bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae
Authors: Mendelman P M , Henritzy L L , Chaffin D O , Lent K , Smith A L , Stull T L , Wiley E A
Published: June 2012

The antimicrobial activities of cefixime, cefpodoxime, and ceftibuten were determined with 18 ampicillin-susceptible (Amps), 13 ampicillin-resistant beta-lactamase-producing (AmprBLP), and 7 ampicillin-resistant non-beta-lactamase-producing (AmprNBLP) strains of Haemophilus influenzae. An effect of inoculum density on apparent MIC, the bactericidal activity of these agents, and the targets of the three cephems were determined. The MICs of cefixime, cefpodoxime, and ceftibuten for 90% of the Amps and AmprBLP isolates were 0.04, 0.08, and 0.08 microgram/ml, respectively. In contrast, the MICs for 90% of the AmprNBLP strains were 0.96, 1.92, and 7.68 micrograms/ml. No significant inoculum effect was observed for any group of strains comparing inocula of 10(3) and 10(5) CFU, whereas only the AmprNBLP isolates showed a marked effect at an inoculum of 10(6) CFU. Although bactericidal levels were achieved for the Amps and AmprBLP strains, tolerance to cefixime and ceftibuten was observed. The bactericidal activity for the AmprNBLP strains was limited, with cefixime showing the highest activity of the three cephems. Penicillin-binding proteins 2, 4, and 5 revealed high affinity, with 50% inhibitory concentration levels below the MIC for all three cephems, suggesting that these are important targets of these agents in H. influenzae. We conclude that the cephems are highly active in vitro against Amps and AmprBLP strains of H. influenzae, but less so against AmprNBLP isolates.
Factors influencing the accumulation of ciprofloxacin in Pseudomonas aeruginosa
Authors: Celesk R A , Robillard N J
Published: June 2012

Ciprofloxacin accumulation in Pseudomonas aeruginosa was measured by a bioassay. Drug accumulation in strain PAO2 was compared with that of three spontaneous ciprofloxacin-resistant mutants selected with 0.5 micrograms of ciprofloxacin per ml. PAO4701 cfxA2 contains a mutation in the gyrA gene, PAO4742 cfxB5 may represent a permeability mutant based on pleiotropic drug resistance, and PAO4700 cfxA1 cfxB1 contains both types of mutations. In all strains, drug accumulation was similar, reaching steady state during the first minute of exposure. Drug accumulation was unsaturable over a range of 5 to 80 micrograms/ml, suggesting that ciprofloxacin accumulates by diffusion in P. aeruginosa. Although all four strains accumulated two- to sevenfold more ciprofloxacin in the presence of the inhibitor carbonyl cyanide m-chlorophenylhydrazone, the cfxB mutants accumulated two- to fourfold less drug than either PAO2 or the cfxA2 mutant. Polyacrylamide gel analysis revealed a protein common to cfxB mutants only, while all strains had similar lipopolysaccharide profiles. The results suggest that ciprofloxacin accumulation in P. aeruginosa is a complex phenomenon that may be affected by both an energy-dependent drug efflux process and outer envelope composition.
Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients
Authors: Hirata C A , Guay D R , Awni W M , Stein D J , Peterson P K
Published: June 2012

The steady-state pharmacokinetics of ciprofloxacin were evaluated in nine elderly patients with lower respiratory tract infections after an intravenous dosage regimen of 200 mg every 12 h (n = 9) and an oral dosage regimen of 750 mg every 12 h (n = 6). Ciprofloxacin concentrations in serum and urine were measured by high-performance liquid chromatography. The peak concentration in serum, total body clearance (CLs), steady-state volume of distribution (Vss), and terminal elimination half-life after intravenous dosing were 3.5 +/- 0.8 micrograms/ml, 4.38 +/- 1.80 ml/min per kg, 1.6 +/- 0.6 liters/kg, and 5.8 +/- 2.4 h, respectively. The peak concentration in serum, time to peak concentration in serum, absorption lag time, and absolute bioavailability (F) after oral dosing were 7.6 +/- 2.2 micrograms/ml, 1.9 +/- 1.0 h, 0.4 +/- 0.5 h, and 7.7 +/- 24.2%, respectively. The elevated drug concentrations in serum samples from the elderly after oral dosing, compared with data obtained from younger subjects, appear to be a function of reduced CLs, renal clearance, and Vss. The increased F observed in some patients may be due to the effect of concomitant or proximate administration of tube feedings, medications which may alter gastric motility or acidity, or decreased first-pass metabolism. The results demonstrate that factors related to age and declining renal function, rather than infectious disease state, may be primary in determining alterations in pharmacokinetic parameters in the elderly. In elderly patients with normal renal function for their age, no dosage adjustment for intravenous or oral ciprofloxacin is necessary.
Study of the metabolism of flucytosine in Aspergillus species by 19F nuclear magnetic resonance spectroscopy
Authors: Chouini-Lalanne N , Malet-Martino M C , Martino R , Michel G
Published: June 2012

The metabolism of flucytosine (5FC) in two Aspergillus species (Aspergillus fumigatus and A. niger) was investigated by 19F nuclear magnetic resonance spectroscopy. In intact mycelia, 5FC was found to be deaminated to 5-fluorouracil and then transformed into fluoronucleotides; the catabolite alpha-fluoro-beta-alanine was also detected in A. fumigatus. Neither 5-fluoroorotic acid nor 5-fluoro-2'-deoxyuridine-5'-monophosphate was detected in perchloric acid extracts after any incubation with 5FC. 5FC, 5-fluorouracil, and the classical fluoronucleotides 5-fluorouridine-5'-mono-, di-, and triphosphates were identified in the acid-soluble pool. Two hydrolysis products of 5-fluorouracil incorporated into RNA, 5-fluorouridine-2'-monophosphate and 5-fluorouridine-3'-monophosphate, were found in the acid-insoluble pool. No significant differences in the metabolic transformation of 5FC were noted in the two species of Aspergillus. The main pathway of 5FC metabolism in the two species of Aspergillus studied is thus the biotransformation into ribofluoronucleotides and the subsequent incorporation of 5-fluorouridine-5'-triphosphate into RNA.
Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam
Authors: Kuck N A , Jacobus N V , Petersen P J , Weiss W J , Testa R T
Published: June 2012

Tazobactam (YTR-830H), a novel beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam for enhancement of the activity of piperacillin against beta-lactamase-producing, piperacillin-resistant clinical isolates. Piperacillin MICs were determined in media containing a fixed concentration of 2 or 4 micrograms of the inhibitors per ml. The higher concentration was generally more effective. Tazobactam was superior to sulbactam in enhancing the spectrum and potency of piperacillin. Although the calvulanic acid combination was more potent, tazobactam was effective for a similar spectrum of resistant gram-negative clinical isolates containing beta-lactamase. MICs were reduced to the susceptible range for Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella spp., and Shigella spp. Combinations with tazobactam and sulbactam, but not clavulanic acid, were effective against Morganella spp. Some antagonism of the activity of piperacillin was observed with clavulanic acid but not with tazobactam or sulbactam. The inhibitors were similarly effective with piperacillin against beta-lactamase-positive Staphylococcus spp. and the Bacteroides fragilis group. Piperacillin-tazobactam was more effective against a broader spectrum of gram-negative enteric bacteria than ticarcillin plus clavulanic acid was. Combinations with tazobactam or clavulanic acid had a broader spectrum of activity than combinations with sulbactam against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In particular, piperacillin with tazobactam or clavulanic acid, but not with sulbactam, inhibited TEM-1, TEM-2, and SHV-1 enzymes. In vitro activity was reflected in vivo. Tazobactam and clavulanic acid were superior to sulbactam in enhancing the therapeutic efficacy of piperacillin in mice infected with beta-lactamase-positive E. coli, K. pneumoniae, Proteus mirabilis, and Staphylococcus aureus. Only combinations with tazobactam and sulbactam were effective against the Morganella infection. Tazobactam has a good potential for enhancing the clinical efficacy of piperacillin.
In vitro activity of dactimicin, a novel pseudodisaccharide aminoglycoside, compared with activities of other aminoglycosides
Authors: Gu J W , Neu H C
Published: June 2012

The in vitro activity of dactimicin, a new pseudodisaccharide aminoglycoside which possesses a formimidoyl group, was compared with those of gentamicin, tobramycin, and amikacin against 500 isolates. Dactimicin inhibited 90% of isolates from the family Enterobacteriaceae at a concentration of less than or equal to 4 micrograms/ml. It was more active than amikacin against Klebsiella pneumoniae, Serratia marcescens, Citrobacter diversus, Enterobacter agglomerans, Yersinia species, and Salmonella species, with an MIC for 90% of the strains (MIC90) of less than or equal to 4 micrograms/ml. The MIC90s for the Pseudomonas aeruginosa isolates were greater than 128 micrograms/ml. Dactimicin did not inhibit most methicillin-resistant Staphylococcus aureus isolates and coagulase-negative staphylococci but had an MIC50 (MIC for 50% of strains tested) of 2 micrograms/ml against methicillin-susceptible S. aureus isolates and coagulase-negative staphylococci. Dactimicin in combination with piperacillin acted synergistically against 75% of Escherichia coli, K. pneumoniae, S. marcescens, and S. aureus isolates. It exhibited an excellent postantibiotic suppressive effect on E. coli. Dactimicin was active against organisms possessing aminoglycoside-modifying enzymes including AAC(2')-b, AAC(3)-III, -IV, and -V, and AAC(6')-Ia, -Ib, Ic, -II, and -IV but was not active against isolates which contained AAC(3)-I and the bifunctional APH(2")-AAC(6')-I. Its lack of activity against P. aeruginosa appeared to be permeability related since in the presence of EDTA P. aeruginosa was susceptible, as were mutant isolates resistant because of permeability barriers.
Comparative in vitro activities of teicoplanin, vancomycin, oxacillin, and other antimicrobial agents against bacteremic isolates of gram-positive cocci
Authors: Gorzynski E A , Amsterdam D , Beam T R , Rotstein C
Published: June 2012

The in vitro activities of teicoplanin and vancomycin were compared with those of six other antimicrobial agents against 460 bacteremic isolates of gram-positive cocci. Teicoplanin was as active as vancomycin but less active than ciprofloxacin against staphylococci. Teicoplanin was the most potent of all agents tested against enterococci and had excellent activity against pneumococci.
Gene amplification contributes to sulfonamide resistance in Escherichia coli
Authors: Nichols B P , Guay G G
Published: June 2012

A sulfathiazole-resistant strain of Escherichia coli was isolated and shown to contain a fourfold tandemly amplified segment of DNA 18 kilobase pairs in length in addition to a mutationally altered dihydropteroate synthase, the target enzyme for sulfonamide inhibition. The amplified DNA contained a gene designated sur that contributed to sulfathiazole resistance when present in greater amounts than those in the wild type. Sulfathiazole resistance was markedly decreased upon loss of the amplified DNA after nonselective growth. Plasmids that contained sur also conferred only weak sulfathiazole resistance on wild-type strains. Comparison of the restriction maps of the amplified DNA, wild-type DNA, and sur-containing plasmids showed that a DNA rearrangement occurred before or concomitant with the DNA amplification event. The DNA rearrangement resulted from an IS5 insertion, which, in conjunction with an IS5 element residing near sur in the wild-type strain, resulted in an -IS5-sur-IS5- configuration. Homologous recombination could account for duplication and subsequent amplification of the sur region. High-copy-number plasmids containing the sur locus did not express a sulfathiazole-resistant dihydropteroate synthase, nor did they overexpress wild-type dihydropteroate synthase. These data suggest that the high level of sulfathiazole resistance in this strain results from a synergistic effect of two different mutations.
Isolation, characterization, and DNA sequence analysis of an AAC(6')-II gene from Pseudomonas aeruginosa
Authors: Shaw K J , Cramer C A , Rizzo M , Mierzwa R , Gewain K , Miller G H , Hare R S
Published: June 2012

The gene encoding a 6'-N-acetyltransferase, AAC(6')-II, was cloned from Pseudomonas aeruginosa plasmid pSCH884. This gene mediates resistance to gentamicin, tobramycin, and netilmicin but not amikacin or isepamicin. The DNA sequence of the gene and flanking regions was determined. The 5'- and 3'-flanking sequences showed near identity to sequences found abutting a variety of different genes encoding resistance determinants. It is likely that the current structure arose by the integration of the 572-base-pair sequence containing the AAC(6')-II gene into a Tn21-related sequence at the recombinational hot spot, AAAGTT. We have compared the sequence of the AAC(6')-II gene to genes of other 6'-N-acetyltransferases. An AAC(6')-Ib protein (encoded by the aacA4 gene; G. Tran Van Nhieu and E. Collatz, J. Bacteriol. 169:5708-5714, 1987) that results in resistance to amikacin but not gentamicin was found to share 82% sequence similarity with the AAC(6')-II protein. We speculate that these two genes arose from a common ancestor and that the processes of selection and dissemination have led to the observed differences in the spectrum of aminoglycoside resistance.
Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals
Authors: Van Cutsem J , Van Gerven F , Janssen P A
Published: June 2012

Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.
Molecular characterization of the gene encoding SHV-3 beta-lactamase responsible for transferable cefotaxime resistance in clinical isolates of Klebsiella pneumoniae
Authors: Nicolas M H , Jarlier V , Honore N , Philippon A , Cole S T
Published: June 2012

In Klebsiella pneumoniae 86-4, cefotaxime resistance was due to a transferable broad-spectrum beta-lactamase, SHV-3. The plasmid-borne gene encoding SHV-3 has been cloned, and the primary structure of the enzyme was deduced from its nucleotide sequence. SHV-3 differs from SHV-1 in two positions. The extended substrate profile of SHV-3 probably results from the substitution of Ser-213 for Gly, as in SHV-2, whereas replacement of Arg-180 by Leu resulted in a decrease in the pI from 7.6 to 7.0. The blashv-3 gene is highly homologous (92% DNA sequence identity) with the chromosomal gene coding for LEN-1 beta-lactamase of K. pneumoniae, suggesting that the origin of the SHV-encoding genes now present on many plasmids may be chromosomal.
Susceptibility to cephalosporins of penicillin-susceptible and penicillin-resistant strains of Neisseria gonorrhoeae from Philadelphia
Authors: Fekete T , Serfass D A , Lafredo S C , Cundy K R
Published: June 2012

Using agar dilution, we determined MICs of penicillin, cefoxitin, ceftriaxone, cefmetazole, tetracycline, and spectinomycin for 129 strains of Neisseria gonorrhoeae. All strains were susceptible to ceftriaxone (MIC range, less than or equal to 0.008 to 0.06 micrograms/ml) and spectinomycin (16 to 32 micrograms/ml). The MICs for 50, 90, and 100% of strains tested were 1.0, 2.0, and greater than 8.0 micrograms/ml; 0.12, 1.0, and greater than 8.0 micrograms/ml; 0.5, 1.0, and 2.0 micrograms/ml; and 1.0, 2.0, and greater than 8.0 micrograms/ml for cefmetazole, penicillin, cefoxitin, and tetracycline, respectively. Seven strains were beta-lactamase producers; eight were chromosomally resistant to penicillin. There was a log-linear relation for non-beta-lactamase-producing strains between the MICs of cefmetazole, cefoxitin, and tetracycline and the MIC of penicillin (Pearson r = 0.787, 0.544, and 0.358, respectively).
Multicenter randomized study of single-dose ofloxacin versus amoxicillin-probenecid for treatment of uncomplicated gonococcal infection
Authors: Black J R , Long J M , Zwickl B E , Ray B S , Verdon M S , Wetherby S , Hook E W , Handsfield H H
Published: June 2012

The safety and efficacy of ofloxacin, 400 mg orally, were compared with those of amoxicillin, 3.0 g, plus probenecid, 1.0 g orally, as single-dose therapy in 201 heterosexual patients (101 men and 100 women) with uncomplicated gonococcal infection. Treatment groups were comparable in age, duration of symptoms, number of sexual partners within the previous month, and number of previous episodes of sexually transmitted diseases. The cure rate for men treated with ofloxacin was 98% (47 of 48), and that for women was 100% (52 of 52). Cure rates for both men and women treated with amoxicillin-probenecid were 96% (51 of 53 men; 46 of 48 women). All 13 patients with positive rectal cultures and 7 of 8 patients with positive pharyngeal cultures treated with ofloxacin were cured. Neither regimen reliably eradicated coexistent infection with Chlamydia trachomatis. The MIC of ofloxacin for all but two of 198 pretreatment isolates was 0.3 microgram/ml or less. The MIC of amoxicillin for 90% of isolates tested was 1.0 microgram/ml. Single oral doses of ofloxacin and of amoxicillin plus probenecid were equally effective for treatment of urethral and cervical gonorrhea. Ofloxacin appears promising as treatment for rectal and pharyngeal infection, but studies with larger numbers of patients with rectal or pharyngeal infection or both are required for confirmation. Relative contraindications in children and possibly pregnant women plus the potential for single-step, high-level resistance may limit the usefulness of quinolone therapy for gonorrhea.
Comparative in vitro activities of new fluorinated quinolones and other antibiotics against coagulase-negative Staphylococcus blood isolates from neutropenic patients, and relationship between susceptibility and slime production
Authors: Venditti M , Santini C , Serra P , Micozzi A , Gentile G , Martino P
Published: June 2012

We evaluated the in vitro antibiotic susceptibilities of 31 coagulase-negative Staphylococcus isolates causing septicemia in neutropenic patients undergoing norfloxacin prophylaxis. All the strains but one were resistant to 1 microgram of norfloxacin per ml. At the same concentration, ciprofloxacin, ofloxacin, imipenem, and pefloxacin were inhibitory for 19 (61%), 19 (61%), 18 (58%), and 14 (45%) of the evaluated strains, respectively. Imipenem had an MBC/MIC ratio of greater than or equal to 32 against 19 (61%) of the evaluated isolates, and resistant subpopulations were detected at 5 micrograms/ml in 16 of 17 oxacillin-resistant strains and in 3 of 14 oxacillin-susceptible or -tolerant strains. Resistance to gentamicin was seen with increased frequency among slime-producing strains.
Effect of norfloxacin on theophylline metabolism
Authors: Davis R L , Kelly H W , Quenzer R W , Standefer J , Steinberg B , Gallegos J
Published: June 2012

The purpose of this study was to investigate the effect of norfloxacin on theophylline elimination. Ten normal volunteers were studied. In a randomized crossover sequence, each subject received 6 mg of aminophylline per kg of body weight by a 30-min intravenous infusion on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. Mean theophylline clearance decreased and mean elimination half-life increased after norfloxacin administration (from 0.036 +/- 0.006 to 0.033 +/- 0.004 liter/h per kg and from 8.7 +/- 1.2 to 9.5 +/- 1.5 h, respectively; P less than 0.05, Wilcoxon signed-ranks test). We conclude that norfloxacin taken in recommended doses for 3 days has a small inhibitory effect on theophylline metabolism that would probably not cause clinically important elevations in theophylline concentrations in most patients.
gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli
Authors: Nakamura S , Nakamura M , Kojima T , Yoshida H
Published: June 2012

The proportion of gyrA and gyrB mutations in quinolone-resistant Escherichia coli strains was examined by introducing cloned wild-type gyrA and gyrB genes. In 25 spontaneous mutants of strain KL16, 13 had gyrA and 12 had gyrB mutations. In eight clinical isolates, five had gyrA mutations and one had a gyrB mutation; mutations in two isolates remained unidentified.
Treatment failure of norfloxacin against Campylobacter pylori and chronic gastritis in patients with nonulcerative dyspepsia
Authors: Mertens J C , Dekker W , Ligtvoet E E , Blok P
Published: June 2012

Several reports have been published to show the in vitro susceptibility of Campylobacter pylori to different classes of antibiotics, including fluoroquinolones. The purpose of this study was to describe the clinical effect of norfloxacin on eradication of C. pylori in patients with gastritis. Endoscopy was performed in 38 patients with symptoms of nonulcerative dyspepsia. Of these, 20 patients had a C. pylori-positive culture. From this group, 17 patients were treated with norfloxacin for 1 month. After therapy, 15 patients still had positive cultures, and in 9 cases the strain was resistant to norfloxacin. These data, which confirm previous studies, support the concept that the in vitro activity of norfloxacin against C. pylori cannot be transposed to an in vivo effect.
Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects
Authors: Blouin R A , Kneer J , Stoeckel K
Published: June 2012

The purpose of this investigation was to evaluate the effect of advanced age on the pharmacokinetics of cefetamet and its prodrug, cefetamet pivoxil. A secondary objective of this study was to assess the effect of food on the absorption of cefetamet pivoxil in the elderly. Twenty-four healthy subjects (twelve young and twelve elderly) received (in a Latin square design) a single-dose, 515-mg infusion of cefetamet, a single 1,000-mg oral dose of cefetamet pivoxil during fasted conditions, and a single 1,000-mg oral dose of cefetamet pivoxil 10 min after a standardized low-fat breakfast. Serial blood and urine samples were collected over a 36-h period and analyzed by high-performance liquid chromatography. Intravenous and oral pharmacokinetic parameters were obtained by using model-independent techniques. The systemic clearance and renal clearance of cefetamet were significantly lower (P less than 0.05) in elderly subjects compared with in young controls after intravenous administration. No significant difference was observed in the apparent volumes of distribution at steady state between the two groups. Consequently, half-life and mean residence time were prolonged. A trend toward a lower renal clearance/creatinine clearance ratio was observed in our elderly population. Oral clearance of cefetamet was only slightly reduced in our elderly subjects, consistent with an increase in plasma half-life. Otherwise, oral pharmacokinetic parameters were comparable between elderly and young subjects. Additionally, the same effects of food were observed on the absorption characteristics of cefetamet (no change in maximum concentration of drug in plasma and an increase in both time to maximum concentration of drug in plasma and bioavailability) in our elderly subjects as in our young volunteers. Age did not appear to alter the deesterification and bioavailability of cefetamet pivoxil. We conclude that the small reduction in the elimination of cefetamet in the elderly would not require dose adjustment for this population.
High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay
Authors: Granich G G , Krogstad D J , Connor J D , Desrochers K L , Sherwood C
Published: June 2012

The use of high-performance liquid chromatography (HPLC) to measure ribavirin in serum and other biological fluids has been limited by endogenous interfering substances. We report an HPLC procedure based on the extraction of ribavirin from serum, plasma, or cerebrospinal fluid with a boronate affinity gel, which uses a 3-methylcytidine internal standard. This assay is sensitive (to 0.4 microM), specific (no interference with 34 commonly prescribed drugs), reproducible (coefficients of variation from 5.4 to 22.4%), and linear (r = 0.999) over the range of clinically relevant concentrations in serum (from 0.5 to 50.0 microM). It also correlates well with the ribavirin radioimmunoassay (r = 0.992). This HPLC assay should be useful for measuring ribavirin in serum and other body fluids during clinical trials.
Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria
Authors: Verdier F , Pussard E , Clavier F , Le Bras J , Gaudebout C
Published: June 2012

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 +/- 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 +/- 75 liters/kg and 2,063 +/- 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 +/- 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.
In vitro and in vivo comparison of the abilities of purine and pyrimidine 2',3'-dideoxynucleosides to inhibit duck hepadnavirus
Authors: Lee B , Luo W X , Suzuki S , Robins M J , Tyrrell D L
Published: June 2012

Four purine and two pyrimidine 2',3'-dideoxynucleosides were studied for their ability to inhibit duck hepadnavirus replication. The purine 2',3'-dideoxynucleosides were more potent antiviral agents than the pyrimidine 2',3'-dideoxynucleosides. The concentration for 50% inhibition of viral replication (IC50) was determined for each of the effective agents. Two drugs with low IC50s, 2,6-diaminopurine 2',3'-dideoxyriboside and 2',3'-dideoxyadenosine, were chosen for in vivo studies. Animals received 10 mg/kg intramuscularly twice daily. Rapid clearance of hepadnavirus DNA from the sera of the animals was seen as a result of treatment with 2,6-diaminopurine 2',3'-dideoxyriboside; however, treatment with 2',3'-dideoxyadenosine did not clear the virus.
Accumulation and transport of cadmium by tolerant and susceptible strains of Mycobacterium scrofulaceum
Authors: Erardi F X , Failla M L , Falkinham J O
Published: June 2012

Cadmium accumulation and transport were studied in two strains of Mycobacterium scrofulaceum differing in their susceptibility to Cd2+ toxicity. A 10-fold excess of either Zn2+ or Mn2+ partially antagonized inhibition of growth by Cd2+. 109Cd2+ uptake by both the tolerant and susceptible strains was temperature dependent and inhibited by a 10-fold excess of either Zn2+ or Mn2+. There were no significant differences in either the kinetics of 109Cd2+ uptake or the retention of accumulated 109Cd2+ by the tolerant and susceptible strains. Both tolerant and susceptible strains removed most of the cadmium from the culture medium, but significantly more was removed by cells of the tolerant strain. Most of the accumulated Cd2+ in the tolerant strain was in the particulate fraction, rather than in the soluble fraction. Intracellular accumulated Cd2+ was primarily in the soluble fraction of the susceptible strain. Increased Cd2+ in culture medium resulted in decreased Mn2+ and Zn2+ in cells of the susceptible strain but did not reduce the Mn2+ and Zn2+ content of cells of the tolerant strain.
Effects of beta-lactamases and omp mutation on susceptibility to beta-lactam antibiotics in Escherichia coli
Authors: Hiraoka M , Okamoto R , Inoue M , Mitsuhashi S
Published: June 2012

Four types of beta-lactamases consisting of a penicillinase type I (TEM-1), a penicillinase type II (OXA-1), a cephalosporinase of Citrobacter freundii, and a cephalosporinase of Proteus vulgaris were introduced into Escherichia coli MC4100 and its omp mutants, MH1160 (MC4100 ompR1) and MH760 (MC4100 ompR2), by transformation. Effects of the combination of the omp mutations and these beta-lactamases on the susceptibility of E. coli strains were studied with 15 beta-lactam antibiotics including cephalosporins, cephamycins, penicillins, imipenem, and aztreonam. The ompR1 mutant, MH1160, lacks OmpF and OmpC, and it showed reduced susceptibility to 11 of the 15 beta-lactam agents. The reduction in susceptibility to cefoxitin, moxalactam, and flomoxef was much greater than reduction in susceptibility to the other agents. When the ompR1 mutant produced the cephalosporinase of C. freundii, the susceptibility of the mutant to 12 of the 15 beta-lactam antibiotics decreased. The reduction in susceptibility of MH1160 to 10 of the 12 agents affected by the enzyme was two- to fourfold greater than that observed in MC4100. Such a synergistic effect was also observed with the cephalosporinase of P. vulgaris and ompR1 mutation against six cephalosporins, moxalactam, and aztreonam.
Ineffectiveness of postexposure prophylaxis of rhinovirus infection with low-dose intranasal alpha 2b interferon in families
Authors: Monto A S , Schwartz S A , Albrecht J K
Published: June 2012

Past studies conducted in Australian and American families have demonstrated that alpha 2b interferon (IFN) is effective in preventing rhinovirus-associated illnesses in exposed family members. IFN had been used by intranasal application for 7 days after exposure (5 x 10(6) IU/day). We used the same approach but with only 5 days of spraying (5 x 10(6) IU on day 1 and 2.5 x 10(6) IU on each subsequent day). This amount has been effective in studies involving seasonal prophylaxis. During the study period, a total of 178 rhinoviruses were isolated from the 199 enrolled families in Tecumseh, Mich. There were 434 courses of IFN use and 434 courses of placebo use. Although rhinoviruses were less frequently isolated from those using IFN than those using the placebo, no differences favoring IFN treatment could be found in any of the symptomatic episodes. In fact, more episodes were observed in IFN recipients than in placebo recipients, although the differences were not statistically significant. Additionally, there was no evidence of modification of the severity of episodes of illness. It was concluded that prevention of rhinovirus illness episodes postexposure required a dosage of at least 5 x 10(6) IU of IFN-alpha 2b.
Decreased permeation of cephalosporins through the outer membrane of Escherichia coli grown in salicylates
Authors: Foulds J , Murray D M , Chai T , Rosner J L
Published: June 2012

Escherichia coli K-12 cells grown in 1 to 5 mM sodium salicylate (SAL) or acetylsalicylate show increased phenotypic resistance to various antibiotics (J. L. Rosner, Proc. Natl. Acad. Sci. USA 82:8771-8774, 1985), including cephalosporins (this study). To determine whether these effects are caused by a decreased uptake of the antibiotics, the permeation of several cephalosporins through the outer membrane was measured. For E. coli K-12 grown in LB broth containing 5 mM SAL or acetylsalicylate, permeation of the outer membrane by the five cephalosporins tested decreased three- to fivefold compared with that in cells not grown in salicylates. Permeation of the outer membrane by cephaloridine decreased within 15 min of the addition of SAL to cells grown in broth and reached a minimum in 1 to 2 h. When cells were transferred from broth with SAL to broth without SAL, their permeability to cephaloridine increased slowly for the first 45 min and more rapidly over the next 1.5 h; the permeability then attained normal levels by 3 h. The permeability changes that occurred after media shifts, either to or from SAL, were prevented by concentrations of chloramphenicol that inhibited protein synthesis. These effects of SAL on outer membrane permeability are fully consistent with their effects on antibiotic resistance and with the report (T. Sawai, S. Hirano, and A. Yamaguchi, FEMS Microbiol. Lett. 40:233-237, 1987) that the outer membranes of SAL-treated cells are deficient in certain porins. Permeation of cephaloridine through the outer membrane also decreased when a virulent strain of E. coli K1 was grown in the presence of as little as 1 to 2 mM SAL. This raises the concern that high levels of salicylates in patients night interfere with cephalosporin or other antibiotic therapies.
Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits
Authors: Täuber M G , Kunz S , Zak O , Sande M A
Published: June 2012

We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P less than 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 log10 CFU/ml; P less than 0.02). The clinical relevance of these observations remains to be determined.
Effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline
Authors: Nguyen V X , Nix D E , Gillikin S , Schentag J J
Published: June 2012

The effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline was studied. In a randomized crossover design, six healthy male volunteers received an infusion of 200 mg of doxycycline hyclate on two occasions separated by 7 days. On one occasion, subjects were given 30 ml of aluminum hydroxide orally four times a day for 4 days, beginning 2 days prior to doxycycline dosing. Blood and urine samples were collected up to 48 and 96 h after the infusion, respectively, and were analyzed by a microbial assay. Values for volume of distribution at steady state, nonrenal clearance, urine recovery, and urine pH were not statistically different among treatment groups. With concomitant antacid therapy, the half-life of intravenous doxycycline was shortened from 16.2 +/- 2.6 to 11.2 +/- 1.2 h (P = 0.003), and total body clearance increased from 37.4 +/- 6.5 to 54.1 +/- 12.3 ml/min (P = 0.008). Area under the concentration-time curve for serum was decreased by 18 to 44%, with a 22 to 41% increase in renal clearance. Although the increase in nonrenal clearance ranged from 11 to 128%, the high variability led to a nonsignificant difference (P = 0.07). Concomitant oral antacid therapy may significantly enhance the clearance of intravenous doxycycline.
Purification and amino acid composition of peptide antibiotic AS-48 produced by Streptococcus (Enterococcus) faecalis subsp. liquefaciens S-48
Authors: Gálvez A , Giménez-Gallego G , Maqueda M , Valdivia E
Published: June 2012

Peptide antibiotic AS-48 was purified to homogeneity by ion-exchange chromatography, gel filtration chromatography, and reversed-phase liquid chromatography. The purified fraction was active against gram-positive and gram-negative bacteria. AS-48 is a basic protein with an isoelectric point of ca. 10.5 and a molecular mass of 7.4 kilodaltons. Its inhibitory activity was markedly affected by sodium dodecyl sulfate and cardiolipin but not by neuraminidase, pectinase, beta-glucosidase, or beta-glucuronidase. Differential scanning calorimetry data suggested that AS-48 molecules lack a compact structure.
Pharmacokinetics and tissue penetration of fluconazole in rabbits
Authors: Walsh T J , Foulds G , Pizzo P A
Published: June 2012

Fluconazole is a new bis-triazole antifungal compound which has in vivo and in vitro activity against Candida spp. and Cryptococcus neoformans and excellent penetration into cerebrospinal fluid. However, little is known about the penetration of fluconazole into tissue sites other than cerebrospinal fluid. We therefore studied by high-pressure liquid chromatography the penetration of fluconazole into nine different tissue sites at times of peak and trough concentrations in plasma in rabbits. Fluconazole penetrated into all tissue sites. Tissue/plasma concentration ratios were greater at time of trough concentrations in plasma than at times of peak concentrations in plasma. The finding that fluconazole penetrated into target organs commonly infected by Candida spp. and C. neoformans further supports the therapeutic potential of fluconazole for disseminated candidiasis or cryptococcosis in immunocompromised hosts.
Susceptibility of Giardia lamblia to aminoglycoside protein synthesis inhibitors: correlation with rRNA structure
Authors: Edlind T D
Published: June 2012

The very limited development of antiparasitic agents targeting protein synthesis stems in part from the belief that parasite and host ribosomes are sufficiently similar to preclude selective toxicity. However, recent studies have revealed that Giardia lamblia rRNA has an unusual size and sequence; consequently, this organism and its homogeneous rRNA provide a useful model for the development of protein synthesis inhibitors with antiparasitic activity. In this study, I determined the sequence and secondary structure of the 3' end of the small-subunit RNA, the target for aminoglycoside inhibitory activity. The primary structure of these 140 nucleotides includes two blocks of sequence highly conserved among other organisms; the remaining sequence, although not conserved, can be folded into a secondary structure common to all rRNAs. The presence of U-1495 within one of the conserved blocks predicts hygromycin susceptibility. Also, a specific base pair (C-1409.G-1491) implicated in paromomycin susceptibility is present; whereas all procaryotes have this base pair, it is absent in many eucaryotes (including mammals). Conversely, kanamycin and apramycin resistance can be predicted from substitution of A-1408 with G. A growth inhibition assay was used to test the susceptibility of G. lamblia to a variety of aminoglycosides. After 48 h, 8 of 11 aminoglycosides tested failed to inhibit growth at a concentration of 200 micrograms/ml. Paromomycin and hygromycin, however, inhibited growth of three strains tested by 50% at 50 to 60 micrograms/ml and by close to 90% at 120 micrograms/ml. These results correlate well with the sequence and secondary-structure analyses. Paromomycin may be clinically useful when the toxicity of standard antigiardial drugs is of concern.
Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels
Authors: Fung-Tomc J , Dougherty T J , DeOrio F J , Simich-Jacobson V , Kessler R E
Published: June 2012

One hundred clinical isolates resistant to ceftazidime and/or cefotaxime were examined for susceptibility to cefepime. The most frequently encountered ceftazidime-cefotaxime-resistant strains belonged to the genera Enterobacter, Pseudomonas, and Citrobacter. Among these strains, 92% were resistant to cefoperazone, 91% were resistant to cefotaxime, 84% were resistant to ceftazidime, and 6% were resistant to cefepime. Of the members of the family Enterobacteriaceae, 57% were resistant to ceftriaxone. The six strains resistant to cefepime were all Pseudomonas aeruginosa and were resistant to both cefotaxime and ceftazidime. Cefepime-resistant P. aeruginosa strains had exceptionally high levels of beta-lactamase activity, higher than the levels found in strains resistant to ceftazidime but susceptible to cefepime. The beta-lactamases from the cefepime-resistant strains were type I (Richmond-Sykes), were constitutively produced, and did not have increased affinity or hydrolytic activity for cefepime. Thus, cefepime was active against most gram-negative bacteria which have developed resistance to the broad-spectrum cephalosporins, and resistance to cefepime in P. aeruginosa appears to be associated with higher beta-lactamase levels than in cefepime-susceptible strains.
Suppression of colds in human volunteers challenged with rhinovirus by a new synthetic drug (R61837)
Authors: al-Nakib W , Higgins P G , Barrow G I , Tyrrell D A , Andries K , Vanden Bussche G , Taylor N , Janssen P A
Published: June 2012

This report describes double-blind placebo-controlled trials of a new synthetic antirhinovirus drug, R61837, which showed it to be effective in suppressing colds in human volunteers challenged with rhinovirus type 9. In one trial, R61837 was given by intranasal spray six times a day, commencing 28 h before virus challenge; treatment continued for 4 days and one dose (total dose, 25 mg). This regimen suppressed symptoms until 48 h after medication ceased, at which time colds developed. In another trial, medication with R61837 commenced at 4 h before virus challenge and continued for a total of 6 days (total dose, 36 mg). The drug produced substantial reductions in both the mean daily clinical score and the mean daily nasal secretion weight compared with patients given the placebo. These differences reached statistical significance for 2 and 4 days, respectively. In a further trial, intranasal R61837 was not effective in treating colds even when given shortly after the onset of symptoms and in doses of up to 15 mg/day.
Changing susceptibility of Pseudomonas aeruginosa isolates from cystic fibrosis patients with the clinical use of newer antibiotics
Authors: Bosso J A , Allen J E , Matsen J M
Published: June 2012

To detect a change in antibiotic susceptibility patterns in Pseudomonas aeruginosa isolates upon the introduction and clinical use of ciprofloxacin, aztreonam, and ceftazidime, MICs for clinical isolates collected before introduction of the antibiotics, during early clinical use, and later were determined for these and seven other antipseudomonal antibiotics. Concomitant resistance to two or more antibiotics was also studied. Over the three study periods, rates of susceptibility to 9 of the 10 antibiotics decreased. The largest decrease occurred with ceftazidime. Analysis of subsets of isolates from patients treated with ciprofloxacin or aztreonam also showed declining susceptibility to the latter but a stabilization of susceptibility to the former after an initial decline. Concomitant resistance within and among antibiotic classes was common.
Minimum antibiotic levels for selecting a resistance plasmid in a gnotobiotic animal model
Authors: Corpet D E , Lumeau S , Corpet F
Published: June 2012

The minimum antibiotic concentrations for selecting an R plasmid in vivo were determined in germfree mice colonized by two isogenic strains of Escherichia coli, one of which carried an R plasmid. Seventy groups of three gnotobiotic mice were given low doses of ampicillin, colistin, flumequin, gentamicin, tetracycline, or streptomycin via drinking water for 2 weeks. The equilibrium between susceptible and resistant populations of bacteria was monitored daily in feces and compared with that of control mice given pure water. This model yielded reproducible data, and dose and response were strongly correlated. The minimum selecting doses ranged from 0.9 to 12.8 micrograms/ml of water, depending on the antibiotic and the R plasmid. The use of mathematical models and complementary in vitro experiments accounted for the effect of the low antibiotic levels.
Activity of ICI 195,739, a new oral triazole, compared with that of ketoconazole in the therapy of experimental murine blastomycosis
Authors: Tucker R M , Hanson L H , Brummer E , Stevens D A
Published: June 2012

ICI 195,739, a novel orally active triazole, proved 50 times as potent as ketoconazole, produced a clinical cure, and completely eradicated residual infection in a murine model of pulmonary blastomycosis. No other previously tested azole has shown similar activity. Fungicidal activity against Blastomyces dermatitidis was seen in vitro at concentrations 1/40 of those achieved in serum with protective doses.
Biological and biochemical characterization of clinical isolates of herpes simplex virus type 2 resistant to acyclovir
Authors: Oliver N M , Collins P , Van der Meer J , Van't Wout J W
Published: June 2012

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.