bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep
Authors: Golenbock D T , Ebert S , Will J A , Proctor R A
Published: June 2012

Lipid X (2,3-diacylglucosamine 1-phosphate) is a novel monosaccharide precursor of lipid A (the active moiety of gram-negative endotoxin) and has been found to be protective against endotoxin administered to mice and sheep and against life-threatening gram-negative infections in mice. Because of the need to design optimal dosing regimens in experimental models of ovine and murine septicemia, the pharmacokinetic profile of lipid X was investigated in sheep and in two strains of mice by using 32P-labeled lipid X. In sheep, peak whole blood lipid X levels after a bolus injection of 100 micrograms of lipid X per kg were 900 ng/ml. An initial rapid distribution phase of 7.98 +/- 0.1 min was observed, followed by a prolonged elimination phase of 3.0 +/- 0.5 h; the area under the curve from time zero to infinity was 428 +/- 27 ng.h/ml. The serum half-lives of lipid X were slightly shorter than whole blood half-lives, suggesting that lipid X associates with cellular elements. Metabolites of lipid X could not be detected in serum over a 4-h period. Lipid X appears to accumulate mainly in the liver, and the tissue distribution of lipid X resembles that of lipopolysaccharide. The elimination rate of lipid X in mice was approximately four times as rapid as that seen in sheep. Lipid X pharmacokinetics in lipopolysaccharide-sensitive DBA/2J mice were virtually identical with those seen in endotoxin-resistant C3H/HeJ mice. The pharmacokinetics described here should greatly aid in the design and interpretation of animal studies investigating the therapeutic applications of lipid X in gram-negative septicemia.
Influence of storage and susceptibility test conditions on stability and activity of LY163892 and four other cephalosporins
Authors: Jorgensen J H , Redding J S , Maher L A
Published: June 2012

A new carbacephem analog of cefaclor, LY163892, was examined along with four other cephalosporins for chemical stability and for antibacterial activity under a variety of susceptibility test conditions. LY163892 was found to be markedly more stable than cefaclor during storage at 4 and 35 degrees C in human serum, human urine, and various bacteriological media. Under these conditions, LY163892 demonstrated stability equal or superior to the stabilities of cephalexin, cephalothin, and cefuroxime. Broth and agar dilution susceptibility tests did not reveal significant differences in LY163892 activity in a variety of test media, although LY163892 MICs were somewhat higher in Mueller-Hinton chocolate agar or Trypticase soy broth (BBL Microbiology Systems, Cockeysville, Md.) than in other media. The activity of LY163892 against selected pathogens was only slightly influenced by the increased or decreased pH of the test medium, in a manner similar to that of the other cephalosporins tested. Thus, the carbacephem structure of LY163892 appears to represent a more stable cephalosporin than cefaclor, while retaining a similar antimicrobial spectrum.
Comparison of antibiotic activities by using serum bactericidal activity over time
Authors: Guglielmo B J , Rodondi L C
Published: June 2012

In evaluating antimicrobial agents with similar spectra of activity, it is difficult to determine equivalent dosage regimens. In vitro potency, pharmacokinetic disposition, and other factors determine the usual dosing regimen. Knowledge of the serum bactericidal activity over time may assist in defining the potency of comparative antimicrobial agents. Cefoxitin and ceftizoxime, cephalosporins with gram-negative aerobic and anaerobic activity, have been promoted as monotherapy in the treatment of intra-abdominal infection. In a randomized, crossover study, six healthy volunteers received single 30-mg/kg doses of cefoxitin and ceftizoxime. Greater serum activity against Escherichia coli and Bacteroides fragilis was observed with ceftizoxime than with cefoxitin. The results suggest that ceftizoxime can be administered in a lower daily dosage than cefoxitin. We propose that the present study may serve as a prototype for future studies attempting to assess equivalent dosing regimens for antibiotics with similar spectra of activity.
Antiviral activities of guanosine analogs in guinea pig embryonic fibroblasts
Authors: Harmenberg J , Stenberg K
Published: June 2012

Previous research has shown that certain antiherpes substances which are activated by thymidine kinase are substantially more active in human fibroblasts than in green monkey kidney cells. The difference has been attributed to the presence of large amounts of intracellular thymidine in the latter cell type. Antiviral guanosine analogs but not thymidine analogs show decreased antiviral activity when used in herpes simplex virus type 1-infected guinea pig fibroblasts. We report the intracellular pools of antiviral di- and triphosphate nucleotides, the monophosphate nucleotide phosphorylating enzyme activities, and the antiviral triphosphate nucleotide stability, studied in herpes simplex virus type 1-infected and uninfected guinea pig fibroblasts. The results were compared with results of parallel experiments done with human fibroblasts and green monkey kidney cells.
Effects of various nucleosides on antiviral activity and metabolism of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus types 1 and 2
Authors: Suzutani T , Machida H , Sakuma T , Azuma M
Published: June 2012

Uptake of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) into herpes simplex virus type 1 (HSV-1)- and 2 (HSV-2)-infected cells was elevated about 190 to 40 times, compared with that into mock-infected human embryo lung fibroblast cells. Uptake was not enhanced by infection with thymidine kinase-negative HSV-1 and HSV-2 mutants, however. In HSV-1-infected cells, 9.7% of BV-araU was phosphorylated to BV-araU triphosphate, but only 1.1% was phosphorylated in HSV-2-infected cells. The antiviral effect, uptake, and turnover of BV-araU were inhibited significantly by thymidine (dThd), moderately by deoxyuridine, and not at all by deoxycytidine. On the other hand, the antiviral activity of acyclovir (ACV) was inhibited only by dThd. The effect of BV-araU was influenced by dThd and dThd phosphates (mono-, di-, and triphosphates), and the effect of ACV was influenced only by dThd, which competitively inhibited the phosphorylation of ACV to ACV monophosphate. The combination of 5-fluorodeoxyuridine (FUdR)-BV-araU or FUdR-ACV had a synergistic effect on HSV-1 and HSV-2 replication. The effect of FUdR on the turnover of BV-araU in HSV-1- and HSV-2-infected cells was analyzed by high-performance liquid chromatography. In HSV-1-infected cells, 86% of the BV-araU was phosphorylated to BV-araU triphosphate, but no effect was observed in HSV-2-infected cells, in which 98% of the BV-araU remained as BV-araU monophosphate.
Effect of lipid composition on activity of liposome-entrapped ampicillin against intracellular Listeria monocytogenes
Authors: Bakker-Woudenberg I A , Lokerse A F , Roerdink F H
Published: June 2012

The effect of lipid composition on the intracellular antibacterial activity of ampicillin-containing liposomes was studied in vitro by using mouse peritoneal macrophages infected with Listeria monocytogenes. Two types of liposomes, a fluid type, consisting of cholesterol-phosphatidylcholine-phosphatidylserine (5:4:1), and a solid type, consisting of cholesterol-distearoylphosphatidylcholine-dipalmitoylphosphatidylglyc ero l (10:10:1), were used. Although the cellular uptake of both types of liposomes was similar, they differed with respect to the rate of intracellular degradation. A correlation was found between the relatively slow degradation of the solid liposomes and a delayed intracellular release of the encapsulated ampicillin, as reflected in absent or delayed intracellular killing of L. monocytogenes.
Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro
Authors: Franzblau S G , O'Sullivan J F
Published: June 2012

Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663).
Activities of compound G2 isolated from alfalfa roots against dermatophytes
Authors: Evron R , Polacheck I , Guizie M , Levy M , Zehavi U
Published: June 2012

An antimycotic agent, compound G2, isolated from alfalfa roots exhibited considerable activity against the six most common dermatophytes. MICs in agar and broth dilutions ranged from 10 to 30 micrograms/ml and from 2 to 10 micrograms/ml, respectively. G2 was fungicidal at 5 to 22 micrograms/ml. Structure and toxicity relations are discussed.
Pharmacokinetics of ofloxacin after single and multiple intravenous infusions in healthy subjects
Authors: Farinotti R , Trouvin J H , Bocquet V , Vermerie N , Carbon C
Published: June 2012

The pharmacokinetics of ofloxacin were investigated in eight healthy male volunteers. A single infusion (200 mg over 0.5 h) was performed on day 1, followed by a washout period of 2 weeks. Repeated administrations were performed for 4 days (200 mg every 12 h). Pharmacokinetic parameters were determined from the plasma decay curves of the single and the last of the multiple administrations. Ofloxacin kinetics after the single dose were best described by a two-phase curve with a total body clearance of 241.6 +/- 43.3 ml min-1, a volume of distribution of 112 +/- 23.1 liters, and an elimination half-life of 5.4 +/- 0.8 h. The extrapolated area under the curve (AUC0-infinity) was 14 +/- 2.3 mg.h liter-1. The pharmacokinetics were not significantly modified by repeated administration, demonstrated mainly by the AUC0-12 value of the last infusion (13.4 +/- 2.2 mg.h liter-1). We conclude that, with intravenous multiple doses every 12 h, the steady state is reached within 24 to 36 h and no abnormal accumulation or changes in pharmacokinetic parameters occur.
Bactericidal activity of M14659 enhanced in low-iron environments
Authors: Mochizuki H , Yamada H , Oikawa Y , Murakami K , Ishiguro J , Kosuzume H , Aizawa N , Mochida E
Published: June 2012

The bactericidal activity of M14659 against Escherichia coli in low-iron environments was investigated and compared with that of ceftriaxone and ceftazidime. The bactericidal activity of M14659 against E. coli in Mueller-Hinton broth was enhanced 30- to 20,000-fold by addition of transferrin, which is an iron-binding protein, whereas the activity of ceftriaxone or ceftazidime was much less strongly affected. This enhancement by transferrin was completely inhibited by saturating the iron-binding capacity of transferrin with FeCl3. M14659 was taken up markedly into bacterial cells in the presence of transferrin, and its uptake was inhibited by the protonophore dinitrophenol, which inhibits active-transport systems coupled to an energized membrane such as the iron transport systems of E. coli. The bactericidal activity of M14659, which chelates Fe3+, was also enhanced in the presence of other iron-binding compounds such as lactoferrin and alpha,alpha'-dipyridyl or in iron-deficient Mueller-Hinton broth (Fe3+ concentration, less than 2 nM) supplemented with FeCl3 at 0.1 to 1.0 microM, but not in unsupplemented iron-deficient Mueller-Hinton broth. The E. coli used in this study was confirmed to derepress iron transport systems in the presence of transferrin, lactoferrin, and alpha,alpha'-dipyridyl and in the iron-deficient Mueller-Hinton broth supplemented with FeCl3 at 0 to 1.0 microM. M14659 also showed an excellent antibacterial activity in vitro against other gram-negative bacteria in the low-iron environments. These findings indicate that M14659 may be actively taken up with Fe3+ into bacterial cells, probably through the iron transport systems under conditions of low iron and, thus, kills bacteria effectively.
In vitro mechanism of inhibition of bacterial cell growth by allicin
Authors: Feldberg R S , Chang S C , Kotik A N , Nadler M , Neuwirth Z , Sundstrom D C , Thompson N H
Published: June 2012

Diallyl thiosulfinate (allicin) is the agent found in garlic which is responsible for the antibacterial and antifungal activity of extracts of this plant. The effect of bacteriostatic concentrations of allicin (0.2 to 0.5 mM) on the growth of Salmonella typhimurium revealed a pattern of inhibition characterized by: (i) a lag of approximately 15 min between addition of allicin and onset of inhibition, (ii) a transitory inhibition phase whose duration was proportional to allicin concentration and inversely proportional to culture density, (iii) a resumed growth phase which showed a lower rate of growth than in uninhibited controls, and (iv) an entry into stationary phase at a lower culture density. Whereas DNA and protein syntheses showed a delayed and partial inhibition by allicin, inhibition of RNA synthesis was immediate and total, suggesting that this is the primary target of allicin action.
Kinetics and inhibition of reverse transcriptase from human and simian immunodeficiency viruses
Authors: Wu J C , Chernow M , Boehme R E , Suttmann R T , McRoberts M J , Prisbe E J , Matthews T R , Marx P A , Chuang R Y , Chen M S
Published: June 2012

Reverse transcriptase from the simian immunodeficiency virus (SIV) was found to have kinetic behavior similar to that of enzyme from the human immunodeficiency virus (HIV). Michaelis constants for the substrates TTP and dGTP and inhibition constants for the inhibitors 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2'-3'-dideoxyguanosine 5'-triphosphate were obtained for SIV reverse transcriptase and were found to be similar to the corresponding values for HIV reverse transcriptase. Thus, the interaction of SIV reverse transcriptase with nucleotide analogs appears to be indistinguishable from that of the HIV enzyme, suggesting that SIV/simian acquired immunodeficiency syndrome (SAIDS) is a potentially good model of AIDS.
Decrease in antimicrobial susceptibility of Bordetella bronchiseptica caused by antigenic modulation and phase variation
Authors: Ishikawa H , Isayama Y , Ohmae K
Published: June 2012

The susceptibilities to 20 antimicrobial agents of Bordetella bronchiseptica variants in C mode and degraded phases were compared with those of their parents in X mode. Increases in MICs of 4- to 32-fold were observed for ampicillin, carbenicillin, erythromycin, novobiocin, rifampin, chloramphenicol, nalidixic acid, and oxolinic acid.
Detection of plasmid-mediated beta-lactamases with DNA probes
Authors: Huovinen S , Huovinén P , Jacoby G A
Published: June 2012

beta-Lactamase identification by colony hybridization with 32P-labeled DNA probes for TEM-1, SHV-1, OXA-1, OXA-2, PSE-1, PSE-2, and PSE-4 was compared with isoelectric focusing in 122 clinical isolates making a variety of enzyme types. All strains producing a probe-type enzyme gave a positive hybridization reaction. Cross-hybridization was observed between TEM-1 and TEM-2 or TLE-1, between SHV-1 and SHV-2, between OXA-1 and OXA-4, between OXA-2 and OXA-3 (weak), between PSE-2 and OXA-6 or OXA-5 (weak), and among PSE-1, PSE-4, and CARB-3. With allowance for such cross-hybridization, only six strains gave false-positive reactions, and the procedure was 99% specific.
Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes
Authors: Tsuji A , Sato H , Kume Y , Tamai I , Okezaki E , Nagata O , Kato H
Published: June 2012

The specific binding of 3H-labeled gamma-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3H]muscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [3H]muscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.
In vitro evaluation of josamycin, spiramycin, and erythromycin against Rickettsia rickettsii and R. conorii
Authors: Raoult D , Roussellier P , Tamalet J
Published: June 2012

The antimicrobial activities of josamycin, erythromycin, and spiramycin against Rickettsia conorii and R. rickettsii were evaluated in two tests: a dye-uptake assay and a plaque assay. The MIC of josamycin was 1 microgram/ml for both species; the MICs of erythromycin and spiramycin were 4 to 8 and 16 to 32 micrograms/ml, respectively, for both species. Only josamycin may be of clinical use in treating spotted fever rickettsiosis. It may be useful in treating pregnant women and young children.
In vitro drug susceptibility of Chlamydia sp. strain TWAR
Authors: Kuo C C , Grayston J T
Published: June 2012

The in vitro susceptibilities of eight Chlamydia sp. strain TWAR isolates were tested against tetracycline, erythromycin, penicillin, ampicillin, sulfisoxazole, and a new drug, trospectomycin. The ranges of inhibitory concentrations of these antimicrobial agents, except for sulfonamide, were similar to those for Chlamydia trachomatis. Sulfisoxazole was not inhibitory at the highest nontoxic concentration tested.
In vitro susceptibility of Alcaligenes denitrificans subsp. xylosoxidans to 24 antimicrobial agents
Authors: Glupczynski Y , Hansen W , Freney J , Yourassowsky E
Published: June 2012

The in vitro susceptibilities of 37 clinical isolates of Alcaligenes denitrificans subsp. xylosoxidans to 24 antimicrobial agents were determined. Imipenem was the only drug with consistent activity (MIC for 90% of isolates, 2 micrograms/ml). Piperacillin, ticarcillin-clavulanic acid, ceftazidime, and co-trimoxazole were active against most strains. All the isolates were resistant to ampicillin, cefazolin, cefuroxime, cefamandole, cefotetan, ceftriaxone, cefotaxime, aztreonam, amdinocillin, and temocillin. Most isolates were resistant to the aminoglycosides tested, including amikacin. Lack of activity was also observed for all new 4-quinolone antimicrobial agents.
Impact of LY146032 on Streptococcus (Enterococcus) faecalis translocation in mice
Authors: Dougherty S H , Hentges D J , Casey S W , Thal W R
Published: June 2012

The susceptibility of Swiss White mice to colonization with Streptococcus (Enterococcus) faecalis was greatly increased when the animals were given 5 mg of streptomycin sulfate per ml in their drinking water. One week after initiation of streptomycin treatment, the mice were challenged orogastrically with graded doses of streptomycin-resistant S. faecalis. The number of S. faecalis cells required to implant the intestinal tract of 50% of untreated mice was 2.9 X 10(9), but was only 4.8 X 10(3) for streptomycin-treated animals. When both groups of mice were challenged orogastrically with 4.6 X 10(6) viable S. faecalis cells, the cecum and small intestine of 100% of the streptomycin-treated animals, but only 10% of the untreated animals, were colonized with the organism. Similarly, translocation of S. faecalis to extraintestinal sites occurred in a majority of streptomycin-treated mice, but in only a small number of untreated mice. Subcutaneous administration of the experimental antibiotic LY146032 (Eli Lilly & Co., Indianapolis, Ind.) to streptomycin-treated mice concomitant with orogastric challenge with 5.5 X 10(5) viable S. faecalis cells resulted in a significant decrease in the incidence of intestinal colonization by the organism, a significant reduction in S. faecalis populations, and the absence of the organism in the liver, spleen, and heart. However, once intestinal colonization had occurred and extraintestinal infections were established, LY146032 did not significantly reduce S. faecalis populations or ameliorate the infections. We conclude that LY146032 effectively prevents translocation of S. faecalis from the intestinal tract of mice but does not resolve established extraintestinal infections.
Oxacillin, cephalothin, and vancomycin tube macrodilution MBC result reproducibility and equivalence to MIC results for methicillin-susceptible and reputedly tolerant Staphylococcus aureus isolates
Authors: Pelletier L L , Baker C B
Published: June 2012

Measurement of antimicrobial killing endpoints of Staphylococcus aureus isolates in tube macrodilution MBC testing has been difficult because of multiple technical factors. A total of 41 fresh clinical isolates and 23 reputedly oxacillin-tolerant strains were examined by a modification of the Taylor MBC method. Oxacillin, cephalothin, and vancomycin MBCs were equal to MICs for most strains and were seldom more than fourfold greater than the corresponding MICs after a 48-h incubation. Oxacillin MBC result reproducibility for S. aureus ATCC 25923 and clinical isolates was better than that of cephalothin and vancomycin, and reproducibility improved after a 48-h incubation. Measurement of the percentage of the initial inoculum remaining after 24 and 48 h of incubation for the strains for which the MBCs were highest confirmed improved killing over a wide range of antimicrobial concentrations after a 48-h incubation. Since S. aureus MBC testing is expensive, is subject to error, and almost always gives results equal to the MIC, we suggest that MBC testing is an experimental reference laboratory test that should not be done by clinical microbiology laboratories. Antimicrobial selection should be based on reproducible and standardized MIC tests.
Size of diffusion pore of Alcaligenes faecalis
Authors: Ishii J , Nakae T
Published: June 2012

The diffusion pore of the outer membrane of Alcaligenes faecalis was shown to be substantially smaller than the Escherichia coli porin pore. In experiments with intact cells, pentoses and hexoses penetrated into the NaCl-expanded periplasm, whereas saccharides of Mr greater than 342 did not. Cells treated with 0.5 M saccharides of Mr greater than 342 weighed 33 to 38% less than cells treated with isotonic solution, suggesting that these saccharides do not permeate through the outer membrane. The diffusion rates of various solutes through the liposome membranes reconstituted from the Mr-43,000 outer membrane protein showed the following characteristics. (i) The relative diffusion rates of pentoses, hexoses, and methylhexoses appeared to be about 1.0, 0.6, and negligibly small, respectively. (ii) The diffusion rate of glucose appeared to be about 1/10th that with the E. coli B porin. (iii) The diffusion rate of gluconic acid was five to seven times higher than that of glucose. (iv) The diffusion rates of beta-lactam antibiotics appeared to be 40 to less than 10% of those with the E. coli B porin.
Susceptibilities of transparent, opaque, and rough colonial variants of Mycobacterium avium complex to various fatty acids
Authors: Saito H , Tomioka H
Published: June 2012

Three different colonial variants of Mycobacterium avium complex were studied for their susceptibilities to capric, lauric, oleic, and linolenic acids. Smooth T variants with transparent and irregularly shaped colonies were much more resistant to all the fatty acids than were the smooth D variants with opaque and dome-shaped colonies. Rough variants with granular and irregularly shaped colonies showed nearly the same susceptibility to the fatty acids as did the smooth T variants.
Comparison of two methods for determining in vitro postantibiotic effects of three antibiotics on Escherichia coli
Authors: Rescott D L , Nix D E , Holden P , Schentag J J
Published: June 2012

The postantibiotic effect (PAE) for 10 isolates of Escherichia coli was measured by two methods after 1 h of exposure to ampicillin, ciprofloxacin, or tobramycin. The reference method involved serial colony counting to determine growth after antibiotic exposure in relation to control growth. A spectrophotometric procedure was developed with the Abbott MS-2 research system. This method measured the time to detection of growth after exposure and compared this with the time for growth detection in control chambers having the same initial colony count. A reference curve of time to growth versus log initial CFU per milliliter was used to standardize control growth. PAE was determined after exposure to antibiotic at two and six times the MIC and with inocula ranging from 10(3) to 10(9) CFU/ml. There was a statistically significant correlation between PAE measured by the spectrophotometric and the reference methods, and the residuals about the regression line were normally distributed. The mean PAE determined by both methods was statistically different for tobramycin-exposed, but not for ampicillin- or ciprofloxacin-exposed, organisms. There was a concentration-dependent PAE for ciprofloxacin and tobramycin. The PAEs for ciprofloxacin (151 min) and tobramycin (108 min) at concentrations six times the MIC were prolonged compared with those measured at two times the MIC (69 and 66 min, respectively). PAE was inversely related to the exposed inoculum for ciprofloxacin and tobramycin. The PAE for E. coli exposed to ampicillin was minimal and was not affected by either concentration or inoculum. The MS-2 method for determining PAE yields similar results, but is less laborious than the reference method.
Pharmacokinetics of cefonicid in patients with skin and skin structure infections
Authors: Heim-Duthoy K L , Peltier G L , Guay D R , Matzke G R
Published: June 2012

The disposition of cefonicid (2 g intravenously every 24 h) was assessed in 15 patients with skin and skin structure infections. Trough and peak concentrations in serum were measured on two successive days to verify the attainment of steady state; and 1 trough and 12 postdose values of the concentration in serum were collected on the following day. Cefonicid concentrations in serum were determined by high-performance liquid chromatography. The cefonicid serum concentration versus time profile after intravenous infusion was clearly biexponential in all patients. The terminal elimination half-life determined by nonlinear regression analysis was 4.63 +/- 1.49 h (mean +/- standard deviation). The steady-state volume of distribution and total body clearance were 0.12 +/- 0.04 liter/kg and 0.369 +/- 0.110 ml/min per kg, respectively. These results are comparable to parameters derived from previous studies in noninfected normal volunteers. Thus, the disposition of cefonicid is not altered in patients with severe skin and skin structure infections.
Haemophilus influenzae penicillin-binding proteins 1a and 3 possess distinct and opposite temperature-modulated penicillin-binding activities
Authors: Malouin F , Bryan L E
Published: June 2012

Upon investigation of penicillin-binding proteins (PBPs) in Haemophilus influenzae strains, five H. influenzae and seven other Haemophilus strains were tested for whole-cell penicillin binding at either 37 or 42 degrees C. Binding of [35S]penicillin G to H. influenzae PBPs 3a and 3b was drastically reduced at 42 degrees C, while PBP 1a showed a temperature-modulated increase in penicillin binding. Further investigation revealed that growth at 42 degrees C causes altered electrophoretic mobility of PBP 3a on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and that cell labeling performed at 42 degrees C showed the differential penicillin binding to target proteins. All Haemophilus spp. tested showed a similar temperature modulation of penicillin binding. Growth measurement and cell viability studies performed at 42 degrees C permitted correlation of PBP 3 temperature sensitivity to H. influenzae resistance to moxalactam at 42 degrees C, and the probable correlation of PBP 1a increased penicillin binding to the more rapid antibacterial activity of penicillin G against H. influenzae at 42 degrees C. Microscopic examination of Haemophilus cells grown at 42 degrees C revealed filamentous cell formation, supporting a role of PBP 3 in the septation process. Results of this study demonstrate that wild-type H. influenzae strains (and possibly all other Haemophilus spp.) possess PBPs 1a and 3, which have distinct and opposite temperature-modulated penicillin-binding activities.
Crystal and molecular structure of the antimalarial agent 4-(tert-butyl)-2-(tert-butylaminomethyl)-6-(4-chlorophenyl)phenol dihydrogen phosphate (WR 194,965 phosphate)
Authors: Karle J M , Karle I L
Published: June 2012

WR 194,965 phosphate, a new antimalarial agent containing a biphenyl ring structure active against chloroquine-resistant Plasmodium falciparum, crystallized in ionic form with a positive charge on the quaternary nitrogen atom. The oxygen and nitrogen atoms of WR 194,965 were hydrogen bonded to the same phosphate group. The nitrogen atom was also hydrogen bonded to a second phosphate group. The phosphate ions formed discrete clusters of four phosphate moieties. The phosphate clusters contained fourfold inversion symmetry. The intramolecular N-O distance in WR 194,965 of 3.073 A (1 A = 0.1 nm) was close to the reported values for N-O distances in the active cinchona alkaloids and may be important for activity. A comparison of the crystalline structure of WR 194,965 with those of mefloquine and quinidine sulfate demonstrated that the regions of the three molecules in the vicinity of the aliphatic nitrogen atom and the oxygen atom superimpose. Much of the remainder of the WR 194,965 molecule spatially overlapped with the combined three-dimensional space defined by quinidine and mefloquine. The crystallographic parameters were: C21H29ClNO+.H2PO4-; Mr = 443.9; symmetry of unit cell, tetragonal; space group, I41/a; parameters of unit cell, a = b = 24.305 +/- 0.002 A, c = 17.556 +/- 0.003 A; V (volume of unit cell) = 10370.9 A3; Z (number of molecules per unit cell) = 16; Dx (calculated density) = 1.137 g cm-3; source of radiation, CuK alpha (lambda = 1.54178 A); mu (absorption coefficient) = 21.3 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) = 3,440; room temperature; final R = 8.2% for 2,508 reflections with [F0] greater than 3 sigma.
Evaluation of ceftriaxone and other antibiotics against Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pneumoniae under in vitro conditions simulating those of serious infections
Authors: Satta G , Cornaglia G , Foddis G , Pompei R
Published: June 2012

In pursuit of an in vitro system capable of reliably predicting the activities of antibiotics in serious infections and in infections occurring in immunocompromised hosts, we evaluated the abilities of four drugs to achieve virtually complete killing of bacterial cells growing in human body fluids in amounts which are very high and close to those likely to be present in serious infections; drug concentrations varied with time as they vary in human bronchial secretions or blood or urine (dynamic concentrations). The rationale for such a test was (i) to set up in vitro conditions as close as possible to those the antibiotics encounter in serious infections and (ii) to hold the drugs capable of almost completely killing the bacteria used in the assay to be highly active in vitro and likely to be the most efficacious in the treatment of serious infections. Among the antibiotics used, ceftriaxone proved to be highly active under conditions simulating pulmonary infections and septicemias caused by Streptococcus pneumoniae (bacteria grown in bronchoalveolar fluid or blood; antibiotic concentrations varying with time as in human bronchial secretions or blood) and under conditions simulating blood and urinary infections caused by Escherichia coli (bacteria grown in human blood or urine; antibiotic concentrations varying as in the various fluids). Gentamicin (not tested against pneumococci) appeared to be highly active only under conditions simulating urinary infections caused by E. coli; aztreonam (not tested against pneumococci) and ampicillin (tested only against pneumococci) did not appear to be highly active under any of the test conditions. Only the combination of gentamicin plus either ceftriaxone or aztreonam appeared to be highly active under conditions simulating serious septicemias and urinary infections caused by Psudomonas aeruginosa.
Purification and characterization of human renal dehydropeptidase I
Authors: Mitsuhashi S , Fuse A , Mikami H , Saino Y , Inoue M
Published: June 2012

Dehydropeptidase I from human kidney was purified over 100-fold. The purified enzyme had an isoelectric point of 4.75, apparent molecular weights of 135,000 by gel filtration and of 66,500 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and an optimal pH of 7.4. Human renal dehydropeptidase I hydrolyzed imipenem, carpetimycins A and B, and Sch 29,482.
Comparison of dosages, intervals, and drugs in the prevention of Pneumocystis carinii pneumonia
Authors: Hughes W T
Published: June 2012

The efficacies of trimethoprim (TMP)-sulfamethoxazole (SMZ), TMP-dapsone, dapsone, and pentamidine were compared for the prevention of Pneumocystis carinii pneumonia in the corticosteroid-treated-rat model. While 11 (73%) of 15 untreated control animals had P. carinii pneumonia after 10 weeks of immunosuppression, none of the animals given 125 mg of dapsone per kg daily, weekly, biweekly, or monthly had evidence of infection. Of the 10 rats given a single dose of dapsone 23 and 50 days after immunosuppression was started, 5 (50%) had P. carinii pneumonia. When three drugs were given separately to groups of 10 rats in single doses biweekly, P. carinii pneumonia occurred in 40% of those treated with TMP-SMZ and in none of those treated with TMP-dapsone; although only 2 of those treated with pentamidine survived for evaluation, both had P. carinii pneumonia. The experiments showed that dapsone is highly effective in chemoprophylaxis for P. carinii pneumonia when given at monthly intervals or more frequently and that dapsone and TMP-dapsone are more effective than is TMP-SMZ when given at biweekly intervals. It seems reasonable to expect that biweekly doses of dapsone or TMP-dapsone would provide an effective and reasonably safe chemoprophylaxis regimen for patients at high risk for P. carinii pneumonia, and studies to test such a scheme are justifiable. Biweekly doses are preferred over monthly doses to allow for occasional inadvertent omission of doses expected from patients.
Activity of E-3846, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats
Authors: Gargallo D , Moros M , Coll R , Esteve M , Parés J , Xicota M A , Guinea J
Published: June 2012

The in vitro antibacterial activity of E-3846, a new fluoroquinolone carboxylic acid derivative with a pyrrol ring substituent at position 7, was evaluated in comparison with norfloxacin and ciprofloxacin. E-3846 was more active than the reference quinolones against Staphylococcus species, including methicillin-resistant strains. E-3846 was similar to ciprofloxacin and more active than norfloxacin against Streptococcus (Enterococcus) faecalis. In general, E-3846 was more active than norfloxacin against members of the family Enterobacteriaceae, but less active than ciprofloxacin. For Pseudomonas aeruginosa, the MICs giving 90% inhibition for E-3846, norfloxacin, and ciprofloxacin were 2, 1, and 0.25 micrograms/ml, respectively. The activity of E-3846 increased at acid pH; in contrast, acid pH caused a pronounced decrease in the activity of norfloxacin and ciprofloxacin. In vivo, E-3846 demonstrated excellent therapeutic efficacy in treating experimental S. faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa cystitis and pyelonephritis in rats.
Efficacy of S26308 against guinea pig cytomegalovirus infection
Authors: Chen M , Griffith B P , Lucia H L , Hsiung G D
Published: June 2012

Prophylactic use of antiviral agents against cytomegalovirus (CMV) is particularly indicated for the immunocompromised host because morbidity and mortality due to CMV occur most frequently following immunosuppression. We have evaluated the new Riker compound S26308 for its therapeutic and prophylactic antiviral activity against CMV in guinea pigs. The efficacy of the compound was assessed in vitro in guinea pig embryo cells and in vivo in both immunocompetent and immunocompromised guinea pigs. Guinea pig CMV plaque formation was reduced only in cells treated with S26308 prior to virus infection. The antiviral activity remained even when the compound was removed after virus absorption and was due to neither virus destruction nor inhibition of cell growth. The frequency of viremia was reduced in guinea pigs for which S26308 therapy was initiated 24 h prior to virus inoculation compared with sham-treated animals. This reduction in the frequency of viremia did not prevent virus spread to target tissues but did result in a reduction of the severity of CMV-induced disease in immunocompromised guinea pigs. Low levels of interferon were detected in supernatants of S26308-treated cells, and interferon was detected in the serum of guinea pigs given S26308. These results indicate that S26308 can induce interferon and reduce CMV infectivity in vivo and in vitro when used prophylactically. This antiviral activity, although modest, was accompanied by beneficial effects on CMV-induced morbidity and mortality. Prophylactic use of S26308 in combination with other therapeutic agents may be a useful strategy against CMV infections.
Relative penicillin G resistance in Neisseria meningitidis and reduced affinity of penicillin-binding protein 3
Authors: Mendelman P M , Campos J , Chaffin D O , Serfass D A , Smith A L , Sáez-Nieto J A
Published: June 2012

We examined clinical isolates of Neisseria meningitidis relatively resistant to penicillin G (mean MIC, 0.3 micrograms/ml; range, 0.1 to 0.7 micrograms/ml), which were isolated from blood and cerebrospinal fluid for resistance mechanisms, by using susceptible isolates (mean MIC, less than or equal to 0.06 micrograms/ml) for comparison. The resistant strains did not produce detectable beta-lactamase activity, otherwise modify penicillin G, or bind less total penicillin. Penicillin-binding protein (PBP) 3 of the six resistant isolates tested uniformly bound less penicillin G in comparison to the same PBP of four susceptible isolates. Reflecting the reduced binding affinity of PBP 3 of the two resistant strains tested, the amount of 3H-labeled penicillin G required for half-maximal binding was increased in comparison with that of PBP 3 of the two susceptible isolates. We conclude that the mechanism of resistance in these meningococci relatively resistant to penicillin G was decreased affinity of PBP 3.
Susceptibility of the Bacteroides fragilis group in the United States: analysis by site of isolation
Authors: Cuchural G J , Tally F P , Jacobus N V , Aldridge K , Cleary T , Finegold S M , Hill G , Iannini P , O'Keefe J P , Pierson C
Published: June 2012

An ongoing survey of the susceptibility of the Bacteroides fragilis group of bacteria was continued at New England Medical Center in 1984 and 1985. A total of 1,229 strains were obtained from eight centers in the United States. These results were compared with those for 1,847 isolates tested in 1981 through 1983. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid (Timentin), which had a less than 1% resistance rate. No metronidazole- or chloramphenicol-resistant isolates were found during the 5 years of the study. Isolates obtained from blood, perinatal, and bone sites of infection were more resistant to a variety of antimicrobial agents. Susceptibility patterns of the members of the B. fragilis group varied at the eight hospitals and among species. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.
Effect of aminoglycoside concentration on reaction rates of aminoglycoside-modifying enzymes
Authors: Bongaerts G P , Vliegenthart J S
Published: June 2012

Reaction rates of several reference aminoglycoside-modifying enzymes were studied at various substrate concentrations. The resulting concentration-response curves showed wide variation in threshold concentration, in curve slope, in enzyme saturation, and in substrate inhibition. Together, the curves of a defined aminoglycoside panel yielded more specific information for each individual aminoglycoside-modifying enzyme tested than did conventional substrate profiles obtained at a single substrate concentration.
Restriction mapping and hybridization studies of a beta-lactamase-encoding fragment from Streptococcus (Enterococcus) faecalis
Authors: Zscheck K K , Hull R , Murray B E
Published: June 2012

A restriction map of a 5.1-kilobase EcoRI fragment encoding an enterococcal beta-lactamase was prepared and compared with the restriction map of a cloned staphylococcal beta-lactamase gene and with the published maps of several other staphylococcal beta-lactamase genes. Comparison and hybridization studies showed that there were identical restriction sites in the region of the bla structural gene but not in the region surrounding this gene.
Pharmacokinetics of two multiple-dose mezlocillin regimens
Authors: Janicke D M , Parker S W , Cafarell R F , Apicella M A , Jusko W J
Published: June 2012

The pharmacokinetics of mezlocillin at two dosages were studied over the course of therapy in 12 patients receiving the drug for the treatment of infections. Patients received an initial dosing regimen of 4 g every 6 h or 5 g every 8 h, which was switched to the alternative regimen after 5 days of treatment. Both drug regimens demonstrated similar pharmacokinetic characteristics, which suggests that the reported dose-dependent elimination of mezlocillin is not an important factor in the clinical use of mezlocillin at the dosages currently used.
Alterations in outer membrane proteins of Pseudomonas aeruginosa associated with selective resistance to quinolones
Authors: Daikos G L , Lolans V T , Jackson G G
Published: June 2012

Electrophoresis of outer membrane proteins in three ciprofloxacin-resistant strains of Pseudomonas aeruginosa isolated during therapy and their in vitro revertants indicated that diminution or loss of a 31- to 32-kilodalton outer membrane protein correlated with resistance in two of the three isolates. Resistance was unstable and caused no cross-resistance with other antibiotics.
Cyclohexane triones, novel membrane-active antibacterial agents
Authors: Lloyd W J , Broadhurst A V , Hall M J , Andrews K J , Barber W E , Wong-Kai-In P
Published: June 2012

The cyclohexane triones are a novel group of synthetic antibacterial agents that are active against gram-positive bacteria, Haemophilus influenzae, and Mycobacterium smegmatis. In general, these compounds behaved in a manner similar to that of hexachlorophene, inhibiting the transport of low-molecular-weight hydrophilic substances into bacteria. Unlike cationic detergents, such as chlorhexidine, they did not cause disruption of the bacterial cytoplasmic membrane over a short time period. The most potent antibacterial cyclohexane trione studied had a reduced ability to inhibit solute transport in comparison with certain less active analogs. Cyclohexane triones may express more than a single type of antibacterial effect.
Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia
Authors: Walzer P D , Kim C K , Foy J , Linke M J , Cushion M T
Published: June 2012

Cationic compounds used in the treatment of veterinary African trypanosomiasis have structural properties similar to those of pentamidine, which has been used in the therapy of human trypanosomiasis and infection with Pneumocystis carinii. We have compared the activities of these drugs and other antimicrobial agents in an immunosuppressed rat model of P. carinii pneumonia. Diminazene, imidocarb, amicarbalide, quinapyramine, and isometamidium showed efficacy greater than or equal to that of pentamidine in the therapy of P. carinii infection, whereas ethidium and methylglyoxal bis(guanylhydrazone) were only slightly active against the organism. Diminazene and pentamidine also exhibited comparable efficacy in P. carinii prophylaxis, alpha-Difluoromethylornithine (DFMO), a polyamine inhibitor, was ineffective therapy when used alone and did not improve the effectiveness of pentamidine or diminazene. Quinine, quinidine, quinacrine, chlorpromazine, spiramycin, Pentostam, Astiban, dehydroemetine, ampicillin, gentamicin, chloramphenicol, and spectinomycin also showed little or no activity against the organism. Thus, in this model anti-P. carinii activity appears to be a common property of veterinary cationic trypanocidal compounds. This should be important in studying structure-activity relationships and in developing new drugs for the treatment of P. carinii infection in humans.
Comparative pharmacokinetics of tromethamine fosfomycin and calcium fosfomycin in young and elderly adults
Authors: Borsa F , Leroy A , Fillastre J P , Godin M , Moulin B
Published: June 2012

The pharmacokinetics of two oral forms of fosfomycin, tromethamine (trometamol) salt and calcium salt, were studied in five young (age, 29 +/- 3 [standard deviation] years) and eight elderly (age, 72 +/- 6 years) adults. The subjects received a single 40-mg/kg (body weight) (approximately equal to 3-g) calcium fosfomycin dose and a 25-mg/kg (approximately equal to 2-g) tromethamine fosfomycin dose in fosfomycin acid form. Blood and urine samples were collected for 24 h. Antibiotic concentrations in serum and urine were measured by microbiological assay. In all subjects, the peak levels of the calcium salt in serum were two- to fourfold lower than those of the tromethamine salt (6 to 7 and 18 to 22 micrograms/ml, respectively), indicating poor intestinal absorption of the calcium form. The elimination half-life of the two oral forms was about 5 h in young adults, and the half-life was only moderately longer in elderly subjects, with large individual variations: 8.28 +/- 5.51 h for tromethamine fosfomycin and 11.80 +/- 6.86 h for calcium fosfomycin. In elderly subjects, absorption of the tromethamine salt form was not modified, but the time to peak level was delayed for the calcium salt (2.58 +/- 0.54 h versus 1.41 +/- 0.67 h in young adults). Pharmacokinetic elimination of the two forms of fosfomycin was only moderately affected in elderly subjects; we observed lower urinary elimination, about 58 versus 28% of the dose in 24-h urines for the tromethamine salt and decreased renal clearance of both forms. However, the dosages of tromethamine and calcium fosfomycin need not be adjusted for elderly subjects who have endogenous creatinine clearances above 50 ml/min per 1.73 m2.