bluuebunny/crossref_metadata_2025 huggingface dataset:
Silver-coated nylon fiber as an antibacterial agent
Authors: MacKeen P C , Person S , Warner S C , Snipes W , Stevens S E
Published: June 2012

A blend of nylon fiber and silver-coated nylon fiber (the latter known as X-static) was used in these experiments. This fiber was bactericidal when bacteria were exposed to it directly or to an extract derived from its prior incubation in salt solution. At ambient temperatures, a rapid exponential decrease of survival occurred, usually after a delay of approximately 1 h. The rate of killing (decrease of survival) increased with an increase in X-static percentage of the fiber blend, temperature of fiber extraction, concentration of Tris buffer present during extraction, and temperature at which bacteria were exposed to the extract. When bacteria were exposed to the extract at 37 degrees C as opposed to ambient temperature, there was no delay in onset of killing. Escherichia coli was generally the indicator organism tested, but comparable results were also found for Pseudomonas, Klebsiella, Staphylococcus, and Streptococcus species. The rate of killing increased with increasing silver ion concentration of the fiber extract, as determined through atomic absorption spectrophotometry. The rate of killing was greater and the onset was earlier with an extract containing silver ions from fiber than with a salt solution containing the same concentration of silver ions from silver nitrate. Studies of the kinetics of ion release suggested that X-static may be an effective, sustained-release antibacterial agent.
Method of evaluating effects of antibiotics on bacterial biofilm
Authors: Prosser B L , Taylor D , Dix B A , Cleeland R
Published: June 2012

Antibiotics are generally not effective against organisms in exopolysaccharide biofilms. A simple method of studying the effect of antibiotics on bacteria in established biofilms is reported. Escherichia coli ATCC 25922 cells grown overnight at 37 degrees C on Mueller-Hinton agar were suspended in buffer and dispensed on 0.5-cm2 catheter disks. The disks were incubated for 1 h at 37 degrees C, washed, transferred to petri dishes containing 20 ml of broth, and incubated at 37 degrees C for 20 to 22 h, at which time thick biofilms were established. Disks were washed, placed in broth or broth containing antibiotic, and incubated at 37 degrees C for 4 h. The disks were removed, and viable counts were determined. This process was repeated at other selected time intervals (e.g., 8 and 24 h). Viable bacterial counts decreased from 10(3) to 10(4) CFU/cm2 in 24 h with 400 micrograms of amdinocillin or cefamandole per ml. A combination containing 400 micrograms of each antibiotic per ml decreased the viable counts to an undetectable level (less than 100 CFU/cm2) in 24 h. Other antibiotics and organisms were also examined in this system.
Purification and characterization of an avian myeloblastosis and human immunodeficiency virus reverse transcriptase inhibitor, sulfated polysaccharides extracted from sea algae
Authors: Nakashima H , Kido Y , Kobayashi N , Motoki Y , Neushul M , Yamamoto N
Published: June 2012

A new reverse transcriptase (RT) inhibitor was extracted and purified from the red alga Schizymenia pacifica. The chromatographic behavior and chemical properties of this sea algal extract (SAE) suggest that it is a sulfated polysaccharide having a molecular weight of approximately 2,000,000. SAE is composed of galactose (73%), sulfonate (20%), and 3,6-anhydrogalactose (0.65%). SAE is a member of the lambda-carrageenan family, based on its infrared spectrum and products of hydrolysis. SAE selectively inhibited human immunodeficiency virus (HIV) RT and replication in vitro. When MT-4 cells were treated with more than 10(4) inhibitory units (IU) of SAE per ml after HIV infection, significant inhibition of viral antigen synthesis was observed. Furthermore, more than 90% of cells were viable in the cultures exposed to 4 X 10(4) to 8 X 10(4) IU of SAE per ml, while almost all the MT-4 cells in the control culture had died by 10 days after HIV infection. The inhibitory effect of SAE on HIV replication was confirmed by plaque reduction assays. The 50% inhibitory dose of SAE was 9.5 x 10(3) IU/ml. Chondroitin sulfate A, dermatan sulfate, heparan sulfate, keratan polysulfate, and heparin also inhibited the RT of avian myeloblastosis virus. SAE immediately inhibited RT activity when added to an assay mixture after the start of the reaction.
In vitro activity of sulfonamides and sulfones against Leishmania major promastigotes
Authors: Peixoto M P , Beverley S M
Published: June 2012

We examined the susceptibility of promastigotes of Leishmania major to sulfonamides and sulfones in vitro. In a completely defined medium only sulfamoxole, sulfaquinoxaline, and dapsone were inhibitory; the concentrations required for 50% inhibition of the rate of growth were 150, 600, and 600 microM, respectively. Eleven other sulfa drugs were ineffective at concentrations up to 2 mM. The growth inhibition was similar to that observed in procaryotes: the cells continued logarithmic growth for several cell doublings before inhibition was observed. Surprisingly, the addition of p-aminobenzoate or folate did not reverse the effects of the active sulfa drugs, the effects of sulfamoxole and methotrexate were additive rather than synergistic, and the addition of thymidine reversed methotrexate but not sulfa-drug inhibition. These results suggest that the mode of action of sulfa drugs on L. major is not by the classical route of inhibition of de novo folate synthesis. Promastigotes could be propagated for more than 40 passages in a completely defined medium in which the only added pterin was biopterin. The folate concentration in this medium was less than 10(-10) to 10(-11) M, as determined by a Leishmania bioassay. Although these data suggest that L. major may be capable of de novo synthesis of folate, the nonclassical mode of action of sulfa drugs, as well as other studies, favors the view that L. major is auxotrophic for folate.
Effect of dose on serum pharmacokinetics of intravenous ciprofloxacin with identification and characterization of extravascular compartments using noncompartmental and compartmental pharmacokinetic models
Authors: Dudley M N , Ericson J , Zinner S H
Published: June 2012

The effect of dose on the pharmacokinetics of ciprofloxacin in serum and urine following single intravenous doses of 100, 150, and 200 mg was studied in nine healthy volunteers. Mean peak levels in serum were 1.4, 2.0, and 3.2 mg/liter for the 100-, 150-, and 200-mg doses, respectively. The data on concentrations in serum were best described by a three-compartment pharmacokinetic model. The terminal half-life (from noncompartmental analysis) averaged between 4.2 and 4.6 h. Average urinary recovery ranged between 45.8 and 48.1%. The average renal clearance of ciprofloxacin was 2.9- to 3.4-fold greater than the measured creatinine clearance. Total serum and renal clearances decreased with increasing dose; however, this was not statistically significant (P greater than 0.05; repeated-measures analysis of variance). Ciprofloxacin was well tolerated by all subjects. In this dose range, ciprofloxacin pharmacokinetics are independent of dose.
Tn1331, a novel multiresistance transposon encoding resistance to amikacin and ampicillin in Klebsiella pneumoniae
Authors: Tolmasky M E , Crosa J H
Published: June 2012

A 7.5-kilobase-pair multiresistance transposon, Tn1331, harboring amikacin resistance was identified as part of Klebsiella pneumoniae plasmid pJHCMW1. Restriction mapping, hybridization, and transposition complementation experiments demonstrated that Tn1331 belongs to the Tn3 family. Its structure is similar to that of Tn3 with the insertion of a DNA fragment encoding resistance to amikacin, kanamycin, and tobramycin.
Susceptibility of Nocardia asteroides to new quinolones and beta-lactams
Authors: Gombert M E , Aulicino T M , duBouchet L , Berkowitz L R
Published: June 2012

The susceptibility of 31 strains of Nocardia asteroides to various quinolones and beta-lactams, as well as coumermycin, amikacin, and minocycline, was determined by the agar dilution technique. Ciprofloxacin was the most active fluoroquinolone tested on a weight basis, as it inhibited approximately 50% of the isolates at achievable drug levels in serum. Ceftriaxone and cefpirome were the most active cephalosporins in this system with MICs of 8 micrograms/ml for 80% of strains tested. Imipenem, amikacin, and minocycline were the most effective agents tested.
Roxithromycin (RU 965): effective therapy for experimental syphilis infection in rabbits
Authors: Lukehart S A , Baker-Zander S A
Published: June 2012

Roxithromycin (RU 965), a new macrolide antibiotic, was shown to be effective for therapy of active syphilis in rabbits. Dark-field-positive lesions were produced in adult male rabbits by intradermal inoculation of approximately 10(6) Treponema pallidum organisms at each of 11 sites. Beginning 7 days after infection, six animals per group were treated with benzathine penicillin G (200,000 U, intramuscularly, weekly for 2 weeks) or roxithromycin (15 mg/kg of body weight, orally, twice daily for 15 days); six animals were not treated. Chancres in untreated animals were dark-field positive throughout the 16-day observation period; all benzathine penicillin-treated rabbits were dark-field negative 1 day after the initiation of therapy. Five of six animals treated with roxithromycin were dark-field negative on day 3 following the initiation of therapy; the sixth animal was dark-field negative by day 6. Lesions in untreated animals reached a mean (+/- standard deviation) maximum diameter of 14.7 +/- 1.91 mm compared with 8.4 +/- 3.6 mm for benzathine penicillin-treated (P less than 0.005) and 10.4 +/- 1.2 mm for roxithromycin-treated (P less than 0.001) animals. Ulceration occurred at 62 of 66 lesions in untreated animals compared with 0 of 66 lesions in each treated group. At 3, 6, and 12 weeks postinfection, Venereal Disease Research Laboratory antibody titers were significantly higher (P less than 0.05) in untreated than in treated animals. Titers in penicillin-treated versus roxithromycin-treated animals were significantly different at 6 weeks postinfection but not at 3 and 12 weeks postinfection. Transfer of tissue from treated rabbits to seronegative recipient animals did not reveal any evidence of persistent infection in the benzathine penicillin- or roxithromycin-treated animals. These findings indicate that benzathine penicillin and roxithromycin, at the doses indicated above, are effective in treating active syphilis in rabbit model.
Effect of antibiotics on toxin production and viability of Clostridium perfringens
Authors: Stevens D L , Maier K A , Mitten J E
Published: June 2012

We have recently reported (D.L. Stevens, K.A. Maier, B.M. Laine, and J.E. Mitten, J. Infect. Dis. 155:220-228, 1987) that clindamycin, rifampin, and tetracycline were more efficacious than penicillin in the treatment of fulminant gas gangrene in mice caused by Clostridium perfringens. We hypothesize that antibiotic efficacy correlated with bactericidal or toxin-suppressing properties of these agents. To investigate the possibility that penicillin is only bacteriostatic against C. perfringens, we performed macrobroth dilution MIC and MBC determinations using C. perfringens ATCC 13124. Mean MICs were equal to MBCs for the following antibiotics (micrograms per milliliter): clindamycin, 0.07; tetracycline, 0.05; rifampin, 0.03; metronidazole, 0.69; and penicillin, 0.27. The MIC/MBCs of chloramphenicol were 1.50/3.10 (micrograms/ml). Because antibiotic efficacy did not correlate with bactericidal activity, we measured alpha-toxin activity and found complete suppression of alpha-toxin activity by tetracycline, metronidazole, rifampin, clindamycin, and chloramphenicol at concentrations equal to the MIC. In contrast, alpha-toxin activity persisted at concentrations of penicillin equal to and above the MIC. The dynamics of bacterial killing and kinetics of alpha-toxin production were next studied in log-phase cultures of C. perfringens with antibiotic concentrations 10 times the MIC. Clindamycin, metronidazole, and rifampin all caused rapid reductions in viability, turbidity, and alpha-toxin activity by 15 to 45 min. In contrast, penicillin demonstrated slower bacterial killing, increased turbidity (62.6% of control), and persistent alpha-toxin activity (80% of control values) for 2 h. Tetracycline and chloramphenicol were the least effective in reducing viability; however, the turbidity of cultures did not increase, and alpha-toxin activity was not detectable. Toxin suppression and rapid bacterial killing may in part explain the observed superior therapeutic efficacy of clindamycin, rifampin, and metronidazole compared with penicillin in the treatment of experimental gas gangrene.
Antibacterial activity and mechanism of action of 3'-azido-3'-deoxythymidine (BW A509U)
Authors: Elwell L P , Ferone R , Freeman G A , Fyfe J A , Hill J A , Ray P H , Richards C A , Singer S C , Knick V B , Rideout J L
Published: June 2012

The thymidine analog 3'-azido-3'-deoxythymidine (BW A509U; azidothymidine [AZT]) had potent bactericidal activity against many members of the family Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Shigella flexneri, and Enterobacter aerogenes. AZT also had bactericidal activity against Vibrio cholerae and the fish pathogen Vibrio anguillarum. AZT had no activity against Pseudomonas aeruginosa, gram-positive bacteria, anaerobic bacteria, Mycobacterium tuberculosis, nontuberculosis mycobacteria, or most fungal pathogens. Several lines of evidence indicated that AZT must be activated to the nucleotide level to inhibit cellular metabolism: AZT was a substrate for E. coli thymidine kinase; spontaneously arising AZT-resistant mutants of E. coli ML-30 and S. typhimurium were deficient in thymidine kinase; and intact E. coli ML-30 cells converted [3H]AZT to its mono-, di-, and triphosphate metabolites. Of the phosphorylated metabolites, AZT-5'-triphosphate was the most potent inhibitor of replicative DNA synthesis in toluene-permeabilized E. coli pol A mutant cells. AZT-treated E. coli cultures grown in minimal medium contained highly elongated cells consistent with the inhibition of DNA synthesis. AZT-triphosphate was a specific DNA chain terminator in the in vitro DNA polymerization reaction catalyzed by the Klenow fragment of E. coli DNA polymerase I. Thus, DNA chain termination may explain the lethal properties of this compound against susceptible microorganisms.
Cloning and expression of genes responsible for altered penicillin-binding proteins 3a and 3b in Haemophilus influenzae
Authors: Malouin F , Schryvers A B , Bryan L E
Published: June 2012

A Haemophilus influenzae strain (T-1,3) possessing clinical beta-lactam resistance due to altered penicillin-binding protein 3 was used to construct a recombinant cosmid gene bank in Escherichia coli. Three of the recombinant cosmids were capable of transforming a susceptible H. influenzae strain (Rdnov) simultaneously to moxalactam resistance and altered the binding of penicillin-binding proteins 3a and 3b to [35S]penicillin G. Restriction endonuclease mapping of one of the recombinant cosmids, pLB100, was performed to facilitate subsequent subcloning of the gene(s) responsible for the altered penicillin-binding protein 3 (a and b) binding phenotype. Subcloning of individual fragments derived from pLB100 indicated that two adjacent fragments of DNA were both capable of transforming a susceptible Haemophilus strain to moxalactam resistance and altered penicillin-binding protein 3 binding. Expression of plasmid-coded proteins in minicells indicated that one fragment coded for a major 55,000-molecular-weight polypeptide and that the second contained a C-terminal coding region that expressed a 28,000-molecular-weight polypeptide when fused to the N-terminal region of the tetracycline resistance gene. Initial attempts at labeling the plasmid-coded proteins expressed in minicells with [35S]penicillin G were unsuccessful.
Activity of cefazolin and two beta-lactamase inhibitors, clavulanic acid and sulbactam, against Bacteroides fragilis
Authors: Fekete T , McGowen J , Cundy K R
Published: June 2012

One hundred clinical isolates of the Bacteroides fragilis group of bacteria were tested by agar dilution for susceptibility to cefazolin alone or in combination with clavulanic acid or sulbactam. For cefazolin, the MIC for 50% of the isolates (MIC50) was 32 micrograms/ml, the breakpoint for susceptibility. With the addition of 0.5 micrograms of clavulanic acid per ml, the MIC for 90% of the isolates (MIC90) was 8 micrograms/ml, well within the achievable range of concentrations in serum or tissue. Similarly, with the addition of 0.5 micrograms of sulbactam per ml, the MIC90 was 16 micrograms/ml. The addition of a higher concentration (4.0 micrograms/ml) of clavulanic acid or sulbactam resulted in MIC90S which were fourfold lower than those with 0.5 micrograms/ml. A fixed ratio of cefazolin-beta-lactamase inhibitor of 4:1 resulted in an MIC50 and MIC90 which were intermediate between the 0.5- and 4.0-micrograms/ml fixed concentration of beta-lactamase inhibitor.
Effect of hemorrhagic shock on cefazolin and gentamicin pharmacokinetics in dogs
Authors: Dickson P L , DiPiro J T , Michael K A , Cheung R P , Hall E M
Published: June 2012

The physiologic response to traumatic injury may alter the disposition of drugs and thereby affect their therapeutic or toxic potential. A study was conducted in 10 mongrel dogs to determine the effect of experimental hemorrhagic shock with resuscitation on the pharmacokinetics of gentamicin and cefazolin. Single simultaneous intravenous doses of gentamicin (3 mg/kg) and cefazolin (25 mg/kg) were administered to each animal on an initial study day, after which serial blood and urine collections were performed. After 1 week, a standard hemorrhagic shock model was applied to each animal. Shock was continued for 1 h, after which the animal was resuscitated with either whole blood or saline. After stabilization for 20 min, a second dose of gentamicin and cefazolin was administered, and blood and urine were again collected. Drug clearance was not significantly altered, except for that of cefazolin after saline resuscitation, for which there was a significant increase in drug clearance. After both methods of resuscitation an increase in the volume of distribution was noted for cefazolin and gentamicin. Drug half-life was noted to be increased after shock for cefazolin by both resuscitation methods and for gentamicin after shock by saline resuscitation. Although alterations of pharmacokinetic parameters were noted, mean concentrations of gentamicin and cefazolin in serum were similar for pre- and postshock phases.
Comparative evaluation of enoxacin, ofloxacin, ampicillin, and chloramphenicol for treatment of experimental Haemophilus influenzae pneumonia
Authors: Kemmerich B , Borner K , Pennington J E
Published: June 2012

A murine model of bacteremic Haemophilus influenzae type b pneumonia was used to evaluate the therapeutic efficacies of the quinolone antimicrobial agents enoxacin and ofloxacin compared with those of ampicillin and chloramphenicol. Ampicillin-susceptible (AS) and ampicillin-resistant (AR) challenge strains were employed. Treatment with enoxacin or ofloxacin produced intrapulmonary killing of H. influenzae that was superior to that achieved with ampicillin (P less than 0.01 to P less than 0.001 for both AS and AR strains). Ofloxacin and enoxacin also provided killing greater than that with chloramphenicol for the AS strain (P less than 0.01 to P less than 0.001). For the AR strain, ofloxacin provided killing greater than that obtained with chloramphenicol (P less than 0.001). Survival from AS strain pneumonia was 60% in enoxacin-treated and 78% in ofloxacin-treated animals compared with 41% for chloramphenicol-treated and 23% for ampicillin-treated groups. We conclude that enoxacin and ofloxacin may be effective antimicrobial agents in treating either AS or AR strains causing H. influenzae pneumonia.
Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro
Authors: Sommadossi J P , Carlisle R
Published: June 2012

The effects of 3'-azido-3'-deoxythymidine (AZT) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine on myeloid and erythroid colony-forming cells were studied by clonogenic assays. Both consistently inhibited granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units in a dose-dependent fashion. Concentrations of AZT and 9-(1,3-dihydroxy-2-propoxymethyl)guanine required for 50% inhibition of CFU-GM were, respectively, 0.9 +/- 0.1 and 2.7 +/- 0.5 microM; those required for 90% inhibition were, respectively, 34.0 +/- 2.8 and 35.7 +/- 3.6 microM. Erythroid burst-forming units were less sensitive to high concentrations of AZT than were CFU-GM.
In vitro activity of a new cyclic lipopeptide antibiotic, LY146032, against gram-positive clinical bacteria
Authors: Huovinen P , Kotilainen P
Published: June 2012

The in vitro activity of LY146032, a novel cyclic lipopeptide antibiotic, was tested against different gram-positive clinical isolates. The activity of LY146032 was clearly higher than that of vancomycin against all isolates tested. However, in some instances rifampin and imipenem showed higher activity than did LY146032.
Comparison of difloxacin, enoxacin, and cefoperazone for treatment of experimental Enterobacter aerogenes endocarditis
Authors: Boscia J A , Kobasa W D , Kaye D
Published: June 2012

This study compared difloxacin administered orally, enoxacin administered orally, and cefoperazone administered intramuscularly for the treatment of experimental Enterobacter aerogenes endocarditis. Difloxacin significantly reduced bacterial counts of vegetations, as compared with enoxacin and cefoperazone. Enoxacin and cefoperazone did not differ significantly. This study demonstrated that difloxacin was significantly more effective than enoxacin and cefoperazone for the treatment of E. aerogenes endocarditis in rabbits.
In vitro activity and beta-lactamase stability of a new monobactam, B0-1165
Authors: Neu H C , Chin N X
Published: June 2012

B0-1165 is a 1-carboxy-1-cyclopropoxyamino,4-fluoromethyl monobactam. It inhibited the majority of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter diversus, Aeromonas hydrophila, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Yersinia enterocolitica, Haemophilus influenzae, Neisseria gonorrhoeae, and Salmonella and Shigella species at less than or equal to 0.125 microgram/ml. Overall, its in vitro activity was similar to that of aztreonam, cefotaxime, and ceftazidime, with minor differences in the MICs for individual isolates. Enterobacter species and Citrobacter freundii which were derepressed for beta-lactamase production and had higher MICs of aztreonam and ceftazidime had MICs that ranged from 4 to 32 micrograms/ml. B0-1165 had activity against Pseudomonas aeruginosa similar to that of aztreonam but lower than that of ceftazidime and carumonam. Pseudomonas maltophilia and other Pseudomonas species were resistant or had MICs of 32 micrograms/ml, as did Acinetobacter species. B0-1165 did not inhibit streptococcal, staphylococcal, or anaerobic species, such as Clostridium and Bacteroides species. B0-1165 was not hydrolyzed to any appreciable extent by common plasmid- and chromosomally Richmond-Sykes type 1a-, 1c-, and 1d-mediated beta-lactamases. It inhibited the Enterobacter cloacae P99 and inducible Pseudomonas aeruginosa beta-lactamases. B0-1165 was a poor inducer of beta-lactamase, but exposing E. cloacae and C. freundii to B0-1165 selected for resistant isolates. Overall, B0-1165 had in vitro properties similar to those of other monobactams currently available or under investigation.
Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy
Authors: Pangon B , Joly V , Vallois J M , Abel L , Buré A , Brion N , Contrepois A , Carbon C
Published: June 2012

To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity.
Correlation between renal membrane binding and nephrotoxicity of aminoglycosides
Authors: Williams P D , Bennett D B , Gleason C R , Hottendorf G H
Published: June 2012

The kinetics of aminoglycoside binding to renal brush border and basolateral membrane vesicles from rat renal cortex were studied by using [3H]amikacin. [3H]amikacin binding to renal membranes was found to be a rapid, saturable process with a fourfold greater affinity for basolateral membranes than for brush border membranes (Kd basolateral = 607 microM; Kd brush border = 2,535 microM). Renal membranes prepared from immature rats (2 to 3 weeks old) exhibited a significantly lower affinity compared with membranes from adults (Kd basolateral = 2,262 microM; Kd brush border = 6,216 microM). Additionally, the inhibitory behavior of several aminoglycosides versus [3H]amikacin binding to brush border membranes revealed the following rank order of potency: neomycin greater than tobramycin approximately gentamicin approximately netilmicin greater than amikacin approximately neamine greater than streptomycin. The relative insensitivity of immature rats to aminoglycoside-induced nephrotoxicity in vivo and the comparative nephrotoxicity of the various aminoglycosides suggest that renal membrane-binding affinity is closely correlated to the nephrotoxic potential of these antibiotics.
Single-dose accumulation pharmacokinetics of tobramycin and netilmicin in normal volunteers
Authors: Winslade N E , Adelman M H , Evans E J , Schentag J J
Published: June 2012

The two-compartment tissue accumulation pharmacokinetics of tobramycin and netilmicin were compared in 11 normal volunteers by using a crossover design. After each 1.0-mg/kg (body weight) dose, serum was collected for 96 h, and complete 24-h urine collections were obtained for a total of 30 days. Two months of washout were required before crossover. Concentrations in serum and urine were measured by radioimmunoassay, and concentrations in serum and urinary excretion rates were simultaneously fitted to a two-compartment pharmacokinetic model. Netilmicin exhibited significantly lower total body clearance (48 versus 90 ml/min) and longer terminal elimination half-life (161 versus 96 h) than tobramycin. As a result of these pharmacokinetic differences, the predicted tissue accumulation of netilmicin at steady state was significantly higher than that of tobramycin (P less than 0.05). Relative rates of aminoglycoside nephrotoxicity probably depend on both the differential tissue uptake (accumulation) and the concentration of the aminoglycoside which produces intracellular toxicity. Because the steady-state tissue accumulation of netilmicin is nearly 2.5 times greater than that of tobramycin, its potency in the production of intracellular toxicity needs to be that much less for the two agents to produce the same incidence of clinical nephrotoxicity.
Monocyclic and tricyclic analogs of quinolones: mechanism of action
Authors: Georgopapadakou N H , Dix B A , Angehrn P , Wick A , Olson G L
Published: June 2012

The mode of action of Ro 13-5478 and Ro 14-9578, monocyclic and tricyclic quinolone analogs, respectively, was examined for Escherichia coli and Staphylococcus aureus. The compounds showed antibacterial activity and effects on cell morphology, replicative DNA biosynthesis, and gyrase-catalyzed DNA supercoiling that were comparable to those shown by nalidixic acid and by oxolinic acid compounds. The results suggest that their site of action is DNA gyrase and that a bicyclic quinolone nucleus is not essential for activity.
Susceptibility to five antimicrobial agents of strains of the Bacteroides fragilis group isolated in Brazil
Authors: De Almeida A E , De Uzeda M
Published: June 2012

The in vitro activity of metronidazole, chloramphenicol, clindamycin, cefoxitin, and carbenicillin was tested by an agar dilution method against 228 strains of the Bacteroides fragilis group isolated from human intestinal microbiota during 1981 and 1982. All the strains were susceptible to metronidazole. Resistance rates for chloramphenicol, clindamycin, cefoxitin, and carbenicillin were 2, 37, 21, and 13%, respectively.
Adrenal response to corticotropin during therapy with itraconazole
Authors: Phillips P , Graybill J R , Fetchick R , Dunn J F
Published: June 2012

Itraconazole is a triazole with a mechanism of action similar to that of ketoconazole. Endocrine side effects of ketoconazole, including impaired cortisol synthesis, have been well documented (A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens, Arch. Intern. Med. 144:2150-2153, 1984). We examined the adrenal response to corticotropin in 10 patients being treated with itraconazole. No impairment of cortisol synthesis could be demonstrated.
Sultamicillin in the treatment of superficial skin and soft tissue infections in children
Authors: Goldfarb J , Aronoff S C , Jaffe A , Reed M D , Blumer J L
Published: June 2012

Fifty-two children with superficial skin and soft tissue infections were randomized to receive sultamicillin or cloxacillin for 7 days. Twenty-one children in each group finished the study. A total of 16 of 21 in the sultamicillin group and 13 of 21 in the cloxacillin group were cured. One child in the sultamicillin group and two in the cloxacillin group failed therapy. Four children who received sultamicillin and six who received cloxacillin had recurrences of lesions. Differences were not statistically significant.
Effect of broad-spectrum parenteral antibiotics on "colonization resistance" of intestinal microflora of humans
Authors: Barza M , Giuliano M , Jacobus N V , Gorbach S L
Published: June 2012

Studies with animals have shown that the normal intestinal microflora protects against colonization by new strains ("colonization resistance") and that this protective effect may be related to the anaerobic component of the microflora. However, colonization resistance has not been shown in humans. We administered cefoxitin, piperacillin, cefoperazone, and aztreonam intravenously to healthy subjects for 9 days and monitored the acquisition of new isolates in the fecal flora. Seven of sixteen antibiotic-treated subjects but none of four untreated controls became colonized by gram-negative bacilli. However, there was no correlation between colonization and the particular drug given or the extent of suppression of anaerobes or of any other component of the fecal microflora. Cefoxitin and piperacillin were associated with the greatest increases in the numbers of drug-resistant bacteria and in fecal beta-lactamase content. The results of this study support the concept that colonization resistance occurs in humans and is diminished by antibiotic administration but fail to support the hypothesis that resistance is related to the anaerobic microflora.
Molecular epidemiology of macrolides-lincosamides-streptogramin B resistance in Staphylococcus aureus and coagulase-negative staphylococci
Authors: Thakker-Varia S , Jenssen W D , Moon-McDermott L , Weinstein M P , Dubin D T
Published: June 2012

Macrolides-lincosamides-streptogramin B (MLS) resistance is commonly found in Staphylococcus aureus and coagulase-negative staphylococci (22 and 45%, respectively, among isolates from three New Jersey hospitals). We have examined representative subsets of 107 MLS-resistant isolates for the molecular nature of the resistance determinant, the erm gene, by dot blot and Southern hybridization analysis. All of 35 S. aureus isolates examined and 39 of 42 coagulase-negative isolates examined were found to harbor the ermA or ermC evolutionary variant. Genes of the ermC class occurred exclusively on a small plasmid similar to or indistinguishable from one (pNE131) previously described in S. epidermidis. Genes of the ermA class occurred exclusively in the chromosome, and restriction patterns indicated that they were part of a transposon, Tn554, characteristic of the classical S. aureus ermA strain. Unlike S. aureus ermA strains examined previously, which harbor Tn554 at a single specific (primary) site, four of our S. aureus isolates had second inserts at different chromosomal sites. The majority of our coagulase-negative isolates had two or more inserts, neither of which occurred at the classical primary site and many of which differed from one another in location (as inferred from restriction patterns). Coagulase-negative staphylococci constitute a large reservoir of the ermA and ermC class of determinants, with clear potential for interspecies spread.
Persistence of an antibiotic resistance plasmid in intestinal Escherichia coli of chickens in the absence of selective pressure
Authors: Chaslus-Dancla E , Gerbaud G , Lagorce M , Lafont J P , Courvalin P
Published: June 2012

We studied eight strains of Escherichia coli resistant to high levels of trimethoprim that were isolated over a 6-week period in a commercial breeding flock of broilers. The strains originated from fecal samples and from a carcass immediately after slaughter. Seven of eight strains belonged to the same infrequent biotype. They were also resistant to ampicillin and streptomycin, and some were resistant to tetracycline and potassium tellurite. All the strains transferred trimethoprim and ampicillin resistance to E. coli. Analysis of the donors and of the transconjugants by agarose gel electrophoresis after digestion by restriction endonucleases and by nucleic acid hybridization indicated that resistance to trimethoprim (dfrI) and to ampicillin (bla TEM-1) was mediated by a 65-kilobase plasmid, pIP1531. Persistence of resistance to trimethoprim and ampicillin in this flock was therefore due to two cumulative factors, both occurring in the absence of selective pressure, namely the dissemination of a particular plasmid between strains and the ability of an atypical E. coli strain to stably colonize many animals.
Penetration of cefotaxime into respiratory secretions
Authors: Fick R B , Alexander M R , Prince R A , Kasik J E
Published: June 2012

The objective of this study was to quantitate cefotaxime and its active metabolite, desacetyl cefotaxime, in the distal airways and to compare these levels to concentrations in plasma. Respiratory secretions were obtained from the subsegmental level in 17 adult patients undergoing fiber-optic bronchoscopy within 2 h after receiving four doses of cefotaxime (2 g intravenously every 6 h). In 11 patients, cefotaxime levels measured by high-pressure liquid chromatography in bronchial secretions were below detectable limits (less than 0.5 mg/liter); however, levels of desacetyl cefotaxime exceeded 1.5 mg/liter in 9 of these 11 patients (range, 1.6 to 10 mg/liter). Concentrations of desacetyl cefotaxime in lung secretions (6.9 +/- 0.85 [standard error] mg/liter) was 77% of mean levels of desacetyl cefotaxime in plasma (8.9 +/- 1.26 mg/liter). In summary, concentrations of desacetyl cefotaxime in bronchial secretions are markedly higher than those of cefotaxime.
Activity of nine antimicrobial agents against Corynebacterium group D2 strains isolated from clinical specimens and skin
Authors: Fernández-Roblas R , Prieto S , Santamaría M , Ponte C , Soriano F
Published: June 2012

The in vitro activities of nine antimicrobial agents against Corynebacterium group D2 strains isolated from clinical specimens and from healthy skin of hospitalized patients were studied. Ciprofloxacin, ofloxacin, norfloxacin, vancomycin, and teicoplanin were very active against these microorganisms. There were no significant differences in susceptibility between clinical and colonizing isolates.
Rimantadine pharmacokinetics after single and multiple doses
Authors: Wills R J , Farolino D A , Choma N , Keigher N
Published: June 2012

Twenty-four healthy adult male volunteers were randomly assigned to one of two rimantadine regimens. The 12 volunteers assigned to regimen 1 orally received a single 100-mg rimantadine tablet followed 5 days later by 100 mg of rimantadine twice a day for 10 days. Volunteers assigned to regimen 2 ingested a single 100-mg rimantadine tablet followed 5 days later by 100 mg once a day for 10 days. The results of the study suggest that the pharmacokinetics of rimantadine are linear and accumulation of the drug during repetitive multiple doses is predictable.
Activity of phenothiazines against medically important yeasts
Authors: Eilam Y , Polacheck I , Ben-Gigi G , Chernichovsky D
Published: June 2012

Two phenothiazine compounds, trifluoperazine and chlorpromazine, inhibited growth in vitro of the five most common pathogenic yeasts, with MICs ranging from 10 to 40 micrograms/ml. Daily intraperitoneal injections of trifluoperazine (4 to 7 mg/kg of body weight) increased the survival of mice experimentally infected with Candida albicans or Cryptococcus neoformans. The potential use of these drugs against fungal meningitis is discussed.
Inhibition by ganciclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information
Authors: St Clair M H , Lambe C U , Furman P A
Published: June 2012

The ability of LM cells, thymidine kinase-deficient LM cells (LMTK-), and LMTK- cells transformed to the LMTK+ phenotype by herpes simplex virus type 1 genetic information (LH7 cells) to anabolize the acyclovir congener ganciclovir was examined. About 50-fold more ganciclovir triphosphate was produced by LH7 cells than by either LM or LMTK- cells. Growth inhibition studies indicated that 180 and 120 microM ganciclovir were required to achieve 50% growth inhibition of LM and LMTK- cells, respectively; only 0.07 microM ganciclovir was necessary to achieve 50% inhibition of LH7 cells. DNA synthesis in the transformed cells was significantly reduced by ganciclovir treatment, whereas ganciclovir had little effect on DNA synthesis in the nontransformed cells. Alkaline sucrose gradient sedimentation analysis of transformed cellular DNA indicated that LH7 DNA synthesized in the presence of ganciclovir chased into mature DNA. Both LM and LH7 DNA synthesized in the presence of ganciclovir exhibited a concentration-dependent reduction in the rate of elongation into mature DNA. Finally, [14C]ganciclovir was incorporated internally into the growing chains of LH7 cells.
Systemic absorption of endotracheally administered aminoglycosides in seriously ill patients with pneumonia
Authors: Crosby S S , Edwards W A , Brennan C , Dellinger E P , Bauer L A
Published: June 2012

A study was performed with 10 hospitalized patients to determine the percentage of an aminoglycoside dose (tobramycin or gentamicin) that is absorbed systemically after being instilled into the endotracheal tube at steady state. All patients were on respirators, had indwelling urinary catheters, and had creatinine clearances estimated to be greater than or equal to 40 ml/min. Tobramycin or gentamicin (40 mg) was instilled every 4 h directly into the endotracheal tube. Nine patients also received systemically a different aminoglycoside from that administered through the endotracheal tube. Urine was collected over a 4-h dosing interval at steady state (after at least 5 doses of the drug). The amount of aminoglycoside excreted over the 4-h interval was measured and expressed as percentage of the dose administered over that period. The range of percentage of dose absorbed was 1.5 to 34%, with a mean of 16.7 +/- 11.4% standard deviation and a median of 16.5%. The coefficient of variation was 68%. Levels of the endotracheally administered aminoglycoside in serum were measured, and all were less than 1.0 microgram/ml. While a large degree of variability in absorption was observed in this study, significant amounts of aminoglycosides could be absorbed in some patients. However, levels apparently did not accumulate in sera of patients with adequate renal function, and an empirical dosage reduction in intravenous aminoglycoside should not be necessary with the addition of endotracheally instilled aminoglycoside in patients with creatinine clearances greater than 40 ml/min.
Effect of vancomycin hydrochloride on Staphylococcus epidermidis biofilm associated with silicone elastomer
Authors: Evans R C , Holmes C J
Published: June 2012

Peritonitis is a major complication of continuous ambulatory peritoneal dialysis. Relapsing peritonitis after the cessation of antimicrobial therapy is frequently reported and often involves Staphylococcus epidermidis. To investigate the potential role of catheter-associated biofilm in the pathogenesis of relapsing peritonitis, we describe an in vitro model permitting the development of an S. epidermidis biofilm on silicone elastomer biomaterial. This model has been used to investigate the ability of vancomycin hydrochloride to kill biofilm-encased organisms by using an antibiotic regimen typical of peritonitis therapy. No significant differences were seen between vancomycin-exposed and control groups in biofilm viable and total cell counts after 10 days. Vancomycin-exposed silicone-associated biofilm populations decreased by only 0.5 log10 CFU/cm2 over the study period. MICs and MBCs for the original S. epidermidis suspension were 3.125 and 6.25 micrograms/ml, respectively. For biofilm homogenate suspensions, MICs were 3.125 micrograms/ml, but MBCs were greater than 400 micrograms/ml. These data indicate that the biofilm organisms associated with an indwelling peritoneal catheter may display a form of tolerance, thereby suggesting one possible mechanism behind relapsing peritonitis.
Penetration of ciprofloxacin into cerebrospinal fluid of patients with bacterial meningitis
Authors: Wolff M , Boutron L , Singlas E , Clair B , Decazes J M , Regnier B
Published: June 2012

We evaluated the diffusion of ciprofloxacin into the cerebrospinal fluid (CSF) in 23 patients with bacterial meningitis or ventriculitis undergoing treatment with other antibiotics. Three successive ciprofloxacin doses of 200 mg were administered intravenously at 12-h intervals, first between days 2 and 4 and again between days 10 and 20 after the admission. Concentrations of ciprofloxacin in plasma and CSF obtained at 60, 120, 240, and 480 min after the third infusion were determined by high-performance liquid chromatography. In addition, serial samples were obtained from ventricular fluid in four patients. The concentrations of ciprofloxacin in CSF ranged from 0.35 to 0.56 micrograms/ml. These concentrations were equal to or higher than the MICs for most of the enterobacteria.
Randomized, single-blind evaluation of cefadroxil and phenoxymethyl penicillin in the treatment of streptococcal pharyngitis
Authors: Pichichero M E , Disney F A , Aronovitz G H , Talpey W B , Green J L , Francis A B
Published: June 2012

A total of 150 children from two pediatric practices with clinical and bacteriologic evidence of acute group A beta-hemolytic streptococcal (GABHS) pharyngitis randomly received cefadroxil monohydrate (75 children) or phenoxymethyl penicillin (75 children). Cefadroxil was given once daily, while penicillin was given three times daily. The treatment groups were similar in age, sex, race, illness severity, and acute GABHS symptomatology. Throat cultures were routine 3 to 5 days after the start of therapy and 2 and 14 days after the end of therapy. The bacterial cure rates were 90% (62 of 69) for cefadroxil-treated patients and 76% (52 of 68) for penicillin-treated patients. This difference was significant (P less than 0.04). The clinical response was satisfactory in 91% of cefadroxil-treated patients and 89% of penicillin-treated patients. We conclude that once-daily cefadroxil is at least as effective as three-times-daily penicillin in producing bacteriologic eradication and clinical symptomatic improvement in children with GABHS pharyngitis.
Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus
Authors: Hamamoto Y , Nakashima H , Matsui T , Matsuda A , Ueda T , Yamamoto N
Published: June 2012

It is generally accepted that human immunodeficiency virus (HIV) is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In this report, we demonstrate the antiviral effect of nucleoside analogs 2',3'-didehydro-2',3'-dideoxythymidine (DHT) and 2',3'-didehydro-2',3'-dideoxycytidine (DHC) by using human T-cell lymphotropic virus type I-carrying MT-4 cells, which are extremely susceptible to HIV infection. These agents efficiently inhibited the cytopathic effects and expression of HIV-specific antigens in MT-4 cells after infection of the virus. Both DHT and DHC also strongly blocked viral replication as determined by our quantitative bioassay system using a plaque-forming assay. These antiviral effects were obtained at concentrations at which the drugs produced little or no toxicity and were comparable to those with 3'-azido-3'-deoxythymidine and 2',3'-dideoxynucleosides. These findings warrant further investigation of the use of DHT and DHC for the treatment of the acquired immunodeficiency syndrome and related diseases.