bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth of group IV mycobacteria on medium containing various saturated and unsaturated fatty acids
Authors: Saito H , Tomioka H , Yoneyama T
Published: June 2012

Seventy-one strains of 15 species of rapidly growing mycobacteria were studied for their susceptibilities to fatty acids with 2 to 20 carbons by the agar dilution method at pH 7.0. Most mycobacteria other than potential pathogens (Mycobacterium fortuitum and Mycobacterium chelonei) were resistant to saturated fatty acids, except for lauric acid (C12:0) (MIC, 6.25 to 25 micrograms/ml) and capric acid (C10:0) (MIC, 50 to 100 micrograms#ml). M. fortuitum and M. chelonei were substantially insusceptible to these fatty acids. Unsaturated fatty acids with 16 to 20 carbons, except for C20:5, were highly toxic to group IV mycobacteria other than M. fortuitum, M. chelonei, Mycobacterium smegmatis, and Mycobacterium phlei, these being highly resistant to all the unsaturated acids, except for C16:1, C18:3, and C20:5. Introduction of double bonds to C16 to C20 fatty acids caused a marked increase in their activities that depended on the increase in the number of double bonds, at least up to three or four. M. fortuitum and M. chelonei were more resistant to the unsaturated fatty acids (particularly to C20:3 and C20:4) than the other group IV mycobacteria.
Comparative in vitro activity and beta-lactamase stability of FR 17027, a new orally active cephalosporin
Authors: Neu H C , Chin N X , Labthavikul P
Published: June 2012

FR 17027, a new orally absorbed cephalosporin ester, inhibited group A and B streptococci and Streptococcus pneumoniae at less than or equal to 0.1 micrograms/ml, which is similar to the inhibition concentration of amoxicillin and cefaclor, and was more active than cephalexin. It was less active (MIC, 25 micrograms/ml) against staphylococci than was cephalexin, and it did not inhibit Streptococcus faecalis or Listeria monocytogenes. FR 17027 inhibited beta-lactamase-producing isolates of Neisseria gonorrhoeae, Haemophilus influenzae, and Branhamella catarrhalis at less than 0.1 micrograms/ml and was more active than cefaclor or cephalexin against these bacteria. FR 17027 inhibited Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, Providencia stuartii, Providencia rettgeri, and Citrobacter diversus at less than or equal to 1 microgram/ml, including isolated resistant to amoxicillin, cephalexin, and cefaclor, but it was less active than ceftizoxime. Some strains of Enterobacter cloacae, Enterobacter agglomerans, Citrobacter freundii, and Enterobacter aerogenes were resistant (MIC, greater than 25 micrograms/ml). FR 17027 did not inhibit Pseudomonas aeruginosa, other Pseudomonas species, Acinetobacter species, or Bacteroides species. Activity was minimally affected by growth conditions. FR 17027 was not hydrolyzed by the common beta-lactamases present in many of the pathogens causing respiratory and urinary tract infections in outpatients.
Correlation between lipopolysaccharide structure and permeability resistance in beta-lactam-resistant Pseudomonas aeruginosa
Authors: Godfrey A J , Hatlelid L , Bryan L E
Published: June 2012

Four beta-lactam-resistant permeability mutants of Pseudomonas aeruginosa PAO503 were studied. The resistance phenotypes were correlated to changes within the lipopolysaccharide. Two of the mutants, PCC1 and PCC19, were shown to differentiate between beta-lactams on the basis of relative hydrophobicity. The more hydrophilic antibiotics were less effective at inhibiting these strains. This phenotype was correlated to the presence of mannose, in measurable quantities, in lipopolysaccharide isolated from these strains. The other two strains, PCC23 and PCC100, differentiated between cephem antibiotics on the basis of electrical charge. The presence of a positive charge markedly increased the relative efficiency of an antibiotic. This correlation did not hold for penam derivatives, with the lower-molecular-weight, dianionic molecules being the most effective. Mutants of this type were changed in the amount of "side chain" sugars or, to minor extent, in their outer membrane protein profiles.
In vitro and in vivo antibacterial activities of K-4619, a new semisynthetic aminoglycoside
Authors: Saino Y , Hattori Y , Koshi T , Kobayashi F , Oda T , Mitsuhashi S
Published: June 2012

The antibacterial activities of K-4619 (3-de-O-methylsporaricin A sulfate) were compared with those of sporaricin A, amikacin, dibekacin, and gentamicin. K-4619 exhibited a high order of activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against Providencia species and Serratia marcescens was the highest of all drugs tested. K-4619 was highly effective against bacteria that produce various aminoglycoside-inactivating enzymes, except for 3-acetyltransferase I. The bactericidal activity of K-4619 was somewhat greater than that of amikacin. The activity of K-4619 against gram-negative bacteria increased at alkaline pH and was hardly affected by inoculum size, addition of horse serum, and composition of the medium. The in vivo protective effect of K-4619 against infections with Klebsiella pneumoniae, S. marcescens, and P. aeruginosa in mice was greater than that of sporaricin A. K-4619 was also active in mice infected with gentamicin- or amikacin-resistant strains bearing some of the aminoglycoside-inactivating enzymes.
Comparative inhibition of bacterial and microsomal 3-ketodihydrosphingosine synthetases by L-cycloserine and other inhibitors
Authors: Sundaram K S , Lev M
Published: June 2012

Eleven compounds were examined for their capacity to inhibit the first enzyme of the sphingolipid pathway, 3-ketodihydrosphingosine synthetase. Of these, L-cycloserine was the most potent, affecting both bacterial and brain microsomal enzymes to a significant degree at 0.04 mM. D- and L-cycloserine irreversibly inactivated the enzyme, indicating a suicide substrate mode of action. L-Cycloserine was a more potent inhibitor of the growth of Bacteroides levii than was D-cycloserine, indicating that inhibition of sphingolipid synthesis could be a factor in the growth inhibition.
Tetracycline diffusion through phospholipid bilayers and binding to phospholipids
Authors: Argast M , Beck C F
Published: June 2012

The ability of tetracycline to pass through phospholipid bilayers by diffusion was investigated. Liposomes did not retain enclosed tetracycline. Accumulation of tetracycline was observed with liposomes containing entrapped Tet repressor protein. These results indicate that the drug can pass through lipid bilayers. The antibiotic was also shown to bind to liposomes and isolated phospholipids.
In vitro activities of teichomycin, fusidic acid, flucloxacillin, fosfomycin, and vancomycin against methicillin-resistant Staphylococcus aureus
Authors: Guenthner S H , Wenzel R P
Published: June 2012

Flucloxacillin, fosfomycin, fusidic acid, teichomycin, and vancomycin were tested against 50 clinical isolates of methicillin-resistant Staphylococcus aureus by a broth macrodilution technique. Teichomycin had a narrow range of activity, similar to that of vancomycin (0.5 to 2.0 micrograms/ml). Fusidic acid had the lowest range of inhibitory activity, with 50 and 90% MICs of 0.19 and 0.35 micrograms/ml, respectively. Flucloxacillin and fosfomycin showed less activity, with MICs up to 32 micrograms/ml.
Activities of cefoxitin and cefotetan against Mycobacterium fortuitum infections in mice
Authors: Saito H , Sato K , Jin B W
Published: June 2012

Mice inoculated intravenously with Mycobacterium fortuitum 18367 were treated subcutaneously with cefoxitin or cefotetan once daily for 4 weeks, beginning 24 h after challenge. Both drugs suppressed spinning disease, and both reduced the severity of renal lesions and the number of organisms in the kidneys and liver but not in the lungs or spleen. These therapeutic effects were dose-dependent.
Effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new antiherpesvirus compound, on synthesis of macromolecules in herpes simplex virus-infected cells
Authors: Cheng Y C , Grill S P , Dutschman G E , Frank K B , Chiou J F , Bastow K F , Nakayama K
Published: June 2012

We examined the effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on viral DNA, RNA, protein, and enzyme synthesis in HeLa cells infected with herpes simplex virus type 1 and type 2. DHPG inhibited virus DNA synthesis in a dose-dependent fashion. This inhibition was not due to the lack of deoxynucleoside triphosphates which are required for DNA synthesis. This compound has no apparent effect on early and late viral RNA synthesis, viral protein synthesis, or viral thymidine kinase, DNA polymerase, and DNase induction in virus-infected cells.
Penetration of pefloxacin into cerebrospinal fluid of patients with meningitis
Authors: Wolff M , Regnier B , Daldoss C , Nkam M , Vachon F
Published: June 2012

We evaluated the diffusion of pefloxacin into the cerebrospinal fluid (CSF) in 15 patients with bacterial meningitis or ventriculitis, 14 of whom were treated with other antibiotics. Three doses of pefloxacin were administered at 12-h intervals to 11 patients intravenously and to 4 patients orally. Individual doses were 7.5 mg/kg in seven patients and 15 mg/kg in eight patients. Plasma and CSF levels were determined by a high-performance liquid chromatographic assay. The concentrations of pefloxacin in CSF were measured 2 h after the third intravenous dose and 4 h after the third oral dose. In patients receiving 7.5 mg/kg, peak levels in plasma ranged from 6.8 to 16 micrograms/ml, and trough levels were from 2 to 7.5 micrograms/ml. Concentrations in CSF ranged from 2.4 to 9 micrograms/ml. In patients receiving 15 mg/kg, peak levels in plasma ranged from 14 to 18.6 micrograms/ml, and trough levels were from 4 to 13.2 micrograms/ml. Concentrations in CSF ranged from 6.5 to 13 micrograms/ml. These preliminary data indicate that pefloxacin diffuses well into the CSF of patients with inflamed meninges.
Improved procedure for determination of flucytosine in human blood plasma by high-pressure liquid chromatography
Authors: Schwertschlag U , Nakata L M , Gal J
Published: June 2012

Several high-pressure liquid chromatography procedures for the determination of flucytosine in serum or plasma have appeared. Some of these suffer from significant disadvantages, and none was applicable in our routine clinical therapeutic-drug-monitoring laboratory. A new high-pressure liquid chromatography assay for flucytosine was therefore developed. A 100-microliter sample of plasma was treated with an aqueous 5-iodocytosine internal-standard solution, and the mixture was deproteinized with trichloroacetic acid. A portion of the protein-free supernatant was diluted with 0.1 M ammonium phosphate, and an aliquot of the resulting solution was injected into the high-pressure liquid chromatography system. Chromatography was performed on a strong-cation-exchange column with a mobile phase containing aqueous ammonium phosphate, phosphoric acid, methanol, and acetonitrile. Detection was at 254 nm. The assay was shown to be linear in the 10 to 200-micrograms/ml drug-concentration range. Forty other drugs were tested for potential interference with the assay, and none was found. For routine use, a single-point working standard containing 75 micrograms of flucytosine per ml was used, giving intraassay coefficients of variation at 50 and 150 micrograms/ml of 1.8 and 2.3% respectively, whereas the day-to-day coefficient of variation at 50 micrograms/ml was 10.0%. Advantages of the procedure include the small sample size, the use of a convenient and reliable internal standard, speed, and simplicity. The assay is highly suitable for routine clinical drug-analysis laboratories.
Bactericidal activity of ceftazidime in serum compared with that of ticarcillin combined with amikacin
Authors: Standiford H C , Drusano G L , Fitzpatrick B , Tatem B , Schimpff S C
Published: June 2012

We compared the bactericidal activity of serum attained 1 and 6 h after the termination of infusions of either ceftazidime (2 g) or ticarcillin plus amikacin (5 g and 7.5 mg/kg, respectively) in 6 volunteers against a panel of the most common pathogens found in the blood of febrile granulocytopenic cancer patients. Ceftazidime consistently produced significantly higher serum bactericidal titers at both 1 and 6 h against all species of gram-negative bacilli. Its performance against Pseudomonas aeruginosa was especially impressive. The geometric mean titer against this organism was 1:41 at 1 h, contrasted with 1:12 for ticarcillin plus amikacin (P = 0.025). However, for Staphylococcus aureus, the geometric mean serum bactericidal titer of ceftazidime was 1:3.6 at 1 h and undetectable at 6 h. Ceftazidime shows promise as single-agent therapy for serious gram-negative bacillary infections. Whether this promise is fulfilled and whether the observed antistaphylococcal activity is adequate for empiric therapy in infected granulocytopenic patients need further investigation.
Production, purification, and characterization of chandramycin, a polypeptide antibiotic from Streptomyces lydicus
Authors: Singh S K , Gurusiddaiah S
Published: June 2012

A plant pathogenic actinomycete identified as Streptomyces lydicus was isolated from the deep-pitted scab lesions of potato tubers. This strain produces a new polypeptide antibiotic named chandramycin. The antibiotic was isolated from culture broth by extraction with organic solvents and purified by chromatography. The purified antibiotic is a light-yellow crystalline compound soluble in water and in most organic solvents. Amino acid analysis of the acid hydrolysates of chandramycin revealed the presence of glycine, cis-methyl proline, valine, beta, beta-dimethylaminobutyric acid, beta-methyl-phenylalanine, and beta-2-thioazolyl-beta-alanine. The amino acid composition of chandramycin is qualitatively similar to that of a known antibiotic, bottromycin A2. Chandramycin showed activity against several gram-positive and a few gram-negative species of bacteria. It showed a strong activity against anaerobic microorganisms. Oral doses of antibiotic when administered up to 466 mg/kg of body weight failed to produce any observable toxic effect in mice.
Evaluation of Sch 29482 in experimental syphilis and comparison with penicillin G benzathine in disseminated disease and localized infection
Authors: Baughn R E , Adams C , Musher D M
Published: June 2012

The present study was designed to assess the in vivo activity of Sch 29482, a new penem antibiotic, against disseminated and localized Treponema pallidum infections in rabbits. Animals were inoculated either intravenously or intradermally. Randomized groups then received 25 or 50 mg of Sch 29482 per kilogram of body weight twice a day for 7 days, two weekly injections of 200,000 U of penicillin G benzathine for comparative purposes, or no antibiotic therapy. In both infection models, striking differences were noted between the untreated control rabbits and rabbits receiving penicillin G benzathine or high-dose Sch 29482. Intravenously infected rabbits did not develop disseminated lesions or orchitis, and chancres produced by intradermal infection regressed and healed rapidly after both treatment regimens. Infectivity studies also suggested that high-dose Sch 29482 and penicillin G benzathine were effective since the testes and lymph nodes of treated animals were free of infectious organisms. Treatment of animals with the lower dose of Sch 29482 represented borderline or suboptimal therapy, with a failure rate of one in four for each infection model.
Susceptibilities of 45 clinical isolates of Proteus penneri
Authors: Fuksa M , Krajden S , Lee A
Published: June 2012

Patterns of susceptibility of 45 Proteus penneri clinical isolates to 14 antimicrobial agents were evaluated by a macrobroth dilution method. All strains were highly susceptible to ceftizoxime, ceftazidime, moxalactam, cefoxitin, gentamicin, tobramycin, netilmicin, and, with few exceptions, to amikacin, piperacillin, and cefoperazone. Most strains were susceptible to cefotaxime and ceftriaxone. All strains were resistant to cefazolin and cefsulodin.
Antimicrobial susceptibility of Branhamella catarrhalis isolates from bronchopulmonary infections
Authors: Ahmad F , McLeod D T , Croughan M J , Calder M A
Published: June 2012

Fifty-four clinical isolates of Branhamella catarrhalis from patients with bronchopulmonary infections were studied. The MICs for 50 and 90% of the isolates and the geometric mean MICs were determined for 11 antimicrobial agents. All the strains were resistant to trimethoprim but were susceptible to clavulanate-potentiated amoxicillin (Augmentin; Beecham Research Laboratories, London), chloramphenicol, co-trimoxazole, erythromycin, cefotaxime, and cefuroxime. Beta-lactamase-negative strains were uniformly susceptible to penicillin and ampicillin.
In vitro activity of A-16686, a potential antiplaque agent
Authors: Pallanza R , Scotti R , Beretta G , Cavalleri B , Arioli V
Published: June 2012

A-16686, a new glycoproteide antibiotic from Actinoplanes sp., was evaluated as a potential antiplaque agent in comparison with chlorhexidine, benzalkonium chloride, and cetylpyridinium chloride. A-16686 had good activity against gram-positive organisms associated with dental plaque (various streptococci, Streptococcus mutans in particular, lactobacilli, Actinomyces viscosus, and Actinomyces naeslundii); most of the strains tested were clinical isolates. It was bactericidal for streptococci (MBC/MIC ratio of less than or equal to 8 for 92% of the strains) and for growing cells of S. mutans briefly exposed to antibiotic (99.9% killing within 5 min of contact with 200 micrograms of A-16686 per ml). It also inhibited the in vitro plaque formation by S. mutans and had good activity against preformed plaques. For most cases, its activity was comparable to those of chlorhexidine, benzalkonium chloride, and cetylpyridinium chloride. A-16686 appears to be a promising antiplaque agent because of the following attributes: narrow spectrum of activity, rapid bactericidal action, lack of selection of resistant mutants, absence of cross-resistance with clinically used antibiotics, nonabsorption by oral route, good tolerability by the oral mucosa (rats and dogs), and physical characteristics (white powder, soluble in water).
Broad-spectrum synergistic antiviral activity of selenazofurin and ribavirin
Authors: Kirsi J J , McKernan P A , Burns N J , North J A , Murray B K , Robins R K
Published: June 2012

The antiviral effects of selenazofurin (2-beta-D-ribofuranosylselenazole-4-carboxamide, selenazole), ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), and 3-deazaguanosine (6-amino-1-beta-D-ribofuranosylimidazo-[4.5-C]pyridin-4(5H)-one) were investigated separately and in various combinations in an in vitro study. The combination interactions were evaluated at seven drug concentrations, graphically (isobolograms) or by using fractional inhibitory concentration indices against mumps, measles, parainfluenza virus type 3, vaccinia and herpes simplex virus type 2 viruses in Vero and HeLa cells. Selenazofurin in combination with ribavirin produced the greatest synergistic antiviral activity. However, the degree of synergy depended on the virus and cell line used. In contrast, selenazofurin combined with 3-deazaguanosine consistently yielded an indifferent or an antagonistic response, or both, whereas the ribavirin-3-deazaguanosine interaction was additive against the same viruses. Single-drug cytotoxicity was minimal for the cytostatic agents selenazofurin and ribavirin but was markedly higher for cytocidal 3-deazaguanosine, as determined by relative plating efficiency after drug exposure. The drug combinations did not significantly increase cytotoxicity (they were only additive) when used on uninfected cells. Therefore, the enhanced antiviral activities of the drug combinations (shown to be synergistic) were due to specific effects against viral replication. These results indicated that in Vero and HeLa cells (i) the combination of selenazofurin and ribavirin produced an enhanced antiviral effect, thus requiring smaller amounts of drug to cause the same antiviral effect relative to a single compound; (ii) selenazofurin when compared with ribavirin and 3-deazaguanosine appeared to have a somewhat different mode of antiviral action; (iii) 3-deazaguanosine combined with selenazofurin was an unsuitable antiviral combination; and (iv) the antiviral activity of 3-deazaguanosine appeared to be due largely to its general overall cytotoxic effect.
Effect of tetracyclines and UV light on oxygen consumption by human leukocytes
Authors: Glette J , Sandberg S , Haneberg B , Solberg C O
Published: June 2012

When polymorphonuclear leukocytes were stimulated with zymosan, a sharp rise in oxygen consumption was observed. In the presence of doxycycline, we observed a further increase in oxygen consumption when the phagocytosing cells were exposed to UV light. When the light was turned off, oxygen consumption of the cells almost ceased, indicating photodamage to polymorphonuclear leukocytes during irradiation. Irradiation of the polymorphonuclear leukocytes for 20 min in the presence of doxycycline (10 micrograms/ml) before phagocytosis completely abolished the rise in oxygen consumption initiated by zymosan. Demethylchlortetracycline and light exposure also caused a marked reduction of polymorphonuclear leukocyte oxygen consumption, whereas oxytetracycline, lymecycline, chlortetracycline, and minocycline had only a slight or no photosensitizing effect. The photodamage induced by doxycycline and demethylchlortetracycline was inhibited by azide and enhanced in deuterium oxide. This was in accordance with singlet oxygen-mediated damage.
Antibacterial activities of nitrothiazole against Campylobacter jejuni and Campylobacter coli
Authors: Hof H , Rieffert M , Sticht-Groh V , Zak O , Schweizer E H
Published: June 2012

Niridazole (Ambilhar) and three other newly synthesized nitrothiazole derivatives were highly active against 19 microaerophilic campylobacters (minimum concentration required to inhibit 50% of strains [MIC50], 0.0075 to 0.015 mg/liter). There were, however, considerable differences in the susceptibility among strains tested, and one nitrothiazole derivative was rather inactive (MIC50, 2 mg/liter). Nitroimidazole derivatives, such as metronidazole and tinidazole, were less active (MIC50, 2 and 4 mg/liter, respectively). The nitrofuran derivatives, such as nitrofurazone and nitrofurantoin, were also less active (MIC50, 1 mg/liter). Niridazole and another potent nitrothiazole derivative killed the campylobacters rapidly at low concentrations. In contrast, much higher concentrations of metronidazole were required to achieve bactericidal values.
Pharmacokinetics of cefotiam administered intravenously and intramuscularly to healthy adults
Authors: Brisson A M , Bryskier A , Millerioux L , Fourtillan J B
Published: June 2012

We studied the pharmacokinetics of cefotiam, a parenteral cephalosporin, at intravenous doses of 0.5, 1, and 2 g and intramuscular doses of 0.5 and 1 g in two groups of eight healthy adult volunteers. The concentrations of cefotiam in plasma were determined over a period of 5 or 6 h and in urine over 24 h, using high-pressure liquid chromatographic procedures. Plasma concentration-time data were fitted to a three-exponential equation for the intravenous administration, and after intramuscular administration, the data were analyzed by a two-compartment or a one-compartment open model. Over the above dosing range and routes of administration, cefotiam pharmacokinetics were essentially linear, with plasma clearances varying from 19.6 to 22.5 liters/h. No significant differences were observed with respect to the terminal half-life (1 h) and the area under the curve versus the dose. Intramuscularly injected cefotiam was 63 to 74% available. The fraction of dose excreted unchanged in urine (0.50 to 0.67) indicated a substantial nonrenal mechanism of elimination. The apparent volume of distribution (about 30 liters) was higher than those of other parenteral cephalosporins.
Itraconazole, a new triazole that is orally active in aspergillosis
Authors: Van Cutsem J , Van Gerven F , Van de Ven M A , Borgers M , Janssen P A
Published: June 2012

Itraconazole is a new orally active triazole derivative with broad-spectrum antifungal activity. This drug is effective in experimental aspergillosis and possesses in vitro activity against various species and strains of Aspergillus. Morphological destruction of inoculated hyphae and complete inhibition of hyphal outgrowth in culture is obtained from 0.07 micrograms ml-1 (10(-7)M) onward. These properties make itraconazole a likely candidate for clinical evaluation in disseminated aspergillosis.
Synergism at clinically attainable concentrations of aminoglycoside and beta-lactam antibiotics
Authors: Hooton T M , Blair A D , Turck M , Counts G W
Published: June 2012

We evaluated the in vitro synergistic activity at clinically attainable concentrations of combinations of aminoglycoside and beta-lactam antibiotics against 30 gentamicin-resistant clinical isolates of gram-negative bacilli. All 56 pairs of 4 aminoglycosides and 14 beta-lactams were evaluated. Combinations with amikacin demonstrated inhibitory synergistic activity in 29% of the assays, as compared with 22% for netilmicin (P = 0.018), 17% for gentamicin (P less than 0.001), and 13% for tobramycin (P less than 0.001). Among the beta-lactams, combinations with cefoperazone, ceftriaxone, or cefpiramide (SM-1652) demonstrated inhibitory synergistic activity most often (39, 38, and 35% of the assays, respectively) and with ceforanide, cefsulodin, and imipenem least often (less than or equal to 8% each). The most active combination was amikacin and ceftriaxone, with which 67% of the assays demonstrated inhibitory synergism. Isolates with high-level resistance to either antibiotic in a combination were unlikely to be inhibited synergistically by the combination. Further, combinations generally demonstrated little synergistic activity against isolates highly susceptible to beta-lactams.
Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii
Authors: Toothaker R D , Elmer G W
Published: June 2012

Saccharomyces boulardii, a yeast used in a number of countries for general and antibiotic-associated gastrointestinal illnesses, was examined for possible application in the prevention of clindamycin-induced mortality in the hamster colitis model. Hamsters were given free access to an aqueous 5% suspension of lyophilized yeast for 3 days before and 10 days after administration of a single oral clindamycin dose of from 0.2 to 0.8 mg/kg. Mortality was recorded in groups of 7 to 20 animals every 24 h for 10 to 30 days. Mean cecal concentrations of S. boulardii were greater than 10(6) CFU/ml throughout the yeast administration period. Yeast treatment significantly decreased cumulative percent mortality by an average of 29%. Death onset was not affected by yeast treatment. Cecitis was present in 86% of moribund animals (N = 95) and was absent in all surviving animals examined (N = 27). Toxigenic Clostridium difficile was isolated from 13 of 14 moribund hamsters examined. No adverse effects of the yeast treatment were observed in animals receiving S. boulardii without clindamycin. The results suggest that S. boulardii warrants further evaluation for the prevention of antibiotic-associated colitis.
Decreased activity of UMP pyrophosphorylase associated with resistance to 5-fluorocytosine in Candida albicans
Authors: Whelan W L , Kerridge D
Published: June 2012

UMP pyrophosphorylase activity was assayed in crude lysates prepared from Candida albicans. Specific activity of UMP pyrophosphorylase was high in clinical isolates which were susceptible to 5-fluorocytosine. Resistant clinical isolates displayed low activity, and partially resistant (heterozygous) isolates displayed intermediate activity. Segregation from the heterozygous state resulted in a homozygous susceptible segregant with high UMP pyrophosphorylase activity and a homozygous resistant segregant with low activity. The observed specific activities were consistent with the hypothesis that specific activity was determined by the sum of the activities due to the dominant (FCY) and recessive (fcy) alleles of the resistance gene. Strains which possessed little UMP pyrophosphorylase activity released uracil into the medium when grown in the absence of 5-fluorocytosine; this result suggested that recycling of intracellular uracil is a normal function of this enzyme.
Addition of rifampin to carboxypenicillin-aminoglycoside combination for the treatment of Pseudomonas aeruginosa infection: clinical experience with four patients
Authors: Yu V L , Zuravleff J J , Peacock J E , DeHertogh D , Tashjian L
Published: June 2012

Four patients infected with Pseudomonas aeruginosa were treated with the triple therapy of carboxypenicillin (carbenicillin or ticarcillin), aminoglycoside (gentamicin or tobramycin), and rifampin. Two patients had P. aeruginosa endocarditis, one had bacteremia associated with granulocytopenia, and one had neurosurgical meningitis. In all four cases, the clinical condition of the patient deteriorated on combined antipseudomonal penicillin and aminoglycoside therapy. All patients had persistent blood cultures (throughout a 3- to 30-day period) or cerebrospinal fluid cultures (throughout a 24-day period) while receiving penicillin-aminoglycoside therapy. Rifampin, 600 mg every 8 h orally, was added to the penicillin-aminoglycoside regimen. All four patients defervesced within 24 h after the initiation of rifampin. In addition, all four patients experienced sterilization of blood and cerebrospinal fluid cultures within 24 h of therapy. The emergence of rifampin-resistant P. aeruginosa was not observed. Ultimately, two patients survived their infection; the other two patients succumbed to complications of their underlying disease. This clinical experience should provide a stimulus for a controlled evaluation of rifampin as a component of multiple drug therapy directed against P. aeruginosa.
Augmentation of the in vitro activity of azlocillin against Bacteroides fragilis by clavulanic acid
Authors: Bansal M B , Chuah S K , Thadepalli H
Published: June 2012

Azlocillin was active against 90% of 154 strains of Bacteroides fragilis at a concentration of 64 micrograms/ml. Twenty-eight strains of B. fragilis with an azlocillin MIC of greater than or equal to 8 micrograms/ml were retested with a combination of azlocillin plus clavulanic acid. Of these strains, 71% showed a 4- to 32-fold decrease in the MIC of azlocillin plus clavulanic acid.
Pharmacokinetics of cefotiam in patients with impaired renal function and in those undergoing hemodialysis
Authors: Konishi K , Ozawa Y
Published: June 2012

The pharmacokinetics of cefotiam were studied after a single intravenous 1.0-g dose to 18 subjects grouped according to their creatinine clearances (CLCR); CLCR was above 75, 75 to 20, and below 20 ml/min per 1.73 m2 in groups 1, 2, and 3, respectively. Cefotiam obeyed two-compartment model kinetics in all three groups. The volume of distribution based on the area under serum concentration-time curve (Varea) was renal function independent, the average value being 0.350 +/- 0.159 liters/kg. The elimination-phase half-life (t1/2 beta) was 0.916 +/- 0.090 h in group 1, 2.03 +/- 1.62 h in group 2, and 7.09 +/- 3.06 h in group 3. Cumulative 24-h urinary excretion accounted for 65 to 93% of the dose in four subjects with CLCRS above 80 ml/min per 1.73 m2 and 19 to 41% in three subjects with CLCRS below 20 ml/min per 1.73 m2. We give recommendations for dosage adjustment in patients with renal insufficiency. The effect of hemodialysis on cefotiam pharmacokinetics was studied in six patients in end-stage renal failure; hemodialysis shortened the average t1/2 beta from 8.02 +/- 4.04 h to 2.74 +/- 2.15 h. We estimated that in a hypothetical anephric patient with a body weight of 60 kg, 6-h hemodialysis would remove 49.7% of the drug present in the body at the start of dialysis.
Mechanism of pyrimethamine resistance in recent isolates of Plasmodium falciparum
Authors: McCutchan T F , Welsh J A , Dame J B , Quakyi I A , Graves P M , Drake J C , Allegra C J
Published: June 2012

Clones of Plasmodium falciparum prepared from recent isolates of infected blood were studied to determine the molecular mechanism of naturally occurring pyrimethamine resistance. Total DNA, as well as thymidylate synthetase and dihydrofolate reductase activities, were characterized from these lines. Restriction analysis of DNA from pyrimethamine-susceptible and -resistant lines of the parasite showed no obvious amplification of any DNA fragment. Further, analysis of DNA from resistant and susceptible lines by centrifugation in cesium chloride-ethidium bromide revealed no extrachromosomal amplification in the resistant line. Comparison of the dihydrofolate reductase enzyme activity in the two lines revealed similar KmS for substrate but a large difference in the inhibition constant for pyrimethamine. Additionally, the enzyme from the resistant line was considerably more stable in vitro than the corresponding enzyme from the susceptible line. The thymidylate synthetase activity in the two lines was similar and unaffected by pyrimethamine. The mechanism of drug resistance in this isolate involves altered properties of the dihydrofolate reductase conferring both a different affinity for the drug and increased stability.
Staphylococcus saprophyticus beta-lactamase production and disk diffusion susceptibility testing for three beta-lactam antimicrobial agents
Authors: Latham R H , Zeleznik D , Minshew B H , Schoenknecht F D , Stamm W E
Published: June 2012

beta-Lactamase production and MIC determinations for penicillin, methicillin, and cephalothin were assessed for 67 strains of Staphylococcus saprophyticus and correlated with results of disk diffusion susceptibility testing. Fifty-five (82%) of the 67 strains produced beta-lactamase, and 40 (77%) of these beta-lactamase-producing strains were susceptible (zone size, greater than 29 mm) by disk diffusion techniques. Although the range of zone sizes for beta-lactamase producers was broad (26 to 36 mm), all 38 strains with a zone size of less than 31 mm by disk diffusion testing were beta-lactamase producers compared with 17 (59%) of 29 with larger zone sizes (P = 0.0000008). The median penicillin MIC for 12 S. saprophyticus strains was 0.25 micrograms/ml and was not related to beta-lactamase production. Although the methicillin MICs for 15 strains were in the susceptible range (4.0 micrograms/ml), interpretation of disk diffusion testing for oxacillin varied greatly among laboratories using identically prepared media and standardized techniques. Criteria presently used to define susceptibility of Staphylococcus aureus to penicillin and oxacillin by disk diffusion are inappropriate for S. saprophyticus. The clinical significance of the beta-lactamase produced by these strains needs further evaluation.
Imipenem therapy of Pseudomonas aeruginosa and other serious bacterial infections
Authors: Winston D J , McGrattan M A , Busuttil R W
Published: June 2012

Imipenem is the first of a new class of beta-lactam antimicrobial agents with remarkable and extremely potent in vitro activity against most commonly isolated bacterial pathogens, including Staphylococcus aureus, enterococcus, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides fragilis, and Hemophilus influenzae. The clinical efficacy and toxicity of imipenem were evaluated in 35 patients with 38 different infections. The overall clinical response was favorable (infections cured or improved) in 89% of the infections (34 of 38). Of the 17 infections with P. aeruginosa, 15 were cured or improved. However, P. aeruginosa isolates resistant to imipenem emerged during the therapy of six infections, and two cases of P. aeruginosa septicemia later relapsed after imipenem therapy. Gastrointestinal toxicity (nausea with or without emesis) occurred in 17% of the patients (6 of 35) but was ameliorated by slowing the rate of intravenous infusion or lowering the dose of imipenem. Except for certain severe P. aeruginosa infections, imipenem is effective and relatively safe therapy for infections caused by susceptible organisms.
Postantibiotic effect of imipenem on Pseudomonas aeruginosa
Authors: Bustamante C I , Drusano G L , Tatem B A , Standiford H C
Published: June 2012

Imipenem (formerly N-formimidoyl thienamycin) and ceftazidime were investigated for their postantibiotic effect on Pseudomonas aeruginosa. Four strains of P. aeruginosa in the logarithmic phase of growth were exposed for 1 and 2 h to concentrations of antibiotics achievable in human serum. Recovery periods of test cultures were evaluated after dilution or addition of beta-lactamase. A consistent postantibiotic effect against all strains was obtained with imipenem but not with ceftazidime. Although ceftazidime did not have a postantibiotic effect, it did suppress the growth of the organisms at concentrations equivalent to one-third of the MIC. The clinical implications of these effects need further evaluation.
Antiherpesvirus action of atropine
Authors: Alarcón B , González M E , Carrasco L
Published: June 2012

The antimuscarinic compound atropine shows an antiherpesvirus effect as measured by the protection of the cell monolayer and the reduction of the formation of new infectious virus. Atropine at a concentration of 200 micrograms/ml blocks the production of new infectious herpes simplex virus-type 1 virions. At that concentration, it has almost no effect on cellular or viral protein synthesis even when atropine is present from the beginning of the infection. The glycosylation of viral proteins is almost totally blocked when atropine is added. Although the viral proteins are underglycosylated, the formation of new herpes simplex virus type 1 virions takes place. The virions formed in the presence of atropine are noninfectious, and their protein composition, as assessed by labeling with [35S]methionine, is similar to that of the control, except that they are not glycosylated.
Multiple-dose pharmacokinetics of imipenem-cilastatin
Authors: Drusano G L , Standiford H C , Bustamante C , Forrest A , Rivera G , Leslie J , Tatem B , Delaportas D , MacGregor R R , Schimpff S C
Published: June 2012

We characterized the pharmacokinetic profile of imipenem-cilastatin administered intravenously to six normal volunteers in a dose of 1,000 mg of each drug every 6 h for 40 doses. The plasma concentrations of imipenem and cilastatin 1 h after the end of a 30-min infusion were 18.7 (+/- 2.1) and 19.1 (+/- 4.6), 20.0 (+/- 3.2) and 17.8 (+/- 4.8), and 23.4 (+/- 2.3) and 19.1 (+/- 3.5) micrograms/ml in the 1st, 17th, and 37th dosing intervals, respectively. The central compartment volumes of distribution for imipenem and cilastatin were 0.16 (+/- 0.05) and 0.14 (+/- 0.03) liter/kg, respectively. Elimination half-lives were short: 0.93 (+/- 0.09) h for imipenem and 0.84 (+/- 0.11) h for cilastatin. Plasma clearances were 12.1 (+/- 0.06) liters/h per 1.73 m2 for imipenem and 12.4 (+/- 1.1) liters/h per 1.73 m2 for cilastatin. Renal clearance accounted for 54% of the plasma clearance of imipenem and 69% of the plasma clearance of cilastatin. The concentrations of imipenem in plasma and urine remained above the MICs of the vast majority of pathogens throughout the dosing interval.
Differential stimulation of lymphocyte cell growth in vitro by cephalosporins
Authors: Leyhausen G , Seibert G , Maidhof A , Müller W E
Published: June 2012

The in vitro effect of three cephalosporins (cefodizime, cefotaxime, and ceftizoxime) on the growth of the following lymphocytes or their derivatives was tested: L 5178y mouse lymphoma cells, Molt-4 cells, and murine splenic lymphocytes. Within the concentration range of 0.1 to 50 microM, the cephalosporins had no effect on L 5178y cell growth. However, Molt-4 cell growth was significantly stimulated by 0.3 to 20 microM cefotaxime and cefodizime but was not influenced by ceftizoxime. Binding studies with [14C]cefotaxime revealed that the Molt-4 cells responding to the drug bind this cephalosporin to their cell surface (1.9 X 10(5) molecules per cell); no significant binding was observed in the assays with L 5178y cells. Determinations of the extractable activities of DNA-synthesizing enzymes from cefodizime-treated Molt-4 cells showed a direct correlation between cell growth and DNA polymerase alpha as well as terminal deoxynucleotidyl transferase activity; the DNA polymerase beta activity remained unchanged. Cefodizime (0.15 to 50 microM) which was added to mouse spleen cell cultures significantly increased [3H]thymidine incorporation into lymphocytes. This stimulatory effect was less pronounced in concanavalin A-stimulated cultures. These findings suggest that some cephalosporins display a growth-stimulating influence on some lymphocyte populations.
Metabolic fate of (E)-5-(2-bromovinyl)-2'-deoxyuridine in herpes simplex virus- and mock-infected cells
Authors: Ayisi N K , De Clercq E , Wall R A , Hughes H , Sacks S L
Published: June 2012

(E)-5-(2-Bromovinyl)-2'-deoxyuridine is a potent antiherpes compound with far better activity against herpes simplex virus type 1 than type 2. To understand the role of drug metabolism in this differential antiviral activity, we examined the metabolic fate of this drug in virus-infected and mock-infected Vero cells by high-pressure liquid chromatography. After 8 h of incubation in which cells were exposed to 10 micrograms of the drug per ml, 63 pmol/10(6) cells of the parent compound was detected in acid-soluble extracts of mock-infected cells. Herpes simplex virus-infected cells, however, incorporated or metabolized, or both, up to 11,310 pmol/10(6) cells. Type 1-infected cells metabolized the drug to the triphosphate where as many as 5,565 pmol/10(6) cells were detected. In contrast, three strains of type 2-infected cells metabolized the drug to the monophosphorylated nucleotide and no further. The amount of drug getting into the cells was virus strain and inoculum dependent. These studies indicate that poor substrate acceptance of (E)-5-(2-bromovinyl)-2'-deoxyuridine monophosphate by herpes simplex virus type 2-specified thymidylate kinase is an important factor in situ in infected cells, preventing anabolism of the parent compound to its active triphosphorylated form. This may account for its type specificity.
In vitro antimicrobial susceptibilities of penicillinase-producing and non-penicillinase-producing strains of Neisseria gonorrhoeae isolated in Durban, South Africa
Authors: Coovadia Y M , Ramsaroop U
Published: June 2012

The in vitro susceptibilities of 22 penicillinase-producing and 32 non-penicillinase-producing strains of Neisseria gonorrhoeae to 13 antimicrobial agents, including the new semisynthetic penicillins and cephalosporins, are reported. Ceftriaxone, ceftazidime, and cefotaxime were the most active agents tested; none of them had an MIC of greater than 0.03 micrograms/ml. Amoxycillin plus clavulanic acid and temocillin also showed good activity against both strains of gonococci.
Effect of hyperbaric oxyhelium gas on response of bacteria to antimicrobial agents in vitro
Authors: Kenward M A , Alcock S R , McKay I C
Published: June 2012

Modern diving techniques can require the treatment of infection in an atmosphere of pressurized oxyhelium gas. The antibiotic susceptibility of 16 species and strains (eight genera) of gram-negative bacilli and 3 species and strains (two genera) of gram-positive cocci to each of 21 antimicrobial agents was assessed in air at atmospheric pressure and in oxyhelium gas at an absolute pressure of 7 bar (ca. 709 kPa). A disk diffusion technique was employed, and significantly different results were obtained in the two atmospheres. The effect of oxyhelium on diameters of growth inhibition varied significantly with the bacterium and with the antibiotic and was particularly marked with certain bacterium-antibiotic combinations. The gram-negative bacilli generally gave reduced zone diameters in oxyhelium, whereas the gram-positive cocci showed a mixture of effects.
Single-dose pharmacokinetics of Ro 17-2301 (AMA-1080), a monocyclic beta-lactam, in humans
Authors: Weidekamm E , Stoeckel K , Egger H J , Ziegler W H
Published: June 2012

Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.
Ciprofloxacin penetration into extravascular spaces in a rabbit model
Authors: Nichol K L , Peterson L R , Fasching C E , Gerding D N
Published: June 2012

Ciprofloxacin penetration into extravascular spaces was studied in a rabbit Visking chamber model. The drug was administered (7 mg/kg) intramuscularly every 4 h for eight doses. Peak and trough drug levels by dose 8 were 1.3 and 0.35 micrograms/ml in serum and 0.61 and 0.50 micrograms/ml in extravascular sites. The ratio of extravascular site to serum free drug area under the drug curve by dose 8 was 91.1%. This potent, new antimicrobial agent appears to distribute freely to extravascular spaces in this animal model.
Mycocerein, a novel antifungal peptide antibiotic produced by Bacillus cereus
Authors: Wakayama S , Ishikawa F , Oishi K
Published: June 2012

A peptide was obtained from culture filtrates of a bacterium which was newly isolated and tentatively named Bacillus cereus SW. The peptide was composed of Asx, Ser, Glx, Leu, Tyr, Pro, and an unknown amino acid in a ratio of 2:1:1:1:1:1:1, but, unless hydrolyzed with HCI, it was ninhydrin reaction negative. The peptide effectively inhibited the growth of all fungi and yeasts so far examined, whereas it inhibited none of the bacteria tested.