bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of aminoglycosides and spectinomycin on the synthesis and release of lipopolysaccharide by Escherichia coli
Authors: Kusser W C , Ishiguro E E
Published: June 2012

The effects of aminoglycosides and spectinomycin on lipopolysaccharide (LPS) synthesis and release by Escherichia coli were studied. LPS synthesis was previously reported to be regulated by the stringent control mechanism. In agreement with this, the control of LPS synthesis in amino acid-deprived relA+ cells was relaxed by spectinomycin, a proven stringent control antagonist, but not by kanamycin, an agent which is ineffective as a stringent control antagonist. The other stringent control antagonists tested (gentamicin, tobramycin, and, to a lesser extent, amikacin) unexpectedly failed to relax the control of LPS synthesis, and this was subsequently shown to be due to their inhibitory action on LPS synthesis. The release of LPS by nongrowing (amino acid-deprived and antibiotic-treated) bacteria was stimulated only under conditions in which the control of LPS synthesis was relaxed.
Topically administered immunoglobulin reduces pulmonary respiratory syncytial virus shedding in owl monkeys
Authors: Hemming V G , Prince G A , London W T , Baron P A , Brown R , Chanock R M
Published: June 2012

A human intravenous immunoglobulin preparation containing neutralizing antibodies to respiratory syncytial virus (RSV) was utilized for intratracheal and topical treatment of laboratory-induced RSV infections in owl monkeys (Aotus trivirgatus). Topically administered antibodies induced significant reductions in RSV shedding in the lower respiratory tract.
Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome
Authors: Moskovitz B L
Published: June 2012

An open-label, multicenter clinical trial assessed the tolerance of HPA-23 (ammonium-21-tungsto-9-antimoniate) in patients with acquired immune deficiency syndrome. Sixty-nine patients were sequentially assigned to receive 0.25, 0.5, 1.0, or 2.0 mg of HPA-23 per kg intravenously 5 days per week for 8 weeks. HPA-23 was fairly well tolerated at doses of 1.0 mg/kg or less; nearly 60% of patients given 2.0 mg/kg discontinued treatment. Twenty-six patients discontinued treatment because of adverse events or concurrent illness. HPA-23 produced dose-related decreases in platelet count and increases in serum glutamine oxalacetic transaminase. There were no changes in immune system function, as determined by total lymphocyte count, T4-cell count, T8-cell count, and T4/T8 ratio. The effects of HPA-23 seemed to be more closely related to the total dose than to the daily dose. No improvement in the clinical status of the patients was observed during the 8 weeks of treatment.
Cilofungin (LY121019), an antifungal agent with specific activity against Candida albicans and Candida tropicalis
Authors: Hall G S , Myles C , Pratt K J , Washington J A
Published: June 2012

Cilofungin (LY121019) is an antifungal agent that interferes with beta-glucan synthesis in the cells walls of fungi. The activity of this agent against 256 clinical isolates of yeasts was determined. It was found to be very active in vitro against Candida albicans (MIC for 90% of isolates [MIC90], less than or equal to 0.31 microgram/ml; minimal fungicidal concentration for 90% of isolates [MFC90], less than or equal to 0.31 micrograms/ml) and C. tropicalis (MIC90, less than or equal to 0.31 microgram/ml; MFC90, less than or equal to 0.31 microgram/ml) and moderately active against Torulopsis glabrata (MIC90 and MFC90, less than or equal to 20 micrograms/ml). All C. parapsilosis, Cryptococcus, and Saccharomyces cerevisiae strains were resistant. The activity of cilofungin was affected by medium and inoculum size. Antibiotic medium no. 3 was used as the standard medium. Isolates of C. albicans and C. tropicalis demonstrated a paradoxical effect in Sabouraud dextrose broth and yeast nitrogen base broth in that growth was partially inhibited at MICs equivalent to those in antibiotic medium no. 3, but growth continued, in many instances, throughout all concentrations tested. There was decreased activity of cilofungin with inocula greater than 10(5) CFU/ml. The temperature and duration of incubation did not affect its activity.
High hepatic excretion in humans of cefpiramide, a new cephalosporin
Authors: Brogard J M , Jehl F , Adloff M , Blickle J F , Monteil H
Published: June 2012

After intravenous administration of 1 g of cefpiramide, the biliary elimination of the drug was studied by using high-performance liquid chromatography. In five healthy volunteers, a mean peak concentration of 339 +/- 107 (standard error of the mean) micrograms/ml was measured in aspirated duodenal fluid during h 2 after administration, and 1.2% of the dose given was recovered over a 4-h period. A maximal concentration of 1,161 +/- 392 micrograms/ml was reached during h 2 in T-tube bile from 10 recently cholecystectomized patients, with a 24-h biliary recovery of 23.1%; urinary recovery over the same period averaged 49.4%. In 10 patients undergoing cholecystectomy, the concentrations in serum, choledochal bile, gallbladder bile, and gallbladder wall 1 h after cefpiramide administration were 157 +/- 21, 1,726 +/- 501, and 84 +/- 33 micrograms/ml and 23 +/- 4 micrograms/g, respectively. These figures represent the highest biliary concentrations attained so far with a beta-lactam antibiotic and are therefore a good prerequisite for treatment of biliary tract infections with cefpiramide.
Isolation, characterization, and cloning of a plasmid-borne gene encoding a phosphotransferase that confers high-level amikacin resistance in enteric bacilli
Authors: Gaynes R , Groisman E , Nelson E , Casadaban M , Lerner S A
Published: June 2012

Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The resistant strains contained an identical 6.8-kilobase plasmid, pRPG101. Transformation of pRPG101 into Escherichia coli produced high-level resistance to amikacin (greater than or equal to 256 micrograms/ml) and kanamycin (greater than or equal to 256 micrograms/ml) but unchanged susceptibilities to gentamicin, netilmicin, and tobramycin. The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro. The location and orientation of the amk gene encoding this APH(3') were determined by analysis of insertions in pRPG101 of the defective gene fusion phage Mu dII1681 (mini-Mulac). Cells containing plasmids with insertions into amk that had the lac operon fused to the amk promoter were selected as Lac+ and amikacin susceptible. A collection of these mini-Mulac insertions was mapped by restriction enzyme analysis. This characterization of amk facilitated its cloning as a 1.8-kilobase EcoRI-Bg/I fragment of pRPG101 into the pUC19 vector. E. coli strains containing this recombinant plasmid had APH(3') activity and demonstrated high-level resistance to amikacin and kanamycin (greater than or equal to 256 micrograms/ml) but were as susceptible to gentamicin, tobramycin, and netilmicin (less than or equal to 1.0 microgram/ml) as the strains harboring the original pRPG101 plasmid.
Antimicrobial synergism against Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome
Authors: Yajko D M , Kirihara J , Sanders C , Nassos P , Hadley W K
Published: June 2012

Pairs of 11 antimicrobial agents were tested in vitro for their ability to act synergistically against three strains of Mycobacterium avium complex isolated from patients with acquired immune deficiency syndrome. From the combinations tested, four drugs (ethambutol, rifampin, ciprofloxacin, and erythromycin) were selected for more extensive study against 20 strains of M. avium complex. The inhibitory and killing synergism obtained with combinations of two, three, or four drugs was assessed by determining the fractional inhibitory concentration index and fractional bactericidal concentration index. Inhibitory synergism occurred against 90 to 100% of the strains for all drug combinations in which ethambutol was included. Killing synergism occurred against 85 to 95% of the strains when ethambutol was used in combinations which included either rifampin or ciprofloxacin. However, killing synergism occurred against only 45% of the strains when drugs were tested at concentrations that can be obtained in patient serum. In other experiments, rifabutin (Ansamycin) gave results that were comparable to those obtained with rifampin. Clofazimine did not show synergistic killing activity at a concentration that is achievable in serum for any of the drugs tested. Our results indicate that there is considerable variability in the antimicrobial susceptibility of M. avium isolates obtained from patients with acquired immune deficiency syndrome. This variability could have significant impact on the clinical response to various therapies.
In vitro and in vivo antibacterial activities of ME1207, a new oral cephalosporin
Authors: Tamura A , Okamoto R , Yoshida T , Yamamoto H , Kondo S , Inoue M , Mitsuhashi S
Published: June 2012

ME1207 (pivaloyloxymethyl ester of ME1206) is a new oral cephalosporin. ME1206 is (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)- acetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)-ethyl]-cephem-4-carboxy lic acid. The susceptibilities of about 1,600 clinical isolates to ME1206 were determined by the agar dilution method. ME1206 showed a broad spectrum of activity against gram-positive and gram-negative bacteria. ME1206 was more active than cefaclor, T-2525, and cefixime against Staphylococcus aureus and Staphylococcus epidermidis. Against gram-negative bacteria, the activity of ME1206 was comparable with that of T-2525, but ME1206 was less active than cefixime. Against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae, ME1206 had high activity (MIC, less than or equal to 0.05 microgram/ml). ME1206 was stable against various beta-lactamases, except beta-lactamases from Providencia rettgeri, Pseudomonas cepacia, and Escherichia coli W3630 (Rms213). The 50% effective doses of ME1207 after oral administration against systemic infections in mice were comparable with those of T-2588 against gram-negative bacteria and about one-fourth that of T-2588 against Staphylococcus aureus Smith.
Enoxacin penetration into human prostatic tissue
Authors: Bergeron M G , Roy R , Lessard C , Foucault P
Published: June 2012

Concurrent enoxacin concentrations in serum and prostatic tissue were determined in 14 patients. The mean ratios of enoxacin concentration in tissue over concentration in serum were 1.4 +/- 0.2 (standard error of the mean). The levels in serum and prostatic tissue were above the MICs for most urinary pathogens.
In vitro susceptibilities of Mycobacterium tuberculosis to 10 antimicrobial agents
Authors: Byrne S K , Crawford C E , Geddes G L , Black W A
Published: June 2012

After preliminary in vitro screening of 10 antimicrobial agents against Mycobacterium tuberculosis, the MICs of the 6 most promising agents against 27 clinical isolates were determined by agar dilution. The two quinolone compounds tested (difloxacin and A-56620) were the most active, each inhibiting 50% of the strains at concentrations of 4 micrograms/ml. M. tuberculosis strains previously shown to be resistant to isoniazid, streptomycin, rifampin, or ethambutol were as susceptible to these quinolone compounds as susceptible strains.
Frequency of in vitro resistance of Pseudomonas aeruginosa to cefepime, ceftazidime, and cefotaxime
Authors: Fung-Tomc J , Huczko E , Pearce M , Kessler R E
Published: June 2012

The selection frequencies of cefepime (BMY 28142), ceftazidime, and cefotaxime resistance among Pseudomonas aeruginosa strains were determined. Cefepime-resistant mutants were not selected by cefepime (frequency, less than 10(-11)). Ceftazidime- and cefotaxime-resistant mutants were isolated at frequencies of 10(-5) to 10(-10) and were often cross-resistant. However, cefepime resistance among ceftazidime- and cefotaxime-resistant mutants was rare. Selected mutants resistant to cefepime constitutively produced 40- to 450-fold more beta-lactamase than did the parent strain.
Improvement of the absorption of oral (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, an anti-varicella-zoster virus drug, in rats and monkeys
Authors: Lake-Bakaar D M , Lindborg B , Datema R
Published: June 2012

In an effort to improve the gastrointestinal absorption of (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [(+/-)2HM-HBG], various salts and esters of the compound were synthesized and pharmacokinetic experiments were performed in rats and monkeys. The sodium or hydrochloride salts and short-chain esters of (+/-)2HM-HBG showed bioavailability characteristics that were equally as poor as those of (+/-)2HM-HBG. However, the esters given as salts tended to be better absorbed than the parent compound. The 6-deoxy and 6-deoxydiacetate analogs were extensively oxidized in vivo and represent prodrugs with considerable potential in improving the absorption of oral (+/-)2HM-HBG.
In vitro activity of cefpodoxime proxetil (U-76,252; CS-807) against clinical isolates of Branhamella catarrhalis
Authors: Sarubbi F A , Verghese A , Caggiano C , Holtsclaw-Berk S , Berk S L
Published: June 2012

Cefpodoxime proxetil (U-76,252; CS-807) is a new esterified oral cephem antibiotic with a broad antibacterial spectrum. Since data regarding the activity of cefpodoxime against Branhamella catarrhalis are limited, we tested its activity against 200 B. catarrhalis isolates. The drug was highly active against beta-lactamase-negative and -positive isolates; 99% of all strains tested showed a cefpodoxime proxetil MIC of less than or equal to 2.0 micrograms/ml.
Effect of attachment of anticandidal antibody to the surfaces of liposomes encapsulating amphotericin B in the treatment of murine candidiasis
Authors: Hospenthal D R , Rogers A L , Beneke E S
Published: June 2012

The effect produced by antibody specific to Candida albicans when attached to liposomes containing amphotericin B was studied in vivo. Liposomal amphotericin B bearing specific immunoglobulin (LAMB-Ab) was compared with the unencapsulated drug (fAMB) and other liposomal amphotericin B formulations in the short-term survival (21 days) of mice with disseminated candidiasis. Both the treatment and prophylaxis of the murine model of candidiasis were explored in these trials. LAMB-Ab increased survival rates in the model more than other liposomal preparations containing amphotericin B. Liposomal amphotericin B compounds as a group prolonged survival over fAMB. Liposomal preparations used for comparison included liposomes with attached nonspecific antibody (LAMB-Ab-), liposomes without antibody (LAMB), and liposomes with unattached specific antibody (LAMB+).
Fluorometric assay for fleroxacin uptake by bacterial cells
Authors: Chapman J S , Georgopapadakou N H
Published: June 2012

A sensitive and convenient method for quinolone determination has been developed, based on the natural fluorescence of the quinolone nucleus. Fleroxacin (Ro 23-6240; AM 833), used as a prototype quinolone in these studies, had an excitation maximum at 282 nm and an admission maximum at 442 nm (pH 3.0). Fluorescence intensity was pH dependent, being maximal at pH 3.0 and linear at quinolone concentrations between 1 and 200 ng/ml. A protocol for the fluorometric monitoring of fleroxacin uptake in Escherichia coli was developed. Intracellular quinolone concentrations measured by the fluorometric assay correlated well with values obtained by the bioassay. The results indicate that the fluorometric assay is an attractive alternative to the more laborious bioassay.
New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance
Authors: Fernandes P B , Baker W R , Freiberg L A , Hardy D J , McDonald E J
Published: June 2012

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.
Molecular analysis of the inhibitory effect of phosphorylated ribavirin on the vesicular stomatitis virus in vitro polymerase reaction
Authors: Fernandez-Larsson R , O'Connell K , Koumans E , Patterson J L
Published: June 2012

The effect of phosphorylated ribavirin on the vesicular stomatitis virus in vitro transcription reaction was examined. Analysis of the kinetics observed when the concentrations of nucleoside triphosphates were varied was performed with vesicular stomatitis virus wild-type standard virions. Double-reciprocal and Eadie-Hofstee plots showed competitive inhibition with all natural nucleoside triphosphates when both ribavirin diphosphate (RDP) and ribavirin triphosphate (RTP) were used. The Km values for ATP obtained for the wild-type polymerase were similar to those reported previously. To further characterize the observed inhibition kinetics, in vitro transcription products synthesized in the presence or absence of RDP and RTP were purified by CsCl centrifugation and were primer extended with oligonucleotides specific for either positive-sense leader or nucleocapsid mRNA transcripts. The ratios of leader to nucleocapsid mRNA were measured from primer-extended in vitro transcription products. It was found that the addition of RDP or RTP did not significantly change the in vitro ratio, suggesting that the polymerase is blocked before it enters the 3' end of the template.
Synergistic therapy by acyclovir and A1110U for mice orofacially infected with herpes simplex viruses
Authors: Ellis M N , Lobe D C , Spector T
Published: June 2012

Clinical effects of the administration of a combination of acyclovir (ACV) and compound A1110U (a 2-acetylpyridine thiocarbonothiohydrazone inactivator of herpes simplex virus [HSV] ribonucleotide reductase) on the development of herpetic skin lesions were studied in athymic and hairless mice infected intracutaneously with different HSV type 1 (HSV-1) strains. ACV was administered topically (5%) or orally (5 mg/ml), while A1110U was applied topically (3%). In all but one experiment, the effect of combination therapy was greater than that calculated for the sum of the individual drug effects in limiting the development of herpetic skin lesions in mice. In several experiments, combination therapy totally eliminated all signs of infection. This synergistic chemotherapeutic efficacy was evident in infections caused by ACV-susceptible as well as several ACV-resistant HSV-1 strains. These results indicate that this combination therapy may provide a significant improvement in clinical responses over single-agent topical therapy.
Use of in vitro topoisomerase II assays for studying quinolone antibacterial agents
Authors: Barrett J F , Gootz T D , McGuirk P R , Farrell C A , Sokolowski S A
Published: June 2012

Several quinolones and antitumor compounds were tested as inhibitors of purified calf thymus topoisomerase II in unknotting, catenation, radiolabeled DNA cleavage, and quantitative nonradiolabeled cleavage assays. The antitumor agents VP-16 (demethylepipodophyllotoxin ethylio-beta-D-glucoside) and ellipticine demonstrated drug-enhanced topoisomerase II DNA cleavage (the concentration of drug that induced 50% of the maximal DNA cleavage in the test system [CC50]) at levels of less than or equal to 5 micrograms/ml. Nalidixic acid, norfloxacin, and oxolinic acid did not induce significant topoisomerase II DNA cleavage, whereas ciprofloxacin did induce some cleavage above background levels. CP-67,015, a new 6,8-difluoro-7-pyridyl 4-quinolone which possesses potent antibacterial activity, inhibited bacterial DNA gyrase at 0.125 micrograms/ml in a nonradioactive DNA cleavage assay. Unlike other quinolones characterized to date, CP-67,015 was shown to strongly enhance topoisomerase II-induced radiolabeled DNA cleavage with a CC50 of 33 micrograms/ml and demonstrated cleavage in a nonradiolabeled DNA cleavage assay with a CC50 of 73 micrograms/ml. The topoisomerase II-mediated cleavage of DNA by CP-67,015 is consistent with its reported clastogenic effect on DNA in cell culture and its positive mutagenic response in mouse lymphoma cells. In vitro topoisomerase II catalytic and cleavage assays are useful for gaining preliminary information concerning the possible interaction(s) of some quinolones with eucaryotic topoisomerase II which may relate directly to their safety (mutagenicity, clastogenicity, or both) in human and veterinary medicinal usage.
Effects on oral and intestinal microfloras of norfloxacin and pefloxacin for selective decontamination in bone marrow transplant patients
Authors: Giuliano M , Pantosti A , Gentile G , Venditti M , Arcese W , Martino P
Published: June 2012

We monitored the modifications of oral and intestinal microfloras of 10 allogeneic bone marrow recipients who received randomly either norfloxacin or pefloxacin (400 mg three times a day) as selective decontamination for infection prevention. After 1 week of treatment, in all patients members of the family Enterobacteriaceae were no longer detectable and in all but one pefloxacin-treated patient enterococci were also eliminated in the intestine. The anaerobic flora was not affected, with the exception of Bacteroides spp., markedly reduced after treatment with pefloxacin. In most patients the most striking effect was the increase in staphylococcal counts. These strains were found to be resistant to both quinolones in the study. Less consistent changes were observed in oral flora. No relevant difference could be demonstrated between the two regimens on bacterial counts either in feces or in saliva. This study shows the efficacy of both quinolones in eradicating gram-negative bacilli in the alimentary tract of bone marrow transplant patients; however, the finding of the overgrowth of resistant gram-positive organisms during treatment with these agents deserves further evaluation.
Inhibitory effects of quinolones on DNA gyrase of Escherichia coli and topoisomerase II of fetal calf thymus
Authors: Hoshino K , Sato K , Une T , Osada Y
Published: June 2012

The in vitro inhibitory effects of quinolones on the bacterial DNA gyrase of Escherichia coli KL-16 and topoisomerase II of fetal calf thymus were compared. All the quinolones tested required higher concentrations to inhibit the topoisomerase II than to inhibit the DNA gyrase, and no correlation existed among their inhibitory activities against both enzymes. However, there was a large difference among the quinolones in their selectivities between the bacterial enzyme and its eucaryotic counterpart. The selectivity of ofloxacin was highest, and the selectivities of CI-934 and nalidixic acid were lowest.
Role of autolysins in the activities of imipenem and CGP 31608, a novel penem, against slowly growing bacteria
Authors: Cozens R M , Markiewicz Z , Tuomanen E
Published: June 2012

The carbapenem imipenem and the penem CGP 31608 demonstrated unusually good bactericidal activity against slowly growing bacteria. In contrast to that of penicillin, the rate of killing was independent of growth rate. In logarithmically growing cells, a decrease in growth rate was paralleled by a decrease in the relative activity of only one of four autolysins measured (membrane-bound endopeptidase), suggesting that autolysis induced by penicillin G may be rate limited by this enzyme. Imipenem, on the other hand, appeared to trigger different autolysins in Escherichia coli, as evidenced by differences in the structure of peptidoglycan after imipenem- versus penicillin-induced autolysis.
Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers
Authors: Polk R E , Healy D P , Sahai J , Drwal L , Racht E
Published: June 2012

Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.
New mechanism for methicillin resistance in Staphylococcus aureus: clinical isolates that lack the PBP 2a gene and contain normal penicillin-binding proteins with modified penicillin-binding capacity
Authors: Tomasz A , Drugeon H B , de Lencastre H M , Jabes D , McDougall L , Bille J
Published: June 2012

Seventeen clinical isolates of Staphylococcus aureus (from the United States and Europe) selected for low (borderline)-level methicillin resistance (MIC of methicillin, 2 to 4 micrograms/ml; MIC of oxacillin, 0.5 to 8 micrograms/ml) were examined for their mechanisms of resistance. Five strains were typical of heterogeneous S. aureus: they gave positive reactions with a DNA probe specific for mec and contained a small fraction (10(-6] of highly resistant cells (MIC, greater than 100 micrograms/ml). The rest of the 12 strains were homogeneous with respect to their methicillin resistance: the MIC of methicillin for all cells was 2 to 4 micrograms/ml, and no cells for which MICs were 50 micrograms/ml or higher were detectable (less than 10(-9]. None of these strains reacted with the mec-specific DNA probe. One representative strain of each group was characterized in more detail. Strain CDC-1, prototype of heterogeneous methicillin-resistant S. aureus, contained penicillin-binding protein (PBP) 2a; its DNA could transform a methicillin-susceptible and novobiocin-resistant recipient to methicillin resistance with ca. 35% linkage to Novr. Introduction of the "factor X" determinant (K. Murakami and A. Tomasz, J. Bacteriol. 171:874-879, 1989) converted strain CDC-1 to high, homogeneous resistance. Strain CDC-6, prototype of the second group of isolates, showed completely homogeneous MICs of methicillin, oxacillin, and cefotaxime. The strain contained modified "normal" PBPs: PBPs 1 and 2 showed low drug reactivity (and/or cellular amounts), and PBP 4 was present in elevated amounts. No PBP 2a could be detected. DNA isolated from strain CDC-6 could transform the methicillin-susceptible and novobiocin-resistant strain to methicillin resistance in a multistep fashion, but this resistance showed no genetic linkage to the Nov marker. We suggest that staphylococci with borderline resistance may contain at least three different classes of mechanism: heterogeneous, methicillin-resistant S. aureus, PBPs of modified drug reactivities, and the previously reported hyperproduction of beta-lactamase (L.K. McDougal and C. Thornsberry, J. Clin Microbiol. 23:832-839, 1986).
Quinolones and coumarins eliminate chloroplasts from Euglena gracilis
Authors: Krajcovic J , Ebringer L , Polónyi J
Published: June 2012

Quinolones and coumarins were potent eliminators of chloroplasts from Euglena gracilis. There was a remarkable similarity between antichloroplastic and antibacterial activities of DNA gyrase inhibitors. Quinolones produced 100% chloroplast-free cells in concentrations which do not affect cell viability. Optimal conditions were exponential growth, continuous illumination, and neutral or slightly alkaline pH. Coumarins were more toxic than quinolones. Among the quinolones, ofloxacin was the most potent in eliminating chloroplasts. Among the coumarins, coumermycin A1 was the most potent. New quinolones and coumermycin A1 were able to induce the complete inability of originally green cells to form green colonies after 24 h of drug exposure, while clorobiocin and novobiocin required several days of exposure. Darkness, heat shock (42 degrees C, 10 min), or simultaneous treatment with chloramphenicol or rifampin decreased the potency of DNA gyrase inhibitors for producing chloroplast-free cells. Remarkably, in cells in which division was blocked by three different methods (resting medium, hyperthermic conditions [37 degrees C], or addition of cycloheximide), new quinolones and coumermycin A1 nevertheless eliminated chloroplasts. The antichloroplastic activity of DNA gyrase inhibitors is additional data suggesting an evolutionary relationship between chloroplasts and eubacteria.
TEM-4, a new plasmid-mediated beta-lactamase that hydrolyzes broad-spectrum cephalosporins in a clinical isolate of Escherichia coli
Authors: Paul G C , Gerbaud G , Bure A , Philippon A M , Pangon B , Courvalin P
Published: June 2012

A clinical isolate of Escherichia coli, strain CB-134, recovered in 1986 from an abdominal abscess, exhibited resistance to penams, oxyimino-beta-lactams including broad-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime), and aztreonam but remained susceptible to cephamycins (cefoxitin, cefotetan) and to moxalactam and imipenem. Clavulanate (2 micrograms/ml) restored the susceptibility of the strain to broad-spectrum cephalosporins and aztreonam. A beta-lactamase with an isoelectric point (pI) of 5.9 was detected in strain CB-134, and the corresponding gene was transferred by conjugation to E. coli together with the associated aminoglycoside resistance determinant [AAC(3)-II] and tetracycline, trimethoprim, and sulfonamide resistance. The beta-lactamase efficiently hydrolyzed cefotaxime and ceftriaxone but only moderately hydrolyzed ceftazidime and was inhibited by clavulanate and sulbactam (1 microM) and by anti-TEM-1 and anti-TEM-2 sera. This extended-spectrum beta-lactamase, conferring resistance to cefotaxime, ceftriaxone, ceftazidime, and aztreonam, was comparable to CTX-1 (TEM-3) but differed from it by pI. Agarose gel electrophoresis of the plasmid DNA indicated that this new enzyme was coded by pUD16, a plasmid of 220 kilobases which belongs to the Inc6 incompatibility group. Hybridization with an intragenic probe for TEM-1 revealed that this beta-lactamase derives from TEM-type beta-lactamases and hence it was named TEM-4.
Structure-activity relationships of tetramethylpiperidine-substituted phenazines against Mycobacterium leprae in vitro
Authors: Franzblau S G , White K E , O'Sullivan J F
Published: June 2012

In a previous study of structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro, compounds containing a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen were most active. Therefore, the effect of substitution at the para positions of the phenyl and anilino groups in tetramethylpiperidine-substituted phenazines was assessed. As determined by radiorespirometry, activity in ascending order was observed in compounds substituted with hydrogens or fluorines, ethoxy groups, methyl groups, chlorines, and bromines and correlated with partition coefficients in octanol-water.
In vitro activities of lomefloxacin, tetracycline, penicillin, spectinomycin, and ceftriaxone against Neisseria gonorrhoeae and Chlamydia trachomatis
Authors: Talbot H , Romanowski B
Published: June 2012

In vitro lomefloxacin was highly active against 208 penicillin-susceptible and -resistant isolates of Neisseria gonorrhoeae. However, its MIC and MBC against 10 isolates of Chlamydia trachomatis were 2 and greater than 4 micrograms/ml, respectively.
In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug
Authors: Woods M G , Diana G D , Rogge M C , Otto M J , Dutko F J , McKinlay M A
Published: June 2012

WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.
Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1
Authors: Koshida R , Cox S , Harmenberg J , Gilljam G , Wahren B
Published: June 2012

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.
Postinfection therapy of arbovirus infections in mice
Authors: Singh I P , Coppenhaver D H , Sarzotti M , Sriyuktasuth P , Poast J , Levy H B , Baron S
Published: June 2012

Most antiviral agents are efficacious prophylactically in vivo, and a few are efficacious for postinfection (p.i.) therapy. To explore possibilities for p.i. therapy of encephalogenic Banzi virus (BZV) and Semliki Forest virus infections in mice, we evaluated candidate antiviral therapies after development of the first clinical signs of infection. The earliest clinical indication of BZV viremia in mice is a rise in core body temperature beginning on day 3 p.i. BZV-infected mice showing elevated core body temperatures (greater than or equal to 37.3 degrees C) on days 3 and 4 p.i. were treated intraperitoneally with the interferon inducer poly(ICLC) (80 micrograms per mouse) and/or specific antiserum. Combined therapy on day 3 of a BZV infection protected over 75% of mice showing clinical evidence of viral disease before treatment. Protection against early brain infection must occur on day 4 p.i., since by that day BZV has started multiplying in the brains of the mice. Significant protection occurred with antiserum alone and increased with poly(ICLC). Similar protection was obtained during Semliki Forest virus viremia, but this infection is so rapid that the first clinical signs are reliably detectable only after viremia.
WIN 57273 is bactericidal for Legionella pneumophila grown in alveolar macrophages
Authors: Edelstein P H , Edelstein M A
Published: June 2012

The in vitro antimicrobial activity of WIN 57273, a new quinolone antimicrobial agent, was determined for 21 Legionella strains, using broth macrodilution and agar dilution testing methods; ciprofloxacin and erythromycin were tested as well. Three different buffered yeast extract media were used for the agar dilution studies, two of which were made with starch rather than charcoal. Broth macrodilution susceptibility testing was performed with buffered yeast extract broth and two Legionella pneumophila strains. Antimicrobial inhibition of L. pneumophila growth in guinea pig alveolar macrophages was also studied, using a method able to detect bacterial killing. The MICs for 90% of the 21 strains of Legionella spp. grown on buffered charcoal yeast extract medium were 0.125 microgram/ml for WIN 57273, 0.25 microgram/ml for ciprofloxacin, and 1.0 micrograms/ml for erythromycin. These MICs were falsely high, because of inhibition of drug activity by the medium used. Use of less drug-antagonistic, starch-containing media did not support good growth of the test strains. The broth macrodilution MICs for two strains of L. pneumophila serogroup 1 were less than or equal to 0.03 microgram/ml for WIN 57273 and ciprofloxacin and 0.125 microgram/ml for erythromycin. WIN 57273, ciprofloxacin, and erythromycin all inhibited growth of L. pneumophila in guinea pig alveolar macrophages at concentrations of 1 microgram/ml, but only WIN 57273 prevented regrowth or killed L. pneumophila after removal of extracellular antimicrobial agent.
Tetracyclines as antiparasitic agents: lipophilic derivatives are highly active against Giardia lamblia in vitro
Authors: Edlind T D
Published: June 2012

Comparisons of the inhibitory activities of different tetracyclines have been reported for Plasmodium falciparum but no other parasites. The in vitro response of the intestinal parasite Giardia lamblia to six tetracyclines in current use was determined. In addition, the experimental drug thiacycline (EMD 33,330) was evaluated. Three groups were discerned, with representative 50 and 90% inhibitory concentrations of, respectively, 36 and 130 (tetracycline), 6.4 and 22 (doxycycline), and 1.8 and 3.4 (thiacycline) micrograms/ml. These dramatic differences in activity correlate with increased lipophilicity.
Comparison of the efficacies of amphotericin B, fluconazole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice
Authors: Van t Wout J W , Mattie H , van Furth R
Published: June 2012

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.
Imipenem concentrations in colorectal surgery and impact on the colonic microflora
Authors: Kager L , Brismar B , Malmborg A S , Nord C E
Published: June 2012

Twenty patients undergoing colorectal surgery were given, as prophylaxis, imipenem-cilastatin intravenously. Ten of them received a dose of 0.5/0.5 g of imipenem-cilastatin at induction of anesthesia, followed by subsequent doses of 0.5/0.5 g every 6 h for 48 h. The other 10 patients were given 1.0/1.0 g imipenem-cilastatin in the same way for 48 h. Samples from serum, intestinal mucosa, and feces were taken for analysis of imipenem concentrations during the day of surgery. The mean concentrations in serum at 1 h after the first imipenem dose were 15.9 +/- 1.7 micrograms/ml for the 0.5-g dose and 68.2 +/- 8.2 micrograms/ml for the 1.0-g dose. The mean half-lives were 1.5 and 1.4 h, respectively, and the mean areas under the serum concentration-time curve were 41.2 +/- 6.0 and 128.3 +/- 13.5 mg.h/liter, respectively. The imipenem concentrations in the intestinal mucosa varied between less than 0.1 and 3.6 mg/kg for the 0.5-g dose and 3.2 and 13.4 mg/kg for the 1.0-g dose. The concentrations in the fecal samples varied between less than 0.1 and 5.0 mg/kg for the 0.5-g dose and 0.7 and 11.3 mg/kg for the 1.0-g dose. Fecal samples were also collected during the investigation period for cultivation of aerobic and anaerobic bacteria. The aerobic bacteria--staphylococci, streptococci, enterococci, and enteroaerobic enterococci, and enterobacteria--were and anaerobic bacteria. The aerobic bacteria--staphylococci, streptococci, enterococci, and enterobacteria--were suppressed significantly during the imipenem prophylaxis period. Among the anaerobic bacteria, cocci, bifidobacteria, eubacteria, lactobacilli, clostridia, fusobacteria, and bacteroides decreased markedly during the same period. The microfloras were normalized after 2 weeks. There were no differences between the patients receiving 0.5-g doses of imipenem and those receiving 1.0-g of imipenem. No postoperative infections occurred.
In vitro interaction between rifampin and clindamycin against pathogenic coagulase-negative staphylococci
Authors: Arditi M , Yogev R
Published: June 2012

The MICs and MBCs for 90% of strains tested (MIC90 and MBC90, respectively) of rifampin for 75 clinical isolates of pathogenic coagulase-negative staphylococci (PCNS) were 0.03 and 0.25 microgram/ml, respectively, while the MIC90 and MBC90 of clindamycin were both greater than 25 micrograms/ml. Although no synergy between rifampicin and clindamycin was found among the 15 strains studied by the checkerboard method, 6 of 12 selected strains showed synergy by the kill-curve method. No antagonism was observed by either method. All 30 strains rapidly developed resistance to rifampin in vitro, and this could be prevented by the simultaneous presence of 1.0 microgram of clindamycin per ml in the 24 methicillin-susceptible PCNS strains. The synergy between rifampin and clindamycin observed in vitro for some strains of PCNS, together with the prevention of emergence of resistance to rifampin by clindamycin, suggests that this antibiotic combination may be useful for the treatment of infections caused by methicillin-susceptible PCNS.
Susceptibility and bactericidal activity studies of four beta-lactamase-producing enterococci
Authors: Patterson J E , Zervos M J
Published: June 2012

beta-Lactamase-producing (Bla+) enterococci are rare but have been reported from several areas. We report another Bla+ enterococcus with high-level gentamicin resistance. Susceptibility and bactericidal activity studies of four Bla+ enterococci against potential alternative antibiotics, including ampicillin-sulbactam, daptomycin, teicoplanin, and vancomycin, are presented.
Mechanisms of quinolone resistance in Escherichia coli: characterization of nfxB and cfxB, two mutant resistance loci decreasing norfloxacin accumulation
Authors: Hooper D C , Wolfson J S , Souza K S , Ng E Y , McHugh G L , Swartz M N
Published: June 2012

Two genetic loci selected for norfloxacin (nfxB) and ciprofloxacin (cfxB) resistance were characterized. Both mutations have previously been shown to confer pleiotropic resistance to quinolones, chloramphenicol, and tetracycline and to decrease expression of porin outer-membrane protein OmpF. nfxB was shown to map at about 19 min and thus to be genetically distinct from ompF (21 min), and cfxB was shown to be very closely linked to marA (34 min). cfxB was dominant over cfxB+ in merodiploids, in contrast to other quinolone resistance mutations. The two loci appear to interact functionally, because nfxB was not expressed in the presence of marA::Tn5. Both nfxB and cfxB decreased the expression of ompF up to 50-fold at the posttranscriptional level as determined in strains containing ompF-lacZ operon and protein fusions. Both mutations also decreased norfloxacin accumulation in intact cells. This decrease in accumulation was abolished by energy inhibitors and by removal of the outer membrane. These findings, in conjunction with those of Cohen et al. (S. P. Cohen, D. C. Hooper, J. S. Wolfson, K. S. Souza, L. M. McMurry, and S. B. Levy, Antimicrob. Agents Chemother. 32:1187-1191, 1988), suggest a model for quinolone resistance by decreased permeation in which decreased diffusion through porin channels in the outer membrane interacts with a saturable drug efflux system at the inner membrane.