None (0%) of the eight septicemic patients from the cefoperazone group, but two of five (40%) from the ampicillin-tobramycin group, were clinical failures. Of the isolated pathogens, 51% were resistant to ampicillin, while the resistance rate was 4% for tobramycin and 1% for cefoperazone (P less than 0.001). Biliary concentrations of cefoperazone were maintained at high levels--236 +/- 87 micrograms/ml up to 12 h after administration. Even in the presence of severe obstruction, cefoperazone levels in the bile and gallbladder wall were above MICs for most pathogens. Cefoperazone may be considered as an excellent alternative in the therapy of severe biliary tract infections.
Novel plasmid-mediated beta-lactamase from Escherichia coli that inactivates oxyimino-cephalosporins
Authors: Matsumoto Y , Ikeda F , Kamimura T , Yokota Y , Mine Y
Published: June 2012

A highly cephem-resistant Escherichia coli strain, FP1546, isolated from the fecal flora of laboratory dogs previously administered beta-lactam antibiotics was found to produce a beta-lactamase, FEC-1, of 48-kilodalton size and pI 8.2. FEC-1 hydrolyzed cefuroxime, cefotaxime, cefmenoxime, and ceftriaxone, as well as the enzymatically less-stable antibiotics cephaloridine, cefotiam, and cefpiramide. Of the oxyimino-cephalosporins, ceftizoxime was fairly stable to FEC-1. FEC-1 differed notably from chromosomal E. coli cephalosporinase, especially in its broad-spectrum substrate profile and its high inhibition by clavulanic acid, sulbactam, and imipenem. A conjugation study revealed that FEC-1 was encoded by a 74-megadalton plasmid, pFCX1. This may be the first instance of a plasmid-mediated oxyimino-cephalosporinase from E. coli.
Composite IS1-tetracycline resistance elements in aerobactin-encoding FIme plasmids from epidemic Salmonella wien
Authors: Casalino M , Nicoletti M , Junakovic N , Maimone F
Published: June 2012

Class B tetracycline resistance determinants have been identified in two aerobactin-encoding FIme plasmids representative of those isolated from epidemic Salmonella wien. Genetic data, restriction enzyme analysis of recombinant and mutant plasmids, and Southern blot hybridizations indicate that in both plasmids the class B determinant so far found and described only on Tn10-like transposons is part of a different genetic element. This composite insertion sequence element is about 7 kilobases long and has copies of insertion sequence IS1 at the ends.
Selective imipenem resistance in Pseudomonas aeruginosa associated with diminished outer membrane permeability
Authors: Studemeister A E , Quinn J P
Published: June 2012

The permeability of the outer membranes of imipenem-susceptible and imipenem-resistant clinical isolates of Pseudomonas aeruginosa was investigated by the liposome swelling assay. Sugars and cephaloridine penetrated rapidly, whereas imipenem penetrated poorly into liposomes constructed from porin-rich outer membrane fractions of the resistant isolates.
Comparative in vitro activity of PD 127,391, a new fluorinated 4-quinolone derivative
Authors: Norrby S R , Jonsson M
Published: June 2012

PD 127,391, a newly developed 4-quinolone chemically similar to ciprofloxacin, was studied in vitro by using agar and broth dilution and two inoculum sizes. PD 127,391 was found to be highly active against gram-negative aerobes, including Pseudomonas aeruginosa and other Pseudomonas spp. Its activity against gram-positive aerobes was better than that of ciprofloxacin.
Pharmacokinetics of itraconazole following oral administration to normal volunteers
Authors: Hardin T C , Graybill J R , Fetchick R , Woestenborghs R , Rinaldi M G , Kuhn J G
Published: June 2012

The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, high-performance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/ml at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng.h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.
In vitro activity of DR-3355, an optically active ofloxacin
Authors: Une T , Fujimoto T , Sato K , Osada Y
Published: June 2012

DR-3355, the S-(-)-isomer of ofloxacin, was generally twice as potent as ofloxacin against a variety of gram-positive and gram-negative pathogens, and its action was bactericidal. The compound was characterized by having the highest level of activity against staphylococci, Bacteroides fragilis, and Peptococcus spp. of the fluorinated quinolones tested, including ofloxacin, ciprofloxacin, fleroxacin, and NY-198. The activity of DR-3355 was not affected by different media, inoculum size, or human serum, but decreased under acidic conditions at pH 5.0 or in human urine.
Berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells, fibronectin, and hexadecane
Authors: Sun D , Courtney H S , Beachey E H
Published: June 2012

Berberine sulfate is an alkaloid extracted from the roots and bark of various plants and possesses antibacterial, antifungal, and antiprotozoal activities. Most studies have focused on the bacteriostatic or bactericidal activities of this compound. In this study, we report that berberine sulfate is bacteriostatic for streptococci and that sub-MICs of berberine blocked the adherence of streptococci to host cells, immobilized fibronectin, and hexadecane. Concentrations of berberine below its MIC caused an eightfold increase in release of lipoteichoic acid from the streptococci. Higher concentrations of berberine directly interfered with the adherence of streptococci to host cells either by preventing the complexing of lipoteichoic acid with fibronectin or by dissolution of such complexes once they were formed. Thus, berberine sulfate interferes with the adherence of group A streptococci by two distinct mechanisms: one by releasing the adhesin lipoteichoic acid from the streptococcal cell surface and another by directly preventing or dissolving lipoteichoic acid-fibronectin complexes.
Chromosomal beta-lactamase expression and resistance to beta-lactam antibiotics in Proteus vulgaris and Morganella morganii
Authors: Yang Y J , Livermore D M
Published: June 2012

Indole-positive members of the Proteeae usually have inducible expression of chromosomal beta-lactamases. Mutants with stably derepressed beta-lactamase expression occur in inducible populations at frequencies in the range of 10(-6) to 10(-8). The contribution of these beta-lactamases to drug resistance was examined in Morganella morganii and Proteus vulgaris. The M. morganii enzyme was a high-molecular-weight (49,000) class I cephalosporinase with low Vmax rates for ampicillin, carbenicillin, and and broad-spectrum cephalosporins. The P. vulgaris enzyme had a lower molecular weight (32,000) and high Vmax rates for ampicillin, cephaloridine, cefotaxime, and ceftriaxone. Imipenem and cefoxitin inactivated the P. vulgaris enzyme but were low-Vmax, low-Km substrates for that of M. morganii. Despite these differences, the two beta-lactamases caused similar resistance profiles. Ampicillin and cephaloridine were strong inducers for both species, and beta-lactamase-inducible strains and their stably derepressed mutants were resistant, whereas basal mutants (those with low-level uninducible beta-lactamase) were susceptible to these two compounds. Mezlocillin, cefotaxime, ceftriaxone, and (usually) carbenicillin were almost equally active against beta-lactamase-inducible organisms and their basal mutants, but were less active against stably derepressed mutants. This behavior reflected the beta-lactamase lability of these drugs, coupled with their weak inducer activity below the MIC. Carbenicillin was a labile strong inducer for a single P. vulgaris strain, and inducible enzyme was protective against the drug in this atypical organism. Cefoxitin and imipenem, both strong inducers below the MIC, were almost equally active against beta-lactamase-inducible organisms and their basal and stably derepressed mutants.
In vivo activity of amikacin alone or in combination with clofazimine or rifabutin or both against acute experimental Mycobacterium avium complex infections in beige mice
Authors: Gangadharam P R , Perumal V K , Podapati N R , Kesavalu L , Iseman M D
Published: June 2012

The in vivo activity of amikacin, used alone or in combination with rifabutin or clofazimine or both, was assessed in the treatment of early and established Mycobacterium avium complex infections in beige mice. Amikacin given alone at a dose of 50 mg/kg, in one, two, or three divided doses, showed remarkable activity. Addition of clofazimine increased the activity significantly, but addition of the third drug, rifabutin, did not further improve the results. Amikacin-containing regimens are worthy of consideration for investigations in patients with M. avium complex infections.
Activity of P536, a UDP-glucose analog, against Trypanosoma cruzi
Authors: Alcina A , Fresno M , Alarcón B
Published: June 2012

P536, a UDP-glucose analog which was previously described as an antiviral agent (M. J. Camaraza, P. Fernández Resa, M. T. García López, F. G. de las Heras, P. P. Mendez-Castrillón, B. Alarcón, and L. Carrasco, J. Med. Chem. 28:40-46, 1985), has a potent and selective activity against the intracellular and extracellular stages of Trypanosoma cruzi in vitro. It had a 50% inhibitory concentration of less than 5 micrograms/ml for T. cruzi extracellular cultured forms (epimastigote) and of 25 micrograms/ml for T. cruzi intracellular forms (amastigote) growing inside J774G8 macrophagelike cells. In contrast, the 50% inhibitory concentration was 100 micrograms/ml or greater for cultured mammalian cells and 180 micrograms/ml for the proliferation of mouse spleen lymphocytes. Furthermore, the addition of P536 (50 micrograms/ml) to T. cruzi-infected J774G8 cells cured the infected macrophages, making them able to grow and function normally. Studies on the mechanism of action of this drug indicated that it inhibited incorporation of [35S]methionine, [3H]thymidine, [3H]mannose, [14C]-N-acetylglucosamine, and [3H]uridine into macromolecules by T. cruzi epimastigotes, the last being the most sensitive.
Comparative effects of cefoxitin and cefotetan on vitamin K metabolism
Authors: Sieradzan R R , Bottner W A , Fasco M J , Bertino J S
Published: June 2012

The effects of cefoxitin and cefotetan on vitamin K metabolism and clotting parameters in five healthy subjects were investigated. No changes in prothrombin time or in the formation of abnormal prothrombin were seen either during or following the cefoxitin or cefotetan phase. However, when phytonadione (10 mg) (vitamin K1) was administered at the completion of each course of antibiotics, formation of vitamin K 2,3-epoxide was observed only during the cefotetan phase. It is probable, therefore, that cefotetan, a cephamycin antibiotic containing the N-methylthiotetrazole side chain, inhibits hepatic vitamin K 2,3-epoxide reductase. While hypoprothrombinemia and formation of abnormal prothrombin were not seen in healthy subjects, the effect of cefotetan on the coagulation status of vitamin K-depleted patients may be adverse.
Antibacterial effect of etoposide in vitro
Authors: Calame W , van der Waals R , Douwes-Idema N , Mattie H , van Furth R
Published: June 2012

Etoposide, an antitumor drug, had an effect in vitro against all strains of gram-positive bacteria studied but not against three gram-negative bacteria. The MICs ranged between 6.2 and 50 micrograms/ml. In short-term-growth experiments, etoposide had a bactericidal efficacy that was 10 to 50 times lower than that of cloxacillin.
Susceptibilities of genital mycoplasmas to the newer quinolones as determined by the agar dilution method
Authors: Kenny G E , Hooton T M , Roberts M C , Cartwright F D , Hoyt J
Published: June 2012

The increasing resistance of genital mycoplasmas to tetracycline poses a problem because tetracycline is one of the few antimicrobial agents active against Mycoplasma hominis, Ureaplasma urealyticum, chlamydiae, gonococci, and other agents of genitourinary-tract disease. Since the quinolones are a promising group of antimicrobial agents, the susceptibilities of M. hominis and U. urealyticum to the newer 6-fluoroquinolones were determined by the agar dilution method. Ciprofloxacin, difloxacin, and ofloxacin had good activity against M. hominis, with the MIC for 50% of isolates tested (MIC50) being 1 microgram/ml. Fleroxacin, lomefloxacin, pefloxacin, and rosoxacin had MIC50s of 2 micrograms/ml. Enoxacin, norfloxacin, and amifloxacin had MIC50s of 8 to 16 micrograms/ml, and cinoxacin and nalidixic acid were inactive (MIC50, greater than or equal to 256 micrograms/ml). Overall, the activities of 6-fluoroquinolones for ureaplasmas were similar to those for M. hominis, with MICs being the same or twofold greater. The most active 6-fluoroquinolones against ureaplasmas were difloxacin, ofloxacin, and pefloxacin, with MIC50s of 1 to 2 micrograms/ml. Ciprofloxacin was unusual in that the MIC50 for M. hominis was 1 microgram/ml, whereas the MIC50 for ureaplasmas was 8 micrograms/ml. Since the MIC50s for the most active quinolones approximate achievable concentrations in blood and urine, quinolones have promise in treating mycoplasmal infections.
Comparison of inhibitory activities of various antiretroviral agents against particle-derived and recombinant human immunodeficiency virus type 1 reverse transcriptases
Authors: Schinazi R F , Eriksson B F , Hughes S H
Published: June 2012

Several known antiretroviral agents were tested for their ability to inhibit the activities of human immunodeficiency virus type 1 reverse transcriptase purified from virions or from a recombinant Escherichia coli strain. The recombinant reverse transcriptase, a polypeptide of 66 kilodaltons, showed inhibition profiles indistinguishable from those of the virion-derived enzyme with all tested compounds, except for suramin and two dextran sulfates. These were more inhibitory to the recombinant enzyme, presumably because the E. coli-derived enzyme was more highly purified. The relative ease with which large quantities of recombinant enzyme can be prepared should facilitate the large-scale screening and identification of new potential inhibitors of the human immunodeficiency virus type 1 reverse transcriptase.
In vitro activities of temafloxacin (A-62254) and four other antibiotics against Chlamydia trachomatis
Authors: Segreti J , Kessler H A , Kapell K S , Trenholme G M
Published: June 2012

The in vitro activity of temafloxacin (A-62254), a new quinolone antibiotic, against 13 strains of Chlamydia trachomatis was determined and compared with those of doxycycline, norfloxacin, ciprofloxacin, and difloxacin. Temafloxacin and difloxacin were the most active quinolones tested, with bactericidal activity comparable to that of doxycycline.
Outer membrane alterations in multiresistant mutants of Pseudomonas aeruginosa selected by ciprofloxacin
Authors: Legakis N J , Tzouvelekis L S , Makris A , Kotsifaki H
Published: June 2012

Spontaneous mutants of Pseudomonas aeruginosa selected by ciprofloxacin were studied for outer membrane alterations. Acquisition of ciprofloxacin resistance was at least partially related to defects in lipopolysaccharide synthesis. When ciprofloxacin resistance was combined with resistance to beta-lactams and aminoglycosides, several alterations in outer membrane proteins were noted.
Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections
Authors: Piercy E A , Barbaro D , Luby J P , Mackowiak P A
Published: June 2012

Thirty-seven patients with methicillin-resistant Staphylococcus aureus infections and/or colonization were treated with oral ciprofloxacin (750 mg twice a day). Clinical cure or improvement of infections occurred in 91% of the patients, and bacteriologic cure occurred in 60%. Ciprofloxacin therapy suppressed methicillin-resistant S. aureus colonization in 55% of the patients. Ciprofloxacin-resistant strains emerged in 6 of the 37 patients.
Characterization of Aeromonas salmonicida mutants with low-level resistance to multiple antibiotics
Authors: Griffiths S G , Lynch W H
Published: June 2012

Aeromonas salmonicida mutants selected for low-level resistance to small-molecular-mass antibiotics occur at frequencies that suggest point mutations and exhibit pleiotropic effects such as a multiple low-level antibiotic resistance, changes in outer membrane protein profiles, and loss of major exoprotease activity. Multiple low-level resistance appeared as the result of decreased outer membrane permeability associated with a change from a 38.5- to a 37-kilodalton (kDa) outer membrane protein. This decreased outer membrane permeability was determined by rates of nitrocefin hydrolysis by periplasmic beta-lactamase activity. The findings described above were supported by isolation of revertant strains selected for regained exoprotease activity, which also lost multiple low-level resistance and possessed outer membrane protein profiles indistinguishable from those of the original parent strains. Exoprotease from parent and revertant strains was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a major extracellular protein of approximately 69 kDa. No accumulation of a protein in this molecular mass range was observed in extracellular or periplasmic fractions from the mutants. The results suggested that exoprotease loss is not simply the result of an inability to export protease from the periplasm because of outer membrane protein changes, as has been reported for certain mutants of some other gram-negative bacteria. Also, several growth conditions were used, including some that have been reported to influence outer membrane protein expression and permeability in other enteric gram-negative bacteria. Although exoprotease expression in A. salmonicida was influenced by these conditions, no major outer membrane protein changes which would correspond to changes observed in the mutants were observed in parent strains.
Enhancing effect of serum ultrafiltrate on the activity of cephalosporins against gram-negative bacilli
Authors: Leggett J E , Craig W A
Published: June 2012

A few studies have suggested that the inhibitory effect of serum on activity of broad-spectrum cephalosporins is less than that predicted by the degree of protein binding. Microdilution MICs of ceftriaxone, cefoperazone, moxalactam, and ceftizoxime were therefore determined against ATCC and clinical strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus in Mueller-Hinton broth containing either human albumin (as 0, 2.5, or 5% solution) or heat-inactivated human serum (as 0, 25, 50, or 95% solution). Arithmetic linear dilutions were used to improve accuracy. For standard bacterial strains, MICs in the presence of 5% albumin were higher than in broth alone by multiples of 10.9 to 21 for ceftriaxone, 5.5 to 16.4 for cefoperazone, 1.9 to 3.7 for moxalactam, and 1.1 to 1.4 for ceftizoxime, as expected by their protein binding. MICs in the presence of 95% serum were similar to those in 5% albumin for all four drugs against S. aureus and P. aeruginosa but were 2.2- to 4.8-fold lower (P less than 0.001) against E. coli and K. pneumoniae. Similar findings were observed at lower protein concentrations and with clinical isolates, except that for some strains of P. aeruginosa MICs were lower in serum than in albumin. Individual sera from five subjects gave comparable results. The addition of serum ultrafiltrate to albumin-containing solutions reduced MICs of ceftriaxone and cefoperazone 1.6- to 7.4-fold against E. coli and K. pneumoniae (P less than 0.01) but did not alter the MICs for S. aureus. Serum may contain an ultrafiltrable component(s) that enhances the activity of third-generation cephalosporins against many gram-negative bacilli.
Inhibition of Pseudomonas aeruginosa exoenzyme expression by subinhibitory antibiotic concentrations
Authors: Grimwood K , To M , Rabin H R , Woods D E
Published: June 2012

We examined the effects of subinhibitory concentrations of ciprofloxacin, tobramycin, and ceftazidime on Pseudomonas aeruginosa exoenzyme expression in vitro and in vivo. Exotoxin A, exoenzyme S, phospholipase C, elastase, and total protease activities were suppressed by antibiotics at concentrations as low as 1/20 of the MIC over a 24-h period in broth. Continuous 10-day exposure of P. aeruginosa DG1 broth cultures to antibiotic levels equal to 1/10 of the MIC reduced exoenzyme S activity in all treatment groups. Elastase activity was reduced only by ciprofloxacin and tobramycin treatment. This suppressive effect of the antibiotics persisted throughout the 10 days and was not influenced by the increase in MIC of ciprofloxacin detected during the course of the experiment. Rats chronically infected with P. aeruginosa were treated with subinhibitory doses of antibiotics and compared with untreated controls. Bacterial numbers in lung homogenates from each of the four study groups were identical. However, the lungs from antibiotic-treated rats had significantly less histological damage than those from control rats (P less than 0.001). The protective effect was greatest for ciprofloxacin and tobramycin. Further, P. aeruginosa isolates from ciprofloxacin- and tobramycin-treated rats demonstrated significantly less exoenzyme S and elastase activity than isolates from untreated rats (P less than 0.001). Isolates from ceftazidime-treated lungs expressed less exoenzyme S activity (P less than 0.001) but an equivalent amount of elastase activity as isolates from controls. The suppression of P. aeruginosa exoenzymes may arrest progressive lung injury during chronic P. aeruginosa lung infections.
Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3'-azido-3'-deoxythymidine
Authors: Johnson V A , Walker B D , Barlow M A , Paradis T J , Chou T C , Hirsch M S
Published: June 2012

Castanospermine and 3'-azido-3'-deoxythymidine (zidovudine) were evaluated in combination against human immunodeficiency virus (HIV) replication in vitro. Castanospermine and 3'-azido-3'-deoxythymidine inhibited HIV type 1 synergistically in acutely infected H9 cells. In addition, they synergistically inhibited both HIV type 1 and HIV type 2 in peripheral blood mononuclear cells. There were no additional toxic effects of these agents in combination. Drug interactions were evaluated by the median-effect principle and the isobologram technique. Combinations of a glycosylation inhibitor, such as castanospermine, with 3'-azido-3'-deoxythymidine deserve consideration for HIV-related chemotherapeutic intervention.
In vitro and in vivo activities of atalaphillinine and related acridone alkaloids against rodent malaria
Authors: Fujioka H , Nishiyama Y , Furukawa H , Kumada N
Published: June 2012

Thirty acridone alkaloids obtained from Citrus, Glycosmis, or Severinia plants (members of the family Rutaceae) were tested for their antimalarial activities in vitro and in vivo. At a concentration of 10 micrograms/ml in vitro, seven of these alkaloids suppressed 90% or more of Plasmodium yoelii, which causes malaria in rodents. Atalaphillinine, when injected intraperitoneally in a daily dose of 50 mg/kg for 3 days into mice infected with 10(7) erythrocytes parasitized with Plasmodium berghei or Plasmodium vinckei, completely suppressed the development of malaria parasites, with there being no obvious acute toxic effects from the tested dose.
Purification and characterization of an antibacterial substance produced by a marine Alteromonas species
Authors: Barja J L , Lemos M L , Toranzo A E
Published: June 2012

An extracellular inhibitory substance produced by the marine Alteromonas strain P-31 (NCMB 2144) was isolated and purified. The inhibitor was a macromolecule with a molecular weight of 90,000 estimated by Sephadex G-100 chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The inhibitory activity was antagonized by proteinase K and beta-amylase and inactivated by heating at 80 degrees C for 30 min. The purified substance exhibited two typical absorption bands in the infrared spectrum at 1,650 and 1,075 cm-1, corresponding to peptide linkages and carbohydrate residues, respectively. These findings allowed us to characterize the antimicrobial compound as a thermolabile glycoprotein. The substance exhibited a broad inhibitory spectrum, being active against clinical and environmental isolates from related and nonrelated taxonomical bacterial groups as well as against the producer strain and other similar marine bacterial strains. The inhibitory glycoprotein did not display cytotoxicity toward mammalian and fish cell lines.
Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites
Authors: Akahane K , Sekiguchi M , Une T , Osada Y
Published: June 2012

The relationship between the chemical structure and epileptogenic activity of quinolones was investigated. When the quinolones were administered intravenously to mice concomitantly with oral biphenylacetic acid, a major metabolite of the nonsteroidal antiinflammatory drug fenbufen, enoxacin, norfloxacin, ciprofloxacin, and pipemidic acid, which have an unsubstituted piperazine moiety at the 7 position of their parent nuclei, provoked clonic convulsions and subsequent death at doses of 6.25 mg/kg or more in a dose-dependent manner. AM-1091 and T-3262, which have an unsubstituted aminopyrrolidine moiety at their 7 positions, were less epileptogenic than the compounds listed above were. In contrast, ofloxacin, AT-4140, and nalidixic acid, which have piperazine substituted with methyl group(s) or no piperazine moiety at their 7 positions, never induced convulsions, even at doses of 100 mg/kg. Lomefloxacin, which has a 3-methyl piperazine, however, provoked convulsions at doses of 6.25 mg/kg or more. In the presence of biphenylacetic acid, all the test quinolones except nalidixic acid competitively inhibited [3H]muscimol binding to receptor sites for gamma-aminobutyric acid (GABA) in vitro. Nalidixic acid did not inhibit the binding at all, even at the highest concentration tested, i.e., 10(-4) M. The 50% inhibition doses for [3H]muscimol binding varied within 4 orders of magnitude or more, between 10(-8) to more than 10(-4) M for various compounds, and there was a close correlation between the epileptogenic activities of quinolones and their inhibitory potencies for [3H]muscimol binding to GABA receptor sites. These results indicate that the epileptogenic activity of quinolones possibly relates to the GABA-like structures of substituents at their 7 positions, which act as antagonists of GABA receptors.
Sodium hexametaphosphate sensitizes Pseudomonas aeruginosa, several other species of Pseudomonas, and Escherichia coli to hydrophobic drugs
Authors: Vaara M , Jaakkola J
Published: June 2012

Many gram-negative bacteria are known to be remarkably resistant to hydrophobic noxious agents by virtue of their outer membranes (OM). We investigated, by using four different assay methods, the ability of sodium hexametaphosphate (HMP) to disrupt this OM barrier. (i) In the growth inhibition assay, HMP was found to sensitize strains of Pseudomonas aeruginosa to all the hydrophobic probes tested (rifampin, fusidic acid, dactinomycin, sodium dodecyl sulfate, and Triton X-100). A concentration of 0.3% HMP decreased the MICs of the probes by a factor of approximately 10, and maximally even a 30-fold sensitization was found with 1% HMP. (ii) In the bactericidal assay, 0.3% HMP decreased the MBC of the hydrophobic probe rifampin by a factor of approximately 30. (iii) In the bacteriolytic assay, 0.1% HMP sensitized the target bacteria to lysis by sodium dodecyl sulfate and Triton X-100. (iv) In the fluorescent-probe binding assay, HMP drastically enhanced the binding of fluorescent N-phenyl naphthylamine to the membranes of the target cells. In addition to P. aeruginosa, P. fluorescens, P. putida, P. fragi, and Escherichia coli were susceptible to the OM permeability-increasing action of HMP, while P. cepacia was resistant.
In vitro effects of three new 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) on Toxoplasma gondii
Authors: Chang H R , Jefford C W , Pechère J C
Published: June 2012

The in vitro effects of three synthetic, cis-fused, bicyclic 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) against intracellular Toxoplasma gondii were studied. Unactivated peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to the 1,2,4-trioxanes at different concentrations. The antitoxoplasmic activity of the drugs was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. Pentatroxane and thiahexatroxane were the most active, exhibiting 90% inhibitory concentrations of 6.8 and 5.3 micrograms/ml, respectively. Furthermore, microscopic examination of the infected macrophages after treatment with pentatroxane, thiahexatroxane, and hexatroxanone at their respective 90% inhibitory concentrations confirmed the inhibition of intracellular growth of T. gondii. Their activities were comparable to those of pyrimethamine (1 micrograms/ml) and pyrimethamine (0.1 micrograms/ml) in combination with sulfadiazine (25 micrograms/ml). Pentatroxane and thiahexatroxane were also able to inhibit intracellular growth of T. gondii within nonprofessional phagocytes (HeLa cells), suggesting that the antitoxoplasmic activity was not caused by a macrophage-specific mechanism, such as macrophage activation. However, the 1,2,4-trioxanes were not active against extracellular T. gondii. Pentatroxane and thiahexatroxane are new, promising compounds that deserve further study to assess their usefulness for treating toxoplasmosis.
Comparative evaluation of cefazolin and clindamycin in the treatment of experimental Staphylococcus aureus osteomyelitis in rabbits
Authors: Mader J T , Adams K , Morrison L
Published: June 2012

A rabbit model for Staphylococcus aureus osteomyelitis was used to compare treatment with clindamycin and cefazolin. Cefazolin (5 mg/kg), cefazolin (15 mg/kg), and clindamycin (70 mg/kg) were injected subcutaneously every 6 h for 28 days. After treatment, S. aureus was found in bone cultures from 22 of 23 control rabbits, 12 of 22 rabbits treated with cefazolin (5 mg/kg), 12 of 23 rabbits treated with cefazolin (15 mg/kg), and 2 of 20 rabbits treated with clindamycin. Drug concentrations in serum, uninfected bone, and infected bone were measured 30 min after cefazolin or clindamycin was injected into a group of rabbits which had been infected for 3 to 4 weeks. Clindamycin gave the highest concentration in infected and uninfected bone. The results of the study showed that clindamycin was superior to cefazolin in the eradication of S. aureus from infected bone in an experimental model.
Rapid nucleic acid assay for detection of bacteria with tetM-mediated tetracycline resistance
Authors: Sanchez-Pescador R , Running J A , Stempien M M , Urdea M S
Published: June 2012

A novel nucleic acid assay has been developed to screen bacterial populations for the presence of the tetM structural gene. The method involves the specific hybridization of several synthetic oligonucleotides to the gene in a crude bacterial lysate solution. As few as 1.5 x 10(4) CFU can be detected with the assay.
Evaluation of cilofungin (LY121019) for treatment of experimental Candida albicans endocarditis in rabbits
Authors: Padula A , Chambers H F
Published: June 2012

The efficacy of cilofungin (LY121019) for aortic valve endocarditis caused by Candida albicans in rabbits was studied. Vegetation titers were similar for cilofungin-treated and untreated rabbits. No rabbit survived beyond 5 days in either group. All rabbits given amphotericin B survived, and titers were reduced. Cilofungin was ineffective in this model.
Interaction of biofilm bacteria with antibiotics in a novel in vitro chemostat system
Authors: Anwar H , van Biesen T , Dasgupta M , Lam K , Costerton J W
Published: June 2012

Pseudomonas aeruginosa was cultivated at low growth rates under iron-limiting conditions on acrylic tiles. Biofilm cells exhibited increased tobramycin resistance compared with that of planktonic cells, and in old biofilms were more resistant than were cells in young biofilms. However, on suspension of the biofilm bacteria, glycocalyx-mediated resistance was lost.
Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males
Authors: Waite N M , Edwards D J , Arnott W S , Warbasse L H
Published: June 2012

Several inhibitors of oxidative drug metabolism inhibit the synthesis of endogenous compounds such as testosterone and cortisol. Since ciprofloxacin is a potent inhibitor of the metabolism of a number of drugs, we studied its effect on serum testosterone and cortisol concentrations in eight healthy male subjects. Blood samples were collected over a 12-h period under baseline conditions and following the first and final doses of ciprofloxacin (500 mg orally every 12 h for 4 days). No significant differences in concentrations or area under the concentration-time curve were found when baseline values were compared with those observed for either testosterone or cortisol after ciprofloxacin administration. These results suggest that ciprofloxacin is unlikely to have either antiandrogenic side effects or clinical utility in lowering testosterone or cortisol concentration.