bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimicrobial activity and beta-lactamase stability of foramidocillin
Authors: Mandell W , Neu H C
Published: June 2012

Foramidocillin is a 6-alpha-formamido penicillin with a 6-beta-acylureido side chain. The majority of the Enterobacteriaceae were inhibited by less than or equal to 1 microgram of foramidocillin per ml, and Pseudomonas aeruginosa was inhibited by 4 micrograms/ml. Foramidocillin had activity comparable to those of ceftazidime, imipenem, and aztreonam against beta-lactamase-producing members of the Enterobacteriaceae and P. aeruginosa, and it inhibited organisms resistant to piperacillin. Foramidocillin did not inhibit gram-positive species or anaerobic gram-negative bacteria. Foramidocillin was not hydrolyzed by the common plasmid-mediated beta-lactamases TEM-1, TEM-2, OXA-2, PSE-4, and SHV-1, by the chromosomal beta-lactamases P99 of Enterobacter cloacae and K1 of Klebsiella oxytoca, or by the Sabath-Abraham enzyme of P. aeruginosa.
Antimicrobial activity of borate-buffered solutions
Authors: Houlsby R D , Ghajar M , Chavez G O
Published: June 2012

A minimal salts medium adjusted to physiological pH and osmolality was buffered with either 0.3% phosphate or 1.2% borate and evaluated for antimicrobial activity. The borate-buffered medium, either with or without a carbon source, exhibited significant antimicrobial activity against 15 Pseudomonas strains, 12 strains of enteric bacteria, and 7 strains of staphylococci. The borate-buffered system appears suitable for use as a generic vehicle for ophthalmic pharmaceutical agents.
Evolution and spread of IncFIV plasmids conferring resistance to trimethoprim
Authors: Campbell I G , Mee B J , Nikoletti S M
Published: June 2012

Twenty-one IncFIV-group plasmids conferring trimethoprim resistance in Escherichia coli isolates from humans and pigs were examined. Three evolutionary lines of plasmids were identified on the basis of restriction enzyme analysis. One was found exclusively in human isolates and another was found in pig isolates, while the third line consisted of plasmids from both sources. All R plasmids readily transferred to laboratory strains, and evidence was found for transfer to other biotypes of E. coli in the environment. The Tpr genes from representatives of the plasmid lines were cloned and compared by restriction analysis and by hybridization with two characterized Tpr dihydrofolate reductase genes. The sequences flanking the Tpr genes were different for each line, but all showed homology with the type 2 dihydrofolate reductase gene, irrespective of whether they were of human or animal origin. There was no hybridization to the type 1 gene. The remarkable degree of similarity among plasmids of the third line provided clear evidence of the exchange of plasmid-bearing E. coli between humans and pigs.
Bactericidal effects of ticarcillin-clavulanic acid against beta-lactamase-producing bacteria in vivo
Authors: Boon R J , Beale A S , Sutherland R
Published: June 2012

The comparative efficacies of ticarcillin and ticarcillin plus clavulanic acid have been determined in the mouse against experimental infections caused by ticarcillin-resistant bacteria. The infections studied comprised an intraperitoneal infection, local tissue infections, pyelonephritis, and pneumonia. Both ticarcillin and clavulanic acid penetrated readily to the sites of infection studied and at the doses employed were present at concentrations of the same order as those obtained in humans after the administration of ticarcillin-clavulanic acid formulations (Timentin; Beecham). At these concentrations, the ticarcillin-clavulanic acid combination caused significant bactericidal effects at the sites of infection against the ticarcillin-resistant strains of Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus investigated. The efficacy of ticarcillin plus clavulanic acid against the infections resistant to therapy with ticarcillin demonstrated the beta-lactamase-inhibitory activity of clavulanic acid in vivo.
Multiple-dose pharmacokinetics of cefonicid in patients with impaired renal function
Authors: Phelps R T , Conte J E
Published: June 2012

The pharmacokinetics of multiple-dose administration of cefonicid to patients with normal and impaired renal function were studied by using high-performance liquid chromatography to measure serial serum and urine concentrations. Eighteen patients received an initial dose of 15 mg/kg intravenously over 12 min plus two or three subsequent modified doses at intervals of 24 to 72 h, depending upon the degree of renal impairment. Six patients chronically requiring hemodialysis and 12 nondialysis subjects (creatinine clearance, 10 to 80 ml/min per 1.73 m2) were studied. The concentrations of cefonicid in serum after the initial dose were best described by an open two-compartment model. The elimination half-life of cefonicid ranged between 5.5 and 84.9 h. Mean peak and trough concentrations in serum for all patients were 178.2 +/- 29.3 micrograms/ml (plus or minus standard deviation) and 39.0 +/- 17.5 micrograms/ml, respectively. Trough concentrations were higher in patients requiring hemodialysis than in nondialysis subjects, but the difference was clinically insignificant. The renal clearance/plasma clearance ratio of cefonicid was linearly related to creatinine clearance and decreased with impaired renal function. Therefore, nonrenal mechanisms of elimination become more important as renal function declines. Since cefonicid concentrations were within the therapeutic range for nearly all dosing intervals, we conclude that the guidelines used for dosage reduction and interval prolongation in this study result in therapeutically adequate concentrations in serum and, at the same time, result in no significant drug accumulation.
Biochemical properties of beta-lactamase produced by Legionella gormanii
Authors: Fujii T , Sato K , Miyata K , Inoue M , Mitsuhashi S
Published: June 2012

beta-Lactamase was purified from a strain of Legionella gormanii. The molecular weight of the purified enzyme was 25,000, and its isoelectric point was 10.5. The enzyme hydrolyzed oxyiminocephalosporins, cephamycins, penicillins, and imipenem. The enzyme activity was inhibited by EDTA, Hg2+, and Cu2+, but not by clavulanic acid, sulbactam, or imipenem.
Determination of aminoglycoside resistance in Staphylococcus aureus by DNA hybridization
Authors: Dickgiesser N , Kreiswirth B N
Published: June 2012

A method is described for identification of the genes conferring aminoglycoside resistance in Staphylococcus aureus by dot-blot and Southern blot techniques. As radioactive probes, fragments of plasmids pAT48, pUBH2, and pH13, carrying the genes for an aminocyclitol-3'-phosphotransferase, an aminocyclitol-4'-adenylyltransferase, and an aminocyclitol-2''-phosphotransferase-aminocyclitol-6'-acetyltransferase, respectively, were used.
Degradation kinetics of imipenem in normal saline and in human serum
Authors: Swanson D J , DeAngelis C , Smith I L , Schentag J J
Published: June 2012

The stability of imipenem in 0.9% sodium chloride and in human serum was measured at controlled temperatures over time. The degradation was characterized by a first-order process and was consistent with an apparent hydrolysis reaction.
In vitro and in vivo efficacy of the combination trimethoprim-sulfamethoxazole against clinical isolates of methicillin-resistant Staphylococcus aureus
Authors: Elwell L P , Wilson H R , Knick V B , Keith B R
Published: June 2012

The in vitro susceptibilities of 16 independent, geographically distinct clinical isolates of methicillin-resistant Staphylococcus aureus to trimethoprim (TMP) in combination with sulfamethoxazole (SMX) were evaluated. Although methicillin-resistant S. aureus strains appear to be universally resistant to SMX, the combination TMP-SMX was found to be synergistic in vitro (in combination, the MICs of both drugs decreased 6- to 25-fold) as well as in vivo (5- to 6-fold reduction in TMP at 50% effective doses).
Aztreonam concentration in abdominal tissues and bile
Authors: Condon R E , Friedhoff L T , Edmiston C E , Levinson B
Published: June 2012

Abdominal tissue, serum, and bile samples were obtained from 37 patients given a single, 2-g intravenous infusion of aztreonam immediately prior to an elective abdominal operation. Samples were obtained at 0 to 6 h after dosing. Mean concentrations in tissues and fluids and specimen/serum rations are reported. Levels in tissue and bile exceeded the reported MICs for 90% of most members of the family Enterobacteriaceae for up to 6 h.
Susceptibility of Haemophilus ducreyi to ampicillin and sulbactam in vitro
Authors: Jones B M , Hafiz S , Duerden B I
Published: June 2012

The MICs of ampicillin, ampicillin plus sulbactam in equal proportions, and a range of ampicillin concentrations with a constant 0.5 micrograms/ml concentration of sulbactam were determined for 66 strains of Haemophilus ducreyi by an agar dilution technique with standardized inocula prepared by ultrasonication. Fifty-five strains were susceptible to ampicillin alone (MIC range, 0.06 to 1 microgram/ml). The MICs for the 11 resistant strains were (micrograms per milliliter): range, 8 to greater than 16; MIC for 50% of the strains tested (MIC50), greater than 16; MIC90, greater than 16; 8 of them produced beta-lactamase. In the presence of an equal concentration of sulbactam, the MICs for ampicillin-resistant strains were lowered to (micrograms per milliliter): range, 0.125 to 2; MIC50, 0.25; MIC90, 1. In the presence of a fixed 0.5-micrograms/ml concentration of sulbactam, the MICs for the resistant strains were (micrograms per milliliter): range, 0.125 to 2; MIC50, 0.125; MIC90, 0.25. Sulbactam-ampicillin appears to be suitable for the treatment of H. ducreyi infections, especially those caused by ampicillin-resistant strains.
Determination of kanamycin concentration in serum by substrate-labeled fluorescent immunoassay
Authors: DeCastro A F , Place J D , Lam C T , Patel C
Published: June 2012

A homogeneous substrate-labeled fluorescent immunoassay was developed for the measurement of kanamycin concentrations in serum. A fluorogenic drug reagent (FDR) (beta-galactosyl-umbelliferone-tobramycin) was prepared that is nonfluorescent under the conditions of the assay but is hydrolyzed upon catalysis by beta-galactosidase to yield a fluorescent product. Binding of the FDR to the antiserum to kanamycin prevented enzyme hydrolysis. The fixed level of FDR in the assay competed with kanamycin in the sample for a limited number of antibody-binding sites. Unbound FDR was hydrolyzed by beta-galactosidase to release a fluorescent product that is proportional to the kanamycin concentration in the sample. The assay exhibited good sensitivity, precision, and accuracy and correlated well with other methods.
Therapeutic efficacy of cefadroxil and cephalexin for pneumonia in a rat test model
Authors: Chisholm D R , DeRegis R G , Behr D A
Published: June 2012

The therapeutic efficacies of cefadroxil and cephalexin were compared in a Streptococcus pyogenes-induced lung infection in rats. Although MICs, rates of in vitro killing in rat serum, and antibiotic serum levels after oral administration were similar for both drugs, cefadroxil was about eight times more effective than cephalexin in reducing the number of viable streptococci at the site of infection. This excellent in vivo bactericidal activity of cefadroxil in lung tissue and bronchial secretions was reflected in the 50% protective dose (PD50) after single or multiple oral treatments. A single treatment given 24 h after infection resulted in a PD50 of 2.8 mg of cefadroxil per kg, compared with 21 mg of cephalexin per kg. When treatment was administered three times, at 24, 27, and 30 h postinfection, the PD50s of cefadroxil and cephalexin were 0.7 and 8.0 mg/kg, respectively. In infected animals, treated 24 h postinfection, the area under the lung tissue concentration versus time curve for cefadroxil was significantly greater than that of cephalexin. This difference in pharmacokinetic behavior may account, at least in part, for the superior therapeutic results obtained with cefadroxil in this experimental pulmonary infection.
Factors influencing the in vitro activity of two new aryl-fluoroquinolone antimicrobial agents, difloxacin (A-56619) and A-56620
Authors: Hirschhorn L , Neu H C
Published: June 2012

The in vitro activity of difloxacin (A-56619) and A-56620, two new aryl-difluoroquinolones, was decreased by magnesium at 9 mM and in assay at pH 5.5 or in urine. Resistance was seen with members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus repeatedly exposed to subinhibitory concentrations of the compounds. The frequency of resistance was similar to that found for other new quinolones.
Penetration of cefuzoname into the cerebrospinal fluid of rabbits
Authors: Haruta T , Yamamoto H , Okura K E , Kuroki S , Kobayashi Y
Published: June 2012

Concentrations of cefuzoname in cerebrospinal fluid (CSF) were determined in a total of 16 rabbits, 5 with healthy meninges, 5 with Staphylococcus aureus meningitis, and 6 with Escherichia coli meningitis. Mean percentages of the maximum concentration of the drug in CSF versus that in serum were 0.57, 3.37, and 4.40% for healthy rabbits, those with staphylococcal meningitis, and those with E. coli meningitis, respectively. The percentages of the area under the concentration-time curve of cefuzoname in CSF versus that in serum were, in the order of healthy group, staphylococcal meningitis group, and E. coli meningitis group, 0.61, 4.99, and 8.04% at 15 to 60 min, 1.44, 7.09, and 12.7% at 15 to 120 min, and 1.87, 8.07, and 15.8% at 15 to 180 min after administration, showing significant differences between the healthy and meningitis groups. All of the values in the E. coli meningitis group were greater than those of the staphylococcal meningitis group, but the differences were not significant. The ratios of the half-life of cefuzoname in CSF to that in serum were 2.10, 1.98, and 3.37 for the healthy, staphylococcal meningitis, and E. coli meningitis groups, respectively, with no significant difference between the three groups. Cefuzoname seems to be among the middle ranks of beta-lactam agents as far as penetration rate is concerned; however, when its potent antibacterial activity and broad spectrum are taken into account, the concentrations in CSF in patients with meningitis seem worth examining.
Comparative in vitro evaluation of cefonicid, cefazolin, and penicillin against viridans group streptococci isolated from blood
Authors: Weinstein M P
Published: June 2012

The in vitro activity of cefonicid against 60 strains of viridans group streptococci isolated from blood of patients with bacteremia and infective endocarditis was compared with those of cefazolin and penicillin. Cefonicid was less active than cefazolin, and both cephalosporins were less active than penicillin. The MIC50 and MIC90 for the strains tested were 0.06 and 1 microgram/ml for penicillin, 0.125 and 8 micrograms/ml for cefazolin, and 4 and 32 micrograms/ml for cefonicid.
Steady-state serum pharmacokinetics of novobiocin and rifampin alone and in combination
Authors: Drusano G L , Townsend R J , Walsh T J , Forrest A , Antal E J , Standiford H C
Published: June 2012

Because of the potential of novobiocin-rifampin for oral therapy of methicillin-resistant Staphylococcus aureus infection, we evaluated the pharmacokinetics of novobiocin and rifampin, alone and in combination, in a randomized, crossover, multiple-dose evaluation (500 mg of novobiocin and 300 mg of rifampin administered orally, twice a day, for 27 doses) in 10 volunteers. The half-lives of novobiocin and rifampin when administered alone were 5.85 +/- 1.20 and 1.46 +/- 0.30 h, respectively; when administered in combination, the half-lives were 2.66 +/- 0.65 and 1.43 +/- 0.29 h, respectively. This difference was significant for novobiocin. The area under the curve also differed significantly for novobiocin when administered in combination. No significant differences were seen in the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, or both for either drug when single and combination therapy groups were compared. A change in clearance of novobiocin rather than a change in absorption is the more likely explanation for these findings. The mechanism remains to be elucidated. Nevertheless, the trough serum concentrations of both novobiocin and rifampin were in excess of the MIC for 90% of strains tested of methicillin-resistant S. aureus, even when coadministered.
Analysis by using DNA probes of the OXA-1 beta-lactamase gene and its transposon
Authors: Ouellette M , Roy P H
Published: June 2012

From recombinant clone pTY27, encoding an OXA-1 beta-lactamase gene, we performed subcloning experiments to more precisely delimit the gene. We describe the use as probes of six different restriction fragments known from subcloning experiments to be within the structural gene or part of the transposable element, Tn2603, flanking the OXA-1 determinant. We showed that the OXA-1 structural gene is slightly related to the OXA-2 determinant and also that sequences within Tn2603 are common to all the OXA- and PSE-producing strains tested. For epidemiological purposes, we began nucleotide sequencing of the OXA-1 determinant, and from preliminary sequence data we synthesized an oligonucleotide 15 bases in length, corresponding to a sequence within the OXA-1 gene. This oligonucleotide was found to be specific for the OXA-1 determinant, because it hybridized only to bacteria producing that beta-lactamase.
Antiherpetic effects of a human alpha interferon analog, IFN-alpha Con1, in hamsters
Authors: Fish E N , Banerjee K , Levine H L , Stebbing N
Published: June 2012

The efficacy of a novel consensus form of human alpha interferon designated IFN-alpha Con1 was evaluated against herpesvirus infections in vitro and in vivo. At comparable antiviral concentrations, natural lymphoblastoid IFN, IFN-alpha Con1, the molecular subtype IFN-alpha, and the hybrid IFN-alpha AD(Bgl) obtained by recombinant DNA methods conferred similar protection against herpes simplex virus type 1 and type 2 (HSV-2) infections of human cells in vitro. Whereas 7 X 10(5) U of IFN-alpha AD(Bgl) administered in 7 intraperitoneal (i.p.) doses between -4 and 96 h relative to infection protected 90% of mice from a lethal HSV-2 infection, a similar treatment regimen with IFN-alpha Con1 conferred no protection. Systemic HSV-2 infection of hamsters was rapidly lethal, but a single i.p. treatment with 10(6) U of either IFN-alpha Con1 or IFN-alpha AD(Bgl) was highly effective and protected 90 and 75% of animals, respectively, when given 6 h before infection; treatment with IFN-alpha Con1 protected 45% of animals when administered 10 h after infection. In addition, IFN-alpha Con1 was highly protective against acute cervicovaginal HSV-2 infection of hamsters when administered either in a single i.p. dose of 10(6) U at -6 or 10 h relative to infection or in multiple i.p. doses of 10(6) U between -6 and 120 h relative to infection. Protection was manifested by a delay in the onset of and a reduction in duration of infection, a reduction in the number of positive cervicovaginal infections, and an increase in the survival rate.
Comparative uptake of gentamicin, netilmicin, and amikacin in the guinea pig cochlea and vestibule
Authors: Dulon D , Aran J M , Zajic G , Schacht J
Published: June 2012

The kinetics of the entry of three aminoglycosides into inner-ear tissues of the guinea pig after acute and chronic administration were compared: gentamicin toxic to the cochlea and the vestibule, amikacin preferentially cochleotoxic, and netilmicin of low ototoxic liability. During constant intravenous infusion, levels of the three drugs in plasma tended to reach a plateau after 1 h, while levels in perilymph did not reach a plateau within 6 h. The drug concentrations in both vestibular and cochlear tissues quickly reached saturation. Amikacin and gentamicin concentrations were similar in vestibular and cochlear tissues, while netilmicin values were somewhat lower. After 1 week of chronic treatment (100 mg of drug per kg of body weight daily subcutaneously), levels of gentamicin and amikacin in tissue were similar to each other and were not significantly different between cochlear and vestibular tissues. Netilmicin concentrations again were somewhat lower in the tissues, but identical to those of the other drugs in the perilymph. After 3 weeks of treatment, all of the drugs were equally distributed in the inner-ear tissues. Release of the drug from the tissues after the 3-week treatment was faster for amikacin (83% decrease after 20 days) than for netilmicin and gentamicin (approximately 50% decrease). There was no correlation, under any of the experimental conditions, between the drug concentrations and their degrees of toxicity. These results demonstrate that selective aminoglycoside ototoxicity cannot be explained by a preferential uptake or accumulation of drugs in the afflicted tissues or in the perilymph.
Susceptibility of Campylobacter pyloridis to three macrolide antibiotics (erythromycin, roxithromycin [RU 28965], and CP 62,993) and rifampin
Authors: Czinn S , Carr H , Aronoff S
Published: June 2012

The presence of Campylobacter pyloridis in the gastric mucosa was recently linked to peptic ulcer disease. This study compared the inhibitory activity of three macrolide compounds (erythromycin, roxithromycin [RU 28965], and CP 62,993) and rifampin against 10 clinical isolates of C. pyloridis. The macrolides were equally effective against the test strains, with MICs ranging from 0.06 to 0.5 microgram/ml; rifampin was less active, with MICs ranging from 0.25 to greater than 1 microgram/ml. Erythromycin and the two new macrolide derivatives are potentially useful agents in the treatment of infections caused by C. pyloridis.
Comparative pharmacokinetics of low- and high-dose ticarcillin
Authors: Guglielmo B J , Flaherty J F , Batman R , Barriere S L , Gambertoglio J G
Published: June 2012

Certain antipseudomonal penicillins, such as mezlocillin, exhibit a nonlinear pharmacokinetic disposition with increasing doses. We evaluated the effect of a single low dose (50 mg/kg) compared with a high dose (80 mg/kg) on the pharmacokinetics of ticarcillin in a crossover trial of eight healthy volunteers. No significant alteration in plasma clearance (130.1 +/- 36.5 versus 120.5 +/- 38.0 ml/min), nonrenal clearance (36.5 +/- 8.4 versus 33.4 +/- 18.5 ml/min), or volume of distribution at steady state (12.8 +/- 3.5 versus 12.3 +/- 4.5 liters) was observed between the low- and high-dose regimens, respectively. The elimination half-life remained unchanged between the two doses (67.9 +/- 14.3 versus 68.0 +/- 12.2 min). Unlike other newer antipseudomonal penicillins, ticarcillin did not display dose-dependent pharmacokinetic behavior with the range of doses used in the clinical setting.
New sodium hydroxide digestion method for measurement of renal tobramycin concentrations
Authors: Gilbert D N , Kohlhepp S J
Published: June 2012

Because of the known propensity of the cationic aminoglycosides to interact with a variety of anionic tissue constituents, it was postulated that present elution methods fail to detect a substantial proportion of the aminoglycoside that accumulates in the kidney. After preliminary experiments documented the pH and temperature stability of tobramycin, a new sodium hydroxide (NaOH) tissue digestion method was applied to renal tissue collected from rats given tobramycin at 80 mg/kg (body weight) per day in two divided doses for 3, 7, 10, 14, and 17 days. Compared with elution with buffer from the renal homogenate, digestion with 1.0 N NaOH at 70 degrees C for 15 min significantly increased the amount of assayable tobramycin (P less than 0.001). The absolute increase varied between 37 and 96%, depending on the number of days of in vivo drug administration. A single trichloroacetic acid (TCA) treatment of the homogenate altered the amount of assayable tobramycin over a range which varied from a decrease of 6% to an increase of 32%. After TCA treatment, it was possible to increase the amount of measurable tobramycin by 17 to 22% by treatment of the TCA-induced precipitate with 1.0 N NaOH. Digestion of renal homogenates with 1.0 N NaOH significantly increases the amount of tobramycin detectable by immunoassay.
Aryl-fluoroquinolone derivatives A-56619 (difloxacin) and A-56620 inhibit mitogen-induced human mononuclear cell proliferation
Authors: Gollapudi S V , Vayuvegula B , Gupta S , Fok M , Thadepalli H
Published: June 2012

Aryl-fluoroquinolone derivatives A-56619 (difloxacin) and A-56620 were found to inhibit human peripheral blood mononuclear cell (MNC) proliferation (measured by [3H]thymidine uptake) that was induced by concanavalin A or monoclonal antibody OKT3. These antimicrobial agents exert their maximum suppressive effect when added within the first 24 h after the onset of culture with concanavalin A. No increase in the concentration of mitogen or the duration of incubation of MNC cultures reversed this inhibitory effect, but the removal of the drug from cultures reversed the suppression of DNA synthesis. A-56619 appeared not to interfere with the triggering of MNC activation by mitogen because it did not inhibit mitogen-induced increase in protein synthesis (measured by [3H]leucine incorporation), interleukin-2 receptor expression (measured by the binding of fluorescein-conjugated monoclonal antibody against interleukin-2 receptor), and cell volume. These findings are considered in terms of possible interference of aryl-fluoroquinolones with mammalian topoisomerase and DNA polymerases.
Astromicin-induced membrane damage in Serratia marcescens
Authors: Umeda A , Murata K , Amako K
Published: June 2012

The morphological changes in Serratia marcescens induced by astromicin were determined by a new technique of electron microscopy, a rapid freezing and substitution fixation technique, and a freeze-fracturing technique. Two structural changes were observed. One was damage to the cytoplasmic membrane, and the other was the accumulation of a large electron-dense mass in the cytoplasm. The damage observed in the cytoplasmic membrane was the disappearance of the unit membrane structure from the thin-sectioned profile of the drug-treated bacteria and the loss of the membrane particles from the fractured surface of the membrane. Damage to the membrane was also suggested by the results of examination of the spheroplasts for stability. The spheroplasts prepared from the drug-treated bacteria were unstable in an osmotically controlled buffer. Most of the spheroplasts were lysed within 3 h, whereas those prepared from control cells were stable for more than 15 h. The electron-dense mass in the cytoplasm was usually seen in the polar region of the cell in close contact with the cell membrane. These structural changes were not specific for astromicin but were also found in gentamicin-treated cells.
Novel morphological changes in gram-negative bacteria caused by combination of bulgecin and cefmenoxime
Authors: Nakao M , Yukishige K , Kondo M , Imada A
Published: June 2012

The mode of action of bulgecin was investigated by examining its bactericidal and bacteriolytic activities, its effect on bacterial morphology, and its interaction with penicillin-binding proteins (PBPs). Bulgecin alone did not show any antibacterial activity against Escherichia coli and Serratia marcescens, but in concert with cefmenoxime, it induced potent growth-inhibitory and bactericidal activities. Electron microscopic examination of E. coli cells exposed to bulgecin combined with cefmenoxime revealed that a bulge developed in the middle of the cell, and additional smaller bulges were formed halfway between the central bulge and the polar ends. At the site of bulge development, vesicular mesosomelike structures appeared in the cytoplasm, the peptidoglycan layer facing them became faint, and the outer membrane protruded to form blebs. These morphological changes were quite different from those caused by the mecillinam-cefmenoxime combination that produces big bulges in E. coli. When S. marcescens was exposed to the combination of bulgecin and cefmenoxime, not only bulge formation, but also branching of the cells was observed. Bulgecin neither showed affinity for any PBPs of E. coli nor affected the binding of cefmenoxime or mecillinam to the PBPs.
In vitro activity and beta-lactamase stability of two oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074)
Authors: Neu H C , Chin N X , Labthavikul P
Published: June 2012

Ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074), two new orally administered aminothiazolyl imimomethoxy cephalosporins, inhibited hemolytic streptococci and Streptococcus pneumoniae at less than or equal to 0.5 micrograms/ml but were less active against staphylococci than were cephalexin and cefaclor. They did not inhibit S. faecalis, S. faecium, Listeria monocytogenes, Corynebacterium JK species, or Pseudomonas aeruginosa. Haemophilus influenzae, Branhamella catarrhalis, and Neisseria gonorrhoeae, including ampicillin-resistant isolates, were inhibited at less than 0.25 micrograms/ml. Both agents inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Salmonella species, Shigella species, Citrobacter diversus, and Aeromonas hydrophila resistant to ampicillin, cephalexin, and cefaclor at less than or equal to 2 micrograms/ml, although many isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to cefotaxime were not inhibited by these agents. A marked inoculum effect was noted for Enterobacteriaceae carrying the Richmond-Sykes type 1A chromosomally mediated beta-lactamases, but plasmid-mediated beta-lactamases did not hydrolyze the compounds. Both drugs inhibited the chromosomally mediated beta-lactamase of E. cloacae, P99.
In vitro activities of Ro 19-5247 and Ro 15-8074, new oral cephalosporins
Authors: Fass R J , Helsel V L
Published: June 2012

The in vitro activities of two new oral cephalosporins, Ro 19-5247 and Ro 15-8074, were compared with the in vitro activities of cefuroxime, cefaclor, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole (TMP-SMZ), and doxycycline against a variety of bacterial species. MIC50s (MICs required to inhibit 50% of strains) of Ro 19-5247 were less than or equal to 0.13 micrograms/ml for streptococci (except Streptococcus faecalis) and Haemophilus influenzae; 0.25 to 2 micrograms/ml for most strains of Enterobacteriaceae, Aeromonas hydrophila, Branhamella catarrhalis, and gram-positive anaerobic bacteria; and 1 to 8 micrograms/ml for methicillin-susceptible staphylococci. MIC50s of Ro 15-8074 were similar to those of Ro 19-5247, except that gram-positive aerobes and anaerobes were less susceptible. Both Ro 19-5247 and Ro 15-8074 had greater in vitro activity against strains of Enterobacteriaceae than did comparative beta-lactams and doxycycline; TMP-SMZ had the broadest spectrum of activity against these organisms. None of the cephalosporins were active against methicillin-resistant staphylococci, S. faecalis, most nonfermenters, or Bacteroides sp. Inoculum size variations affected MICs in a species-dependent manner for beta-lactams and unpredictably for TMP-SMZ but had little effect for doxycycline. Bactericidal activity was consistent with beta-lactams, inconsistent with TMP-SMZ, and uncommon with doxycycline.
Antibiotic-resistant bacteria in surveillance stool cultures of patients with prolonged neutropenia
Authors: Wingard J R , Dick J , Charache P , Saral R
Published: June 2012

The value of stool surveillance for antibiotic-resistant gram-negative bacteria was analyzed in 86 neutropenic bone marrow transplant patients. Twice-weekly specimens were inoculated onto culture medium containing gentamicin plus carbenicillin. The recovered organisms were identified to the species level and tested for antibiotic susceptibility. Forty-eight resistant organisms were recovered from 35 patients. Thirteen isolates persistently colonized patients. Escherichia coli (29%) and Pseudomonas aeruginosa (19%) were the most frequently recovered organisms. Although most organisms were recovered while patients were on antibiotics, 15 isolates, including eight of nine resistant P. aeruginosa, were detected before antibiotics were initiated. The duration of antibiotic use was longer for patients persistently colonized than for those not colonized (P = 0.03). Of the 15 resistant organisms which caused infection, 12 were detected in the surveillance cultures. Infections by antibiotic-resistant organisms occurred more frequently in patients colonized than in those not colonized (P = 0.006) and more frequently in patients persistently colonized than in those colonized only once (P = 0.01). The absence of colonization or persistent colonization correlated well with the absence of infection (negative predictive values of 94 and 91%, respectively).
Antifungal macrodiolide from Streptomyces sp
Authors: Jois H R , Sarkar A , Gurusiddaiah S
Published: June 2012

Aerobic fermentation cultures of Streptomyces sp. produced an antifungal macrodiolide. This new antibiotic consists of two units of homononactic acid linked to form a cyclic diester. An unknown polypeptide was also isolated in trace quantities. The antibiotic with polypeptide complex showed high levels of antifungal activity compared with that of the macrodiolide alone. The macrodiolide also showed a stimulatory effect on some species of fungi. The production, purification, and characterization of these compounds are reported.
Mutation within the herpes simplex virus DNA polymerase gene conferring resistance to (R)-9-(3,4-dihydroxybutyl)guanine
Authors: Chiou H C , Kerns K M , Coen D M
Published: June 2012

Five herpes simplex virus mutants known or presumed to contain mutations in their DNA polymerase genes conferring resistance to acyclovir and arabinosyladenine also proved to exhibit some degree of resistance to (R)-9-(3,4-dihydroxybutyl)guanine (buciclovir). For one mutant, a buciclovir resistance mutation was mapped to a region of the viral DNA polymerase gene proposed to encode the deoxynucleoside 5'-triphosphate binding domain. These data implicate the viral polymerase as a target of buciclovir action that contributes to its antiviral selectivity.
Characterization of a beta-lactamase-specifying plasmid isolated from Eikenella corrodens and its relationship to a commensal Neisseria plasmid
Authors: Rotger R , García-Valdés E , Trallero E P
Published: June 2012

A 9.4-kilobase plasmid encoding penicillin, streptomycin, and sulfonamide resistance was isolated from a beta-lactamase-producing Eikenella corrodens strain. This plasmid appears to be identical to a resistance plasmid common to saprophytic Neisseria strains.
Antigenic relationships among penicillin-binding proteins 1 from members of the families Pasteurellaceae and Enterobacteriaceae
Authors: Schryvers A B , Wong S S , Bryan L E
Published: June 2012

Penicillin-binding proteins (PBPs) from Haemophilus influenzae RD purified by a combination of affinity chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and electroelution were used to immunize rabbits to obtain specific antisera. Antisera directed against PBP 1 (1b) of H. influenzae cross-reacted with representative organisms of the family Pasteurellaceae and with many members of the family Enterobacteriaceae but not with other gram-negative organisms. Immunization with purified PBP 3 of H. influenzae produced antisera that reacted with PBP 1 (1b) of H. influenzae and showed the same cross-reactive pattern with other species as the anti-PBP 1 antiserum. A 24,000-molecular-weight polypeptide of H. influenzae, not radiolabeled by [35S]penicillin, reacted with antisera against purified PBPs 1 (1a, 1b), 2, and 3. The results suggest that antigenic epitopes are shared among similar PBPs from related species and even among different PBPs within the same species.
Pharmacokinetics and sputum penetration of ciprofloxacin in patients with cystic fibrosis
Authors: Smith M J , White L O , Bowyer H , Willis J , Hodson M E , Batten J C
Published: June 2012

Levels of ciprofloxacin in serum and sputum were studied for eight patients with cystic fibrosis who were infected with Pseudomonas aeruginosa. Patients were studied in a steady state on a dosage of 500 mg every 8 h. Peak levels in serum ranged from 1.27 to 5.6 mg/liter (mean, 3.16 +/- 1.27), and absorption was rapid, the time to peak concentration ranging from 0.5 to 3.0 h (mean, 1.5 +/- 0.9). The antibiotic penetrated sputum well, achieving areas under the curve of approximately 46% of those obtained in serum.
Bioassay for SF 86-327, a new antifungal agent
Authors: Kan V L , Henderson D K , Bennett J E
Published: June 2012

A bioassay with Trichophyton mentagrophytes is described for SF 86-327, an allylamine antifungal agent. SF 86-327 serum concentrations were measured by bioassay in 117 serum sampler from five patients receiving 500 mg/day. The peak, trough, and area under the concentration-time curve were determined after the first dose and at steady state. Drug accumulation occurred with prolonged therapy.
Xylotubercidin against herpes simplex virus type 2 in mice
Authors: De Clercq E , Robins M J
Published: June 2012

Of a series of newly synthesized derivatives of the pyrrolo[2,3-d]pyrimidine nucleosides tubercidin, toyocamycin, and sangivamycin, the xylosyl analog of tubercidin, xylotubercidin, exhibited the greatest potency and selectivity against herpes simplex virus type 2 (HSV-2) in vitro. At dosage regimens that were not toxic for the host, xylotubercidin proved efficacious in various HSV-2 animal model infections. When applied topically at 0.25, 0.5, or 1% in dimethyl sulfoxide or when administered systemically (intraperitoneally) at 12.5 or 25 mg/kg per day, xylotubercidin suppressed the development of herpetic skin lesions and the paralysis and mortality associated therewith in hairless mice inoculated intracutaneously with HSV-2. In this model, acyclovir was effective only if administered topically at 5 or 10% in dimethyl sulfoxide. When administered intraperitoneally over a dosage range of 10 to 50 mg/kg per day, xylotubercidin achieved a significant reduction in the mortality rate of mice infected intraperitoneally with HSV-2. Under the same conditions, acyclovir did not offer any protection even when administered at doses up to 250 mg/kg per day. Xylotubercidin thus appears to have considerable potential for both topical and systemic treatment of HSV-2 infections.
Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin
Authors: Henry N K , Wilson W R , Geraci J E
Published: June 2012

We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.
Noninvasive and quantitative 19F nuclear magnetic resonance study of flucytosine metabolism in Candida strains
Authors: Vialaneix J P , Chouini N , Malet-Martino M C , Martino R , Michel G , Lepargneur J P
Published: June 2012

19F nuclear magnetic resonance was used for a noninvasive and quantitative study of flucytosine (FC; 5-fluorocytosine) metabolism in two strains of Candida albicans and one strain of Candida tropicalis with various susceptibilities to FC. Three intracellular fluorinated metabolites were detected in the highly susceptible strain, F-nucleotides (Fnt), F-nucleosides, and 5-fluorouracil (5FU). Fnt were partially converted into 5FU when the spectra of the yeasts were recorded at 37 degrees C without perfusion, but the intensities of the signals were not modified at 4 or 37 degrees C if the cells were perfused. In the acid extract, the Fnt signal was resolved into three distinct peaks; none of them was attributable to 5-fluoro-2'-deoxyuridine-5'-monophosphate. The same signals were detected in the partially resistant strain, but only 5FU was observed in the highly resistant strain; the resistance of the latter strain therefore was primarily due to a defect in UMP pyrophosphorylase. At the end of the incubation period, only FC and released 5FU were present in the culture media. The concentration of the intracellular fluorinated metabolites was increased if the strain was susceptible to FC. The total amount of metabolized FC was very similar for the highly susceptible and the partially resistant strains, but the percentage of Fnt was much higher in the former (38%) than in the latter (8%); the mild resistance of the partially resistant strain therefore was attributed to the decreased activity of UMP pyrophosphorylase.
Involvement of penicillin-binding protein 2 with other penicillin-binding proteins in lysis of Escherichia coli by some beta-lactam antibiotics alone and in synergistic lytic effect of amdinocillin (mecillinam)
Authors: Gutmann L , Vincent S , Billot-Klein D , Acar J F , Mrèna E , Williamson R
Published: June 2012

Compared with cefotaxime, ceftazidime, moxalactam, and aztreonam, ceftriaxone produced the best lytic and bactericidal effects when each was added at about 10 times the MIC to Escherichia coli W7. When each of these antibiotics was added at its MIC, only bacteriostasis occurred, but the simultaneous addition of amdinocillin (mecillinam) was synergistic in causing rapid lysis and bactericidal effects. Induction of lysis of two E. coli mutants containing either a thermosensitive penicillin-binding protein (PBP) 2 or 3 by relatively PBP 3-specific (aztreonam) and PBP 2-specific (amdinocillin) antibiotics indicated that inhibition of only PBPs 2 and 3 can cause lysis. Examination of the interactions of cefotaxime, aztreonam, and cefsulodin, with or without amdinocillin, with their targets suggested that other combinations of PBPs could be involved in the onset of lysis. However, inhibition of both PBPs 2 and 3 may explain the better lysis-inducing activity of ceftriaxone (which binds well to both of these PBPs), as well as the synergistic effect of amdinocillin when added together with low concentrations of other beta-lactam antibiotics that interact with PBP 3.
In vitro susceptibility of gram-positive cocci to paldimycin
Authors: Pohlod D J , Saravolatz L D , Somerville M M
Published: June 2012

Paldimycin (U-70138F) is a new antimicrobial agent with activity against gram-positive cocci. Clinical isolates of staphylococci and streptococci were tested. MICs were higher in Mueller-Hinton broth than in nutrient broth. Change in pH had minimal effect on the MICs in either broth. When inoculum size was varied, an inoculum effect was observed. The gram-positive cocci tested were generally more susceptible to paldimycin than to vancomycin.
Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides
Authors: Thormar H , Isaacs C E , Brown H R , Barshatzky M R , Pessolano T
Published: June 2012

Lipids in fresh human milk do not inactivate viruses but become antiviral after storage of the milk for a few days at 4 or 23 degrees C. The appearance of antiviral activity depends on active milk lipases and correlates with the release of free fatty acids in the milk. A number of fatty acids which are normal components of milk lipids were tested against enveloped viruses, i.e., vesicular stomatitis virus, herpes simplex virus, and visna virus, and against a nonenveloped virus, poliovirus. Short-chain and long-chain saturated fatty acids had no or a very small antiviral effect at the highest concentrations tested. Medium-chain saturated and long-chain unsaturated fatty acids, on the other hand, were all highly active against the enveloped viruses, although the fatty acid concentration required for maximum viral inactivation varied by as much as 20-fold. Monoglycerides of these fatty acids were also highly antiviral, in some instances at a concentration 10 times lower than that of the free fatty acids. None of the fatty acids inactivated poliovirus. Antiviral fatty acids were found to affect the viral envelope, causing leakage and at higher concentrations, a complete disintegration of the envelope and the viral particles. They also caused disintegration of the plasma membranes of tissue culture cells resulting in cell lysis and death. The same phenomenon occurred in cell cultures incubated with stored antiviral human milk. The antimicrobial effect of human milk lipids in vitro is therefore most likely caused by disintegration of cellular and viral membranes by fatty acids. Studies are needed to establish whether human milk lipids have an antimicrobial effect in the stomach and intestines of infants and to determine what role, if any, they play in protecting infants against gastrointestinal infections.
Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans
Authors: Georgopapadakou N H , Dix B A , Smith S A , Freudenberger J , Funke P T
Published: June 2012

Eight antifungal agents were examined for effects on lipid biosynthesis and membrane integrity in Candida albicans. Lipids were labeled in vivo or in vitro with [14C]acetate and analyzed by thin-layer and gas chromatography. Membrane integrity was measured by a recently developed [14C]aminoisobutyric acid radiolabel release assay. The imidazole antifungal agents miconazole, econazole, clotrimazole, and ketoconazole, at concentrations inhibiting ergosterol biosynthesis (0.1 microM), decreased the ratio of unsaturated to saturated fatty acids in vivo but not in vitro. Similarly, naftifine, tolnaftate, and the azasterol A25822B, at concentrations inhibiting ergosterol biosynthesis (10, 100, and 1 microM, respectively), decreased the ratio of unsaturated to saturated fatty acids in vivo only. This suggests that the effect on fatty acids observed with ergosterol biosynthesis inhibitors may be secondary to the effect on ergosterol. With imidazoles, oleic acid antagonized inhibition of cell growth but not inhibition of ergosterol. This suggests that, with the C-14 demethylase inhibitors, decreased unsaturated fatty acids, rather than decreased ergosterol, are responsible for growth inhibition. Cerulenin, previously reported to be a potent inhibitor of both fatty acid and ergosterol biosynthesis, was found in the present study to inhibit the former (at 5 microM) but not the latter (up to 100 microM). Of the antifungal agents tested, econazole and miconazole (at 100 microM) produced complete release of [14C]aminoisobutyric acid, which is consistent with membrane damage.