bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro studies of investigational beta-lactams as possible therapy for Pseudomonas aeruginosa endocarditis
Authors: Zar F A , Kany R J
Published: June 2012

The inadequacy of the present medical therapy of Pseudomonas aeruginosa endocarditis prompted an investigation of the in vitro activities of aztreonam, cefsulodin, and imipenem compared with that of ticarcillin against 37 strains of P. aeruginosa isolated from patients with endocarditis. Inhibitory and bactericidal activities were studied for each beta-lactam alone and in combination with tobramycin. All agents showed excellent inhibitory activity. Imipenem was the most inhibitory beta-lactam yet lacked inhibitory synergy against 95% of the strains and bactericidal synergy against 62%. Tolerance to imipenem was seen in six strains. Aztreonam alone was bactericidal against 46% of the strains (at 16 micrograms/ml) and showed bactericidal synergy in 70%. Cefsulodin alone was even less active but similar to aztreonam synergistically. Ticarcillin and tobramycin inhibited all strains as single agents and showed universal bactericidal synergy in combination. None of the new beta-lactams showed consistent superiority to the presently used agent, ticarcillin.
Multiresistance plasmid from commensal Neisseria strains
Authors: Pintado C , Salvador C , Rotger R , Nombela C
Published: June 2012

Antibiotic-resistant commensal strains of Neisseria spp. and Branhamella catarrhalis were isolated from throat cultures, on the basis of their capacity to grow in the presence of penicillin, streptomycin, or sulfamethoxazole-trimethoprim. Several strains, which belonged to different species of Neisseria, were resistant to beta-lactams, streptomycin, sulfamethoxazole, and trimethoprim, harbored a 6.0-megadalton plasmid with identical HinfI restriction patterns, and produced beta-lactamase and streptomycin phosphotransferase. The resistance determinants for beta-lactams, streptomycin, and sulfamethoxazole, but not for trimethoprim, were transferred from all these strains to Escherichia coli by conjugation or transformation. The resulting transconjugants or transformants acquired the plasmid and the capacity to produce beta-lactamase and streptomycin phosphotransferase. The 6.0-megadalton plasmid complemented a mutation which determines production of thermosensitive dihydropteroate synthetase in E. coli. We conclude that an R plasmid coding for beta-lactamase, streptomycin phosphotransferase, and a sulfonamide-resistant dihydropteroate synthetase is common to these strains.
Susceptibility of intra- and extracellular Mycobacterium avium-intracellulare to cephem antibiotics
Authors: Nozawa R T , Kato H , Yokota T , Sugi H
Published: June 2012

Intra- and extracellular susceptibility of 35 clinically isolated Mycobacterium avium-intracellulare strains to cefotaxime (CTX), ceftizoxime (CZX), and cefoperazone was studied. MICs for 50% of the isolates in vitro were 6.25 micrograms/ml for CTX and CZX and 25 micrograms/ml for cefoperazone. A strain susceptible to CTX (MIC, 0.78 micrograms/ml) and CZX (MIC, 1.56 micrograms/ml) infected human peripheral blood mononuclear cells in the presence of 20% autologous plasma. The mycobacteria replicated exclusively in monocytes under the above culture condition. Concentrations of CZX 1- to 16-fold higher than its in vitro MIC had little effect on intracellular replication of the strain. A concentration of CTX 16-fold higher than its in vitro MIC was bacteriostatic to the mycobacteria, but CTX of lower concentrations showed no effect on intracellular replication. Thus, ineffectiveness of the cephems on the therapy of M. avium-intracellulare infection was suggested.
In vitro activities of 47 antimicrobial agents against three Campylobacter spp. from pigs
Authors: Gebhart C J , Ward G E , Kurtz H J
Published: June 2012

The in vitro activities of 47 antimicrobial agents against 30 isolates of Campylobacter species from pigs were determined by the agar dilution technique. The isolates were obtained from pigs with proliferative enteritis and included 10 strains each of Campylobacter coli, Campylobacter sputorum subsp. mucosalis, and "Campylobacter hyointestinalis Gebhart et al." (this name is not on the Approved Lists). Carbadox, furazolidone, nitrofurantoin, gentamicin, and dimetridazole were the most active drugs, inhibiting all three Campylobacter species with a MIC for 50% of the isolates of 2 micrograms/ml or less. Trimethoprim-sulfamethoxazole, cefazolin, sulfachloropyridazine, novobiocin, vancomycin, sulfathiazole, cyclohexamide, bacitracin, p-arsanilic acid, and colistin were the least active, with MICs for 50% of the isolates ranging from 16 to greater than or equal to 128 micrograms/ml.
Antibacterial effect of lactoperoxidase and myeloperoxidase against Bacillus cereus
Authors: Tenovuo J , Mäkinen K K , Sievers G
Published: June 2012

An oral periodontopathic bacterium, Bacillus cereus, was inhibited both by lactoperoxidase (LP) and myeloperoxidase (MP) antimicrobial systems. With the LP-SCN--H2O2 system, the growth inhibition was directly proportional to the amount of OSCN- ions present. The OSCN-, which is the principal oxidation product of the LP (or MP)-SCN--H2O2 system at neutral pH, is a normal component of human saliva. The oxidation products of both peroxidase systems inhibited the growth of the bacteria. This inhibition was associated with reduced extracellular release of collagenase activity from the cells. With LP, the antimicrobial efficiency of the oxidizable substrates was SCN- greater than I-, and with MP, the efficiency was I- greater than Cl- greater than SCN-, respectively. LP did not oxidize Cl-.
Antimicrobial therapy of experimental meningitis caused by Streptococcus pneumoniae strains with different susceptibilities to penicillin
Authors: McCracken G H , Sakata Y
Published: June 2012

The pharmacokinetics and bacteriological efficacies of penicillin G, ceftriaxone, vancomycin, and imipenem were determined in rabbits with experimental meningitis caused by Streptococcus pneumoniae strains with different penicillin susceptibilities. Drug dosages were adjusted to attain peak concentrations in serum that were similar to those observed in infants and children. In animals infected with a penicillin-susceptible (MBC, 0.008 micrograms/ml) pneumococcus, penicillin G and ceftriaxone reduced the number of organisms in cerebrospinal fluid (CSF) by greater than or equal to 4.14 log10 CFU/ml after single doses and after 9-h continuous infusions. A single large dose (50 mg/kg) of penicillin G was comparatively ineffective (-2.15 log10 CFU/ml) against a relatively penicillin-resistant (MBC, 0.5 micrograms/ml) strain, whereas ceftriaxone therapy resulted in a 3.66- and 4.77-log10 CFU/ml reduction after single doses and 9-h continuous infusions, respectively. In animals in which meningitis was caused by a penicillin-resistant (MBC, 8.0 micrograms/ml) pneumococcus, a single dose of penicillin (50 or 150 mg/kg) or of ceftriaxone failed to lower the number of organisms in CSF. Vancomycin and imipenem reduced the counts in CSF by at least 2.19 and 4.10 log10 CFU/ml after single doses and 9-h infusions, respectively. In all experiments, a bactericidal titer of greater than or equal to 1:8 in CSF was necessary to achieve a maximal bacteriological effect.
Activities of the tetrahydrofuran derivative, BA-41,799, against Plasmodium cynomolgi infections in rhesus monkeys
Authors: Schmidt L H
Published: June 2012

BA-41,799, a tetrahydrofuran derivative that at one time attracted considerable interest as an antimalarial agent because of a combination of structural novelty with activities against infections with Plasmodium berghei and Plasmodium berghei yoelii in mice, has been evaluated for its capacities to effect prophylaxis and radical cure in rhesus monkeys challenged or already infected with sporozoites of the drug-susceptible Ro strain or the pyrimethamine-resistant Ro/PM strain of Plasmodium cynomolgi, and for its capacity to effect suppressive cure of infections with trophozoites of these strains. At doses up to the maximum tolerated, BA-41,799 had only marginal activity against infections with the Ro strain and none against the Ro/PM strain. On the basis of past experiences, the above results suggest that BA-41,799 would have little to offer for prophylaxis, radical cure, or suppression of human infections with Plasmodium vivax.
Single-dose ceftriaxone versus multiple-dose trimethoprim-sulfamethoxazole in the treatment of acute urinary tract infections
Authors: Iravani A , Richard G A
Published: June 2012

Fifty-four college women with symptoms of lower urinary tract infections were randomly treated, 25 with 500 mg of ceftriaxone in a single intramuscular dose and 29 with 160 mg of trimethoprim-800 mg of sulfamethoxazole orally twice daily for 7 days. At 1 week after treatment, 23 patients (92%) in the ceftriaxone group and 28 patients (96%) in the trimethoprim-sulfamethoxazole group were cured. Responses of the patients with positive or negative antibody-coated bacteria tests were not significantly different. Four patients (16%) in the ceftriaxone group developed diarrhea and malaise. One patient (4%) in the trimethoprim-sulfamethoxazole group had medication discontinued because of headaches. Leukopenia was found in one patient (4%) in the ceftriaxone group and four patients (14%) in the trimethoprim-sulfamethoxazole group.
Involvement of oxidative damage in erythrocyte lysis induced by amphotericin B
Authors: Brajtburg J , Elberg S , Schwartz D R , Vertut-Croquin A , Schlessinger D , Kobayashi G S , Medoff G
Published: June 2012

Lysis of human erythrocytes induced by amphotericin B was retarded when the oxygen tension of the incubation mixture was reduced or when the antioxidant catalase was added; lysis was accelerated when cells were preincubated with the prooxidant ascorbate. In the atmosphere of reduced oxygen tension, the erythrocytes containing carboxyhemoglobin lysed at a slower rate than did the cells containing oxyhemoglobin. Consistent with a role for oxidative damage in lysis, the mixture of erythrocytes and amphotericin B showed an increase in malonyldialdehyde, the product of peroxidation, which paralleled the progression of hemolysis. In contrast, the permeabilizing effect of amphotericin B, measured as a decrease in intracellular K+, was not affected by changes in oxygen tension, catalase, or ascorbate treatment. These results imply that oxidant damage is involved in the lytic, but not in the permeabilizing, action of amphotericin B.
Mechanism of action and selective toxicity of ascamycin, a nucleoside antibiotic
Authors: Osada H , Isono K
Published: June 2012

An unidentified Streptomyces sp. produces two nucleoside antibiotics, ascamycin and its dealanyl derivative. In contrast to the broad antibacterial activity of dealanylascamycin against various gram-negative and gram-positive bacteria, ascamycin showed selective toxicity against Xanthomonas citri and X. oryzae. Both ascamycin and dealanylascamycin inhibited the protein synthesis of X. citri, but only dealanylascamycin inhibited that of Escherichia coli. In cell-free systems from E. coli and X. citri, both antibiotics, at ca. 0.04 micrograms/ml, inhibited the polyuridylate-directed synthesis of polyphenylalanine by ca. 50%. These data suggest that ascamycin cannot permeate the bacterial membrane. The dealanylating activity toward ascamycin was found only on the cell surface of bacteria susceptible to ascamycin. Dealanylascamycin must then have been transported into cytoplasm, where it inhibited protein synthesis.
Efficacy and safety of aztreonam-clindamycin versus tobramycin-clindamycin in the treatment of lower respiratory tract infections caused by aerobic gram-negative bacilli
Authors: Rodríguez J R , Ramírez-Ronda C H , Nevárez M
Published: June 2012

A total of 80 patients were randomized to receive either aztreonam or tobramycin for the treatment of lower respiratory tract infections caused by gram-negative bacilli; all these patients received clindamycin concomitantly. A total of 53 patients were randomized to receive aztreonam-clindamycin; of these, 46 were clinically evaluable and 39 were bacteriologically evaluable. Of the 46 clinically evaluable patients, 41 were considered cured, 3 failed to be cured, and 2 died during the study period of unrelated causes. Of the 39 bacteriologically evaluable patients, 36 were considered cured, and 3 failed to be cured. There were 26 clinically evaluable patients in the group randomized to receive tobramycin-clindamycin. Of them, 22 patients were considered cured, 3 failed to be cured, and 1 died of unrelated causes during the study period. There were 18 bacteriologically evaluable patients in the tobramycin-clindamycin group; 17 were cured, and 1 failed to be cured. The most common pathogens isolated from the patients were Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. All of the isolated organisms were susceptible to both tested antibiotics, except for a strain of Pseudomonas cepacia resistant to both tested antimicrobial agents and a strain of Enterobacter aerogenes and one of P. aeruginosa that were resistant to aztreonam. Very few adverse reactions related to the antibiotics were seen. These effects, when present, were transient and comparable in both studied groups, except for renal-function tests, which were altered in 7.7% of the patients randomized to receive tobramycin-clindamycin and in none of the patients randomized to receive aztreonam-clindamycin. Aztreonam-clindamycin is safe and effective for the treatment of lower respiratory tract infections caused by aerobic gram-negative bacilli when the organisms are susceptible.
Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent
Authors: Ryder N S
Published: June 2012

SF 86-327 is a new antimycotic agent of the allylamine type. Its primary action appears to be the inhibition of ergosterol biosynthesis at the point of squalene epoxidation, as was previously found with the related compound naftifine. Biosynthesis was measured by incorporation of [14C]acetate into sterols in cells of Candida albicans, Candida parapsilosis, Torulopsis glabrata, and the dermatophyte Trichophyton mentagrophytes. There was a positive correlation between the SF 86-327 concentrations needed for inhibition of growth and of sterol synthesis in these four fungi. The greater antifungal efficacy of SF 86-327 in comparison with naftifine was also reflected in the relative activities of the two compounds as sterol synthesis inhibitors. Inhibition was maximal at neutral pH. A similar degree of inhibition was found in cell-free extracts when [14C]mevalonate was used as substrate. In all cases, inhibition of sterol synthesis was accompanied by a parallel accumulation of labeled squalene. SF 86-327 and naftifine had no significant effect on initial enzymes of the ergosterol pathway, measured by incorporation of [14C]acetyl coenzyme A, or on steps distal to squalene epoxidation, measured by conversion of labeled squalene 2,3-epoxide or lanosterol. Both allylamines were highly selective for fungal, as opposed to mammalian, sterol biosynthesis. SF 86-327 caused slight inhibition of squalene epoxidation in a rat liver cell-free system, but at concentrations three to four orders of magnitude greater than those required for inhibition of the fungal pathway.
Penetration of aztreonam into human bronchial secretions
Authors: Bechard D L , Hawkins S S , Dhruv R , Friedhoff L T
Published: June 2012

Nine intubated patients were given a single, 2-g intravenous dose of aztreonam over 5 min. Samples of serum and bronchial secretion were obtained 2, 4, and 8 h after administration and assayed for aztreonam content. The mean concentrations in bronchial secretion ranged from 1.9 to 5.2 micrograms/ml and tended to be highest at 4 h. The concentrations in bronchial secretion varied from patient to patient, but each patient had one or more bronchial secretion samples that contained at least 2.7 micrograms of drug per ml.
In vitro studies of BMY-28142, a new broad-spectrum cephalosporin
Authors: Bodey G P , Ho D H , LeBlanc B
Published: June 2012

BMY-28142 was compared with other broad-spectrum antibiotics against gram-positive cocci and gram-negative bacilli. BMY-28142 was highly active against all gram-negative bacilli and especially against Enterobacter cloacae, Serratia marcescens, and Morganella morganii. Its in vitro activity suggests that BMY-28142 should prove to be useful for the treatment of gram-negative bacillary infections.
Development of plasmid-mediated resistance in Vibrio cholerae during treatment with trimethoprim-sulfamethoxazole
Authors: Dupont M J , Jouvenot M , Couetdic G , Michel-Briand Y
Published: June 2012

The persistence of Vibrio cholerae, biotype el tor, in a patient treated with trimethoprim-sulfamethoxazole was due to the acquisition of a conjugative resistance plasmid. The plasmid, with a molecular size of 72 megadaltons, belonged to incompatibility group 6-C and conferred resistance to ampicillin, chloramphenicol, sulfonamide, and trimethoprim.
Clinical trial of the efficacy and safety of ticarcillin and clavulanic acid
Authors: Roselle G A , Bode R , Hamilton B , Bibler M , Sullivan R , Douce R , Staneck J L , Bullock W E
Published: June 2012

Forty-three hospitalized patients were treated with a new antibiotic combination containing ticarcillin plus the beta-lactamase inhibitor, clavulanic acid, in a fixed combination for intravenous use. A variety of infections were treated, including pneumonia, bacteremia, urinary tract infection, and osteomyelitis. Of 50 episodes of infection in 43 patients, 44 clinical cures were obtained, with 5 patients improving and 1 patient failing to respond to treatment. In vitro susceptibility testing of 101 clinical isolates was notable for the rarity of resistance to the combination antibiotic. Of specific interest, all 14 isolates of Staphylococcus aureus were susceptible to ticarcillin plus clavulanic acid, whereas only 2 of the 14 isolates were susceptible to ticarcillin alone. Adverse reactions to the study drug were minimal; eosinophilia, unaccompanied by other allergic phenomena, and oral candidiasis were most frequent. Overall, the combination of ticarcillin with the beta-lactamase inhibitor, clavulanic acid, appears to be a safe and effective drug for the treatment of infections caused by susceptible organisms.
Uptake, accumulation, and egress of erythromycin by tissue culture cells of human origin
Authors: Martin J R , Johnson P , Miller M F
Published: June 2012

The ability of erythromycin A base to penetrate and accumulate in tissue culture cells of human origin was investigated. The antibiotic was highly concentrated by early passage cells of normal bronchus, kidney, liver, lung, and skin and by cancer cells derived from breast, liver, and lung. Intracellular levels 4 to 12 times that of the extracellular milieu were obtained in both early-passage and transformed cells. The total quantity of erythromycin accumulated depended on the extracellular concentration of antibiotic, but the cellular/extracellular ratios were, for the most part, independent of the initial extracellular drug concentration. In all cell types tested, the accumulated antibiotic rapidly egressed when cells were incubated in antibiotic-free medium. Bioactivity assays demonstrated that the expelled drug was unmetabolized, fully active antibiotic. The concentration of erythromycin by a variety of human cell types probably accounts, in part, for the effectiveness of the antibiotic against intracellular parasites such as Legionella and Chlamydia spp.
Influence of the developmental state of valvular lesions on the antimicrobial activity of cefotaxime in experimental enterococcal infections
Authors: Sullam P M , Drake T A , Täuber M G , Hackbarth C J , Sande M A
Published: June 2012

Cefotaxime has little antimicrobial activity in vitro against most strains of enterococci, as measured by conventional MICs and MBCs. However, the MICs of cefotaxime against many enterococci are markedly reduced by the addition of serum to the test medium. To assess the relevance of this observation in vivo, we examined the efficacy of cefotaxime in experimental Streptococcus faecalis endocarditis. Since response to antimicrobial agents may vary with the degree of vegetation development, therapeutic efficacy was assessed both in rabbits with newly formed vegetations and in rabbits with well-developed endocardial lesions. Peak serum levels of cefotaxime (50.1 +/- 20.0 micrograms/ml) exceeded the MIC in medium supplemented with serum (4 micrograms/ml), but not in Mueller-Hinton broth alone (greater than 64 micrograms/ml). After 4 days of therapy, animals with newly formed lesions (therapy initiated 1 h after infection, transvalvular catheters removed) had lower mean vegetation bacterial titers than did untreated controls. Among animals with mature vegetations (therapy initiated 12 h after infection, catheters indwelling), the rate of mortality was significantly reduced by cefotaxime therapy. However, no difference in vegetation titers was observed. Thus, cefotaxime demonstrated antienterococcal activity within newly formed vegetations, but did not inhibit bacterial proliferation within well-established vegetations.
In vitro activity and mechanism of action of A21978C1, a novel cyclic lipopeptide antibiotic
Authors: Eliopoulos G M , Thauvin C , Gerson B , Moellering R C
Published: June 2012

The in vitro activity of A21978C1, a novel cyclic polypeptide antibiotic, was compared with those of vancomycin, teichomycin, and several beta-lactam antibiotics against gram-positive bacteria. The new drug was at least as active as vancomycin against all species of streptococci and staphylococci tested, including methicillin-resistant Staphylococcus aureus and penicillin-resistant pneumococci. Activity of the drug was found to be strongly correlated with the calcium concentration in test media. Against enterococci, A21978C1 was bactericidal at concentrations near the MIC (MIC for 100% of the strains, 2 micrograms/ml), but combining that drug with gentamicin resulted in bactericidal synergism by time-kill methods. Studies were undertaken to examine the mechanism of action of the drug. A21978C1 did not interact with penicillin-binding proteins of bacterial cell membranes. No direct effect of the drug on the synthesis of DNA, RNA, or protein by a susceptible strain of Streptococcus faecalis could be demonstrated. However, A21978C1 inhibited peptidoglycan synthesis in early-log-phase cultures of both Streptococcus faecalis and Staphylococcus aureus.
Isolation of streptomycin-nonproducing mutants deficient in biosynthesis of the streptidine moiety or linkage between streptidine 6-phosphate and dihydrostreptose
Authors: Ohnuki T , Imanaka T , Aiba S
Published: June 2012

Eight streptidine idiotrophic mutants (SD20, SD81, SD141, SD189, SD245, SD261, SD263, and SD274) which required streptidine to produce streptomycin were derived from Streptomyces griseus ATCC 10137 by UV mutagenesis. By both the characterization of intermediates accumulated by the idiotrophs and the assay of enzymes involved in streptidine biosynthesis, the biochemical lesions of the mutants were deduced as follows: SD20 and SD263, transamination; SD81, SD261, and SD274, phosphorylation; SD141, transamidination; SD189, dehydrogenation; SD245, linkage between streptidine 6-phosphate and dihydrostreptose. An accumulation of streptidine 6-phosphate was found in SD245 to impair its aminotransferase activity. This finding suggests that aminotransferase activity might have been negatively controlled by the end product, streptidine 6-phosphate, of the streptidine biosynthetic pathway.
Isopenicillin N synthetase of Penicillium chrysogenum, an enzyme that converts delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N
Authors: Ramos F R , López-Nieto M J , Martín J F
Published: June 2012

The tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine, an intermediate in the penicillin biosynthetic pathway, is converted to isopenicillin N by isopenicillin N synthetase (cyclase) of Penicillium chrysogenum. The cyclization required dithiothreitol and was stimulated by ferrous ions and ascorbate. Co2+ and Mn2+ completely inhibited enzyme activity. Optimal temperature and pH were 25 degrees C and 7.8, respectively. The reaction required O2 and was stimulated by increasing the dissolved oxygen concentration of the reaction mixture. Purification of the enzyme to a single major band in polyacrylamide gel electrophoresis was achieved by protamine sulfate precipitation, ammonium sulfate fractionation (50 to 80% of saturation), DEAE-Sephacel chromatography, and gel filtration on Sephacryl S-200. The estimated molecular weight was 39,000 +/- 1,000. The apparent Km of isopenicillin N synthetase for delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine was 0.13 mM. The enzyme activity was strongly inhibited by glutathione, which acts as a competitive inhibitor. A good correlation was observed between the isopenicillin N synthetase activity in extracts of four different strains of P. chrysogenum (with widely different penicillin-producing capability) and the amount of penicillin production by these strains.
Peroxidase-mediated oxidation of isoniazid
Authors: Shoeb H A , Bowman B U , Ottolenghi A C , Merola A J
Published: June 2012

Oxidation of isonicotinic acid hydrazide (isoniazid) by horseradish peroxidase at the expense of H2O2 yielded reactive species which were able to reduce nitroblue tetrazolium and bleach p-nitrosodimethylaniline. Nicotinic acid hydrazide oxidation did not cause these effects. At slightly alkaline pH, oxidation of isonicotinic acid hydrazide by horseradish peroxidase proceeded at the expense of molecular O2, and the reaction was oxygen consuming. The addition of H2O2 abolished O2 consumption. Bovine liver catalase enhanced the rate of nitroblue tetrazolium reduction and decreased the maximal velocity of the reaction proportionately to catalase concentration. During oxidation of isonicotinic acid hydrazide by horseradish peroxidase-H2O2, splitting of the heme group of horseradish peroxidase took place as shown by the disappearance of the Soret and minor bands in the visible region of the spectrum.
Effect of L-cysteine on the activity of penicillin antibiotics against Clostridium difficile
Authors: Markowitz S M , Williams D S
Published: June 2012

We observed elevated MICs of penicillin antibiotics while performing agar dilution susceptibility testing of strains of Clostridium difficile on supplemented brain heart infusion agar, an effect which was completely eliminated by the exclusion of L-cysteine from the medium. L-Cysteine antagonizes the activity of penicillins against C. difficile, most likely by direct inactivation of the antibiotic.
Mutually exclusive inhibition of herpesvirus DNA polymerase by aphidicolin, phosphonoformate, and acyclic nucleoside triphosphates
Authors: Frank K B , Cheng Y C
Published: June 2012

Dual inhibitor studies were performed to examine the interaction of aphidicolin, phosphonoformate, 9-(2-hydroxyethoxymethyl)guanine triphosphate, and 9-(1,3-dihydroxy-2-propoxymethyl)guanine triphosphate with herpes simplex virus DNA polymerase. Kinetic data indicated that inhibition by one agent prevents simultaneous inhibition by a second agent, producing a mutually exclusive inhibition pattern. This suggested that binding sites on the DNA polymerase molecule for these compounds are kinetically overlapping. These findings should be taken into consideration for the design of future antiviral compounds and combination chemotherapy protocols.
Inhibition of mycobacteria by garlic extract (Allium sativum)
Authors: Delaha E C , Garagusi V F
Published: June 2012

Thirty strains of mycobacteria, consisting of 17 species, were inhibited by various concentrations of garlic extract incorporated in Middlebrook 7H10 agar. The concentration required ranged from a low of 1.34 mg/ml to a high of 3.35 mg/ml of media. When there were multiple strains of a species, a mean inhibitory concentration was determined for that species. Six strains of Mycobacterium tuberculosis required a mean inhibitory concentration of 1.67 mg/ml of media.
In vitro antibacterial activity of BMY-28142, a new extended-spectrum cephalosporin
Authors: Vuye A , Pijck J
Published: June 2012

The in vitro activity of BMY-28142 was compared with that of cefotaxime, ceftazidime, moxalactam, and imipenem against 639 clinical isolates and a number of in vitro-selected resistant mutants. BMY-28142 was the most potent compound against the members of the family Enterobacteriaceae with a MIC for 90% of the strains of 0.12 micrograms/ml. The activity against Pseudomonas aeruginosa was comparable to that of ceftazidime and imipenem. Strains of staphylococci were moderately susceptible to BMY-28142 (MIC required to inhibit 90% of strains, 4 micrograms/ml), but Streptococcus faecalis isolates were resistant. The activity of the five compounds was inoculum dependent for several gram-negative species. By a single-step selection procedure, resistant mutants were selected from strains of Citrobacter freundii, Enterobacter cloacae, and P. aeruginosa. The mutant frequencies with the cephalosporins, including BMY-28142, ranged between 10(-6) and 10(-8). BMY-28142 was the most active cephalosporin against these resistant organisms, most of them strong beta-lactamase producers. It inhibited all mutants of C. freundii and E. cloacae at 2 micrograms/ml and all mutants of P. aeruginosa at 32 micrograms/ml. Imipenem on the other hand was as active on all of these resistant organisms as on the parent strains.
In vitro and in vivo antibacterial activities of dactimicin, a novel pseudodisaccharide aminoglycoside, compared with those of other aminoglycoside antibiotics
Authors: Matsuhashi Y , Yoshida T , Hara T , Kazuno Y , Inouye S
Published: June 2012

When compared with astromicin, amikacin, gentamicin, and sisomicin, dactimicin was similar to astromicin in in vitro activity and was more active than amikacin and gentamicin against the clinical isolates of Serratia marcescens, but less active against Pseudomonas aeruginosa. Dactimicin and astromicin were active against many gentamicin- and amikacin-resistant bacteria expressing aminoglycoside-modifying enzymes, with the exception of aminoglycoside 3-acetyltransferase. However, dactimicin was more resistant than astromicin to inactivation by aminoglycoside 3-acetyltransferase, probably owing to the protective action of the formimidoyl group. The in vivo activity of dactimicin, assessed by the 50% effective doses against systemic infections in mice, was similar or superior to that of astromicin and was superior or inferior to that of amikacin depending on the strains tested.
Comparative studies on the modes of action of the antirhinovirus agents Ro 09-0410, Ro 09-0179, RMI-15,731, 4',6-dichloroflavan, and enviroxime
Authors: Ninomiya Y , Aoyama M , Umeda I , Suhara Y , Ishitsuka H
Published: June 2012

Modes of action of five antirhinovirus agents were compared. Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 were active preferentially against human rhinovirus. Serotypes of the virus varied in their susceptibility to these three agents, whereas Ro 09-0179 and enviroxime showed activity against all the serotypes of the virus tested to date. Ro 09-0410, RMI-15,731, and 4',6-dichloroflavan inactivated the virus directly, although 4',6-dichloroflavan did so only slightly. Inactivation by 4',6-dichloroflavan and RMI-15,731 was associated with the binding of the agents to the virus, since the infectivity, reduced by exposure to the agents, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]Ro 09-0410 to human rhinovirus type 2 was inhibited by unlabeled Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 but not by Ro 09-0179 or enviroxime. Furthermore, subtypes resistant to both 4',6-dichloroflavan and RMI-15,731 showed cross-resistance to Ro 09-0410 and vice versa. On the other hand, sublines resistant to these three agents were not cross-resistant to Ro 09-0179 or enviroxime. These results indicate (i) that Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 exert their activities through the same mode of action, namely, binding to or interaction with some specific site on the viral capsid protein, and (ii) that the binding or interaction sites for these three agents are either the same or very close to each other.
Inhibition of human cytomegalovirus by combined acyclovir and vidarabine
Authors: Spector S A , Kelley E
Published: June 2012

The inhibition of human cytomegalovirus (HCMV) isolates by acyclovir (ACV) and vidarabine (ara-A) was assessed by using an infectious-center plaque-reduction assay. When fixed concentrations of 4.5 micrograms of ACV and 250 ng of ara-A per ml were compared singly and in combination, the viral inhibition resulting from the ACV-ara-A combination was synergistic for three of four HCMV clinical isolates studied and additive for one HCMV isolate. An additional four HCMV strains obtained at postmortem examination from the lungs of bone marrow transplant patients were assessed for sensitivity to ACV-ara-A by using the dose required for 50% viral inhibition (ID50) as the endpoint. The mean ID50 of ACV for the four HCMV isolates was 12.3 micrograms/ml, whereas the mean ID50 of ara-A was 3.4 micrograms/ml. When 1 microgram of ara-A per ml (which yielded a mean plaque reduction of 23.6%) was combined with ACV, a mean of 5.2 micrograms of ACV per ml was required for 50% viral inhibition. The sum of the fractional inhibitory concentrations for each of the four HCMV isolates was less than 1, indicating synergy by the ACV-ara-A combination. Although DNA synthesis in growing human embryonic lung fibroblast (HEL) cells, as determined by [3H]thymidine incorporation, was diminished to 61% of that in untreated control cells when 22.5 micrograms of ACV and 1 microgram of ara-A per ml were used, there was no additive inhibition of DNA synthesis when the two-drug combination was used. HEL cell growth remained at 97% of control cell growth at 72 h when concentrations as high as 45 micrograms of ACV combined with 1 microgram of ara-A per ml were used.
Suppression of intrinsic resistance to penicillins in Staphylococcus aureus by polidocanol, a dodecyl polyethyleneoxid ether
Authors: Bruns W , Keppeler H , Baucks R
Published: June 2012

With polidocanol, it was possible to reduce the MIC as well as the MBC of methicillin, oxacillin, penicillin G, and ampicillin against resistant staphylococci. The strongest effects were obtained with methicillin and oxacillin. All strains tested could be resensitized to these penicillins independent of the original resistance levels. Polidocanol was not inhibitory by itself for Staphylococcus aureus. Furthermore, it did not inhibit the activity of staphylococcal beta-lactamase. This permits the conclusion that an intrinsic resistance mechanism is affected by this substance. Its action cannot be simply explained by an improved accessibility of the penicillin targets as uptake, and binding of methicillin and penicillin G in resistant cells was not changed by polidocanol. On the other hand, the lysis induced by combinations of this substance with small amounts of a penicillin was antagonized by chloramphenicol. This suggests that autolytic enzymes are involved in the polidocanol effect and possibly in the intrinsic resistance mechanism itself. Before polidocanol can trigger lysis, the penicillin must act first in some way. As could be seen with a susceptible strain, the resulting lysis did not exceed that obtained with penicillins alone. Thus, polidocanol does not exhibit an independent lytic mechanism but obviously is able to substitute penicillins in their lytic action.
In vitro activity of cefbuperazone, a new cephamycin, against anaerobic bacteria
Authors: Prabhala R H , Thadepalli H , Rao B , Bansal M B , Marshall R
Published: June 2012

The 90% MIC of cefbuperazone (BMY 25182) was 32 micrograms/ml for Bacteroides fragilis and Bacteroides spp., 128 micrograms/ml for Fusobacterium and Clostridium spp., 64 micrograms/ml for Eubacterium and Peptococcus spp., 8 micrograms/ml for Actinomyces spp., and 32 micrograms/ml for Peptostreptococcus spp. The level of activity of cefbuperazone was higher against B. fragilis and lower against anaerobic cocci than those of related cephalosporins, i.e., cefoxitin, cefoperazone, cefotaxime, ceftizoxime, and cefmenoxime. However, the activity of cefbuperazone was comparable to that of moxalactam against all groups tested. Size of inoculum and type of media used did not alter the MICs of cefbuperazone for B. fragilis. Cefbuperazone showed synergistic activity when combined with cefoxitin against resistant strains of B. fragilis.
Once-daily ceftriaxone for skin and soft tissue infections
Authors: Gordin F M , Wofsy C B , Mills J
Published: June 2012

We prospectively compared once-daily administration of ceftriaxone with cefazolin given every 8 h for the treatment of skin and soft tissue infections. Thirty-one patients received cefazolin for a mean of 4.5 days, and 26 patients received ceftriaxone for a mean of 4.0 days. All patients had a satisfactory response. Adverse reactions were few and reversible. Ceftriaxone given as a single daily intramuscular injection is effective therapy for skin and soft tissue infections.
Effects of urinary pH on renal interactions between probenecid and cefsulodin in rabbits
Authors: Dromer F , Contrepois A , Brion N , Klein C , Carbon C
Published: June 2012

The effect of urinary pH on renal interaction of cefsulodin and probenecid was tested in rabbits. Probenecid was reabsorbed in acidic urine (fractional excretion [FE] = 8 +/- 4%) and secreted in alkaline urine (FE = 492 +/- 258%). Renal excretion of cefsulodin alone was not affected by the urinary pH (FE = ca. 100%). In acidic urine, probenecid significantly reduced tubular secretion of cefsulodin (FE = 74 +/- 8%). An inverse pattern was observed in alkaline urine (FE = 122 +/- 18%).
Effects of apalcillin on platelet function in normal volunteers
Authors: Gentry L O , Wood B A , Natelson E A
Published: June 2012

We investigated the effects of apalcillin on blood coagulation and platelet function. The drug was administered to 21 human volunteers in daily intravenous doses of 75, 150, and 225 mg/kg. These doses evoked abnormalities in platelet aggregation similar to those found with piperacillin and mezlocillin and less striking than those produced by carbenicillin and ticarcillin. Plasma coagulation as measured by prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen concentration was not affected. There were consistent and major reductions in plasma antithrombin III activity, particularly at the two higher dose levels. Of 21 patients, 7 (33%) also manifested maculopapular skin rashes which resolved after discontinuation of the drug.
Antibacterial action of colistin (polymyxin E) against Mycobacterium aurum
Authors: David H L , Rastogi N
Published: June 2012

Mycobacterium aurum was susceptible to the antibiotic colistin (polymyxin E),which had an MIC of 5 micrograms/ml and an apparent bactericidal effect at concentrations above 50 micrograms/ml. Treatment of actively growing cells with sublethal concentrations of colistin (15 micrograms/ml) resulted in synchronized cell division once the antibiotic was removed. Under conditions of synchronized cell growth, one cycle of DNA replication lasted 120 min and one cycle of cell division lasted about 180 min. Although the antibiotic treatment during synchronization experiments did not produce apparent changes in the bacterial envelope, it was accompanied by the accumulation of a polysaccharide-like substance in the bacterial cytoplasm which gradually decreased after the removal of antibiotic and by an increase in the number of mesosomes at 3 h after antibiotic removal. This step was closely linked to the doubling time of bacteria. Lethal concentrations of colistin of 50 and 100 micrograms/ml, which caused about 90 and 99% cell death, respectively, produced significant cytoplasmic membrane injuries, patchy appearance of the cell wall outer polysaccharide layer, and little cell lysis. These data indicate that the cytoplasmic membrane is a site of action of colistin and raise a question as to whether an outer bilayer exists in mycobacteria, at least functionally.
Five novel plasmid-determined beta-lactamases
Authors: Medeiros A A , Cohenford M , Jacoby G A
Published: June 2012

Five novel plasmid-determined beta-lactamases named TLE-1, OXA-4, OXA-5, OXA-6, and OXA-7 were detected in ampicillin-resistant isolates of Escherichia coli and carbenicillin-resistant strains of Pseudomonas aeruginosa. TLE-1 resembled TEM-1 in substrate profile and reactions with inhibitors but differed in isoelectric point (5.55) and enzyme banding pattern on flat-bed electrofocusing.OXA-4, OXA-5, OXA-6, and OXA-7 hydrolyzed oxacillin, methicillin, and cloxacillin readily but differed from OXA-1, OXA-2, and OXA-3 in substrate profiles, inhibitor reactions, and isoelectric points (7.5 to 7.8).OXA-4 and OXA-6 were unusual for members of the OXA group in their sensitivity to inhibition by cloxacillin. OXA-5 and OXA-7 had isoelectric points close to that of SHV-1, emphasizing the need in beta-lactamase classification for studies in addition to isoelectric focusing. These five new enzymes bring the number of plasmid-determined beta-lactamases known in gram-negative organisms to more than 20. The evolution of such enzymatic diversity remains to be explored.
Structure and mode of action of microcin 7, an antibacterial peptide produced by Escherichia coli
Authors: Garcia-Bustos J F , Pezzi N , Mendez E
Published: June 2012

Microcin 7 is a small peptide produced and excreted to the culture medium by stationary-phase Escherichia coli cells harboring the pMccC7 plasmid (formerly named pRYC7). This peptide inhibited the growth of the enterobacteria phylogenetically closer to E. coli, apparently by blocking protein biosynthesis. The molecule was degraded with trypsin, and the resulting fragments were purified and sequenced. The results show that microcin 7 is a linear heptapeptide blocked at both ends.
Structural similarities of the staphylococcin-like peptide Pep-5 to the peptide antibiotic nisin
Authors: Sahl H G , Grossgarten M , Widger W R , Cramer W A , Brandis H
Published: June 2012

The staphylococcin-like peptide Pep-5 was shown to be a complex mixture of closely related and strongly basic peptides. Five peptides were purified by high-pressure liquid chromatography on reversed-phase and gel filtration columns and further characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and amino acid analysis. Four peptides have molecular weights of ca. 3,500, whereas one is of double size. All contain the thioether amino acid lanthionine and a large number of lysine residues per molecule. The amino terminus of the main active peptide is blocked; the carboxy-terminal end is formed by a lysine residue. The data obtained for Pep-5 suggest striking structural similarities to the peptide antibiotics nisin and subtilin.
Studies on 44 081 R.P., a new antirhinovirus compound, in cell cultures and in volunteers
Authors: Zerial A , Werner G H , Phillpotts R J , Willmann J S , Higgins P G , Tyrrell D A
Published: June 2012

A synthetic compound, 2-[(1,5,10,10a-tetrahydro-3H-thiazolo[3,4b]isoquinolin-3-ylidene) amino]-4-thiazoleacetic acid (S), 44 081 R.P., inhibits the multiplication of rhinoviruses in cell cultures. Of the 69 rhinovirus strains and serotypes that have been studied, 39% were inhibited at a concentration of 7 micrograms/ml, far below that which affects cellular metabolism (250 micrograms/ml). Preliminary data indicate that the compound inhibits some early events of virus replication but that some cellular functions are also involved in its mechanism of action. Despite its antiviral activity in vitro, the compound, when self-administered intranasally as a 0.2% solution to volunteers from the day before to 5 days after inoculation with a human rhinovirus strain, had no significant effect on rhinorrhea, clinical score, or laboratory evidence of infection.
Effect of temocillin and moxalactam on platelet responsiveness and bleeding time in normal volunteers
Authors: Nunn B , Baird A , Chamberlain P D
Published: June 2012

The effects of temocillin and moxalactam on platelet responsiveness and bleeding time were examined in healthy male volunteers. In the first study, moxalactam (4 g intravenously every 12 h) was given to six subjects; template bleeding times were at least doubled in five subjects 12 to 14 h after 7 doses (P = 0.008) and in all six subjects 12 to 14 h after 13 doses (P = 0.004). ADP-induced primary aggregation was approximately halved after 7 (P = 0.026) and 13 doses (P = 0.008), and there was a markedly increased tendency toward disaggregation. Collagen-induced aggregation was also halved, but the effect only reached statistical significance after 13 doses (P = 0.008). There was essentially no effect on primary aggregation in response to the thromboxane receptor agonist U46619 or to platelet activating factor. Temocillin (4 g intravenously every 12 h) was given to eight subjects, three of whom had participated in the moxalactam study 8 weeks earlier. Temocillin had no significant effect on template bleeding time 12 to 14 h after 7 or 13 doses. However, in four subjects, the endpoint may have been less abrupt. There was no significant effect on ADP-induced primary aggregation or responsiveness to collagen. Even after 13 doses of temocillin, secondary aggregation in response to normal concentrations of ADP was demonstrable in the platelet-rich plasma of all eight subjects. Neither antibiotic had any effect on prothrombin times. Thus, with methodology that readily detected the effects of moxalactam on hemostasis, we were unable to demonstrate any unequivocal deleterious effects of temocillin at its maximum recommended dose. Temocillin may therefore be particularly useful for the treatment of many gram-negative infections in patients at increased risk of clinical bleeding.
Role of the phosphoroclastic reaction of Clostridium pasteurianum in the reduction of metronidazole
Authors: Lockerby D L , Rabin H R , Laishley E J
Published: June 2012

To demonstrate the importance of electron siphoning by the metronidazole reductase system from reduced ferredoxin to the mechanism of action of the drug in Clostridium pasteurianum, the effects of the reduction of metronidazole on the phosphoroclastic reaction were studied. Metronidazole concentrations between 0.5 and 5 mM caused a significant increase in acetyl phosphate production by the phosphoroclastic reaction compared to the control system without metronidazole. When this enzymatic reaction was assayed by standard manometric techniques under nitrogen gas, two simultaneous effects of electron siphoning were demonstrated: (i) the electrons from reduced ferredoxin were initially consumed for the reduction of metronidazole instead of being evolved as H2 via the ferredoxin-linked hydrogenase and (ii) phosphoroclastic activity was stimulated, with augmented production of CO2 and acetyl phosphate. This work further supports the notion of preferential scavenging of electrons away from ferredoxin-linked enzymatic reactions by metronidazole reductase(s) in C. pasteurianum.
In vitro efficacy of sulbactam combined with ampicillin against anaerobic bacteria
Authors: Wexler H M , Harris B , Carter W T , Finegold S M
Published: June 2012

An ampicillin-sulbactam combination was compared with ampicillin alone, chloramphenicol, clindamycin, and metronidazole against 272 strains of anaerobic bacteria. Chloramphenicol and ampicillin-sulbactam were the most effective, inhibiting 98 to 99% of strains tested at breakpoint (16 micrograms/ml). The combination of sulbactam and ampicillin was much more effective than ampicillin alone against Bacteroides fragilis strains but did not differ substantially from ampicillin alone against Fusobacterium spp., gram-positive rods, and gram-positive cocci.