bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the bactericidal activity of beta-lactam antibiotics on slowly growing bacteria cultured in the chemostat
Authors: Cozens R M , Tuomanen E , Tosch W , Zak O , Suter J , Tomasz A
Published: June 2012

The bactericidal activity of 23 beta-lactam antibiotics was compared in slowly growing bacteria cultured in a chemostat. In an attempt to mimic possible in vivo conditions, slowly growing cultures were produced by limitation of iron, glucose, phosphate, or magnesium. Only select antibiotics remained effectively bactericidal against slowly growing cells. For these compounds, the rate of antibiotic-induced loss of viability was a constant when killing was expressed per generation (in contrast to absolute time) in that slowly growing bacteria were killed proportionately more slowly. Individual antibiotics differed greatly, however, in their specific bactericidal activities against slowly growing cells, i.e., in the absolute degree of killing elicited during exposure of the bacteria to MIC equivalents of the drugs. Specific bactericidal activities varied not only with drug structure but also with the bacterial strains and, to a lesser extent, with the nature of the growth-limiting nutrient. In slowly growing cultures exposure to the low drug concentrations studied here (near MIC) caused killing without detectable lysis. Antibiotics with high specific bactericidal activities were capable of rapidly killing cultures of slowly growing pathogens despite extremely long generation times approaching those reported for in vivo growth rates.
Properties of the penicillin-binding proteins of four species of the genus Bacteroides
Authors: Piddock L J , Wise R
Published: June 2012

The penicillin-binding proteins (PBPs) of four species of the genus Bacteroides were examined in cell envelope preparations from exponentially growing cultures and intact cells. Upon examination by sodium dodecyl sulfate-polyacrylamide electrophoresis, three major high-molecular-weight PBPs (molecular weight, 58,000 to 82,000) were resolved, and low-molecular-weight PBPs were seen in all strains except Bacteroides fragilis. The sporadic appearance of PBP 4 in B. fragilis (molecular weight, approximately 45,000) was shown not to be influenced by the concentration of free iron available in the medium or by the stage of growth at which the batch culture was harvested. No PBP that was inhibited by an aerobic environment was demonstrated. The affinity of 35 beta-lactam antibiotics for the PBPs from envelope preparations was examined and correlated with the morphological response. Most compounds bound initially to PBP 2 and then PBP 1, correlating with a primary response of filamentation and then spheroplasting and lysis. Compounds such as clavulanic acid bound to PBP 3 at concentrations causing round cells. Based on the data from this study, it is proposed that the three high-molecular-weight PBPs of Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides ovatus correlate to the three high-molecular-weight PBPs of Escherichia coli and that the PBPs of Bacteroides species perform the same enzymic role in cell wall biosynthesis as their counterparts in E. coli. Therefore, the components of PBP 1 are involved in cell elongation, PBP 2 is involved in septum formation, and PBP 3 is involved in maintenance of cell shape (i.e., PBP 2 in Bacteroides spp. = PBP 3 in E. coli, and PBP 3 in Bacteroides spp. = BPB 2 in E. coli).
Penetration of ceftriaxone into human pleural fluid
Authors: Benoni G , Arosio E , Cuzzolin L , Vaona B , Raimondi M G , Lechi A
Published: June 2012

The pharmacokinetics of ceftriaxone were studied for seven patients with pleural effusion of various etiologies. All patients received 1 g of antibiotic, administered as an intravenous bolus. The pleural fluid had a high total protein content (6.0 g/dl). Ceftriaxone levels in plasma and in pleural fluid were determined by the agar well diffusion technique. Total and free drug concentrations in pleural fluid reached 7 to 8.7 and 3.8 to 2.3 micrograms/ml, respectively, in 4 to 6 h. The disappearance of the drug from the pleural fluid was very slow. In these patients, therapeutic ceftriaxone levels were present for at least 53 h in pleural fluid.
Transfer of beta-lactamase-associated cefoxitin resistance in Bacteroides fragilis
Authors: Cuchural G J , Tally F P , Storey J R , Malamy M H
Published: June 2012

A cefoxitin-resistant Bacteroides fragilis isolate, TAL 4170, which inactivates cefoxitin, was able to transfer beta-lactamase-mediated cefoxitin resistance to a susceptible B. fragilis recipient. Cefoxitin-resistant transconjugants acquired a new beta-lactamase with a pI of 8.1 and were able to inactivate cefoxitin and retransfer cefoxitin resistance. No plasmids were detected in the donor or transconjugants.
Antibacterial activity of niridazole against Salmonellae
Authors: Bannatyne R M , Jackowski J , Grant R B
Published: June 2012

Fifty-six strains, representing eight species of salmonellae of diverse geographic origin and possessing a variety of antimicrobial resistance profiles, were tested for susceptibility to niridazole by the agar dilution method. Calculated MICs for 50 and 90% of strains were 4.8 and 16.0 mg/liter, respectively, with a susceptibility range of 0.25 to 32 mg/liter. No obvious species differences were noted. Niridazole was found to be rapidly and powerfully bactericidal. No significant difference was detected between MICs and MBCs. Except for a strain-dependent effect with a subset of multiply resistant salmonella isolates, no inoculum effect was demonstrated.
Antimicrobial spectrum of Ro 15-8074/001, a new oral cephalosporin
Authors: Thomas M G , Lang S D
Published: June 2012

The activity of Ro 15-8074/001 was compared with that of cefaclor, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, norfloxacin, and ceftriaxone against 225 clinical isolates. It was more active than cefaclor, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole against members of the family Enterobacteriaceae and Haemophilus influenzae and had activity similar to that of cefaclor against nonenterococcal streptococci. It was not usefully active against Pseudomonas aeruginosa, Streptococcus faecalis, or most isolates of staphylococci.
Effect of amiloride on the intracellular sodium and potassium content of intact Streptococcus faecalis cells in vitro
Authors: Giunta S , Galeazzi L , Turchetti G , Sampaoli G , Groppa G
Published: June 2012

Amiloride at millimolar concentrations caused marked changes in the growth-dependent intracellular balance of Na+ and K+ in Streptococcus faecalis. These results, whether specific to transport processes or resulting from indirect yet unknown mechanisms, constitute the first evidence of an effect of amiloride on bacterial electrolytes.
Bactericidal activity of ciprofloxacin against amikacin- and cefotaxime-resistant gram-negative bacilli and methicillin-resistant staphylococci
Authors: Simberkoff M S , Rahal J J
Published: June 2012

The MICs and MBCs of ciprofloxacin were determined for clinical isolates of antibiotic-resistant aerobic bacteria. Decreased susceptibility to ciprofloxacin of cefotaxime- and amikacin-resistant Serratia marcescens and amikacin-resistant Pseudomonas aeruginosa strains were noted. The data suggest that ciprofloxacin susceptibility should be carefully monitored in treating patients with hospital-acquired bacterial infections.
Single-dose tioconazole compared with 3-day clotrimazole treatment in vulvovaginal candidiasis
Authors: Stein G E , Gurwith D , Mummaw N , Gurwith M
Published: June 2012

A total of 80 patients were equally randomized to receive a single dose of 6.5% tioconazole ointment or a 3-day course of 100-mg clotrimazole vaginal tablets for the treatment of vulvovaginal candidiasis. Of the 32 evaluable patients treated with tioconazole, 27 (84%) remained asymptomatic 4 weeks posttreatment, compared with 28 of 33 patients (85%) treated with clotrimazole. A total of 34 patients in each group could be evaluated for mycological response based on culture results 1 and 4 weeks after treatment. Twenty patients (59%) who received tioconazole and twenty-one patients (62%) who received clotrimazole remained culture negative 4 weeks after therapy. Of 40 patients who received tioconazole, 12 (30%) experienced local irritation or itching, compared with 2 of 40 patients (5%) treated with clotrimazole (P less than 0.01). Single-dose tioconazole ointment was as effective as a 3-day course of clotrimazole tablets, but significantly more patients in the tioconazole-treated group experienced local side effects.
Anticandidal activities of terconazole, a broad-spectrum antimycotic
Authors: Tolman E L , Isaacson D M , Rosenthale M E , McGuire J L , Van Cutsem J , Borgers M , Van den Bossche H
Published: June 2012

Terconazole is a new triazole ketal derivative with broad-spectrum in vitro and in vivo antifungal activities. This study further characterizes the effects of terconazole in vitro on yeast cell growth, viability, and morphology. Terconazole inhibited the growth of Candida albicans ATCC 44859 in a concentration-related manner, but with modest effects noted at levels from 10(-8) to 10(-5) M when the yeast was grown on media favoring the cell form. The inhibitory potency of terconazole on yeast cell viability varied with the strain and species of Candida tested. The susceptibility of C. albicans ATCC 44859 to terconazole was markedly enhanced when the yeast was grown on Eagle minimum essential medium, which favors mycelium formation. The effects of terconazole on the morphology of yeast cells (grown on Eagle minimum essential medium) were shown by phase-contrast and electron microscopy. There is a progression of changes, from loss of mycelia formation at 10(-8) M terconazole through complete necrosis at 10(-4) M.
Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug
Authors: Fox M P , Otto M J , McKinlay M A
Published: June 2012

WIN 51711, a potent new antipicornavirus drug, has been shown to inhibit an early event in the replication cycle of human poliovirus type 2 and human rhinovirus type 2. WIN 51711 was not virucidal and had no measurable effect on the adsorption of [3H]uridine-labeled virions to cells. When virion penetration of the plasma membrane was determined through loss of sensitivity to neutralizing antisera, WIN 51711 had no effect on poliovirus penetration, but inhibited rhinovirus penetration by 40%. In the presence of WIN 51711, exposure of neutral red-encapsidated virus-infected cells to light at 3 h postinfection resulted in a 3-log reduction in the number of infectious centers, indicating that WIN 51711 maintained the viral RNA in the encapsidated state after penetrating the cell membrane. The inhibition of uncoating by WIN 51711 in the neutral red assay was found to be concentration dependent, with a concentration of 0.03 micrograms/ml resulting in a 90% inhibition of uncoating. Sucrose gradient sedimentation of lysates from whole cells infected with [3H]uridine-labeled poliovirus showed that poliovirions remained intact in the presence of WIN 51711, but were uncoated in the absence of drug. WIN 51711 also prevented thermal inactivation of poliovirus infectivity, indicating a direct stabilizing effect of this compound on virion capsid conformation.
Metabolism of ribavirin in respiratory syncytial virus-infected and uninfected cells
Authors: Smee D F , Matthews T R
Published: June 2012

The metabolism of ribavirin to its mono-, di-, and triphosphate derivatives was examined in uninfected and respiratory syncytial virus-infected cells. The degree of phosphorylation was dose dependent upon extracellular ribavirin concentration. The major species formed was the triphosphate, with mono- and diphosphates being approximately 12 and 4% of the triphosphate, respectively. Amounts of triphosphate formed in infected cells were up to 2.6-fold greater than those in uninfected cells. Upon drug removal, ribavirin triphosphate degradation was very rapid, with decay half-lives of 70 to 100 min. Actinomycin D inhibited triphosphate production and also neutralized the antiviral effect of ribavirin.
Disposition of cefotaxime and desacetyl cefotaxime during continuous ambulatory peritoneal dialysis
Authors: Heim K L , Halstenson C E , Comty C M , Affrime M B , Matzke G R
Published: June 2012

The disposition of cefotaxime (CTX) and desacetyl cefotaxime (DAC) was studied in eight noninfected patients on continuous ambulatory peritoneal dialysis. Each patient received a single intravenous (i.v.) infusion and an intraperitoneal (i.p.) instillation of 2 g of CTX. Multiple blood and dialysate samples were collected during the 72-h period after drug administration. The half-life, steady-state volume of distribution, and total body clearance of CTX following i.v. administration were 2.2 +/- 1.0 h (mean +/- standard deviation), 0.17 +/- 0.03 liters/kg, and 81.0 +/- 31.0 ml/min, respectively. No significant differences were observed in these parameters after i.p. administration. The continuous ambulatory peritoneal dialysis clearances of CTX and DAC were 1.82 +/- 0.43 and 2.84 +/- 0.70 ml/min, respectively, after i.v. administration. The bioavailability of CTX after i.p. instillation was 74.6 +/- 21.3%. Peak peritoneal dialysate CTX and DAC concentrations of 264.3 and 25.8 mg/liter, respectively, were observed after i.p. dosing. Administration (i.v.) of 2 g every 12 h or i.p. instillation of 2 g every 24 h may be used for the treatment of i.p. infections with highly susceptible organisms (MIC less than 1.0 microgram/ml).
Susceptibility of Eikenella corrodens to newer and older quinolones
Authors: Goldstein E J , Citron D M , Vagvolgyi A E , Gombert M E
Published: June 2012

The susceptibilities of 44 clinical strains and a reference strain (ATCC 23834) of Eikenella corrodens were determined by agar dilution. All isolates were very susceptible (MICs, less than 2 micrograms/ml) to amifloxacin, ciprofloxacin, difloxacin, enoxacin, norfloxacin, ofloxacin, and Win 35439.
Interaction between rifampin and fusidic acid against methicillin-resistant coagulase-positive and -negative staphylococci
Authors: Farber B F , Yee Y C , Karchmer A W
Published: June 2012

We studied the interaction between rifampin and fusidic acid against a group of staphylococci. Of the 20 coagulase-positive strains studied, checkerboard studies revealed synergy in 3 and indifference in 17; time-kill studies revealed synergy in 18 of 19 coagulase-positive strains at both 24 and 48 h. Of the 19 coagulase-negative strains, checkerboard studies revealed synergy in 6 and indifference in 13; time-kill studies revealed synergy in 6 of 18 coagulase-negative strains at 24 h and in 17 of 18 coagulase-negative strains at 48 h. The combination of rifampin and fusidic acid warrants further evaluation in the therapy of staphylococcal disease.
Comparative efficacy of ciprofloxacin and ceftriaxone in experimental arthritis caused by Escherichia coli
Authors: Bayer A S , Norman D C , Blomquist I K
Published: June 2012

Ciprofloxacin was compared with ceftriaxone in a rabbit model of septic arthritis caused by Escherichia coli. Both agents significantly reduced mean E. coli counts in septic joint fluid (P less than 0.0005 versus untreated controls) and also within infected synovial tissue (P less than 0.01 versus controls). Ciprofloxacin regimens caused a higher frequency (P less than 0.05) of synovial tissue sterilization (53%) than did ceftriaxone (25%).
Clinical evaluation of rosoxacin for the treatment of chancroid
Authors: Haase D A , Ndinya-Achola J O , Nash R A , D'Costa L J , Hazlett D , Lubwama S , Nsanze H , Ronald A R
Published: June 2012

One hundred seven men with Haemophilus ducreyi-positive chancroid were assigned to receive 300 mg of rosoxacin as a single dose or 150 mg twice daily for 3 days. Ulcers and buboes were followed clinically and bacteriologically for 1 month. Of 40 evaluable males on the 3-day regimen, 38 (95%) were cured, while only 14 of 23 (61%) males on the single-dose regimen were cured; this regimen was discontinued. There was one ulcer relapse at day 21 in both groups; the one relapse in the single-dose group had a persistent culture-positive bubo. Eight of nine (89%) buboes followed to the endpoint on the 3-day rosoxacin regimen were cured, versus three of six (50%) on the single-dose regimen. Adverse effects were mainly related to the central nervous system but were minor and did not require intervention. None of the treatment failures was due to organisms resistant to rosoxacin, and failure of the single-dose regimen presumably was related to duration of tissue levels rather than to drug resistance. Administration of 150 mg of rosoxacin twice daily for 3 days is an effective regimen for the therapy of chancroid and is a reasonable alternative to other short-course regimens.
In vitro and in vivo studies of the effect of aztreonam on platelet function and coagulation in normal volunteers
Authors: Tartaglione T A , Duma R J , Qureshi G D
Published: June 2012

The in vitro effects of aztreonam on platelet aggregation were compared with those of cefotaxime, moxalactam, piperacillin, and carbenicillin. In addition, the in vivo effects of intravenously administered aztreonam on blood coagulation and platelet function were examined in 10 normal male volunteers in a randomized crossover study. In vitro, at concentrations of greater than 6.25 mM (2.7 mg/ml), aztreonam inhibited ADP-induced platelet aggregation in a dose-dependent manner. The effect was less than that produced by equimolar concentrations of cefotaxime, moxalactam, piperacillin, or carbenicillin. At all concentrations tested, aztreonam and cefotaxime inhibited epinephrine-induced aggregation least. All antibiotics inhibited collagen-induced aggregation, but only at inordinately high concentrations (25 mM). In vivo studies in 10 male subjects, randomly infused intravenously with 2 g of aztreonam or saline placebo every 6 h for 21 consecutive doses in a single-blind crossover study, revealed no evidence of bleeding or visible adverse side effects. Although plasma coagulation and platelet adhesion remained within normal limits in all subjects throughout the study, inhibition of ADP-induced platelet aggregation significantly (P less than 0.0001) increased on days 3 and 6, but still was below 40%. With the exception of one subject who had a mean template bleeding time of 7.3 min (normal, 2 to 7 min at 95% confidence limits) on day 6 of aztreonam administration, all volunteers exhibited bleeding times within the normal range. No abnormalities in platelet morphology were observed. Mean peak serum aztreonam concentrations on days 1 and 6 were 90.1 +/- 16.7 and 95.9 +/- 13.7 micrograms/ml, respectively; accumulation did not occur. Thus, in normal volunteers, aztreonam produced no significant recognizable abnormalities of hemostasis after 6 days of maximal recommended doses.
Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers
Authors: Huang Y C , Colaizzi J L , Bierman R H , Woestenborghs R , Heykants J
Published: June 2012

Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 micrograms/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+/- 82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (+/- 68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (+/- 33.5) and 89.0 (+/- 23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension of the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400- and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.
In vitro activity of ketoconazole against herpes simplex virus
Authors: Pottage J C , Kessler H A , Goodrich J M , Chase R , Benson C A , Kapell K , Levin S
Published: June 2012

The effects of ketoconazole alone and in combination with acyclovir and adenine arabinoside upon the replication of herpes simplex virus types 1 and 2 (HSV-1 and -2) were investigated by using a yield reduction assay. Ketoconazole demonstrated antiviral activity against HSV-1 and -2 and synergistic antiviral activity when it was combined with acyclovir. Combinations of ketoconazole with adenine arabinoside resulted in either interference or indifference. The effects of ketoconazole upon the protein synthesis of HSV-2-infected cells were also determined in an effort to define the mechanism of action for the antiviral activity of ketoconazole. There was no reduction of HSV proteins when compared with acyclovir. These findings suggest that further investigations of the use of ketoconazole for the treatment of HSV infections are warranted.
Action of lombazole, and inhibitor of fungal ergosterol biosynthesis, on Staphylococcus epidermidis
Authors: Barug D , Bastiaanse H B , van Rossum J M , Kerkenaar A
Published: June 2012

Lombazole had no effect on respiration at any tested concentration and had little effect on the K+ permeability of Staphylococcus epidermidis. Of the major metabolic processes investigated in this bacterium, only de novo synthesis of the cell envelope was inhibited by lombazole well in advance of an effect on growth. The time course of inhibition indicated that lombazole exerted its primary effect via inhibition of lipid synthesis; other induced changes, such as reduced synthesis of lipoteichoic acid and cell wall components, were considered to be secondary effects. Although the precise site of action in S. epidermidis has to be established, the absence of alterations in lipid patterns after treatment with lombazole suggests the toxicant may affect an essential step in lipid biosynthesis. In Candida albicans, lombazole inhibited the sterol C-14 demethylation step in the ergosterol biosynthesis pathway.
Rate of bactericidal activity for Streptococcus faecalis of a new quinolone, CI-934, compared with that of amoxicillin
Authors: Yourassowsky E , Van der Linden M P , Lismont M J , Crokaert F , Glupczynski Y
Published: June 2012

The rate of bactericidal activity of a new quinolone, CI-934, was compared with that of amoxicillin for 20 strains of Streptococcus faecalis. At 10 and 100 micrograms/ml, the bactericidal activity of CI-934 was more rapid at 6 h than that of amoxicillin. A paradoxical effect (a killing rate higher at 1 microgram/ml than at 100 micrograms/ml at 6 h) was observed for 19 of the 20 strains with amoxicillin and for 1 of the 20 strains with CI-934. It remains to be demonstrated whether in vivo studies will confirm the results obtained in vitro.
Therapy of experimental cerebral nocardiosis with imipenem, amikacin, trimethoprim-sulfamethoxazole, and minocycline
Authors: Gombert M E , Aulicino T M , duBouchet L , Silverman G E , Sheinbaum W M
Published: June 2012

A mouse model of cerebral nocardiosis was used to determine relative antibiotic efficacy by reducing bacterial colony counts per gram of brain tissue. The antimicrobial agents employed were demonstrated in vitro to be inhibitory to most strains of Nocardia asteroides at very low concentrations. The agents used in this study were imipenem-cilastatin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Antibiotics were administered every 4 h for 72 h before animal sacrifice. Bacterial colony counts were assayed at various time points before the completion of therapy. Imipenem-cilastatin and amikacin were the most effective agents tested. Trimethoprim-sulfamethoxazole was less effective than imipenem and amikacin but more effective than minocycline. Minocycline did not eradicate intracerebral organisms and was similar to saline (control) in its effects.
Pharmacokinetics of a new quinolone, AM-833, in mice, rats, rabbits, dogs, and monkeys
Authors: Kusajima H , Ishikawa N , Machida M , Uchida H , Irikura T
Published: June 2012

The pharmacokinetics of AM-833 [6,8-difluoro-1-(2-fluoroethyl)-1, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid] were studied in mice, rats, rabbits, dogs, and monkeys by reversed-phase high-performance liquid chromatography. AM-833 was rapidly and completely absorbed from the digestive tracts of mice, rats, and dogs. About half of AM-833 bound to rat and dog serum proteins. Drug levels in lung, spleen, liver, and kidney tissues of rats and dogs were greater than the respective levels in serum but lower in brain tissue. Drug levels in tissues declined with the decrease in levels in serum. AM-833 penetrated rapidly and well into inflammatory exudate of rats. Elimination half-lives in serum were species dependent, ranging from 1.57 h in rabbits to 9.42 h in dogs. Profiles of drug levels in serum were dose related over a single dose range from 2 to 40 mg/kg and not modified significantly during multiple dosing in dogs. Unchanged AM-833 was excreted in urine and bile in both rats and dogs. The metabolism of AM-833 was suggested by evidence that 24-h total recovery of unchanged AM-833 in urine and bile accounted for about half of the intravenous dose in rats.
Comparative clinical efficacy of single oral doses of cefuroxime axetil and amoxicillin in uncomplicated gonococcal infections
Authors: Fong I W , Linton W , Simbul M , Hinton N A
Published: June 2012

Cefuroxime axetil (1.5 g) was compared with amoxicillin (3 g), both given as a single oral dose combined with probenecid (1 g) for the treatment of uncomplicated gonorrhea. Of 60 evaluable patients receiving amoxicillin, 55 (91.7%) were cured, whereas 55 (96.5%) of the 57 patients receiving cefuroxime axetil were cured (P greater than 0.1). Both drugs were well tolerated.
In vitro activity of Ro 23-6240, a new difluoroquinolone derivative, compared with that of other antimicrobial agents
Authors: Manek N , Andrews J M , Wise R
Published: June 2012

Ro 23-6240 is a new difluorinated quinolone antimicrobial agent. Its in vitro activity against a wide range of bacteria was compared with those of other quinolones and beta-lactams. Generally, members of the family Enterobacteriaceae were inhibited by low concentrations of Ro 23-6240 (MIC90 [MIC for 90% of isolates tested], less than or equal to 1 microgram/ml). Ninety percent of Staphylococcus aureus (including methicillin-resistant strains) and Neisseria gonorrhoeae isolates were inhibited by 0.5 microgram/ml. Pseudomonas aeruginosa (MIC90, 2 micrograms/ml) and Bacteroides fragilis (MIC90, 4 micrograms/ml) showed intermediate susceptibility, and Streptococcus pneumoniae (MIC90, 8 micrograms/ml) was less susceptible. Strains resistant to nalidixic acid were less susceptible to all the quinolones tested. The protein binding of Ro 23-6240 (5 micrograms/ml) was 27%.
Comparison of cyclacillin and amoxicillin for therapy for acute maxillary sinusitis
Authors: Scheld W M , Sydnor A , Farr B , Gratz J C , Gwaltney J M
Published: June 2012

Cyclacillin, a new aminosalicylic semisynthetic penicillin, was compared with amoxicillin for the therapy of acute bacterial maxillary sinusitis in 80 patients (ages, 12 to 70 years) in a prospective, double-blind, randomized clinical trial. Direct sinus aspirations for quantitative culture were done for all patients before and after 10 days of therapy. Both drugs were administered at a dosage of 500 mg orally three times daily. Among culture-positive patients, clinical cure was achieved in 23 of 26 patients and 25 of 27 patients treated with cyclacillin and amoxicillin, respectively, for an overall cure rate of 91%. Bacteriologic failure occurred in 9% (4 of 44 patients); 3 of the 4 failures were in the cyclacillin group. There was no correlation between clinical or bacteriologic cure and the results of sinus transillumination (clear, dark) at follow-up. Initial direct sinus aspirates were positive in 57 of 80 cases (70%): 25 (44%) of these were the result of Streptococcus pneumoniae and 23 (40%) were the result of Haemophilus influenzae. All of these isolates were susceptible (MIC, less than or equal to 0.5 microgram/ml) to both study drugs; no ampicillin-resistant H. influenzae was recovered. On day 10 of therapy, mean concentrations of both drugs in serum were 2.5 to 2.7 micrograms/ml, but no antibiotic was detectable in 20 of 21 simultaneous sinus aspirates. Adverse effects (rash, diarrhea) were infrequent and similar in both groups. Cyclacillin appears equivalent to amoxicillin in the therapy of acute maxillary sinusitis.
Clinical comparison of piperacillin and cefoxitin in patients with bacteriologically confirmed infections
Authors: McCloskey R V
Published: June 2012

The objective of this double-blind study was to compare the efficacy and safety of piperacillin with that of cefoxitin in patients with bacterial infections. Seventy hospitalized patients were treated with intravenous piperacillin (18 g/day) or cefoxitin (12 g/day) for a mean period of 11.5 days. Multiple serious underlying conditions were present in 91% of the patients in both treatment groups. The infection sites were the respiratory, urinary, and gastrointestinal tracts, the skin and skin structures, and the bones. Among the patients with evaluated courses of therapy, 87% (20 of 23) of the patients in the piperacillin-treated group and 90% (19 of 21) of the cefoxitin-treated patients were cured or improved. Multiple sites of infection were present in 6 patients given piperacillin and in 11 patients given cefoxitin. Gram-negative aerobic bacteria were the most frequently isolated organisms (56% of isolates). In each treatment group, 91% of the pathogens were eradicated. Three piperacillin-treated patients (9%) and four cefoxitin-treated patients (11%) had adverse clinical effects related to therapy; most of the effects were moderate in intensity. In conclusion, both piperacillin and cefoxitin were clinically safe and effective antibiotics for the treatment of these patients, most of whom had severe underlying conditions.
Activity of SM-4470, a new imidazole derivative, against experimental fungal infections
Authors: Ichise K , Tanio T , Saji I , Okuda T
Published: June 2012

The antifungal activity of orally active SM-4470, (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazole-1-yl)-2-propanol hydrochloride, was compared with that of ketoconazole. SM-4470 showed twofold-higher activity than ketoconazole in the oral treatment of systemic infection with Candida albicans in mice. In addition, SM-4470 was effective against aspergillosis in mice, but ketoconazole was ineffective. The efficacy of SM-4470 was similar to that of ketoconazole in curing experimental candidal vaginitis in rats and trichophytosis in guinea pigs, although its serum concentrations in these animals were lower than those of ketoconazole. These data suggest that SM-4470 may be of value in the treatment of both systemic and superficial fungal infections in humans.
Synthesis and antimicrobial activity of a series of caespitin derivatives
Authors: Van der Schyf C J , Dekker T G , Fourie T G , Snyckers F O
Published: June 2012

Chemical modification of the naturally occurring phlorophenone antimicrobial agent caespitin is described. These modifications include variations in the phenone side chain, substitution with prenyl, allyl, and benzyl in the 4-position of the phlorophenone nucleus, and ring cyclizations via etherification to give furan and chroman compounds. Several of these derivatives show enhanced in vitro potency over caespitin. Studies on the development of microbial resistance against these compounds show that no or very little resistance developed after several passes of these compounds in representative microbial strains.
Suppression of scrapie infection in mice by heteropolyanion 23, dextran sulfate, and some other polyanions
Authors: Kimberlin R H , Walker C A
Published: June 2012

Studies of polyanions that suppress scrapie have been done to pinpoint the cell types in the lymphoreticular system which are important in pathogenesis and to suggest possible prophylactic or therapeutic strategies for the unconventional slow viruses. A regime of three daily injections of the inorganic heteropolyanion HPA-23 reduced the effective scrapie dose by more than 99%; i.e., some mice survived peripherally injected doses of 100 50% lethal dose units. The effect was greatest when the first dose of HPA-23 was given 4 h after injecting scrapie, but it declined rapidly as this interval was increased, and there was virtually no effect 2 days after infection. A single dose of high-molecular-weight organic polyanions such as carrageenan or dextran sulfate (DS-500) greatly reduced (i.e., greater than 99%) the efficiency of scrapie infection. In contrast to HPA-23, DS-500 was equally effective whether given 4 days before or 8 h after the time of infection. The antiscrapie effect of DS-500 appeared to be independent of its activity as a B-cell mitogen and of its ability to produce a cytotoxic blockade of phagocytic cells. DS-500 probably caused the aggregation and loss from blood of scrapie inoculum which was present immediately after injection, but it had additional effects on scrapie at later times.
Antimicrobial therapy of experimental endocarditis caused by nutritionally variant viridans group streptococci
Authors: Henry N K , Wilson W R , Roberts R B , Acar J F , Geraci J E
Published: June 2012

Rabbits with nutritionally variant viridans group streptococcal experimental endocarditis were treated three times daily for 3 days with procaine penicillin (1.2 X 10(6) U) alone or together with low-dose streptomycin (2 mg/kg), high-dose streptomycin (8 mg/kg), low-dose gentamicin (0.32 mg/kg), or high-dose gentamicin (1.05 mg/kg). The mean 0.5-h serum concentrations of streptomycin were 5.3 and 22.5 micrograms/ml in the low- and high-dose group, respectively, and the concentrations of gentamicin were 0.7 and 2.5 micrograms in the low- and high-dose groups, respectively. The combination of procaine penicillin with each dose of aminoglycoside was significantly more effective (P less than 0.001) than was procaine penicillin alone. In combination with procaine penicillin, the higher dose of streptomycin was significantly more effective (P less than 0.02) than the lower dose of streptomycin. The higher dose of streptomycin was not significantly more effective than either dose of gentamicin. The results of treatment with the high or low dose of gentamicin were virtually identical.
Efficacy of alcohol-based hand rinses under frequent-use conditions
Authors: Larson E L , Eke P I , Laughon B E
Published: June 2012

Fifty volunteers randomly assigned to one of five hand washing agents (10 subjects per agent)--a nonantiseptic liquid soap (control), an antiseptic hand rinse containing 60% isopropyl alcohol (IPA) with emollients (Alc A), an antiseptic hand rinse containing 70% IPA and 0.5% chlorhexidine gluconate with emollients (Alc B), an antiseptic containing 4% chlorhexidine gluconate and 4% IPA (CHG), and 70% IPA--washed their hands 15 times per day for 5 days under supervision by using a standardized technique and measured amounts of test agent. Microbiologic samples of hand flora were obtained at base line and after hand washes 1 and 15 on test days 1 and 5. After the initial hand wash there were significant reductions over base line in aerobic and anaerobic log CFU among those using Alc A, CHG, and IPA. By the end of the first day of hand washing (15 washes), there were 2-log or greater reductions in aerobic counts among subjects using all antiseptics, but no significant reductions in controls. By the end of day 5, all agents produced significant reductions in aerobic (P = 0.0002) and anaerobic (P = 0.002) counts over control soap. Subject assessment of effects of hand washing on the skin and overall satisfaction varied significantly by product (P = 0.04 and 0.05, respectively). We conclude that alcohol-based hand rinses are highly efficacious, and such products are recommended as a health care personnel hand wash, particularly when sink and running water are inaccessible.
Effect of saturable serum protein binding on the pharmacokinetics of unbound cefonicid in humans
Authors: Dudley M N , Shyu W C , Nightingale C H , Quintiliani R
Published: June 2012

Previous studies have demonstrated high, concentration-dependent serum protein binding of cefonicid. To determine the in vivo pharmacokinetic significance of these observations, the pharmacokinetics of both total and unbound (non-protein-bound) cefonicid was studied in six volunteers after a single intravenous dose of 30 mg/kg. Saturable serum protein binding was observed in vivo; the mean +/- standard deviation free fraction of cefonicid was 17.6 +/- 6.1% immediately after administration and declined to a constant value of approximately 2% as total serum concentrations fell below 100 micrograms/ml. This nonlinear binding was associated with a pronounced decline in unbound serum cefonicid concentrations during the first 3 h after administration, with low or undetectable unbound drug concentrations by 12 h. Renal clearance of total cefonicid averaged 21.1 ml/min per kg and did not vary with time; in contrast, the mean +/- standard deviation unbound cefonicid renal clearance increased from 5.7 +/- 2.1 to 10.8 +/- 1.6 ml/min per kg with time (P less than 0.02). This study may partially explain the poor results obtained with single daily dosing of cefonicid in endocarditis. Dosage regimens of certain antimicrobial agents with high, saturable serum protein binding and extensive renal tubular secretion may be most appropriately designed based on unbound drug pharmacokinetics.
Comparative methods for detection of thymidine kinase-deficient herpes simplex virus type 1 strains
Authors: Harmenberg J , Sundqvist V A , Gadler H , Levén B , Brännström G , Wahren B
Published: June 2012

Four methods for analyzing viral susceptibility to antiviral substances were compared. In two methods viral products were measured: late viral proteins were measured by an enzyme-linked immunosorbent assay and viral DNA was measured by DNA hybridization. Infectious virus was quantified in the other two assays as the number of plaques and the yield of virus. The enzyme-linked immunosorbent assay procedure in our hands detected the smallest amounts (lowest proportions) of thymidine kinase-deficient herpes simplex virus type 1 mixed with wild-type virus. The thymidine kinase-deficient proportion of the herpes simplex virus type 1 isolate increased rapidly in the presence of acyclovir in cell culture.
Enhancement of ketoconazole penetration across the blood-brain barrier of mice by dimethyl sulfoxide
Authors: Iwen P C , Miller N G
Published: June 2012

Mice were treated with ketoconazole with and without dimethyl sulfoxide. Concentrations of ketoconazole at 3 and 5 h after treatment were significantly higher in serum (P less than 0.05) and brain tissue homogenate (P less than 0.01) of mice treated with dimethyl sulfoxide than in those of mice not treated with dimethyl sulfoxide.
High-level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of streptococcal tetM determinant
Authors: Morse S A , Johnson S R , Biddle J W , Roberts M C
Published: June 2012

Recently, strains of Neisseria gonorrhoeae have been isolated which are highly resistant to tetracycline (MICs of 16 to 64 micrograms/ml). This resistance was due to the acquisition of the resistance determinant tetM, a transposon-borne determinant initially found in the genus Streptococcus and more recently in Mycoplasma hominis, Ureaplasma urealyticum, and Gardnerella vaginalis. In N. gonorrhoeae, the tetM determinant was located on a 25.2-megadalton plasmid. This plasmid arose from the insertion of tetM into the 24.5-megadalton gonococcal conjugative plasmid. The tetM determinant could be transferred to suitable recipient strains of N. gonorrhoeae by both genetic transformation and conjugation.
Lack of emergence of resistant fecal flora during successful prophylaxis of traveler's diarrhea with norfloxacin
Authors: Johnson P C , Ericsson C D , Morgan D R , Dupont H L , Cabada F J
Published: June 2012

Norfloxacin, a new quinolone carboxylic acid derivative, was compared with an identical-appearing placebo preparation in a prospective, randomized, double-blind trial for prevention of traveler's diarrhea among 120 U.S. students arriving in Mexico. Prophylaxis was continued for 2 weeks. Diarrhea was defined as four unformed stools in 24 h plus an additional symptom of enteric disease. In the norfloxacin prophylaxis group, 4 of 56 subjects (7%) experienced diarrhea, compared with 36 of 59 subjects (61%) in the placebo group. The difference was significant (P less than 0.0001). In contrast to our previous experience with use of trimethoprim-sulfamethoxazole to prevent traveler's diarrhea, quantitative stool cultures in the norfloxacin-treated group revealed a significant decline of normal aerobic fecal flora during prophylaxis (P less than 0.0005). Among stool samples from norfloxacin-treated subjects, 32 of 38 (84%) cultured on day 7 and 34 of 37 (92%) cultured on day 14 had no gram-negative bacilli. After norfloxacin was discontinued, fecal flora returned to pretreatment levels. No gram-negative aerobic flora resistant to norfloxacin were found during weekly quantitative cultures before, during, or after therapy.
Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers
Authors: Colaizzi P A , Coniglio A A , Poynor W J , Vishniavsky N , Karnes H T , Polk R E
Published: June 2012

Mezlocillin was previously reported to exhibit dose-dependent pharmacokinetics. These reports suggest that it may be possible to administer a relatively large dose at a longer interval than is usual and still achieve therapeutic concentrations in serum. In a randomized, crossover study, we compared concentrations of mezlocillin in serum after a single dose and at steady state in 12 healthy volunteers who received 4 g every 6 h and 5 g every 8 h. A slight, but statistically significant, dose-dependent effect was observed upon the area under the concentration-time curve and total body clearance. No accumulation was observed with either schedule. Although concentrations in serum were higher after the 5-g dose, the more frequent administration of the 4-g dose schedule produced serum concentrations above the MIC for susceptible bacteria for a greater portion of the day. In the absence of clear guidelines from human studies which relate serum concentrations to clinical response, the available data indicate that the more frequent dosage schedule is appropriate for severe infections.
Difloxacin metabolism and pharmacokinetics in humans after single oral doses
Authors: Granneman G R , Snyder K M , Shu V S
Published: June 2012

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.
Contribution of two different mechanisms to erythromycin resistance in Escherichia coli
Authors: Arthur M , Courvalin P
Published: June 2012

Escherichia coli BM2570 was resistant to high levels of erythromycin by two different mechanisms. The two genes conferring resistance to erythromycin in BM2570 were carried by a 150-kilobase self-transferable plasmid, pIP1527, and were cloned separately in E. coli. A single polypeptide with an Mr of 27,000 was encoded by the gene erxA and conferred high-level resistance to macrolide, lincosamide, and streptogramin B-type antibiotics by a mechanism other than drug inactivation. This resistance phenotype, not previously reported for a clinical isolate of enterobacteria, was probably due to modification of the ribosomes. The gene ereB encoded an enzyme with an Mr of 51,000 which inactivated erythromycin and oleandomycin. The two different mechanisms specified by erxA and ereB contributed in more than an additive fashion to the high level of resistance to erythromycin conferred by plasmid pIP1527 to E. coli BM2570.
In vitro activity of ME1401, a new antifungal agent
Authors: Yamaguchi H , Uchida K , Hiratani T , Hara T , Fukuyasu H , Kazuno Y , Inouye S
Published: June 2012

The in vitro antifungal activity of ME1401, a potential topical antifungal agent, was compared with that of haloprogin, clotrimazole, miconazole, tolnaftate, and ciclopirox olamine by using an agar dilution procedure. ME1401 showed a broad antifungal spectrum and inhibited all of the 428 strains of 52 species of pathogenic yeasts and filamentous fungi tested at concentrations ranging from 0.01 to 12.5 micrograms/ml. In general, the activity of ME1401 was comparable or superior to that of clotrimazole and was greater than that of haloprogin and the other reference drugs under the conditions used. Only tolnaftate was superior to ME1401 in its activity against clinical isolates of Trichophyton rubrum. ME1401 showed no cross-resistance with any of the reference drugs and exhibited potent fungicidal activity.
Pharmacokinetics of [14C]teicoplanin in male rats after single intravenous dose
Authors: Bernareggi A , Cavenaghi L , Assandri A
Published: June 2012

The pharmacokinetic profile of [14C]teicoplanin was studied in male Sprague-Dawley rats given a single 10,000-U/kg intravenous dose. The disposition of the antimicrobial activity in the body was estimated by a three-compartment open model. Plasma concentration data were fitted to a three-exponent equation. The profile of total 14C in plasma was similar to that of the microbiological activity. The cumulative recovery of total 14C 5 days after drug administration averaged 76.3% of the administered dose in the urine and 8.7% in the feces. The residual dose remaining in the animal carcasses was 11.1%. Teicoplanin was widely distributed in the body. In almost all organs, the maximum concentration of [14C]teicoplanin was already reached at the first time of killing, which was 0.25 h after the administration of drug. The liver, kidneys, skin, and fat contained most of the residual dose found in the animal carcasses 120 h after administration and behaved as a deep compartment with the adrenal glands and spleen.