bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium avium-M. intracellulare isolates from patients with or without acquired immunodeficiency syndrome
Authors: Horsburgh C R , Cohn D L , Roberts R B , Masur H , Miller R A , Tsang A Y , Iseman M D
Published: June 2012

Susceptibility testing and serotyping were performed on 57 isolates of Mycobacterium avium-M. intracellulare from patients with acquired immunodeficiency syndrome (AIDS) and 75 isolates from patients without AIDS. Susceptibility patterns and serotypes of AIDS isolates were significantly different from those of non-AIDS isolates. These results may partially explain the poor therapeutic response of M. avium-M. intracellulare infections in AIDS patients.
Antimicrobial activity of Ro 15-8074, active metabolite of a new oral cephalosporin (Ro 15-8075), against 7,775 recent clinical isolates
Authors: Jones R N , Fuchs P C , Barry A L , Ayers L W , Gerlach E H , Gavan T L
Published: June 2012

Susceptibility testing of 7,775 recent clinical isolates from four medical centers showed Ro 15-8074 to be 2-to greater than 8-fold more active than either cefaclor or cefuroxime against the Enterobacteriaceae. Ro 15-8074 MICs for 50% of the strains tested were greater than or equal to 32 micrograms/ml for Staphylococcus spp., enterococci, Pseudomonas aeruginosa, and Pseudomonas maltophilia. beta-Lactamase hydrolysis experiments failed to demonstrate significant Ro 15-8074 inactivation by commonly encountered chromosomal or plasmid-mediated enzymes (P99, K1, K14, TEM, and CARB).
Association between colistin resistance and broad-spectrum recipient deficiency in Klebsiella pneumoniae
Authors: Lamousin-White M , O'Callaghan R J
Published: June 2012

A colistin-resistant mutant of Klebsiella pneumoniae served well as a donor but not as a recipient in conjugation. A nearly 1,000-fold difference between colistin-susceptible and colistin-resistant forms of this strain was observed by using donors of plasmids of four incompatibility groups. Recipient efficiency was not restored by filter matings.
In vitro activity of A-56268 (TE-031) and four other antimicrobial agents against Chlamydia trachomatis
Authors: Segreti J , Kessler H A , Kapell K S , Trenholme G M
Published: June 2012

The in vitro activity of A-56268 (TE-031), a new macrolide antibiotic, against 11 strains of Chlamydia trachomatis was determined and compared with that of four other antibiotics. A-56268 was the most active drug tested. Doxycycline, trimethoprim-sulfamethoxazole, and erythromycin had good activity but were less active in vitro than A-56268.
Oxacillin killing curve patterns of Staphylococcus aureus isolates by agar dilution plate count method
Authors: Woolfrey B F , Lally R T , Ederer M N , Gresser-Burns M
Published: June 2012

The bactericidal dynamics of oxacillin against four Staphylococcus aureus isolates with known 24-h "persister" percentages were studied by using the agar dilution plate count method. Isolates were selected to provide a representative spectrum whose individual 24-h trough intrinsic persister percentages ranged from greater than 1 to less than 0.01%. Resultant agar dilution plate count method killing curve patterns were found to be reproducible and served to characterize each isolate. The paradoxical effect was observed for each isolate, with paradoxical peaks tending to develop and diminish sequentially during the course of oxacillin action. The observed strain-dependent dynamics of oxacillin killing underscore the artifactual nature of the so-called tolerance phenomenon and negate the usefulness of MBCs and MBC/MIC ratios for the characterization of S. aureus isolates.
Activity of (+)-cyclaradine (Sch 31172) against herpes simplex virus in vitro and in vivo
Authors: Schwartz J , Ostrander M , Butkiewicz N J , Lieberman M , Lin C , Lim J , Miller G H
Published: June 2012

(+)-Cyclaradine (Sch 31172) is the carbocyclic derivative of adenosine arabinoside (9-beta-D-arabinofuranosyladenine). Because it is not deaminated by deaminase in serum, as is adenosine arabinoside, (+)-cyclaradine is about 2 to 5 times more active in vitro against herpes simplex virus. (+)-Cyclaradine has in vitro activity nearly equivalent to that of phosphonoformate but is significantly less active than acycloguanosine (acyclovir; ACV), trifluorothymidine, or 9-(1,3-dihydroxy-2-propoxymethyl)guanine. The absolute ratios of in vitro activities are difficult to determine because of variability among virus strains, inoculum size, and dependence on the tissue culture cell line in which the comparative test is carried out. (+)-Cyclaradine is active against TK-, ACV-resistant mutants. In the guinea pig model of vaginal herpes simplex virus infection, (+)-cyclaradine is only slightly less active than ACV when both molecules are nearly equivalently bioavailable; thus, the large difference in activity seen in vitro is not reflected in this in vivo model system.
Improved DNA hybridization method for detection of acyclovir-resistant herpes simplex virus
Authors: Swierkosz E M , Scholl D R , Brown J L , Jollick J D , Gleaves C A
Published: June 2012

A simplified DNA hybridization method was developed to detect acyclovir-resistant isolates of herpes simplex virus. Herpes simplex virus-infected cell cultures in microtiter plates were treated with concentrations of acyclovir ranging from 8 to 0.015 micrograms/ml. At 48 h postinfection, infected cells were lysed by a one-step procedure and lysates were absorbed to membranes. Without further treatment, membranes were hybridized by using a herpes simplex virus-specific radioiodinated probe. The membranes were then washed and counted in a gamma counter. The elapsed time for assay performance was 4 h. Parallel plaque reduction assays were performed for comparison. The mean 50% inhibitory dose of in vivo- and in vitro-derived acyclovir-resistant, thymidine kinase-negative isolates was greater than 2 micrograms/ml by DNA hybridization. The 50% inhibitory dose of acyclovir-susceptible, thymidine kinase-positive isolates ranged from 0.01 to 1.1 micrograms/ml. This assay is simple and objective and should facilitate antiviral susceptibility testing in diagnostic laboratories.
Efficacy of orally administered penicillin V for prophylaxis of experimentally induced streptococcal endocarditis
Authors: Pujadas R , Escriva E , Jane J , Galera M C , Fava P , Garau J , Mirelis B
Published: June 2012

Four oral penicillin V regimens were compared for the ability to prevent Streptococcus sanguis infection of experimentally induced valvular heart lesions in rabbits. Challenge doses of 10(4), 10(6), and 10(8) CFU of a penicillin-susceptible strain of S. sanguis were used in this study. Measured by recovery of test organisms from endocardial lesions, the lowest-concentration inoculum was infective for 53% of the recipients; the higher-concentration inocula were infective for all recipients. A single-oral-dose penicillin V regimen (36 mg/kg of body weight) prevented endocarditis when rabbits were challenged with 10(4) CFU, but protection diminished with increasing inoculum concentrations. In contrast, addition of a second penicillin V dose (18 mg/kg of body weight) administered with a 7-h interval between doses achieved fully effective prophylaxis against even the highest inoculum tested (10(8) CFU). A repeated set of experiments in which half the dose of penicillin V was administered showed significantly reduced protection against S. sanguis endocarditis.
Nucleotide sequence changes in thymidine kinase gene of herpes simplex virus type 2 clones from an isolate of a patient treated with acyclovir
Authors: Kit S , Sheppard M , Ichimura H , Nusinoff-Lehrman S , Ellis M N , Fyfe J A , Otsuka H
Published: June 2012

To identify the nucleotide changes that occur in drug-induced thymidine kinase (TK) mutants of herpes simplex virus type 2 (HSV-2), we compared the nucleotide sequences of the tk genes of two mutant HSV-2 clones isolated from a patient who had been treated with acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV] with the nucleotide sequence of the parental TK+ HSV-2(8703) strain isolated from the same patient. One of the mutants, TK-altered (TKA) HSV-2(9637), was ACV resistant but induced the incorporation of [14C]thymidine into the DNA of infected rabbit skin cells. The nucleotide sequence of the tk gene of mutant TKA HSV-2(9637) had a single change (G to A) at nucleotide 668, which would cause an arginine-to-histidine substitution at amino acid residue 223 of the TK polypeptide. The second ACV-resistant mutant, TK- HSV-2(8710), did not induce detectable incorporation of [14C]thymidine into the DNA of infected rabbit skin cells. This mutant exhibited a deletion of a single base at nucleotide 217 of its nucleotide sequence. This deletion would cause a frameshift mutation at amino acid residue 73 and chain termination at amino acid residue 86 of the TK polypeptide. The nucleotide sequence of TK+ HSV-2(8703) was the same as that of the laboratory strain, TK+ HSV-2(333). The nucleotide sequence of a bromodeoxyuridine-resistant TK- HSV-2(333) mutant of TK+ HSV-2(333) also exhibited a single-base deletion, but at nucleotide 439. This deletion would cause a frameshift mutation at amino acid residue 147 and chain termination at amino acid residue 182. The frameshift mutations of TK- HSV(8710) and TK- HSV-2(333), respectively, occurred in sequences in which C was repeated three times and G was repeated seven times. The results raise the possibility that TK- frameshift mutations of HSV-2 may be common.
Role of extracellular iron in the action of the quinone antibiotic streptonigrin: mechanisms of killing and resistance of Neisseria gonorrhoeae
Authors: Cohen M S , Chai Y , Britigan B E , McKenna W , Adams J , Svendsen T , Bean K , Hassett D J , Sparling P F
Published: June 2012

The quinone antibiotic streptonigrin is believed to kill bacteria by promoting formation of oxygen radicals. This antibiotic has also been used to select resistant bacterial mutants, some of which vary in iron utilization. We examined the effects of streptonigrin on Neisseria gonorrhoeae and several types of gonococcal mutants. Streptonigrin (0.025 microgram/ml) efficiently killed gonococcal strain FA1090, and this effect depended on iron. Streptonigrin-resistant mutant FA6271 had normal iron uptake but was moderately deficient in total iron. Resistance most likely resulted from failure of FA6271 to divert electrons to streptonigrin, as demonstrated by a reduction in KCN-insensitive respiration (a hallmark of the action of quinones) and superoxide formation. Other mutants selected for inability to use human iron-binding proteins (strains FA6273 and FA6275) had no increase in streptonigrin MIC and no decrease in KCN-insensitive respiration. Mutants did not demonstrate an increase in superoxide dismutase or catalase. Streptonigrin killing of gonococci depended on a reaction(s) in which extracellular iron was important, presumably because iron was required for catalysis of hydroxyl radical. The results suggest that a membrane component may be a target for the actions of streptonigrin.
Influence of cation supplements on activity of netilmicin against Pseudomonas aeruginosa in vitro and in vivo
Authors: Barry A L , Miller G H , Thornsberry C , Hare R S , Jones R N , Lorber R R , Ferraresi R , Cramer C
Published: June 2012

In vitro studies were performed with 74 Pseudomonas aeruginosa isolates which were collected during a multicenter trial. The isolates were obtained from 70 patients who had been treated with netilmicin as the only antipseudomonal antibiotic. Clinically, 83% of the patients were cured or improved, and 64% of the Pseudomonas isolates were eliminated by chemotherapy. The 74 clinical isolates and 38 additional isolates with known mechanisms of aminoglycoside resistance were tested in three separate laboratories by disk diffusion methods and by microdilution tests with three broth media (Mueller-Hinton broth with full, half, and no cation supplements). Isolates that responded to netilmicin therapy and those that failed to respond were all susceptible by the disk test, and most were susceptible by microdilution tests with unsupplemented broth. However, over half of the clinical isolates appeared to be resistant when cations were added to the broth medium. Strains capable of producing enzymes that inactivate netilmicin were resistant by all methods tested. Broth dilution and agar dilution results were most comparable when half of the recommended cation supplements was added to Mueller-Hinton broth. Further consideration should be given to reducing the concentration of cations that are added to Mueller-Hinton broth when netilmicin susceptibility tests are being performed. However, additional studies with other aminoglycosides are needed before appropriate testing conditions can be standardized.
Molecular target of the antileishmanial action of sinefungin
Authors: Nolan L L
Published: June 2012

Sinefungin, a natural nucleoside isolated from cultures of Streptomyces incarnatus and S. griseolus, is structurally related to S-adenosylhomocysteine and S-adenosylmethionine. Sinefungin has been shown to inhibit the development of various fungi and viruses, but its major attraction to date resides in its potent antiparasitic activity. This compound has been reported to display antiparasitic activity against malarial, trypanosomal, and leishmanial species. Very little is known about the antiparasitic mode of action of sinefungin. We found that S-adenosylmethionine was capable of reversing the inhibitory growth effects of sinefungin in Leishmania mexicana and that dATP was capable of reversing inhibitory effects of the drug on DNA polymerase activity when pyrophosphate release was measured. However, when incorporation of [3H]dTTP was used to measure DNA polymerase activity, no inhibition could be observed. Inhibition of DNA polymerase activity by sinefungin occurred only during the initial stages of purification of this enzyme, and inhibition by aphidicolin, a known DNA polymerase inhibitor, paralleled the inhibition by sinefungin. Neither sinefungin nor aphidicolin inhibited partially purified DNA polymerase. S-Adenosylmethionine synthetase was partially purified, and sinefungin, at levels active in vitro, had no significant effect. Sinefungin was significantly suppressive against both L. donovani and L. braziliensis panamensis infections in hamsters when compared with meglumine antimonate (Glucantime).
Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro
Authors: Baba M , Pauwels R , Balzarini J , Herdewijn P , De Clercq E , Desmyter J
Published: June 2012

The combined antiviral effects of various 2',3'-dideoxynucleosides and ribavirin on the replication of human immunodeficiency virus type 1 in MT-4 cells have been examined. Ribavirin antagonized the antiviral activity of the pyrimidine 2',3'-dideoxynucleosides (3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxythymidin-2'-ene, 2',3'-dideoxycytidine, and 2',3'-dideoxycytidin-2'-ene), but enhanced the antiviral activity of the purine 2',3'-dideoxynucleosides (2',3'-dideoxyadenosine and 2',3'-dideoxyguanosine). Combinations of the 2',3'-dideoxynucleosides with each other were also examined. These combinations resulted in an additive to subsynergistic effect.
Value of antibiotic levels in serum and cardiac vegetations for predicting antibacterial effect of ceftriaxone in experimental Escherichia coli endocarditis
Authors: Joly V , Pangon B , Vallois J M , Abel L , Brion N , Bure A , Chau N P , Contrepois A , Carbon C
Published: June 2012

In a rabbit model of Escherichia coli endocarditis, we studied the penetration into infected vegetations and the antibacterial effect of ceftriaxone. Ceftriaxone was given at different dosages, alone or with an interfering agent, diclofenac, a nonsteroidal anti-inflammatory drug, to determine the predictive value of the antibiotic levels in serum or infected vegetations on the antibacterial efficacy. Diclofenac increased the serum terminal half-life of ceftriaxone and increased its extravascular diffusion in tissue cage fluid, as well as in infected vegetations, allowing us to obtain various antibiotic concentrations in the infected site. Two hours after the fourth injection, around the time of peak level in serum, we observed a linear relationship between (i) serum and local antibiotic levels in vegetations, (ii) local antibiotic levels in a range of 142 to 600 X MBC and bacterial titer (log10 CFU/g) in vegetations, and (iii) serum antibiotic levels in a range of 800 to 1,400X MBC and bacterial titer in vegetations. In vivo, antibacterial effect was obtained only with high antibiotic levels in vegetations (greater than or equal to 220X MBC). This was confirmed by incubating vegetations sampled from infected animals in rabbit serum containing ceftriaxone (ex vivo experiment). Given once daily at a therapeutic dosage (30 mg/kg) for 4 days, ceftriaxone exhibited good efficacy (log10 CFU/g of vegetation = 2.41 +/- 2.7 versus 7.41 +/- 0.92 in control animals) and prevented regrowth of bacteria until 24 h after the last injection. We concluded that (i) provided the dose is sufficient, a long-acting cephalosporin can prove effective in severe gram-negative infections even when given infrequently, and (ii) serum antibiotic levels around the peak value, reflecting high effective local levels, could predict the therapeutic efficacy and represent a simple test to monitor the clinical course of a severe infectious process.
Norfloxacin resistance in a clinical isolate of Escherichia coli
Authors: Aoyama H , Sato K , Kato T , Hirai K , Mitsuhashi S
Published: June 2012

Analysis of DNA gyrase supercoiling and of norfloxacin uptake in Escherichia coli GN14176, a moderately norfloxacin-resistant clinical isolate, indicated that resistance was associated with both an altered drug target and a reduction in drug uptake.
Pharmacokinetics of metronidazole in patients with alcoholic liver disease
Authors: Lau A H , Evans R , Chang C W , Seligsohn R
Published: June 2012

The pharmacokinetics of metronidazole was evaluated in eight patients with alcoholic liver disease. Metronidazole (7.5 mg/kg) was administered to each patient intravenously. Serial blood samples were obtained after the dose. Serum metronidazole concentrations were determined by high-performance liquid chromatography. The following pharmacokinetic parameters (mean +/- standard deviations) were obtained: half-life, 18.31 +/- 6.06 h; elimination rate constant, 0.042 +/- 0.013 h-1; volume of distribution, 0.77 +/- 0.16 liters/kg; and total body clearance, 0.51 +/- 0.11 ml/min per kg. Compared with subjects with normal liver function, patients with liver disease showed a reduction in drug elimination rate and total body clearance. The half-life of metronizadole in serum and volume of distribution were increased. Large variations of these parameters were also observed among the patients. On the basis of these observations, a reduced dose of metronidazole should be given to patients with alcoholic liver disease to avoid accumulation of metronidazole and its metabolites. Monitoring of drug concentration in serum may also be necessary to optimize therapy.
Vancomycin entry into lung lymph in sheep
Authors: May D G , Stratton C W , Denney W D , Watts F L , Bernard G R , Branch R A
Published: June 2012

The distribution of antibiotics into target tissues is a crucial factor in therapeutic efficacy. To estimate the availability of systemically administered vancomycin to the interstitial fluid in the lung, we have used a sheep model with a chronic pulmonary lymph fistula to collect simultaneously series of plasma and pulmonary lymph specimens during a 6-h period after an intravenous dose of vancomycin (7 mg/kg). After a minor delay in transit from blood to lymph, vancomycin was completely distributed to pulmonary lymph with a ratio of free drug in lymph to free drug in plasma of 0.9. This suggests that vancomycin is an excellent choice for treating pulmonary infections by susceptible organisms.
Pharmacokinetics and distribution of ticarcillin-clavulanic acid (Timentin) in experimental animals
Authors: Woodnutt G , Kernutt I , Mizen L
Published: June 2012

The pharmacokinetics and distribution of ticarcillin and clavulanic acid were studied in rats and rabbits after intravenous coadministration of the compounds. The elimination half-lives for ticarcillin and clavulanic acid were similar in both rats (ticarcillin, 0.22 h; clavulanic acid, 0.24 h) and rabbits (ticarcillin, 0.38 h; clavulanic acid, 0.31 h). Both compounds distributed widely throughout rat tissues, and the patterns of distribution were similar to those observed for other beta-lactams. Values for penetration into rat pleural, peritoneal, and subcutaneous fluids calculated from the equation (AUCfluid/AUCserum) X 100, where AUC is the area under the concentration-time curve, were between 83 and 93% for ticarcillin and 86 and 103% for clavulanic acid. Values for penetration into tissue cages in rabbits were 139% +/- 45% for ticarcillin and 109% +/- 22% for clavulanic acid. The penetration of clavulanic acid into rabbit cerebrospinal fluid was higher (P less than 0.05) (4.0% +/- 0.61%) than that of ticarcillin (1.3% +/- 0.53%). Overall, the results show that ticarcillin and clavulanic acid distribute readily throughout body tissues and fluids and predict that the penicillin and beta-lactamase inhibitor would be present together at sites of infection.
Computer automated structure evaluation of quinolone antibacterial agents
Authors: Klopman G , Macina O T , Levinson M E , Rosenkranz H S
Published: June 2012

The Computer Automated Structure Evaluation (CASE) program was used to study a series of quinolone antibacterial agents for which experimental data pertaining to DNA gyrase inhibition as well as MICs against several strains of gram-positive and gram-negative bacteria are available. The result of the analysis was the automatic generation of molecular fragments relevant to the respective biological endpoints. The potential significance of these major activating-inactivating fragments to the biological activity is discussed.
Comparative effects of enoxacin and norfloxacin on human colonic microflora
Authors: Edlund C , Lidbeck A , Kager L , Nord C E
Published: June 2012

Ten healthy volunteers received 400 mg of enoxacin and another ten healthy volunteers received 200 mg of norfloxacin orally twice a day for 7 days. Fecal specimens were collected before, during, and after drug administration to study the impact of enoxacin and norfloxacin on the normal colonic microflora. On day 7, the mean concentrations of enoxacin and norfloxacin were 350 and 950 mg/kg of feces, respectively. Enoxacin and norfloxacin affected the colonic microflora in similar ways. The number of strains of the family Enterobacteriaceae was markedly suppressed during drug administration, whereas the gram-positive and anaerobic microfloras were not significantly altered. Two weeks after withdrawal of the drugs, the colonic microflora had returned to normal.
Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children
Authors: Hemming V G , Rodriguez W , Kim H W , Brandt C D , Parrott R H , Burch B , Prince G A , Baron P A , Fink R J , Reaman G
Published: June 2012

Respiratory syncytial virus (RSV)-infected cotton rats (Sigmadon hispidus) and owl monkeys (Aotus trivirgatus) showed significant reductions in RSV shedding from their respiratory tracts following parenteral therapy with human intravenous immunoglobulin (IVIG) containing high titers of RSV-neutralizing antibody. Because this therapy was well tolerated and appeared safe, a double-blind, placebo-controlled IVIG immunotherapy pilot study was performed on 35 hospitalized, RSV-infected infants and children. The treatment was well tolerated and resulted in significant reductions in nasal RSV shedding and in improvements in transcutaneous oximetry readings. However, the mean duration of hospitalization was not reduced by IVIG treatment. Followup to date has revealed no harmful effects resulting from immunotherapy of RSV infections. These studies appear to refute the hypothesis that passively acquired antibody may exacerbate RSV bronchiolitis or pneumonia in infants. Studies with larger numbers of seriously ill children will be required to determine if immunoglobulin G immunotherapy of RSV infections in infants is of clinical value.
Single- and multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans
Authors: Weidekamm E , Portmann R , Suter K , Partos C , Dell D , Lücker P W
Published: June 2012

Fleroxacin (Ro 23-6240; AM-833) is a new trifluorinated quinolone exhibiting high activity against a broad spectrum of gram-negative and gram-positive bacteria. Healthy male volunteers received, according to a randomized scheme, oral doses of 200, 400, or 800 mg of fleroxacin in tablet form, an intravenous infusion of 100 mg, or 400 mg of fleroxacin orally together with 1,000 mg of probenecid. Fleroxacin is characterized pharmacokinetically by a long elimination half-life (9 to 10 h) and high concentrations in plasma (e.g., maximum concentration of 2.3 micrograms/ml after an oral dose of 200 mg). The volume of distribution clearly exceeds 1 liter/kg and suggests a good tissue penetration. Within 60 h, the cumulative urinary recovery of unchanged drug amounted to 50 to 60% of the dose. The renal clearance of unbound drug was 137 ml/min, and probenecid had no significant effect on renal elimination. A good linear correlation (r = 0.999) was found between doses from 100 to 800 mg and the resulting values of area under the concentration-time curve. The absolute bioavailability of the administered tablet was practically 100%. During oral multiple dosing of 800 or 1,200 mg of fleroxacin once a day over 10 consecutive days, the accumulation of the drug in plasma was close to the theoretically predicted value of 1.3 and reflected the persistence of linear pharmacokinetics.
3'-Azido-3'-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase
Authors: St Clair M H , Richards C A , Spector T , Weinhold K J , Miller W H , Langlois A J , Furman P A
Published: June 2012

Reverse transcriptase was purified from human immunodeficiency virus (HIV). It utilized the artificial primer-template poly(rA)-oligo(dT)12-18 more efficiently than activated calf thymus DNA, poly(rI)-oligo(dC)12-18, poly(rC)-oligo(dG)12-18, or poly(rCm)-oligo(dG)12-18. Maximum activity was observed at pH 7.0 to 7.6 in the presence of 5 mM MgCl2 and 100 mM KCl. 3'-Azido-3'-deoxythymidine triphosphate competed with dTTP for binding to HIV reverse transcriptase. Different kinetic constants were obtained with different primer-templates. Km and Ki values of 2.8 and 0.04 microM, respectively, were obtained with poly(rA)-oligo(dT)12-18. The corresponding values were 1.2 and 0.3 microM, respectively, with activated calf thymus DNA and 0.3 and 0.01 microM, respectively, with extracted virus and native template. Inhibition of the host cell DNA polymerases alpha and beta was considerably weaker. The Km and Ki values obtained with activated calf thymus DNA as the primer-template were 2.4 and 230 microM, respectively, for DNA polymerase alpha and 6.0 and 73 microM, respectively, for DNA polymerase beta. 3'-Azido-3'-deoxythymidine triphosphate could also serve as an alternate substrate for HIV reverse transcriptase. The resulting incorporation of 3'-azido-3'-deoxythymidine triphosphate into poly(rA)-oligo(dT)12-18 caused chain termination and premature deceleration of the reaction. The terminated primer could not be elongated when incubated with dTTP and HIV reverse transcriptase.
Synergistic antifungal activity and reduced toxicity of liposomal amphotericin B combined with gramicidin S or NF
Authors: Hopfer R L , Mehta R , Lopez-Berestein G
Published: June 2012

Amphotericin B (AmpB) disrupts membrane integrity by binding to sterols in fungal and mammalian cell membranes. The gramicidins, which form pores in all membranes but exhibit poor antifungal activity, are too toxic to mammalian cells to be used systemically. This study demonstrated synergistic antifungal activity of free and liposomal forms of AmpB when combined with the free and liposomal forms of gramicidin S and gramicidin NF against five Candida strains. In vitro erythrocyte lysis was prevented by using the liposomal forms of all drugs tested alone or in combination. Presumably, AmpB increases accessibility of the fungal cell membrane to the gramicidins, while liposome encapsulation decreases the rate of transfer of the drugs to the mammalian cell membrane. Liposome encapsulation of inactive or toxic drugs, used in combination with liposomal AmpB, may give new life to drugs previously believed to be inactive or too toxic for therapeutic consideration.
Outer membrane penetration by (2,3)-methylenepenams
Authors: Chapman J S , Georgopapadakou N H
Published: June 2012

The penetration of the Escherichia coli outer membrane by two sterically restricted analogs of penicillin G was determined. The analog corresponding to the "open" conformation of penicillin G penetrated faster than the "closed"-form analog did, and both analogs penetrated faster than penicillin G did. The results suggest that the conformation of the beta-lactam nucleus may affect penetrability via the porin-mediated pathway.
Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice
Authors: Kobayashi G S , Travis S J , Medoff G
Published: June 2012

Fluconazole (UK-49,858) was compared with amphotericin B in treating histoplasmosis in female AKR mice immunosuppressed with either cyclophosphamide or cortisone. Both drugs protected animals from a lethal challenge with Histoplasma capsulatum, but neither regimen resulted in cures since viable organisms were cultured from spleens of survivors.
Pharmacokinetics of the acyclureidopenicillins piperacillin and mezlocillin in the postpartum patient
Authors: Martens M G , Faro S , Feldman S , Cotton D B , Dorman K , Riddle G D
Published: June 2012

The postpartum patient experiences numerous physiologic alterations, which may affect the pharmacokinetics of certain drugs. Six patients received either piperacillin or mezlocillin intravenously immediately after delivery. Serum half-life and clearance were, respectively, 82.4 min and 202 +/- 105 ml/min for mezlocillin and 32.9 min and 456 +/- 88 ml/min for piperacillin. The data revealed that mezlocillin and piperacillin have significantly different pharmacokinetic reactions in the postpartum patient at the doses used.
Clinical study evaluating efficacy of praziquantel in clonorchiasis
Authors: Yangco B G , De Lerma C , Lyman G H , Price D L
Published: June 2012

In 74 patients with clonorchiasis, the efficacy and safety of praziquantel was evaluated in a two-phase study: a double-blind, randomized controlled trial of praziquantel versus placebo (42 patients) and an open study (32 patients). All but one of the patients were Laotians. The intensity of clonorchiasis was light in 85% (63 of 74) and moderate in 15% (11 of 74) of the patients. Cure based on our established criteria was noted in 67 of 67 patients (100%) treated with praziquantel at a dose of 75 mg/kg per day. In contrast, four patients (20%) in the placebo group, each with light infection, ceased passing eggs and were, according to our established protocol, considered spontaneous cures (P less than 0.0001). Adverse effects of praziquantel were transient and included nausea and vomiting (15%), vertigo (12%), hepatomegaly (4.5%), headache (1.5%), rash (1.5%), and hypotension (1.5%). Of 20 patients who received placebo, 1 (5%) developed transient skin rash, fever, and chills. Clinically minor and transient, but statistically significant, changes in hemoglobin, total protein in serum, and levels of uric acid, cholesterol, and bilirubin in serum were noted. Results of this study showed that praziquantel is safe, well tolerated, and effective and should be considered as the drug of choice for treatment of clonorchiasis. In moderate infections, a second course of praziquantel therapy may be necessary to eliminate infection.
Efficacy and safety of oral ciprofloxacin for treatment of serious urinary tract infections
Authors: Fass R J
Published: June 2012

Eighty-three patients with serious urinary tract infections were treated with oral ciprofloxacin. Of these patients, 79 were hospitalized, and 41 had known structural or neurologic abnormalities of the urinary tract. The most common pathogens were members of the family Enterobacteriaceae (MICs, less than or equal to 0.06 microgram/ml), Pseudomonas aeruginosa (MICs, 0.13 to 2 micrograms/ml), and Enterococcus faecalis (MICs, 0.5 to 2 micrograms/ml). Sixty-eight patients were able to be evaluated for determining efficacy; all responded symptomatically, and all urinary pathogens were eradicated on days 3 to 5 of treatment. Five patients, who were treated for a relatively short duration (2 to 10 days), relapsed 5 to 9 days posttreatment. Six patients became colonized with yeasts during treatment, and seven patients developed bacterial reinfections 5 to 9 days posttreatment. All patients whose infections relapsed or who developed infections with new organisms had neurogenic bladders, structural abnormalities of the genitourinary tract, or urinary catheters. There was no instance of bacteria developing resistance during treatment. Ciprofloxacin probably caused nausea with or without vomiting in 7 of the 83 patients, headache in 3 patients, and mild elevation of hepatic enzymes in 2 patients; other adverse reactions were observed but were probably not drug related. Oral ciprofloxacin was effective and safe for the treatment of serious urinary tract infections caused by a variety of bacterial pathogens.
Comparative study of intraperitoneal and intravenous vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis
Authors: Morse G D , Farolino D F , Apicella M A , Walshe J J
Published: June 2012

The pharmacokinetic characteristics of vancomycin were investigated in eight patients undergoing continuous ambulatory peritoneal dialysis. A crossover design was used. Four noninfected patients received both a 15-mg/kg (body weight) intravenous dose and a 30-mg/kg intraperitoneal (i.p.) dose. Bioavailability ranged from 0.35 to 0.65 after i.p. administration. i.p. absorption was rapid, with concentrations in serum of 8.8 +/- 6 micrograms/ml noted at 1 h peak values of 30.4 +/- 7 micrograms/ml at 6 h. A slow distribution phase was apparent, with a terminal elimination phase emerging after 12 to 24 h. Vancomycin was eliminated slowly, with a mean total clearance of 5.0 +/- 1.3 ml/min, and concentrations in serum were 7.0 +/- 1.2 micrograms/ml at 168 h. The mean serum half-life was 91.7 +/- 28.1 h, and similar pharmacokinetics were noted after intravenous administration. Subsequently, four patients with catheter-related exit site or tunnel infections received a 30-mg/kg i.p. dose of vancomycin and displayed a similar kinetic pattern. This method of administering vancomycin achieved therapeutic serum and end-dwell dialysate concentrations over a 1-week period, represents a simple, cost-effective therapy which avoids the possibility of infusion-related toxicity, and deserves further investigation in patients with continuous ambulatory peritoneal dialysis-related peritonitis.
Alterations in peptidoglycan of Neisseria gonorrhoeae induced by sub-MICs of beta-lactam antibiotics
Authors: Garcia-Bustos J F , Dougherty T J
Published: June 2012

Exposure of Neisseria gonorrhoeae to sub-MICs of selected beta-lactam antibiotics caused distortion of normal cell morphology. Analysis of the peptidoglycan indicated that the cells were accumulating increased quantities of disaccharide pentapeptide in their cell walls. The O-acetylated form of the disaccharide pentapeptide was not detected among the major peaks. The correlation of antibiotic binding to gonococcal penicillin-binding protein 2 and accumulation of non-O-acetylated disaccharide pentapeptide suggested an explanation for the previously observed relationship of penicillin-binding protein 2 and O-acetylation of peptidoglycan.
Effect of broad-spectrum parenteral antibiotics on composition of intestinal microflora of humans
Authors: Giuliano M , Barza M , Jacobus N V , Gorbach S L
Published: June 2012

We compared the effects of four beta-lactam drugs with widely differing antibacterial and pharmacological properties on the composition of the intestinal flora. Cefoxitin, piperacillin, cefoperazone, and aztreonam were given intravenously for 9 days to healthy volunteers. Cefoperazone reduced the numbers of aerobic and anaerobic bacteria to undetectable levels. At the other extreme, cefoxitin had little effect on the normal flora. Aztreonam markedly reduced the numbers of aerobes, whereas piperacillin had a variable effect on both aerobic and anaerobic bacteria. There was extensive overgrowth of enterococci in subjects given cefoxitin or aztreonam, which have little activity against this species, and of yeasts in subjects given cefoperazone or piperacillin. Cefoperazone reached concentrations of 2,727 to 8,840 micrograms/g in the feces, whereas the other agents were generally undetectable. These results show that the new beta-lactam antibiotics produce widely varying effects on the fecal microflora after parenteral administration and that these effects are consistent with the antibacterial and pharmacological properties of the drugs.
Entry of ketoconazole into Candida albicans
Authors: Boiron P , Drouhet E , Dupont B , Improvisi L
Published: June 2012

To define characteristics that determine the entry of ketoconazole (KTZ) into Candida albicans cells, we studied the uptake of [3H]KTZ. The cells rapidly and markedly concentrated the drug: 30% of the final 80-fold intracellular concentration was attained in less than 1 min, and greater than 60% was attained in 10 min. Penetration of [3H]KTZ at an extracellular concentration higher than 0.1875 microM (0.1 microgram/ml) occurred by a simple diffusion mechanism. At lower concentrations, accumulation of the drug was an active, energy-requiring process, dependent at least in part on glycolysis, and pH dependent (optimal pH, 6.6). The active transport system had a high binding affinity (Km = 50 nM) and a high maximum velocity of uptake (Vmax = 1.4 mumol min-1 10(-7) cells). It was not possible to displace intracellular [3H]KTZ with high concentrations of unlabeled KTZ or other antifungal agents. These findings suggest that KTZ is rapidly taken up, highly concentrated, and tightly bound to cellular components of C. albicans.
Molecular genetic analysis of cephalosporinase production and its role in beta-lactam resistance in clinical isolates of Enterobacter cloacae
Authors: Nicolas M H , Honore N , Jarlier V , Philippon A , Cole S T
Published: June 2012

Two strains of Enterobacter cloacae were isolated from a patient before (strain MHN1) and during (strain MHN2) treatment with moxalactam and gentamicin. Strain MHN1 exhibited inducible ampC cephalosporinase production. In contrast, strain MHN2 expressed the enzyme constitutively at a 3,000-fold higher level. With the Escherichia coli ampC gene as a hybridization probe it was shown that the genomic arrangement of the ampC region was the same in both strains. To gain more insight into regulatory phenomena, the ampC genes were cloned, and their expression was studied in E. coli K-12. The ampC gene from MHN1 behaved normally and conferred inducible beta-lactam resistance. A regulatory region of at least 800 base pairs involved in controlling repression-induction was located immediately upstream of ampC. Surprisingly, when present in E. coli the ampC gene from MHN2 no longer overproduced the cephalosporinase, and inducible expression was observed. This indicates that in MHN2 stable cephalosporinase overproduction is controlled by another factor which is not linked to the ampC gene.
Molecular hybridization versus isoelectric focusing to determine TEM-type beta-lactamases in gram-negative bacteria
Authors: Jouvenot M , Deschaseaux M L , Royez M , Mougin C , Cooksey R C , Michel-Briand Y , Adessi G L
Published: June 2012

Isoelectric focusing and molecular hybridization with a TEM DNA probe were used to screen for TEM beta-lactamase in 328 bacterial isolates representing 11 gram-negative genera. The TEM enzyme was detected in 50% of isolates, and nine additional types of beta-lactamase could be identified in 36.9% of isolates. The TEM gene was detected in 53.6% of isolates. The results obtained by both methods were concordant in 92.7% of the entire sample. In situ colony hybridization with a specific probe therefore appears to be a convenient method to screen rapidly for the presence of homologous genetic sequences among a large number of isolates. Positive hybridization was observed for 16 isolates in which no TEM beta-lactamase was detected by isoelectric focusing. The significance of this hybridization remains to be determined.
Organization of two sulfonamide resistance genes on plasmids of gram-negative bacteria
Authors: Swedberg G
Published: June 2012

The organization of two widely distributed sulfonamide resistance genes has been studied. The type I gene was linked to other resistance genes, like streptomycin resistance in R100 and trimethoprim resistance in R388 and other recently isolated plasmids from Sri Lanka. In R388, the sulfonamide resistance gene was transcribed from a promoter of its own, but in all other studied plasmids the linked genes were transcribed from a common promoter. This was especially established with a clone derived from plasmid R6-5, in which transposon mutagenesis showed that expression of sulfonamide resistance was completely dependent on the linked streptomycin resistance gene. The type II sulfonamide resistance gene was independently transcribed and found on two kinds of small resistance plasmids and also on large plasmids isolated from clinical material.
Effect of Candida morphology on amphotericin B susceptibility
Authors: Nugent K M , Couchot K R , Gray L D
Published: June 2012

We showed that brief exposures to amphotericin B (AmB) inhibited the induction of new Candida germ tubes and the lengthening of partially induced germ tubes. Blastoconidia with germ tubes were more susceptible to AmB killing, and this varied directly with the induction period and the AmB exposure period. AmB did not preferentially affect germ tube adherence to fibrin matrices.
Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and 2'-nor-cyclic GMP on adenovirus replication in vitro
Authors: Baba M , Mori S , Shigeta S , De Clercq E
Published: June 2012

The inhibitory effects of 20 selected antiviral compounds on the replication of adenoviruses (types 1 to 8) in vitro were investigated. While 18 compounds were ineffective, 2 compounds, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA] and 9-[(2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]guanine P-oxide (2'-nor-cyclic GMP), were highly effective against all adenovirus types assayed in human embryonic fibroblast cultures. Their 50% inhibitory doses were 1.1 microgram/ml for (S)-HPMPA and 4.1 micrograms/ml for 2'-nor-cyclic GMP. They were nontoxic for the host cells at the effective antiviral doses.
Single-dose ciprofloxacin at 100 versus 250 mg for treatment of uncomplicated urinary tract infections in women
Authors: Garlando F , Rietiker S , Täuber M G , Flepp M , Meier B , Lüthy R
Published: June 2012

Two single-dose regimens of ciprofloxacin, 100 and 250 mg, were compared in the treatment of uncomplicated urinary tract infections in women. Cure rates 5 days after therapy did not significantly differ, being 16 of 19 (84%) with the 100-mg dose and 17 of 19 (89%) with the 250-mg dose. Ciprofloxacin was well tolerated.
Acyclovir prophylaxis for herpes simplex virus infection
Authors: Gold D , Corey L
Published: June 2012

ACV is an effective agent for the treatment and prophylaxis of HSV infections in both IC and immunologically normal individuals. The drug is well tolerated in both populations and is not significantly associated with clinical or laboratory toxicities. Because of the great potential benefit and low risk, organ transplant recipients and patients with hematologic malignancies undergoing induction chemotherapy should be screened routinely for HSV antibodies; seropositive individuals should receive prophylactic ACV during the period of most profound immunosuppression. Immunologically normal individuals with frequently recurring genital HSV or serious complications associated with outbreaks are candidates for long-term suppression with ACV.
Norfloxacin versus thiamphenicol for treatment of uncomplicated gonorrhea in Rwanda
Authors: Bogaerts J , Martinez Tello W , Verbist L , Piot P , Vandepitte J
Published: June 2012

In an open prospective study, single oral doses of norfloxacin (800 mg) and thiamphenicol (2.5 g) were used to treat, respectively, 122 and 46 consecutive patients with uncomplicated gonorrhea. Neisseria gonorrhoeae was eradicated from 119 (97.5%) patients treated with norfloxacin and from 35 (76.0%) patients treated with thiamphenicol. Norfloxacin treatment failure was not related to drug resistance or to insufficient absorption of the drug. Thiamphenicol failure correlated with low in vitro susceptibility of the infecting strain. In a single oral dose of 800 mg, norfloxacin appeared to be an excellent alternative treatment regimen for uncomplicated gonorrhea in an area with a high prevalence of penicillin-resistant gonococci.
Activity of A-56268 compared with that of erythromycin and other oral agents against aerobic and anaerobic bacteria
Authors: Chin N X , Neu N M , Labthavikul P , Saha G , Neu H C
Published: June 2012

A-56268 was compared with erythromycin, roxithromycin (RU 28965), and perorally administered antimicrobial agents. Its in vitro activity was similar to that of erythromycin and slightly greater than that of roxithromycin, with beta-hemolytic streptococci and Streptococcus pneumoniae inhibited by less than 2 micrograms of A-56268 per ml (50% inhibited by 0.06 microgram/ml). Streptococcus pyogenes, S. agalactiae, S. Pneumoniae, and S. faecalis resistant to erythromycin were resistant to A-56268, and 4 micrograms/ml inhibited 90% of Haemophilus influenzae isolates.