bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture
Authors: Geary T G , Divo A A , Jensen J B
Published: June 2012

Calmodulin inhibitors are toxic for a variety of protozoa. Chlorpromazine, calmidazolium, and trifluoperazine inhibited the incorporation of [3H]hypoxanthine and [3H]phenylalanine into Plasmodium falciparum organisms in cultures with 50% inhibitory concentrations varying from 5.1 microM (with calmidazolium) to 48 microM (with chlorpromazine), the former being more sensitive than the latter. However, these concentrations also immediately dissipated rhodamine 123 from the parasite mitochondrion. Similar concentrations inhibit other protozoa, as well as mammalian cells, and the possibility that mitochondrial function rather than that of calmodulin is the target of these drugs should be considered.
Antimicrobial susceptibility of Aeromonas species isolated from patients with diarrhea
Authors: San Joaquin V H , Scribner R K , Pickett D A , Welch D F
Published: June 2012

In vitro susceptibility to 17 antimicrobial agents was determined for Aeromonas caviae, A. hydrophila, and A. sobria isolated from feces of patients with diarrhea. The three Aeromonas species shared a similar susceptibility pattern, except to cephalothin. Of the oral antimicrobial agents, the quinolones, followed by chloramphenicol, were most active; trimethoprim-sulfamethoxazole and tetracycline had good but variable activity.
Comparison of in vitro activity of quinolone antibiotics and vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus by time-kill kinetic studies
Authors: Foster J K , Lentino J R , Strodtman R , DiVincenzo C
Published: June 2012

Quinolone antibiotics have been proposed as possible alternatives to vancomycin for methicillin-resistant Staphylococcus aureus infections. We investigated the activities of amifloxacin, ciprofloxacin, norfloxacin, and vancomycin by time-kill kinetic studies. Antibiotic concentrations of 0, 1.0, and 4.0 times the MIC were used against four strains of gentamicin- and methicillin-resistant S. aureus. Staphylococci were plated onto ciprofloxacin-containing agar at all time points, in repeat time-kill kinetic studies. Macrobroth dilution MICs and MBCs were determined. Ciprofloxacin levels were measured by bioassay. Replica plating was performed from the original susceptible inoculum (MIC, 0.125 micrograms/ml) onto ciprofloxacin-supplemented agar. At 4.0 times the MIC, only with ciprofloxacin was there regrowth at 24 and 48 h. All four strains of staphylococci grew on agar supplemented with 1 microgram of ciprofloxacin per ml; three of four grew on agar supplemented with 2 micrograms of ciprofloxacin per ml. MICs and MBCs for these resistant clones ranged from 8 to 32 micrograms/ml. No degradation in activity or amount of ciprofloxacin could be detected in the bioassay. Replica-plated staphylococci grew on agar containing 1 microgram/ml but not higher concentrations of ciprofloxacin at 48 h. Amifloxacin and norfloxacin sustained bactericidal activity comparable to that of vancomycin. We conclude that heteroresistant subpopulations of gentamicin- and methicillin-resistant S. aureus can emerge under antibiotic selection pressure. Such resistant clones may then mutate in the presence of subinhibitory concentrations of antibiotic to higher levels of ciprofloxacin resistance.
In vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria and beta-lactamase stability of RS-533, a novel carbapenem
Authors: Neu H C , Chin N X , Saha G , Labthavikul P
Published: June 2012

RS-533 is a novel carbapenem antibiotic. Its activity was compared with that of imipenem and the new cephalosporins, aztreonam, piperacillin, and tobramycin. RS-533 had activity comparable to that of imipenem, inhibiting the majority of the Enterobacteriaceae, streptococci, staphylococci, and Bacteroides species at concentrations of less than or equal to 2 micrograms/ml. RS-533 inhibited Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to ceftazidime, aztreonam, and cefoperazone, but RS-533 did not inhibit all methicillin-resistant Staphylococcus aureus or Pseudomonas maltophilia. It inhibited tobramycin-resistant members of the Enterobacteriaceae and Pseudomonas aeruginosa. RS-533 was stable against attack by common chromosomal and plasmid-mediated beta-lactamases and was an effective inhibitor of many beta-lactamases.
Continuous sampling for determination of pharmacokinetics in rat cerebrospinal fluid
Authors: Meulemans A , Vicart P , Mohler J , Vulpillat M , Pocidalo J J
Published: June 2012

A method for determining drug concentration relationships between plasma and cerebrospinal fluid (CSF) in rats is described. Continuous CSF samples were collected directly from the third anterior ventricle with an indwelling cannula inserted through the bregma point, and drug concentrations were determined by high-pressure liquid chromatography and radioimmunoassay micromethods. Three antibiotics with different abilities to cross the blood-CSF barrier (chloramphenicol, piperacillin, and gentamicin) were tested. This method was found to be reproducible for each drug even if the antibiotic levels were low and the sample volumes very small. Peak CSF concentrations occurred between 0.75 and 1.25 h after injection for all three antibiotics. Percent penetration values at 1 h were 50, 1.2, and 5.4% for chloramphenicol, piperacillin, and gentamicin, respectively.
Penetration of cefixime into fibrin clots and in vivo efficacy against Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus
Authors: Bergeron M G , Turcotte A
Published: June 2012

The experimental model of infected fibrin clots in rabbits was used to study the penetration and in vivo activity of cefixime against Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. The respective MICs of cefixime against these strains were 0.25, 2, and 8 micrograms/ml. The clots were infected with 10(6) to 10(8) CFU/g. Groups of four animals for each strain received an intravenous injection of 100 mg of cefixime per kg over 30 min. High peak levels were observed in serum (146.5 micrograms/ml) and clots (15.8 micrograms/g), and the antibiotic was still detectable in the clots (0.6 micrograms/g) 24 h after administration. The respective serum and clot elimination half-lives were 0.7 and 5.0 h. The mean serum protein binding was 23.8 +/- 3.8%. Cefixime was highly bactericidal against K. pneumoniae and E. coli and reduced, over a 24-h period, their respective colony counts by 7.8 log10 and 6.2 log10 CFU/g of fibrin. It was less effective against S. aureus but still reduced the bacterial counts by 2.8 log10 CFU/g of fibrin. The present results demonstrate that cefixime, a new broad-spectrum oral cephalosporin, has a long tissue half-life which ensured, at the dose given here, good in vivo bactericidal activity against both gram-positive and gram-negative bacteria up to 24 h after administration of the antibiotic.
Inhibition of replication and cytopathic effect of human T cell lymphotropic virus type III/lymphadenopathy-associated virus by 3'-azido-3'-deoxythymidine in vitro
Authors: Nakashima H , Matsui T , Harada S , Kobayashi N , Matsuda A , Ueda T , Yamamoto N
Published: June 2012

Human T cell lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus is the etiologic agent of the acquired immune deficiency syndrome (AIDS) and AIDS-related complex. The effect of 3'-azido-3'-deoxythymidine (AZT) on the HTLV-III/lymphadenopathy-associated virus infection was quantitatively studied with HTLV type I-carrying MT-4 cells. The AZT compound inhibited HTLV-III-induced cytopathic effect and virus-specific antigen expression in MT-4 cells at concentrations of 5 and 10 microM. In addition, a plaque-forming assay was performed to assess the effect of AZT on virus replication in MT-4 cells freshly infected with HTLV-III and in continuous HTLV-III-producing Molt-4/HTLV-III cells. Results showed that AZT efficiently and effectively inhibited the replication of HTLV-III in infected MT-4 cells. AZT is a strong inhibitor of reverse transcriptase activity of HTLV-III as a triphosphate, to such a degree that even 1.0 pM azido-TTP inhibits 50% of reverse transcriptase activity. However, it did not show any effect in the HTLV-III-producing cell line Molt-4/HTLV-III. Thus, AZT has no effect on virus replication of an already integrated virus. When 5 microM AZT was added to HTLV-III-infected MT-4 within 20 h after infection, a striking suppressive effect was noticed. This concentration was much lower than that which inhibits the growth of MT-4 cells. These results confirm those found in a previous report (H. Mitsuya, K. J. Weinhold, P. S. Furman, H. S. Clair, S. N. Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry, and S. Broder, Proc. Natl. Acad. Sci. USA 82:7096-7100, 1985) and suggest that AZT might be used as an experimental antiviral agent for AIDS and AIDS-related complex.
Activity of ciprofloxacin against multiply resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, and group JK corynebacteria
Authors: Venezio F R , Tatarowicz W , DiVincenzo C A , O'Keefe J P
Published: June 2012

The susceptibilities of multiply resistant clinical isolates of Pseudomonas aeurginosa to ciprofloxacin, norfloxacin, and several beta-lactam and aminoglycoside antibiotics were evaluated. Ciprofloxacin also was compared with methicillin and vancomycin against methicillin-resistant Staphylococcus epidermidis and group JK corynebacteria. Ciprofloxacin exhibited the lowest MICs and MBCs for 90% of the isolates among all of the antibiotics tested against P. aeruginosa. In addition, ciprofloxacin exhibited excellent bactericidal activity against the gram-positive organisms. Clinical trials are necessary to confirm the in vitro results and monitor for emergence of resistance.
Protection of mice from lethal influenza virus infection with high dose-short duration ribavirin aerosol
Authors: Wyde P R , Wilson S Z , Gilbert B E , Smith R H
Published: June 2012

An aerosol generated from a reservoir containing 60 mg of ribavirin per ml given for 2 h twice daily for 4 days afforded the same high level of protection against lethal influenza virus infection of mice as a longer, conventional treatment schedule (20 mg/ml given for 11 h daily for 4 days). Incremental decreases in ribavirin concentration made while maintaining the 2-h intermittent schedule provided progressively less protection of mice. Mice exposed to the 60-mg/ml doses had significantly increased pulmonary and serum drug levels when compared with mice given 20 mg of drug per ml, these increases were transient, and no evidence of pulmonary intolerance was detected. These studies suggest that protective effects of ribavirin against influenza virus infection can be achieved without untoward effects if higher doses and shorter periods of administration are used.
In vitro activity of A-56619 (difloxacin), A-56620, and other new quinolone antimicrobial agents against genital pathogens
Authors: Liebowitz L D , Saunders J , Fehler G , Ballard R C , Koornhof H J
Published: June 2012

The in vitro activities of two new carboxyquinolones, A-56619 (difloxacin) and A-56620, were compared with those of ciprofloxacin, norfloxacin, and ofloxacin against genital tract pathogens. All the quinolones were highly active against Neisseria gonorrhoeae. A-56619 had the lowest MICs against Chlamydia trachomatis (MIC range, 0.125 to 0.25 micrograms/ml) and Haemophilus ducreyi (MIC for 90% of isolates tested, 0.1 micrograms/ml).
Comparative efficacy of ketoconazole and mebendazole in experimental trichinosis
Authors: Hess J A , Chandrasekar P H , Mortiere M , Molinari J A
Published: June 2012

The therapeutic efficacy of ketoconazole and mebendazole was studied in ICR/CD-1 mice infected with Trichinella spiralis for 17 to 20 weeks. Efficacy of both drugs was over 70% when compared with results in control mice. This study indicates that both ketoconazole and mebendazole should be considered in the treatment of trichinosis in humans.
Early effects of beta-lactams on aminoglycoside uptake, bactericidal rates, and turbidimetrically measured growth inhibition in Pseudomonas aeruginosa
Authors: Miller M H , Feinstein S A , Chow R T
Published: June 2012

In vitro studies of tircarcillin or cefsulodin combined with [3H]tobramycin were performed with Pseudomonas aeruginosa. The rate of bacterial killing, the uptake of tobramycin, and the effects on optical density were measured. Both beta-lactams increased the uptake of subinhibitory concentrations of tobramycin. This result was quantitatively associated with a 2- to 4-h time-kill potentiation and confirmed earlier studies on the mechanism of beta-lactam-aminoglycoside synergy in Escherichia coli (P. H. Plotz and B. D. Davis, Science 135:1067-1068, 1962).
Role of porins in intrinsic antibiotic resistance of Pseudomonas cepacia
Authors: Parr T R , Moore R A , Moore L V , Hancock R E
Published: June 2012

The measured outer membrane permeability of Pseudomonas cepacia to the beta-lactam nitrocefin was low: approximately 10 times less than that of Escherichia coli and comparable to that of Pseudomonas aeruginosa. The purified P. cepacia porin demonstrated an average single channel conductance in 1 M KCl of 0.23 nS.
Effect of oral ofloxacin on fecal bacteria in human volunteers
Authors: Pecquet S , Andremont A , Tancrède C
Published: June 2012

Intestinal members of the family Enterobacteriaceae were eliminated in five human volunteers treated with oral ofloxacin for 5 days. No emergence of resistant Enterobacteriaceae was observed. Counts of group D streptococci were significantly reduced. Colonization by Candida sp. was observed in all five volunteers during ofloxacin treatment. The anaerobic flora was fairly stable from one sample to another before treatment and was not substantially modified by ofloxacin.
Characterization of impermeability variants of Pseudomonas aeruginosa isolated during unsuccessful therapy of experimental endocarditis
Authors: Bayer A S , Norman D C , Kim K S
Published: June 2012

We characterized five amikacin-resistant variants of Pseudomonas aeruginosa isolated from aortic valve vegetations during unsuccessful therapy of experimental endocarditis. These organisms were cross resistant to other aminoglycosides. No aminoglycoside-modifying enzymes were produced by these strains. However, all five variants demonstrated significant defects in permeability and intracellular uptake of [3H]amikacin when compared with the amikacin-susceptible parental strain (0 to 26% of that of the parental strain; mean, approximately 15%). The permeability defects were unstable in vitro, with normalization after serial passage in antibiotic-free media. The variants grew as nonpigmented, small-colony types, with in vitro generation times approximately 1.5 to 2 times longer than that of the parental strain (30 to 40 versus 20 min, respectively). Two impermeability variants were compared with the parental strain for ability to induce experimental endocarditis in rabbits with aortic catheters. Both variants were virulent in vivo; however, mean bacterial densities in vegetations were approximately 2.5 log10 CFU/g lower in animals challenged with the variants than in animals challenged with the parental strain, probably reflecting a slower in vivo growth rate.
Inhibiting effect of (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine on varicella-zoster virus replication in cell culture
Authors: Abele G , Karlström A , Harmenberg J , Shigeta S , Larsson A , Lindborg B , Wahren B
Published: June 2012

The activity and mode of action of the new nucleoside analog (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG) against varicella-zoster virus (VZV) were determined. In cell culture, replication of different strains of VZV was inhibited to 50% by 0.4 to 0.7 microM 2HM-HBG, while 685 microM was required to inhibit 50% of the DNA synthesis in uninfected human lung fibroblasts. A thymidine kinase-negative VZV strain was not inhibited by 100 microM 2HM-HBG. Inhibition of VZV replication was not reversible after 7 to 14 days of incubation, depending on the multiplicity of VZV. 2HM-HBG was shown to be selectively phosphorylated by purified VZV thymidine kinase, with an inhibition constant of 32.5 microM. The antiviral activity of 2HM-HBG in cell culture was decreased by the addition of deoxythymidine and deoxycytidine but not by other ribo- or deoxyribonucleosides.
Pharmacokinetics and metabolism of an intravenously administered penem (Sch 34343) in humans
Authors: Lin C C , Lim J , Radwanski E , Kim H K , Marco A , Lapiguera A , DiGiore C , Symchowicz S
Published: June 2012

The pharmacokinetics of Sch 34343, a new broad-spectrum penem antibiotic, was studied in subjects receiving 1 g of 14C-labeled drug by intravenous administration. At the end of a 30-min intravenous infusion, the mean maximum concentration of drug in serum was 39 micrograms/ml for unchanged Sch 34343 and 49 mu eq/ml for total radioactivity. The mean serum half-lives of Sch 34343 were 0.16 h for the distribution phase and 0.80 h for the elimination phase. The total body clearance of Sch 34343 was 7.52 ml/min per kg, and the mean apparent volume of distribution was 525 ml/kg. Over a 4-day period, mean urinary excretion of radioactivity accounted for 87.9% of the dose, and mean urinary excretion of unchanged Sch 34343 accounted for 23.6% of the dose. The total radioactivity in feces on days 0 to 6 accounted for only 0.8% of the dose. In serum from 0.5 and 1 h, unchanged Sch 34343 represented the major radioactive peak, with negligible amounts of several metabolites. In urine, there were at least six metabolites in addition to Sch 34343. The amount of unchanged Sch 34343 accounted for 33% of radioactivity in samples of urine from 0 to 2 h, 22% in urine from 2 to 4 h, 15% in urine from 4 to 8 h, and 0% in urine from 8 to 12 h.
Effect of fetal exposure to gentamicin on kidneys of young guinea pigs
Authors: Lelievre-Pegorier M , Gilbert T , Sakly R , Meulemans A , Merlet-Benichou C
Published: June 2012

Clearance experiments were performed with young pups born of guinea pigs given a daily injection of 4 mg of gentamicin per kg (body weight) from days 48 to 54 of gestation (term, 68 days). For 3-day-old animals, the glomerular filtration rate was similar to that measured in control guinea pigs of the same age whose mothers were given saline during the same period of gestation. The same applied to fractional excretion of water, urea, total solutes, Na, K, Ca, and Mg but not to fractional phosphate excretion, which increased significantly in the gentamicin group when compared with the controls (mean +/- standard error, 21.7 +/- 4.9 versus 7.3 +/- 1.8%; P less than 0.05; n = 6 for both). The glomerular volume of the juxtamedullary nephrons diminished by about 40%, and their proximal tubule length decreased by about 20%. The glomerular volume of the superficial nephrons also diminished, by about 30%, but their proximal tubule length did not change. The gentamicin concentration was higher in the renal cortex than in the medulla (13.1 +/- 2.6 versus 5.7 +/- 2.2 micrograms/g [dry wt]; P less than 0.01; n = 6 for each). It decreased significantly from days 3 to 20 in both tissues. No functional impairment of the kidney was found in 10-day-old animals, and normal or even supranormal morphometry of the nephrons was observed in the 20-day-old animals. It is concluded that fetal exposure to gentamicin impairs proximal tubular function in the developing animal and might also adversely affect glomerular and tubular growth. However, both the functional and morphometric impairments of nephrons are transitory.
Alanine aminopeptidase and beta 2-microglobulin excretion in patients receiving vancomycin and gentamicin
Authors: Rybak M J , Frankowski J J , Edwards D J , Albrecht L M
Published: June 2012

The effects of vancomycin, gentamicin, and combination vancomycin-gentamicin treatments on alanine aminopeptidase (AAP) and beta 2-microglobulin (beta 2M) elimination in 30 hospitalized patients were assessed and compared with elimination in a control group. Twenty-four-hour urine excretion values for AAP and beta 2M were determined on treatment day 1 and day 5 for patients receiving the three treatment regimens and for the control group. AAP excretion values for the vancomycin-treated group were not found to be statistically different from those of the control group. Both the gentamicin and the vancomycin-gentamicin groups had statistically higher AAP excretion values on treatment day 1 as well as on treatment day 5 when compared with the vancomycin and control groups. AAP excretion on day 5 of treatment was highest for the vancomycin-gentamicin group. Overall, beta 2M elimination was variable in all treatment groups. Although the beta 2M values were elevated as early as day 1 in all treatment groups, they were significantly elevated only in the vancomycin-gentamicin group on day 1 and only in the gentamicin group on day 5 compared with the vancomycin and the control groups. AAP appears to be a sensitive indicator of renal tubular damage. The combination of vancomycin and gentamicin results in greater AAP excretion than does either agent alone.
Detection of relatively penicillin G-resistant Neisseria meningitidis by disk susceptibility testing
Authors: Campos J , Mendelman P M , Sako M U , Chaffin D O , Smith A L , Sáez-Nieto J A
Published: June 2012

Beginning in 1985, relatively penicillin G-resistant (Penr) meningococci which did not produce beta-lactamase were isolated from the blood and cerebrospinal fluid of patients in Spain. We identified 16 Penr (mean MIC, 0.3 microgram/ml; range, 0.1 to 0.7 microgram/ml) and 12 penicillin-susceptible (Pens; mean MIC, less than or equal to 0.06 microgram/ml) strains of Neisseria meningitidis by the agar dilution technique using an inoculum of 10(4) CFU and questioned which disk susceptibility test would best differentiate these two populations. We compared the disk susceptibility of these strains using disks containing 2 (P2) and 10 (P10) U of penicillin G, 2 (Am2) and 10 (Am10) micrograms of ampicillin, and 1 microgram of oxacillin (OX1). We also investigated susceptibility with disks containing 30 micrograms of each of cephalothin (CF30), cefoxitin (FOX30), cefuroxime (CXM30), and cefotaxime (CTX30) and 75 micrograms of cefoperazone (CFP75) and determined by cluster analysis any correlation with the zone diameters obtained with P2 disks. Using the P2 and AM2 disks (in contrast to the P10 and AM10 disks), we correctly differentiated all the Penr from Pens isolates. In addition, the zone diameters with the P2 disk gave the best correlation with the penicillin G MIC determinations. All 16 Penr strains and 3 of 12 Pens strains showed zone diameters of 6 mm around OX1 disks, limiting the usefulness of OX1 disks. The zone diameters obtained with CF30, CXM30, and OX1 disks correlated with those obtained with the P2 disk, which suggests that these antibiotics have similar effects on these strains. In contrast, the data obtained with FOX30, CTX30, and CFP75 disks did not cluster with those obtained with the P2 disk, which suggests that there was a difference in the bacterial target or reflects their greater activity. We conclude that the P2 disk tests more readily identify Penr meningococci than do the standard P10 disk tests.
Disk diffusion susceptibility testing of Branhamella catarrhalis with ampicillin and seven other antimicrobial agents
Authors: Doern G V , Tubert T
Published: June 2012

A total of 74 clinical isolates of Branhamella catarrhalis were characterized with respect to their ampicillin, amoxicillin-clavulanate, cephalothin, cefaclor, erythromycin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole MICs and zones of inhibition. Disk diffusion tests were performed according to the guidelines of the National Committee for Clinical Laboratory Standards with two different media (Mueller-Hinton agar and chocolate Mueller-Hinton agar) and plates incubated under two atmospheric conditions (ambient air and 5 to 7% CO2). Optimum disk diffusion test results were obtained with Mueller-Hinton agar plates incubated in ambient air with all eight antimicrobial agents. On the basis of comparisons of MICs versus zones of inhibition, the following zone diameter interpretive criteria were defined for testing B. catarrhalis with disks containing 10 micrograms of ampicillin: greater than or equal to 38 mm, susceptible; 20 to 37 mm, moderately susceptible; less than or equal to 19 mm, resistant. The respective MIC correlates were less than or equal to 0.06, 0.125 to 0.5, and greater than or equal to 1.0 micrograms/ml. Because of the absence of frankly resistant test organisms, it was not possible to make definitive recommendations pertaining to disk diffusion tests with amoxicillin-clavulanate, cephalothin, cefaclor, erythromycin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. Evidence is presented, however, which suggests that the current National Committee for Clinical Laboratory Standards disk diffusion interpretive criteria for nonfastidious bacteria can be applied to B. catarrhalis, at least as they pertain to the susceptible category with cephalothin, amoxicillin-clavulanate, erythromycin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. With cefaclor, a zone diameter of greater than or equal to 21 mm was determined to adequately define the susceptible category.
Effect of quinolones and other antimicrobial agents on cell-associated Legionella pneumophila
Authors: Havlichek D , Saravolatz L , Pohlod D
Published: June 2012

We evaluated the in vitro susceptibility of Legionella pneumophila ATCC 33152 (serogroup I) to 13 antibiotics alone and in combination with rifampin (0.1 mg/liter) by three methods. Extracellular susceptibility was determined by MIC determinations and time kill curves in buffered yeast extract broth, while intracellular susceptibility was determined by peripheral human monocytes in RPMI 1640 culture medium. Antibiotic concentrations equal to or greater than the broth dilution MIC inhibited or killed L. pneumophila by the time kill method, except this was not the case for trimethoprim-sulfamethoxazole. Antibiotic concentrations below the broth dilution MIC did not inhibit Legionella growth. The only antibiotic-rifampin combinations which produced improved killing of L. pneumophila by the time kill method were those in which the logarithmic growth of L. pneumophila occurred during the experiment (rosoxacin, amifloxacin, cinoxacin, trimethoprim-sulfamethoxazole, clindamycin, and doxycycline). Neither direct MICs nor time kill curve assays accurately predicted intracellular L. pneumophila susceptibility. Rifampin, erythromycin, ciprofloxacin, rosoxacin, enoxacin, amifloxacin, gentamicin, clindamycin, and doxycycline all inhibited intracellular L. pneumophila growth at readily achievable concentrations in serum. Cefoxitin and thienamycin showed no inhibition of growth, although they were present extracellularly at concentrations that were 20 to 1,000 times their broth dilution MICs. Clindamycin was the only antibiotic that was able to inhibit intracellular L. pneumophila growth at an extracellular concentration below its MIC. The gentamicin (5 mg/liter)-rifampin combination was the only antibiotic-rifampin combination which demonstrated decreased cell-associated Legionella survival in this model of in vitro susceptibility.
Activity of terbinafine in experimental fungal infections of laboratory animals
Authors: Petranyi G , Meingassner J G , Mieth H
Published: June 2012

The allylamine derivative terbinafine is the first antifungal agent with primary fungicidal properties against dermatophytes which acts systemically after oral application as well as locally after topical application. Comparative oral studies carried out with griseofulvin and ketoconazole in model infections such as guinea pig trichophytosis and microsporosis revealed terbinafine to be superior to the reference compounds both clinically and mycologically. An excellent antimycotic activity of terbinafine was also demonstrable after topical treatment of guinea pig dermatophytoses caused by Trichophyton mentagrophytes or Microsporum canis. Results of comparative chemotherapeutic studies carried out with econazole and tolnaftate demonstrated superior efficacy of terbinafine in the treatment of both trichophytosis and microsporosis. Skin infections of guinea pigs caused by Candida albicans and vaginal candidiasis in rats proved to be responsive to a topical application of terbinafine also. However, the reference compounds, clotrimazole and miconazole, exhibited activity superior to that of terbinafine in both models.
Dosage, timing, and route of administration of cyclosporin A and nonimmunosuppressive derivatives of dihydrocyclosporin A and cyclosporin C against Schistosoma mansoni in vivo and in vitro
Authors: Chappell L H , Thomson A W , Barker G C , Smith S W
Published: June 2012

The prophylactic and therapeutic effects of cyclosporin A (CsA) against percutaneous Schistosoma mansoni infection in MF1 mice were dose related and dependent on the temporal relationship between drug administration and infection. Antischistosomal activity, assessed by worm recovery from the host 6 weeks after infection, was most effective (complete worm elimination) when CsA was administered at the time of infection. Oral administration of CsA was less effective than subcutaneous injection, and no prophylactic activity was demonstrated by the former route. Derivatives of dihydrocyclosporin A and cyclosporin C, which have been reported to exert only poor immunosuppressive activity, exhibited efficacy against S. mansoni similar to that of CsA and were also less effective when given orally. Subcutaneous, but not oral CsA reduced cercarial skin penetration and transformation success; the derivative of dihydrocyclosporin A, however, was without effect. Moreover, CsA, but not the derivative of dihydrocyclosporin A, reduced the number of worms established after intraperitoneal injection of cercariae. These data provide further insight into the antischistosomal activity of cyclosporins, which appears to be distinct from their immunomodulatory properties, since parasite killing was retained both in immunologically disparate mice and with poorly immunosuppressive cyclosporin derivatives.
Contribution of beta-lactamase hydrolysis and outer membrane permeability to ceftriaxone resistance in Enterobacter cloacae
Authors: Marchou B , Bellido F , Charnas R , Lucain C , Pechère J C
Published: June 2012

Mechanisms of ceftriaxone resistance were examined in Enterobacter cloacae. Clones were selected from four strains: susceptible (S), resistant (R1), selected by plating on ceftriaxone-containing agar, and highly resistant (R2), selected in ceftriaxone-treated mice infected with S clones. According to 14C-labeled beta-lactam binding assays, ceftriaxone resistance was not associated with altered target proteins. R1 and R2 clones stably produced 50 to 1,500 times more beta-lactamase than S clones; this production increased after cefoxitin induction in all S and some R1 clones. Experiments conducted with strain 218 suggested that ceftriaxone resistance involved beta-lactamase hydrolysis. Half-lives for the beta-lactamase-beta-lactam complexes at 37 degrees C were 0.4 and 2.2 min for ceftriaxone and Sch 34343, a drug not affected by the resistance, respectively; in chromatography experiments, 218 intact R1 cells (2 x 10(9) to 3 x 10(9) CFU) suspended in ceftriaxone-containing buffer (2 micrograms/ml) hydrolyzed 80% of the antibiotic in 30 min. Three observations also suggested decreased permeability in some clones, (i) Most of the R1 and R2 clones showed decreased expression of outer membrane proteins of 37,000 to 38,000 molecular weight (37K to 38K proteins) by electrophoresis, often associated with increased amounts of 42K protein. (ii) [14C]Sch 34343 labeling of intact cells proceeded more slowly in 218 R2 (with altered 37K to 38K proteins) than in 218 R1 (without this alteration), a difference persisting after competition with unlabeled cloxacillin. Delays in binding were not caused by different enzymatic activities, since 218 R1 and 218 R2 produce, in similar amounts, beta-lactamases undistinguishable in isoelectric point and Km of cephaloridine. (iii) Intact cells from 218 R2 hydrolyzed ceftriaxone more slowly (20% in 30 min) than did those from 218 R1. In 218 R1, beta-lactamase overproduction was responsible for a 15- to 200-fold increase in the MIC's of ceftriaxone, ceftazidime, carbenicillin, piperacillin, moxalactam, aztreonam, carumonam, and BMY 28142. Imipenem and Sch 34343 were not affected; an additional three- to fivefold increase in the MIC's of these antibiotics (with the exception of piperacillin, imipenem, Sch 34343), seen with 218 R2, was associated with decreased permeability.
Disk diffusion susceptibility testing of the Bacteroides fragilis group
Authors: Horn R , Bourgault A M , Lamothe F
Published: June 2012

The susceptibilities of 225 isolates of the Bacteroides fragilis group to six antibiotics were determined by a new disk diffusion test in Wilkins-Chalgren agar and by the standard agar dilution method. For disk diffusion, the bacteria were directly suspended in saline and immediately swabbed onto 15-cm agar plates. Disks of cefoxitin (30 micrograms), chloramphenicol (30 micrograms), clindamycin (2 micrograms), moxalactam (30 micrograms), imipenem (10 micrograms), and ticarcillin (75 micrograms) were applied, and the plates were incubated at 37 degrees C in an anaerobic atmosphere. Zone sizes were measured at 24 h. The results of disk diffusion and agar dilution were compared by regression analysis by the method of least squares and by the error rate-bounded method. Zones were easily measured for 216 strains (96%). The correlation between the MICs and diameters of inhibition for cefoxitin, clindamycin, moxalactam, and ticarcillin was generally good. A correlation could not be established for chloramphenicol and imipenem, as there were too few resistant strains. With the recommended resistance breakpoints, the following susceptible and resistant zone diameter breakpoints could be established: cefoxitin, less than or equal to 19 and greater than or equal to 21 mm; clindamycin, less than or equal to 14 and greater than or equal to 18 mm; moxalactam, less than or equal to 21 and greater than or equal to 25 mm; and ticarcillin, less than or equal to 15 and greater than or equal to 16 mm. By applying these zone criteria, the percentage of false-susceptible strains was less than 1% and of false-resistant strains was less than 4% for the drugs tested.
Mechanism of renal excretion of carumonam in rats, rabbits, dogs, and monkeys
Authors: Kita Y , Imada A
Published: June 2012

The mechanism of the renal excretion of carumonam (CRMN) was investigated in rats, rabbits, dogs, and monkeys. Stop-flow analysis in dogs demonstrated that CRMN is exclusively excreted by glomerular filtration. There was no specific CRMN peak corresponding to the peak of p-aminohippuric acid (PAH) secretion or to the trough of Na+-K+ reabsorption in the stop-flow pattern. Although the PAH peak disappeared when probenecid was administered, the CRMN stop-flow pattern showed no change. In rabbits, however, the CRMN concentration peak corresponding with the PAH peak was detected in the stop-flow pattern; the CRMN peak disappeared when probenecid was administered. The pharmacokinetic parameters in plasma, such as the area under the concentration-time curve, the half-life, and the clearance rate, were affected by probenecid in rats, rabbits, and monkeys, but not in dogs. The results suggest that the renal excretion of CRMN in dogs takes place exclusively through glomerular filtration. In rats, rabbits, and monkeys, however, CRMN is excreted through both glomerular filtration and renal tubular secretion.
Tolerance and disposition of cefpimizole in normal human volunteers after intramuscular administration
Authors: Novak E , Lakings D B , Paxton L M
Published: June 2012

Cefpimizole sodium (AC-1370, U-63196E) was administered intramuscularly in doses from 100 mg (0.5 ml) to 2,000 mg (two 3.5-ml doses) to healthy human volunteers in three double-blind placebo and positive-controlled (cefotaxime, cephalothin) single-dose studies and in two multiple-dose studies. Mild transient pain was observed at the injection site, but no erythema, petechia, necrosis, or atrophy was noted. Creatinine phosphokinase values were increased during the study in the cefpimizole- and placebo-treated groups but began to return to normal toward the end of the study period (day 5). They were not paralleled by a similar magnitude of elevation in serum glutamic oxalacetic transaminase and lactate dehydrogenase or by pain and tenderness. There were no clinically meaningful or statistically significant changes (P greater than 0.5) or trends in vital signs and no other patterns of drug-related clinical abnormalities noted in any of the laboratory measurements evaluated (hematology, chemistry, urinalysis). No serious side effects occurred during or after the study. Cefpimizole was well tolerated locally and systemically by all the subjects at all administered dosage levels. Cefpimizole concentrations in serum (microbiological assay) remained above 1 microgram/ml at 12 h after drug administration for all dose levels. The median peak concentrations in plasma for the 500- and 1,000-mg twice-daily dosages of cefpimizole were, respectively, 21.6 and 45.5 micrograms/ml on day 1, 16.2 and 43.7 micrograms/ml on day 3, and 20.1 and 41.4 micrograms/ml on day 6 of the study. The apparent terminal disposition half-life throughout the study was about 2.0 h. The median amounts of cefpimizole excreted in the urine for the first 12 h of each day evaluated were 370 and 1,071 mg on day 1, 416 and 972 mg on day 3, and 370 and 975 mg on day 6 for the 500- and 1,000-mg twice-daily dosages, respectively. Dose proportionally of cefpimizole was obtained for the 500- and 1,000-mg and the 2,000-mg groups. The absorption, distribution, and elimination of cefpimizole after multiple-dose intramuscular administration were uniform, were linear in relation to dose, and did not result in drug accumulation.
Ampicillin killing curve patterns of Haemophilus influenzae type b isolates by agar dilution plate count method
Authors: Woolfrey B F , Gresser-Burns M E , Lally R T
Published: June 2012

The responses of 20 ampicillin-susceptible Haemophilus influenzae type b clinical isolates to the bactericidal action of ampicillin were studied by using a modified agar dilution plate count method. A well-defined paradoxical effect was observed in each of the 24-h killing curve patterns for 19 of the 20 isolates, the remaining isolate showing a less-well-defined but suggestive paradoxical effect after 48 h of ampicillin exposure. For each isolate, the lowest 24-h persister percentage representing maximum killing (paradoxical trough percentage) occurred over a narrow range of concentrations immediately above the MIC, with such paradoxical trough percentages for the 20 isolates ranging from greater than 0.1 to less than 0.001%. Three isolates selected to represent slow, intermediate, and rapid responses were investigated by repetition of 24-h studies and by determination of expanded killing curve patterns. Resultant agar dilution plate count killing curve patterns were found to be reproducible and strain dependent and served to characterize each isolate. The paradoxical effect became more distinct with the prolongation of ampicillin action. Maximum killing was again evident for a narrow range of ampicillin concentrations immediately above the MIC, with persister percentages rising rapidly over the next few ampicillin concentrations to peak at 1 to 2 log10 increments higher than trough percentages. Based on the broad range of responses observed for the 20 isolates, the consistent presence of the paradoxical effect, and the time-dependent nature of bactericidal action, we suggest that the MBC and MBC/MIC ratios are inadequate indices of bactericidal action and that the all-or-none concept of "antimicrobial tolerance" should be abandoned.
Biliary excretion of imipenem-cilastatin in hospitalized patients
Authors: Graziani A L , Gibson G A , MacGregor R R
Published: June 2012

Imipenem-cilastatin concentrations in bile were measured in 12 cholecystectomy patients (group 1) and 12 patients with common duct drainage (group 2). Six patients in each group received 0.5 g, and six received 1.0 g intravenously over 30 to 60 min. In group 1, bile was collected a mean of 85 min postinfusion. The mean concentrations of imipenem in bile were 1.3 microgram/ml after the 0.5-g dose and 3.5 micrograms/ml after the 1.0-g dose. The mean concentrations of cilastatin in bile were 9.0 micrograms/ml after the 0.5-g dose and 38.0 micrograms/ml after the 1.0-g dose. In patients with common duct drainage, bile was collected predose and 0 to 2, 2 to 3, 3 to 4, and 4 to 6 h postinfusion. Peak imipenem concentrations in bile were 4.4 micrograms/ml after the 0.5-g dose and 8.6 micrograms/ml after the 1.0-g dose. Peak cilastatin concentrations in bile were 4.6 micrograms/ml for the 0.5-g dose and 10.9 micrograms/ml for the 1.0-g dose. Peak imipenem concentrations in bile occurred a mean of 2.3 h after administration of the drug; cilastatin peak concentrations occurred at a mean of 2.4 h. Less than 0.3% of each drug was recovered in the bile. Our results suggest that imipenem enters bile by simple diffusion and in most patients attains concentrations sufficient to inhibit susceptible organisms. In contrast, cilastatin had a bimodal entry into bile. Some patients had very high concentrations in bile, whereas others had very low or undetectable concentrations, suggesting that cilastatin may be actively secreted into the bile.
Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones
Authors: Hardy D J , Swanson R N , Hensey D M , Ramer N R , Bower R R , Hanson C W , Chu D T , Fernandes P B
Published: June 2012

The in vitro and in vivo properties of a new 1-difluorophenyl-6-fluoroquinolone, temafloxacin hydrochloride (A-62254), were compared with those of difloxacin and ciprofloxacin. Temafloxacin hydrochloride was as active as ciprofloxacin and difloxacin against staphylococci and as active as ciprofloxacin and 2 twofold dilutions more active than difloxacin against streptococci. Against gram-negative enteric bacteria and Pseudomonas aeruginosa, temafloxacin hydrochloride was 2 twofold dilutions more active than difloxacin but 2 to 4 twofold dilutions less active than ciprofloxacin. The MICs of temafloxacin hydrochloride and difloxacin were increased by 2 to 5 twofold dilutions in urine at pH 6.5 compared with 4 to 5 twofold-dilution increases in the MICs of ciprofloxacin. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were increased by 1 to 3 twofold dilutions in serum. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were the same or within 1 to 2 twofold dilutions at pHs 6.5, 7.2, and 8.0. When administered orally in mouse protection tests, temafloxacin hydrochloride was as active as difloxacin and 5 to 10 times more active than ciprofloxacin against infections with Staphylococcus aureus and streptococci. Against infections with gram-negative enteric bacteria and P. aeruginosa, temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin. Temafloxacin hydrochloride was three times less active than difloxacin but was five times more active than ciprofloxacin against infections with Salmonella typhimurium. Temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin against P. aeruginosa and Proteus mirabilis pyelonephritis in mice. The peak serum concentration and serum half-life of temafloxacin hydrochloride in mice were approximately one-half and one-sixth, respectively, that of difloxacin after oral administration. The peak serum concentration of temafloxacin hydrochloride in mice after oral administration was six times higher than that of ciprofloxacin, and the serum half-life was equal to that of ciprofloxacin.
N-methylisatin-beta-4',4'-diethylthiosemicarbazone, an inhibitor of Moloney leukemia virus protein production: characterization and in vitro translation of viral mRNA
Authors: Ronen D , Sherman L , Bar-Nun S , Teitz Y
Published: June 2012

The mode of inhibition of N-methylisatin-beta-4',4'-diethylthiosemicarbazone (M-IBDET) on Moloney leukemia virus production was studied. Drug treatment of infected cells did not alter the amounts or sizes of the 35S and 22S subgenomic viral RNAs. The translation abilities of poly(A)+ RNA derived from M-IBDET-treated cells was also unaffected, as judged by cell-free translation analysis. Poly(A)+ RNA derived from M-IBDET-treated cells directed translation of equal amounts of viral gag precursors, gPr-80gag and Pr-65gag, as did poly(A)+ RNA prepared from untreated cells. The addition of M-IBDET to a cell-free translation system programmed with either total poly(A)+ RNA extracted from infected cells or hybrid-selected viral RNA inhibited the synthesis of viral protein precursors. An examination of the effect of M-IBDET on polysomes engaged in the translation of viral proteins revealed a fourfold accumulation of polysomal virus-specific RNA in drug-treated cells. These results suggest that the inhibition of Moloney leukemia virus by M-IBDET involves a block in the translation of viral RNA rather than interference with viral RNA transcription.
Comparative activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in experimental pneumonia in leukopenic rats
Authors: Roosendaal R , Bakker-Woudenberg I A , van den Berghe-van Raffe M , Vink-van den Berg J C , Michel M F
Published: June 2012

The antibacterial activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in vivo were compared. Although there was only a minor difference between the MBCs of both drugs, the bacterial killing rate of ciprofloxacin in vitro was very fast in comparison with that of ceftazidime. Similarly, the intravenous administration of ciprofloxacin at 1 h after bacterial inoculation resulted in effective bacterial killing in the lungs of leukopenic rats. This killing was dose dependent, in contrast to the dose-independent bactericidal effect of ceftazidime. The high antibacterial activity of ciprofloxacin in the lungs as compared with that of ceftazidime was also reflected in its therapeutic efficacy in K. pneumoniae pneumonia and septicemia in leukopenic rats when these infections were treated at 6-h intervals over 4 days, starting at 5 h after bacterial inoculation. Concentrations of ciprofloxacin and ceftazidime in lung tissue were not significantly different. Regarding the antibacterial activity of both drugs against K. pneumoniae in relation to the bacterial growth rate in vitro and in the lungs of leukopenic rats, ciprofloxacin killed K. pneumoniae organisms that were not actively growing, whereas ceftazidime did not. In addition, it was demonstrated that when the intravenous administration of antibiotic was delayed from 1 h up to 24 h after bacterial inoculation, ceftazidime lost its antibacterial activity in the lungs and blood of leukopenic rats, whereas ciprofloxacin was still very effective. These data suggest that the capacity of an antibiotic to kill bacteria at a slow growth rate may be relevant for its therapeutic effect in established infections, in which slowly growing bacteria form a substantial part of the total bacterial population.
In vitro susceptibility of Haemophilus influenzae to cefixime
Authors: Powell M , Williams J D
Published: June 2012

The in vitro activity of cefixime against 2,458 clinical isolates of Haemophilus influenzae was determined. All the strains were inhibited by less than or equal to 2 micrograms of cefixime per ml, and the modal MIC was 0.03 micrograms/ml. Activity was unaffected by the presence of beta-lactamase produced by 157 isolates. Nineteen of the twenty-four isolates for which cefixime MICs were greater than or equal to 0.5 micrograms/ml were beta-lactamase negative but showed reduced susceptibility to ampicillin.