bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic action of nafcillin and ampicillin against ampicillin-resistant Haemophilus influenzae type b bacteremia and meningitis in infant rats
Authors: Yogev R , Kabat W J
Published: June 2012

Infant rats with bacteremia and meningitis induced by ampicillin-resistant Haemophilus influenzae type b were treated with ampicillin and nafcillin, alone or in combination. Neither ampicillin alone (in 19 animals) nor nafcillin alone (in 20 animals) sterilized the blood or cerebrospinal fluid of any treated infant rat. When the combination of ampicillin and nafcillin was used, blood cultures were negative in 18 of 19 infant rats, and cerebrospinal fluid cultures were sterile in 15 of 19 when cultured 30 h after initiation of treatment. In vitro results demonstrated definite synergism between ampicillin and nafcillin against ampicillin-resistant H. influenzae type b. The study suggests that such synergism also exists in vivo.
Inhibition of dengue virus replication by amantadine hydrochloride
Authors: Koff W C , Elm J L , Halstead S B
Published: June 2012

The effect of amantadine hydrochloride (1-adamantanamine hydrochloride) on dengue virus replication was examined in vitro. Amantadine decreased the titers of all four types of dengue viruses grown in LLC-MK2 cells by greater than 90% at concentrations of 50 micrograms/ml. There was no evidence for any cytopathic effect of the drug at concentrations less than 100 micrograms/ml. Studies of the time of addition showed that the antiviral effect was maximal when drug was added to virus cultures immediately after the viral adsorption period. In addition, amantadine caused a marked reduction in the growth of dengue virus type 2 in both human and rhesus peripheral blood leukocytes without affecting cell viabili ty. These findings demonstrate that amantadine significantly inhibits the replication of dengue viruses in vitro and indicate a need to determine the efficacy of this drug against dengue virus infections in vivo.
Beta-lactamase-producing isolates of Bacteroides species from children
Authors: Brook I , Calhoun L , Yocum P
Published: June 2012

Two hundred twenty-four isolates of Bacteroides sp. were recovered from recurrently inflamed tonsils, infected peritoneal fluid, abscesses, wounds, and burns of hospitalized children. Isolates were examined for beta-lactamase production by the chromogenic cephalosporin analog 87/312 methodology. Altogether, 119 isolates were beta-lactamase producers. Of these, 53 were in the B. fragilis group, 28 were in the B. melaninogenicus groups, 12 were B. oralis, 4 were B. ruminicola subsp. brevis, and 22 were Bacteroides sp. Of 28 beta-lactamase-producing strains of B. melaninogenicus, 25 were recovered from tonsils. These observations indicate that in pediatric patients there is a significant incidence of beta-lactamase producers among anaerobes other than B. fragilis.
Microdilution aminoglycoside susceptibility testing of Pseudomonas aeruginosa and Escherichia coli with a cation-supplemented inoculum
Authors: Cherne J E , Peterson L R
Published: June 2012

The use of cation supplementation in aminoglycoside susceptibility testing of Pseudomonas aeruginosa by microdilution produced MIC agreement (+/- one doubling dilution) with agar dilution testing 89% of the time as compared with 35% of the time with unsupplemented controls.
Effects of impaired renal function, hemodialysis, and peritoneal dialysis on the pharmacokinetics of mezlocillin
Authors: Kampf D , Schurig R , Weihermüller K , Förster D
Published: June 2012

The pharmacokinetics of mezlocillin were examined in 8 patients with normal renal function (inulin clearance, > 80 ml/min per 1.73 m2), 32 patients with moderately reduced renal function (inulin clearances, 80 to 5 ml/min per 1.73 m2), and 12 patients maintained by hemodialysis or peritoneal dialysis because of severely impaired renal function. A single dose of 60 mg of mezlocillin per kg of body weight was infused intravenously over 30 min. Antibiotic concentrations in plasma, urine, and dialysate were determined by the agar diffusion technique. The half-life of mezlocillin increased with decreasing renal function from an average of 53 min in subjects with normal function to 165 min in oligoanuric patients. The urinary recovery of this drug in 24 h decreased from 65% at a glomerular filtration rate of 92 ml/min to 7.6% at a glomerular filtration rate of 6.7 ml/min. Volume of distribution was not changed by the renal insufficiency, amounting on the average to 22.5% of body weight. Intermittent hemodialysis or peritoneal dialysis contributed to only a minor degree to the 24-h mezlocillin kinetics. The pharmacokinetic properties of mezlocillin permit a normal dosage over wide ranges of renal insufficiency; however, when the glomerular filtration rate is below 10 ml/min, the dosage interval should be increased from 8 to 12 h.
In vitro antimicrobial susceptibility of Actinobacillus actinomycetemcomitans
Authors: Slots J , Evans R T , Lobbins P M , Genco R J
Published: June 2012

The agar dilution technique was used for determination of the antibiotic susceptibilities of 57 oral isolates and 2 nonoral isolates of Actinobacillus actinomycetemcomitans. Tetracycline, minocycline, and chloramphenicol inhibited more than 96% of the strains tested at a concentration of less than or equal to 2 micrograms/ml; 89% of the strains were inhibited by 2 micrograms of carbenicillin per ml. The other antimicrobial agents tested were less active. Approximately 10% of the A. actinomycetemcomitans strains were resistant to ampicillin, erythromycin, and penicillin G at concentrations of 32 to 64 micrograms/ml. These data suggest that tetracycline and minocycline may be valuable drugs in the treatment of A. actinomycetemcomitans infections.
Mode of action of copper complexes of some 2,2'-bipyridyl analogs on Paracoccus denitrificans
Authors: Smit H , van der Goot H , Nauta W T , Pijper P J , Balt S , de Bolster M W , Stouthamer A H , Verheul H , Vis R D
Published: June 2012

Copper complexes of 2,2'-bipyridyl and related compounds and CuSO4 inhibited the growth of paracoccus denitrificans. The copper(I) complex of 2,9-dimethyl-1,10-phenanthroline [Cu(DMP)2NO3] showed the highest activity, whereas the copper(II) complex of 1,10-phenanthroline and CuSO4 inhibited the growth to a lesser extent. The uncomplexed ligands (1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline) showed little activity, but in the presence of noninhibitory amounts of CuSO4 this activity increased markedly. Copper ions therefore proved to be essential for the growth-inhibitor effect. The extent of inhibition appeared to be strongly dependent on the initial cell density and on the growth medium. No selective inhibition of deoxyribonucleic acid, ribonucleic acid, or protein synthesis was observed with Cu(DMP)2NO3. Respiratory electron transport of P. denitrificans appeared to be strongly inhibited by Cu(DMP)2NO3 and to a somewhat lesser extent by CuSO4. Both aerobic and anaerobic respirations were inhibited to the same extent, and from the cytochrome redox kinetics it is concluded that the site of this inhibition in the respiratory electron transport chain must be located before cytochrome b. Cu(DMP)2NO3 did not significantly influence the H+/O ratio with whole cells of P. denitrificans, suggesting that the efficiency of oxidative phosphorylation is not affected by CU(DMP)2NO3. Growing cultures of P. denitrificans showed a decrease in intracellular potassium ion content in the presence of increasing amounts of Cu(DMP)2NO3. It is concluded that interference with the cytoplasmic membrane, resulting in inhibition of respiratory electron transport, probably constitutes the main mode of action of copper complexes of 2,2'-bipyridyl analogs on P. denitrificans.
Antiviral activity of arildone on deoxyribonucleic acid and ribonucleic acid viruses
Authors: Kim K S , Sapienza V J , Carp R I
Published: June 2012

Arildone (3 micro/ml) reduced the replication of murine cytomegalovirus, Semliki Forest virus, vesicular stomatitis virus, and coxsackievirus A9 by 64, 68, 94, and 98%, respectively. When the plaque reduction method was used to evaluate the antiviral effect for the viruses, a concentration of 3 to 5 micrograms/ml yielded a 50% reduction in plaque numbers. The effect of arildone on virus replication was greatest when the drug was present from the time of inoculation. The effectiveness decreased as the time interval from the inoculation of the virus to the addition of the drug increased. The removal of the drug from infected cells by washing readily reversed the effect, and viral replication resumed at a significant level. Infectivity of these viruses was not inactivated by the drug. Tissue culture cells used for viral growth and assay grew well in arildone (3 micrograms/ml), with cell yields that were comparable to those for cultures in the absence of drug. At 3 micrograms/ml there were minimal effects of the drug on the uptake of 3H-labeled amino acids and [3H]-thymidine into cells. Furthermore, incorporation of these precursors was not affected. However, there was a reduction in uptake of [3H]uridine into the acid-soluble pool and a concomitant reduction in incorporation into acid-insoluble counts.
In vitro activity of chloramphenicol and thiamphenicol analogs
Authors: Neu H C , Fu K P
Published: June 2012

The in vitro activity of three fluorine analogs of chloramphenicol in which the hydroxyl group at position 3 had been replaced with a fluorine was compared with that of chloramphenicol and thiamphenicol. Compound SCH 24893 was the most active agent against staphylococci and Bacteroides strains, and compound SCH 25298 was the most active against Haemophilus, Neisseria, enterococcus, and Klebsiella strains. Serratia marcescens and Pseudomonas aeruginosa strains resistant to chloramphenicol were resistant to the compounds. The agents inhibited all of the Shigella, Salmonella, Staphylococcus aureus, and enterococcus strains resistant to chloramphenicol. They inhibited most (82%) of Escherichia coli and half of the Klebsiella pneumoniae strains which were resistant to chloramphenicol. Isolates in which resistance to chloramphenicol was shown to be plasmic mediated and due to chloramphenicol transacetylase were inhibited by all three agents.
Induction of beta-lactamase by various beta-lactam antibiotics in Enterobacter cloacae
Authors: Minami S , Yotsuji A , Inoue M , Mitsuhashi S
Published: June 2012

The induction of beta-lactamase in Enterobacter cloacae GN5797 was studied by using 23 beta-lactam antiobiotics, including newly introduced drugs, as inducers. the beta-lactam antibiotics can be classified into three groups on the basis of their inducer activity. Among the tested cephalosporins, cephamycin derivatives such as cefoxitin, cefmetazole, and YM09330 had high inducer activity even at low drug concentrations. On the other hand, cefoperazone, cefsulodin, piperacillin, and apalcillin showed low inducer activity when compared with the other cephalosporins.
Susceptibility of Legionella pneumophila to twenty antimicrobial agents
Authors: Edelstein P H , Meyer R D
Published: June 2012

Thirty-three isolates of Legionella pneumophila, all except one of which were clinical isolates, were tested against 20 antimicrobial agents by using an agar dilution technique. Erythromycin, rifamp]in, and rosaramycin were the most active agents tested. Aminoglycosides, chloramphenicol, and cefoxitin also inhibited the organisms at low concentrations. Other agents, including moxalactam, cefoperazone, and cephalosporins, exhibited moderate to little activity. Tetracycline, doxycycline and minocyeline were apparently inactivated by charcoal-yeast extract medium. There was slight inoculum dependence noted with most of the antimicrobials tested, particularly the beta-lactam agents. There was no consistent difference in susceptibility between Center for Disease Control-supplied stock strains and recent clinical isolates, but there were marked differences with some agents. Susceptibility testing needs to be standardized in view of the influence of inoculum size, strain variation, and the medium used.
Transduction of methicillin resistance in Staphylococcus aureus: recipient effectiveness and beta-lactamase production
Authors: Stewart G C , Rosenblum E D
Published: June 2012

The effectiveness of Staphylococcus aureus strain 8325-4 as a recipient for the transduction of methicillin resistance requires the presence of a penicillinase plasmid but was found to be independent of the lysogenic state of the recipient. Effectiveness is conferred by the plasmid in either the autonomous or integrated states, although the transduction rate is higher in the former. Once established, the maintenance and expression of methicillin resistance were independent of continued carriage of the plasmid deoxyribonucleic acid. Analysis of penicillinase plasmid mutants indicated that beta-lactamase production was the plasmid function responsible for recipient effectiveness. Supportive evidence included the abrogation of recipient effectiveness by the beta-lactamase inhibitor clavulanic acid and the elimination of a plasmid requirement with recipient strains carrying a chromosomal beta-lactamase determinant. A possible role for beta-lactamase production in the transduction of methicillin resistance is discussed.
In vitro susceptibility of varicella-zoster virus to acyclovir
Authors: Biron K K , Elion G B
Published: June 2012

The in vitro susceptibility of five strains of varicella-zoster virus to acyclovir was examined by the plaque-reduction method in human diploid lung cells. The 50% effective doses of acyclovir ranged from 2.06 microM to 6.28 microM in a 7-day assay, with a mean of 3.65 microM. Irreversible inhibition of plaque formtation was achieved by drug doses exceeding the 50% effective dose for plaque reduction but nontoxic to the cells. Studies on the relative in vitro susceptibility of varicella-zoster virus and herpes simplex virus types 1 and 2 to acyclovir suggested that varicella-zoster virus is two- to eightfold less susceptible to the drug. The antiviral potency of acyclovir for varicella-zoster virus in vitro was compared with that of several other nucleoside analogs. Analysis of the metabolism of acyclovir in varicella-zoster virus-infected WI-38 cells revealed that, as with herpes simplex virus types 1 and 2, the formation of the triphosphate forms of the drug is specific to viral infection.
Biosynthesis of daunorubicin glycosides: role of epsilon-rhodomycinone
Authors: McGuire J C , Thomas M C , Stroshane R M , Hamilton B K , White R J
Published: June 2012

Daunorubicin (daunomycin; NSC 82151) is a fermentation-derived anthracycline antibiotic that is clinically useful in the treatment of human leukemias. Daunorubicin itself is found rarely in microbial fermentations, but is present normally in the form of glycoside derivatives that yield the free drug on simple acid hydrolysis. A major by-product of daunorubicin fermentations is usually the structurally related anthracyclinone epsilon-rhodomycinone. We have used mutants of a daunorubicin-producing Streptomyces species to study the biosynthetic relationship between epsilon-rhodomycinone and daunorubicin. We found that exogenously added epsilon-rhodomycinone can be converted to daunorubicin glycosides by a nonproducing mutant and by a mutant that produces daunorubicin glycosides but not epsilon-rhoeomycinone. Molar conversion efficiences were in the 15 to 30% range. The latter mutant was also shown to convert exogenous 14C-labeled epsilon-rhodomycinone to 14C-labeled daunorubicin glycosides, again at conversion efficiencies of about 25%. The same biotransformation was observed with daunorubicin production strain C5, which normally accumulates both epsilon-rhodomycinone and daunorubicin glycosides. A significant percentage (16 to 37%) of exogenously added epsilon-[14C]rhodomycinone was metabolized by strain C5, and 22 to 32% of the metabolized radioactivity could be recovered as daunorubicin glycosides. A mathematical model of epsilon-rhodomycinone metabolism was constructed based on plausible assumptions concerning the kinetics of epsilon-rhodomycinone accumulation and catabolsim. When analyzed according to this model, our data indicate that most (63 to 73%), but not all, of the daunorubicin glycosides accumulated in the experiments with production strain C5 derived from epsilon-rhodomycinone. A pathway network for the biosynthesis of daunorubicin glycosides is proposed that is in agreement with these data. In this proposed pathway network, epsilon-rhodomycinone is an intermediate in one of at least two pathways which yield daunorubicin glycosides.
Lack of toxicity of acyclovir to granulocyte progenitor cells in vitro
Authors: McGuffin R W , Shiota F M , Meyers J D
Published: June 2012

Granulocyte progenitor cells were grown with acyclovir to study potential marrow toxicity. Concentrations of up to 220 microM had little effect on progenitor cell growth.
Prevalence of ampicillin-resistant strains of Haemophilus influenzae causing systemic infection
Authors: Lerman S J , Brunken J M , Bollinger M
Published: June 2012

Surveillance of Haemophilus influenzae bacteremia and meningitis in Omaha during the 6-year period 1974 to 1979 revealed no upward trend in ampicillin resistance. The overall proportion was 5%, and the annual prevalence ranged from 0 to 9%.
In vitro activity of cefoperazone against nonfermenters and Aeromonas hydrophila
Authors: Fass R J
Published: June 2012

The in vitro activity of cefoperazone against 380 strains (33 species and unnamed groups) of nonferenters and 20 strains of Aeromonas hydrophila was studied by a microdilution method of determining minimal inhibitory concentrations. For comparison, the activities of ampicillin, ticarcillin, and cefamandole were simultaneously studied. Cefoperazone was the most active drug against Pseudomonas sp., Achromobacter xylosoxidans, Flavobacterium meningosepticum. Flavobacterium sp. (group IIb), Group IVc biotype 2, Group Ve, and Aeromonas hydrophila. Against other organisms it was equivalent in activity to or less active than comparative antibiotics. The only organisms which were usually resistant to 128 microgram of cefoperazone per ml were strains of Flavobacterium odoratum and Group IIk biotype 1.
Neomycin inhibition of adenosine triphosphatase: evidence for a neomycin-phospholipid interaction
Authors: Lipsky J J , Lietman P S
Published: June 2012

The inhibition of canine renal sodium potassium adenosine triphosphatase (ATPase) by neomycin was examined. Neomycin inhibited ATPase nearly maximally at 0.02 mM. The inhibition was temperature dependent with a decrease in inhibition occurring at temperatures below 21 degrees C, a temperature which corresponded to a change in activation energy of the ATPase as determined by Arrhenius plot. Preincubation of the ATPase with phosphoinositides was found to prevent the inhibition by neomycin. Other phospholipids were not found to prevent the inhibition. These results indicate a possible interaction between neomycin and the phosphoinositides of the ATPase complex.
In vitro activity of N-formimidoyl thienamycin (MK0787), a crystalline derivative of thienamycin
Authors: Horadam V W , Smilack J D , Montgomery C L , Werringloer J
Published: June 2012

N-Formimidoyl thienamycin (MK0787) is a derivative of thienamycin, a unique, new beta-lactam antibiotic. Its activity against 285 aerobic and facultatively anaerobic clinical isolates was compared with the activities of cephalothin, ampicillin, penicillin G, ticarcillin, and tobramycin. All of the 285 isolates, with the exception of 1 Staphylococcus epidermidis isolate, were inhibited by a concentration of N-formimidoyl thienamycin of less than or equal to 8 micrograms/ml. More than 50% of all isolates were inhibited by the lowest concentration of N-formimidoyl thienamycin tested (0.125 micrograms/ml); 98% of Staphylococcus aureus and 80% of S. epidermidis isolates were inhibited by N-formimidoyl thienamycin at a concentration of 0.125 micrograms/ml. Only 2 of 45 enterococci were not inhibited by 1 microgram of N-formimidoyl thienamycin per ml, and this drug was the most active agent tested against 162 gram-negative bacilli. It inhibited more than 95% of the gram-negative isolates at a concentration of less than or equal to 2 micrograms/ml. N-Formimidoyl thienamycin was as active or more active than tobramycin against Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis and substantially more active than ticarcillin. All 16 isolates of Klebsiella pneumoniae were inhibited by less than or equal to 0.5 micrograms of N-formimidoyl thienamycin per ml. The marked in vitro activity of this drug against a wide variety of clinical isolates makes it a promising new antibiotic.
Synergistic activity of piperacillin in combination with beta-lactamase inhibitors
Authors: Neu H C , Fu K P
Published: June 2012

Clavulanic acid and a penicillanic acid sulfone, when combined individually with piperacillin, synergistically inhibited various Enterobacteriaceae, Staphylococcus aureus, and Bacteroides fragilis. Clavulanic acid and piperacillin synergistically inhibited 91 of 170 (55%) isolates tested. Synergy was most often found against piperacillin-resistant bacteria: 65 of 69 isolates (94%). Although the penicillanic acid sulfone acted synergistically with piperacillin, inhibiting 62 of 170 strains (33%), the concentration of clavulanic acid required for synergy generally was less than that of penicillanic acid sulfone. Combination of piperacillin and cefotaxime, an inhibitor of type 1 beta-lactamases, rarely was synergistic and was antagonistic for several species. The combination of piperacillin with potent beta-lactamase inhibitors made piperacillin active against those isolates of Escherichia coli and Klebsiella and Bacteroides species, as well as selected other species, that are resistant to piperacillin by virtue of their production of beta-lactamases.
Permeabilizing and hemolytic action of large and small polyene antibiotics on human erythrocytes
Authors: Brajtburg J , Medoff G , Kobayashi G S , Elberg S , Finegold C
Published: June 2012

The effects of large polyenes (heptaenes and the "degenerate heptaene" nystatin) on human erythrocytes were found to occur in three separate stages. Stage I was a reversible increase in cell membrane permeability to monovalent cations and occurred at low antibiotic concentrations. At intermediate antibiotic concentrations, an irreversible increase in cell membrane permeability to cations (stage II) occurred, which then led to swelling of cells and hemolysis (stage III). Hemolysis could be prevented by sucrose, mannitol, or melezitose, but stages I and II still occurred under these conditions. The effects of the small polyenes (pentaenes and a tetraene) occurred in only one stage. Changes in cell membrane permeability (stages I and II) were not noted before hemolysis (stage III) even in the presence of carbohydrate. Carbohydrates gave only weak, transient protection from the hemolytic action of small polyenes, probably because the membrane damage induced by these antibiotics was more extensive than that induced by the large polyenes. In the presence of sucrose, large polyenes were able to inhibit the hemolytic action of small polyenes, implying that both antibiotics have the same binding sites.
Influence of extracellular K+ or Mg2+ on the stages of the antifungal effects of amphotericin B and filipin
Authors: Brajtburg J , Medoff G , Kobayashi G S , Elberg S
Published: June 2012

The macrolide heptaene amphotericin B (AmB) induced concentration-dependent effects on Saccharomyces cerevisiae which were separable into two distinct stages. At low concentrations the drug inhibited the growth of the yeast and reversible changed cell permeability to Na+ and K+. At high levels it was lethal. The intracellular K+ concentration of cells with reversible damage (stage I) could be increased by addition of K+ to the medium, but cells irreversibly damaged (stage II) were not able to retain K+. The addition of K+ to the medium did not influence the growth-inhibitory or killing action of AmB. Addition of Mg2+ to cultures increased S. cerevisiae resistance to the killing effects of AmB. At low concentrations of AmB, growth inhibition was also decreased by extracellular Mg2+, but at higher concentration of AmB, growth inhibition was increased, probably because the prevention by Mg2+ of the lethal effect allowed expression of the inhibitory effect in a greater range. Simultaneous addition of K+ and Mg2+ markedly decreased both the inhibitory and lethal action of AmB at all concentrations. Filipin, a pentaene macrolide, had only lethal effects, which were unaffected when K+ was added to the medium but were diminished when medium was supplemented with Mg2+.
Comparative susceptibilities of clinical isolates of Serratia marcescens to newer cephalosporins, alone and in combination with various aminoglycosides
Authors: Markowitz S M , Sibilla D J
Published: June 2012

We examined 100 clinically significant isolates of Serratia marcescens for susceptibility to newer cephalosporin and cephamycin antibiotics, alone and in combination with various aminoglycosides. Moxalactam and cefotaxime were the most effective agents; all isolates were inhibited by 25 and 50 micrograms/ml, respectively. All strains were susceptible to amikacin at concentrations safely achievable in serum, whereas gentamicin, netilmicin, and tobramycin inhibited 63, 63, and 16% of the isolates, respectively. Moxalactam, cefotaxime, and amikacin were active against gentamicin-susceptible and gentamicin-resistant strains. Studies of synergy revealed that moxalactam and cefotaxime, in combination with netilmicin or amikacin, were often synergistic and infrequently antagonistic against cephalothin- and gentamicin-resistant strains. These results suggest that moxalactam and cefotaxime, alone or in combination, may be efficacious in treating infections due to multiply antibiotic-resistant S. marcescens.
Characterization of beta-lactamase-deficient (bla) mutants of the R plasmid R1 in Escherichia coli K-12 and comparison with similar mutants of RP1
Authors: Crowlesmith I , Howe T G
Published: June 2012

Thirty-eight mutants of R1, an R plasmid specifying the type IIIa (TEM) beta-lactamase, were isolated; these mutants are partially or totally unable to synthesize the type IIIa beta-lactamase. The loss of beta-lactamase activity was associated with a reduction in the level of penicillin resistance conferred by the mutants upon their host strain. At least two of the mutants synthesized a beta-lactamase with altered substrate specificity. These properties are compared with those of two beta-lactamase-deficient mutants of plasmid RP1. The results suggest that, for both R plasmids, penicillin resistance is entirely attributable to the presence of beta-lactamase activity. The properties of two R1 derivatives, pUB251 and pUB252, which have phenotypes similar to that of RP1, support this conclusion.
Stimulation of leucomycin production by magnesium phosphate and its relevance to nitrogen catabolite regulation
Authors: Omura S , Tanaka Y , Kitao C , Tanaka H , Iwai Y
Published: June 2012

Addition of magnesium phosphate [Mg3(PO4)2 x 8H2O] to a complex medium or to an ammonium ion-containing, chemically defined medium stimulated leucomycin production by Streptomyces kitasatoensis. Ammonium ions in high concentrations inhibited leucomycin production, but their limitation by magnesium phosphate led to the high production of the antibiotic.
Relative resistance to erythromycin in Chlamydia trachomatis
Authors: Mourad A , Sweet R L , Sugg N , Schachter J
Published: June 2012

Recent Chlamydia trachomatis isolates were tested in a tissue culture system for susceptibility to tetracycline, erythromycin, rosaramicin, rifampin, and clindamycin. Rifampin was the most active drug (minimal inhibitory concentration, less than or equal to 0.02 microgram/ml). Tetracycline and rasaramicin were highly active, with a concentration of less than or equal to 0.25 microgram/ml being chlamydicidal. Clindamycin was least active on a weight basis, requiring up to 16 microgram/ml to prevent the passage of chlamydiae into a drug-free tissue culture system. Relative resistance to erythromycin was detected; two isolates were capable of limited replication in 1 microgram/ml.
Pharmacology, Tolerance, and Antiviral Activity of Vidarabine Monophosphate in Humans
Authors: Whitley Richard J. , Tucker Bruce C. , Kinkel Arlyn W. , Barton Nancy H. , Pass Robert F. , Whelchel John D. , Cobbs C. Glenn , Diethelm Arnold G. , Buchanan Robert A.
Published: June 2012

Vidarabine (adenine arabinoside) is a purine nucleoside useful in humans for therapy of herpes simplex virus encephalitis and herpes zoster virus infections in immunocompromised patients. However, the potential usefulness of vidaribine is limited by its poor solubility, which requires continuous infusion in relatively large volumes of intravenous fluid. Vidarabine 5′-monophosphate is highly soluble and has the advantage that it can be administered intermittently intramuscularly or intravenously. In a clinical, pharmacokinetic study, plasma levels and urinary excretion of vidarabine 5′-monophosphate were determined after intravenous and intramuscular administration in 29 immunosuppressed patients with herpes simplex or zoster virus infections at dosages of 15 to 30 mg/kg per day administered for 5 days. As determined by high-pressure liquid chromatography, vidarabine 5′-monophosphate was metabolized in a fashion comparable to the metabolism of vidarabine and its major metabolite in plasma was arabinosyl hypoxanthine. After administration, 40 to 50% of the vidarabine 5′-monophosphate was recovered from the urine as arabinosyl hypoxanthine, and 3 to 4% was recovered as vidarabine. Determinations of areas under the curve for arabinosyl hypoxanthine were not statistically different by dosage for intramuscular or intravenous routes of administration. At all dosages studied, viral clearance appeared to occur with therapy. The advantage of increased solubility will lead to controlled clinical investigations in which vidarabine 5′-monophosphate is administered by intramuscular or intravenous routes against targeted human herpesvirus infections.
Penicillin-binding proteins of penicillin-susceptible and intrinsically resistant Neisseria gonorrhoeae
Authors: Dougherty T J , Koller A E , Tomasz A
Published: June 2012

The penicillin-binding proteins (PBPs) of Neisseria gonorrhoeae were investigated by using [3H]benzylpenicillin of high specific activity. This made it possible to label the PBPs both in cytoplasmic membranes and in the membranes of actively growing cells (in vivo labeling). A total of 20 strains isolated from different geographic locales showed the same pattern of three major PBPs, which had molecular weights of approximately 90,000, 63,000, and 48,000. Five clinical isolates of intrinsically penicillin-resistant gonococci each exhibited reduced penicillin binding of PBPs 1 and 2. The construction of an isogenic set of transformants with increasing levels of penicillin resistance indicated that the penA gene was associated with a decrease in penicillin binding fo PBP 2. Decreased binding to PBP 1 is likely to accompany the newly reported pem and tem genes, which govern to highest level of penicillin resistance.
Identification of tetracycline-resistant R-plasmids in Streptococcus agalactiae (group B)
Authors: Burdett V
Published: June 2012

In this report, 30 tetracycline-resistant clinical isolates of group B Streptococcus were examined to assess the extent to which tetracycline resistance is plasmid mediated. Of these, 27 showed no physical or genetic evidence of plasmid-mediated resistance; however, one conjugative and two small (3.5 X 10(6)-dalton) multicopy non-self-transmissible tetracycline resistance plasmids were identified. The conjugative plasmid was transmissible to Streptococcus faecalis as well as to Streptococcus agalactiae (group B). The two nonconjugative plasmids were readily mobilized by a number of sex factors into these same two backgrounds and, in addition, readily transformed Streptococcus sanguis Challis to tetracycline resistance. Due to readily available sites for several site-specific endonuycleases, these small, multicopy plasmids should prove useful as cloning vehicles in this host system.
Synthesis of 3-O-demethylfortimicins
Authors: Martin J R , Johnson P , Tadanier J , Goldstein A
Published: June 2012

Treatment of fortimicin B with lithium in ethylamine gave 3-O-demethylfortimicin B. The latter was converted by methodology developed with fortimicin B to 3-O-demethylfortimicin A, 4-N-sarcosyl-3-O-demethylfortimicin B, 4-N-beta-alanyl-3-O-demethylfortimicin B, and 4-N-(beta-aminoethyl)-3-O-demethylfortimicin B. 3-O-demethylfortimicin A and the 4-N-acyl-3-O-demethylfortimicins B had appreciably higher antibacterial activities than the corresponding parent fortimicins. Most significant was the increased activity of 3-O-demethylfortimicin A relative to fortimicin A against a variety of strains of Pseudomonas aeruginosa.
Compound A49759, the 3-O-demethyl derivative of fortimicin A: in vitro comparison with six other aminoglycoside antibiotics
Authors: Jones R N , Thornsberry C , Barry A L , Packer R R , Baker C N , Badal R E
Published: June 2012

O-Demethylfortimicin A (compound A49759) was tested against 445 bacteria, and the results were compared with those obtained with fortimicin A, amikacin, gentamicin, netilmicin, sisomicin, and tobramycin. A49759 was found to be active and bactericidal against the Enterobacteriaceae, nonfermentative gram-negative bacilli, and Staphylococcus aureus. A49759 was two- to fourfold more active than fortimicin A against most species tested, but generally fourfold less active than amikacin against this population of Pseudomonas aeruginosa (85% inhibited at less than or equal to 16 microgram of amikacin per ml and 85% inhibited at less than or equal to 64 microgram of A49759 per ml). Only amikacin and A49759 were resistant to most aminoglucoside-inactivating enzymes and also had significant antipseudomonal activity. Amikacin was inactivated by aminoglycoside 6'-acetyltransferase, and A49759 was inactivated by aminoglycoside 3-acetyltransferase. The minimal inhibitory concentrations of all tested aminoglycosides were increased by augmenting the inoculum size.
Plasmids in Corynebacterium diphtheriae and diphtheroids mediating erythromycin resistance
Authors: Schiller J , Groman N , Coyle M
Published: June 2012

Plasmids were isolated from erythromycin-resistant Corynebacterium diphtheriae and skin coryneforms. Six erythromycin-resistant C. diphtheriae strains, isolated from cutaneous lesions, all contained a 9.5-megadalton (Mdal) plasmid. Loss of resistance was associated with the deletion of a 1-Mdal segment from the plasmid or, less frequently, with loss of the plasmid. Two erythromycin-resistant diphtheroids were isolated from similar skin lesions. One contained a 38-Mdal plasmid that was lost in the conversion to erythromycin susceptibiliy. The other diphtheroid contained a 30- and a 14-Mdal plasmid. Erythromycin-susceptible derivatives of this strain were not recovered. Restriction enzyme analysis indicated that the 9.5-Mdal plasmids in the C. diphtheriae strains are very similar, if not identical, and that each of the deleted plasmids has lost the same 1-Mdal segment. However, the restriction patterns of the plasmids in the two diphtheroids are not closely related to each other nor to the plasmids in the C. diphtheriae strains.
Comparison of sensititre dried microtitration trays with a standard agar method for determination of minimum inhibitory concentrations of antimicrobial agents
Authors: Reeves D S , Holt A , Bywater M J , Wise R , Logan M N , Andrews J M , Broughall J M
Published: June 2012

A total of 222 clinical isolates were used to test the accuracy of Sensititre dried microtitration trays for determining minimum inhibitory concentrations (MICs) of antimicrobial agents. In comparison with an agar dilution technique, 89.5% of all the pairs of results were within one doubling dilution. The 2,420 pairs of MIC results with finite values gave a corresponding figure of 86.8%. Exclusion of sulfisoxazole results, which demonstrated a significant interlaboratory variation in accuracy, raised this value to 89.1%. Very good differentiation of beta-lactamase-producing strains of Staphylococcus aureus (24 of 24 giving an MIC greater than or equal to 0.25 micrograms/ml) and Haemophilus influenzae (3 of 3 giving an MIC greater than or equal to 32 micrograms/ml) was obtained with the Sensititre system. This method also clearly distinguished erythromycin-resistant S. aureus strains (7 of 7 giving an MIC greater than 32 micrograms/ml) from the susceptible strains (26 of 28 giving an MIC less than or equal to 0.5 microgram/ml plus 1 strain at 1.0 microgram/ml and 1 at 2.0 micrograms/ml). Sensititre offers an accurate and convenient method of determining MICs comparable to those obtained with the agar dilution procedure, with the advantage of an extended shelf life when stored at room temperature.
Influence of inoculum size on activity of cefoperazone, cefotaxime, moxalactam, piperacillin, and N-formimidoyl thienamycin (MK0787) against Pseudomonas aeruginosa
Authors: Corrado M L , Landesman S H , Cherubin C E
Published: June 2012

Forty clinical isolates of Pseudomonas aeruginosa were tested for their susceptibility to cefoperazone, cefotaxime, moxalactam, piperacillin, N-formimidoyl thienamycin (MK0787), and gentamicin at three different inocula. At an inoculum of 5 x 10(3) colony-forming units (CFU) per ml, the minimum inhibitory concentrations (in micrograms per milliliter) for 90% of isolates (MIC90) were as follows: gentamicin, 1; N-formimidoyl thienamycin, 2; cefoperazone, 4; piperacillin, 8; moxalactam, 16; and cefotaxime, 16. When the inoculum was increased to 5 x 10(5) CFU/ml, the MIC90 for all drugs tested increased. Among the beta-lactam antibiotics, N-formimidoyl thienamycin and cefoperazone had the lowest MIC90 (8 micrograms/ml) at this inoculum. When the inoculum was increased further to 5 x 10(7) CFU/ml, an MIC90 could be determined only for gentamicin and N-formimidoyl thienamycin (4 and 8 micrograms/ml, respectively). Indeed, the MIC50 for moxalactam, cefotaxime, cefoperazone, and piperacillin was 128 micrograms/ml or more at this inoculum. The minimum bactericidal concentration for 90% of isolates (MBC90) at an inoculum of 5 x 10(5) CFU/ml ranged from 8 micrograms/ml for gentamicin and N-formimidoyl thienamycin to 128 micrograms/ml for cefotaxime. At the highest inoculum, however, whereas the MBC90 for gentamicin and N-formimidoyl thienamycin remained at 8 micrograms/ml, the MBC90 for each of the other drugs was greater than 128 micrograms/ml. N-Formimidoyl thienamycin was the only drug tested for which an MIC100 and MBC100 (MIC and MBC for 100% of isolates) could be determined, and these were not significantly different from the MIC90 and MCB90.
Phosphonopeptide antibacterial agents related to alafosfalin: design, synthesis, and structure-activity relationships
Authors: Atherton F R , Hall M J , Hassall C H , Holmes S W , Lambert R W , Lloyd W J , Ringrose P S
Published: June 2012

Dipeptide variants of alafosfalin (L-alanyl-L-1-aminoethylphosphonic acid) with substantial differences in potency and antibacterial spectrum in vitro and in vivo have been synthesized. Certain dipeptides with alternatives to the L-alanyl residue had broader antibacterial spectra; activity against Pseudomonas aeruginosa was included. Some compounds had better in vivo activity than alafosfalin when introduced into infected rodents orally, but for the majority of the more active phosphonodipeptides, parenteral administration was more effective. Certain oligopeptides derived from the more active phosphonodipeptides possessed good in vitro activity against an extended range of organisms; they included Haemophilus influenzae, Streptococcus faecalis, and Streptococcus pneumoniae. The in vivo activity of some of these phosphono-oligopeptides was significantly greater than that of the parent dipeptide and correlated well with the in vitro results. This indicates that phosphono-oligopeptides exert part of their in vivo action directly, in addition to that arising from smaller peptides produced by peptidase cleavage.
Activity of mecillinam alone and in combination with other beta-lactam antibiotics
Authors: Fass R J
Published: June 2012

The in vitro activities of mecillinam, ticarcillin, cefamandole, and cefoxitin, singly and in all possible combinations, against 53 clinical isolates were studied by a checkerboard method of determining minimal inhibitory concentrations. For selected representative strains, bactericidal activity was determined by minimal bactericidal concentrations and killing curves. Mecillinam was the least active antibiotic against gram-positive cocci, Pseudomonas aeruginosa, and Bacteroides fragilis and the most active against Enterobacteriaceae. Reproducibility of mecillinam minimal inhibitory concentrations for susceptible Enterobacteriaceae was often poor, however, due to minor variations in inoculum size. When mecillinam resistance was observed with Enterobacteriaceae, partial inhibition could be demonstrated at concentrations below minimal inhibitory concentrations, and bacterial cells were consistently ovoid or round; under those conditions the addition of a second study antibiotic resulted in marked synergistic inhibition and killing which was independent of inoculum size and susceptibility to the second antibiotic. In contrast, synergy with mecillinam against mecillinam-susceptible strains or with other antibiotic combinations against any species was not consistently observed.
Ro 13-9904, a long-acting broad-spectrum cephalosporin: in vitro and in vivo studies
Authors: Angehrn P , Probst P J , Reiner R , Then R L
Published: June 2012

Ro 13-9904, a new parenteral cephalosporin, was found to have high in vitro activity against Enterobacteriaceae and other gram-negative bacteria, including various isolates resistant to cefuroxime, cefamandole, cefoxitin, and cefazolin. It showed promising activity against Pseudomonas aeruginosa. Although inhibitory against Staphylococcus aureus at concentrations readily achievable in plasma, it was less potent against this pathogen than cefamandole, cefazolin, or cefuroxime. Isolates of Streptococcus faecalis were uniformly resistant to all the cephalosporins tested. Ro 13-9904 was more active than cefotaxime against Proteus mirabilis, Neisseria gonorrhoeae, Neisseria meningitidis, and Haemophilus influenzae, but less active against S. aureus. Ro 13-9904 was stable to various types of beta-lactamases. Its therapeutic efficacy against experimental septicemias in mice was equal to or slightly superior to that of cefotaxime and SCE-1365 when the antibiotics were administered in repeated subcutaneous doses after bacterial challenge. Cefoperazone, and particularly cefamandole nafate, cefazolin, and mezlocillin were less effective. Although structurally related to cefotaxime and SCE-1365, Ro 13-9904 was found to differ from them in one important respect, namely, in having a long duration of action; this was observed with single-dose treatment given before bacterial challenge. Its broad spectrum of activity coupled with favorable pharmacokinetic properties make Ro 13-9904 a promising compound for clinical studies.
R-factor responsible for an outbreak of multiply antibiotic-resistant Klebsiella pneumoniae
Authors: Courtney M A , Miller J R , Summersgill J , Melo J , Raff M J , Streips U N
Published: June 2012

Seven serotypes of Klebsiella pneumoniae isolated from different patients demonstrated resistance to the same eight antibiotics. A plasmid carrying resistance determinants to these antibiotics and mercury salts could be transferred in toto to a plasmidless strain of Escherichia coli. All E. coli transconjugants showed the same antibiotic resistance pattern. Digestion with restriction endonucleases yielded patterns that were identical for each of the R-factor transferred from the multiply resistant serotypes. Moreover, deoxyribonucleic acid-deoxyribonucleic acid hybridization demonstrated identity between the probe, pMAC20 (an R-factor from one serotype), and all R-factors isolated from the multiply resistant strains of K. pneumoniae and the E. coli transconjugants tested.
Pharmacokinetics of mecillinam in health subjects
Authors: Gambertoglio J G , Barriere S L , Lin E T , Conte J E
Published: June 2012

Mecillinam is an amidino penicillinate derivative with a broad spectrum of activity against many gram-negative bacilli. Moreover, marked in vitro synergy against these organisms occurs when mecillinam is combined with other beta-lactam antibiotics. The purpose of this study was to determine the pharmacokinetic disposition of this antibiotic. A single dose of 10 mg/kg was administered to 12 healthy volunteers as a 15-min intravenous infusion. Multiple plasma and urine samples were collected at frequent intervals for 8 and 24 h, respectively. Plasma samples were assayed for mecillinam by using a specific high-pressure liquid chromatographic assay developed in our laboratory. Peak plasma levels ranged from 34 to 80 micrograms/ml, and after 4 h, plasma levels were 0.7 to 1.9 microgram/ml. The mean terminal plasma half-life was 51.1 +/- 8.6 min. The mean steady-state volume of distribution was calculated to be 0.23 +/- 0.04 liter/kg. The mean plasma and renal clearances were 3.5 +/- 0.4 and 2.5 +/- 0.4 ml/min per kg, respectively. The mean percentage of the dose excreted unchanged in the urine at 4 h was 67 +/- 5%; 71 +/- 6% was recovered in 24 h. Urine concentrations at 4 h were far above the minimum inhibitory concentration for susceptible gram-negative organisms.
Morphological expressions of antibiotic synergism against Pseudomonas aeruginosa as observed by scanning electron microscopy
Authors: Waisbren S J , Hurley D J , Waisbren B A
Published: June 2012

Antibiotic-induced changes in Pseudomonas aeruginosa were observed by means of a scanning electron microscope. Seven frequent and five less frequent morphological changes were noted. The frequent changes were: (i) elongation; (ii) chain formation; (iii) nub formation; (iv) spheroplasts; (v) surface holes or pits; (vi) super-elongation; and (vii) increased filamentation. The less frequent changes were: (i) rounded ends; (ii) streptococcal forms; (ii) stalked nubs; (iv) surface bulges; and (v) convoluted surfaces. A morphological equivalent of antibiotic synergism was found in which changes were noted due to synergistic combinations of antibiotics that were not observed when the antibiotics were used alone or when a nonsynergistic combination of antibiotics was used.
Comparative in vitro susceptibility of yeasts to amphotericin B and three methyl ester derivatives
Authors: Oblack D L , Hewitt W L , Martin W J
Published: June 2012

The in vitro antifungal activities of two N-aminoacyl derivatives of amphotericin B methyl ester (AME) were compared by tube dilution with those of amphotericin B and AME, using 60 isolates representing 10 yeast species. A total of 70% of the strains were inhibited by concentrations of the N-aminoacyl AME derivatives that were within a twofold dilution of the amphotericin B or AME minimum inhibitory concentration. The fungicidal activity of the N-aminoacyl AME derivatives was 3- to 16-fold lower than that of amphotericin B for 8 of 10 species. A considerable spectrum of antifungal activity was observed for N-aminoacyl derivatives of AME, which represents a new class of water-soluble polyene antibiotics.