bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydroxyquinolines Inhibit Ribonucleic Acid-Dependent Deoxyribonucleic Acid Polymerase and Inactivate Rous Sarcoma Virus and Herpes Simplex Virus
Authors: Rohde Wolfgang , Mikelens Peter , Jackson Jean , Blackman Jane , Whitcher Jack , Levinson Warren
Published: June 2012

8-Hydroxyquinoline and several of its derivatives inactivate the transforming ability of Rous sarcoma virus and inhibit its ribonucleic acid-dependent deoxyribonucleic acid polymerase activity. The copper complex of these metal-binding ligands is as active as the free ligand. The activity of the 8-hydroxyquinolines is approximately 50-fold more effective than another group of metal-binding compounds that we have tested, the thiosemicarbazones. In contrast to the potency of the 8-hydroxyquinolines to inactivate Rous sarcoma virus, no intracellular inhibition of transformation could be demonstrated at a concentration that did not affect the growth and appearance of the cells. Cellular deoxyribonucleic acid synthesis was inhibited to a greater extent than was ribonucleic acid or protein synthesis. The phenomenon of “concentration quenching” was observed with high concentrations of drug, causing less inhibition of deoxyribonucleic acid synthesis than was observed with lower concentrations. Herpes simplex virus type 1 was inactivated also by the 8-hydroxyquinolines and their copper complexes. No intracellular inhibition of plaque formation was observed. Treatment with 8-hydroxyquinoline sulfate had no effect on the resolution of herpetic keratitis in rabbits. Some 8-hydroxyquinolines bind to deoxyribonucleic acid in the presence of copper, a phenomenon that may be important in their antiviral activity.
Renal Extraction of Gentamicin in Anesthetized Dogs
Authors: Chiu Peter J. S. , Brown Arthur , Miller George , Long James F.
Published: June 2012

The tubular handling of gentamicin (G) and its intrarenal distribution were determined to elucidate the mechanism of G accumulation in the kidney. At a serum level of 11.1 ± 0.5 μg/ml (10 animals), as maintained by constant infusion for 5 h, serum Na
+
and K
+
, arterial pressure, effective renal plasma flow and glomerular filtration rate remained undisturbed. The clearance values in milliliters per minute for G, inulin, and
p
-aminohippuric acid were 40.3 ± 1.8, 49.9 ± 2.8, and 132 ± 14, respectively. The ratio of clearance of G to clearance of inulin was 0.82 ± 0.04 (
P
< 0.005), suggesting net reabsorption of G by the renal tubules. The renal cortex/serum ratio for G was 11.9 ± 2.1, and the medulla/serum ratio was 2.7 ± 0.4, indicating greater uptake of G by the cortex. The extraction ratio of
p
-aminohippuric acid was 0.74 ± 0.03. In contrast, the extraction ratio of G was 0.20 ± 0.03, which was significantly lower than that of inulin (0.30 ± 0.04). It is concluded that the accumulation of G in the cortex was due to tubular reabsorption. Probably some of the reabsorbed G became trapped in the epithelial cells after crossing the luminal membrane, whereas some returned to the circulation.
Inhibition of
Neisseria gonorrhoeae
by a Bacteriocin from
Pseudomonas aeruginosa
Authors: Morse Stephen A. , Vaughan Patrick , Johnson Deanne , Iglewski Barbara H.
Published: June 2012

Supernatants from broth-grown cultures of
Pseudomonas aeruginosa
PA 103 exhibited bactericidal activity against
Neisseria gonorrhoeae
. The concentration of the bactericidal substance increased significantly after induction by mitomycin C. Purification was effected by salt fractionation, chromatography on diethylaminoethyl-cellulose, and sedimentation by centrifugation at 100,000 ×
g
for 90 min. Electron microscopy of this purified preparation revealed structures resembling R-type pyocins in both the contracted and uncontracted state. Pyocins in the contracted state were observed in association with the gonococcal cell surface. No loss of bactericidal activity was observed after treatment with proteolytic enzymes. Standard pyocin typing procedures identified the pyocin pattern as 611 131. The bactericidal activity of this pyocin was examined on various species of
Neisseria
. Out of 56 strains of
N. gonorrhoeae
from disseminated and nondisseminated infections, all were susceptible to pyocin 611 131. However, only 3 of 20 strains of
N. meningitidis
and 5 of 16 strains of
N. lactamica
were susceptible. The bactericidal activity that pyocin 611 131 has for
N. gonorrhoeae
and other species of
Neisseria
is significant because it departs from the expected specificity that heretofore has distinguished bacteriocins from most “classical” antibiotics.
Antimicrobial Susceptibility of
Propionibacterium acnes
and Related Microbial Species
Authors: Hoeffler U. , Ko H. L. , Pulverer G.
Published: June 2012

The minimal inhibitory concentrations of 32 antimicrobial agents were established for 73 strains of
Propionibacterium acnes
and four related species (
P. granulosum, P. avidum, Corynebacterium minutissimum
, and
C. parvum
). Most strains showed good susceptibility to those agents usually considered active against gram-positive organisms. With the exception of
C. minutissimum
, the strains tested revealed more or less identical susceptibility ranges. The lowest minimal inhibitory concentrations were observed with benzylpenicillin, ampicillin, cephalothin, rifampin, erythromycin, clindamycin, and minocycline.
C. minutissimum
was more susceptible to gentamicin, sisomicin, tobramycin, and fusidic acid but more resistant to most other drugs than were the other species examined.
Bacteriocin Production by
Neisseria gonorrhoeae
Authors: Lawton William D. , Bellinger Mary Ann , Schling Marion , Gaafar Hassan A.
Published: June 2012

Seventeen apparently unrelated isolates of
Neisseria gonorrhoeae
out of 2,123 tested produced a diffusible growth-inhibitory substance against other gonococci. The inhibitor was destroyed by trypsin, not blocked by bovine serum albumin, and not soluble in chloroform-methanol; each isolate was resistant to the inhibitor it produced. Thus, the substance differs from previously described gonococcal inhibitors, and since it fits the description of a bacteriocin we designated it gonocin. The use of gonocin for typing was complicated by the observation that susceptibility to gonocin appears to depend on the gonococcal colony type.
Laboratory Evaluation of BL-S786, a Cephalosporin with Broad-Spectrum Antibacterial Activity
Authors: Leitner F. , Misiek M. , Pursiano T. A. , Buck R. E. , Chisholm D. R. , DeRegis R. G. , Tsai Y. H. , Price K. E.
Published: June 2012

Biological and physicochemical properties of BL-S786 were compared with those of cephalothin, cephaloridine, and cefazolin. With few exceptions, BL-S786 was more active than the reference compounds against major gram-negative pathogenic species and its antibacterial spectrum was broader than that of cephalosporins currently available for clinical use. Although BL-S786 was generally less active than the control cephalosporins against gram-positive pathogens, it inhibited their growth at concentrations that should readily be achieved in humans after standard parenteral dosage.
Streptococcus faecalis
, a species relatively unsusceptible to cephalosporins in general, was an exception. BL-S786 was an effective bactericidal agent for strains of various gram-negative organisms. After intramuscular administration to mice, BL-S786 achieved high concentrations in blood, and its biological half-life was longer than that of the other three cephalosporins.
Effect of Renal Failure and Dialysis on the Serum Concentration of the Aminoglycoside Amikacin
Authors: Madhavan T. , Yaremchuk K. , Levin N. , Pohlod D. , Burch K. , Fisher E. , Cox F. , Quinn E. L.
Published: June 2012

Serum and dialysate levels of amikacin were determined at appropriate intervals after a 300-mg intravenous dose as a continuous infusion in six patients with end-stage renal failure undergoing hemodialysis and in three patients on peritoneal dialysis. The mean serum half-life of amikacin was 3.75 h during (or after) hemodialysis and 29 h during (or after) peritoneal dialysis. Although not on hemodialysis in the same six patients, the serum half-life was 28 h. The results indicate that the maintenance dose of amikacin should be markedly decreased in patients with severe renal failure even if they are treated with peritoneal dialysis, and that serial serum antibiotic concentrations are essential to prevent cumulative toxicity of the drug.
Antitrichomonad Action, Mutagenicity, and Reduction of Metronidazole and Other Nitroimidazoles
Authors: Lindmark Donald G. , Müller Miklós
Published: June 2012

Twelve 4- and 5-nitroimidazole derivatives, including metronidazole and two of its metabolites, tinidazole, dimetridazole, and nimorazole, were tested for antitrichomonad action on
Tritrichomonas foetus
(KV
1
) and
Trichomonas vaginalis
(ATCC 30001) for mutagenicity on a nitroreductase-positive (TA 100) and a nitroreductase-deficient (TA 100-FR
1
) strain of
Salmonella typhimurium
, as well as for the reducibility of the nitro group by
T. foetus
homogenates. Compounds with activity <1% of that of metronidazole are regarded as inactive. All antitrichomonad compounds induce mutations and can be reduced.
S. typhimurium
TA 100 gave mutations under both aerobiosis and anaerobiosis; TA 100-FR
1
, however, gave mutations only under anaerobiosis. Certain compounds that are reducible, and the nonreducible derivatives, were inactive. Metronidazole and its inactive 4-nitro analogue were reduced in a four-electron process in ferredoxin- or methyl viologen-mediated reactions with the same velocity. The results underscore the role of the reduction of the nitro group in the antitrichomonad and in the mutagenic activity of nitroimidazoles.
Selection and Characterization of Strains of
Staphylococcus aureus
Displaying Unusual Resistance to Aminoglycosides
Authors: Wilson Stephen G. , Sanders Christine C.
Published: June 2012

Susceptibility tests with aminoglycosides against
Staphylococcus aureus
have revealed discrepancies between the minimal inhibitory concentrations and the minimal bactericidal concentrations. To further evaluate these discrepancies, kill curves were performed against a susceptible strain of
S. aureus
with five different aminoglycosides (amikacin, kanamycin, tobramycin, gentamicin, sisomicin) at concentrations up to 16-fold above the minimal inhibitory concentration. Results revealed the presence of small subpopulations of cells capable of growth within 24 h in concentrations of aminoglycoside up to eightfold above the minimal inhibitory concentration for the parent strain. These subpopulations occurred at a frequency of ≥10
−7
parent cells, were not physiologically different from the susceptible parent strains, and were present in approximately one-half of 30 strains of
S. aureus
tested. The resistance of these subpopulations was approximately eightfold higher than that of the parent for all five aminoglycosides and was independent of concentration or type of aminoglycoside used to select them. This resistance was not due to extracellular degradation of drug and was stable over eight transfers in drug-free medium, except when selected by gentamicin or sisomicin.
Can Mannitol Reduce Amphotericin B Nephrotoxicity? Double-Blind Study and Description of a New Vascular Lesion in Kidneys
Authors: Bullock Ward E. , Luke Robert G. , Nuttall Charles E. , Bhathena Dinyar
Published: June 2012

Eleven patients with systemic mycotic infections were treated with amphotericin B, 1 mg/kg, on alternate days. Five patients also received mannitol (M), 1 g/kg, in the amphotericin infusion, while six served as controls (C). Renal function studies prior to therapy were repeated at a total cumulative amphotericin B dosage of 25 mg/kg; renal biopsies were obtained from 10 patients. Inulin and creatinine clearances decreased in both the C and M groups, significantly so in the latter. Urinary concentrating ability of five patients (2C, 3M) decreased as did the capacity of three (1C, 2M) to acidify urine after an acid load. Neither the peak and valley levels of amphotericin B in serum nor the urinary excretion thereof differed between the C and M groups. Striking vacuolization of smooth muscle cells, previously unrecognized, was observed in the media of arterioles and arteries in all renal biopsies. Tubular calcification was present in both groups. In summary, M therapy (1 g/kg) did not protect against the nephrotoxicity of amphotericin B. A unique lesion of the renal vasculature secondary to amphotericin B is described.
Comparison of the Antibacterial Activity of Nine Cephalosporins Against
Enterobacteriaceae
and Nonfermentative Gram-Negative Bacilli
Authors: Verbist Ludo
Published: June 2012

The in vitro antibacterial activity of nine cephalosporins (cephalothin, cephaloridine, cephalexin, cefazolin, cefamandole, cefuroxime, cefatrizine, cefoxitin, and cefazaflur) was determined against 344 strains of
Enterobacteriaceae
and 99 nonfermentative gram-negative bacilli. Cefamandole, cefazaflur, and cefuroxime were the most active cephalosporins against the
Enterobacteriaceae
(with the exception of
Serratia marcescens
). However, cefoxitin was the only cephalosporin that inhibited all 30
S. marcescens
strains in a concentration of 16 μg/ml and was by far the most active compound against selected cephalothin-resistant strains of
Escherichia coli, Klebsiella
, and
Proteus mirabilis. Acinetobacter
spp. were inhibited best by cefuroxime, but none of the cephalosporins had appreciable activity against the
Pseudomonas
spp.
Differential Effects of 5-Methylmercapto-2′-Deoxyuridine on the Replication of Herpes Simplex Virus Type 1 in Two Cell Systems
Authors: Hardi Robert , Hughes R. G. , Ho Y. K. , Chadha K. C. , Bardos T. J.
Published: June 2012

5-Methylmercapto-2′-deoxyuridine (MeMUdR), a structural analogue of thymidine (TdR), inhibits herpes simplex virus type 1 production in mouse L (Lb) cells at concentrations that are not inhibitory to viral growth in monkey kidney (CV-1) cells. It is moderately toxic to Lb cells but not to CV-1 cells at a concentration that causes 95% inhibition of viral replication in Lb cells. MeMUdR is incorporated into cellular and viral deoxyribonucleic acid (DNA) in both systems, but to a significantly higher level (compared with thymidine) in Lb cells. These results indicate that MeMUdR is a substrate for enzymes leading to DNA synthesis and suggest that the biological function of herpes simplex virus type 1 DNA is impaired only when the incorporation of MeMUdR into the DNA reaches a relatively high level.
Antiviral Activity of BL-3849A, a Low-Molecular-Weight Oral Interferon Inducer
Authors: Kern Earl R. , Hamilton John R. , Overall James C. , Glasgow Lowell A.
Published: June 2012

Oral administration of BL-3849A to adult mice resulted in peak serum interferon titers of 4,000 units from 15 to 30 h after administration, with detectable levels persisting until 48 h. After intraperitoneal (i.p.) inoculation, peak serum interferon titers of 1,000 to 3,000 units were noted between 9 and 18 h. Multiple injections of the inducer by either route resulted in a marked decrease in the interferon response with each successive dose. In mice infected intranasally with the Rochester mouse virus strain of encephalomyocarditis virus, oral treatment with BL-3849A reduced mortality when initiated either 18 h before or 1 h after infection. In contrast, administration of drug by the i.p. route decreased mortality only if begun before infection. In mice inoculated i.p. with encephalomyocarditis virus, treatment by both the oral and the i.p. route decreased the mortality whether initiated 18 h before or 1 h after infection. Treatment by the oral, but not the i.p., route reduced mortality of mice inoculated i.p. with Semliki forest virus or
Herpesvirus hominis
type 2. BL-3849A appeared to be as effective as tilorone hydrochloride, but less effective than polyriboinosinic-polyribocytidylic acid, in the treatment of these viral infections of mice.
Suppression of the Lytic and Bactericidal Effects of Cell Wall-Inhibitory Antibiotics
Authors: Lopez Ruben , Ronda-Lain Conchita , Tapia Alfonso , Waks Susan B. , Tomasz Alexander
Published: June 2012

The bacteriolytic effect of beta-lactam antibiotics on
Bacillus subtilis
and on
Streptococcus pneumoniae
was found to be a function of the pH; lysis was suppressed if the pH of the pneumococcal culture was below 6.0 during penicillin treatment. In the case of
B. subtilis
, growth at pH 6.6 prevented penicillin-induced lysis. In pneumococci, the addition of trypsin to the growth medium also protected against lysis. The pH-dependent protection phenomenon resembled in several respects the antibiotic “tolerance” of pneumococci with a defective autolytic system. (i) At the pH nonpermissive for lysis, the bacteria retained their normal sensitivity to beta-lactam and to other cell wall inhibitors; however, instead of lysis, the drug-treated bacteria simply stopped growing. Loss of viability of the cells was also greatly reduced. (ii) Protection against lysis was independent of the dose and chemical nature of the cell wall inhibitors. (iii) The protection effect was reversible; lysis and loss of viability could be triggered by a postincubation of the drug-treated bacteria at the pH permissive for lysis.
Variation in the Susceptibility of Strains of
Staphylococcus aureus
to Oxacillin, Cephalothin, and Gentamicin
Authors: Mayhall C. G. , Medoff G. , Marr J. J.
Published: June 2012

Three cases of staphylococcal bacteremia caused by organisms that were inhibited by low concentrations of oxacillin, but were resistant to the killing effects of oxacillin, stimulated us to screen 60 clinical isolates of
Staphylococcus aureus
for their susceptibility to oxacillin, cephalothin, and gentamicin. All 60 strains were inhibited by low concentrations of the antibiotics. The antibiotics were bactericidal against 27 of the 60 strains and only bacteriostatic against the other 33 after 24 h of incubation. However, after 48 h of incubation, the antibiotics were also bactericidal against the latter group.
Susceptibility of Respiratory Tract Anaerobes to Orally Administered Penicillins and Cephalosporins
Authors: Busch David F. , Kureshi Lubna Afzal , Sutter Vera L. , Finegold Sydney M.
Published: June 2012

Anaerobic bacteria recovered from airway-related infections were tested by agar dilution against selected penicillins and cephalosporins available for oral administration. Against 136 isolates, penicillins G and V showed comparable activity, particularly when pharmacological differences were considered. Although many isolates were exquisitely susceptible to the penicillins, only 55% of the
Bacteroides
species and 72% of all isolates were inhibited at 0.5 μg of penicillin G per ml. Results for penicillin V at 1 μg/ml were similar (59 and 73%). The two cephalosporins were more active at achievable levels, inhibiting 94 to 95% of
Bacteroides
and 95 to 96% of all isolates at 8 μg/ml. These levels represent approximately 50% of the reported peak serum levels after oral administration of 625 mg of the penicillins and 500 mg of the cephalosporins. Dicloxacillin and nafcillin were tested against 50 isolates. The two were comparably active on a weight basis; dicloxacillin was more active when pharmacological differences were considered, but did not match the other penicillins or the cephalosporins.
Effects of Antibiotics on Metabolism of Peptidoglycan, Protein, and Lipids in
Bifidobacterium bifidum
subsp.
pennsylvanicus
Authors: Molenkamp G. C. , Veerkamp J. H.
Published: June 2012

The formation of cell envelope components of
Bifidobacterium bifidum
subsp.
pennsylvanicus
was studied by measuring the incorporation of [
3
H]glycine,
14
C-labeled fatty acids, and
N
-benzoyl-[
14
C]glucosamine into the membrane protein, membrane lipids, and cell wall peptidoglycan, respectively. Inhibition of peptidoglycan synthesis by antibiotics (penicillin G, vancomycin,
d
-cycloserine, and bacitracin) and by the omission of glucosamine-containing growth factors caused a marked decrease in glycine incorporation into cellular as well as membrane protein, which was accompanied by a considerable enhancement of fatty acid incorporation. The uncoupling of protein and lipid synthesis led to the release of marked amounts of lipids from the cell under these conditions. Arrestment of protein synthesis by antibiotics (chloramphenicol, tetracycline, and actinomycin D) decreased peptidoglycan and lipid synthesis only partially, but did not lead to lipid release. Mg
2+
deficiency of the medium caused about 60% inhibition of growth and lipid synthesis, but protein synthesis and especially peptidoglycan synthesis were much less inhibited. Staphylococcin 1580 arrested the growth and also the synthesis of protein and peptidoglycan. However, the synthesis and turnover of lipids were considerably increased and a release of large amounts of lipids was observed. Peptidoglycan and cellular protein did not show any turnover either during normal growth or after the inhibition of cell wall and protein synthesis.
Combination of Bacteriostatic and Bactericidal Drugs: Lack of Significant In Vitro Antagonism Between Penicillin, Cephalothin, and Rolitetracycline
Authors: Daschner Franz D.
Published: June 2012

Although it is generally believed that bactericidal and bacteriostatic drugs should not be combined in vivo, in vitro experiments using the checkerboard dilution technique revealed no antagonism between penicillin/cephalothin and rolitetracycline but rather additive or synergistic activity of either drug combination in 40 to 50% of 20
Escherichia coli
, and 14
Staphylococcus aureus
strains. Slight antagonism occurred only between 3 and 8 h after combining penicillin/cephalothin and rolitetracycline in either bacteriostatic or bactericidal concentrations, but not after 24 h of incubation, nor was antagonism found with combinations of these drugs in bacteriostatic concentrations. Neither bacteriostatic nor bactericidal activity of penicillin/cephalothin and rolitetracycline was inhibited by pretreatment of one
E. coli
strain with bacteriostatic rolitetracycline or bacteriostatic penicillin/cephalothin concentrations. Penicillin and cephalothin could exert a bactericidal effect after 2-h exposure of the
E. coli
strain to bacteriostatic rolitetracycline concentrations. Combined action of subinhibitory penicillin and rolitetracycline concentrations resulted in more pronounced inhibition of growth than either drug alone. The higher activity of penicillin/cephalothin in combination with rolitetracycline on some
E. coli
and
S. aureus
strains might be due to a better access of rolitetracycline into bacterial cells whose cell walls have been weakened by cell wall-active, bactericidal drugs. Thus, growth of penicillin-induced spheroplasts of
E. coli
and stable staphylococcal L-forms was inhibited by much lower concentrations of rolitetracycline than were the corresponding parent cells with intact cell walls.
Cefamandole: In Vitro and Clinical Pharmacokinetics
Authors: Griffith R. S. , Black H. R. , Brier G. L. , Wolny J. D.
Published: June 2012

Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes
Haemophilus influenzae
, most strains of
Enterobacter
, and many strains of indole-positive
Proteus
and
Bacteroides
, with a lower minimal inhibitory concentration for
Escherichia coli, Klebsiella
, etc. Concentrations of drug in the serum after the parenteral injection of cefamandole exceed manyfold the minimal inhibitory concentrations of over 82% of the bacteria studied. Approximately 65 to 85% is excreted in a biologically active form in the urine. This antibiotic offers advantages of antibacterial effectiveness and at the same time retains the safety of penicillin G and cephalothin in animals.
Antifungal Properties of Electrically Generated Metallic Ions
Authors: Berger T. J. , Spadaro J. A. , Bierman Richard , Chapin S. E. , Becker R. O.
Published: June 2012

A qualitative and quantitative investigation was undertaken to study the susceptibility of unicellular eucaryotic organisms (yeasts) to metallic cations generated by low levels of direct current. Results were characteristic of effects obtained previously using clinical and standard bacteria test organisms. The present study demonstrated that anodic silver (Ag
+
) at low direct currents had inhibitory and fungicidal properties. Broth dilution susceptibility tests were made on several species of
Candida
and one species of
Torulopsis
. Growth in all isolates was inhibited by concentrations of electrically generated silver ions between 0.5 and 4.7 μg/ml, and silver exhibited fungicidal properties at concentrations as low as 1.9 μg/ml. The inhibitory and fungicidal concentrations of electrically generated silver ions are lower than those reported for other silver compounds.
Comparison of the Epidemiology of Bacterial Resistance to Mecillinam and Ampicillin
Authors: Anderson J. D. , Adams Monica A. , Barrington Jane C. , Spence W. N. , Shepherd C. A.
Published: June 2012

Mecillinam is a new type of β-lactam antibiotic (an amidinopenicillanic acid) that is particularly active against
Enterobacteriaceae
and is taken orally as in the form of an ester, pivmecillinam. Assessment of any new antibiotic should include a survey of levels of bacterial resistance and investigation of its capacity to select resistant organisms or harm the commensal flora. Antibiotic resistance patterns of 2,000
Enterobacteriaceae
isolated from the urine of patients with significant urinary tract infections were therefore determined. Mecillinam-resistant
Enterobacteriaceae
were found to be much less common than ampicillin-amoxycillin-resistant organisms both in the community and in hospital patients. Most ampicillin-resistant
Enterobacteriaceae
from infected urines were susceptible to mecillinam, but the relatively rare mecillinam-resistant organisms were usually resistant to ampicillin and cephaloridine. The fecal flora of 26 healthy volunteers who served as controls or were given repeated courses of therapeutic doses of either ampicillin or pivmecillinam was studied. Pivmecillinam had only a transient effect on the aerobic fecal flora and in contrast to ampicillin did not increase populations of resistant
Enterobacteriaceae
, which would be a potential hazard to the patient and contaminate the environment.
l
-Glyceraldehyde 3-Phosphate, a Bactericidal Agent
Authors: Tang Chu-Tay , Engel Robert , Tropp Burton E.
Published: June 2012

At a concentration of 2.5 mM,
dl
-glyceraldehyde 3-phosphate has a bactericidal effect upon
Escherichia coli
. The glycerol 3-phosphate transport system is required for the entry of the biologically active
l
-enantiomer.
l
-Glyceraldehyde must be phosphorylated by the cell to exert its full effect upon growth. The addition of
dl
-glyceraldehyde 3-phosphate to a culture of
E. coli
caused no preferential inhibition of the accumulation of deoxyribonucleic acid, ribonucleic acid, or phosphoglycerides, although protein accumulation was less affected. Studies with mutant strains ruled out catabolic glycerol 3-phosphate dehydrogenase, anabolic nicotinamide adenine dinucleotide (phosphate):
sn
-glycerol 3-phosphate oxidoreductase, and fructose 1,6-diphosphate aldolase as the primary sites of action.
l
-Glyceraldehyde 3-phosphate is a competitive inhibitor of
sn
-glycerol 3-phosphate in the reactions catalyzed by acyl coenzyme A:
sn
-glycerol 3-phosphate acyltransferase (

K
i

of 1.8 mM) and cytidine 5′-diphosphate-diglyceride:
sn
-glycerol 3-phosphate phosphatidyltransferase (

K
i

of 2.7 mM). A

K
m

mutant for the former enzyme was susceptible to the inhibitor.
l
-Glyceraldehyde 3-phosphate does not affect acyl coenzyme A:lysophosphatidate acyltransferase activity. In vivo, phosphatidylethanolamine and phosphatidylglycerol accumulation are inhibited to the same extent by the addition of
dl
-glyceraldehyde 3-phosphate to a culture of
E. coli
.
Effects of Amphotericin B on Macrophages and Their Precursor Cells
Authors: Lin Hsiu-San , Medoff Gerald , Kobayashi George S.
Published: June 2012

The effect of amphotericin B (AmB) treatment on the mononuclear phagocyte system of mice was investigated. Peritoneal macrophages from mice that received AmB treatment showed a higher phagocytic and antibacterial activity than those from normal untreated mice. When the levels of macrophage precursor cells in bone marrow and spleen were followed in mice after AmB treatment, an eightfold increase in the splenic content of limited stem cells for both macrophages and granulocytes (colony-forming units in culture) and a threefold increase in the number of pluripotent hemopoietic stem cells (colony-forming units in spleen) were observed on day 4. These were also accompanied by a slight increase in the colony-forming units in spleen and in culture in femoral marrows. AmB was capable of inducing a large number of peritoneal colony-forming cells in the peritoneum, and caused a significant rise in the serum level of colony-stimulating factor. No significant change in the level of blood monocytes was noted, although a transient increase in the proportion of neutrophils was observed within 24 h after AmB treatment.
Comparison of the Binding Properties of Two 6β-Amidinopenicillanic Acid Derivatives That Differ in Their Physiological Effects on
Escherichia coli
Authors: Spratt Brian G.
Published: June 2012

The 6-β-amidinopenicillanic acid derivative, mecillinam, was highly specific in its action on the growth of
Escherichia coli
. Concentrations from the minimal inhibitory concentration (0.05 μg/ml) up to at least 200 μg/ml resulted in the conversion of
E. coli
rods into osmotically stable spherical cells without significantly inhibiting cell growth or causing cell lysis. A second amidinopenicillanic acid derivative [6-([4-morpholinylmethylene] amino) penicillanic acid] showed identical effects on cell growth at concentrations from its minimal inhibitory concentration (0.2 μg/ml) up to at least 5 μg/ml but, at higher concentrations, increasing amounts of lysis occurred. Neither of these compounds showed the immediate inhibition of cell division that is observed with typical β-lactam antibiotics. We have compared the binding of these two amidinopenicillanic acids to the individual penicillin-binding proteins of
E. coli
. Both compounds showed a high specificity of binding to penicillin-binding protein 2 at low concentrations. At higher concentrations mecillinam still maintained its high specificity for protein 2 and very little binding of mecillinam to any of the other binding proteins was detected with concentrations up to 1 mg/ml. The morpholino compound, however, showed extensive binding to proteins 1 and 4, and slight binding to proteins 5 and 6 at high concentrations. The morpholino compound therefore combined both the physiological properties and the binding properties of mecillinam with some of those of typical penicillins and cephalosporins. Lysis probably occurs at high concentrations of morpholino compound because it binds to penicillin-binding protein 1, since this is believed to be the target with which β-lactams interact to inhibit cell elongation.
Microassay for Amphotericin B
Authors: Bannatyne Robert M. , Cheung Rose , Devlin Hanna R.
Published: June 2012

Depending on the hematocrit, duplicate or triplicate determinations of serum amphotericin B concentration may be made on as little as 100 μl of capillary blood obtained by finger prick. In an accurate plate diffusion bioassay, using
Paecilomyces varioti
as the indicator organism, levels of the drug in the therapeutic range can be determined fast enough for clinicians to modify their next dose.
Cefoxitin Activity Against Multiply Antibiotic-Resistant
Klebsiella pneumoniae
In Vitro
Authors: Jackson Roger T. , Thomas Frank E. , Alford Robert H.
Published: June 2012

Due to the emergence of cephalothin- and gentamicin-resistant
Klebsiella pneumoniae
at this institution, we investigated the in vitro activity of two new cephalosporin compounds—cefoxitin and cefamandole. Whereas both drugs were active against cephalothin- and gentamicin-susceptible isolates of
Klebsiella
, only cefoxitin exhibited significant activity against cephalothin- and gentamicin-resistant isolates. Seventeen of 20 (85%) of the cephalothin- and gentamicin-resistant isolates were inhibited by ≤12.5 μg of cefoxitin per ml. The minimum bactericidal concentration in broth of representative isolates equaled the agar dilution minimum inhibitory concentration. Kirby-Bauer disk susceptibility testing correlated well with the agar dilution minimum inhibitory concentration. Cephalothin and cefamandole resistance of isolates could be correlated with antibiotic degradation by β-lactamase. Cephalothin and cefamandole evoked only a transient decrease in viable bacterial cell count with rapid inactivation of antibiotics, and full regrowth of the organisms. Cefoxitin, on the other hand, was quite effective in vitro against multiply resistant
Klebsiella
. No β-lactamase degradation of cefoxitin was detected. Growth curves with antibiotics indicated rapid killing of cephalothin- and gentamicin-resistant isolates by cefoxitin.
Evaluation of Various Analogues of Tilorone Hydrochloride Against Venezuelan Equine Encephalitis Virus in Mice
Authors: Kuehne Ralph W. , Pannier Wallace L. , Stephen Edward L.
Published: June 2012

The antiviral activity of tilorone hydrochloride and three of its analogues (11,002, 11,567, and 11,877) was assessed by oral and intraperitoneal (i.p.) administration to Venezuelan equine encephalitis (VEE) virus-infected mice. Significant increases in the percentage of survival (
P
< 0.01) were apparent after oral administration of tilorone and analogue 11,877 at dosages of 250 and 500 mg/kg. Neither tilorone nor 11,877 increased percentage of survival when dosages of 31.25 to 500 mg/kg were given by the i.p. route. Orally administered analogue 11,002 was effective against 100 mouse intracranial median lethal doses (MICLD
50
) of VEE virus at doses at 250 to 1,000 mg/kg; doses of 31.25 to 250 mg/kg given i.p. were effective against 10 MICLD
50
. Oral dosages of 250 to 1,000 mg of analogue 11,567 per kg were active against 100 MICLD
50
of virus. By the i.p. route, 250 mg of 11,567 per kg protected mice against 1,000 MICLD
50
, and a dose of 125 mg/kg protected against 100 MICLD
50
. Oral treatment of VEE infection with analogue 11,567 24 h after subcutaneous inoculation of VEE virus resulted in no significant increase in the percentage of survivors. All survivors of these studies were susceptible to rechallenge 21 days after the first inoculation of virus.
Pharmacokinetics of Amikacin During Hemodialysis and Peritoneal Dialysis
Authors: Regeur Lisbeth , Colding Hanne , Jensen Herluf , Kampmann Jens P.
Published: June 2012

The pharmacokinetics of amikacin were examined in six bilaterally nephrectomized patients undergoing hemodialysis and in four patients with a minimal residual renal function undergoing peritoneal dialysis. The mean elimination half-life before the dialysis was 86.5 h in the anephric patients and 44.3 h in the patients with minimal residual kidney function. The results from the anephric patients suggest that some extrarenal elimination of amikacin may occur. The mean volume of distribution was about 25% of the total body weight. This is in accordance with values reported from subjects with normal renal function. During hemodialysis the half-life decreased to less than 10% (5.6 h) of the pretreatment value. The effectiveness of peritoneal dialysis was less as the half-life decreased to only about 30% (17.9 h) of the pretreatment value. During the dialyses a significant correlation between the half-life of amikacin and the decrease in blood urea and serum creatinine was demonstrated. The pharmacokinetic data were used to make dosage regimen recommendations for the treatment of patients undergoing intermittent hemodialysis or peritoneal dialysis.
Effects of Purines and Pyrimidines on the Fungistatic Activity of 5-Fluorocytosine in
Aspergillus
Species
Authors: Wagner Gerald E. , Shadomy Smith
Published: June 2012

The ability of some exogenously supplied purines, pyrimidines, and their nucleosides to antagonize the in vitro fungistatic activity of 5-fluorocytosine (5-FC) in
Aspergillus
species was examined. All compounds tested except thymidine were capable of altering the minimal inhibitory concentration of 5-FC for seven strains of aspergilli tested. In most instances, there was a reciprocal correlation between the ability of a compound to antagonize the fungistatic activity of 5-FC and the quantity of 5-FC taken up by cells in the presence of the compound over a 72-h period.
Bone Marrow Toxicity Associated with 5-Fluorocytosine Therapy
Authors: Kauffman Carol A. , Frame Peter T.
Published: June 2012

Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 μg/ml or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.
Changes in Superhelical Density of Closed Circular Deoxyribonucleic Acid by Intercalation of Anti-R-Plasmid Drugs and Primaquine
Authors: Allison Richard G. , Hahn Fred E.
Published: June 2012

The following compounds, which possess anti-R-plasmid activity (Hahn and Ciak, 1976) in decreasing order, were shown by viscometric titration to change systematically the superhelical density of closed circular PM2 deoxyribonucleic acid in the manner of intercalators: ethidium bromide, quinacrine, acridine orange, quinine, chlorpromazine, chloroquine, and methylene blue. The same effect was caused by the antimalarial drug primaquine, which has not been tested for antiplasmid activity.
Development of a Chemically Defined Medium for the Synthesis of Actinomycin D by
Streptomyces parvulus
Authors: Williams W. Kenneth , Katz Edward
Published: June 2012

A chemically defined medium, consisting of
d
-fructose,
l
-glutamic acid,
l
-histidine, K
2
HPO
4
, MgSO
4
·7H
2
O, ZnSO
4
·7H
2
O, CaCl
2
·2H
2
O, FeSO
4
·7H
2
O, CoCl
2
·6H
2
O, and deionized water, was developed for synthesis of high yields (500 to 600 μg/ml) of actinomycin D by
Streptomyces parvulus
. Under these nutritional conditions, growth and actinomycin formation did not follow a typical trophophase-idiophase pattern. The amino acids appeared to have a sparing action on the utilization of
d
-fructose which was slowly and incompletely metabolized during mycelium development and antibiotic production. A significant repression of actinomycin synthesis by
S. parvulus
was observed when
d
-glucose (0.01 to 0.25%) was added to the culture medium. The repression was not due to a decline in the pH of the medium during glucose catabolism.
Combined Antiviral Effects of Interferon, Adenine Arabinoside, Hypoxanthine Arabinoside, and Adenine Arabinoside-5′-Monophosphate in Human Fibroblast Cultures
Authors: Bryson Yvonne J. , Kronenberg L. H.
Published: June 2012

Adenine arabinoside and human interferon are currently being evaluated in clinical trials against herpes- and poxvirus infections. Interferon production is also a normal antiviral response. It is therefore important to examine the combined actions of interferon and antiviral arabinosides for possible synergy or antagonism. We have examined the antiviral activities of human fibroblast interferon, adenine arabinoside, hypoxanthine arabinoside, and adenine arabinoside 5′-monophosphate individually, using plaque inhibition of vaccinia and herpes simplex type 2 viruses in human skin fibroblast cultures. By combining doses of interferon and arabinosides that, acting alone, give intermediate degrees of plaque inhibition, we were able to compare the combined antiviral activity with that calculated from the activity of each inhibitor alone, assuming that the activities are statistically independent. Our results show that the plaque-inhibitory activities of interferon and the arabinosides tested are statistically independent. The results also show that the arabinosides do not destabilize the antiviral state previously induced by interferon, and that interferon pretreatment does not interfere with subsequent arabinoside action in infected cells. We have also found that arabinosides do not affect the induction of interferon synthesis by either Newcastle disease virus or double-stranded ribonucleic acid, and are not themselves interferon inducers.
Comparative Human Oral Clinical Pharmacology of Cefadroxil, Cephalexin, and Cephradine
Authors: Pfeffer Morris , Jackson Andre , Ximenes Jose , De Menezes Jairo Perche
Published: June 2012

At equivalent oral doses, cefadroxil has a longer serum half-life, slower urinary excretion rate, greater area under the serum level versus time curve than cephalexin or cephradine, and peak serum concentrations that are 75 to 80% those of cephalexin. The calculated, apparent in vivo volume of distribution of cefadroxil is greater than that of cephalexin. These properties infer greater persistence of cefadroxil in serum and urine and more prolonged in vivo bacterial exposure to cefadroxil than to cephalexin or cephradine. Neither cefadroxil nor cephalexin demonstrates drug accumulation on repeated administration. The serum levels achieved by cefadroxil are unaffected by food. The pharmacokinetic properties of cefadroxil are supportive of the development of clinical efficacy data which could indicate that cefadroxil could be administered at 12-h intervals.
Comparison of the Actions of 5-Fluorouracil and Ftorafur in
Escherichia coli
Authors: Saunders Priscilla P. , Chao Lian-Yu
Published: June 2012

The actions of 5-fluorouracil (FU) and Ftorafur (NCS 148958) were compared in
Escherichia coli
B3 to determine if Ftorafur can act in ways other than through the production of FU. Very high concentrations of Ftorafur relative to FU were necessary to achieve a comparable inhibition of cell growth. Inhibition by both agents could be reversed by uracil. An FU-resistant strain and an Ftorafur-resistant strain were isolated and found to be cross-resistant to Ftorafur and FU, respectively.
Terminal Stages in the Biosynthesis of Tylosin
Authors: Seno E. T. , Pieper R. L. , Huber F. M.
Published: June 2012

Tylosin, a macrolide antibiotic, was co-produced with four structurally similar antibiotics in fermentation cultures of
Streptomyces fradiae
. Macrocin, desmycosin, lactenocin, and relomycin were found to be components of a common pathway that functions in tylosin biosynthesis. Data obtained by the addition of the purified
14
C-labeled antibiotics to cultures of
S. fradiae
revealed that macrocin and desmycosin were direct precursors of tylosin, whereas lactenocin was an immediate precursor of both macrocin and desmycosin. Incubation of these cultures with [
14
C]tylosin resulted in an equivalent distribution of radioactive label between relomycin and an unidentified component. The kinetics of incorporation of label into the two species were similar, suggesting that both were derived directly from tylosin. A system that supported that methylation of macrocin to tylosin by cell-free extracts of
S. fradiae
was developed. A proposed scheme defining the terminal stages of tylosin biosynthesis is presented.
In Vitro Activity of Cinoxacin, Ampicillin, and Chloramphenicol Against
Shigella
and Nontyphoid
Salmonella
Authors: Rubinstein Ethan , Shainberg Bracha
Published: June 2012

The in vitro antibacterial activity of cinoxacin was compared with that of ampicillin and chloramphenicol against 26 strains of nontyphoid
Salmonella
and 44 strains of
Shigella
. Cinoxacin was found to have a lower minimal inhibitory concentration than ampicillin and chloramphenicol against all
Salmonella
and
Shigella sonnei
strains. Cinoxacin had minimal inhibitory concentrations similar to those of chloramphenicol but lower than those of ampicillin against
Shigella flexneri
and
S. boydii
strains.
Therapeutic Evaluation of Minocycline and Tetracycline for Mixed Anaerobic Infection in Mice
Authors: Hill Gale B.
Published: June 2012

Minocycline has demonstrated greater in vitro activity against anaerobic bacteria than its parent compound, tetracycline. In vivo therapeutic efficacy of the two drugs was tested against a mixed anaerobic infection in a mouse model.
Fusobacterium necrophorum
plus
F. nucleatum
injected intraperitoneally produced progressive intrahepatic and occasional extrahepatic abscesses, which were measured at autopsy. Three treatment regimens were tested, single daily doses of antibiotic being administered by oral gavage: four doses begun at 2 or 24 h after challenge and 14 doses begun 3 weeks after challenge when abscesses were well developed. Autopsy was not performed until several weeks after completion of treatment to assess long-term effects. Based on the number of mice without lesions, the median effective dose (ED
50
) in milligrams per kilogram per dose for minocycline was significantly lower than that for tetracycline with each regimen tested. With the 2-h (immediate therapy) regimen and the 24-h-delayed therapy regimen, minocycline was 30 and 6 times, respectively, more effective against hepatic abscesses than tetracycline on a weight basis. With each antibiotic, abscesses outside the liver were more resistant to therapy, although again minocycline was more effective. In the treatment of developed abscesses (3-week-delayed regimen), minocycline was effective (ED
50
<16 mg/kg), whereas tetracycline was ineffective (ED
50
>256 mg/kg). Minocycline has demonstrated greater therapeutic efficacy in vivo than tetracycline in this experimental infection, which is similar, in certain aspects, to human anaerobic infection. These data support further evaluation of the clinical usefulness of minocycline.
125
I Radioimmunoassay of Netilmicin
Authors: Stevens Paul , Young Lowell S. , Hewitt William L.
Published: June 2012

We report a radioimmunoassay for the new semisynthetic aminoglycoside netilmicin with a sensitivity of 480 pg per tube and a correlation coefficient of 0.94 between this radioimmunoassay and a microbioassay for measurement of netilmicin in serum.
Synergistic Action of Erythromycin and Cefamandole Against
Bacteroides fragilis
Subsp.
fragilis
Authors: Griffith R. S. , Brier G. L. , Wolny J. D.
Published: June 2012

Erythromycin and cefamandole have exhibited synergistic activity against eight strains of
Bacteroides fragilis
subsp.
fragilis
. In concentrations of only 0.25 to 0.5 μg of erythromycin per ml (easily obtainable with oral therapy), less than 0.4 μg (0.015 to 1.0) of cefamandole per ml inhibited the
B. fragilis
strains. In the presence of the erythromycin, the potency of cefamandole was increased more than 100-fold. On the basis of the mechanism of action of these two antibiotics, the synergism may be related to inhibition of beta-lactamase formation by the erythromycin, removal of the bacterial cell wall by the cefamandole permitting erythromycin penetration to the ribosomal level, and decreasing inoculum effect.
Antimicrobial Therapy of Experimental Group B Streptococcal Infection in Mice
Authors: Deveikis A. , Schauf V. , Mizen M. , Riff L.
Published: June 2012

Group B beta-hemolytic streptococci (GB-BHS) frequently cause severe infection in newborns. Previous in vitro studies showed accelerated killing of GB-BHS by ampicillin plus gentamicin as compared with ampicillin alone. To extend the in vitro observations, mice were infected experimentally with GB-BHS and treated with gentamicin plus ampicillin or ampicillin alone. Untreated mice died within 10 to 48 h. Compared with treatment with ampicillin alone, ampicillin-and-gentamicin therapy resulted in improved survival when the antibiotics were given in established infection or as a single dose at the time of infection. Ampicillin and gentamicin accelerated the clearing of bacteremia as compared with treatment with ampicillin alone. In view of these findings, the therapy of GB-BHS infection in newborns and other patients should be reconsidered in that a combination of ampicillin or penicillin G plus gentamicin might be superior to the use of ampicillin or penicillin G alone.