bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection by unsaturated lecithin against the imidazole antimycotics, clotrimazole and miconazole
Authors: Yamaguchi H
Published: June 2012

The activity of egg lecithin in preventing the antifungal action of the two imidazole antimycotics, clotrimazole and miconazole, was confirmed. However, addition of this phospholipid could not relieve an existing imidazole inhibition. Compared with egg lecithin, reduced egg lecithin showed no such protective effect. The addition of egg lecithin to an aqueous suspension of the imidazole drugs changed the absorption profile of the imidazole, suggesting a low solubility and, consequently, a lower effective concentration; however, the addition of reduced egg lecithin did not produce any change in the adsorption. These results indicate that the preventive effect of egg lecithin on imidazole inhibition may be a consequence of preferential in vitro interaction of the drug with unsaturated phospholipid to form a hydrophobic complex.
Penicillin-netilmicin synergism against Streptococcus faecalis
Authors: Korzeniowski O M , Wennersten C , Moellering R C , Sande M A
Published: June 2012

The combination of penicillin plus netilmicin was synergistic in vitro against 28 strains of Streptococcus faecalis and compared favorably with penicillin in combination with gentamicin. Similarly, penicillin plus netilmicin was as effective as penicillin plus gentamicin in the therapy of 67 rabbits with enterococcal endocarditis produced with a streptomycin-susceptible (S) or a streptomycin-resistant (R) strain of S. faecalis. After 5 days of infection, control rabbits had bacterial titers of 10(10) colony-forming units (CFU)/g of vegetation. Those treated with penicillin plus netilmicin had mean titers of 10(5.2) and 10(5.1) CFU/g for S and R strains, respectively, and those treated with penicillin plus gentamicin had mean valve titers of 10(5.8) CFU/g for both strains. After 10 days of therapy, mean valve titers with penicillin plus netilmicin were 10(3.8) and 10(4.7) CFU/g, and with penicillin plus gentamicin they were 10(4.5) and 10(5.4) CFU/g for S and R strains, respectively. Thus, if netilmicin proves to be less toxic than other aminoglycoside antibiotics, it may have potential usefulness in the therapy of enterococcal endocarditis.
Nephrotoxicity of netilmicin in combination with non-aminoglycoside antibiotics
Authors: Hagstrom G L , Luft F C , Yum M N , Sloan R S , Maxwell D R
Published: June 2012

To assess the possibility that non-aminoglycoside antibiotics may adversely affect the nephrotoxicity of the new semisynthetic aminoglycoside netilmicin, we gave ampicillin, carbenicillin, methicillin, cefamandole, and clindamycin, either singly or in combination with netilmicin, at two dose concentrations in rats. Results were compared as to the effect of netilmicin given singly and to saline-injected and noninjected controls. Antibiotic combinations resulted in no greater nephrotoxicity than did netilmicin alone. Netilmicin concentrations in renal tissue were high, and these levels were not consistently affected by the other drugs. The data suggest that in rats the nephrotoxicity of netilmicin is not affected adversely by the presence of non-aminoglycoside antibiotics.
Rapid determination of serum 5-fluorocytosine levels by high-performance liquid chromatography
Authors: Diasio R B , Wilburn M E , Shadomy S , Espinel-Ingroff A
Published: June 2012

A method for the rapid, quantitative determination of 5-fluorocytosine (5-FC) in serum by high-performance liquid chromatography (HPLC) has been developed. After initially ultrafiltrating the serum, a portion was injected onto a cation exchange column. 5-FC was separated by using an ammonium-phosphate buffer as the mobile phase and detected by ultraviolet absorption at 254 nm. Quantitation of 5-FC was based on the linear relationship between peak area in the chromatograms and known concentrations of 5-FC in a set of serum standards (prepared by adding from 10 to 200 micrograms of 5-FC to 1-ml aliquots of pooled human serum). This method was compared with the standard microbiological method for 5-FC. Advantages of the HPLC method include: Determination of 5-FC levels within 30 min; lack of interference from other antimicrobial drugs, particularly amphotericin B; more accurate determination of true 5-FC level, particularly at concentrations of less than 25 micrograms/ml or greater than 100 micrograms/ml; and ease with which the assay may be automated for routine use.
In vitro activity of chlorhydroxyquinoline against mycoplasma species
Authors: Cosgrove R F , Baines S
Published: June 2012

The in vitro activities of 5-chloro-8-hydroxyquinoline (CHQ) against single strains of 12 different species of mycoplasma and the impacts of repeated exposure of these strains to CHQ on their susceptibility to this agent have been studied. On initial exposure, the minimal inhibitory concentrations for these strains ranged from 0.24 to 1.92 micrograms of CHQ per ml of test medium; activities remained unchanged during 10 serial transfers in CHQ-containing medium.
Aminoglycoside Modification by Gentamicin-Resistant Isolates of
Staphylococcus aureus
Authors: Scott David F. , Wood David O. , Brownell George H. , Carter Mary Jo , Best Gary K.
Published: June 2012

Three clinical isolates of
Staphylococcus aureus
, which were previously shown to contain a 50S plasmid conferring resistance to several aminoglycosides, were examined for modifying enzymes. Both the wild-type and heat-cured derivatives of the isolates were screened for acetyl-, adenylyl-, and phosphotransferase activities. The substrates were gentamicin, amikacin, and netilmicin; the results indicated that even though all three activites were present, the phosphotransferase reaction was most responsible for resistance to these antibiotics. The absence of any of the modifying activites in cured derivatives of the three isolates supports the conclusion that aminoglycoside resistance in these strains is conferred by a plasmid.
Comparative Physiological Effects of Incorporated Amino Acid Analogs In
Escherichia coli
Authors: Pine Martin J.
Published: June 2012

The relative toxicities of several incorporated analogs of phenylalanine, methionine, arginine, and proline were assessed by a variety of criteria in a derivative of
Escherichia coli
15 requiring the antagonized amino acids. Toxicity of the analog-substituted cell protein was most consistently indicated by its insolubility at graded temperatures, its increased breakdown, the relative suppression of further cell growth, and lethality. The relative toxicity of poorly utilized analogs could be judged clearly only by the first two criteria. Toxicity generally increased as follows: selenomethionine < 2,5-dihydrophenylalanine and
m
-fluorophenylalanine <
o
-fluorophenylalanine and norleucine < ethionine <
p
-fluorophenylalanine < azetidine-2-carboxylate < canavanine. The overall perturbation of cell protein structure indicated by the toxicity of the methionine and phenylalanine analogs correlated with their alteration of charge and bulk and was greatly modified by minor positional modifications of fluorine. Among the more specific functional impairments, the activity and heat stability of β-galactosidase were lowered in parallel by substitutions of phenylalanine and methionine analogs, but not in the usual order of toxicity. Flagella were transiently motile with
p
-fluorophenylalanine, moderately motile with
m
-fluorophenylalanine, and fully motile with all methionine analogs. Usually the analog incorporations were no more than bacteriostatic in
E. coli
strains, canavanine killing only the
E. coli
15 substrain extensively in minimal media. Selenomethionine supported indefinite growth of procaryotes such as
Bacillus subtilis
and certain
E. coli
strains, but only upon supplementation, at least initially, with many nonessential metabolites.
Clinico-Pharmacological Studies of Sisomicin in Ill Children
Authors: Marks M. I. , Vose A. , Hammerberg S. , Dugal R.
Published: June 2012

Sisomicin, at 4.5 mg/kg per day, was prescribed for the therapy of serious bacterial infections of hospitalized infants, children, and adolescents. Eleven children received full treatment courses, with 10 clinical and 9 bacteriological cures. Three patients with underlying disease (two cystic fibrosis and one aplastic anemia) accounted for the failures. Mean half-life was 98.3 min (range, 26.1 to 159.3), and peak serum concentrations 10 min after intravenous infusion were similar (5 to 6 μg/ml) on days 1, 3, and 5 of therapy. Mean urinary concentrations were 54.3 μg/ml; 31 to 47% of the drug was excreted within the 8-h dosage interval. The drug was tolerated well by all patients; however, one patient, receiving the longest duration of therapy (26 days), developed reversible nephrotoxicity.
Nitrate Reduction: New Method for Testing the Antibiotic Susceptibility of
Haemophilus influenzae
Authors: Fleming Winifred , Fierer Joshua
Published: June 2012

We have developed a new micro-broth-dilution assay for determining the antimicrobial susceptibility of
Haemophilus influenzae
. This assay is based on the ability of viable
H. influenzae
to reduce nitrates to nitrites. Bacterial viability is detected by a positive nitrite reaction rather than visible turbidity. The nitrate reduction assay was compared with a standard microassay using 51 isolates of
H. influenzae
and six beta-lactam antibiotics. Although there was good agreement between the two methods, the nitrate reduction assay was more sensitive in detecting viable bacteria, and so established a more accurate estimate of the minimal inhibitory concentration. The nitrate reduction assay offered the additional advantage that it could be used to determine the minimal bactericidal concentration without having to subculture the broth. Ampicillin, penicillin, and cefamandole were equally effective in vitro against susceptible strains (minimal inhibitory concentrations, 0.125 to 0.5 μg/ml), whereas all three antibiotics were ineffective against two beta-lactamase-producing strains. Using the nitrate reduction assay, resistance to cefamandole was detectable with inoculum sizes ranging from 10
4
to 10
6
colony-forming units per ml, while the turbidity assay detected resistance only with the largest inoculum.
Activity of Three 8-Hydroxyquinoline Derivatives Against In Vitro Dental Plaque
Authors: Tanzer J. M. , Slee A. M. , Kamay B. , Scheer E.
Published: June 2012

Three 8-hydroxyquinoline derivatives, assessed using an in vitro preformed dental plaque model system, were differentially inhibitory for four plaque-forming microorganisms.
Incidence and Characteristics of Antibiotic-Tolerant Strains of
Staphylococcus aureus
Authors: Bradley J. J. , Mayhall C. G. , Dalton H. P.
Published: June 2012

Thirty clinical isolates of
Staphylococcus aureus
were tested for tolerance to oxacillin, cephalothin, and gentamicin by using killing curves and broth dilution susceptibility tests. Tolerance was defined as the presence of≥100 colony-forming units per ml remaining after 24 h of incubation of the killing curve suspensions. Nineteen of 30 isolates were tolerant to oxacillin and cephalothin, but none was tolerant to gentamicin. Among the tolerant isolates, there was a wide spectrum of tolerance, with from 0.2 to 43% of the colony-forming units in the starting inoculum remaining after 18 to 24 h of incubation. Tolerance was unrelated to phage type or to any of several other characteristics studied.
Azlocillin and Mezlocillin: New Ureido Penicillins
Authors: Fu Kwung P. , Neu Harold C.
Published: June 2012

The activity of azlocillin and mezlocillin, new semisynthetic ureido penicillins, was investigated and compared with that of other known β-lactam antibiotics. At a concentration of 25 μg/ml, azlocillin inhibited 74% of
Enterobacter
, 97% of
Proteus mirabilis
, 64% of
Citrobacter
, 91% of
Pseudomonas aeruginosa
, and 82% of
Bacteroides
strains tested. Mezlocillin inhibited 86% of
Shigella
, 96% of
Enterobacter
, 80% of indole-positive
Proteus
, 88% of
Bacteroides
, and 63% of
Pseudomonas
strains tested. Azlocillin was more active against
Pseudomonas
than was ticarcillin, carbenicillin, or mezlocillin. Mezlocillin was more active than carbenicillin and ampicillin against
Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Acinetobacter, Serratia
, and
Bacteroides
. Azlocillin and mezlocillin were less active than cefazolin against β-lactamase-producing
E. coli
and
Klebsiella
strains but more active than cefazolin against
Enterobacter
, indole-positive
Proteus, Acinetobacter, Citrobacter
, and
Serratia
strains. Both compounds showed activity equivalent to that of cefoxitin against
Bacteroides
isolates. Both agents were destroyed by many of the β-lactamases from gram-negative organisms.
Therapeutic Failures with Miconazole
Authors: Fisher John F. , Duma Richard J. , Markowitz Sheldon M. , Shadomy Smith , Espinel-Ingroff Ana , Chew William H.
Published: June 2012

A retrospective review of therapeutic failures of miconazole in three patients is presented. Miconazole, a new imidazole derivative, is a broad-spectrum antifungal agent purportedly effective topically, orally, and parenterally against a number of species of fungi. Three patients with the following culturally proven deep fungal infections were treated with miconazole: (i) destructive arthritis (
Sporothrix schenckii)
, (ii) meningoencephalitis (
Cryptococcus neoformans
), and (iii) disseminated aspergillosis (
Aspergillus fumigatus
). All the organisms were susceptible in vitro to 1.56 μg or less of miconazole per ml using a broth dilution technique. In each patient, miconazole administered intravenously in dosages of 30 mg/kg per day failed to control or eradicate infection. Miconazole serum levels ranged from <0.5 to 4.35 μg/ml as determined by radial diffusion bioassay. Cerebrospinal fluid levels were virtually undetectable. In one patient (
C. neoformans
), miconazole was given intraventricularly in doses of 15 mg without response. Therapeutic failures were attributed to suboptimal body fluid levels of miconazole. The reason(s) for such low levels of activity was not clear, but may have been poor penetrance into tissues, in vitro inactivation, and/or unusually rapid excretion. Untoward reactions from miconazole included fever, chills, nausea, vomiting, and phlebitis.
Comparison of Serum Bactericidal Activity Among Three Antimicrobial Combinations
Authors: Murillo Jorge , Standiford Harold C. , Schimpff Stephen C. , Tatem Beverly A.
Published: June 2012

Three antimicrobial combinations, ticarcillin plus cephalothin (T+C), ticarcillin plus gentamicin (T+G), and cephalothin plus gentamicin (C+G), were administered to 105 febrile granulocytopenic cancer patients at the Baltimore Cancer Research Center as part of a multi-institutional prospective randomized antibiotic trial. The sera from 32 of these patients (T+C−10 patients, T+G−10 patients, and C+G−12 patients) obtained 1 h post-antibiotic administration were examined for bactericidal activity against 11 strains each of the most common pathogens infecting the granulocytopenic host:
Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli
, and
Staphylococcus aureus
. Each of the three antibiotic regimens produced a high degree of bactericidal activity in these sera against
S. aureus
and
E. coli. P. aeruginosa
was equally, although poorly, killed by sera containing ticarcillin (T+G, T+C), whereas C+G produced no measurable serocidal activity (
P
< 0.05). Sera with C+G killed
K. pneumoniae
more effectively than T+G; T+C produced the least killing effect of the three regimens against this organism (
P
< 0.05). The bactericidal activity of the serum from these 32 patients supplements the overall clinical results of the multi-institutional antibiotic trial and suggests that T+G is a useful initial regimen for empiric therapy of febrile episodes in granulocytopenic cancer patients.
Differences in Susceptibilities of Virulent Strains and Avirulent Strains of
Neisseria gonorrhoeae
to Antimicrobial Agents
Authors: Lim Daniel V.
Published: June 2012

Virulent cells (T1 colony type) and avirulent cells (T4 colony type) of
Neisseria gonorrhoeae
were grown in a defined liquid medium in the presence of different antimicrobial agents. Bacteria of T1 colony type were found to be more resistant than bacteria of T4 colony type to the inhibitory effects of specific concentrations of ampicillin (0.50 μg/ml) and penicillin (0.01 μg/ml). Bacteria of T4 colony type, however, were found to be more resistant to the effects of chloramphenicol (0.40 μg/ml), erythromycin (0.10 μg/ml), spectinomycin (10.00 μg/ml), and tetracycline (0.30 μg/ml). The differences in susceptibilities of these bacteria to the antibiotics investigated were not due to differences in growth rate or to differences in permeability. The data suggest that virulent gonococci and avirulent gonococci have unique properties that affect their susceptibilities to certain antimicrobial agents.
Bactericidal Activity of Cephalosporins in an In Vitro Model Simulating Serum Levels
Authors: Nishida Minoru , Murakawa Takeo , Kamimura Toshiaki , Okada Naohiko
Published: June 2012

The bactericidal activity of cefazolin, cephaloridine, and cephalothin in a simulated intramuscular study (500 mg) and a simulated intravenous drip infusion study (2 g/2 h) is reported. In both model systems, the bactericidal activity of cefazolin surpassed that of cephalothin, and there were certain differences between cefazolin and cephaloridine in the simulated intramuscular study when human serum was used as a medium. In a routine reference static system, the drug levels were constant at the simulated peak level of each cephalosporin by both routes. In this system the three cephalosporins were equal in activity. In a third experiment, the effect of drug concentrations and exposure time on bactericidal activity of the cephalosporins was studied. The bactericidal activity of cephaloridine was the strongest of the three drugs when exposure time was 2 h and drug concentration was less than four times the minimal inhibitory concentration. At concentrations above four times the minimum inhibitory concentration, all three cephalosporins were equal in activity when the exposure time was 2 h.
Pharmacokinetics of Cefaclor and Cephalexin: Dosage Nomograms for Impaired Renal Function
Authors: Spyker Daniel A. , Thomas Bruce L. , Sande Merle A. , Bolton W. Kline
Published: June 2012

The pharmacokinetics of cefaclor and cephalexin were characterized in patients with creatinine clearances ranging from 0 to 147 ml/min. Each of 24 fasted subjects received a single 500-mg oral dose of cefaclor, and 13 of these subjects later received 500 mg of cephalexin. Serum and urine levels of the antibiotics were measured by bioassay. The serum half-lives were highly correlated with corrected creatinine clearance (cefaclor
r
= 0.92, cephalexin
r
= 0.94). Linear regression estimates of the half-life of cefaclor were 2.3 h in the anephric patient and 40 min in the patient with a corrected creatinine clearance of 100 ml/min. For cephalexin, corresponding half-lives were 15.4 h and 58 min. We present a dosage nomogram for calculating the appropriate adjustments to the loading dose based on patient weight and maintenence dose based on corrected creatinine clearance.
Erythrocyte Surface: Novel Determinant of Drug Susceptibility in Rodent Malaria
Authors: Fitch Coy D. , Ng Roland C. K. , Chevli Rekha
Published: June 2012

To study the role of the erythrocyte membrane in the process of chloroquine accumulation, surface polypeptides were digested with a nonspecific protease from
Streptomyces griseus
. This treatment activated a saturable process of chloroquine accumulation with an affinity and a specificity similar to those of mouse erythrocytes infected with
Plasmodium berghei
CS (chloroquine susceptible). Studies of competitive inhibitors of chloroquine accumulation yielded the following approximate values for

K
i

: amodiaquine, 2 × 10
−7
M; quinacrine, 5 × 10
−7
M; quinine, 2 × 10
−6
M; and mefloquine, 2 × 10
−5
M. Lack of a substrate requirement distinguished this process from the one used by
P. berghei
and permitted the protease to be used in studies of infected erythrocytes. Protease treatment of erythrocytes infected with
P. berghei
CR (chloroquine resistant) produced a dramatic transformation. Instead of describing a sigmoid curve, the process of chloroquine accumulation became saturable and substrate dependent, with a

K
diss

of approximately 10
−8
M; i.e., protease-treated erythrocytes infected with
P. berghei
CR now behaved similarly to those infected with
P. berghei
CS. Coating the erythrocyte surface with albumin completely inhibited the protease-activated process of chloroquine accumulation. These findings are presented as evidence that erythrocyte surface components determine the affinity with which chloroquine is accumulated and thereby determine whether or not the malaria parasite will be susceptible to the drug.
In Vitro Activity of Rosamicin and Erythromycin Against a Group of Nonfermenting Gram-Negative Bacilli
Authors: DiPersio Joseph R. , Krafczyk Theodore L.
Published: June 2012

The in vitro inhibitory activity of rosamicin and erythromycin against 283 strains of nonfermenting, gram-negative bacilli was determined by using a broth dilution procedure. Rosamicin demonstrated greater activity than erythromycin against most strains tested. A number of species demonstrated significantly lower minimum inhibitory concentrations to rosamicin and would fall within the therapeutic range of the drug based on current pharmacological data.
Pharmacology of Intraperitoneal Cefazolin in Patients Undergoing Peritoneal Dialysis
Authors: Kaye Donald , Wenger Norma , Agarwal Brajesh
Published: June 2012

Cefazolin was added to dialysis fluid in nine patients with renal failure undergoing peritoneal dialysis with 2 liters/h per exchange. With 50 mg/liter (three patients), the first measurable mean serum concentration was 3.7 μg/ml (range, 2.4 to 4.9 μg/ml) after three exchanges and was 30.3 μg/ml (range, 13.3 to 44.3 μg/ml) after 24 exchanges. After 18 to 24 more exchanges without cefazolin, the mean serum concentration was 12.3 μg/ml (range, 3.8 to 24.6 μg/ml). The mean concentration in the dialysis outflow was 26.9 μg/ml (range, 2.5 to 58.5 μg/ml). With 150 mg/liter (six patients), the mean serum concentration was 5.2 μg/ml (range, 3.6 to 7.8 μg/ml) after the first exchange and 8.4 (range, 6.1 to 14.0 μg/ml), 15.0 (range, 8.2 to 23.5 μg/ml), and 71.9 (range, 26.2 to 142.1 μg/ml) μg/ml after the second, third, and twenty-fourth exchanges, respectively. After 17 to 24 more exchanges without cefazolin, the mean serum concentration was 38.2 μg/ml (range, 15.4 to 65.7 μg/ml). The mean concentration in the dialysis outflow was 71.4 μg/ml (range, 21.9 to 150.8 μg/ml). After 1 g of cefazolin was given intraperitoneally with no more dialysis, serum concentrations rose by a mean of 62.5 μg/ml (range, 18.9 to 107.8 μg/ml). The maximum rise occurred within 2 h with two-thirds of the rise occurring within 30 min. During the subsequent 22 h levels dropped to 65.4% of the peak.
Single and Combination Antibiotic Therapy of
Staphylococcus aureus
Experimental Endocarditis: Emergence of Gentamicin-Resistant Mutants
Authors: Miller Michael H. , Wexler Marjorie A. , Steigbigel Neal H.
Published: June 2012

The efficacy of nafcillin and gentamicin used alone and in combination at doses giving serum concentrations comparable to those achieved in patients was studied in rabbits with experimental
Staphylococcus aureus
endocarditis. The organism used was a penicillinase-producing, methicillin-susceptible, clinical isolate. The addition of gentamicin to nafcillin significantly increased the rate of killing of organisms in valvular vegetations, compared to the effect of nafcillin alone. Gentamicin alone delayed mortality but was not effective in reducing the bacterial populations of the vegetations. Bacteremia persisted in the animals treated with gentamicin alone, in contrast to the groups treated with nafcillin or the combination. Selection of a subpopulation of aminoglycoside-resistant small-colony variants occurred in animals treated with gentamicin alone. This variant was subsequently employed in the rabbit model and produced endocarditis, metastatic infection, and bacteremia comparable to those caused by the parent strain. Animals with infection produced by the variant died later than animals infected by the parent strain. Nafcillin was equally effective in reducing the population of both parent and variant strains in vitro and in therapy of the infected animals. Population studies showed the variant to be a mutant emerging at a rate of 1.9 × 10
−7
. It was shown to differ from the parent strain in coagulase and hemolysin production, colonial morphology, and aminoglycoside susceptibility, but was similar by light and electron microscopy and in phage type, pigmentation of colonies, deoxyribonuclease production, mannitol fermentation, and growth rate.
HEp-2 Cell- and Herpes Simplex Virus Type 1- Induced Deoxythymidine Kinases: Inhibition by Derivatives of 5-Trifluoromethyl-2′-Deoxyuridine
Authors: Wigdahl Brian L. , Parkhurst J. Rodney
Published: June 2012

5-Trifluoromethyl-2′-deoxyuridine (F
3
Thd), its free base and nucleotide triphosphate derivative, along with the nucleotide monophosphate and nucleotide triphosphate of deoxythymidine (dThd), were investigated as inhibitors of HEp-2 cell deoxythymidine kinase (dTK) and herpes simplex virus type 1 (HSV-1)-induced dTK. 5-Trifluoromethyluracil did not inhibit cellular or viral dTK. F
3
dThd competitively inhibited phosphorylation of dThd by both the HEp-2 cell- and the HSV-1-induced dTK. The

K
mapp

for dThd and the

K
Iapp

for the alternate substrate, F
3
dThd, were 3.5 and 22.5 μM for the HEp-2 cell dTK and 63.5 and 71.0 μM for the HSV-1-induced dTK. dThd-5′-PPP at 10 μM inhibited HEp-2 cell- and HSV-1-induced dTK by 94 and 22%, respectively. In comparison, 10 μM F
3
dThD-5′-PPP inhibited HEp-2 cell- and HSV-1-induced dTK 95 and 15%, respectively. These data indicate that F
3
dThd-5′-PPP may mimic dThd-5′-PPP feedback regulation of cellular and viral dTK.
Penetration of Clindamycin into Decubitus Ulcers
Authors: Berger Stephen A. , Barza Michael , Haher Jane , McFarland James J. , Louie Samuel , Kane Anne
Published: June 2012

Forty tissue samples, primarily of skin and bone, were obtained from 29 patients undergoing excision of decubitus ulcers after intravenous injection of 600 mg of clindamycin. Antibiotic concentrations exceeded 2.5 μg/g in 80% of the samples. In 50% of the instances, tissue levels were greater than those simultaneously present in the serum.
Analysis of the Interactions Between Piperacillin, Ticarcillin, or Carbenicillin and Aminoglycoside Antibiotics
Authors: Chanbusarakum Puangpetch , Murray Patrick R.
Published: June 2012

Enhanced activity against clinical isolates of
Pseudomonas aeruginosa
was demonstrated with piperacillin, ticarcillin, and carbenicillin in combination with gentamicin, tobramycin, and amikacin.
Susceptibility of
Campylobacter fetus
subsp.
jejuni
to Twenty-Nine Antimicrobial Agents
Authors: Vanhoof R. , Vanderlinden M. P. , Dierickx R. , Lauwers S. , Yourassowsky E. , Butzler J. P.
Published: June 2012

The activity of 29 antimicrobial agents was tested against 95 strains of
Campylobacter fetus
subsp.
jejuni
isolated from human stools. Furazolidone and gentamycin were the most active agents. The tetracyclines, erythromycin, and chloramphenicol were very active against most of the strains, but with each antibiotic a few resistant strains were found. The penicillins were relatively inactive, and the cephalosporins tested were only active against occasional strains.
Effect of β-Lactam Antibiotics on In Vitro Peptidoglycan Cross-Linking by a Particulate Fraction from
Escherichia coli
K-12 and
Bacillus megaterium
KM
Authors: Oka Tetsuo , Fujita Hironori
Published: June 2012

The binding constants of several β-lactam antibiotics towards penicillin-binding components in
Escherichia coli
K-12 (Spratt, Eur. J. Biochem.
72:
341–352, 1977) and the antibiotic concentrations required to inhibit the peptidoglycan transpeptidase of
E. coli
50% were compared. Penicillin-binding component 1B may have been the transpeptidase working in vitro. The structure-activity relationships of β-lactam antibiotics and the mechanisms of action in
E. coli
and
Bacillus megaterium
are discussed.
Antimalarial Activities of WR-194,965, an α-Amino-
o
-Cresol Derivative
Authors: Schmidt L. H. , Crosby Ruth
Published: June 2012

Pilot appraisals of the activities of WR-194,965 and WR-204,165, two closely related
o
-cresol derivatives (both Mannich bases), in owl monkeys infected with the multidrug-resistant Vietnam Smith strain of
Plasmodium falciparum
showed that these compounds had similar levels of efficacy. Total course doses effecting 90% cures (CD
90
s) were 27 and 37 mg/kg of body weight for the respective compounds, values almost identical to the CD
90
of mefloquine (a highly promising 4-quinolinemethanol) against infections with the same strain, and the CD
90
s of chloroquine against infections with 4-aminoquinoline-susceptible strains. Expanded studies of the activities of WR-194,965 against infections with the Smith strain of
P. falciparum
and Vietnam Palo Alto strain of
P. vivax
, designed to guide projected evaluations in human volunteers, showed: (i) that the activity of this compound was a function of total dose administered, with single doses as effective as the same amount delivered in three or seven successive daily fractions; (ii) that all regimens effected rapid clearance of parasitemia; and (iii) that based on CD
90
s, this agent was twice as active against infections with the Palo Alto strain of
P. vivax
as against the Smith strain of
P. falciparum
. These findings, together with results of preclinical pharmacological studies pursued elsewhere, provided support for studies in human volunteers now underway.
Effect of Feeding Chlortetracycline on the Reservoir of
Salmonella typhimurium
in Experimentally Infected Swine
Authors: Williams Robert D. , Rollins Larry D. , Pocurull Dorothy W. , Selwyn Murray , Mercer H. Dwight
Published: June 2012

Swine were fed either a diet containing 110 mg of chlortetracycline (CTC) per kg (100 g/ton) or a control diet and were inoculated orally with
Salmonella typhimurium
that was either susceptible or resistant to CTC. The quantity, duration, and prevalence of fecal elimination of
S. typhimurium
, as well as the effect of CTC on the transmission of
S. typhimurium
from infected to uninfected swine, were determined. When animals were infected with CTC-resistant
S. typhimurium
, CTC increased the quantity (
P
< 0.05), duration (
P
< 0.05), and prevalence (
P
< 0.01) of fecal shedding, the transmission from infected to uninfected swine, and the recovery of the infecting organism at necropsy. When animals were infected with CTC-susceptible
S. typhimurium
, CTC reduced the quantity (between 7 and 10 days postinfection) (
P
< 0.01), duration (
P
< 0.05), and prevalence (
P
< 0.05) of fecal shedding, the transmission from infected to uninfected swine, and the recovery of the infecting organism at necropsy. Resistance to tetracycline was transferred in vivo to 4 and 6% of the susceptible infecting
S. typhimurium
recovered from the untreated and treated groups, respectively. The increased reservoir of
S. typhimurium
and the transfer of resistance to susceptible
S. typhimurium
have implications for both animal and public health.
Effect of Two Cancer Chemotherapeutic Agents on the Antibacterial Activity of Three Antimicrobial Agents
Authors: Moody Marcia R. , Morris Maureen J. , Young Viola Mae , Moyé Lemuel A. , Schimpff Stephen C. , Wiernik Peter H.
Published: June 2012

Cancer chemotherapeutic agents and antibacterial antibiotics are often given concomitantly. Daunorubicin, cytosine arabinoside, and three antibiotics (gentamicin, amikacin, and ticarcillin) were tested individually and in combinations to determine their antimicrobial activity against
Pseudomonas aeruginosa, Klebsiella pneumoniae
, and
Escherichia coli
. These cytotoxic agents are commonly employed in the therapy of acute nonlymphocytic leukemia for remission induction therapy, and these antimicrobial agents are used in infection therapy. The maximum concentrations of the two cytotoxic drugs were chosen to be twice the known peak plasma levels of commonly employed dosage schedules. Neither of the cancer chemotherapeutic agents, alone or in combination, demonstrated bactericidal activity at the levels tested. However, in the presence of these agents, the antimicrobial activity of gentamicin and amikacin, although not that of ticarcillin, was depressed for 11 of 15
K. pneumoniae
strains and 8 of 15
P. aeruginosa
strains, but for none of the strains of
E. coli
. This level of decreased activity occasionally resulted in a minimal inhibitory concentration of the tested aminoglycoside well above the standard serum levels. Daunorubicin was more likely to antagonize gentamicin than was cytosine arabinoside.
Improved Susceptibility Disk Assay Method Employing an Agar Overlay Technique
Authors: Anderson Blondell
Published: June 2012

Susceptibility disks impregnated with 35 different antibiotics were assayed by the current
Code of Federal Regulations
method and by a new method employing an agar overlay. The new method, a simplified analytical procedure, exhibited improvement in zone definition and an increase in dose response. Assays performed by the new method were accurate and precise. The agar overlay technique appears to be superior to the current
Code of Federal Regulations
method.
Effects of Thiamphenicol and Chloramphenicol in Inhibiting
Neisseria gonorrhoeae
Isolates
Authors: Duck P. D. , Dillon J. R. , Eidus L.
Published: June 2012

Thiamphenicol was compared with penicillin, tetracycline, and chloramphenicol for its ability to inhibit 530 isolates of
Neisseria gonorrhoeae
, including 13 penicillinase-producing isolates. Thiamphenicol proved to be as active as chloramphenicol in inhibiting all of the isolates.
Inhibition of β-Lactamase in
Neisseria gonorrhoeae
by Sodium Clavulanate
Authors: Miller J. Michael , Baker Carolyn N. , Thornsberry Clyde
Published: June 2012

Sodium clavulanate at subinhibitory concentrations affected the activity of penicillin G, ampicillin, or amoxicillin on β-lactamase-positive strains of
Neisseria gonorrhoeae
as demonstrated by marked reduction in the minimal inhibitory concentrations of the drugs for the organisms. The compound did not affect the activity of these penicillins on β-lactamase-negative strains of
N. gonorrhoeae
. It also had no effect on the activity of cefoxitin against either β-lactamase-negative or -positive strains. The reduction in minimal inhibitory concentrations of the penicillins for the β-lactamase-positive organisms brought about by sodium clavulanate is probably due to inhibition of the β-lactamase by the compound.
Treatment of Experimental Herpesvirus Infections with Phosphonoformate and Some Comparisons with Phosphonoacetate
Authors: Kern Earl R. , Glasgow Lowell A. , Overall James C. , Reno John M. , Boezi John A.
Published: June 2012

Phosphonoformate (PF) at a concentration of 5 to 10 μg/ml inhibited the growth of type 1 strains of herpes simplex virus (HSV) in tissue culture, whereas 20 to 30 μg/ml was required for inhibition of type 2 strains and about 50 μg/ml was required for murine cytomegalovirus. In mice inoculated intraperitoneally or intracerebrally with HSV or intraperitoneally with murine cytomegalovirus, treatment with 250 to 400 mg of PF per kg twice daily for 5 days had only minimal effectiveness. When mice were inoculated intravaginally (i.vg.) with HSV type 2 and treated i.vg. with 10% PF beginning 3 h after viral inoculation, treatment was effective in completely inhibiting viral replication in the genital tract. If i.vg. therapy was initiated 24 h after infection, when the mice had a mean virus titer of 10
5
plaque-forming units in vaginal secretions, a significant reduction in the mean virus titer was observed on days 3, 5, and 7 after infection as compared with control animals. In guinea pigs treated i.vg. with 10% PF beginning 6 h after i.vg. inoculation with HSV type 2 there was also complete inhibition of viral replication in the genital tract, and no extenal lesions developed. When therapy was initiated 24 h after infection there was a 4 to 5-log decrease in viral titers on days 3, 5, and 7 of the infection and a slight delay in the development of external lesions.
Effects of Nucleoside Analogs on Epstein-Barr Virus-Induced Transformation of Human Umbilical Cord Leukocytes and Epstein-Barr Virus Expression in Transformed Cells
Authors: Henderson Earl E. , Long Walter K. , Ribecky Renee
Published: June 2012

Two methods of assay, measuring (i) stimulation of host cell DNA synthesis by [
3
H]thymidine incorporation and (ii) morphological transformation in microtiter plates, were employed to determine what effect treatment during infection with adenine arabinoside or 5-iodo-5′-amino-2′,5′-dideoxyuridine has on Epstein-Barr virus (EBV) (B95-8)-induced transformation of human umbilical cord leukocytes. It was found that adenine arabinoside inhibited EBV-induced transformation in a dose-dependent manner in both assays, beginning at drug concentrations (<2 μg/ml) which had little effect on either spontaneous or phytohemagglutinin-induced host cell DNA synthesis. Adenine arabinoside was more effective in inhibiting morphological transformation than EBV-induced host DNA synthesis. Adenine arabinoside treatment was also effective in reducing both EB viral capsid antigen expression and production of biologically active extracellular transforming virus in EBV-transformed cells. In contrast, 5-iodo-5′-amino-2′,5′-dideoxyuridine, which inhibited herpes simplex virus replication, had little effect on EBV-induced transformation as measured by either method of assay. However, 5-iodo-5′-amino-2′,5′-dideoxyuridine was found to be effective in inhibiting viral capsid antigen expression and production of extracellular transforming virus in EBV-transformed cells.
Autoradiographic Localization of [
3
H]Gentamicin in the Proximal Renal Tubules of Mice
Authors: Kuhar Michael J. , Mak Linda L. , Lietman Paul S.
Published: June 2012

The site of localization of [
3
H]gentamicin within mouse kidney is shown to be the proximal renal tubule by coincidence of the radioactivity, as visualized by autoradiography, and the mucopolysaccharide-rich microvilli characteristic of proximal convoluted tubules, as visualized by histochemical staining.
Lack of Correlation Between β-Lactamase Production and Susceptibility to Cefamandole or Cefoxitin Among Spontaneous Mutants of
Enterobacteriaceae
Authors: Ott John L. , Turner J. R. , Mahoney David F.
Published: June 2012

A large number of cultures of gram-negative bacteria were examined for their susceptibility to various concentrations of cefamandole, cefoxitin, carbenicillin, and nalidixic acid. Heterogeneity of susceptibility was demonstrated in individual cultures to all of these antibiotics. Resistant clones isolated from cefamandole or cefoxitin plates were examined for β-lactamase production. Approximately 13% of 262 resistant clones acquired the ability to produce a β-lactamase. Examination of the substrate profile of the β-lactamases from some of these clones revealed no change in the specific activity of these enzymes for cefamandole, cephaloridine, or compound 87/312 as compared with their parental enzymes. This study clearly shows that some resistant clones do not produce β-lactamases, whereas some susceptible strains produced significant amounts of these enzymes. We conclude from these findings that little correlation exists between β-lactamase production and decreased susceptibility to cefamandole or cefoxitin. The results suggest the possibility that characteristics other than β-lactamase production may be responsible for resistance in
Enterobacteriaceae
.
Pyrrolo(1,4)benzodiazepine Antitumor Antibiotics: Biosynthetic Studies on the Conversion of Tryptophan to the Anthranilic Acid Moieties of Sibiromycin and Tomaymycin
Authors: Hurley Laurence H. , Gairola Chandrachuranand
Published: June 2012

Biosynthetic intermediates between tryptophan and the anthranilate moieties of tomaymycin and sibiromycin have been suggested, based upon a combination of feeding experiments with either carbon-14-labeled substrates or competition experiments between radiolabeled tryptophan and unlabeled intermediates. In the case of sibiromycin and tomaymycin, substitution of the aromatic ring most likely takes place at the kynurenine stage. Feeding experiments with the anthramycin culture were inconclusive, most likely because of the cell impermeability.
Mechanism of Aminoglycoside Antibiotic Resistance in Anaerobic Bacteria:
Clostridium perfringens
and
Bacteroides fragilis
Authors: Bryan L. E. , Kowand S. K. , Van Den Elzen H. M.
Published: June 2012

Cell-free amino acid incorporation using ribosomes from strains of either
Clostridium perfringens
or
Bacteroides fragilis
was shown to be susceptible to inhibition by streptomycin and gentamicin. Ribosomes bound dihydrostreptomycin as effectively as ribosomes from
Escherichia coli
. No inactivation of streptomycin or gentamicin was detected by cell extracts of either anaerobic bacterial species.
B. fragilis
, grown without added hemin, menadione, and fumarate, and
C. perfringens
did not show any time-dependent accumulation of dihydrostreptomycin or gentamicin at concentrations tested. Decreased resistance to aminoglycosides and time-dependent uptake of dihydrostreptomycin at 500 μg/ml was observed with
B. fragilis
grown with hemin, menadione, and fumarate. With the last additions, cytochrome
b
was detected by cytochrome spectra of
B. fragilis
. These results demonstrate that anaerobic bacteria unable to carry out oxygen- or nitrate-dependent electron transport are resistant to streptomycin and gentamicin because of failure to transport aminoglycosides. The induction of fumarate-dependent electron transport in
B. fragilis
is associated with some aminoglycoside transport that is of poor efficiency relative to bacteria with electron transport to oxygen or nitrate.
Outer-Membrane Penetration Barriers as Components of Intrinsic Resistance to Beta-Lactam and Other Antibiotics in
Escherichia coli
K-12
Authors: Scudamore R. Allan , Beveridge Terrance J. , Goldner Morris
Published: June 2012

A new technique has been devised to investigate the penetration of antibiotics through the gram-negative outer membrane; the application here was to study intrinsic resistance of
Escherichia coli
K-12. Exponential cells in broth were briefly treated with 2.5 mM ethylenediaminetetraacetic acid at 5°C to disrupt the outer membrane penetration barrier, and the response of treated and untreated cells to antibiotics was compared by turbidimetry. A barrier index was derived to describe the ability of 7 beta-lactam and 10 other antibiotics to penetrate the outer membrane of strain Y10. There was correlation between the molecular weight and log
10
barrier index (
r
= 0.59,
P
≅ 0.01). The envelope mutant D22 (
envA
) had low barrier indexes for erythromycin, rifampin, ampicillin, and cloxacillin. For the beta-lactams, outer membrane penetration and affinity for inner membrane target site(s) triggering cell lysis were measured as independent components of the overall activity; although penetration and overall activity varied greatly, the affinities of most were within a narrow range.
HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria
Authors: Neu Harold C. , Aswapokee Nalinee , Aswapokee Prasit , Fu Kwung P.
Published: June 2012

The in vitro activity of HR 756, 7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoximino)acetamido] cephalosporanic acid, was investigated against 659 isolates. HR 756 inhibited
Neisseria
and
Haemophilus
species at concentrations similar to those needed with ampicillin. It inhibited β-lactamase-producing
N. gonorrhoeae
and
H. influenzae
. HR 756 was the most active compound tested against members of the
Enterobacteriaceae
, inhibiting most isolates of
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, Enterobacter
, and
Shigella
at concentrations of less than 0.1 μg/ml. It was twice as active as carbenicillin against
Pseudomonas aeruginosa
and inhibited
Bacteroides fragilis
as well as cefoxitin. HR 756 killed
E. coli, Staphylococcus aureus
, and
P. aeruginosa
at rates similar to other β-lactam antibiotics.
Application of Oxygen-Enriched Aeration in the Production of Bacitracin by
Bacillus licheniformis
Authors: Flickinger M. C. , Perlman D.
Published: June 2012

The physiological effects of controlling the dissolved oxygen tension at 0.01, 0.02, and 0.05 atm by the use of oxygen-enriched aeration were investigated during growth and bacitracin production by
Bacillus licheniformis
ATCC 10716. Up to a 2.35-fold increase in the final antibiotic yield and a 4-fold increase in the rate of bacitracin synthesis were observed in response to O
2
-enriched aeration. The increase in antibiotic production was accompanied by increased respiratory activity and an increase in the specific productivity of the culture from 1.3 to 3.6 g of antibiotic per g of cell mass produced. Oxygen enrichment of the aeration decreased medium carbohydrate uptake and the maximum specific growth rate of
B. licheniformis
from 0.6 h
−1
to as low as 0.15 h
−1
, depending upon the level of enrichment and the conditions of oxygen transfer rate (impeller speed). The response of this culture to O
2
enrichment suggests that this method of controlling the dissolved oxygen tension for antibiotic-producing cultures may simulate conditions that would occur if the carbon source were fed slowly, as is often employed to optimize antibiotic production. Analysis of the biologically active bacitracins produced by
B. licheniformis
ATCC 10716 suggested that the ratio of biologically active peptides was not changed by O
2
enrichment, nor were any new biologically active compounds formed.
Resistance of African Green Monkey Kidney Cell Lines to Actinomycin D: Drug Uptake in 37 RC Cells After Persistent Inhibition of Transcription
Authors: Benedetto Arrigo , Cassone Antonio , Delfini Carlo
Published: June 2012

37 RC cells, a cultured line derived from African green monkey kidneys, survived long treatments with actinomycin D (AMD; 0.1 to 0.5 μg/ml) under strong inhibition of ribonucleic acid synthesis and blocking of cell division. One aspect of the complex cellular response to this treatment was a progressive lowering of the influx rate of AMD and, consequently, of its endocellular concentration, leading to a late resurgence of transcription. Overall protein synthesis decreased in AMD-treated cells, but more of the residual protein was exported to the cell surface, a fact associated with the development of numerous strands of endoplasmic reticulum and Golgi bodies in the cytoplasm. The lowering of AMD influx during the treatment was not simply due to the decay of protein synthesis, and there was no evidence for a carrier-mediated transport of the drug. It was paralleled by, but seemingly not related to, modifications in cellular microtubules and microfilaments. The rate of AMD influx was restored to levels comparable to those of untreated cells by short exposure to ethylenediaminetetraacetic acid and trypsin. It is concluded that the changes in plasma membrane of 37 RC cells, creating an obstacle to the influx of AMD after long treatment with this drug, probably consist of an accumulation and/or a different distribution of glycoproteins or other surface components on the cell surface.