Showing papers in "Antimicrobial Agents and Chemotherapy in 1980"
TL;DR: This method was used to determine the minimal lethal concentrations of semi-synthetic penicillins for S. aureau isolates, one of which was tolerant to the killing action of penicillin.
Abstract: The lack of a standardized, statistically reliable method for in vitro determinations of the minimal lethal or bactericidal concentrations of antibiotics has complicated analyses of isolates of Staphylococcus aureus which appear to be inhibited but not killed by the usual concentrations of cell wall-active antibiotics. We describe a method which identifies some of the covariants involved in determinations of minimal lethal concentrations. Lethality was defined as a 99.9% reduction in the initial inoculum of bacteria after 24 h of incubation. We limited the sample volume to 0.01 ml to minimize the inhibitory effect of antibiotic and corresponding rejection values, which detected lethality with a high degree of sensitivity and specificity. When the number of colonies on subculture was equal to or less than the rejection value, the antibiotic was considered lethal for the test organism. Rejection values encompassed initial inocula from 10(5) to 10(7) colony-forming units per ml for single and duplicate samples and allowed for 1 or 5% variability in pipette volumes and errors in initial inoculum determinations. This method was used to determine the minimal lethal concentrations of semi-synthetic penicillins for S. aureau isolates, one of which was tolerant to the killing action of penicillin.
489 citations
TL;DR: Ketoconazole, an orally active antimycotic drug, is a potent inhibitor of ergosterol biosynthesis in Candida albicans when added to culture media which support yeast or mycelial growth or to cultures containing outgrown mycelium.
Abstract: Ketoconazole, an orally active antimycotic drug, is a potent inhibitor of ergosterol biosynthesis in Candida albicans when added to culture media which support yeast or mycelial growth or to cultures containing outgrown mycelium. This inhibition coincides with accumulation of sterols with a methyl group at C-14 and can thus be attributed to an interference with one of the reactions involved in the removal of the 14 alpha-methyl group of lanosterol. When administered to rats infected with C. albicans, ketocanazole also inhibits fungal synthesis of ergosterol. A six-times-higher dose is required to effect cholesterol synthesis by rat liver.
266 citations
TL;DR: This assay proved to be a reliable, rapid method of determining 50% inhibitory concentrations that correlated well with clinically achievable drug levels and the results of clinical trials.
Abstract: The relative antiviral activities of four drugs against contemporary strains of influenza A and B viruses were determined in Madin-Darby canine kidney cell monolayers with a plaque inhibition assay. This assay proved to be a reliable, rapid method of determining 50% inhibitory concentrations that correlated well with clinically achievable drug levels and the results of clinical trials. Contemporary strains of influenza A viruses (subtypes H1N1, H3N2, HSW1N1) required amantadine hydrochloride and rimantadine hydrochloride 50% inhibitory concentrations in the range of 0.2 to 0.4 microgram/ml, whereas 50% inhibitory concentrations ranged from approximately 50 to 100 micrograms/ml against influenza B viruses. Ribavirin was approximately 10-fold less active than amantadine hydrochloride against influenza A viruses, and the ribavirin 50% inhibitory concentrations against both influenza A and B viruses ranged from 2.6 to 6.8 micrograms/ml. Inosiplex had no antiviral activity in this test system.
262 citations
TL;DR: Multiply drug-resistant South African pneumococci showed several types of major alterations in their penicillin-binding protein (PBP) pattern compared with that of a penicillus-susceptible laboratory strain of Streptococcus pneumoniae.
Abstract: Multiply drug-resistant South African pneumococci (with penicillin minimal inhibitory concentrations ranging from 0.2 to 12.5 microgram/ml) showed several types of major alterations in their penicillin-binding protein (PBP) pattern compared with that of a penicillin-susceptible laboratory strain of Streptococcus pneumoniae (R6; penicillin minimal inhibitory concentration = 0.006 microgram/ml). Genetic transformants were obtained by using South African pneumococcus (strain 8249) deoxyribonucleic acid as donor and the competent cells of strain R6 as recipient; seven classes of transformants with progressively higher penicillin resistance were isolated, and their PBPs were tested. The PBP patterns exhibited a gradual shift from a pattern similar to that of the recipient to a pattern resembling that of the donor strain as the level of penicillin resistance increased.
258 citations
TL;DR: One mutant is described which induced high levels of TK but was highly resistant to ACV and retained virulence for mice, and was attenuated when injected into mice.
Abstract: Mice infected with three different isolates of herpes simplex virus (HSV) and treated with acyclovir (acycloguanosine; ACV) showed low levels of virus replication during the acute phase of infection However, virus isolated from such treated mice did not show increased resistance to ACV In contrast, resistant virus was readily isolated in vitro by passaging HSV in the presence of the drug The degree of resistance was determined, in part, by the nature of the cells used to test the virus The majority of ACV-resistant strains induced low or undetectable levels of HSV-specified thymidine kinase (TK), the enzyme responsible for phosphorylating ACV in infected cells The TK-resistant strains were attenuated when injected into mice as indicated by reductions in virus replication, inflammation, and establishment of latent infections in sensory ganglia The reduced virulence of the TK- strains was most marked after intracerebral inoculation, where the lethal dose was increased more than 100-fold compared with the parental isolates However, one mutant is described which induced high levels of TK but was highly resistant to ACV and retained virulence for mice
242 citations
TL;DR: A significant incidence of polyene resistance in an oncology subpopulation was documented, suggesting a need for susceptibility testing in patients who are at high risk for development of drug-resistant fungal pathogens.
Abstract: The development of resistance to amphotericin B and nystatin in yeast isolates was determined. Organisms recovered from patients on the oncology service, undergoing extensive chemotherapy for acute leukemia and bone marrow transplantation, were compared with yeasts recovered from patients on other services in the same hospital over a 7-month period. An agar dilution method was used to assay the susceptibility for each antibiotic; resistance was defined as a minimal inhibitory concentration of greater than or equal to 2 micrograms/ml for amphotericin B and greater than or equal to 16 micrograms/ml for nystatin. None of 625 isolates from 238 patients on non-oncology services demonstrated polyene resistance. Resistance only occurred in a subpopulation of oncology patients, in which 55 isolates (7.4%) from six patients (8.6%) exhibited polyene resistance. Resistance yeasts included Candida albicans (three strains), Candida tropicalis (one strain), and Torulopsis glabrata (two strains). All of the patients from whom resistant yeasts were recovered had experienced extensive chemotherapy with cytotoxic agents, granulocytopenia, and long-term treatment with both antibacterial and polyene antibiotics. Resistance to 2 micrograms of amphotericin B per ml and to 16 micrograms of nystatin per ml was associated with loss or marked depression of ergosterol in the cell membrane as measured by ultraviolet spectra. A significant incidence of polyene resistance in an oncology subpopulation was documented, suggesting a need for susceptibility testing in patients who are at high risk for development of drug-resistant fungal pathogens.
226 citations
TL;DR: Several changes accompanied the development of resistance: the relative affinity to penicillin of whole cells, isolated membranes, and two major PBPs after in vivo or in vitro labeling decreased, and one additional PBP appeared in four of five relatively resistant strains with an MIC of 0.25 microgram/ml and higher.
Abstract: Penicillin-binding properties and characteristics of penicillin-binding proteins (PBPs) were investigated in several clinical isolates of Streptococcus pneumoniae differing in their susceptibilities to penicillin (minimal inhibitory concentration [MIC], 0.03 to 0.5 microgram/ml) and compared with the penicillin-susceptible strain R36A (MIC, 0.07 microgram/ml). Several changes accompanied the development of resistance: the relative affinity to penicillin of whole cells, isolated membranes, and two major PBPs after in vivo or in vitro labeling decreased (with increasing resistance). Furthermore, one additional PBP (2') appeared in four of five relatively resistant strains with an MIC of 0.25 microgram/ml and higher. PBP 3 maintained the same high affinity toward penicillin in all strains under all labeling conditions.
221 citations
TL;DR: Most nalidixic acid-resistant bacteria were susceptible to AM-715, and cross-resistance was not observed between AM-6fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Abstract: AM-715 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid] is a new nalidixic acid analog. AM-715 has a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria. The antibacterial activity of AM-715 was greater than those of pipemidic acid and nalidixic acid. AM-715 had higher antibacterial activity against Pseudomonas aeruginosa than did gentamicin. Most nalidixic acid-resistant bacteria were susceptible to AM-715, and cross-resistance was not observed between AM-715 and various antibiotics. The minimal concentration of AM-715 required to inhibit the growth of 75% of the total number of clinical isolates was as follows: Escherichia coli, 0.04 mug/ml; Klebsiella pneumoniae, 0.1 mug/ml; Serratia marcescens, 0.88 mug/ml; Enterobacter spp., 0.076 mug/ml; Staphylococcus aureus, 1.10 mug/ml; P. aeruginosa, 0.38 mug/ml; and nalidixic acid-resistant strains of gram-negative bacteria, 0.62 mug/ml. AM-715 at minimal inhibitory concentrations or at slightly higher concentrations had bactericidal activity against various species of bacteria. The effect of inoculum sizes on minimal inhibitory concentrations and minimal bactericidal concentrations of AM-715 against gram-negative bacteria was smaller than on those of pipemidic acid and nalidixic acid. The dose-response curve of AM-715 indicated a steep gradient, and the 50% inhibited doses of AM-715 were 0.014 mug/ml against E. coli ML4707 and 0.21 mug/ml against P. aeruginosa NC-5.
203 citations
TL;DR: 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.
Abstract: 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.
202 citations
TL;DR: MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.
Abstract: The practical application of thienamycin, a novel beta-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most beta-lactam antibiotics, such as Pseudomonas aeurginosa, Serratis, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal activity usually occurs at the minimal inhibitory concentration endpoint. Activity was reduced only at the highest inoculum densities tested and by a lessor factor than was observed with reference beta-lactam antibiotic active against P. aeruginosa and beta-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.
201 citations
TL;DR: GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most beta-lactamases, and produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine.
Abstract: GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most beta-lactamases. Its in vitro activities were of the same order as those of cefotaxime against most gram-negative bacteria, were clearly inferior to cefotaxime against Staphylococcus aureus, but were significantly more active against Pseudomonas aeruginosa. Against the 25 strains used, GR 20263 was significantly more active than any of the other agents tested: piperacillin, azlocillin, gentamicin, amikacin, and carbenicillin. GR 20263 protected mice against experimental infections with P. aeruginosa more effectively than other beta-lactam antibiotics; its general effectiveness in this test was comparable with gentamicin. Studies on human volunteers showed that it produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine. Intramuscular and intravenous injections were well tolerated by the volunteers, and there were no untoward side effects.
TL;DR: Among the tested cephalosporins, cephamycin derivatives such as cefoxitin, cefmetazole, and YM09330 had high inducer activity even at low drug concentrations, while cefoperazone,cefsulodin, piperacillin, and apalcillin showed low inducers activity when compared with the other cep Halosporin derivatives.
Abstract: 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.
TL;DR: The penicilllin-binding proteins of several gram-positive and gram-negative bacteria have been examined and it is indicated that there is a wide variation in both the number and the amount of PBPs in different bacteria, and taxonomically related bacteria tend to have similar PBP patterns.
Abstract: The penicilllin-binding proteins (PBPs) of several gram-positive and gram-negative bacteria have been examined. The results indicate that: (i) PBPs are membrane proteins with molecular weights ranging from 40,000 to 120,000. When extracted with Triton X-100 from sonicated cells, they appear to fall into two patterns: one found in rods and the other in spheres. A major difference is in the low-molecular-weight component, which is usually the major PBP in bacilli but a minor one in cocci. (ii) There is a wide variation in both the number and the amount of PBPs in different bacteria, and taxonomically related bacteria tend to have similar PBP patterns. These patterns often correlate with the affinity of PBPs for penicillin and other beta-lactam antibiotics. (iii) The low-molecular-weight component usually releases penicillin spontaneously with a half-life of 10 min or less. Most, but not all, PBPs release bound penicillin in the presence of neutral hydroxylamine (0.2 to 0.8 M).
TL;DR: A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM; its antiviral activity was not reversed by deoxycytidine.
Abstract: A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM. Cytotoxicity was minimal, as determined by trypan blue dye exclusion with norman Vero, WI-38, and NC-37 cell proliferation; the 50% inhibitory dose was 4 to 10 microM in a 4-day assay. When compared with other antiviral drugs, FIAC was active at much lower concentrations than arabinosylcytosine, iododeoxyuridine, and arabinosyladenine. It was slightly more active against herpes simplex virus type 1 than acycloquanosine and slightly more toxic to normal cells. FIAC was about 8,000 times more active against the replication of wild-type herpes simplex virus type 1 than against a mutant strain lacking the expression of virus-specified thymidine kinase. Since FIAC appears to be preferentially phosphorylated by the viral enzyme, this is probably responsible, at least in part, for the selectivity of its antiviral actions. Although FIAC appears to be an arabinosylcytosine analog, its antiviral activity was not reversed by deoxycytidine. The minimal cytotoxicity exhibited by FIAC for normal cells, however, was reversed by equimolar concentrations of deoxycytidine. Thymidine, which reversed the antiviral activity, was effective only when used in great excess.
TL;DR: The construction of an isogenic set of transformants with increasing levels of penicillin resistance indicated that the penA gene was associated with a decrease inPenicillin binding fo PBP 2, and decreased binding to PBP 1 is likely to accompany the newly reported pem and tem genes, which govern to highest level of peniillin resistance.
Abstract: 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.
TL;DR: Two small, multicopy plasmids should prove useful as cloning vehicles in this host system due to readily available sites for several site-specific endonuycleases.
Abstract: 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.
TL;DR: It is suggested that the membrane energization associated with active aminoglycoside accumulation requires electron transport for the generation of a protonmotive force.
Abstract: Gentamicin uptake and killing were studied in aminoglycoside-susceptible wild-type Staphylococcus aureus strains and aminoglycoside-resistant small-colony mutants selected by gentamicin from these strains. In wild-type S. aureus three phases of gentamicin accumulation were noted, and killing occurred during the last and most rapid phase of uptake. Uptake and killing were abolished by anaerobic growth and sodium azide, suggesting that energy-dependent active drug transport required respiration. Treatment of wild-type strains with the uncouplers N,N'-dicyclohexyl carbodiimide (DCCD) and carbonyl cyanide-m-chlorophenyl hydrazone showed disparate effects on gentamicin uptake, producing enhanced and diminished accumulations, respectively. Small-colony mutants demonstrated markedly deficient uptake compared with the wild-type strains and were not killed by gentamicin in concentrations up to 10 mug/ml. Several classes of aminoglycoside-resistant mutant strains are described. One mutant strain was a menadione auxotroph which, when grown in the presence of menadione, exhibited normal gentamicin uptake and killing. Gentamicin uptake and killing in this strain were abolished by KCN when the strain was grown in a medium supplemented with menadione. The membrane adenosine triphosphatase inhibitor DCCD was lethal for this mutant but not for other mutants or wild-type strains. Preincubation with menadione prevented the lethal effect of DCCD, and this strain demonstrated normal gentamicin accumulation when exposed to both DCCD and menadione. A second mutant strain demonstrated both gentamicin uptake and killing in the presence but not the absence of DCCD. Studies with small-colony mutants of S. aureus indicated that the defect in aminoglycoside uptake is very likely related to an inability to generate or maintain energized membranes from respiration. These studies suggest that the membrane energization associated with active aminoglycoside accumulation requires electron transport for the generation of a protonmotive force.
TL;DR: In vitro activity of a new crystalline derivative of thienamycin, N-formimidoyl thien amycin (MK0787), was tested against 46 laboratory reference strains and 2,158 clinical isolates of gram-positive and -negative bacteria, including anaerobes, and compared with cefoxitin, cefaxolin, carbenicillin, and amikacin.
Abstract: The in vitro activity of a new crystalline derivative of thienamycin, N-formimidoyl thienamycin (MK0787), was tested against 46 laboratory reference strains and 2,158 clinical isolates of gram-positive and -negative bacteria, including anaerobes, and compared with cefoxitin, cefaxolin, carbenicillin, and amikacin. MK0787 was significantly more active than the reference antibiotics against most bacteria tests. MK0787 was 16- to 500-fold more active than the other antibiotics against Staphylococcus aureus, Streptococcus pneumoniae, and group A and group B streptococci, inhibiting most isolates at concentrations less than 0.031 micrograms/ml. The inhibition concentration against over 90% of 156 strains of Streptococcus faecalis was 1 micrograms/ml. MK0787 had slightly less activity than carbenicillin against Haemophilus influenzae. The minimal inhibitory concentrations of MK0787 against strains of Enterobacter spp., Citrobacter spp., Serratia marcescems. Pseudomonas aeruginosa, and Clostridium difficile that are resistant to currently available antibiotics were less than or equal to 4 micrograms/ml. The only species found resistant to MK0787 was Pseudomonas maltophilia, which was equally nonsusceptible to the other reference antibiotics.
TL;DR: A 79-year-old female developed endocarditis and meningitis due to an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae, which resulted in bacteriological and clinical cure.
Abstract: A 79-year-old female developed endocarditis and meningitis due to an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae. Carbenicillin and gentamicin therapy resulted in bacteriological and clinical cure. The mechanism of resistance of ampicillin-resistant, non-beta-lactamase-producing strains of H. influenzae is unknown.
TL;DR: The binding of 14 structurally diverse beta-lactam antibiotics to penicillin-binding proteins of Staphylococcus aureus and Streptococcus faecalis was studied, and the results were examined in the context of the antibacterial activity of the compounds.
Abstract: The binding of 14 structurally diverse beta-lactam antibiotics to penicillin-binding proteins of Staphylococcus aureus and Streptococcus faecalis was studied, and the results were examined in the context of the antibacterial activity of the compounds. Penicillin-binding proteins 1 (molecular weight, 87,000) and 3 (molecular weight, 75,000) of S. aureus and penicillin-binding proteins 1 (molecular weight, 105,000) and 3 (molecular weight, 79,000) of S. faecalis bound beta-lactam antibiotics at concentrations comparable to minimum inhibitory concentrations and might therefore be essential. The low affinity of S. faecalis penicillin-binding proteins, relative to that of S. aureus penicillin-binding proteins, toward most beta-lactam antibiotics is probably responsible for the resistance of the former organism to most of these compounds.
TL;DR: Recent Chlamydia trachomatis isolates tested in a tissue culture system for susceptibility to tetracycline, erythromycin, rosaramicin, rifampin, and clindamycin were found to be susceptible to these drugs.
Abstract: 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.
TL;DR: The pharmacokinetics of the new cephalosporin Ro-13-9904 were studied in six healthy male volunteers receiving a 500-mg dose as a bolus intravenously and the mean elimination half-life was considerably longer than that of other beta-lactam compounds.
Abstract: The pharmacokinetics of the new cephalosporin Ro-13-9904 were studied in six healthy male volunteers receiving a 500-mg dose as a bolus intravenously. Tissue penetration of the antibiotic was estimated by using a cantharides blister method. The data obtained fitted a two-compartment open model. The mean elimination half-life was about 8 h, which is considerably longer than that of other beta-lactam compounds. The distribution volume was 4.3 liters in the central compartment. Levels of Ro 13-9904 in blister fluid exceeded those in serum after 6.5 h. Approximately 60% of the antibiotic was excreted in the urine.
TL;DR: Two hundred twenty-four isolates of Bacteroides sp.
Abstract: 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.
TL;DR: Differences in chemical structure were shown to cause major and selective changes in the affinities of the beta-lactams for the PBPs Only 4 of the 28 compounds tested induced a specific morphological effect (enlargement of the equatorial region) under the particular conditions tested.
Abstract: The interactions of several beta-lactam antibiotics with the penicillin-binding proteins (PBPs) of Streptococcus pneumoniae have been studied using whole organisms treated with such antibiotics and subsequently with [3H]benzylpenicillin. Differences in chemical structure were shown to cause major and selective changes in the affinities of the beta-lactams for the PBPs Only 4 of the 28 compounds tested induced a specific morphological effect (enlargement of the equatorial region) under the particular conditions tested. In 12 of the 18 beta-lactams studied, a close correlation was found between the minimal inhibitory concentrations and the concentrations required to half-saturate PBP2b. However, such a correlation was no longer apparent when the bacteria were treated with the antibiotics at their minimal inhibitory concentrations. These findings are discussed in the context of various approaches that have been used to identify the growth-inhibitory targets of beta-lactam antibiotics in bacteria.
TL;DR: Computer surveillance of routine hospital laboratory results was able to detect and trace the gene and the plasmid and measure their effect on resistance prevalence and found that this 56.5-megadalton plasmids of incompatibility group M carried three other resistance genes.
Abstract: The 2'' aminoglycoside nucleotidyltransferase, AAD (2''), which adenylates gentamicin, tobramycin, and kanamycin, became prevalent over several months in multiple strains and species of Enterobacteriaceae isolated at one hospital. Eight plasmids with the gene for this enzyme purified from different strains and species isolated at different times had similar EcoRI digestion fragments, indicating that the gene had disseminated on one plasmid without transposition. This 56.5-megadalton plasmid of incompatibility group M, which also carried three other resistance genes, spread, at first, largely in one strain of Klebsiella pneumoniae, which later disappeared. It transferred to some strains which tended not to colonize other patients and later circulated predominantly in Serratia marcescens. Computer surveillance of routine hospital laboratory results was able to detect and trace the gene and the plasmid and measure their effect on resistance prevalence.
TL;DR: Staphylococcus epidermidis isolates containing subpopulations resistant to 100 microgram of methicillin per ml were found on the chests of only 3 of 80 patients before cardiac surgery, whereas these highly resistant staphylitis isolates were isolated from the chest wounds of 43 of80 patients 5 days postoperatively.
Abstract: Staphylococcus epidermidis isolates containing subpopulations resistant to 100 microgram of methicillin per ml were found on the chests of only 3 of 80 (4%) patients before cardiac surgery, whereas these highly resistant staphylococci were isolated from the chest wounds of 43 of 80 (54%) patients 5 days postoperatively. The percentage of patients colonized with methicillin-resistant S. epidermidis increased with time postoperatively. Methicillin-resistant postoperative isolates also contained organisms resistant to other antibiotics frequently used during these patients' hospitalizations. The percentages of patients with organisms resistant to various antibiotics were: nafcillin (100%), penicillin (100%), cephalothin (93%), cefamandole (80%), streptomycin (67%), and gentamicin (20%). Preoperative methicillin-susceptible isolates were generally susceptible to other antibiotics. Two patients with S. epidermidis prosthetic valve endocariditis caused by multiple antibiotic-resistant isolates were among the study patients. Antibiotic susceptibility patterns of each isolate from these two patients were identical to those of postoperative chest isolates from the same patient.
TL;DR: Intraperitoneal administration of drug begun 72 h after inoculation in regimens equivalent to aerosol afforded less protection than aerosol treatment, and the combination treatment reflected the loss of ribavirin activity.
Abstract: Ribavirin, amantadine, and the two drugs in combination given in small-particle aerosol were highly effective in the treatment of influenza A infection in mice. Treatment was started 72, 96, and 120 h after inoculation and was given continuously for 4 days. With increasing delay in start of treatment, there was a pronounced reduction in effectiveness of ribavirin but not in that of amantadine. The combination treatment reflected the loss of ribavirin activity. Leukocyte infiltration and virus titers in the lungs were inversely related to the effectiveness of treatment. Influenza B infection treated 72 h after inoculation responded only to ribavirin, as indicated by the criteria described for influenza A. Intraperitoneal administration of drug begun 72 h after inoculation in regimens equivalent to aerosol afforded less protection than aerosol treatment.
TL;DR: In vitro susceptibility tests were performed on 84 strains of Clostridium difficile to 11 antimicrobial agents, showing that a major portion of the strains were relatively susceptible to the antimicrobial agent implicated in causing the disease.
Abstract: In vitro susceptibility tests were performed on 84 strains of Clostridium difficile to 11 antimicrobial agents. All isolates were from the stools of patients with antibiotic-associated diarrhea or colitis in which there was a cytopathic toxin that was neutralized by Clostridium sordellii antitoxin. Over 95% of the strains were susceptible to vancomycin, penicillin G, ampicillin, and metronidazole at concentrations of 4 microgram/ml. Susceptibility to clindamycin was variable; 60% of the strains were susceptible at 1 microgram/ml, and 9% were resistant at 128 microgram/ml. Studies of individual isolates showed that a major portion of the strains were relatively susceptible to the antimicrobial agent implicated in causing the disease.
TL;DR: Poor antibacterial activity was shown toward the gram-negative bacilli, i.e., Pseudomonas, Klebsiella-Enterobacter, Shigella, Escherichia coli, and Proteus.
Abstract: Antibacterial activity of 65 2-acetylpyridine thiosemicarbazones and related compounds was determined by using clinical isolates of nine bacterial genera. Minimal inhibitory concentrations (MICs) of 0.002 to 0.062 micrograms/ml were obtained with 23% of the compounds for Neisseria gonorrhoeae and 0.016 to 0.062 micrograms/ml with 17% of the compounds for N. meningitidis. Staphylococcus aureus was inhibited in the MIC range of 0.125 to 0.5 micrograms/ml by 18% of the thiosemicarbazones, whereas 26% inhibited group D enterococcus with an MIC of 0.25 to 2.0 micrograms/ml. Poor antibacterial activity was shown toward the gram-negative bacilli, i.e., Pseudomonas, Klebsiella-Enterobacter, Shigella, Escherichia coli, and Proteus.
TL;DR: Experiments clearly demonstrated an easy access of beta-lactam antibiotics to these proteins in the mutant and an efficient exclusion from the same targets in the wild type.
Abstract: Pseudomonas aeruginosa K 799/WT and a mutant of this strain, P. aeruginosa K 799/61 ("mutant 61"), that is very sensitive to most beta-lactam antibiotics tested were used to assess the importance of penetration barriers in the resistance of P. aeruginosa to penicillins and cephalosporins. The affinities of various beta-lactams to the penicillin-binding proteins found in membranes prepared from both strains were compared by measuring their competition for the binding of benzyl[14C] penicillin to each of these proteins. Only minor differences between the wild type and the mutant 61 were found. The high sensitivity of the mutant therefore cannot be attributed to drastic alterations of these target proteins, nor can the resistance of the wild type be ascribed to penicillin-binding proteins with low affinities for beta-lactams. Experiments in which the ease of penetration of beta-lactams into the penicillin-binding proteins was measured with exponentially growing intact cells instead of membranes, however, clearly demonstrated an easy access of beta-lactam antibiotics to these proteins in the mutant and an efficient exclusion from the same targets in the wild type.