bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative activities of selected combinations of acyclovir, vidarabine, arabinosyl hypoxanthine, interferon, and polyriboinosinic acid-polyribocytidylic acid complex against herpes simplex virus type 2 in tissue culture and intravaginally inoculated mice
Authors: Crane L R , Milne D A , Sunstrum J C , Lerner A M
Published: June 2012

The effects of double and triple combinations of acyclovir (ACV), adenine arabinoside (ara-A), arabinosyl hypoxanthine, or interferon on herpes simplex virus type 2 in mouse embryo fibroblasts were measured. These in vitro data were compared with results obtained in mice infected intravaginally with herpes simplex virus type 2 and treated intraperitoneally with low- and high-dose combinations of ACV, ara-A, or polyriboinosinic-polyribocytidylic acid(poly-L-lysine)carboxymethylcellulose complex [poly IC(LC)], an interferon inducer. Although all double combinations and one triple combination evoked synergistic reactions in vitro, results did not necessarily predict in vivo observations. In vivo synergy was observed when combinations of ACV and ara-A and low doses of ara-A-ACV-poly IC(LC) were used. However, toxicity was seen with full-dose nucleoside-poly IC(LC) doublets. The full-dose ACV-ara-A combination completely prevented progression beyond vaginitis, with all animals surviving. The ara-A-ACV results observed in mice, together with in vivo data of others, suggest that this combination might prove clinically useful for certain herpes simplex virus type 2 infections.
Pharmacokinetics and bacteriological efficacies of apalcillin and cefpiramide in experimental pneumococcal meningitis
Authors: Sato K , Shelton S , Nelson J D
Published: June 2012

Rabbits with experimentally induced pneumococcal meningitis were given single 25-mg/kg doses of apalcillin or cefpiramide. Mean percentages of the drug concentration in cerebrospinal fluid versus that in blood serum were 7.6% with apalcillin and 3.9% with cefpiramide. Bactericidal activity in cerebrospinal fluid resulted in mean reductions of from 4 to 5 log10 CFU/ml, and cerebrospinal fluid cultures became sterile for four of six animals treated with each drug.
Comparative activities of the beta-lactamase inhibitors YTR 830, sodium clavulanate, and sulbactam combined with amoxicillin or ampicillin
Authors: Aronoff S C , Jacobs M R , Johenning S , Yamabe S
Published: June 2012

YTR 830, a new beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam against aminopenicillin-resistant clinical isolates. At a concentration of 8 micrograms/ml, YTR 830 was as effective as clavulanate or sulbactam in reducing the aminopenicillin MICs. Combined with amoxicillin, YTR 830 is a potentially useful agent for therapy of many bacterial infections.
Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane
Authors: Tidwell R R , Geratz J D , Clyde W A , Rosenthal K U , Dubovi E J
Published: June 2012

Intraperitoneal administration of bis(5-amidino-2-benzimidazolyl)methane at well-tolerated daily doses of 25 mg/kg subsequent to challenge and for 3 days thereafter effected over a 1-log reduction in the amount of virus recovered from lungs of cotton rats inoculated intratracheally with respiratory syncytial virus. When animals were immunosuppressed to prolong virus shedding, the reduction in recovered virus achieved with a 7-day dosing schedule of bis(5-amidino-2-benzimidazolyl)methane exceeded 2 logs.
Activities of respository preparations of cycloguanil pamoate and 4,4'-diacetyldiaminodiphenylsulfone, alone and in combination, against infections with Plasmodium cynomolgi in rhesus monkeys
Authors: Schmidt L H , Rossan R N
Published: June 2012

The studies summarized in this report were concerned with the capacities of repository preparations of cycloguanil pamoate (CGT-P) to protect rhesus monkeys against infections with drug-susceptible and pyrimethamine-resistant strains of Plasmodium cynomolgi. Administered intramuscularly as a suspension in an oleaginous vehicle, CGT-P (i) provided long-term protection against single and repetitive challenges of rhesus monkeys with sporozoites of the drug-susceptible B and Ro strains, (ii) effected prompt clearance of parasitemia in established infections, and (iii) delayed relapse. Protection was equated to absence of parasites on thick blood films, negative results when blood was transferred to susceptible recipients, and inability to activate infection by splenectomy. Eventual loss of protection was not related to emergence of parasites resistant to cycloguanil (CGT). Although protection varied from monkey to monkey, its mean duration was related directly to size of CGT-P dose and size of particles in the suspension. Urinary excretion studies indicated that protection persisted as long as the daily output of CGT did not fall below that attained with the parenterally administered hydrochloride salt at a dose equivalent to 0.015 mg of CGT per kg. Studies on infections with the resistant Ro/PM strain showed that the activity of CGT-P was compromised severely by resistance to pyrimethamine. Attempts to minimize this liability by concomitant administration of 4,4'-diacetyldiaminodiphenylsulfone met with limited success. These results suggest that even the best of the repository preparations of CGT-P, with or without 4,4'-diacetyldiaminodiphenylsulfone, would be useful only in areas where Plasmodium falciparum and Plasmodium vivax are fully susceptible to chlorguanide and pyrimethamine.
Hydroxylamine technique for in vitro prevention of penicillin inactivation of tobramycin
Authors: Falkowski A J , Creger R J
Published: June 2012

Hydroxylamine was evaluated and found to be a highly effective agent for the in vitro prevention of penicillin inactivation of tobramycin. This inactivation reaction resulted in an underestimation of tobramycin concentrations and was dependent on time, temperature, amount and type of penicillin, and amount of tobramycin. Plasma samples containing tobramycin and three clinically relevant concentrations of ticarcillin, carbenicillin, azlocillin, or piperacillin were incubated with and without hydroxylamine, and tobramycin concentrations were monitored at 0, 12, 24, 48, and 72 h. The inactivation reaction was found to be completely inhibited by hydroxylamine (1 mg/ml) compared with a 27 to 50% loss of measured tobramycin concentration in the unprotected tobramycin-penicillin samples. Hydroxylamine did not interfere with the Emit enzyme immunoassay (Syva Co.) at either high or low tobramycin concentrations. Hydroxylamine was effective in inhibiting the tobramycin inactivation at both room and refrigerator temperatures and was 100% effective in protecting tobramycin on a 1:1 molar basis.
In vitro antibacterial properties of BRL 36650, a novel 6 alpha-substituted penicillin
Authors: Basker M J , Edmondson R A , Knott S J , Ponsford R J , Slocombe B , White S J
Published: June 2012

BRL 36650 is a new type of penicillin in which a formamido group has been introduced into the 6 alpha-position of the nucleus. The compound is highly active against aerobic gram-negative bacteria and is stable to a wide range of beta-lactamases produced by these organisms. Against members of the family Enterobacteriaceae, BRL 36650 was considerably more active than piperacillin, particularly against beta-lactamase-producing strains, and showed a similar level of activity to moxalactam, aztreonam, and the third-generation cephalosporins cefotaxime and ceftazidime. Against Pseudomonas aeruginosa and other Pseudomonas species, BRL 36650 was more active than piperacillin, cefoperazone, and aztreonam and compared favorably with ceftazidime. BRL 36650 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains, and against Acinetobacter calcoaceticus. Clinical isolates of Enterobacter species and P. aeruginosa which showed markedly reduced susceptibility to cefotaxime, ceftazidime, and aztreonam were only slightly less susceptible to BRL 36650. Against Bacteroides fragilis and most gram-positive bacteria, BRL 36650 showed only a low level of activity. BRL 36650 was found to be only 35% bound to human serum protein, and the antibacterial activity was little affected by the presence of serum. In contrast, the composition of the test medium influenced the activity of BRL 36650 slightly, and an antagonistic effect could be demonstrated between the compound and a component of certain Mueller-Hinton media.
In vitro susceptibility of anaerobic bacteria to ciprofloxacin (Bay o 9867)
Authors: Prabhala R H , Rao B , Marshall R , Bansal M B , Thadepalli H
Published: June 2012

About 80% of 70 clinical isolates of Bacteroides fragilis were inhibited by 4 micrograms of ciprofloxacin (Bay o 9867) per ml. The 90% MIC of ciprofloxacin was 8 micrograms/ml for other Bacteroides species, 2 micrograms/ml for Peptococcus species, 8 micrograms/ml for Peptostreptococcus species, and 16 micrograms/ml for Clostridium and Eubacterium species.
Synergistic activities of combinations of beta-lactams, fosfomycin, and tobramycin against Pseudomonas aeruginosa
Authors: Takahashi K , Kanno H
Published: June 2012

The effects of antibiotic combinations against Pseudomonas aeruginosa infections frequently found in hospitalized patients were investigated. By means of an agar plate dilution checkerboard method, combinations of piperacillin-fosfomycin, cefoperazone-fosfomycin, and cefsulodin-fosfomycin were synergistic against 80.0, 85.0, and 82.6% of the strains tested. The mean fractional inhibitory concentration indices of piperacillin-fosfomycin, cefoperazone-fosfomycin, and cefsulodin-fosfomycin were 0.48, 0.42, and 0.46, respectively. The synergistic activities of these combinations were enhanced by the addition of a small amount of tobramycin, 0.25 micrograms/ml.
Selection of multiple antibiotic resistance by quinolones, beta-lactams, and aminoglycosides with special reference to cross-resistance between unrelated drug classes
Authors: Sanders C C , Sanders W E , Goering R V , Werner V
Published: June 2012

The ability of three quinolones, two beta-lactams, and one aminoglycoside to select resistant mutants was examined in tests with 30 isolates of commonly encountered nosocomial pathogens. Ciprofloxacin and norfloxacin, two new quinolone derivatives, were no more likely to select resistant mutants than amikacin, whereas nalidixic acid, an older quinolone derivative, was the most likely of the six drugs examined to select resistant mutants. Mutational frequencies of 10(-7) to 10(-8) were observed in most instances. In general, the mutants were 8 to 16 times less susceptible to the drug used for selection. Although most quinolone-selected mutants were cross-resistant only to other drugs within this class, certain mutants of Klebsiella pneumoniae selected by nalidixic acid, ciprofloxacin, or norfloxacin were also less susceptible to beta-lactam antibiotics. This unusual pattern of multiple drug resistance was associated with changes in outer membrane proteins of the organism. Multiple drug resistance was also observed in beta-lactam-selected mutants of Enterobacter cloacae and Pseudomonas aeruginosa (beta-lactams), amikacin-selected mutants of Providencia stuartii and P. aeruginosa (aminoglycosides), and beta-lactam- or amikacin-selected mutants of Serratia marcescens (beta-lactams plus aminoglycosides). These results underscore the need to examine carefully the frequency with which resistance to any new antibiotic develops, as well as the patterns of multiple drug resistance which may occur simultaneously.
Lack of reproducibility of macrodilution MBCs for Staphylococcus aureus
Authors: Pelletier L L
Published: June 2012

MBCs of methicillin, oxacillin, penicillin G, cephalothin, vancomycin, and gentamicin were determined by a standard broth macrodilution technique for 101 clinical isolates of methicillin-susceptible Staphylococcus aureus. Increased killing (more than 99.9%) was observed after 48 versus 24 h of incubation for many strains, and cross tolerance to antimicrobial bactericidal activity (less than 99.9% killing) was frequently observed among antimicrobial agents. However, these in vitro measurements of bactericidal activity against S. aureus were not reproducible.
Effect of azone and propylene glycol on penetration of trifluorothymidine through skin and efficacy of different topical formulations against cutaneous herpes simplex virus infections in guinea pigs
Authors: Spruance S L , McKeough M , Sugibayashi K , Robertson F , Gaede P , Clark D S
Published: June 2012

Tropical formulations of 5-trifluoromethyl-2'-deoxyuridine (TFT) containing different concentrations of TFT, Azone (Nelson Research and Development, Irvine, Calif.), and propylene glycol were evaluated for their potential efficacy in the treatment of cutaneous herpes simplex virus infections by in vitro studies of TFT penetration through skin and in vivo studies of therapeutic activity against herpes simplex virus type 1 infections in the dorsal cutaneous guinea pig model. Azone dramatically increased TFT penetration through human and guinea pig skin. Unexpectedly, high concentrations of propylene glycol were also associated with increased penetration. Studies in the guinea pig model revealed increased efficacy with Azone-propylene glycol-containing formulations, consistent with the in vitro drug diffusion results. A formulation containing 1% TFT, 5% Azone, and 80% propylene glycol decreased lesion area, in comparison to the drug vehicle control, more effectively than 5% acyclovir in polyethylene glycol (reduction of 70 versus 46%, P = 0.03). These studies demonstrate the value of penetration-enhancing agents and the need for careful preclinical evaluations in the development of topical antiviral agents.
In vitro activity of CGP 31523A, a broad-spectrum cephalosporin, in comparison with those of other agents
Authors: Wise R , Cross C , Andrews J M
Published: June 2012

The in vitro activity of CGP 31523A, a new aminothiazolyl cephalosporin, was compared with those of cefoxitin, cefuroxime, moxalactam, piperacillin, ciprofloxacin, and other beta-lactams, when appropriate, against 533 recent clinical isolates and known resistant strains of bacteria. The MICs of CGP 31523A required to inhibit 90% (MIC90S) of the members of the family Enterobacteriaceae, Neisseria gonorrhoeae, and Streptococcus pneumoniae were less than or equal to 0.25 micrograms/ml. Of Staphylococcus aureus (excluding methicillin-resistant strains) and Haemophilus influenzae, 90% were susceptible to 0.5 micrograms/ml. Pseudomonas aeruginosa and Lancefield group D streptococci were resistant to CGP 31523A (MIC90, greater than or equal to 128 micrograms/ml). The activity against Bacteroides fragilis was modest (MIC90, 32 micrograms/ml). The susceptibility of known beta-lactamase-producing strains suggested that CGP 31523A was resistant to many beta-lactamases (but not those of Bacteroides fragilis). The serum protein binding of CGP 31523A was about 73%. The primary target site of CGP 31523A in Escherichia coli appeared to be penicillin-binding protein 3.
Controlled trial of enviroxime against natural rhinovirus infections in a community
Authors: Miller F D , Monto A S , DeLong D C , Exelby A , Bryan E R , Srivastava S
Published: June 2012

The therapeutic effect of intranasally administered enviroxime was tested against naturally occurring common colds. The double-blind evaluation was carried out in Tecumseh, Mich., during a period when rhinoviruses are usually the principal pathogen. Rhinovirus transmission followed the typical pattern during this period of study. Although there were trends indicating greater therapeutic effectiveness for enviroxime when certain nasal symptoms were considered, there were no consistent statistically significant differences between treated and untreated groups. Results were unchanged when illnesses in different periods or associated with rhinovirus isolation were examined. It was concluded that no therapeutic effect of enviroxime was demonstrated.
Antibiotic uptake by alveolar macrophages of smokers
Authors: Hand W L , Boozer R M , King-Thompson N L
Published: June 2012

Cigarette smoking, particularly when associated with chronic pulmonary disease, increases the risk of respiratory tract infection. Thus, we elevated the uptake of antibiotics by alveolar macrophages (AM) obtained by bronchoalveolar lavage from persons who smoke and have associated pulmonary abnormalities, circumstances which adversely affect certain macrophage functions. The entry of radiolabeled drugs into AM was determined by a velocity-gradient centrifugation technique, and uptake was expressed as the ratio of cellular to extracellular antibiotic concentration (C/E). Cefamandole and penicillin G were taken up poorly by the AM obtained from smokers (C/E less than or equal to 1). Cellular levels of isoniazid, gentamicin, and tetracycline were similar to their extracellular concentrations. The lipid-soluble drugs lincomycin, chloramphenicol, and rifampin were concentrated severalfold by the AM from smokers (C/E = 3 to 11). Ethambutol also entered macrophages readily (C/E = 11). Erythromycin and clindamycin were massively concentrated by the AM from smokers (C/E = 23 to 56). The AM of smokers accumulated a lipid-soluble antibiotic (rifampin) and actively transported agents (erythromycin propionate, clindamycin) more avidly than did the AM of nonsmokers. Augmented uptake of these antibiotics by the AM of smokers may be related to structural and functional alterations induced by smoking.
Duration of effect of interferon aerosol prophylaxis of vesicular stomatitis virus infection in mice
Authors: Wyde P R , Sun C S , Wilson S Z , Knight V
Published: June 2012

Mice were exposed for 8 h to continuous small-particle aerosols containing natural mouse alpha interferon (estimated dosage 100 U per mouse) or one of two concentrations of hybrid recombinant alpha interferon A/D bgl (estimated dosages of 100 and 10,000 U per mouse, respectively). On days 1, 3, 5, 7, and 9 after exposure to these interferons, three mice from each group were inoculated intranasally with 100 PFU of vesicular stomatitis virus. Control mice were exposed to aerosols of saline or inoculated intraperitoneally with either natural mouse alpha interferon (350 U) or one of two doses of hybrid recombinant alpha interferon A/D bgl (350 or 35,000 U) and challenged similarly. Of mice injected intraperitoneally, only those given 35,000 U of hybrid recombinant alpha interferon A/D bgl 24 h before virus challenge were protected from pulmonary infection, compared with the saline-treated control mice. Of mice given 100 U of either interferon by small-particle aerosol, only those exposed 24 h before inoculation of vesicular stomatitis virus had reduced pulmonary titers of the virus. However, of mice given ca. 10,000 U of hybrid recombinant alpha interferon A/D bgl by small-particle aerosol, all groups except those exposed 9 days before virus inoculation had significantly reduced lung virus titers.
Activities of new quinoline derivatives against genital pathogens
Authors: Aznar J , Caballero M C , Lozano M C , de Miguel C , Palomares J C , Perea E J
Published: June 2012

The in vitro activities of four quinoline carboxylic acids against 48 strains of Neisseria gonorrhoeae, 10 of Chlamydia trachomatis, and 32 of Ureaplasma urealyticum were compared. Ciprofloxacin was the most active against N. gonorrhoeae and C. trachomatis but had poor bactericidal activity against U. urealyticum, whereas ofloxacin showed the most bactericidal activity against U. urealyticum but was less active than ciprofloxacin against the two former pathogens. Norfloxacin and enoxacin were less active against all the studied pathogens.
Oral acyclovir therapy of genital herpes simplex virus type 2 infections in guinea pigs
Authors: Ellis M N , Barry D W
Published: June 2012

Oral acyclovir was evaluated for its effectiveness in treating guinea pigs with primary herpes simplex virus type 2 infections. Guinea pigs inoculated intravaginally with acyclovir-susceptible strains (for which 50% inhibitory concentrations of acyclovir in cell culture were found to be in the range of 0.15 to 1.2 micrograms/ml) and treated with 5.0 mg of acyclovir per ml in the drinking water beginning 48 h postinfection showed significant reductions in lesion severity. This dosage produced serum acyclovir levels of 1.3 micrograms/ml. Lower concentrations of oral acyclovir (less than or equal to 2.5 mg/ml in the drinking water), which produced serum acyclovir levels of less than 1.0 microgram/ml, were less consistently effective against these same virus strains. When an acyclovir-resistant isolate (for which the 50% inhibitory concentration of acyclovir in cell culture was found to be 8.5 micrograms/ml) was used to initiate infection, treatment with 5 or 10 mg/ml (yielding serum levels of 1.3 and 3.5 micrograms/ml) in the drinking water had only minimal clinical benefit. However, the degree of response was difficult to determine because of the attenuated disease produced by the acyclovir-resistant virus. In vitro virus sensitivity may be predictive of the serum drug levels that need to be obtained to produce a successful response to therapy.
Pharmacokinetics of cefotiam in humans
Authors: Rouan M C , Lecaillon J B , Guibert J , Modai J , Schoeller J P
Published: June 2012

After intravenous bolus injections of 0.5, 1, and 2 g of cefotiam to three healthy volunteers, the mean (+/- standard deviation) total plasma clearances measured for each dose were, respectively, 26.8 +/- 2.7, 22.8 +/- 0.8, and 17.8 +/- 0.9 liters/h; the terminal elimination half-lives were 54.0 +/- 0.1, 68 +/- 15, and 98 +/- 36 min; and the renal clearances were 16.0 +/- 2.9, 13.3 +/- 1.4, and 11.3 +/- 2.6 liters/h. The 24-h urinary recovery was independent of the dose and averaged 53% of the dose. After intramuscular administration of 1 g of cefotiam to three healthy volunteers, a mean (+/- standard deviation) peak concentration of 16.6 +/- 5.1 micrograms/ml was reached at 0.75 to 1 h post dosing. The concurrent intramuscular administration of lidocaine and cefotiam did not modify the kinetics of cefotiam. During a constant-rate infusion, the steady-state plasma clearance decreased slightly when the infusion rate was increased. There was no trend towards accumulation of cefotiam in plasma during chronic treatment with 1 g intravenously every 12 h for 10 days.
In vitro susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to cefmetazole
Authors: Casal M J , Rodriguez F C , Benavente M C
Published: June 2012

The in vitro susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to cefmetazole was studied by the agar dilution method. At a concentration of 16 micrograms/ml or lower, 44 isolates (96%) of M. fortuitum and 8 isolates (40%) of M. chelonei were inhibited.
Activities of the modified polyene N-D-ornithyl amphotericin methyl ester and the azoles ICI 153066, Bay n 7133, and Bay l 9139 compared with those of amphotericin B and ketoconazole in the therapy of experimental blastomycosis
Authors: Lefler E , Brummer E , Perlman A M , Stevens D A
Published: June 2012

We studied the efficacy of new experimental antifungal drugs, which represent molecular modifications of present active agents, in a murine model of blastomycosis. Ketoconazole, previously the best azole drug studied and which is protective when administered orally, was superior to a new oral imidazole, Bay l 9139, and a new oral triazole, Bay n 7133. A new oral triazole, ICI 153066, was markedly more effective than ketoconazole and is the only oral drug studied which came close to producing complete sterilization of all visceral infection in all animals treated. Amphotericin B, a polyene given parenterally, was shown to be more efficacious than any drug studied. It completely sterilized the infection. A modified polyene, N-D-ornithyl amphotericin methyl ester, was only slightly less effective on a milligram-per-kilogram basis.
Establishment of MICs of moxalactam for control and reference anaerobic organisms in agar dilution and microdilution techniques
Authors: Sutter V L , Emmerman J , Randall E , Zabransky R J , Birk R J
Published: June 2012

The MICs of moxalactam were determined for eight National Committee for Clinical Laboratory Standards control and reference strains and for Fusobacterium nucleatum ATCC 10953 by agar and microdilution techniques. The recommended MIC for the control strain Bacteroides fragilis in both agar and microdilution tests is 0.5 micrograms/ml. Recommended MICs for Bacteroides thetaiotaomicron ATCC 29741 and Clostridium perfringens ATCC 13124 by agar dilution are 8 and 0.063 micrograms/ml, respectively. These two strains gave inconsistent results in microdilution tests. Variation in results with microdilution procedures was seen, which illustrates problems in reading endpoints and with modifications of media. Recommended MICs for the reference strains are presented.
Genetic and biochemical properties of AER-1, a novel carbenicillin-hydrolyzing beta-lactamase from Aeromonas hydrophila
Authors: Hedges R W , Medeiros A A , Cohenford M , Jacoby G A
Published: June 2012

A novel carbenicillin-hydrolyzing beta-lactamase has been discovered in a blood isolate of Aeromonas hydrophila. The enzyme resembles plasmid-determined carbenicillinases in substrate profile but differs in isoelectric point (pI 5.9) and molecular weight (22,000) and has been termed AER-1. No evidence for a plasmid location could be obtained in A. hydrophila, but the AER-1 gene and resistance to chloramphenicol, streptomycin, and sulfonamide could be transferred by mobilization with IncP plasmids to Escherichia coli, where the gene cluster inserted at a unique chromosomal site. The linked resistances are similar to those found on multiresistance beta-lactamase transposons, but since insertion of the A. hydrophila gene cluster was site specific and recA+ dependent, the cluster is not a functional transposon.
In vitro activities of and mechanisms of resistance to antifol antimalarial drugs
Authors: Milhous W K , Weatherly N F , Bowdre J H , Desjardins R E
Published: June 2012

Certain drugs that interfere with folate metabolism (sulfones, sulfonamides, and inhibitors of dihydrofolate reductase) play an important role in the chemotherapy and prophylaxis of malaria. The activities and mechanisms of action of these drugs are regarded as similar in most respects to their activities against procaryotic microorganisms. Believed incapable of utilizing intact exogenous folates, plasmodia have been regarded as dependent on de novo synthesis of required folate cofactors. The present investigation, conducted in pursuit of a method for testing the in vitro susceptibility of Plasmodium falciparum to antifol antimalarial drugs, produced evidence that earlier assumptions about the folate metabolism of this organism are not correct. Three of four isolates of P. falciparum were successfully maintained in a culture medium depleted of folic acid and p-aminobenzoic acid. The antimalarial activities of sulfonamides and dihydrofolate reductase inhibitors were, furthermore, variably antagonized by the presence of folic acid and p-aminobenzoic acid in the culture medium. Optimum conditions for assessment of antifol antimalarial activity in vitro therefore require precise control of these factors in the culture medium. Our results suggest that resistance to antifol antimalarial drugs involves a complex of factors related to both the de novo synthesis of active folate cofactors and the ability to utilize exogenous intact folates in various forms.
Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes during in vitro culture and its relationship to chloroquine resistance
Authors: Verdier F , Le Bras J , Clavier F , Hatin I , Blayo M C
Published: June 2012

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes (RBC) was studied in vitro before and during culture by measuring the chloroquine gradient between the cells and medium (C/M) by high-pressure liquid chromatography. The C/M values were 5.9 +/- 2.7 (n = 23) for uninfected RBC, 13 to 34 for six chloroquine-susceptible isolates (concentration required to inhibit 50% of parasite growth, less than 100 nmol/liter) in partially infected RBC (parasitemia from 0.3 to 5%) (n = 28), and 8.4 to 4.9 for four chloroquine-resistant isolates (concentration required to inhibit 50% of parasite growth, 320 to 1,500 nmol/liter) in partially infected RBC (parasitemia from 0.4 to 5%) (n = 26). Two isolates were studied before and after adaptation to continuous culture. C/M was found to decrease (34.2 to 2.1 and 19.3 to 4.9), whereas the concentration required to inhibit 50% of parasite growth increased (35 to 1,400 and 54 to 1,500 nmol/liter), thus indicating the acquisition of chloroquine resistance. These results demonstrate that chloroquine uptake decreased in RBC in which the infective strain, initially susceptible, became resistant in culture and imply that the drug is bound to ferriprotoporphyrin IX to a lesser extent or that a parasite protein competes with ferriprotoporphyrin IX to a greater extent. We suggest that genotypic modifications in the mechanism of chloroquine uptake might occur in the parasite.
Aztreonam therapy in experimental meningitis due to Haemophilus influenzae type b and Escherichia coli K1
Authors: McCracken G H , Sakata Y , Olsen K D
Published: June 2012

The penetration of aztreonam into cerebrospinal fluid was 7 to 15% and 9 to 25%, respectively, in experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. Aztreonam was effective in reducing the number of organisms in cerebrospinal fluid after single-dose and continuous infusion administration, and the median bactericidal titers in cerebrospinal fluid were 1:32 against both meningeal pathogens.
Microcin E492, a low-molecular-weight peptide antibiotic which causes depolarization of the Escherichia coli cytoplasmic membrane
Authors: de Lorenzo V , Pugsley A P
Published: June 2012

Microcin E492 is a 5,000- to 7,000-molecular-weight peptide antibiotic which depolarizes the cytoplasmic membrane of sensitive Escherichia coli K-12 cells. The microcin has many features in common with colicin V but is distinguished from it by the absence of microcin E472 immunity in ColV+ strains and by the fact that colicin V-insensitive Cir mutants of E. coli K-12 are microcin sensitive. Neither of the two plasmids detected in the producing strain of Klebsiella pneumoniae appear to carry the determinants for microcin E492 production or immunity, which is in contrast to the situation found hitherto with other microcins and colicins.
Response of Legionella pneumophila to beta-lactam antibiotics
Authors: Weisholtz S , Tomasz A
Published: June 2012

Legionella pneumophila Philadelphia strain 1 grown in vitro contained five penicillin-binding proteins that were accessible to the antibiotic in membrane preparations and in live cells as well. The bacterium had reasonably low MICs of several beta-lactam antibiotics and was susceptible to both the bactericidal and the lytic activity of these drugs. An unusual feature of the response of this bacterium to penicillin treatment was that cell lysis as determined by decrease in culture turbidity and release of intracellular macromolecules was not accompanied by degradation of the peptidoglycan.
Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs
Authors: Desjardins-Giasson S , Beaubien A R , Cauchy M J
Published: June 2012

The purpose of this study was to determine whether a multiple-sampling procedure could be used in guinea pigs to study the kinetics of amikacin in perilymph. Amikacin was infused intravenously for 6 h into conscious anesthetized guinea pigs, and the concentrations of the drug in plasma and perilymph were measured. From each anesthetized guinea pig, five to six perilymph samples were collected from one ear, and one sample was collected from the other ear at 6 h. The concentrations of amikacin in perilymph were dose proportional and increased slowly during the 6-h infusion. However, after 6 h of intravenous infusion, the concentrations of amikacin in perilymph of the multiply sampled ears were significantly higher than those of the singly sampled ears, indicating that the multiple-sampling procedure should not be used as is to study the kinetics of amikacin in perilymph. Amikacin concentrations in perilymph were linearly related to amikacin concentrations in plasma in pentobarbital-anesthetized animals, as had previously been observed for conscious guinea pigs. However, the slope of the regression line was only 0.09 for anesthetized animals compared with 0.24 for conscious animals. Drug concentrations in plasma were found to be threefold higher in anesthetized animals, whereas drug levels in perilymph were the same in both groups at similar dosing rates. These results indicate that the amikacin concentration in perilymph is not solely dependent upon its concentration in plasma and that other factor(s) can affect the entry of amikacin into the inner ear.
Covalent binding of moxalactam to cephalosporinase of Citrobacter freundii
Authors: Murakami K , Yoshida T
Published: June 2012

The inhibition of Citrobacter freundii cephalosporinase activity by moxalactam is shown to be due to the formation of a transiently stable covalent complex, probably acyl enzyme. The covalent complex formed was identified by coelution of [14C] moxalactam with the enzyme by using Sephadex G-25 gel filtration in the presence of 5.7 M guanidine hydrochloride and by analytical isoelectric focusing. Both the side-chain carboxyl group and the 7 alpha-methoxy group of moxalactam were necessary to stabilize the complex. Moxalactam is racemic with respect to the alpha carbon of the 7 beta-acylamino side chain, and the complex with the R epimer (half-life, 4.6 min) decomposed much more rapidly than that formed with the S epimer (half-life, 130 min). For other beta-lactam antibiotics that were stable to beta-lactamase, the half-lives of enzyme-antibiotic complexes were less than 4 min.
Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections
Authors: Feinberg A , Leyland-Jones B , Fanucchi M P , Hancock C , Fox J J , Watanabe K A , Vidal P M , Williams L , Young C W , Philips F S
Published: June 2012

The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.
Relationship between butirosin biosynthesis and sporulation in Bacillus circulans
Authors: Nam D H , Ryu D D
Published: June 2012

The relationship between butirosin biosynthesis and certain biochemical characteristics related to sporulation in a strain of Bacillus circulans NRRL B-3313 was examined. The cellular content of dipicolinic acid increased while the amount of poly-beta-hydroxybutyrate decreased with changes in antibiotic productivity. Oligosporogenous mutants failed to synthesize the antibiotic and to degrade poly-beta-hydroxybutyrate. These observations suggest that spore formation may be related to antibiotic production in this strain of B. circulans.
Regulation of penicillin-binding protein activity: description of a methicillin-inducible penicillin-binding protein in Staphylococcus aureus
Authors: Rossi L , Tonin E , Cheng Y R , Fontana R
Published: June 2012

The penicillin-binding proteins (PBPs) of two methicillin-resistant strains of Staphylococcus aureus (R2 and R1) were analyzed in cells grown in the absence and in the presence of methicillin. Under the former condition, strain R2 showed the typical PBP pattern of beta-lactam-susceptible strains, while strain R1 showed a markedly increased amount of PBP-3. Under the latter condition, on the other hand, a novel PBP (PBP-2a) located between PBP-2 and -3 was detected in strain R2, while strain R1 appeared to synthesize an even greater amount of PBP-3, in respect to untreated cells. Both R2 PBP-2a and R1 PBP-3 showed a very low affinity for methicillin, which was consistent with the MICs for the respective strains.
Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles
Authors: Ruhr E , Sahl H G
Published: June 2012

The peptide antibiotic nisin was shown to cause a rapid efflux of amino acids and Rb+ from the cytoplasm of gram-positive bacteria (Staphylococcus cohnii 22, Bacillus subtilis W 23, Micrococcus luteus ATCC 4698, and Streptococcus zymogenes 24). It strongly decreased the membrane potential of cells as judged by the distribution of the lipophilic tetraphenylphosphonium cation. Ascorbate-phenazine methosulfate-driven transport of L-proline by cytoplasmic membrane vesicles was blocked after addition of nisin, and accumulated amino acids were released from the vesicles. Soybean phospholipid (asolectin) vesicles were not affected by nisin. The data suggest that the cytoplasmic membrane is the primary target and that membrane disruption accounts for the bactericidal action of nisin.
Occurrence of a beta-lactam-inducible penicillin-binding protein in methicillin-resistant staphylococci
Authors: Ubukata K , Yamashita N , Konno M
Published: June 2012

The mechanism of methicillin resistance was investigated in methicillin-resistant staphylococci (MRS) and in variants which had lost methicillin resistance. Phase-contrast microscopy showed that cells swelled at low concentrations of beta-lactam antibiotics in both MRS and variants which had lost methicillin resistance. Cells of variants which had lost methicillin resistance were lysed easily when higher concentrations of antibiotic were used. In contrast, MRS cells remained swollen at even higher concentrations of antibiotics. Furthermore, bacterial growth was inhibited at antibiotic concentrations much lower than MICs for MRS. Examination of the penicillin-binding proteins (PBPs) in MRS revealed that a new PBP-2' (molecular weight, 74,000) was induced in large quantity by exposure to beta-lactams. PBP-2' was produced constitutively in variants of MRS which had lost a penicillinase plasmid. The induction of PBP-2' by beta-lactams was not detected in variants which had lost methicillin resistance. High concentrations of beta-lactam were required for saturation of PBP-2'. The optimum antibiotic concentration for the induction of PBP-2' varied with the beta-lactam used as the inducer, and PBP-2' was produced in a larger amount at 32 degrees C than at 37 degrees C. From these results, we suggest that the mechanism of methicillin resistance depends on the induction of PBP-2', which may function as a detour enzyme for PBP-2 or PBP-3 or may be a particular enzyme involved in peptidoglycan synthesis.
Comparative pharmacokinetics of ceftazidime in fibrin clots and cardiac vegetations in rabbits with Staphylococcus aureus endocarditis
Authors: McColm A A , Ryan D M
Published: June 2012

The penetration of ceftazidime, administered in a dose of 100 mg/kg intramuscularly, into cardiac vegetations and subcutaneously implanted fibrin clots was compared in rabbits with experimental Staphylococcus aureus endocarditis. Significant pharmacokinetic differences between the time-concentration curves for the two compartments were observed. Concentrations of ceftazidime in vegetations peaked at 30 min after dosing at a level slightly lower than that in plasma and thereafter declined in parallel with concentrations in plasma throughout the 8-h sampling period. Concentrations in fibrin clots increased more slowly than those in plasma and vegetations, reaching a maximum at 120 min. This was followed by a slow elimination phase yielding concentrations in excess of concurrent plasma and vegetation levels and a greater area under the curve. These features were observed for both large (2-ml volume) and small (0.1-ml volume) clots. Contrary to previous reports, these observations suggest that fibrin clots do not provide an accurate model for predicting antibiotic concentrations in cardiac vegetations produced in endocarditis and that concentrations of antimicrobial agents in vegetations can be predicted more accurately from concomitant plasma levels.
Systemic absorption and persistence of tioconazole in vaginal fluid after insertion of a single 300-mg tioconazole ovule
Authors: Houang E T , Lawrence A G
Published: June 2012

After vaginal insertion of a 300-mg ovule of tioconazole in 10 patients with vaginal candidiasis, the mean concentration in plasma was 21.2 ng/ml (range, 10.6 to 35.8 ng/ml) at 8 h and was not measurable at 24 h in 9 of 10 patients. The mean vaginal concentration at 24 h was 21.4 mg/liter (range, 2.4 to 50 mg/liter) and remained detectable in 7 of 9 and 2 of 9 patients after 48 and 72 h, respectively.
In vitro activity of cefbuperazone against Bacteroides spp
Authors: Dias M B , Jacobus N V , Gorbach S L , Tally F P
Published: June 2012

The activity of cefbuperazone was tested in vitro against 287 clinical isolates of Bacteroides spp. Cefbuperazone showed good activity against B. fragilis, B. vulgatus, and other Bacteroides species, comparable to that of cefoxitin. It was relatively ineffective against B. distasonis and the B. thetaiotaomicron-ovatus group and was not active against cefoxitin-resistant Bacteroides spp.
Comparative efficacy and selectivity of some nucleoside analogs against Epstein-Barr virus
Authors: Lin J C , Smith M C , Pagano J S
Published: June 2012

The effects of (2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluridine (FMAU), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouridine (FIAU), (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG or BW B759U) on the replication of Epstein-Barr virus (EBV) in vitro were evaluated and compared with that of acyclovir (ACV). The relative potencies of these drugs, on the basis of anti-EBV activity, were: FIAC = FIAU greater than FMAU greater than DHPG greater than BVdU greater than ACV; on the basis of the therapeutic index they were: BVdU greater than DHPG greater than FIAC greater than ACV greater than FIAU greater than FMAU. Differential inhibition of EBV-associated polypeptides by these drugs was observed.
Studies with temocillin in a hamster model of antibiotic-associated colitis
Authors: Boon R J , Beale A S
Published: June 2012

Hamsters given the new penicillin temocillin, either orally or by injection, did not develop antibiotic-associated colitis, whereas animals given the control antibiotics cefoxitin or clindamycin developed the disease, which is characterized by marked hemorrhagic cecitis and high cecal levels of Clostridium difficile cytotoxin.
Open, prospective study of the clinical efficacy of ciprofloxacin
Authors: Ramirez C A , Bran J L , Mejia C R , Garcia J F
Published: June 2012

One hundred patients with infections mostly outside of the urinary tract were studied in a prospective, open manner to ascertain the effectiveness and safety of ciprofloxacin in a variety of clinical situations. There were 41 instances of bacteremia, including 38 with Salmonella typhi, and 21 respiratory, 17 skin and skin structure, 11 bone or joint, 6 gastrointestinal, and 4 urinary tract infections. The patients were given 500 mg of ciprofloxacin orally every 12 h for 2 to 107 days (mean, 15.1 days). Microorganisms isolated disclosed susceptibilities comparable to those reported previously, with a MIC for 90% of the strains of 0.25 microgram/ml. For Streptococcus pneumoniae the MIC for 90% of the strains was 0.03 microgram/ml, and it was higher for Pseudomonas aeruginosa (0.5 microgram/ml), although still in the therapeutic range. Levels in blood were lower than those reported in other series, and no accumulation of the drug during treatment was detected. In 88 instances there was resolution of the infectious process, in 7 there was improvement, in 3 there was a failure to respond, and in 2 the clinical response was indeterminate. Bacteriological eradication was documented in 87 infections. Despite extensive clinical and laboratory examinations before, during, and after therapy, no major abnormalities related to therapy were seen; only one patient required discontinuation of ciprofloxacin due to gastrointestinal intolerance. Ciprofloxacin is an effective and safe therapeutic alternative in many tissue infections caused by susceptible microorganisms.
Cefotaxime diffusion into cerebrospinal fluid of children with meningitis
Authors: Asmar B I , Thirumoorthi M C , Buckley J A , Kobos D M , Dajani A S
Published: June 2012

Cefotaxime diffused consistently and in therapeutic levels into the cerebrospinal fluid (CSF) of 13 children successfully treated for bacterial meningitis. CSF cefotaxime levels early (6.0 micrograms/ml) and late (1.2 micrograms/ml) in treatment were severalfold the MBCs for the infecting organisms. After a single 40-mg/kg dose to each of five infants with ventriculostomies, mean CSF levels of cefotaxime were 6.4, 5.7, and 4.5 micrograms/ml at 2, 4, and 6 h, respectively.
A gene probe for TEM type beta-lactamases
Authors: Cooksey R C , Clark N C , Thornsberry C
Published: June 2012

A restriction fragment of plasmid pBR322 bearing the TEM-1 beta-lactamase structural gene was electroeluted from agarose gels after digestion with EcoRI and HinfI. The 1-kilobase fragment was 32P-labeled and used to examine genetic relationships with nucleic acids encoding seven other beta-lactamase classes. The probe hybridized only with TEM-2 and OXA-2 class plasmids.