bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental pharmacokinetics of moxalactam
Authors: Reed M D , Aronoff S C , Myers C M , Husak M P , Bertino J S , Blumer J L
Published: June 2012

A pharmacokinetic evaluation of moxalactam was performed with 30 infants and children with documented or suspected bacterial infections arising outside the central nervous system. Each child received 50 mg of moxalactam per kg infused intravenously over a period of 15 min every 8 h. A total of 26 children were studied after receiving the first dose; 20 of these, along with 4 additional patients, were evaluated after receiving continuous therapy for at least 3 days. After the first dose, the elimination half-life, apparent volume of distribution, and plasma clearance averaged 1.59 h, 0.331 liter/kg, and 100.9 ml/min per 1.73 m2, respectively. The biodisposition of the moxalactam epimers was also evaluated, with similar overall results. No differences in pharmacokinetic parameters were observed when the first-dose values were compared with those obtained at the steady state. Age-dependent changes in moxalactam elimination were observed for children of less than or equal to 1 year of age, suggesting that a dosage reduction may be necessary for children of less than or equal to 2 months of age.
Comparison of ketoconazole, Bay N7133, and Bay L9139 in the treatment of experimental vaginal candidiasis
Authors: Sobel J D , Muller G
Published: June 2012

The efficacies of ketoconazole and two new imidazole preparations, Bay N7133 and Bay L9139, were compared in a rat model of experimental candida vaginitis. With a dosage regimen of 10 mg/kg by gavage for 5 days, the cure rate for ketoconazole was 96% as compared with rates of 23 and 29% for Bay N7133 and Bay L9139, respectively (P less than 0.001). Follow-up vaginal cultures at 30 days revealed a relapse in only 1 of 27 rats treated with ketoconazole. Our subsequent experiment in which ketoconazole regimens of 10 mg/kg were compared with Bay N7133 and Bay L9139 regimens of 25 mg/kg demonstrated cure rates of 100, 15, and 82% for the respective agents.
Efficacy of BRL 25000 against Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii in urinary tract infections
Authors: Nakazawa H , Hashimoto T , Nishiura T , Mitsuhashi S
Published: June 2012

Synergism between amoxicillin and clavulanic acid was not expected against cephalosporinase-producing bacterial strains because clavulanic acid has little inhibitory action on cephalosporinases. However, in a clinical trial of BRL 25000 (amoxicillin-clavulanic acid), excellent results were obtained in complicated urinary tract infections caused by Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii strains which produced cephalosporinase and were highly resistant to amoxicillin alone. The good clinical efficacy of BRL 25000 in such urinary tract infections was probably due to the fact that the urinary concentration of clavulanic acid was higher than its minimal inhibitory concentrations for these strains.
Effect of N, N'-dicyclohexylcarbodiimide and nigericin on Staphylococcus aureus susceptibility to gentamicin
Authors: Mandel L J , Eisenberg E S , Simkin N J , Miller M H
Published: June 2012

The abilities of the H+-ATPase inhibitor N, N'-dicyclohexylcarbodiimide and the antibiotic ionophore nigericin to enhance the bactericidal effect of subinhibitory concentrations of gentamicin in two strains of Staphylococcus aureus were studied. Each compound significantly increased both gentamicin uptake and killing. The use of agents which alter the plasma membrane energy state is a novel approach to enhance the activity of conventional antibiotics.
In vitro activity of rodogyl against putative periodontopathic bacteria
Authors: Quee T C , Roussou T , Chan E C
Published: June 2012

The minimal inhibitory concentrations of Rodogyl (composite tablet of metronidazole and spiramycin), metronidazole-spiramycin mixture, spiramycin, metronidazole, and tetracycline were determined for selected putative periodontopathic microorganisms. Rodogyl was active against almost all strains, including Bacteroides species and the anaerobic spirochetes. Synergism of the component drugs in the Rodogyl combination was noted against Propionibacterium species. Spiramycin activity against Actinomyces species was enhanced in the presence of metronidazole.
Diethylcarbamazine citrate, an antifilarial drug, stimulates human granulocyte adherence
Authors: King C H , Greene B M , Spagnuolo P J
Published: June 2012

Incubation with diethylcarbamazine citrate caused significant augmentation of human neutrophil and eosinophil adherence to tissue culture plastic. This effect was dose dependent and cell dependent, with eosinophils showing greater sensitivity and a greater adhesive response to the drug than did neutrophils. Eosinophils preincubated with diethylcarbamazine citrate demonstrated decreased adhesive responses to other adherence-augmenting stimuli. Use of Fc-treated plastic augmented diethylcarbamazine citrate-stimulated neutrophil (but not eosinophil) adherence. Direct stimulation of host effector cell adherence may explain, in part, the therapeutic action of diethylcarbamazine citrate in vivo.
Antibacterial activity of DL 473, a C3-substituted rifamycin derivative
Authors: Neu H C
Published: June 2012

DL 473 is a 3-[(4-cyclopentyl-1-piperazinyl)iminomethyl] rifamycin SV derivative which inhibited staphylococci, streptococci (including Streptococcus faecalis, Listeria species, and Bacteroides species. DL 473 was less active than rifampin against these species. DL 473 did not inhibit Enterobacteriaceae nor most Pseudomonas species. A combination of DL 473 and vancomycin or nafcillin tested against staphylococci was primarily additive and antagonism was not encountered.
Correlation of in vitro time-kill curves and kinetics of bacterial killing in cerebrospinal fluid during ceftriaxone therapy of experimental Escherichia coli meningitis
Authors: Decazes J M , Ernst J D , Sande M A
Published: June 2012

Ceftriaxone was highly active in eliminating Escherichia coli from the cerebrospinal fluid of rabbits infected with experimental meningitis. However, concentrations equal to or greater than 10 times the minimal bactericidal concentration had to be achieved to ensure optimal efficacy (rate of kill, 1.5 log10 CFU/ml per h). In contrast to other beta-lactams studied in this model, ceftriaxone concentrations in cerebrospinal fluid progressively increased, whereas serum steady state was obtained by constant infusion. The percent penetration was 2.1% after 1 h of therapy, in contrast to 8.9% after 7 h (P less than 0.001). In vitro time-kill curves done in cerebrospinal fluid or broth more closely predicted the drug concentrations required for a maximum cidal effect in vivo than that predicted by determinations of minimal inhibitory or bactericidal concentrations.
Stability of gentamicin, tobramycin, and amikacin in combination with four beta-lactam antibiotics
Authors: Glew R H , Pavuk R A
Published: June 2012

The stability of the aminoglycosides gentamicin, tobramycin, and amikacin stored in combination with carbenicillin, piperacillin, cefotaxime, and moxalactam was evaluated at four temperatures (25, 4, -8, and -70 degrees C) over a 3-week period. Amikacin was the most stable of the aminoglycosides and demonstrated no loss of activity when stored with either carbenicillin or piperacillin. Gentamicin and tobramycin were inactivated by carbenicillin and piperacillin at 25 and 4 degrees C, with aminoglycoside activity declining substantially after 8 to 48 h of storage; virtually no loss of gentamicin or tobramycin activity occurred with storage at -8 or -70 degrees C. Cefotaxime and moxalactam produced no degradation of any of the three aminoglycosides.
Comparative in vitro activities of ten antimicrobial agents against bacterial enteropathogens
Authors: Carlson J R , Thornton S A , DuPont H L , West A H , Mathewson J J
Published: June 2012

The in vitro susceptibilities of 50 strains of Salmonella spp., 80 strains of Shigella spp., and 50 enterotoxigenic Escherichia coli, 14 Yersinia enterocolitica, 6 Aeromonas hydrophila, 4 Plesiomonas shigelloides, 9 Vibrio parahaemolyticus, and 30 Campylobacter jejuni strains that were recently isolated from worldwide sources were determined for 10 antimicrobial agents. The antimicrobial agents tested included ampicillin, bicozamycin, doxycycline, enoxacin (CI-919), erythromycin, furazolidone, amdinocillin, norfloxacin, trimethoprim, and trimethoprim-sulfamethoxazole. Ampicillin resistance occurred frequently in strains of Salmonella and Shigella spp. and enterotoxigenic E. coli strains. The most active agents against all of the bacteria tested were enoxacin and norfloxacin. Furazolidone and amdinocillin were also highly active against the majority of strains. Trimethoprim and trimethoprim-sulfamethoxazole were inhibitory at low concentrations against all test except C. jejuni isolates. The in vitro results of this study confirm the high prevalence of bacterial resistance to ampicillin. However, this work also identifies four antimicrobial agents, enoxacin, furazolidone, norfloxacin, and amdinocillin, that would be appropriate for further testing in clinical trials.
Pharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis
Authors: Cohen D , Appel G B , Scully B , Neu H C
Published: June 2012

The pharmacokinetic parameters of ceftriaxone in eight patients with end-stage renal disease were determined during dialysis and during the interdialysis period. The mean half-life, clearance, and apparent volume of distribution during dialysis were 16 h, 722 ml/h, and 16.7 liters, respectively. During the interdialysis period, the half-life was 14 h, clearance was 739 ml/h, and volume of distributions was 14 liters. Individual variability in plasma concentrations occurred even in patients with apparently normal hepatic function. Based on these parameters, a dose of 1 g every 24 h would yield concentrations in excess of the concentrations needed to inhibit most gram-positive and gram-negative aerobic species.
Novel synergism of two antifungal agents, copiamycin and imidazole
Authors: Uno J , Shigematsu M L , Arai T
Published: June 2012

Copiamycin, a macrocyclic lactone antifungal antibiotic, was found to potentiate the antifungal effect of imidazole compounds, ketoconazole in particular. The potentiation of two nominally fungistatic agents in vitro was substantiated by a marked reduction of the minimum inhibitory and minimum fungicidal concentrations when the drugs were used in combination. The effectiveness of this synergistic combination was also demonstrated in experimental murine candidosis. Evidence is presented to suggest that this combined effect is due, at least in part, to the ionophoretic property of copiamycin. Whereas amphotericin B induces a marked increase in cellular permeability, this antibiotic does not possess the ionophoretic action of copiamycin, indicating that the enhancement of copiamycin activity and significant reduction of amphotericin B activity by ketoconazole pretreatment can be ascribed not only to changes in membrane permeability of the test organisms, but also to the different action mechanisms of copiamycin and amphotericin B. It is thus plausible that the strong synergism of copiamycin with imidazole compounds is related to the ionophoretic activity of the antibiotic. Further studies on the biochemical mechanism of this synergistic effect are being conducted together with an assessment of the clinical significance of this drug combination.
Antibacterial activity of norfloxacin in the gastrointestinal tracts of rats
Authors: Frimodt-Møller P C , Jensen K M , Madsen P O
Published: June 2012

The capacities of norfloxacin (MK-0366) and neomycin to reduce the numbers of bacteria in the gastrointestinal tracts of rats were evaluated. Results of a 3-day treatment with norfloxacin were compared with those of a 3-day treatment with neomycin. Both drugs significantly decreased gram-negative and gram-positive bacteria. Norfloxacin effected a significantly greater reduction in numbers of gram-negative bacteria than did neomycin. Norfloxacin also significantly increased the number of anaerobic bacteria. Although neomycin reduced gram-positive bacteria more effectively than did norfloxacin, this difference between the two drugs was not significant. Norfloxacin merits further study for potential as a bowel sterilant.
In vitro activity of ciprofloxacin (Bay o 9867)
Authors: Fass R J
Published: June 2012

The in vitro activities of ciprofloxacin (Bay o 9867) and seven comparative antimicrobial agents against 664 aerobic and facultatively anaerobic bacterial isolates were studied. Minimal inhibitory concentrations (MICs) of ciprofloxacin were less than or equal to 2 micrograms/ml for Enterobacteriaceae, less than or equal to 8 micrograms/ml for nonfermentative gram-negative bacilli, less than or equal to 4 micrograms/ml for gram-positive cocci, less than or equal to 0.03 micrograms/ml for Aeromonas hydrophila and Pasteurella multocida, and less than or equal to 1 microgram/ml for Listeria monocytogenes. MICs for multi-drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa were less than or equal to 4 micrograms/ml. Ciprofloxacin MICs were consistently 0 to 4 (usually 2 to 3) dilution steps lower than those of a related drug, norfloxacin (P less than 0.0001). For most species, they were lower than MICs of cefotaxime, aztreonam, theinamycin, mezlocillin, trimethoprim-sulfamethoxazole, and amikacin. With all eight drugs, increasing the inoculum size by 100-fold had a variable effect on MICs which was species related. Ciprofloxacin is a potent broad-spectrum new antimicrobial agent.
Effect of azlocillin on uric acid levels in serum
Authors: Ernst J A , Sy E R
Published: June 2012

Uric acid levels in serum were observed to fall precipitously in a group of 20 hospitalized asthmatic patients receiving azlocillin, bronchodilators, and steroids. None of the 20 hospitalized controls receiving the antiasthma therapy without azlocillin showed any decline in their uric acid levels. The levels for the azlocillin-treated group fell from a mean of 6.4 mg/dl to mean of 2.3 mg/dl, whereas those for the control group initially were 7.0 mg/dl and fell only to a mean of 6.5 mg/dl.
Lack of efficacy of AMP against recrudescent genital herpes infections in guinea pigs
Authors: Fraser-Smith E B , Smee D F , Matthews T R
Published: June 2012

AMP was evaluated for its efficacy against herpes simplex virus type 2 genital infections in guinea pigs. Vaginally infected animals were treated twice a day with AMP at 50 mg/kg per dose for 2 weeks. Subcutaneous doses were started 10 weeks postinfection. AMP treatment did not reduce the number of animals with recrudescent episodes when compared with saline-treated controls. In addition, AMP treatment did not reduce either the number of lesions or the duration of the recrudescent episodes which did develop. These results suggest that AMP has no effect on recrudescent herpes simplex virus type 2 vaginal infections.
Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with Plasmodium cynomolgi in rhesus monkeys
Authors: Schmidt L H
Published: June 2012

Evaluation of 200 8-aminoquinolines for the capacities to effect radical cure of infections with sporozoites of Plasmodium cynomolgi in rhesus monkeys led to identification of 34 derivatives with activity equal or superior to that of primaquine and to characterization of substituents on the quinoline nucleus and side chain that favored or prejudiced curative activity. Of the 34 derivatives, 19 were as active as primaquine, 9 were twice as active, and 6 were four times as active. With respect to nuclear substituents, all were methoxy substituted at position 6; 24 had one and 10 had two additional substituents. The additions with most favorable impact on activity included methyl substituents at positions 4 and 2 and alkoxy, fluoro, and a group of 3- or 4-substituted phenoxy substituents at position 5. With respect to 8-amino substituents, 14 of the 15 derivatives more active than primaquine, and 13 of the 19 as active as primaquine, carried a branched alkyl chain, four to five carbons in length, between the 8- and terminal amino groups. Proximity of branching to the 8-amino group could be an important determinant of curative activity; however, the effect of such branching was not predictable. All 15 derivatives more active than primaquine and a substantial fraction of those comparable to primaquine in activity have sufficient structural novelty to merit evaluation for tolerability and radical curative activity in humans, with reasonable prospects that one or more would be better tolerated than primaquine and superior to this drug for cure of Plasmodium vivax infections.
Genetic and enzymatic basis of hygromycin B resistance in Escherichia coli
Authors: Rao R N , Allen N E , Hobbs J N , Alborn W E , Kirst H A , Paschal J W
Published: June 2012

A plasmid conferring resistance to the aminocyclitol antibiotic hygromycin B was isolated from Escherichia coli. The gene conferring resistance to this drug was cloned in pBR322, and the gene was localized to a fragment of ca. 1,510 base pairs. Resistance to hygromycin B is determined by an aminocyclitol phosphotransferase that modifies hygromycin B and structurally related antibiotics. The specific modification of hygromycin B is a phosphorylation of the hydroxyl on the 4 position of the cyclitol ring (hyosamine). The presence of the phosphotransferase in E. coli correlates with reduced accumulation of [14C]hygromycin B.
High-pressure liquid chromatographic quantitation of azlocillin
Authors: Weber A , Opheim K E , Wong K , Smith A L
Published: June 2012

We describe a rapid, precise, and simple procedure for the quantitation of azlocillin in serum and in aqueous solutions by high-pressure, reverse-phase liquid chromatography. This method uses a single precipitation step, detection by dual-wavelength monitoring (220 and 254 nm), and quantitation by comparison with an internal standard. The 10-micron C18 muBondapak column was eluted with 45% (vol/vol) methanol-65% (vol/vol) phosphate buffer. The precision was 4.2 and 5.6% at 50 and 10 micrograms/ml, respectively. The assay was linear up to concentrations of 100 micrograms/ml, with recoveries of 90.4 to 110.5% from serum. The assay was sensitive to 0.4 micrograms of azlocillin per ml. The short turnover time (14 min) and small serum sample size (20 microliters) make the assay ideal for therapeutic drug monitoring and clinical pharmacokinetic studies.
Subinhibitory concentrations of antibiotics alter fibronectin binding to Staphylococcus aureus
Authors: Proctor R A , Olbrantz P J , Mosher D F
Published: June 2012

Fibronectin, a high-molecular-weight glycoprotein, is found in plasma and on mammalian cell surfaces. Recent reports have suggested that bacterial-fibronectin interactions play a role in bacterial attachment to host cells. Subinhibitory concentrations of lincosamines, erythromycin, and chloramphenicol decreased fibronectin binding to Staphylococcus aureus, whereas beta-lactam antibiotics enhanced this interaction.
Interaction of cefotaxime and aminoglycosides against enterococci in vitro
Authors: Elliott A M , Karam G H , Cobbs C G
Published: June 2012

The antibacterial activities of cefotaxime, gentamicin, tobramycin, and amikacin as well as the combinations of cefotaxime and aminoglycosides were tested against 50 strains of enterococci. Synergy studies were performed by the time-kill method, and with this technique the combination of cefotaxime plus gentamicin appeared to be more active than the combination of cefotaxime plus tobramycin or cefotaxime plus amikacin. Results of this in vitro study suggest cefotaxime and gentamicin may provide some activity against enterococci, although not sufficient to substitute for proven therapy such as penicillin-ampicillin and gentamicin.
Effect of ketoconazole and amphotericin B on encapsulated and non-encapsulated strains of Cryptococcus neoformans
Authors: Smith D , McFadden H W , Miller N G
Published: June 2012

Growth inhibition studies were done on an encapsulated and non-encapsulated strain of Cryptococcus neoformans at the minimal inhibitory concentration and one-half the minimal inhibitory concentration of ketoconazole and amphotericin B alone and in combination. Growth of both strains was significantly inhibited by ketoconazole, amphotericin B, and the combined drugs at the minimal inhibitory concentration of each drug over a 5-day period. Calculation of the expected inhibition of growth for both strains with both drugs showed antagonism at 24 h followed by an additive effect and synergy for the remaining 4 days of the assay. Although similar results were obtained for both strains with one-half the minimal inhibitory concentration, an additive effect was observed with the drug combination at 24 h for the encapsulated strain, and an antagonistic effect was observed with the non-encapsulated strain.
Comparison of in vitro activity of FCE 22101, a new penem, with those of other beta-lactam antibiotics
Authors: Wise R , Andrews J M , Danks G
Published: June 2012

The in vitro activity of FCE 22101, a new semisynthetic penem derivative, was compared with that of ceftriaxone, moxalactam, imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK 0787), cefuroxime, ceftazidime, and other beta-lactams, when appropriate, against 472 recent isolates and known beta-lactam-resistant strains. The minimum inhibitory concentrations of FCE 22101 against 90% of the members of the family Enterobacteriaceae, Haemophilus influenzae, Staphylococcus aureus, Lancefield group D streptococci, and Bacteroides spp. were between 0.5 and 4 micrograms/ml. Methicillin-resistant strains of Staphylococcus aureus were susceptible. Ninety percent of the Neisseria gonorrhoeae and Streptococcus pneumoniae strains were susceptible to 0.25 microgram of FCE 22101 per ml. Pseudomonas aeruginosa strains were resistant to FCE 22101 (minimum inhibitory concentration, greater than 128 micrograms/ml). The susceptibility of known, characterized beta-lactamase-producing strains of the Enterobacteriaceae suggested that FCE 22101 is resistant to many beta-lactamases. Generally, FCE 22101 was slightly less active than imipenem, moxalactam, ceftriaxone, and ceftazidime against members of the Enterobacteriaceae and considerably more active than the cephalosporins (including moxalactam) against Staphylococcus aureus. The human serum protein binding of FCE 22101 was about 40%, and human serum had little effect on the activity.
Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine
Authors: Pfeffer M , Gaver R C , Ximenez J
Published: June 2012

Cefatrizine was administered intravenously and orally at dose levels of 250, 500, and 1,000 mg to normal male volunteers in a crossover study. Intravenous pharmacokinetics were dose linear over this range; mean peak plasma concentrations at the end of 30-min infusions were, respectively, 18, 37, and 75 micrograms/ml, total body clearance was 218 ml/min per 1.73 m2, renal clearance was 176 ml/min per 1.73 m2, and mean retention time in the body was 1.11 h. Cumulative urinary excretion of intact cefatrizine was 80% of the dose, and half-lives ranged from 1 to 1.4 h. Steady-state volume of distribution was 0.22 liters/kg. On oral administration, the absolute bioavailabilities of cefatrizine were 75% at 250 and 500 mg and 50% at 1,000 mg. The mean peak plasma concentrations and peak times were, respectively, 4.9, 8.6, and 10.2 micrograms/ml at 1.4, 1.6, and 2.0 h, mean residence times were 2.4, 2.6, and 3.1 h, and mean absorption times were 1.3, 1.6, and 1.9 h. Oral renal clearance and half-life values corresponded well to the intravenous values. Cumulative urinary excretion of intact cefatrizine (as percentage of dose) was 60 at 250 mg, 56 at 500 mg, and 42 at 1,000 mg. It is hypothesized that the lack of oral dose linearity between the 500- and 1,000-mg doses is due to a component of cefatrizine absorption by a saturable transport process. Relative absorption at the high dose would be sufficiently slow that an absorption "window" would be passed before maximum bioavailability could be attained. It is not expected that the observed bioavailability decrease at doses exceeding 500 mg will have any therapeutic significance, since clinical studies are establishing efficacy for a recommended unit dosage regimen of 500 mg.
Pharmacokinetics of metronidazole in patients undergoing peritoneal dialysis
Authors: Cassey J G , Clark D A , Merrick P , Jones B
Published: June 2012

After a single 500-mg intravenous dose of metronidazole, plasma and dialysate levels were measured over a 7.5-h period in five patients undergoing peritoneal dialysis for terminal renal failure. Approximately 10% of this dose was removed by dialysis during that period, and therapeutic levels were maintained in plasma. No routine adjustment in the dosage of metronidazole appears necessary in patients undergoing peritoneal dialysis.
Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection
Authors: Spruance S L , McKeough M B , Cardinal J R
Published: June 2012

Inadequate penetration of antiviral agents through the stratum corneum of the skin may be one of the limiting factors in the topical therapy of recurrent cutaneous herpes simplex virus infections in humans. In vitro studies of the penetration of the nucleoside analog acyclovir (ACV) through guinea pig skin demonstrated a marked increase in drug flux when ACV was formulated in dimethyl sulfoxide (DMSO), compared with water or polyethylene glycol (PEG) as the vehicle. To examine whether the increased transcutaneous flux of ACV effected by DMSO was meaningful in vivo, topical 5% ACV in DMSO was evaluated for the treatment of cutaneous herpes simplex virus infection in guinea pigs and compared with topical 5% ACV in PEG. When compared with infection sites treated with the vehicle alone, ACV in DMSO produced a greater percent reduction than did ACV in PEG in median lesion number (8 versus 58%; P less than 0.001), median lesion area (35 versus 73%; P = 0.001), and median lesion virus titer (21 versus 84%; P = 0.08). We conclude that DMSO is a highly effective vehicle for topical administration of ACV and is superior to PEG in our model. Careful choice of vehicle and consideration of transcutaneous penetration may be important for realization of the full potential of topical antiviral therapy in humans.
Phenothiazine compounds inhibit in vitro growth of pathogenic free-living amoebae
Authors: Schuster F L , Mandel N
Published: June 2012

The phenothiazine compounds trifluoperazine dihydrochloride and chlorpromazine hydrochloride have in vitro activity against the pathogenic free-living amoebae Naegleria fowleri, Acanthamoeba culbertsoni, and Acanthamoeba polyphaga. Drug concentrations of 10 microM were amoebastatic; concentrations of 50 microM were either amoebastatic or amoebicidal. Concentrations of 100 microM were generally amoebicidal. The mechanism of drug action is unclear. It may reflect sensitivity of amoeba calcium regulatory protein to the phenothiazine compounds or may be due to the lipophilic action of the drugs on the amoeba plasma membrane. Accumulation of these drugs in the central nervous system makes them potentially useful chemotherapeutic agents in humans for treatment of amoebic meningoencephalitis caused by N. fowleri and Acanthamoeba spp.
In vitro susceptibilities of 40 Campylobacter fetus subsp. jejuni strains to niridazole and metronidazole
Authors: Freydière A M , Gille Y , Tigaud S , Vincent P
Published: June 2012

The activities of niridazole and metronidazole were compared by an agar dilution method against 40 strains of Campylobacter fetus subsp. jejuni of human origin. Niridazole had a markedly higher activity than metronidazole.
Ceftriaxone levels in blood and tissue during cardiopulmonary bypass surgery
Authors: Bryan C S , Morgan S L , Jordan A B , Smith C W , Sutton J P , Gangemi J D
Published: June 2012

One gram of ceftriaxone was given intravenously to 15 patients approximately 2 h before cardiopulmonary bypass surgery. Ceftriaxone levels in plasma (mean +/- standard deviation) were 60.4 +/- 18.8 micrograms/ml (range, 17.0 to 96.0 micrograms/ml) at the beginning of bypass, 44.2 +/- 16.6 micrograms/ml (range, 9.4 to 78.6 micrograms/ml) at the end of bypass, and 19.6 +/- 9.6 micrograms/ml (range, 4.2 to 47.1 micrograms/ml) the following morning, 18.1 to 24.7 h after infusion of ceftriaxone. Concentrations in the sternal bone were 4.7 +/- 2.1 micrograms/g (range, 1.0 to 10.1 micrograms/g; tissue-to-plasma ratios, 0.066 +/- 0.036). Concentrations in the atrial appendage were 7.7 +/- 1.8 microgram/g (range, 3.6 to 10.2 micrograms/g; tissue-to-plasma ratios, 0.143 +/- 0.062). These data suggest that a single dose of ceftriaxone might be useful for prevention of infection due to susceptible pathogens.
Interaction of metronidazole with DNA repair mutants of Escherichia coli
Authors: Yeung T C , Beaulieu B B , McLafferty M A , Goldman P
Published: June 2012

It has been proposed that one of metronidazole's partially reduced intermediates interacts either with DNA to exert a bactericidal effect or with water to form acetamide. To test this hypothesis we have examined the effect of metronidazole on several mutants of Escherichia coli that are defective in DNA repair. UV-susceptible RecA- and UvrB- point mutants have an increased susceptibility to metronidazole as manifested by both a decreased minimal inhibitory concentration and a greater bactericidal response to metronidazole in resting cultures. By these criteria, however, we find that UvrB- deletion mutants, which lack the ability to reduce nitrate and chlorate, are no more susceptible to metronidazole than is the wild type. We find, however, that these deletion mutants also lack the ability to reduce metronidazole and thus possibly to form its reactive species. When metronidazole's bactericidal effect is expressed in terms of the concurrent accumulation of acetamide derived from metronidazole, then all RecA- and UvrB- mutants are killed more efficiently than their wild types. The data are consistent, therefore, with metronidazole's lethal effect being mediated by a partially reduced intermediate on the metabolic pathway between metronidazole and acetamide. Defects in other aspects of the DNA repair system do not confer this increased susceptibility to the proposed intermediate. A Tag- mutant, for example, which is defective in 3-methyl-adenine-DNA glycosylase, does not have this increased susceptibility to the presumed precursor of acetamide. Thus, these results provide further support for the hypothesis that the bactericidal effect of metronidazole is mediated by a partially reduced intermediate in the metabolic conversion of metronidazole to acetamide and suggest that this intermediate interacts with DNA to produce a lesion similar to that caused by UV light.
Pharmacology of Cefuroxime as the 1-acetoxyethyl ester in volunteers
Authors: Harding S M , Williams P E , Ayrton J
Published: June 2012

Cefuroxime axetil is a new orally absorbed prodrug of the antibiotic cefuroxime. The results of pharmacological studies in 52 healthy volunteers are presented. Intact cefuroxime axetil was not detected in the systemic circulation, indicating that deesterification to yield cefuroxime occurs rapidly after absorption. The bioavailability as measured by urinary recovery of cefuroxime was 40 to 50% if the drug was taken after food and 30% if the drug was taken after overnight fasting. Absorption was similar for three different formulations at 500 mg and independent of dose over the range of 250 mg to 1 g. When the drug was taken after food, serum levels and urinary recoveries were significantly greater for cefuroxime than for ampicillin, but when the drug was taken after fasting the values were similar for the two drugs. The kinetic behavior of cefuroxime axetil and ampicillin was not influenced by repeated dosing at 250 mg. Cefuroxime axetil was well tolerated. Although changes in bowel flora and habit were noted during repeated dosing, these changes were no greater than with ampicillin.
Comparison of the effects of mezlocillin, carbenicillin, and placebo on normal hemostasis
Authors: Ballard J O , Barnes S G , Sattler F R
Published: June 2012

Mezlocillin was compared with carbenicillin and 0.9% NaCl as placebo in a double-blind manner to determine its effect in vivo on hemostasis in normal volunteers. Eighteen subjects were randomized to receive mezlocillin, 4 g every 6 h; carbenicillin, 7.5 g every 6 h; or placebo, 50 ml every 6 h, each given for 20 intravenous doses unless the template bleeding time after 10 doses was greater than 15 min. Template bleeding times were determined before the dose 1 and 1 h after doses 10 and 20. Five of six (83%) subjects receiving carbenicillin developed template bleeding time prolongation to greater than 21 min, and two of six (33%) subjects receiving mezlocillin and one of six (17%) subjects receiving carbenicillin had mild template bleeding time prolongations of less than 13 min. Coagulation studies (prothrombin time, partial thromboplastin time, and thrombin time) were normal in all subjects, and blood salicylate levels were negative. Thus, in standard therapeutic doses, mezlocillin was less likely than carbenicillin to prolong the template bleeding time above normal (P = 0.04) and, when prolongation occurred with mezlocillin, it was mild. These data support the selective use of mezlocillin in patients at increased risk for bleeding and who require therapy with an antipseudomonal penicillin.
Homology among arsenate resistance determinants of R factors in Escherichia coli
Authors: Mobley H L , Silver S , Porter F D , Rosen B P
Published: June 2012

Escherichia coli bearing R factors R773 or R46 or hybrid recombinant plasmids carrying the arsenic resistance determinants derived from these plasmids synthesized inducible polypeptides of similar apparent molecular weights when exposed to arsenite salts (R773 derivative, 64,000 and 16,000; R46 derivative, 62,000, 16,500, and 13,500). In addition, both plasmids encoded energy-dependent arsenate efflux systems and demonstrated DNA sequence homology by filter blot hybridization. Human isolates of arsenate- and arsenite-resistant enterobacteria were tested for homology with the arsenate operon of R773 by colony blot hybridization. Approximately one-third of the isolates hybridized strongly, and two-thirds showed little or no evidence of homology, suggesting the presence of two or more genetically distinct arsenate resistant determinants.
Comparative in vitro activities of cefpiramide and apalcillin against anaerobic bacteria
Authors: Wexler H , Carter W T , Harris B , Finegold S M
Published: June 2012

The in vitro activities of two new antimicrobial agents, apalcillin and cefpiramide (SM-1652), were evaluated against 324 strains of anaerobic bacteria. Apalcillin (a penicillin derivative) and cefpiramide (a semisynthetic cephalosporin) were compared with piperacillin, moxalactam, and cefoxitin. Organisms studied included the Bacteroides fragilis group, other Bacteroides species, fusobacteria, clostridia, nonsporeforming gram-positive rods, and anaerobic cocci. Piperacillin was found to be the most active overall, inhibiting 96% of the strains tested at its achievable level in serum (128 micrograms/ml). Apalcillin was comparable in activity to piperacillin, inhibiting 93% of anaerobes tested at this concentration. The other antibiotics inhibited ca. 80% of the strains at 32 micrograms/ml. In terms of activities against particular species, apalcillin was active against 75% of B. fragilis group strains and 97 to 100% of all other anaerobes. Cefpiramide inhibited 37% of B. fragilis group strains at 32 micrograms/ml and 68% at 64 micrograms/ml (a level that may be achievable with this drug). Cefpiramide inhibited 92% of all other anaerobes at 32 micrograms/ml and 95% at 64 micrograms/ml. The clostridia other than Clostridium perfringens were the most resistant (84% inhibited at 32 micrograms/ml and 95% inhibited at 64 micrograms/ml).
Source of methylmalonyl-coenzyme A for erythromycin synthesis: methylmalonyl-coenzyme A mutase from Streptomyces erythreus
Authors: Hunaiti A A , Kolattukudy P E
Published: June 2012

Streptomyces erythreus produces erythromycin, presumably from methylmalonyl-coenzyme A (CoA), which could be generated by the isomerization of succinyl-CoA. In S. erythreus cultures, [1,4-14C,2,3-3H]succinate was incorporated into erythromycin with a doubling of the 3H/14C ratio. This result is consistent with the hypothesis that succinyl-CoA is isomerized to methylmalonyl-CoA before incorporation into the macrocyclic lactone of erythromycin. The presence of methylmalonyl-CoA mutase, which catalyzes this isomerization, was demonstrated in cell-free extracts prepared from this organism. Consistent with the suggested role for this enzyme, methylmalonyl-CoA mutase activity increased over 12-fold at the time of the most rapid antibiotic production, and the activity level drastically declined when the antibiotic production ceased. The mutase was partially purified from this organism with DEAE-cellulose, ammonium sulfate precipitation, and affinity chromatography on a B12-coenzyme Sepharose column. The enzyme was stimulated 2.5-fold by the addition of B12-coenzyme. The enzyme showed a typical Michaelis-Menten type substrate saturation patterns, with KmS of 0.31 mM and 0.09 microM for methylmalonyl-CoA and B12-coenzyme, respectively, and a V of 0.5 mumol/min per mg. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme showed a major band with a molecular weight of 63,000. The properties of this enzyme appear to be fairly similar to those of the mutase previously obtained from other sources.
Increased phagocytosis and killing of Escherichia coli treated with subinhibitory concentrations of cefamandole and gentamicin in isolated rat livers
Authors: Andreana A , Perna P , Utili R , Dilillo M , Ruggiero G
Published: June 2012

Our purpose was to study whether treatment of Escherichia coli with subinhibitory concentrations of either cefamandole or gentamicin could change bacterial susceptibility to the serum bactericidal effect and to the phagocytic and killing activity of the rat liver reticuloendothelial system. Bacteria were grown overnight with 1/5 or 1/10 of the MIC of each antibiotic. At one-fifth of the MIC, cefamandole induced filamentous elongated bacteria whose viability was decreased by 75%. The susceptibility of control and antibiotic-treated bacteria to serum was tested by measuring the survival of organisms exposed to different concentrations of rat serum in vitro. Susceptibility of bacteria to hepatic macrophage activity was tested by following the hepatic clearance of bacteria after they were added to the perfusate of the isolated rat liver. E. coli treated with subinhibitory concentrations of cefamandole or gentamicin appeared somewhat more resistant to the lytic activity of serum at a concentration of 4%, but not at 20%. Bacteria treated with 1/5 or 1/10 of the MIC of cefamandole or with 1/5 of the MIC of gentamicin were significantly more susceptible to phagocytosis and to the bactericidal activity of liver macrophages. Cefamandole appeared more potent than gentamicin in inducing these effects. The results suggest that subinhibitory levels of antibiotics may alter bacterial cell surface (cefamandole) or may impair the expression of antiphagocytic material (gentamicin), thus favoring phagocytosis and killing by macrophages. Our study provides evidence that antibiotics at subinhibitory concentrations may cooperate with host defence mechanisms against bacterial infections.
Inhibition of cellular alpha DNA polymerase and herpes simplex virus-induced DNA polymerases by the triphosphate of BW759U
Authors: St Clair M H , Miller W H , Miller R L , Lambe C U , Furman P A
Published: June 2012

The triphosphate form of the acyclovir analog BW759U (9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine) inhibited the DNA polymerases (EC 2.7.7.7) from several strains of herpes simplex virus type 1. Two acyclovir triphosphate-resistant DNA polymerases were as sensitive to BW759U-triphosphate as were the DNA polymerases induced by wild-type viruses (Ki = 0.05 to 0.1 microM). The Ki value for cellular alpha DNA polymerase was 35- to 50-fold greater than those for the DNA polymerases induced by the various herpes simplex virus strains investigated. Incubation of Vero cells infected by the KOS strain of herpes simplex virus type 1 with the acyclovir analog resulted in the formation of substantial quantities of (9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine) triphosphate.
Comparison of properties of woodchuck hepatitis virus and human hepatitis B virus endogenous DNA polymerases
Authors: Hantz O , Ooka T , Vitvitski L , Pichoud C , Trepo C
Published: June 2012

The principal properties of the DNA polymerases of woodchuck hepatitis virus and human hepatitis B virus were compared. The enzymes of both viruses exhibited optimal activities in the same range of pH, ionic strength, and MgCl2 concentration. Like human hepatitis B virus DNA polymerase, the woodchuck hepatitis virus DNA polymerase was strongly inhibited by phosphonoformic acid but not by phosphonoacetic acid and aphidicolin. Similar inhibition patterns for both enzymes were observed with arabinofuranosyl nucleotides (9-beta-D-arabinofuranosyladenine-5'-triphosphate, 1-beta-D-arabinofuranosylcytosine-5'-triphosphate, 1-beta-D-arabinofuranosylthymine-5'-triphosphate) and dideoxythymidine triphosphate, whereas no effect was obtained with corresponding nucleosides. The therapeutic significance of these results and the relevance of the woodchuck as an experimental animal model for the study of human hepatitis B virus infections are discussed.
Effects of the nucleoside analog 2'-nor-2'-deoxyguanosine on human cytomegalovirus replication
Authors: Tocci M J , Livelli T J , Perry H C , Crumpacker C S , Field A K
Published: June 2012

The nucleoside analog 2'-nor-2'-deoxyguanosine (2'NDG) effectively inhibits the replication of several laboratory and clinical isolates of human cytomegalovirus. These isolates included viruses obtained from congenitally infected infants and patients suffering from acquired immune deficiency syndrome. The dose of 2'NDG that inhibited cytomegalovirus plaque formation ranged from 0.1 to 1.6 micrograms/ml. At 10 micrograms/ml, 2'NDG completely blocked the production of virus progeny but not the expression of immediate early and early virus gene functions. Cytomegalovirus DNA was not detectable in 2'NDG-treated virus-infected human embryo lung cells when assayed by CsCl density gradient centrifugation. In contrast, the guanosine analog acyclovir at 100 micrograms/ml did not inhibit the production of virus or the synthesis of cytomegalovirus DNA. In virus-infected cells, 2'NDG and acyclovir at 10 and 100 micrograms/ml, respectively, inhibited the incorporation of [3H]thymidine and 32Pi into cellular DNA by ca. 50%. Uninfected human embryo lung cells grown in these concentrations of acyclovir or 2'NDG exhibited a slightly transient lag phase but, overall, cell growth was not retarded, and there was no decrease in cell viability. The extended lag in cell division was not due to inactivation or breakdown of the antiviral compounds but may be due in part to a temporary decrease in cellular DNA synthesis.
Role of granulocytes in the prevention and therapy of experimental Streptococcus sanguis endocarditis in rabbits
Authors: Meddens M J , Thompson J , Mattie H , van Furth R
Published: June 2012

The contributions of granulocytes to the prevention and therapy of Streptococcus sanguis endocarditis with procaine benzylpenicillin (PBP) was investigated in rabbits. Depletion of granulocytes by treatment with mechlorethamine appeared to have no significant effect on either the prophylactic or therapeutic activities of PBP. Administration of 3,000 IU of PBP before inoculation with S. sanguis retarded the course of the endocarditis for only 24 h whether granulocytes were normal or depressed in numbers. Prophylaxis with either 15,000 or 30,000 IU of PBP was equally effective in non-granulocytopenic and granulocytopenic rabbits. Treatment of established infections with PBP at doses of 3,000 to 300,000 IU of PBP at 12-h intervals for 48 h was equally effective in rabbits with normal and depressed numbers of granulocytes. The effect of 3,000 IU of PBP was equivalent, however, to that of granulocytes alone, as shown by the fact that the numbers of CFU per gram of vegetation in the granulocytopenic rabbits treated with this dose of PBP and in the non-PBP-treated control rabbits were not significantly different.
Cefuroxime treatment of bacterial meningitis in infants and children
Authors: Sirinavin S , Chiemchanya S , Visudhipan P , Lolekha S
Published: June 2012

Recently, ampicillin- and chloramphenicol-resistant strains of Haemophilus influenzae type b and multiply-resistant Salmonella strains have appeared in some areas of the world. Therefore, alternative drug therapy for infections caused by these organisms is being sought. We used cefuroxime to successfully treat five children with H. influenzae type b meningitis and two children with Salmonella meningitis. Four H. influenzae type b isolates and one Salmonella isolate were resistant to ampicillin, chloramphenicol, and cotrimoxazole. Each of the patients received 200 to 250 mg of cefuroxime per kg per day in four divided doses for 14 to 21 days. The concentrations of cefuroxime in cerebrospinal fluid at 2 h after intravenous 50-mg/kg doses were 6.4 +/- 1.7 (mean +/- standard deviation) and 3.6 +/- 2.2 micrograms/ml on days 2 and 14 of treatment, respectively. The level of drug in cerebrospinal fluid was 1.34 +/- 1.3 micrograms/ml in children without meningitis. The mean cefuroxime concentration in subdural fluid samples from each of three patients was 12.6, 15, and 25.2 micrograms/ml. Cefuroxime is recommended as an alternative drug for the treatment of H. influenzae type b meningitis, but additional information is necessary before cefuroxime can be recommended for therapy of Salmonella meningitis.
Common beta-lactamase-specifying plasmid in Haemophilus ducreyi and Neisseria gonorrhoeae
Authors: Anderson B , Albritton W L , Biddle J , Johnson S R
Published: June 2012

Eighty-nine strains of Haemophilus ducreyi from a chancroid epidemic in Orange County, California, were examined for plasmid content. Seventy-eight (88%) of these isolates were found to contain a plasmid of 3.2 megadaltons which conferred beta-lactamase production. Restriction endonuclease digests indicated that this was the same plasmid that was found in some strains of beta-lactamase-producing Neisseria gonorrhoeae.
Novel carbapenem derivative SF2103A: studies on the mode of beta-lactamase inactivation
Authors: Yamaguchi A , Hirata T , Sawai T
Published: June 2012

A novel carbapenem, SF2103A, is a strong inhibitor of various types of beta-lactamase. Equimolar concentrations of SF2103A completely inactivated the cephalosporinases of Proteus vulgaris and Citrobacter freundii and type Ib and type II penicillinases mediated by R plasmids in a progressive manner. The inactivation of the two penicillinases and P. vulgaris cephalosporinase was apparently irreversible; however, when the inactivated enzymes were separated from excess SF2103A by gel filtration, they showed very slow reactivation. The hydrolysis of SF2103A by these three beta-lactamases was below the limit of detection. It is concluded that SF2103A acts as a tight-binding competitive inhibitor for the penicillinases and P. vulgaris cephalosporinase. In contrast, the inactivation of C. freundii cephalosporinase by SF2103A was evidently reversible. The rate constant of reactivation of the enzyme was compatible with the turnover rate of the enzyme in the steady state of SF2103A hydrolysis. Thus, SF2103A simply acts as a poor substrate for C. freundii cephalosporinase.