bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of action of cinodine, a glycocinnamoylspermidine antibiotic
Authors: Greenstein M , Speth J L , Maiese W M
Published: June 2012

The mechanism of action of cinodine, a glycocinnamoylspermidine antibiotic, was investigated. Upon addition of cinodine to growing cultures of Escherichia coli, a rapid decline in viable cell numbers was observed. Culture turbidity continued to increase for a short period before plateauing. Microscopic examination indicated that the antibiotic-treated cells continued to elongate with subsequent formation of serpentine-like structures. Radioisotopic-labeling studies of E. coli demonstrated that deoxyribonucleic acid (DNA) synthesis was immediately and irreversibly inhibited upon addition of cinodine. Ribonucleic acid synthesis was reduced after a significant delay, whereas protein synthesis remained unaffected. There was a minor degree of inhibition of incorporation of radiolabeled diaminopimelic acid into cell wall material. Cinodine likewise inhibited bacteriophage T7 DNA synthesis in infected E. coli cells. After inhibition of E. coli DNA synthesis by cinodine, intracellular DNA degradation was observed. Equilibrium dialysis studies demonstrated that the drug physically bound to DNA. These data indicate that cinodine functions as a potent irreversible inhibitor of bacterial and phage DNA synthesis.
Lack of Interference of Guanosine with Ribavirin Aerosol Treatment of Influenza A Infection in Mice
Authors: Knight Vernon , Wilson Samuel Z. , Alling David W. , Moore Rebecca V. , Longoria Rose M.
Published: June 2012

Guanosine or guanosine 5′-monophosphate did not reduce the protective effect of ribavirin aerosol in influenza virus A/Aichi/68 H3N2 infection of mice. Both compounds partially interfered with the action of a wide range of ribavirin concentrations against influenza virus A/WSN replication in cell culture.
Failure of probenecid to alter the pharmacokinetics of ceforanide
Authors: Jovanovich J F , Saravolatz L D , Burch K , Pohlod D J
Published: June 2012

This investigation evaluated the effect of probenecid on ceforanide concentrations in eight healthy volunteers. Each volunteer was given 1 or 2 g of ceforanide either alone or with 1 g of probenecid. Concentrations of ceforanide in plasma, urine, and saliva were then measured. Probenecid did not alter the plasma concentrations of ceforanide, nor did it affect the urinary excretion of this agent. Ceforanide was not secreted into saliva in any detectable amount either when administered alone or with probenecid. It is not clear why probenecid has a negligible effect on ceforanide concentrations in plasma. It may be that tubular secretion plays less of a role in the excretion of ceforanide than expected, or that the physical properties of ceforanide prevent probenecid from affecting its excretion.
Serum Bactericidal Activity of Moxalactam and Cefotaxime With and Without Tobramycin Against
Pseudomonas aeruginosa
and
Staphylococcus aureus
Authors: Lagast H. , Zinner S. H. , Klastersky J.
Published: June 2012

Serum bactericidal activity was determined against 10 strains each of
Pseudomonas aeruginosa
and
Staphylococcus aureus
in serum from volunteers 1 and 6 h after intravenous infusion of cefotaxime, tobramycin, and the combination; or of moxalactam, tobramycin, and the combination. High serum bactericidal activity against
P. aeruginosa
was found significantly more frequently with moxalactam plus tobramycin than with cefotaxime, moxalactam, and tobramycin alone or with cefotaxime plus tobramycin.
Effects of Adenosine Monophosphate on the Reactivation of Latent Herpes Simplex Virus Type 1 Infections of Mice
Authors: Blue William T. , Winland Roger D. , Stobbs Darlene G. , Kirksey Donny F. , Savage Russell E.
Published: June 2012

Adenosine monophosphate pretreatment of mice with latent herpes simplex virus type 1 infections significantly reduced the rate of reactivation of latent virus. Adenosine monophosphate pretreatment did not, however, eradicate latent virus.
Mode of antibiotic action of 4-hydroxy-3-nitrosobenzaldehyde from Streptomyces viridans
Authors: Yang C C , Leong J
Published: June 2012

The free ligand, deferroviridomycin A, and its iron(II) complex, viridomycin A, were detected in culture supernatant fluids of Streptomyces viridans 1671 and were structurally characterized as 4-hydroxy-3-nitrosobenzaldehyde and tris(4-hydroxy-3-nitrosobenzaldehydato-N3,O4)ferrate(II), respectively. We investigated the antibiotic activity of the above compounds and of the chemically synthesized bis copper(II), tris cobalt(III), and tris nickel(II) complexes against Escherichia coli NIHJ, Salmonella typhimurium LT-2Z, Staphylococcus aureus 209P, Streptococcus faecium 10541, and Bacillus cereus, T. The free ligand and its kinetically labile copper(II) and nickel(II) complexes displayed activity against all of the above organisms, whereas the kinetically inert iron(II) and cobalt(III) complexes displayed activity only against S. aureus and B. cereus. The antibiotic activity of the substitutionally labile metal complexes was attributed to dissociation of the free ligand. The mode of antibiotic action of the free ligand against E. coli appears to be interference with the structural and functional integrity of the cell membrane.
Cefazolin and moxalactam pharmacokinetics after simultaneous intravenous infusion
Authors: Polk R E , Kline B J , Markowitz S M
Published: June 2012

A high-performance liquid chromatographic method for the measurement of moxalactam concentrations in serum was modified to permit the simultaneous measurement of both moxalactam and cefazolin. We then studied whether the simultaneous administration of both moxalactam and cefazolin to normal subjects would produce profiles of serum concentration versus time which were the same as those obtained after the administration of each drug individually. Six healthy adults received a 30-min infusion of cefazolin (10 mg/kg), followed in 2 days by the same dose of moxalactam. After 2 days, both antibiotics were administered together. A two-compartment model was found to adequately characterize the data, and the serum concentration curve for each drug when given alone was statistically identical to that obtained after simultaneous administration. Cefazolin was found to produce a significantly greater peak serum concentration (105 +/- 14 versus 81 +/- 21 microgram/ml) and a significantly greater area under the curve (218 +/- 42 versus 157 +/- 19 . microgram h/ml). The terminal half-life of moxalactam was not significantly longer than for cefazolin (2.2 +/- 0.6 versus 2.0 +/- 0.6 h, respectively). The method of simultaneous administration may have distinct advantages over conventional methods for studies of comparative tissue penetration.
Influence of age on tobramycin pharmacokinetics in patients with normal renal function
Authors: Bauer L A , Blouin R A
Published: June 2012

The influence of age on tobramycin half-life, volume of distribution, and clearance was examined in 77 patients with infections due to gram-negative bacteria. All patients had normal renal function and hematocrits, were within 20% of their ideal body weight, did not receive penicillin antibiotics concurrently, and had a fever. Twenty-five patients were between 20 and 39 years of age, 23 patients were 40 to 59 years old, and 29 patients were in the age group 60 to 79 years. The mean half-lives were 2.3, 2.2, and 2.4 h, respectively, for the three age groupings. The average clearance and volume of distribution terms were, respectively, 1.34 ml/min per kg and 0.25 liter/kg for the younger group, 1.44 ml/min per kg and 0.26 liter/kg for the middle age group, and 1.25 ml/min per kg and 0.25 liter/kg for the older group. There was no significant difference among the three groups for any of the parameters (P less than 0.05, analysis of variance). Correlation coefficients determined from individual plots of the three pharmacokinetic parameters versus age revealed no correlation between any parameter and age. Forty-five percent of the patients required doses greater than the recommended maximum (5 mg/kg per day) to achieve desired steady-state concentrations. Since tobramycin pharmacokinetics do not change as age increased, doses do not need to be arbitrarily changed in older patients with normal renal function.
Comparative In Vitro Activity of New Beta-Lactam Antibiotics Against Anaerobic Bacteria
Authors: Rolfe Rial D. , Finegold Sydney M.
Published: June 2012

Several new beta-lactam antimicrobial agents have been introduced in the last few years. In this investigation, the in vitro activities of several recently introduced cephalosporins (cefoperazone, cefotaxime, ceftazidime, and ceftizoxime), moxalactam, and
N
-formimidoyl thienamycin were compared with those of cefoxitin, clindamycin, and metronidazole against 203 strains of anaerobic bacteria. At achievable serum levels, all of the antimicrobial agents were active against essentially 100% of the strains of anaerobic gram-positive cocci,
Clostridium perfringens, Leptotrichia buccalis
, and species of
Selenomonas, Veillonella
, and
Eubacterium
. Clindamycin, metronidazole, and
N
-formimidoyl thienamycin were the most active agents against the
Bacteroides fragilis
group, inhibiting all strains at concentrations which can be achieved in serum. Of the remaining agents tested against the
B. fragilis
group, cefoxitin (which required 64 μg/ml to inhibit 90% of the strains) was the most active, followed by cefoperazone (128 μg/ml), cefotaxime (128 μg/ml), moxalactam (128 μg/ml), ceftizoxime (256 μg/ml), and ceftazidime (>256 μg/ml). Important differences in cephalosporin susceptibility among species of the
B. fragilis
group were observed. Metronidazole and
N
-formimidoyl thienamycin were the most active drugs against species of clostridia other than
C. perfringens
; the other antibiotics displayed poor activity, although this is partly due to inclusion of a relatively large number of strains of
Clostridium difficile
which were very resistant to several of the cephalosporins. Only metronidazole was active against all species of
Fusobacterium
. Clindamycin and
N
-formimidoyl thienamycin displayed excellent activity against gram-positive, non-spore-forming bacilli, requiring ≤8 μg/ml to inhibit 100% of the strains. Ceftazidime, cefoperazone, and moxalactam were bactericidal for 25 strains of
B. fragilis
at concentrations equal or close to those required for inhibition. On the basis of its activity in vitro,
N
-formimidoyl thienamycin appears to be the most promising of the new beta-lactam antibiotics for the treatment of infections involving anaerobic bacteria.
Susceptibility of zygomycetes to amphotericin B, miconazole, and ketoconazole
Authors: Eng R H , Person A , Mangura C , Chmel H , Corrado M
Published: June 2012

Susceptibility to amphotericin B, miconazole, and ketoconazole was determined for 25 clinical isolates of zygomycetes in yeast nitrogen base broth and human serum. In yeast nitrogen base broth, 7 of 25 isolates were susceptible to an imidazole or amphotericin B. In serum, all were resistant to the imidazoles and inhibited by amphotericin B, the current drug of choice for infections caused by zygomycetes.
Characteristics of rifampin-resistant variants obtained from clinical isolates of Staphylococcus aureus
Authors: Moorman D R , Mandell G L
Published: June 2012

Twenty clinical isolates of Staphylococcus aureus were examined to determine the frequency of rifampin-resistant variants. All isolates were highly susceptible to rifampin, with mean minimum inhibitory concentrations of 0.11 +/- 0.1 microgram/ml and mean minimum bactericidal concentrations of 0.22 +/- 0.2 microgram/ml. The frequency of isolation of resistant variants was similar to all rifampin concentrations tested. Rifampin-resistant variants maintained their resistance upon daily subculture in rifampin-free broth. Rifampin-susceptible S. aureus exhibited a growth and survival advantage over the rifampin-resistant mutants both in pure cultures and in mixtures with rifampin-resistant antecedents. A comparison of the virulence for mice of five susceptible isolates and their 100 microgram/ml-rifampin-resistant variants showed that two of the resistant variants were less virulent than the susceptible strains via intraperitoneal challenge, whereas three of the resistant variants were less virulent by intravenous challenge (P less than 0.05).
Comparison of vancomycin disposition in rats with normal and abnormal renal functions
Authors: Engineer M S , Ho D H , Bodey G P
Published: June 2012

Vancomycin levels in the tissues and urine of rats with renal damage were compared with those of control rats. Renal damage was induced by a single intravenous injection of uranyl nitrate. After 5 days, when the plasma urea nitrogen levels had increased 7- to 22-fold, a single intraperitoneal vancomycin injection of 10 mg/kg yielded significantly higher plasma and tissue levels in these rats than in the control rats that did not receive uranyl nitrate. At 73 h after the vancomycin injection, the plasma vancomycin concentration in the rats with renal damage was 1.8 +/- 1.1 microgram/ml (mean +/- standard deviation), whereas in control rats the level had fallen to 0.004 +/- 0.002 microgram/ml. Control rats excreted 50.5% of a single dose in the urine within the 3 days, whereas rats with renal damage excreted only 35.6%. These results indicate that vancomycin pharmacokinetics is affected by renal function in rats. Therefore, the drug should be used very cautiously in patients with impaired renal function. The serum levels must be monitored, and the frequency and size of doses may have to be reduced.
Effects of amphotericin B on hepatitis B virus
Authors: Kessler H A , Dixon J , Howard C R , Tsiquaye K , Zuckerman A J
Published: June 2012

We investigated the effects of amphotericin B (AmB) on the ultrastructure and biochemistry of hepatitis B virus (HBV) and hepatitis B surface antigen (HBsAg) particles. These effects were compared with those reported for AmB and other polyene antibiotics on other lipid-enveloped viruses and artificial membranes. Treatment of HBV particles with concentrations of AmB ranging from 5 to 250 microgram/ml resulted in (i) an increase in HBV deoxyribonucleic acid polymerase activity as the concentration of Amb increased; (ii) changes in the electron microscopic appearance of HBV ranging from increased penetration of negative stain into the lipid envelope to disruption of the virus; and (iii) an increase in density form 1.165 to 1.225 g/ml. In addition, AmB treatment of HBsAg particles resulted in disruption into a nonparticulate HBsAg-reactive fraction and an HBsAg-AmB complex fraction with no HBsAg immunoreactivity.
Comparative activity of mezlocillin, penicillin, ampicillin, carbenicillin, and ticarcillin against gram-positive bacteria and Haemophilus influenzae
Authors: Sanders C C
Published: June 2012

The in vitro activity of mezlocillin was compared to penicillin G, ampicillin, carbenicillin, and ticarcillin in tests with 195 gram-positive bacteria and 20 Haemophilus influenzae. Against gram-positive isolates excluding enterococci, penicillin was the most active drug, followed by ampicillin, mezlocillin, carbenicillin, and ticarcillin. Ampicillin was the most active of the five drugs against enterococci, whereas mezlocillin was the most active drug against 14 strains of ampicillin-susceptible H. influenzae.
Cefotaxime Treatment of Pelvic Inflammatory Disease
Authors: Monson Thomas P. , Miller Timothy T. , Nolan Charles M.
Published: June 2012

We studied cefotaxime in the treatment of gonococcal and nongonococcal pelvic inflammatory disease. Cefotaxime was uniformly effective against gonococcal pelvic inflammatory disease. However, 4 of 11 patients with nongonococcal pelvic inflammatory disease had a suboptimal response.
In vitro susceptibility of Campylobacter fetus subsp. jejuni to N-formimidoyl thienamycin, rosaramicin, cefoperazone, and other antimicrobial agents
Authors: Ahonkhai V I , Cherubin C E , Sierra M F , Bokkenheuser V D , Shulman M A , Mosenthal A C
Published: June 2012

The activities of 11 antimicrobial agents against 36 strains of Campylobacter fetus subsp. jejuni were studied by a broth microdilution method. All strains were susceptible to 7 of the 11 antimicrobial agents. Of the newer agents tested N-formimidoyl thienamycin (MK0787) and rosaramicin had very good activity, whereas cefotaxime, moxalactam, and cefoperazone had poorer activity.
Comparison of radioimmunoassay with a new immunofluorescent method (FIAX) for measuring tobramycin in serum
Authors: Bruckner D A , Hindler J A , Martin W J , Palmer R
Published: June 2012

A new immunofluorescent method (FIAX) was compared with a radioimmunoassay procedure for the determination of tobramycin serum concentrations. When assaying three tobramycin control sera repeatedly, within-run and run-to-run variations by the FIAX method were all within acceptable limits, and no statistically significant differences were found. Results of 155 sera from patients who had been treated with tobramycin showed a correlation coefficient of 0.93 between the two methods. The FIAX method represents another practical alternative for determining tobramycin serum levels.
Clinical efficacy of cefotaxime in serious infections
Authors: Karakusis P H , Feczko J M , Goodman L J , Hanlon D M , Harris A A , Levin S , Trenholme G M
Published: June 2012

Thirty-five patients underwent 38 treatment courses with cefotaxime. Documented infections included 11 bacteremias, 7 cases of nosocomial pneumonia, 6 surgical wound infections, 3 bone infections, 1 biliary infection, and 1 urinary tract infection. Granulocytopenic patients with fever received 15 courses of empiric cefotaxime therapy alone; in 8 courses, no definite site of infection or pathogen was isolated. Broad-spectrum antibiotics had been administered to 23 patients before cefotaxime. Thirty-seven bacterial pathogens were isolated from 25 patients. Three such pathogens were resistant to cefotaxime and required alternative therapies. Pathogenic isolates included 13 Serratia marcescens, 12 Pseudomonas aeruginosa, 4 Escherichia coli, 2 Klebsiella pneumoniae, 2 Providencia stuartii, 1 Enterobacter cloacae, 1 Haemophilus influenzae, 1 Enterococcus, and 1 Staphylococcus aureus. Of the treatment courses, 25 of 38 resulted in a favorable response to cefotaxime, including 9 of 15 in granulocytopenic patients. Superinfection was seen in one patient. The emergence of resistance was documented in another patient. Of 15 patients with multiply resistant pathogens, 12 improved with cefotaxime. Of 12 patients with Pseudomonas aeruginosa, 6 favorably responded. Possible complications of cefotaxime were observed in 14 of 42 treatment courses. Cefotaxime is most useful in treatment of infections due to multiply resistant, gram-negative pathogens other than Pseudomonas aeruginosa.
Temperature Effect on the Susceptibility of Methicillin-Resistant
Staphylococcus aureus
to Four Different Cephalosporins
Authors: Canawati Hanna N. , Witte Joyce L. , Sapico Francisco L.
Published: June 2012

Forty isolates of methicillin-resistant
Staphylococcus aureus
were tested for in vitro susceptibility to cephalothin, cefamandole, cefotaxime, and moxalactam, using the disk diffusion and microbroth dilution methods at incubation temperatures of 30 and 35°C. Resistance to all four antibiotics was more clearly evident at an incubation temperature of 30°C.
High-level aminoglycoside resistance in group A, B, G, D (Streptococcus bovis), and viridans streptococci
Authors: Horodniceanu T , Buu-Hoï A , Delbos F , Bieth G
Published: June 2012

Of 20 clinical isolates of group A, B, G, D (Streptococcus bovis), and viridans streptococci, 5 transferred their antibiotic resistance markers into streptococcal recipients at a low frequency (10(-4) to 10(-8)) in the apparent absence of extrachromosomal elements. All strains carried genetic markers for high-level resistance to streptomycin, kanamycin, neomycin, lividomycin A, and ribostamycin, as well as resistance to macrolides and related drugs, tetracycline, and chloramphenicol.
Potential Liabilities of Gentamicin Homogeneous Enzyme Immunoassay
Authors: Carlson Larry G. , Delaney Collene J. , Plorde James J.
Published: June 2012

We report two potential liabilities of the homogeneous enzyme immunoassay for the determination of serum gentamicin. One is a considerable loss of precision and accuracy at the ends of the calibration curve, and the other is an apparent loss of gentamicin with storage at −60°C.
In vitro susceptibility of varicella-zoster virus to E-5-(2-bromovinyl)-2'-deoxyuridine and related compounds
Authors: De Clercq E , Descamps J , Ogata M , Shigeta S
Published: June 2012

The in vitro susceptibility of eight strains of varicella-zoster virus (VZV) to E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was examined in human embryonic fibroblasts by the following techniques: inhibition of focus formation by either cell-free VZV (4-day assay) or cell-associated VZV (2-day assay), inhibition of viral antigen formation (2-day assay), and inhibition of viral cytopathogenicity (15-day assay). The 50% inhibitory dose (ID50) of BVDU ranged from 0.001 microgram/ml (2-day assay) to 0.01 microgram/ml (15-day assay). BVDU appeared highly selective in its anti-VZV activity since even at concentrations as high as 100 micrograms/ml, BVDU did not markedly affect the viability of the host cells. The ID50 of BVDU for VZV was comparable to that of IVDU (E-5-(2-iodovinyl)-2'-deoxyuridine). Both drugs inhibited the replication of VZV at a much lower concentration than did other antiviral compounds such as iododeoxyuridine, ethyldeoxyuridine, arabinosylcytosine, arabinosyladenine, phosphonoacetic acid, iododeoxycytidine, and acycloguanosine. BVDU and IVDU were virtually inactive against a thymidine kinase-deficient VZV mutant, suggesting that phosphorylation by the viral enzyme is responsible, at least in part, for the selective anti-VZV activity of the compounds.
Effect of clindamycin, erythromycin, lincomycin, and tetracycline on growth and extracellular lipase production by propionibacteria in vitro
Authors: Unkles S E , Gemmell C G
Published: June 2012

Two propionibacteria identified as Propionibacterium acnes and Propionibacterium granulosum were grown anaerobically in the presence of growth subinhibitory concentrations (0.25 and 0.5 minimal inhibitory concentrations) of clindamycin, erythromycin, lincomycin, and tetracycline. Viable counts and assays of extracellular lipase were performed on samples taken at 24-h intervals over a 96-h period. The results showed that lincomycin and clindamycin could inhibit the production of the enzyme by both strains with little effect on their growth rates. Tetracycline caused inhibition of lipase production by P. granulosum only. Although production of the enzyme by P. acnes was delayed in the presence of tetracycline, the final titer was the same as the control. Erythromycin had little effect on growth and enzyme production of either strain. It is possible, therefore, that certain antibiotics used in acne therapy may act not only as bactericidal agents but also as inhibitors of enzyme production under non-growth-limiting conditions.
Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers
Authors: Barriere S L , Gambertoglio J G , Lin E T , Conte J E
Published: June 2012

The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 micrograms/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 ml/min per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 micrograms/ml. Dose of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.
Regulation of cephamycin C synthesis, aspartokinase, dihydrodipicolinic acid synthetase, and homoserine dehydrogenase by aspartic acid family amino acids in Streptomyces clavuligerus
Authors: Mendelovitz S , Aharonowitz Y
Published: June 2012

The effect of the cephalosporin precursors and amino acids of the aspartic acid family on antibiotic production by Streptomyces clavuligerus was investigated DL-meso-Diaminopimelate and L-lysine each stimulated specific antibiotic production by 75%. A fourfold increase in specific production was obtained by simultaneous addition of the two compounds. The stimulation could be further increased by adding valine to the two effectors. In the streptomycetes the alpha-aminoadipyl side chain of the cephalosporin antibiotics is derived from lysine. Streptomycetes, like other bacteria, are expected to produce lysine from aspartic acid; therefore, the feedback control mechanisms operating in the aspartic acid family pathway of S. clavuligerus, which may affect the flow of carbon to alpha-aminoadipic acid, were investigated. Threonine inhibited antibiotic production by 41% when added to minimal medium at a concentration of 10 mM. Simultaneous addition of 10 mM lysine completely reversed this inhibition. The aspartokinase of S. clavuligerus was found to be subject to concerted feedback inhibition by threonine and lysine. Threonine may act to limit the supply of lysine available for cephamycin C biosynthesis via this concerted mechanism. Single or simultaneous addition of any other amino acid of the aspartate family in the in vitro assay did not inhibit aspartokinase activity. Activity was stimulated by lysine. Aspartokinase biosynthesis was partially repressed by methionine or isoleucine at concentrations higher than 10 mM. Methionine, but not isoleucine, inhibited cephamycin C synthesis by 27% when added to minimal medium at a concentration of 10 mM. Dihydrodipicolinate synthetase, the first specific enzyme of the lysine branch, was not inhibited by lysine but was partially inhibited by high concentrations of 2,6-diaminopimelate and alpha-aminoadipate; it was slightly repressed by diaminopimelic acid. Homoserine dehydrogenase activity was inhibited by threonine and partially repressed by isoleucine. It appears that S. clavuligerus aspartokinase is a key step in the control of carbon flow toward alpha-aminoadipic acid.
Mutation of Pseudomonas aeruginosa specifying reduced affinity for penicillin G
Authors: Godfrey A J , Bryan L E
Published: June 2012

A mutant of Pseudomonas aeruginosa strain PAO503 was isolated after ethane-methane-sulfonate mutagenesis and selection of ticarcillin. The mutant, PCC17, displayed reduced affinity for [14C] penicillin G at all of its penicillin-binding proteins as well as a general increase in resistance to all the beta-lactam antibiotics tested. The mutation designated pbpA has been mapped by FP-2-mediated conjugation and was located distal to the proA locus and 33% linked to it. The two loci were not cotransducible with phage F116L. PCC17 and exconjugants produced from it had similar phenotypes, displayed the reduced affinity for [14C] penicillin G, had similar resistance profiles, and had an increased amount of protein corresponding to penicillin-binding protein 6. On back mutation the pbpA locus reverted to the PAO503 phenotype.
Rapid radiometric serum test for antibiotic activity
Authors: D'Antonio R G , Camargo E E , Gedra T , Wagner H N , Charache P
Published: June 2012

We have developed a 4-h radiometric method to predict the bacteriostatic endpoint by the tube dilution method. A mixture of [U-14C] glucose, [guanido-14C] arginine, and [U-14C] glycine was used to monitor the metabolic activity of both gram-positive and gram-negative organisms. The tube dilution method and the radiometric method were performed in parallel in 18 clinical serum samples. In the radiometric method, the samples were separated into control and test portions and serially diluted in Mueller-Hinton broth. Antibiotics in the control portion were inactivated with penicillinase or cellulose phosphate or both. The radioactive mixture and a 1-h culture of the patient's infecting organisms were added to all vials. The 14CO2 production after a 3-h incubation at 37 degrees C was measured, and the percent inhibition was determined for each vial by using the control vials as reference (no inhibition). Radiometric dose-response curves obtained for all samples showed that, by using a greater than or equal to 60% inhibition at 1:8 dilution, the radiometric method correctly predicted the outcome of the tube dilution method in 16 or 18 clinical samples.
Comparative in vitro study of SQ26,776
Authors: Fainstein V , Weaver S , Bodey G P
Published: June 2012

A new monocyclic beta-lactam antibiotic, SQ26,776, was evaluated in vitro against clinical isolates, and its activity was compared with that of other cephalosporins, penicillins, and aminoglycosides. This compound was very active against the majority of the aerobic gram-negative bacilli tested, including 47 multiresistant strains. It had no activity against the gram-positive cocci. It also showed activity comparable to that of moxalactam, ceftazidime, ceftriaxone, thienamycin, and tobramycin. It was superior to mezlocillin. The in vitro activity suggests that SQ26,776 should prove useful in settings in which the most likely pathogens are gram-negative bacilli.
Examination of Pseudomonas aeruginosa-gentamicin discrepancies encountered in an Autobac I-disk diffusion comparison
Authors: Mayo J B , Kiehn T E , Wong B , Bernard E M , Armstrong D
Published: June 2012

Seven Pseudomonas aeruginosa strains found to be susceptible to gentamicin by the Autobac I system and resistant by the Bauer-Kirby disk diffusion method were tested for the presence of mixed populations of cells. Double zones of inhibition randomly appeared on gentamicin disk diffusion plates, and susceptible and resistant subpopulations were isolated from these plates. Growth kinetic studies of separated strains and mixed subpopulations indicated that the susceptible organisms grew rapidly and were read as susceptible at 5 h with the Autobac I system. Resistant organisms entered a sustained lag phase and did not achieve sufficient turbidity to be read as resistant with the Autobac I system before 6 h. Thus, a false reading of susceptible could be obtained with the Autobac I system, depending on the ratio of susceptible organisms to resistant organisms selected for testing. A mixed susceptible and resistant population could be recognized by extending the incubation time of the Autobac I cuvette or by using other susceptibility methods to test isolates with light-scattering indexes of less than 1.0.
Penetration of cefoxitin into cerebrospinal fluid of infants and children with bacterial meningitis
Authors: Feldman W E , Moffitt S , Manning N S
Published: June 2012

Three consecutive doses of 75 mg of cefoxitin per kg were given intravenously every 6 h (225 mg/kg), in addition to penicillin or ampicillin, to 24 patients on days 4 and 5 and 9 and 10 of therapy for meningitis. Haemophilus influenzae b was isolated from cerebrospinal fluid (CSF) of 21 patients, Streptococcus pneumoniae from 2 patients, and Neisseria meningitidis from 1 patient. The median minimal inhibitory and bactericidal concentrations of cefoxitin for 16 isolates of H. influenzae b were 0.312 and 0.625 micrograms/ml, respectively. Sixteen of 18 isolates of H. influenzae b and S. pneumoniae were killed by 2.5 micrograms of cefoxitin per ml. Mean levels in CSF peaked at 1 h at 6 and 4.9 micrograms/ml on days 5 and 10, respectively. CSF levels on days 5 and 10 were greater than or equal to twice the median minimal inhibitory and bactericidal concentration in 20 and 18 patients, respectively. However, bacterial levels in CSF were greater than or equal to 2.5 micrograms/ml in only 11 of 23 patients on days 5 and 10. No significant adverse effects were found. These data indicate that at this dosage, cefoxitin may not reach levels in the CSF required for killing all susceptible strains of H. influenzae b and S. pneumoniae.
Influence of Urinary pH on the Pharmacokinetics of Cinoxacin in Humans and on Antibacterial Activity In Vitro
Authors: Barbhaiya Rashmi H. , Gerber Andreas U. , Craig William A. , Welling Peter G.
Published: June 2012

The impact of acidification and alkalinization of the urine on the pharmacokinetics of cinoxacin was examined after single 500-mg oral doses were administered to nine healthy male volunteers. Acidic and alkaline conditions were achieved by repeated oral doses of ammonium chloride or sodium bicarbonate, respectively. Plasma cinoxacin levels in all subjects were adequately described in terms of one-compartment-model kinetics with first-order absorption and elimination. Acidification and alkalinization treatment had no effect on cinoxacin absorption or distribution. The mean elimination half-life of cinoxacin in plasma was 1.1, 2.0, and 0.6 h in control subjects and with acidification and alkalinization of urine, respectively. Recovery of intact cinoxacin in samples of urine collected 0 to 36 h after cinoxacin administration represented 65% of the dose in control subjects and urine acidification and 80% of the dose with alkalinization of urine. The mean renal clearance of cinoxacin was 76, 118, and 278 ml/min with acidification, control, and alkalinization, respectively, and renal clearance was highly correlated with urinary pH. Urine concentrations of cinoxacin were significantly higher with alkalinization compared with control values during the first 4 h after drug administration. Urine cinoxacin concentrations were reduced somewhat by acidification, but these tended not to be significantly different from control values. Changes in cinoxacin elimination owing to urine pH are less pronounced in humans than in dogs. The antibacterial activity of cinoxacin against some common urinary tract pathogens was pH dependent. A four- to eightfold reduction in cinoxacin activity was generally observed at pH 8 compared with lower pH values. However, in view of the high levels of cinoxacin which are obtained in both acidic and basic urine, the impact of urine pH on cinoxacin antibacterial efficacy would be of minor clinical importance.
Penem derivatives: beta-lactamase stability and affinity for penicillin-binding proteins in Escherichia coli
Authors: Ohya S , Utsui Y , Sugawara S , Yamazaki M
Published: June 2012

Penem derivatives, a new group of beta-lactam antibiotics with potent activities against a wide range of bacteria, including Pseudomonas aeruginosa, were tested for their stability against hydrolysis by beta-lactamases purified from clinical isolates of Morganella morganii. Proteus vulgaris, and Escherichia coli and by a penicillinase from Bacillus cereus. Penems having 6 alpha substituents, such as hydroxyethyl, hydroxymethyl, and ethyl groups, were very stable against hydrolysis by each of the enzymes. Penems having no 6 alpha substituents were easily hydrolyzed by P. vulgaris and E. coli enzymes, whereas they were rather stable against hydrolysis by M. morganii and B. cereus enzymes, a typical cephalosporinase and penicillinase, respectively. Affinity of the penems for E. coli penicillin-binding proteins (PBPs) was also tested. beta-Lactamase-stable penems having a 6 alpha-hydroxyethyl group showed high affinity for PBP-4, -5, and -6 as well as for PBP-1A, -1Bs, and -2. However, the penems having no 6 alpha substituents showed a far lower affinity for PBP-4, -5, and -6 than that shown by the corresponding 6 alpha-hydroxyethyl penems. Among the penems tested, affinity for PBP-4, -5, and -6 was closely related to their beta-lactamase stability, as was the case among cephamycins and cephalosporins. Effects of the penems on the morphology of a strain of E. coli are also described.
Stability of antimicrobial agents in peritoneal dialysate
Authors: Sewell D L , Golper T A
Published: June 2012

The stability of cephapirin, gentamicin, penicillin G, nafcillin, ticarcillin, and vancomycin was tested in peritoneal dialysate at 25 degrees C for 24 h. All of the antimicrobial agents were stable except penicillin G, which lost 25% of activity over 24 h (P less than 0.01). The once-daily preparation of drug-dialysate solution is feasible for the treatment of peritonitis in patients on continuous ambulatory peritoneal dialysis.
Relative avidity of etruscomycin to cholesterol and ergosterol
Authors: Nedeau P , Gruda I , Medoff G , Brajtburg J
Published: June 2012

Two methods, biological and spectroscopic, were used to determine the avidity of the polyene antibiotic Etruscomycin for cholesterol and ergosterol. The biological method consisted of measuring the inhibitory potency of both sterols on the Etruscomycin-induced damage to erythrocytes and fungi. The spectroscopic method consisted of recording of series of differential spectra in a number of solvents of different composition. The results obtained showed that cholesterol protected erythrocytes and candida albicans against the damaging action of Etruscomycin more efficiently than ergosterol did and that Etruscomycin-cholesterol complexes were more resistant to interruption by organic solvents than Etruscomycin-ergosterol complexes. These results and their comparison with the results obtained with other polyene antibiotics indicate that Etruscomycin resembles filipin in that it binds more avidly to cholesterol than to ergosterol. This implies that the length of the hydrophobic chain rather than the presence of the amino sugar determines sterol preference. The spectral method that we used can have general application for the quantitative measurement of complex formation between polyenes and sterols.
Biosynthesis of monobactam compounds: origin of the carbon atoms in the beta-lactam ring
Authors: O'Sullivan J , Gillum A M , Aklonis C A , Souser M L , Sykes R B
Published: June 2012

The biosynthesis of monobactams by strains of Chromobacterium violaceum, Acetobacter sp., and Agrobacterium radiobacter was studied. Monobactams were produced during logarithmic growth by C. violaceum and Acetobacter sp. and during late log growth on glycerol and in stationary phase by A. radiobacter. The addition of various amino acids failed to significantly stimulate monobactam production in any of the producing organisms. Several 14C-amino acids and pyruvate were incorporated in vivo into monobactams. Serine, glycine, and cysteine were better incorporated than alanine or aspartate, whereas an excess of nonradioactive serine depressed the incorporation of labelled cysteine, glycine, and pyruvate. A comparison of [1-14C] glycine and [2-14C] glycine incorporation data suggests that glycine was first converted to serine. With a mixture of [U-14C[serine and [3-3H]serine, C. violaceum synthesized a monobactam with a complete retention of tritium, whereas with a [U-14C] cystine and [3-3H] cystine mixture, there was an extensive loss of C-3 tritium. Acetobacter sp. and A. radiobacter also utilized the double-labeled serine without the loss of tritium in their respective monobactams. It appears, therefore that in the three organisms, the carbon atoms of the beta-lactam ring of the monobactam are derived directly from serine without the loss of the C-3 hydrogen atoms, probably by an SN2 ring closure mechanism. With [methyl-14C] methionine, most of the radioactivity in the monobactam from Acetobacter sp. was in the methyl moiety of the beta-lactam ring methoxyl group.
Comparative pharmacokinetics and tissue penetration of sulbactam and ampicillin after concurrent intravenous administration
Authors: Brown R M , Wise R , Andrews J M , Hancox J
Published: June 2012

A combination of 500 mg each of sulbactam and ampicillin was administered intravenously into six healthy male volunteers, and subsequent serum and blister fluid levels were measured. Both dogs had similar serum half-lives of about 1 h. The concentrations of sulbactam in serum and blister fluid were about 1.5 times those of ampicillin, and appeared to be pharmacokinetically well matched when administered in equal doses.
Anion-exchange extraction of cephapirin, cefotaxime, and cefoxitin from serum for liquid chromatography
Authors: Fasching C E , Peterson L R
Published: June 2012

An anion-exchange column technique for extraction of antibiotics from serum proteins has been developed for use in the assay of cephapirin, cefotaxime, and cefoxitin by high-pressure liquid chromatography. Anion-exchange extraction of cephapirin from serum samples by this technique was compared with protein precipitation methods, using 6% trichloroacetic acid or absolute ethanol. Column extraction gave improved quantitative drug recovery and reduced background serum interferences in the resultant chromatograms when evaluated against protein precipitation. Comparisons of this method with microbiological assay gave statistically equivalent results. Twelve patient samples were assayed for cephapirin, and no interferences were encountered from the 22 systemic agents these subjects were receiving. The anion-exchange technique for antibiotic extraction provides a rapid, precise, and quantitative antibiotic assay when used with liquid chromatography.
Pharmacokinetics of potassium clavulanate in combination with amoxicillin in pediatric patients
Authors: Nelson J D , Kusmiesz H , Shelton S
Published: June 2012

Two dosages of a liquid suspension formulation of amoxicillin and potassium clavulanate were tested in 34 infants and children. The smaller dosage resulted in suboptimal plasma concentrations. With a greater dosage (3.3 mg of clavulanate per kg and 13.3 mg of amoxicillin per kg), the mean peak plasma concentrations were 1.6 micrograms clavulanic acid per ml and 4.9 micrograms amoxicillin per ml.
In vitro potentiation of cephalosporins by alafosfalin against urinary tract bacteria
Authors: Arisawa M , Ohshima J , Ohsawa E , Maruyama H B
Published: June 2012

Potentiating activity of alafosfalin was examined in detail with 8 cephalosporins and mecillinam against 164 urinary bacteria representing 8 genera. Alafosfalin was generally comparable in activity to cefamandole and mecillinam but superior to other cephalosporins tested. When the minimal fractional inhibitory concentration indices were compared, synergism was observed with all of the beta-lactams tested for all species except Streptococcus faecalis. Marked synergism was observed with Escherichia coli, Citrobacter, and enterobacter and, among the drugs tested, with cefamandole and mecillinam. Although alafosfalin is inactive against Pseudomonas aeruginosa, potentiation was seen with cefsulodin. The most favorable combination ratio of alafosfalin/cephalosporin to elicit potentiation was determined for each species and occurred in a rather narrow range of combinations (1:4 to 4:1 in general).
Comparative effects of moxalactam and gentamicin on human polymorphonuclear leukocyte functions
Authors: Burgaleta C , Martínez-Beltrán J , Bouza E
Published: June 2012

The in vitro effects of moxalactam and gentamicin on chemotactic, phagocytic, and microbicidal activities of human polymorphonuclear leukocytes have been studied. Incubation of cells with moxalactam (25 to 400 micrograms/ml) resulted in a 10 to 15% inhibition of leukocyte chemotaxis (P less than or equal to 0.10). Incubation of cells with gentamicin (5 to 40 micrograms/ml) inhibited chemotaxis more than 50% (P less than or equal to 0.50). Neither moxalactam nor gentamicin had any effect on phagocytic or microbicidal capacities of leukocytes.
Impairing effect of food on ketoconazole absorption
Authors: Männistö P T , Mäntylä R , Nykänen S , Lamminsivu U , Ottoila P
Published: June 2012

Single oral doses of ketoconazole (200 mg) or miconazole (250 mg) were given in a randomized cross-over study to 10 healthy volunteers. Ketoconazole with administered (i) after fasting (both brand 1 [Orion Pharmaceutical Co.] and brand 2 [Janssen Pharmaceutica] were tested), (ii) after a standardized meal (660 kilocalories; 2,772 kJ) (brand 1), and (iii) with 300 ml of orange juice (pH 3.8) (brand 1). Miconazole was administered after fasting. Venous blood samples for high-performance liquid chromatography determinations of ketoconazole and gas chromatographic analyses of miconazole were drawn periodically up to 24 h. The concentrations of ketoconazole in sera attained with the two brands were not statistically different. The peak concentrations of ketoconazole attained with brand 1 were 4.1 +/- 0.3 micrograms/ml (mean +/- standard error of the mean) after fasting, 2.3 +/- 0.3 micrograms/ml after the standardized meal (P less than 0.01), and 3.6 +/- 0.2 micrograms/ml with orange juice. The peak concentrations were reached in 1.4, 2.3 (P less than 0.05), and 1.8 h, respectively, whereas the areas under the serum concentration-time curves were 14.4 +/- 2.21, 8.6 +/- 1.33 (P less than 0.05), and 13.4 +/- 1.30 micrograms.h/ml, respectively. The half-lives (1.7 to 2 h) did not vary significantly among the different regimens. Compared with ketoconazole, oral absorption of miconazole was poor (peak concentration, 0.47 +/- 0.7 micrograms/ml; time to reach the peak concentration, 2.6 h; area under the serum concentration-time curve, 1.10 +/- 0.20 micrograms.h/ml).
Inhibitors of DNA precursor metabolism in Dictyostelium discoideum
Authors: Deering R A , Michrina C A
Published: June 2012

The effects of various inhibitors of DNA precursor metabolism were studied on Dictyostelium discoideum growing in a defined axenic medium. Fluorodeoxyuridine was an effective inhibitor of growth at 20 micrograms/ml; this inhibition was not reversed by thymidine, suggesting that in this organism fluorodeoxyuridine is not acting on thymidylate synthetase alone. Removal of the required nutrient, folic acid, from the medium resulted in a lower maximum level of growth than in the control. The inclusion of adenine, guanine, serine, and thymidine in the minus-folic acid medium allowed the final growth level to approach that of the control. Methotrexate, a folic acid analog and dihydrofolate reductase inhibitor, blocked growth completely at 200 micrograms/ml; its effect was partly reversed by the addition of adenine, guanine, serine, and thymidine. Aminopterin, another folic acid analog, had only a temporary effect on cell multiplication, followed by a return to exponential growth. Trimethoprim was ineffective up to 200 micrograms/ml. Hydroxyurea blocked growth in the concentration range of 150 to 300 micrograms/ml. These results indicate that several of these inhibitors are effective for altering thymidine monophosphate synthesis in D. discoideum and hence may be useful for studies of DNA replication and repair and for the isolation and characterization of thymidine-requiring mutants.
Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex
Authors: Fitch C D , Chevli R , Banyal H S , Phillips G , Pfaller M A , Krogstad D J
Published: June 2012

Ferriprotoporphyrin IX (FP) and a chloroquine-FP complex lysed isolated Plasmodium falciparum parasites as judged by decreases in the turbidity of parasite suspensions and by ultrastructural changes. Exposure of parasite suspensions to 50 microM FP or to a complex formed from 50 microM FP and 20 MicroM chloroquine reduced the number of identifiable parasites and caused swelling and loss of internal detail in those that were identifiable. The amount of lysis was dose-dependent over the range of 10 to 50 microM FP. Formation of a chloroquine-FP complex reduced, but did not eliminate, the toxicity of FP. Since there is evidence indicating that a chloroquine-FP complex forms when chloroquine-susceptible parasites are exposed to chloroquine, we suggest that accumulation of this complex may account for the chemotherapeutic effect of chloroquine against P. falciparum.