bluuebunny/crossref_metadata_2025 huggingface dataset:
Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome
Authors: Mills J , Leoung G , Medina I , Hopewell P C , Hughes W T , Wofsy C
Published: June 2012

All patients with the acquired immunodeficiency syndrome treated for their first episode of Pneumocystis carinii pneumonia at San Francisco General Hospital between 1 April 1985 and 15 July 1985 were evaluated for their response to treatment with dapsone (100 mg/day) by mouth for 21 days. Of 44 patients evaluated, 18 were eligible for the study. Of these 18 patients, the conditions of 7 of them worsened or failed to improve during treatment with dapsone and they were considered treatment failures. These patients were changed to standard therapy after 4 to 8 days of dapsone therapy. The remaining 11 patients (61%) improved within 3 to 10 days after dapsone therapy was started. Side effects of dapsone therapy were noted in 6 of 11 patients (of these 11 patients, 5 had a rash, 1 had a rash and abnormal liver enzymes, and 1 had abnormal liver enzymes), but in none of the patients were these side effects severe enough to require the cessation of medication. Based on comparison with historical controls, oral dapsone therapy alone appeared to be less effective than standard therapy or the combination of dapsone plus trimethoprim for P. carinii pneumonia in patients with acquired immunodeficiency syndrome.
Outer membrane permeation of Bacteroides fragilis by cephalosporins
Authors: Yotsuji A , Mitsuyama J , Hori R , Yasuda T , Saikawa I , Inoue M , Mitsuhashi S
Published: June 2012

Outer membrane permeation of Bacteroides fragilis by cephalosporins was examined by a previously described method. The permeation parameters of cephalosporins in B. fragilis were close to 10(-5) cm3/min per microgram of cell dry weight. These values were about an order of magnitude lower than those in Escherichia coli. In B. fragilis, the permeation was not directly proportional to the hydrophilicity of cephalosporins, and the ion selectivity was weak.
Detection of two different kanamycin resistance genes in naturally occurring isolates of Campylobacter jejuni and Campylobacter coli
Authors: Tenover F C , Elvrum P M
Published: June 2012

A total of 225 isolates of Campylobacter jejuni and 54 isolates of Campylobacter coli were screened for resistance to kanamycin. Among these, five resistant isolates of C. jejuni and six resistant isolates of C. coli, all with different plasmid patterns, were identified. Each contained at least one plasmid greater than or equal to 41 kilobases in size. The MIC of kanamycin for all 11 strains was determined to be greater than or equal to 256 micrograms/ml by an agar dilution method. In addition, all of the strains exhibited resistance to tetracycline (greater than or equal to 16 micrograms/ml). Eight of the 11 strains transferred the kanamycin resistance phenotype to other Campylobacter strains by conjugation. DNA from 9 of the 11 strains hybridized to a DNA probe specific for the 3'-O-aminoglycoside phosphotransferase type III gene. The remaining two strains also failed to show homology with DNA probes specific for the genes encoding 3'-O-aminoglycoside phosphotransferase types I, II, and III. The novel kanamycin resistance gene was cloned into the vector pBR322 and was expressed in Escherichia coli. Phosphocellulose paper binding assays on sonicates of the E. coli strain carrying the cloned kanamycin determinant demonstrated significant activity against kanamycin, neomycin, and amikacin but not against butirosin, gentamicin, tobramycin, or lividomycin, suggesting that the enzyme is the product of a 3'-O-aminoglycoside phosphotransferase type of aminoglycoside resistance gene.
Rapid susceptibility testing of Mycobacterium tuberculosis by bioluminescence assay of mycobacterial ATP
Authors: Nilsson L E , Hoffner S E , Anséhn S
Published: June 2012

Mycobacterial growth was monitored by bioluminescence assay of mycobacterial ATP. Cultures of Mycobacterium tuberculosis H37Rv and of 25 clinical isolates of the same species were exposed to serial dilutions of ethambutol, isoniazid, rifampin, and streptomycin. A suppression of ATP, indicating growth inhibition, occurred for susceptible but not resistant strains within 5 to 7 days of incubation. Breakpoint concentrations between susceptibility and resistance were determined by comparing these results with those obtained by reference techniques. Full agreement was found in 99% of the assays with the resistance ratio method on Lowenstein-Jensen medium, and 98% of the assays were in full agreement with the radiometric system (BACTEC). A main advantage of the bioluminescence method is its rapidity, with results available as fast as with the radiometric system but at a lower cost and without the need for radioactive culture medium. The method provides kinetic data concerning drug effects within available in vivo drug concentrations and has great potential for both rapid routine susceptibility testing and research applications in studies of drug effects on mycobacteria.
Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli
Authors: Sun D , Abraham S N , Beachey E H
Published: June 2012

We investigated the influence of berberine sulfate, an ancient Chinese antibiotic, upon the adhesion of uropathogenic Escherichia coli to erythrocytes and epithelial cells. Although berberine sulfate in increasing concentrations had no effect on bacterial growth or on the synthesis of major outer membrane proteins of the E. coli organisms, it increasingly blocked adhesion. The decreased adhesion was accompanied by a reduction in the synthesis of fimbrial subunits and in the expression of assembled fimbriae. These results suggest that the anti-infectious activity of berberine sulfate in E. coli-induced urinary tract infections may be mediated by the selective suppression of the synthesis and assembly of fimbriae by uropathogenic organisms.
Genetic determinant of the ROB-1 beta-lactamase in bovine and porcine Pasteurella strains
Authors: Livrelli V O , Darfeuille-Richaud A , Rich C D , Joly B H , Martel J L
Published: June 2012

The ROB-1 beta-lactamase, previously described in Haemophilus influenzae, has been found in the genus Pasteurella. In three bovine strains of Pasteurella multocida and Pasteurella haemolytica, ROB-1 production was determined by plasmids of 4.4 kilobases. In one porcine strain of Pasteurella aerogenes, the enzyme seems to be chromosomally encoded.
Double-blind, randomized comparison of 24 weeks of norfloxacin and 12 weeks of norfloxacin followed by 12 weeks of placebo in the therapy of complicated urinary tract infection
Authors: Sheehan G J , Harding G K , Haase D A , Thomson M J , Urias B , Kennedy J K , Hoban D J , Ronald A R
Published: June 2012

We evaluated the benefits of prolonging norfloxacin therapy from 12 to 24 weeks for complicated urinary tract infection in a double-blind, randomized, placebo-controlled study. During the second 12 weeks, norfloxacin was superior to placebo (P less than 0.05) in suppressing bacteriuria. Adverse effects were common but mostly confined to the initial 12 weeks.
Effects of antimicrobial agents on growth and chemotaxis of Trichomonas vaginalis
Authors: Sugarman B , Mummaw N
Published: June 2012

The motility of viable Trichomonas vaginalis organisms is readily demonstrable in a clinical wet mount or cultured specimens. We attempted to determine whether migration is a dynamic process such that the organisms move to avoid exposure to toxic antimicrobial agents. With the use of axenic cultures of T. vaginalis that were radiolabeled and assayed for chemotaxis in plastic multiwelled plates with a membrane filter inserted to trap organisms, the response of clinical isolates to various antimicrobial agents was studied. Chemotaxis was readily demonstrable and dependent upon factors including time of incubation, media used, and viscosity of media. Nitroimidazoles (e.g., metronidazole) which readily inhibited the growth of these organisms also caused significant chemorepulsion after minutes of exposure. The antifungal imidazoles ketoconazole and miconazole inhibited growth nearly as readily and caused chemorepulsion, but to a lesser degree. The spermicide Nonoxynol-9 also inhibited growth and caused significant chemorepulsion. The minimal concentrations of many compounds which inhibited growth were very similar to those which caused significant chemorepulsion. Imidazole and antibiotics (e.g., penicillin) which did not inhibit growth did not induce any chemotactic effects. Chemotaxis of T. vaginalis is an active and dynamic process, and the organisms display chemorepulsion shortly after exposure to toxic antimicrobial agents, well before toxicity can be demonstrated.
Efficacy of NY-198 against experimental Legionnaires disease
Authors: Kohno S , Yamaguchi K , Dohtsu Y , Koga H , Hayashi T , Hirota M , Saito A , Hara K
Published: June 2012

The in vitro and in vivo effects of NY-198 against Legionella pneumophila were compared with those of ciprofloxacin. The MIC of NY-198 against 15 standard reference strains of Legionella of various species, between 0.03 and 0.125 micrograms/ml, was the same as that of ciprofloxacin. The peak concentration of NY-198 in the lungs and sera of guinea pigs with experimentally induced Legionella pneumonia was higher than that of ciprofloxacin after oral administration. The overall survival rate was higher in animals treated with NY-198 than in those treated with ciprofloxacin. Thus, NY-198 appears valuable in the treatment of Legionnaires disease.
Emergence of fluoroquinolone resistance in Bacteroides fragilis accompanied by resistance to beta-lactam antibiotics
Authors: Kato N , Miyauchi M , Muto Y , Watanabe K , Ueno K
Published: June 2012

The in vitro susceptibilities of a group of 93 isolates of Bacteroides fragilis collected from 1983 to 1984 to six fluoroquinolones were compared with those of a group of 93 isolates collected from 1986 to 1987. The recently collected strains were less susceptible than the older strains to all of the agents tested. Norfloxacin-resistant (MIC, greater than 100 micrograms/ml) strains were less susceptible to cefoxitin and piperacillin than norfloxacin-susceptible strains.
In vitro activities of PD 117,596 and reference antibiotics against 448 clinical bacterial strains
Authors: Smith R P , Baltch A L , Hammer M C , Conroy J V
Published: June 2012

The in vitro activity of PD 117,596, a new fluoroquinolone antibiotic, was tested against 448 bacterial isolates (15 genera) by agar dilution (inoculum, 10(4) CFU per spot). The activity of PD 117,596 was compared with that of 15 antibiotics against 327 gram-negative strains and with that of 8 other antibiotics against 121 gram-positive strains. PD 117,596 demonstrated the best activity against Klebsiella spp., Enterobacter spp., Acinetobacter spp., Serratia marcescens, and Branhamella catarrhalis (MICs for 90% of the isolates [MIC90S], 0.008 to 0.25 microgram/ml). PD 117,596 (MIC90, 0.25 microgram/ml) was at least twofold more active than ciprofloxacin against Pseudomonas aeruginosa and Pseudomonas spp. PD 117,596 and ciprofloxacin were similar in activity against Escherichia coli, Proteus mirabilis, Haemophilus influenzae, H. parainfluenzae, Neisseria gonorrhoeae, Legionella pneumophila, and Campylobacter jejuni (MIC90, 0.002 to 0.125 microgram/ml). PD 117,596 was more active than ciprofloxacin against streptococcal groups A, B, C, and G, S. pneumoniae, and enterococci (MIC90S, 0.06 to 0.125 microgram/ml). Against Staphylococcus aureus, including methicillin-resistant isolates, PD 117,596 (MIC90S, 0.03 to 0.06 microgram/ml) was 4- to 16-fold more active than ciprofloxacin and was most active against Corynebacterium spp. PD 117,596 appears to be the most active fluoroquinolone to date, with excellent activity against gram-positive bacteria and enhanced activity against gram-negative aerobic-facultative bacteria.
Antimicrobial susceptibilities of southern African isolates of Haemophilus ducreyi
Authors: Dangor Y , Miller S D , Exposto F da L , Koornhof H J
Published: June 2012

We determined the antimicrobial susceptibilities of 122 recent clinical isolates of Haemophilus ducreyi to 24 antimicrobial agents. All isolates produced beta-lactamase and were resistant to penicillins. The majority of strains were also resistant to tetracycline, doxycycline, and sulfamethoxazole. All isolates were susceptible to macrolides, quinolones, extended-spectrum cephalosporins, spectinomycin, rifampin, and amoxycillin-clavulanate. Reduced susceptibility to minocycline, co-trimoxazole, and kanamycin was noted. Chloramphenicol and thiamphenicol resistance was noted for the first time among southern African strains.
Interaction of FCE 22101 with penicillin-binding proteins of Staphylococcus aureus
Authors: Tonin E A , Fontana R
Published: June 2012

FCE 22101 is a new penem characterized by a broad spectrum of activity which includes activity against methicillin-resistant strains of Staphylococcus aureus. The interaction of FCE 22101 with penicillin-binding protein 2a of a methicillin-resistant S. aureus strain has been investigated in the present study. In competition experiments, the penem showed a very low affinity for this protein, and a concentration more than 4 times the MIC was required for penicillin-binding protein 2a saturation. When the classical competitive procedure was modified by increasing the time of incubation of either membranes or growing cells with FCE 22101, the antibiotic showed a much higher affinity for penicillin-binding protein 2a and saturated the protein at a concentration close to the MIC, with slow kinetics.
Influence of two quinolones, ofloxacin and pefloxacin, on human myelopoiesis in vitro
Authors: Pallavicini F , Antinori A , Federico G , Fantoni M , Nervo P
Published: June 2012

The influence of ofloxacin and pefloxacin on human myelopoiesis in vitro was investigated. Drug concentrations varied from 0.5 to 50 micrograms/ml, and the effect on granulomonocyte precursors was evaluated on cell cultures in agar. Our results indicate that ofloxacin and pefloxacin do not induce inhibition of myelopoiesis.
Production of a streptomycin-Park nucleotide complex by Streptomyces griseus
Authors: Szabó I , Penyige A , Barabás G , Szabó G , Dinya Z
Published: June 2012

A compound (compound X) with antibacterial activity was isolated from early-exponential-phase cultures of the streptomycin producer Streptomyces griseus and from protoplast cultures of the same strain. The protoplast cultures produced a larger amount of compound X than did the young hyphae. Both the mycelia and the protoplasts incorporated 14C-labeled myo-inositol, a precursor of streptomycin, into compound X, which has an amino acid content related to that of the cell wall peptidoglycan of the producer strain. Compound X may contain a streptomycin molecule covalently bound to a cell wall precursor unit, i.e., to a Park nucleotide (J. T. Park, J. Biol. Chem. 194:897-904, 1952), through the glutamic acid of the pentapeptide component.
Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells
Authors: Zafriri D , Ofek I , Adar R , Pocino M , Sharon N
Published: June 2012

Inhibition of bacterial adherence to bladder cells has been assumed to account for the beneficial action ascribed to cranberry juice and cranberry juice cocktail in the prevention of urinary tract infections (A. E. Sobota, J. Urol. 131:1013-1016, 1984). We have examined the effect of the cocktail and juice on the adherence of Escherichia coli expressing surface lectins of defined sugar specificity to yeasts, tissue culture cells, erythrocytes, and mouse peritoneal macrophages. Cranberry juice cocktail inhibited the adherence of urinary isolates expressing type 1 fimbriae (mannose specific) and P fimbriae [specific for alpha-D-Gal(1----4)-beta-D-Gal] but had no effect on a diarrheal isolate expressing a CFA/I adhesin. The cocktail also inhibited yeast agglutination by purified type 1 fimbriae. The inhibitory activity for type 1 fimbriated E. coli was dialyzable and could be ascribed to the fructose present in the cocktail; this sugar was about 1/10 as active as methyl alpha-D-mannoside in inhibiting the adherence of type 1 fimbriated bacteria. The inhibitory activity for the P fimbriated bacteria was nondialyzable and was detected only after preincubation of the bacteria with the cocktail. Cranberry juice, orange juice, and pineapple juice also inhibited adherence of type 1 fimbriated E. coli, most likely because of their fructose content. However, the two latter juices did not inhibit the P fimbriated bacteria. We conclude that cranberry juice contains at least two inhibitors of lectin-mediated adherence of uropathogens to eucaryotic cells. Further studies are required to establish whether these inhibitors play a role in vivo.
Mechanism of penicillin killing in the absence of bacterial lysis
Authors: McDowell T D , Reed K E
Published: June 2012

Exposure of group A streptococci (a nonlytic-death phenotype) to benzylpenicillin (penicillin G) produced a dose-dependent, rapid, and extensive hydrolysis of total cellular RNA, with the subsequent loss of hydrolysis products from the cell. This loss of RNA correlated well with loss of viability and was not accompanied by solubilization of the cell wall or comparable losses of either protein or DNA. Simultaneous treatment with penicillin G and either chloramphenicol or rifampin resulted in reduced levels of killing and the complete inhibition of RNA loss. These findings define a new mechanism of penicillin G-induced killing in the absence of cell wall disruption and suggest a basis for drug-induced antagonism of penicillin G-mediated nonlytic death.
Phosphorylation of 3'-azido-2',3'-dideoxyuridine and preferential inhibition of human and simian immunodeficiency virus reverse transcriptases by its 5'-triphosphate
Authors: Eriksson B F , Chu C K , Schinazi R F
Published: June 2012

3'-Azido-2',3'-dideoxyuridine-5'-triphosphate was found to be a potent and highly selective inhibitor of human immunodeficiency virus type 1 and simian immunodeficiency virus reverse transcriptases. The affinity of 3'-azido-2',3'-dideoxyuridine-5'-triphosphate for the reverse transcriptases was similar to that observed for 3'-azido-3'-deoxythymidine-5'-triphosphate. Both compounds were competitive inhibitors with respect to the normal substrate dTTP and served at least 100 times better as substrates than did dTTP. In contrast, cellular DNA polymerase alpha showed an about 60-times-higher preference for dTTP as substrate than for either inhibitor. The phosphorylation of thymidine in human peripheral blood mononuclear cell extracts was inhibited in a competitive manner by both 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine, with apparent inhibition constants of 290 and 3.4 microM, respectively. The Michaelis-Menten constant, Km, for thymidine was 7.0 microM. 3'-Azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine both served as substrates, with apparent Km values of 67 and 1.4 microM, respectively. The maximal rates of phosphorylation with 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine were 40 and 30%, respectively, of the rate with thymidine. The different affinities of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine for the thymidine kinase and the Km values observed with these compounds as substrates may explain the difference in effects on human immunodeficiency virus type 1 replication in infected peripheral blood mononuclear cells observed when equimolar concentrations of the two compounds are compared.
Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH39304
Authors: Perfect J R , Wright K A , Hobbs M M , Durack D T
Published: June 2012

We studied the pharmacokinetics and in vivo antifungal action of SCH39304, a new antifungal azole compound, in rabbits. It crossed the blood-cerebrospinal fluid barrier in the presence or absence of meningeal inflammation, reaching approximately 60% of the simultaneous concentrations in serum. In the treatment of experimental cryptococcal meningitis, SCH39304 was as effective as fluconazole in reducing yeast counts in the subarachnoid space. SCH39304 and fluconazole both were highly effective against candida endophthalmitis, sterilizing the vitreous humor and the choroid and retina. SCH39304 suppressed candida endocarditis and reduced yeast counts in the kidney at all doses tested. SCH39304 was effective in the treatment of experimental cryptococcal meningitis and disseminated candidiasis. Further investigations in humans are warranted.
Comparative in vitro activity and beta-lactamase stability of FK482, a new oral cephalosporin
Authors: Neu H C , Saha G , Chin N X
Published: June 2012

FK482 is an oral aminothiazolyl hydroxyimino cephalosporin with a C-3 vinyl group. Its activity was compared with those of cephalexin, cefuroxime, cefixime, and amoxicillin-clavulanate. FK482 inhibited 90% of Staphylococcus aureus isolates at 1 micrograms/ml and 90% of Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae isolates at less than or equal to 0.012 micrograms/ml, superior to cephalexin and cefuroxime and similar to cefixime. It did not inhibit oxacillin-resistant S. aureus. FK482 inhibited 90% of Enterococcus faecalis isolates at 8 micrograms/ml. Although 90% of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella species, and Shigella species isolates were inhibited by less than or equal to 2 micrograms/ml, FK482 was less active than cefixime against Citrobacter, Enterobacter, Morganella, Serratia, and Providencia species, with MICs for many isolates of greater than 8 micrograms/ml. FK482 inhibited Haemophilus influenzae and Neisseria gonorrhoeae at concentrations comparable to that of cefixime and superior to those of cephalexin and cfaclor. Bacteroides and Pseudomonas species were resistant. FK482 was not hydrolyzed by the TEM-1 and TEM-2 beta-lactamases but was hydrolyzed by TEM-3 and the Proteus vulgaris enzyme. It had a high affinity for chromosomal beta-lactamases.
In vitro activity of amifloxacin against outer membrane mutants of the family Enterobacteriaceae and frequency of spontaneous resistance
Authors: Watanabe M , Inoue M , Mitsuhashi S
Published: June 2012

Amifloxacin showed potent inhibitory activity against DNA gyrase of Escherichia coli. The difference in the susceptibilities of lipopolysaccharide-deficient Salmonella typhimurium mutants and their parent strain was less than twofold, and the difference in the susceptibilities of porin-deficient E. coli mutants and their parent strain was less than twofold. There was cross resistance among the quinolone group of agents; however, the decrease in MIC for norB mutants was slightly lower than that of other fluoroquinolones. Cell lysis was induced with combined treatment of amifloxacin and sodium dodecyl sulfate in E. coli. The frequency of mutants spontaneously resistant to amifloxacin was extremely low in all species tested.
BRO beta-lactamases of Branhamella catarrhalis and Moraxella subgenus Moraxella, including evidence for chromosomal beta-lactamase transfer by conjugation in B. catarrhalis, M. nonliquefaciens, and M. lacunata
Authors: Wallace R J , Steingrube V A , Nash D R , Hollis D G , Flanagan C , Brown B A , Labidi A , Weaver R E
Published: June 2012

Two closely related beta-lactamases, BRO-1 and BRO-2 (formerly called Ravasio and 1908), are found in Moraxella (Branhamella) catarrhalis. We screened strains of B. catarrhalis recovered in the United States since 1952 and identified the first beta-lactamase-positive isolate in August 1976. The prevalence of the enzymes among 394 clinical isolates from one Texas hospital has averaged 75% since testing began in 1983. Screening of isolates of Moraxella subgenus Moraxella revealed the BRO enzymes in two other human respiratory tract species, M. lacunata and M. nonliquefaciens, beginning in 1978. A different beta-lactamase with a pI of 6.4 predominated in other species of subgenus Moraxella. BRO-2 had a different isoelectric focusing pattern and was produced in lesser amounts than BRO-1, but the two enzymes were indistinguishable by substrate or inhibitor profile. BRO enzymes from B. catarrhalis, M. nonliquefaciens, and M. lacunata could be transferred by conjugation and, for B. catarrhalis, also by transformation to B. catarrhalis. Plasmid bands were demonstrated in 90% of M. nonliquefaciens and in one previously reported strain of B. catarrhalis, but no change in plasmid profiles was seen in beta-lactamase-positive recombinants, supporting previous studies that suggested the beta-lactamase genes are chromosomal.
Antimicrobial susceptibility in gram-negative bacteremia: are nosocomial isolates really more resistant?
Authors: McGowan J E , Hall E C , Parrott P L
Published: June 2012

Bloodstream isolates of gram-negative aerobic bacilli from nosocomial infections are more likely to be resistant to antimicrobial agents than isolates from community-acquired cases are. It is not clear, however, how much this is due to the markedly different distribution of organisms in the two groups. We compared the susceptibilities of organisms of a given species which caused community-acquired bacteremia with the susceptibilities of isolates from nosocomial cases. Nine antimicrobial agents were tested against 1,077 isolates which were obtained during a 4-year nonepidemic period. Marked differences in crude rates of resistance were noted for all isolates from nosocomial cases versus all isolates from cases acquired in the community. When results were adjusted for the different organism distributions in the two groups, statistically significant differences were found for only six drug-organism pairs; in each of these, resistance rates were higher in nosocomial isolates. However, when results were further adjusted for the effect of multiple analyses, no significant differences were seen. The major factor leading to the greater prevalence of antimicrobial resistance in our hospital organisms was the markedly different distribution of organisms in the nosocomial and community-acquired groups. For individual organisms, greater resistance in nosocomial strains was confined to certain drugs. Factors that influence differences in organism distribution may not be solely the result of antimicrobial use.
Antileishmanial activities of 2,4-diaminoquinazoline putative dihydrofolate reductase inhibitors
Authors: Berman J D , King M , Edwards N
Published: June 2012

2,4-Diaminoquinazoline analogs of folate were assessed as antileishmanial agents and as dihydrofolate reductase inhibitors. Against Leishmania major in human macrophages in vitro, two compounds with tertiary amines attached directly to the quinazoline ring were remarkably active. The 50% effective doses were in the picogram per milliliter range (12 to 91 pg/ml), and the in vitro therapeutic indices were approximately 10(5). These compounds were 1,000 times more active on an absolute basis and had a 100 times more favorable therapeutic index than any compound previously tested in this model. Antileishmanial activity was not correlated with activity against Leishmania mexicana promastigote reductase, which suggests that folate utilization in general, rather than reductase activity specifically, was being inhibited.
Pharmacokinetics of amphotericin B in children
Authors: Benson J M , Nahata M C
Published: June 2012

Amphotericin B is the most effective agent for the majority of systemic fungal infections but often causes toxicity, and specific dosage guidelines for amphotericin B in pediatric patients are lacking. The purpose of this study was to characterize the pharmacokinetics of amphotericin B in children. Twelve patients (mean age, 6.6 years; range, 4 months to 14 years) receiving amphotericin B, 0.68 +/- 0.34 mg/kg per day (mean plus or minus standard deviation), were studied. Four to eight blood samples were collected during a 24-h period and analyzed by high-pressure liquid chromatography. The peak concentration of amphotericin B in serum was 2.9 +/- 2.8 micrograms/ml. The mean total clearance, apparent volume of distribution, and elimination half-life were 0.46 +/- 0.20 ml/min per kg, 0.76 +/- 0.52 liters/kg, and 18.1 +/- 6.6 h, respectively. Total clearance decreased with age (p less than 0.01). In children aged 8 months to 9 years, the mean total clearance was 0.57 +/- 0.15 ml/min per kg, and in children older than 9 years, it was 0.24 +/- 0.02 ml/min per kg. Interpatient variation in the clearance and volume of distribution of amphotericin B was greater than threefold and greater than eightfold, respectively. However, pharmacokinetic parameters did not change in two stable patients who were studied again. Because clearance decreased substantially with age, older children may require lower doses of amphotericin B per kilogram to decrease the potential for toxicity.
Effect of age on the intracortical accumulation kinetics of gentamicin in rats
Authors: Beauchamp D , Gourde P , Bergeron M G
Published: June 2012

We have evaluated the influence of age on the intracortical accumulation kinetics of gentamicin in conscious male rats by using a short-term infusion model. Animals were infused with gentamicin over a 6-h period and achieved individual steady-state levels in serum ranging from 0.5 to 12 micrograms/ml. Young rats were about 3 months old, and old rats were about 6 months old. The steady-state elevation of concentrations of gentamicin in serum was associated with a linear increase of the cortical concentrations in both groups. However, the accumulation of gentamicin was lower in the renal cortex of the old rats than in the renal cortex of the young rats. We conclude that the intrarenal uptake of gentamicin is modified during aging. Further studies must be undertaken to better understand the role of age on the mechanism of uptake and the toxicity of aminoglycosides.
Synergistic effect of quinolones and oxacillin on methicillin-resistant Staphylococcus species
Authors: Rohner P , Herter C , Auckenthaler R , Pechère J C , Waldvogel F A , Lew D P
Published: June 2012

Various combinations of antistaphylococcal antimicrobial agents have been tested against 17 selected Staphylococcus isolates, including methicillin-susceptible and methicillin-resistant strains of S. aureus and coagulase-negative Staphylococcus species. With the checkerboard technique the following combinations were tested: oxacillin-ofloxacin, oxacillin-temafloxacin, oxacillin-fleroxacin, vancomycin-fleroxacin, gentamicin-fleroxacin, and rifampin-fleroxacin. Against methicillin-resistant staphylococci the combination oxacillin-quinolone tested at 35 degrees C always showed a fractional inhibitory concentration (FIC) index of less than 0.75, which is interpreted as synergistic or additive. Equal or more synergistic effects were observed at 30 degrees C. In contrast, when methicillin-susceptible Staphylococcus species were tested, the FIC for the combination oxacillin-quinolone was always 1 or 2, which is considered to be indifferent. For the other mentioned combinations the FICs were also 1 or 2. Killing kinetics showed synergistic or additive bactericidal activity for the combination oxacillin-ofloxacin against methicillin-resistant Staphylococcus species, killing 1.5 to 2.8 log10 CFU more of these per ml than did the most active drug after 24 h of incubation. This difference was not observed for methicillin-susceptible strains. In vitro evidence for the potential clinical use of quinolones in treating infections due to methicillin-resistant staphylococci in combination with a beta-lactamase-resistant penicillin is provided.
Binding and killing of bacteria by bismuth subsalicylate
Authors: Sox T E , Olson C A
Published: June 2012

Bismuth subsalicylate (BSS) is a compound without significant aqueous solubility that is widely used for the treatment of gastrointestinal disorders. BSS was able to bind bacteria of diverse species, and these bound bacteria were subsequently killed. A 4-log10 reduction of viable bacteria occurred within 4 h after a 10 mM aqueous suspension of BSS was inoculated with 2 x 10(6) Escherichia coli cells per ml. Binding and killing were dependent on the levels of inoculated bacteria, and significant binding but little killing of the exposed bacteria occurred at an inoculum level of 2 x 10(9) E. coli per ml. Intracellular ATP decreased rapidly after exposure of E. coli to 10 mM BSS and, after 30 min, was only 1% of the original level. Extracellular ATP increased after exposure to BSS, but the accumulation of extracellular ATP was not sufficient to account for the loss of intracellular ATP. The killing of bacteria exposed to BSS may have been due to cessation of ATP synthesis or a loss of membrane integrity. Bactericidal activity of BSS was also investigated in a simulated gastric juice at pH 3. Killing of E. coli at this pH was much more rapid than at pH 7 and was apparently due to salicylate released by the conversion of BSS to bismuth oxychloride. It is proposed that the binding and killing observed for BSS contribute to the efficacy of this compound against gastrointestinal infections such as traveler's diarrhea.
Microbial glycosylation of erythromycin A
Authors: Kuo M S , Chirby D G , Argoudelis A D , Cialdella J I , Coats J H , Marshall V P
Published: June 2012

Erythromycin A (compound 1) was inactivated by Streptomyces vendargensis ATCC 25507 in fermentation. The inactivation product was isolated and characterized by nuclear magnetic resonance and mass spectroscopy as 2'-(O-[beta-D-glucopyranosyl])erythromycin A (compound 2). The MICs of compounds 1 and 2 were determined. Compound 2 lacked antibiotic activity when tested against several gram-positive pathogens, as well as S. vendargensis.
In vitro and in vivo activities of piritetrate (M-732), a new antidermatophytic thiocarbamate
Authors: Iwata K , Yamashita T , Uehara H
Published: June 2012

Piritetrate (M-732), a new topical antifungal agent belonging chemically to the thiocarbamates, was demonstrated to possess a potent selective antidermatophytic activity. In terms of its MICs in susceptibility testing, mainly done by using Sabouraud dextrose agar plates, piritetrate exhibited several- to 10-fold-stronger antidermatophytic activity than tolnaftate, a reference thiocarbamate. Furthermore, piritetrate was found to show a broader antifungal spectrum than tolnaftate; relatively many species and strains of dematiaceous fungi, dimorphic fungi, and some other filamentous fungi as well as a few strains of Cryptococcus neoformans were fairly susceptible to piritetrate, while almost all the tested species and strains were resistant to tolnaftate. All the tested species of the genus Candida were, however, resistant to both compounds. Variables which can influence antimicrobial activity caused few changes in the MICs of either compound against Trichophyton mentagrophytes; however, an increase in the inoculum size resulted in a significant increase in the MICs. The antidermatophytic activities of piritetrate and tolnaftate were fungistatic but not fungicidal. Piritetrate also exhibited a more potent in vitro anti-T. mentagrophytes activity than clotrimazole or tolciclate. Piritetrate and tolnaftate had no antibacterial activity. The in vivo activity of topically administered piritetrate against experimental dermal infection of guinea pigs with T. mentagrophytes was more effective than that of tolnaftate both mycologically and clinically. Piritetrate manifested no acute toxicity in laboratory animals when administered even in large quantities by the oral, intraperitoneal, and topical routes.
In vitro activities of cefcanel and some other cephalosporins against Pasteurella multocida
Authors: Holst E , Rollof J , Miörner H
Published: June 2012

Thirty-five strains of Pasteurella multocida from humans and animals were tested for susceptibility to five cephalosporins by a broth dilution method. Cefcanel showed high activity against all isolates (MIC and MBC, less than or equal to 0.64 micrograms/ml). The corresponding figure for cefaclor and cefuroxime was 2.56 micrograms/ml. Cefadroxil and cephalexin were the least active compounds tested.
Selective inhibition of human immunodeficiency virus type 1 replication by the (-) but not the (+) enantiomer of gossypol
Authors: Lin T S , Schinazi R , Griffith B P , August E M , Eriksson B F , Zheng D K , Huang L A , Prusoff W H
Published: June 2012

The (-) enantiomer of gossypol but not the (+) enantiomer had good antiviral activity in peripheral blood mononuclear cells against human immunodeficiency virus type 1 at a concentration more than 20-fold lower than that required for cytotoxicity; however, in H9 cells the (-) enantiomer, although more potent as an antiviral agent, was more cytotoxic.
Effects of free and liposomal amphotericin B and gramicidin S alone and in combination on potassium leakage from human erythrocytes and Candida albicans
Authors: Midez J A , Hopfer R L , Lopez-Berestein G , Mehta R T
Published: June 2012

We studied the toxic effects of amphotericin B and gramicidin S, alone and in combination, using free and liposome-encapsulated drugs. In vitro toxic effects of the drugs on human erythrocytes and Candida albicans were determined by measuring leakage of intracellular potassium ions (K+). Liposomal formulations of both drugs greatly reduced K+ leakage from human erythrocytes, whereas liposomal gramicidin S, but not liposomal amphotericin B, prevented K+ leakage from C. albicans. In both free and liposomal forms, the combinations of drugs produced decreased toxicity to erythrocytes compared with the drugs alone. This protective effect was more apparent with liposomal combinations than with free drug combinations. A significant increase in fungal cell toxicity was observed, however, when free and liposomal drug combinations were tested against C. albicans. The results suggest that optimal concentrations of liposomal drug combinations (amphotericin B and gramicidin S) may provide increased toxicity against fungal cells and simultaneously protect mammalian cells.
Amikacin, ciprofloxacin, and imipenem treatment for disseminated Mycobacterium avium complex infection of beige mice
Authors: Inderlied C B , Kolonoski P T , Wu M , Young L S
Published: June 2012

The Mycobacterium avium complex (MAC) is a common cause of disseminated infection in patients with acquired immunodeficiency syndrome and is increasingly seen as a cause of infection in other immunocompromised patients. Traditional antimycobacterial therapy often is ineffective, and there is a clear need for antibiotics with proven activity against the MAC. Three agents, amikacin, ciprofloxacin, and imipenem, were tested in vitro for activity against MAC strain 101. Amikacin was bacteriostatic, with an MIC of 4.8 micrograms/ml, which is significantly lower than the concentration in serum obtained with standard dosing. Imipenem and ciprofloxacin had little or no activity alone (MICs, greater than 16 and 4.7 micrograms/ml, respectively), but when they were combined with amikacin there was bactericidal activity. Each agent was tested individually and in combination by using the beige mouse model of disseminated MAC infection. There was no mortality in a group of animals infected with MAC 101 and treated with amikacin alone; also, there was a significant decrease in the infection of the blood, liver, and spleen. There was no apparent improvement in therapeutic effectiveness when amikacin was combined with the other agents. Neither ciprofloxacin nor imipenem was active as a single agent, which was consistent with the in vitro activities of these agents. Amikacin in combination with traditional antimycobacterial agents warrants further study as potential therapy for disseminated MAC infections.
Ciprofloxacin therapy for methicillin-resistant Staphylococcus aureus infections or colonizations
Authors: Smith S M , Eng R H , Tecson-Tumang F
Published: June 2012

Thirty patients were treated for colonization or for skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. Three treatment regimens were evaluated, each progressively more aggressive. Our regimen was 750 mg of ciprofloxacin twice daily for 5 days, the second regimen was 750 mg of ciprofloxacin twice daily for 10 to 14 days, and the final regimen was 750 mg of ciprofloxacin twice daily plus 300 mg of rifampin twice daily for 21 days. It appears that ciprofloxacin alone produced an initial eradication rate in at least one site in 50% of the patients, regardless of whether the treatment was for 5 or up to 14 days. All of the patients with eradication became recolonized within 1 week posttherapy. When rifampin was combined with ciprofloxacin, the eradication rate was 100% when the isolates were susceptible to both agents, and these patients remained free of methicillin-resistant S. aureus at 1-week and 1-month follow-ups.
Escherichia coli susceptible to glycopeptide antibiotics
Authors: Shlaes D M , Shlaes J H , Davies J , Williamson R
Published: June 2012

Mutants of Escherichia coli susceptible to vancomycin were isolated after mutagenesis with nitrosoguanidine. One such mutant was studied extensively. Multiple regression analysis of the relationship between physical properties of 20 glycopeptides and their in vitro activities against the vancomycin-susceptible mutant revealed a significant correlation with molecular mass (P = 0.007). pI, hydrophobicity, and affinity of the glycopeptide for the pentapeptide target were not as important for activity. This suggested that a block of access of the antibiotic to its target could be the major factor determining activity. Outer membrane proteins of the vancomycin-susceptible mutant, resistant parent, and revertant strains appeared normal. The mutant exhibited increased susceptibility to both erythromycin and fusidic acid which was lost in single-step revertants to vancomycin resistance. Polymyxin B nonapeptide was synergistic with erythromycin and fusidic acid against the parent and revertant but not against the susceptible mutant. Analysis of the susceptibilities of control strains of E. coli and Salmonella typhimurium with known defects in lipopolysaccharide (LPS) synthesis revealed that core LPS mutants (Re chemotype) were phenotypically similar to the E. coli mutant under study. However, the LPS core of the mutant migrated slightly less rapidly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than wild-type or revertant core LPS and did not resemble Re chemotype LPS core obtained from Salmonella rfaC and rfaD mutants. These data suggest that defects in LPS core structure other than loss of heptose moieties may also be important in loss of resistance to large, hydrophilic molecules such as glycopeptides.
Inducible, transferable resistance to vancomycin in Enterococcus faecalis A256
Authors: Shlaes D M , Bouvet A , Devine C , Shlaes J H , al-Obeid S , Williamson R
Published: June 2012

A strain of Enterococcus faecalis (A256) was isolated from the urine of a patient with urinary sepsis and was found to exhibit susceptibilities (micrograms per milliliter) to various glycopeptides as follows: vancomycin, 256; teicoplanin, 16; 62208, 512; 62211, 4; and 62476, 16. As judged by growth rates before and after exposure to sub-MICs of glycopeptides, vancomycin and 62476 induced self-resistance, 62208 and 62211 induced slight self-resistance, and teicoplanin did not induce self-resistance. Vancomycin induced cross-resistance to all other glycopeptides tested, as judged both in growth experiments and by direct measurement of inhibition of peptidoglycan synthesis in cells exposed to sub-MICs of vancomycin. Thus, the spectra of activity of the glycopeptides were not correlated with their patterns of induction. There was a correlation between the increased synthesis of a 39-kilodalton (kDa) protein located in the cytoplasmic membrane and the induction of resistance. Protoplasts of A256 were susceptible to inhibition of peptidoglycan synthesis by vancomycin at levels similar to those for susceptible strains. Vancomycin resistance was transferable on filters from the parent strain to E. faecalis JH2-2 at a frequency of about 10(-7), and the 39-kDa protein was also inducible by glycopeptides in these transconjugants. We conclude that A256 is resistant to glycopeptides by virtue of the synthesis of a 39-kDa cytoplasmic membrane protein, that this protein is probably involved in preventing access of the glycopeptides to their peptidoglycan targets, and that this resistance is transferable, probably by conjugation.
Fleroxacin resistance in Escherichia coli
Authors: Chapman J S , Bertasso A , Georgopapadakou N H
Published: June 2012

Spontaneous fleroxacin-resistant mutants of Escherichia coli K-12 were isolated at a frequency of 10(-10) to 10(-11) mutants per CFU plated. All mutants exhibited quinolone-resistant replicative DNA biosynthesis, and 4 of 11 mutants also had decreased amounts of OmpF or OmpC porin. None of the mutants had changes solely in porin proteins.
In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection
Authors: Gladue R P , Bright G M , Isaacson R E , Newborg M F
Published: June 2012

Azithromycin, a novel azalide antibiotic, concentrated in human and mouse polymorphonuclear leukocytes (PMNs), murine peritoneal macrophages, and mouse and rat alveolar macrophages, attaining intracellular concentrations up to 226 times the external concentration in vitro. In murine peritoneal macrophages, azithromycin achieved concentration gradients (internal to external) up to 26 times higher than erythromycin. The cellular uptake of azithromycin was dependent on temperature, viability, and pH and was decreased by 2,4-dinitrophenol. Azithromycin did not decrease phagocyte-mediated bactericidal activity or affect PMN or macrophage oxidative burst activity (H2O2 release or Nitro Blue Tetrazolium reduction, respectively). Azithromycin remained in cells for several hours, even after extracellular drug was removed. However, its release was significantly enhanced by phagocytosis of Staphylococcus aureus (82 versus 23% by 1.5 h). In vivo, 0.05 micrograms of azithromycin was found in peritoneal fluids of mice 20 h after oral treatment with a dose of 50 mg/kg. Following caseinate-induced PMN infiltration, there was a sixfold increase in peritoneal cavity azithromycin to 0.32 micrograms, most of which was intracellular. Therefore, the uptake, transport, and later release of azithromycin by these cells demonstrate that phagocytes may deliver active drug to sites of infection.
Anti-herpes simplex virus activity of 5-substituted 2-pyrimidinone nucleosides
Authors: Lewandowski G A , Grill S P , Fisher M H , Dutschman G E , Efange S M , Bardos T J , Cheng Y C
Published: June 2012

Several 5-substituted 2-pyrimidinone 2'-deoxyribonucleoside (PdR) analogs were examined for their anti-herpes simplex virus (HSV) activity in cell culture. The order of potency of their antiviral activities against HSV type 1 (HSV-1) and HSV-2 was iodo PdR approximately ethynyl PdR approximately propynyl PdR. The antiviral action of iodo PdR is dependent on the ability of HSV to induce virus-specified thymidine kinase in infected cells. Several HSV-1 variants with altered thymidine kinase changed their sensitivity to iodo PdR, whereas HSV-1 variants with altered DNA polymerase were as sensitive as the parental virus to iodo PdR. Continuous presence of iodo PdR for more than one virus replication cycle was required for optimal antiviral activity. Iodo PdR (100 microM) had no activity against Epstein-Barr virus DNA replication in P3HR-1 cells. With an oral, an intraperitoneal, or a subcutaneous route of injection, iodo PdR administered twice a day for 2.5 days could prevent the death of mice infected with HSV-2. This in vivo activity is unlikely to be related to the potential conversion of iodo PdR to iododeoxyuridine, since iodo PdR is not a substrate of xanthine oxidase.