bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative pharmacokinetics and serum inhibitory activity of clindamycin in different dosing regimens
Authors: Flaherty J F , Rodondi L C , Guglielmo B J , Fleishaker J C , Townsend R J , Gambertoglio J G
Published: June 2012

The comparative pharmacokinetics and serum inhibitory effects of clindamycin were evaluated in six healthy male subjects given multiple-dose infusions of the following regimens in a crossover fashion: 600 mg every 6 h, 900 mg every 8 h, and 1,200 mg every 12 h. Serial blood samples were obtained after the last dose in each regimen and analyzed for clindamycin by a sensitive and specific high-performance liquid chromatography assay technique. Clindamycin pharmacokinetics were estimated by using noncompartmental methods, and serum inhibitory titers were serially determined against Bacteroides fragilis ATCC 25285 and evaluated by using area under the serum inhibitory curve (AUIC). Maximum and minimum concentrations in plasma averaged 12.2 +/- 1.6 and 1.2 +/- 0.6, 16.3 +/- 4.0 and 0.9 +/- 0.5, and 16.8 +/- 2.5 and 0.4 +/- 0.2 micrograms/ml for the 600-, 900-, and 1,200-mg regimens, respectively. Clindamycin plasma clearance and elimination half-life averaged 23.3 +/- 4.0 liters/h and 1.9 +/- 0.4 h for the 600-mg regimen, 25.6 +/- 8.2 liters/h and 2.1 +/- 0.4 h for the 900-mg regimen, and 26.4 +/- 4.7 liters/h and 2.1 +/- 0.4 h for the 1,200-mg regimen. These results were not significantly different. Apparent volume of distribution increased significantly for the 1,200-mg regimen compared with the 600-mg regimen. Mean maximum reciprocal serum inhibitory titers were 96 +/- 35, 101 +/- 43, and 160 +/- 78 for the 600-, 900-, and 1,200-mg regimens, respectively. Minimum reciprocal serum inhibitory titers averaged 12 +/- 4, 6 +/- 3, and 5 +/- 2 for the low-, medium-, and high-dose regimens, respectively. Mean AUIC increased roughly in proportion to dose. Similar daily values for the area under the concentration-time curve and for AUIC for each of the regimens suggest similar daily drug exposure and serum inhibitory activity. A regimen of 1,200 mg every 12 h may represent an alternative dosing strategy for clindamycin.
Construction of a probe for the aminoglycoside 3-V-acetyltransferase gene and detection of the gene among endemic clinical isolates
Authors: Barg N L
Published: June 2012

A recent surveillance study at Vanderbilt University Medical Center indicated that 8.5% of the gram-negative bacilli isolated were resistant to gentamicin. To determine what proportion of current gentamicin-resistant isolates elaborated aminoglycoside 3-V-acetyltransferase [AAC(3)-V], a probe for this gene was constructed from a 975-base-pair PstI-SalI fragment of the nonconjugative R plasmid pCER954b. This plasmid was first isolated at Vanderbilt University Medical Center from epidemic strains of Serratia marcescens. Nineteen isolates determined to produce AAC(3)-V by MIC profile all reacted with the probe. The probe did not hybridize with DNA from organisms producing 10 other aminoglycoside-modifying enzyme types. With this probe, 30 (36%) of 84 gentamicin-resistant, gram-negative bacilli elaborated AAC(3)-V. Of these 30 isolates, 25 contained a conjugative plasmid that transferred gentamicin resistance. In contrast to other medical centers, at Vanderbilt a sizable number of gentamicin-resistant, gram-negative bacilli produced AAC(3)-V. This resistance determinant, initially identified in an epidemic Serratia strain, has persisted and become incorporated into currently isolated endemic strains of gram-negative bacilli.
Fluconazole in the treatment of Candida-associated denture stomatitis
Authors: Budtz-Jørgensen E , Holmstrup P , Krogh P
Published: June 2012

A double-blind trial was carried out to study the effect of oral administration of fluconazole in the treatment of Candida-associated denture stomatitis. The study group consisted of 38 denture stomatitis patients who harbored yeasts, predominantly Candida spp., in significant numbers as determined by culture from the lesions. Half of the patients received 50 mg of fluconazole per day orally for 14 days, and the other half received placebo capsules. The following parameters were studied: degree of palatal erythema, presence of yeast cells (by plate count and microscopy of smears), identification to the species level of dominant yeast organisms, biotyping of Candida albicans, and treatment-related side effects. A significant reduction of erythema was seen after treatment with fluconazole, but the inflammation showed partial relapse 2 to 4 weeks after treatment was terminated. Reduced soreness of the oral mucosa was reported by six of the patients in the fluconazole group. No significant clinical or yeast flora changes were observed in the placebo group. Extensive changes in the yeast flora were observed in the fluconazole group, both in quantity and in composition of yeast species and C. albicans strains (biotypes), which perhaps indicated differences in pathogenicity and fluconazole susceptibility among various yeast species and C. albicans strains. Fluconazole did not produce any changes in the results of blood and urine analyses. The results indicate that fluconazole is a safe and well-tolerated antimycotic drug. The transient clinical and antimycotic effect may have been due in part to the possibility that therapeutic concentrations of the drug were not reached beneath the fitting denture surface and within the denture plaque.
Iron-regulated outer membrane proteins of Escherichia coli K-12 and mechanism of action of catechol-substituted cephalosporins
Authors: Curtis N A , Eisenstadt R L , East S J , Cornford R J , Walker L A , White A J
Published: June 2012

Selected aminothiazolyl-oxime cephalosporin congeners substituted at C-3' with a catechol moiety were used to probe the basis of the enhanced antibacterial activity against Escherichia coli K-12 often associated with chemical modifications of this type. Evidence is presented for a tonB-dependent illicit transport of the compounds across the outer membrane of E. coli K-12, the process involving jointly and specifically the Fiu and Cir iron-regulated outer membrane proteins. Thus, both tonB and fiu cir mutants showed a comparably reduced susceptibility to the probe compounds, whereas mutants singularly lacking any one of the six iron-regulated outer membrane proteins (Fiu, FepA, FecA, FhuA, FhuE, and Cir) or lacking any combination of any two of these proteins (except Fiu plus Cir) did not show this resistance. Mutants devoid of all six iron-regulated outer membrane proteins were no more resistant to the probe compounds than fiu cir or tonB strains. In addition to the latter genes, the products of the exbB and possibly the exbC loci were necessary for maximal antibacterial potency. A dependence of antibacterial activity on the level of expression of the uptake system components was noted. Comparison of penicillin-binding protein target affinity with antibacterial activity suggested a possible periplasmic accumulation of active compounds by E. coli K-12. Free vicinal hydroxyl groups of the catechol residue were a primary chemical requirement for recognition by the uptake pathway and thus for high antibacterial activity.
Heterogeneity of class I beta-lactamase expression in clinical isolates of Pseudomonas aeruginosa
Authors: Sanders C C , Gates M L , Sanders W E
Published: June 2012

Expression of chromosomal beta-lactamase was examined in 85 clinical isolates of Pseudomonas aeruginosa. beta-Lactamase assays with and without cefoxitin induction revealed four phenotypes of enzyme expression: low basal, inducible; moderate basal, inducible; moderate basal, constitutive; and high basal, constitutive. The isoelectric points of the major beta-lactamase bands were 9.4, 9.2, and 8.4. These results indicate that there is a limited heterogeneity in expression of chromosomal beta-lactamase of P. aeruginosa.
Ganciclovir pharmacokinetics during renal impairment
Authors: Lake K D , Fletcher C V , Love K R , Brown D C , Joyce L D , Pritzker M R
Published: June 2012

Limited information is available concerning the use of ganciclovir (GCV) in patients with severe renal impairment. The pharmacokinetics of GCV were studied in a heart transplant recipient requiring hemodialysis. The total body clearance was calculated to be approximately 5% of that previously reported for patients with normal renal function. GCV was removed by hemodialysis; a single 4-h procedure decreased the concentration in plasma by approximately 50%. GCV can be safely administered to patients with renal insufficiency if concentrations in plasma are monitored.
In vitro assay to demonstrate high-level erythromycin resistance of a clinical isolate of Treponema pallidum
Authors: Stamm L V , Stapleton J T , Bassford P J
Published: June 2012

We have previously demonstrated that cells of Treponema pallidum freshly extracted from infected rabbit testes can be intrinsically radiolabeled with [35 S]methionine to very high specific activities. In this study we used the inhibition of [35 S]methionine incorporation into trichloroacetic acid-precipitable protein in vitro as an assay to test the susceptibilities of three different pathogenic treponemal strains to various antibiotics. In general, the results correlated very well with the known efficacies of these antibiotics in treating human patients with syphilis. One of the strains tested, however, a clinical isolate of T. pallidum designated street strain 14, was found to exhibit high-level resistance to erythromycin and a closely related macrolide, roxithromycin (RU 965). Street strain 14 was originally isolated from a human patient with active secondary syphilis who failed to respond to erythromycin therapy. Thus, our results indicate that an erythromycin-resistant strain of T. pallidum can be responsible for erythromycin treatment failure. In addition, street strain 14 treponemes were found to be generally less susceptible by this assay to a variety of antibiotics than were treponemes of the T. pallidum Nichols strain. These findings suggest that the outer envelope of street strain 14 treponemes may be generally less permeable to antibiotics than is that of Nichols strain treponemes.
Differences in resistance to reinfection with low and high inocula of Trypanosoma cruzi in chagasic mice treated with nifurtimox and relation to immune response
Authors: Cabeza Meckert P , Chambó J G , Laguens R P
Published: June 2012

Reinfection of chronic chagasic mice after treatment with nifurtimox resulted in different outcomes according to the number of parasites used for inoculation. Nifurtimox-treated chagasic animals injected with 2,500 trypomastigotes developed higher parasitemia and increased mortality compared with nontreated chagasic mice. When reinfection was done with 25 trypomastigotes, treated and nontreated animals showed similar parasitemias and mortalities, which were significantly higher in nonchagasic controls infected for the first time. Immunological studies showed that treatment with nifurtimox led to a decrease in anti-Trypanosoma cruzi antibodies engaged in parasite destruction, inducing either complement-dependent lysis or antibody-dependent cytotoxicity, but no difference in anti-T. cruzi cell-mediated immunity was found between treated and nontreated chagasic animals. It is concluded that treatment with nifurtimox leads to a loss of resistance to reinfection with a large number of trypanosomes, which is maintained with challenge with a few parasites, and that these two thresholds of premunition are probably associated with humoral and cell-mediated anti-T. cruzi immune responses, respectively.
In vitro activities of 39 antimicrobial agents for Branhamella catarrhalis and comparison of results with different quantitative susceptibility test methods
Authors: Doern G V , Tubert T A
Published: June 2012

The in vitro activities of 39 antimicrobial agents were assessed versus 74 clinical isolates of Branhamella catarrhalis. Resistance was observed only with penicillin and ampicillin and then only with beta-lactamase-producing strains. The results of in vitro susceptibility tests with agar dilution and broth microdilution procedures were found to be comparable. The results of broth tube macrodilution tests were, in general, one twofold-concentration increment higher.
Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers
Authors: Lam Y W , Duroux M H , Gambertoglio J G , Barriere S L , Guglielmo B J
Published: June 2012

The effect of protein binding on antibiotic efficacy is controversial. The pharmacologic effect of an antibiotic is believed to be related to its unbound concentration at the site of infection. It is unknown whether antibiotics with a low degree of serum protein binding are clinically superior to antibiotics that are highly protein bound. In a randomized, crossover investigation, the serum bactericidal activities of a single dose of ceftazidime (30 mg/kg) and cefoperazone (30 mg/kg) were studied in six healthy volunteers against three clinical isolates of Pseudomonas aeruginosa for which both antibiotics had similar MICs and MBCs. Serum samples were collected over 12 h. The total and unbound antibiotic concentrations were determined by high-pressure liquid chromatography. Mean peak total concentrations of ceftazidime and cefoperazone in serum were 101.7 +/- 18.6 and 264.1 +/- 149.6 micrograms/ml, respectively. Due to its lower protein binding (21 +/- 6%), ceftazidime had significantly higher unbound concentrations in serum than did the highly bound cefoperazone (91.5 +/- 2%). Mean peak unbound concentrations were 78.5 +/- 12.5 and 24.2 +/- 17.8 micrograms/ml for ceftazidime and cefoperazone, respectively. The unbound concentration of ceftazidime at each sampling time was higher than that of cefoperazone. Although total concentrations were consistently higher than the MICs, serum containing cefoperazone showed minimal bactericidal activity against the isolates. In contrast, despite lower total concentrations, ceftazidime had greater antibacterial activity than cefoperazone. Serum bactericidal activity was more closely related to unbound rather than total antibiotic concentrations. Our data support the concept that only the unbound drug is microbiologically active.
Polycation binding to isolated lipopolysaccharide from antibiotic-hypersusceptible mutant strains of Escherichia coli
Authors: Rocque W J , Fesik S W , Haug A , McGroarty E J
Published: June 2012

Lipopolysaccharide (LPS) samples isolated from a parent and two antibiotic-hypersusceptible mutant strains of Escherichia coli were analyzed for polycation affinity and level of binding. Purified salts of the LPSs from the parent strain, UB1005, and from one of the mutant strains, DC1, bound similar amounts of sodium and magnesium, but the samples from the second mutant strain, DC2, had significantly greater amounts of counterions bound per phosphate than did the other two isolates. The 31P nuclear magnetic resonance spectra indicated that, compared with LPS from the parental strain, the sample from strain DC1 was similar but the DC2 sample contained fewer diphosphodiester and more diphosphomonoester groups. Motion within the lipid A head group regions of the magnesium salts of the three isolates was dramatically different, as revealed by an electron spin resonance probe. The binding of the cations to the LPS aggregates was measured by the displacement of this cationic spin probe from the LPS samples. The polycations polymyxin, gentamicin, and spermine displaced more probe from samples of the two mutant strains than from that of the parental strain. The sample from the most antibiotic-susceptible strain, DC2, had the highest affinity for all the polyvalent cations tested. The results indicate that antibiotic hypersusceptibility can result from at least two distinct alterations in LPS structure. The decrease in diphosphodiesters and increase in diphosphomonoesters in the LPS of the DC2 sample resulted in more acidic phosphate moieties and a more antibiotic-susceptible cell. In contrast, the alterations in the LPS of DC1 that resulted in antibiotic hypersusceptibility of the cell were not in the phosphate substituents. In both mutants, however, hypersusceptibility resulted in an alteration in LPS structure that increased the affinity of the molecules for polycations.
Influence of cephalosporins and iron on surface protein antigens of Klebsiella pneumoniae in vivo
Authors: Kadurugamuwa J L , Anwar H , Brown M R , Hengstler B , Kunz S , Zak O
Published: June 2012

The outer membrane protein (OMP) profiles of Klebsiella pneumoniae grown in a rabbit peritonitis model in the presence or absence of cephalosporins were investigated. Six high-molecular-weight OMPs (Mr 69,000 to 83,000) were induced under iron-depleted conditions in vitro. Three of these proteins (the 69,000-Mr protein [69K protein] and the 70K and 78K proteins) and trace amounts of the 73K and 75K proteins were induced in the OM of bacteria infecting the peritoneal cavity of rabbits. Addition of iron either to the growth medium in vitro or to the peritoneum in vivo repressed the expression of these proteins. Cephaloridine had no significant effect on the OMP profiles. An additional 56,000-Mr protein was observed in the OM of bacteria cultivated in vivo in the presence of CGP 17520 and also to a lesser extent in vivo under conditions of iron excess. A difference in recognition of OM antigens between cells grown in vitro and in vivo was observed by immunoblotting techniques. The 26K, 27.5K, and 28.5K antigens present in the OM of cells grown in vitro (but not in vivo) were recognized by antibodies raised against bacteria cultivated in vitro under conditions of iron depletion, but were not recognized by antisera raised against bacteria harvested directly from infections. Antisera raised against a nonencapsulated K. pneumoniae strain caused no agglutination of encapsulated K. pneumoniae grown in vivo in the absence of cephalosporins. Rapid agglutination was observed with this antiserum when the same encapsulated strain was grown in vivo in the presence of either cephalosporin, indicating less occlusion of critical antigens by the capsule.
In vitro activity of cefoperazone plus sulbactam compared with that of other antimicrobial agents against anaerobic bacteria
Authors: Wexler H M , Finegold S M
Published: June 2012

The activity of two cefoperazone-sulbactam combinations against anaerobic bacteria was tested and compared both with that of cefoperazone alone and with that of other commonly used antimicrobial agents. Imipenem was the most active of the tested agents, followed by chloramphenicol, metronidazole, and cefoperazone-sulbactam (90 to 100% of bacterial growth inhibited). Clindamycin and cefoxitin inhibited approximately 80%, cefoperazone inhibited 63%, and penicillin G inhibited 47% of the strains tested. The agents were variable in activity against the Bacteroides fragilis group, with percents susceptible as follows: cefoperazone-sulbactam, imipenem, metronidazole, and chloramphenicol, 99 to 100%; cefoxitin and clindamycin, approximately 80%; cefoperazone, 49%; and penicillin G, 15.5%.
Aminoglycoside binding sites in the inner ears of guinea pigs
Authors: Tran Ba Huy P , Deffrennes D
Published: June 2012

With [125I]gentamicin as radioligand, the presence of aminoglycoside binding sites and kinetics of gentamicin binding to homogenates of organs of Corti, vestibular maculae, livers, spleens, and hearts of guinea pigs were investigated. The effects of temperature, osmolarity, 2,4-dinitrophenol, and digitonin on gentamicin binding were assessed. The affinities of several aminoglycosides for binding sites were tested. Gentamicin bound to cochlear and vestibular structures in a rapid and saturable fashion at a single class of noninteracting binding sites with Kds of 1.2.10(-6) and 3.10(-7) M and maximal binding capacities of 1.3 nmol and 43 pmol/mg of protein, respectively. In the liver, spleen, and heart, binding remained low and appeared to be nonspecific. In the organ of Corti, gentamicin uptake was unaffected by alterations in temperature or medium osmolarity or by 2,4-dinitrophenol, indicating that the uptake represented binding and not active transport. Digitonin at 10 nM increased markedly the uptake at 37 and 4 degrees C, suggesting the presence of internal binding sites. Various aminoglycosides compete for a common binding site.
In vitro activity of lomefloxacin, a new quinolone antimicrobial agent, in comparison with those of other agents
Authors: Wise R , Andrews J M , Ashby J P , Matthews R S
Published: June 2012

The in vitro activity of lomefloxacin (SC-47111; NY-198), a new difluorinated quinolone, was compared with those of ofloxacin, ciprofloxacin, fleroxacin, amoxicillin, cefuroxime, and trimethoprim against 585 recent clinical isolates and other strains with known mechanisms of resistance. The MICs of lomefloxacin against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and staphylococci were between 0.25 and 4 micrograms/ml. Ninety percent of Neisseria sp. and Haemophilus influenzae were susceptible to less than or equal to 0.06 micrograms/ml, and streptococci (including Streptococcus pyogenes, Streptococcus pneumoniae, and enterococci) and Bacteroides fragilis were susceptible to 8 micrograms/ml. Lomefloxacin was comparable in activity to fleroxacin and ofloxacin, but it was less active than ciprofloxacin. There was cross-resistance between the quinolone group of antimicrobial agents. The protein binding of lomefloxacin was 15.4%, and serum had little effect on the activity of the compound. However, urine at pH 5.0 decreased the activity by two- to eightfold compared with that at pH 7.0
Comparative in vitro activity of a new fluorinated 4-quinolone, T-3262 (A-60969)
Authors: Espinoza A M , Chin N X , Novelli A , Neu H C
Published: June 2012

The in vitro activity of a new quinolone, T-3262 [A-60969; DL-7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1-, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid monohydrate], was compared with those of ciprofloxacin, ofloxacin, ceftazidime, imipenem, and gentamicin. T-3262 inhibited 90% of isolates of the family Enterobacteriaceae at a concentration of less than or equal to 0.25 micrograms/ml. It was two to four times more active than ofloxacin and similarly or slightly less active than ciprofloxacin. Ninety percent of isolates of Pseudomonas aeruginosa were inhibited at 0.5 micrograms/ml. It was 4- to 8-fold more active than ciprofloxacin and 8- to 16-fold more active than ofloxacin against Pseudomonas cepacia and Pseudomonas maltophilia, which were resistant to imipenem and gentamicin. Most Haemophilus influenzae, Neisseria gonorrhoeae, and Branhamella catarrhalis isolates were inhibited at concentrations of less than or equal to 0.008 micrograms/ml. The MIC for 90% of the Staphylococcus aureus isolates, including methicillin-resistant S. aureus, was 0.12 micrograms/ml; that for Staphylococcus epidermidis was 0.5 micrograms/ml, as was that for Enterococcus faecalis. It inhibited 90% of Bacteroides fragilis isolates at 2 micrograms/ml, considerably more active than ciprofloxacin and ofloxacin. The frequency of spontaneous point mutational resistance was less than 10(-10) for members of the family Enterobacteriaceae and Pseudomonas spp. Resistant strains could be selected by repeated subculture. Similar to other quinolones, its activity could be affected by culture conditions. T-3262 showed a postantibiotic suppressive effect on Escherichia coli, P. aeruginosa, and S. aureus.
In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity
Authors: Watanabe N , Katsu K , Moriyama M , Kitoh K
Published: June 2012

E1040 is a new parenteral cephalosporin with a broad antibacterial spectrum and potent antipseudomonal activity. The compound was four- to eightfold more active than ceftazidime and cefsulodin against Pseudomonas aeruginosa (MIC of E1040 for 90% of strains tested [MIC90], 3.13 micrograms/ml). E1040 also showed a potent activity against other glucose-nonfermentative rods, including Acinetobacter species. The activities of E1040 against most species of the family Enterobacteriaceae were roughly comparable to the activities of ceftazidime and cefmenoxime and exceeded that of cefotiam. Against Citrobacter freundii (MIC90, 0.78 micrograms/ml), Enterobacter cloacae (MIC90, 3.13 micrograms/ml), and Enterobacter aerogenes (MIC90, 0.2 micrograms/ml), E1040 was 16- to 256-fold more active than ceftazidime and cefmenoxime. The activities of E1040 against gram-positive cocci and anaerobes were comparable to those of ceftazidime, but the compound was less active than cefmenoxime. E1040 was at least as resistant as ceftazidime and cefmenoxime to hydrolysis by various beta-lactamases and showed high affinities for penicillin-binding protein 3 of both Escherichia coli and P. aeruginosa.
Phase I study of a murine monoclonal anti-lipid A antibody in bacteremic and nonbacteremic patients
Authors: Harkonen S , Scannon P , Mischak R P , Spitler L E , Foxall C , Kennedy D , Greenberg R
Published: June 2012

Nine patients with suspected gram-negative bacterial sepsis were studied to determine the safety, pharmacokinetics, and immunogenicity of XMMEN-0E5, a murine immunoglobulin M monoclonal antibody directed against the core lipid A region of bacterial endotoxin. Antibody was administered by single intravenous infusion of 1 to 4 h duration at doses ranging from 0.1 to 15 mg/kg. Five patients had positive blood cultures for gram-negative bacteria, one patient had Torulopsis septicemia, one patient had gram-negative bacterial meningitis, and two patients were culture negative. No evidence of antibody-mediated toxicity was observed at any dose level. The serum half-life of the antibody was approximately 10 h at doses of 0.1 to 7.5 mg/kg and approximately 18 h at a dose of 15 mg/kg. No apparent difference in clearance of antibody was observed between bacteremic and nonbacteremic patients. Human anti-mouse antibodies were detected in the sera of three evaluable patients that received doses equal to or greater than 2.0 mg/kg but not in patients that received lower doses of antibody. This study demonstrates that XMMEN-0E5 is well tolerated at doses from 0.1 to 15 mg/kg and may be immunogenic at doses of 2.0 mg/kg and above. Controlled trials to establish the efficacy of this antibody in the treatment of gram-negative bacteremia are indicated.
Renal pharmacokinetic changes of gentamicin during enterococcal pyelonephritis
Authors: Auclair P , Lessard C , Bergeron M G
Published: June 2012

In the present study, the renal pharmacokinetics of gentamicin was investigated in pyelonephritic rats infected with Streptococcus (Enterococcus) faecalis. Four days after the induction of infection, animals were given either a single dose of gentamicin or two daily injections for 7 days. The treated animals were evaluated from 1 h to 6 months posttreatment. After a single injection, limited pharmacokinetic variations were observed, whereas after 14 injections infected kidneys demonstrated significantly higher concentrations and a more extended renal elimination phase of the antibiotic. Analysis of the area under the curve of the concentration in kidney versus time showed more marked renal accumulation by the infected and long-term treated animals than by normal animals or those receiving only one injection of aminoglycoside. Renal function remained normal in both the infected and normal animals treated with this aminoglycoside. These results demonstrate that S. faecalis pyelonephritis disturbs the renal handling of gentamicin and may increase the susceptibility of the kidney to aminoglycosides.
Ciprofloxacin therapy of experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus
Authors: Fernandez-Guerrero M , Rouse M , Henry N , Wilson W
Published: June 2012

Ciprofloxacin was more effective (P less than 0.01) than either imipenem or nafcillin therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis in rabbits after 2 or 3 days of treatment. There was no significant difference between results of treatment of methicillin-susceptible S. aureus experimental endocarditis with ciprofloxacin and results with the combination of nafcillin and gentamicin. Ciprofloxacin was more effective (P less than 0.01) than vancomycin therapy of experimental methicillin-resistant S. aureus endocarditis after 3 days of treatment. After 5 days of treatment, there was no significant difference between the results of treatment of experimental methicillin-resistant S. aureus endocarditis with ciprofloxacin and results with vancomycin.
High-level tetracycline resistance resulting from TetM in strains of Neisseria spp., Kingella denitrificans, and Eikenella corrodens
Authors: Knapp J S , Johnson S R , Zenilman J M , Roberts M C , Morse S A
Published: June 2012

Similar to Neisseria gonorrhoeae, tetracycline-resistant isolates of N. meningitidis, Kingella denitrificans, and Eikenella corrodens contained 25.2-megadalton plasmids carrying the TetM determinant. In contrast, tetracycline-resistant N. subflava biovar perflava-N. sicca and N. mucosa isolates carried the TetM determinant in the chromosome.
In vitro and in vivo antibacterial activities of T-3262, a new fluoroquinolone
Authors: Fujimaki K , Noumi T , Saikawa I , Inoue M , Mitsuhashi S
Published: June 2012

T-3262, a new fluoroquinolone, showed a broad spectrum of activity against gram-positive and gram-negative bacteria. T-3262 had most potent activity against gram-positive cocci, such as Staphylococcus, Streptococcus, and Enterococcus spp. The MICs of T-3262 for 90% of strains tested were between 0.05 and 1.56 micrograms/ml. Against members of the family Enterobacteriaceae and Pseudomonas aeruginosa, the activities of T-3262 were almost equal to those of ciprofloxacin. Obligate anaerobes were also susceptible to T-3262. T-3262 was bactericidal for one strain each of Staphylococcus aureus, Escherichia coli, and P. aeruginosa at concentrations near its MIC; and fluoroquinolones, including T-3262, inhibited DNA gyrase activity at low concentrations. The 50% effective dose of T-3262 after oral administration against systemic infections with S. aureus in mice was about 6 times lower than that of ofloxacin and about 20 times lower than that of norfloxacin.
Isolation and characterization of a penicillinase from Pseudomonas cepacia 249
Authors: Prince A , Wood M S , Cacalano G S , Chin N X
Published: June 2012

Pseudomonas cepacia has an inducible beta-lactamase which is responsible for its novel ability to catabolize beta-lactam compounds. The gene encoding this enzyme, penA, was cloned from a genomic library of P. cepacia 249 on the broad-host-range cosmid pLAFR. This separated the penA gene from the gene encoding a second beta-lactamase in P. cepacia 249. Expression of penA was inducible in an Escherichia coli host strain by low levels of penicillin. The 33,500-molecular-weight enzyme had penicillinase activity not inhibited by clavulanic acid or sulbactam and was highly active against piperacillin and azlocillin. In comparison with other inducible beta-lactamases produced by gram-negative organisms, the penA enzyme had many properties which were similar to those of the penicillinase produced by Alcaligenes faecalis. It was unlike the ampC-type cephalosporinase produced by Pseudomonas aeruginosa.
Ganciclovir prophylaxis for cochlear pathophysiology during experimental guinea pig cytomegalovirus labyrinthitis
Authors: Woolf N K , Ochi J W , Silva E J , Sharp P A , Harris J P , Richman D D
Published: June 2012

The effectiveness of the antiviral agent ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) against guinea pig cytomegalovirus was tested in vitro in guinea pig embryonic fibroblasts and in vivo in an experimental guinea pig cytomegalovirus labyrinthitis model. In vitro, ganciclovir completely prevented guinea pig cytomegalovirus infection of guinea pig embryonic fibroblasts at concentrations above 32.6 micrograms/ml. In vivo, antibody-negative animals had an average 17-dB elevation in their auditory nerve compound action potential thresholds (P less than 0.01, t test) and showed signs bilaterally of guinea pig cytomegalovirus labyrinthitis 8 days after intrathecal inoculation of virus. Ganciclovir administration starting 1 day before inoculation prevented the development of both cochlear histopathologic change and hearing loss. Guinea pig cytomegalovirus meningitis was observed in both the drug-treated and untreated groups. High-pressure liquid chromatography confirmed the presence of ganciclovir in the serum, perilymph, and cerebrospinal fluid of the drug recipients. Prophylactic ganciclovir thus can protect the cochlea from the histopathologic changes and hearing loss normally associated with experimental guinea pig cytomegalovirus labyrinthitis.
Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals
Authors: Hayashi T , Watanabe Y , Kumano K , Kitayama R , Yasuda T , Saikawa I , Katahira J , Kumada T , Shimizu K
Published: June 2012

The protective effect of piperacillin against the nephrotoxicity of cephaloridine and gentamicin was examined in experimental animals. In rabbits, piperacillin was infused at a dose of 1 mg/kg (body weight) per min over 225 min and cephaloridine (300 mg/kg) was intravenously administered as a bolus 45 min after the start of a drip infusion. Blood urea nitrogen, serum creatinine, and N-acetyl-beta-D-glucosaminidase (NAG) in urine were measured as the renal toxicological parameters before and 24 h after cephaloridine dosing. Although the single administration of cephaloridine significantly elevated these parameters, the elevation was prevented by the concomitant administration of piperacillin. The protective effect of piperacillin was superior to those of cephalothin and fosfomycin. In rats, piperacillin (1,000 mg/kg) was intravenously administered and immediately followed by the intramuscular administration of gentamicin (100 mg/kg) every 24 h for 5 days. When piperacillin was concomitantly administered with gentamicin, the elevations of blood urea nitrogen, serum creatinine, and urinary NAG were significantly lower than when gentamicin was given alone. The concomitant administration of piperacillin resulted in a significant protective effect against the nephrotoxicity of cephaloridine in rabbits and of gentamicin in rats. Histopathological observation also supported the protective effect of piperacillin. The protective mechanism of piperacillin might be the inhibition of transport from the peritubular side to tubular cells for cephaloridine and from both the peritubular and luminal sides for gentamicin.
Concentrations of flucloxacillin in heart valves and subcutaneous and muscle tissues of patients undergoing open-heart surgery
Authors: Frank U , Schmidt-Eisenlohr E , Schlosser V , Spillner G , Schindler M , Daschner F D
Published: June 2012

Thirty-seven patients were given a single, 2-g intravenous bolus injection of flucloxacillin prior to open-heart surgery. Within 12 h, flucloxacillin concentrations in serum and heart valves declined from 125.2 to 4.4 micrograms/ml and from 16.5 to 3.7 micrograms/g, respectively. Concentrations in subcutaneous tissue and muscle were almost identical, declining from 14.7 or 14.2 micrograms/g to undetectable levels after 8 to 10 h.
Is apalcillin nephrotoxic?
Authors: Fillastre J P , Moulin B , Godin M , Frelon J H
Published: June 2012

Apalcillin is a new semisynthetic penicillin used as a sodium salt. More than 4,000 patients have been treated with this antibiotic, but increased serum creatinine levels were noted in 18 cases. In 5 of these cases, apalcillin was possibly responsible, and in 13 it was doubtful. We decided to study renal function of normal volunteers treated with 4 g of apalcillin. Three periods were studied: a pretreatment control period of 80 min followed by a treatment period of 60 min and a posttreatment period of 40 min. Inulin and p-aminohippurate (PAH) infusion were continued during all three periods. At the beginning of the treatment period, 2 g of apalcillin was injected as a bolus, followed by infusion of 2 g of apalcillin over 1 h. Urinary volume was measured every 20 min. Creatinine, insulin, and PAH clearances and urinary excretion of sodium, potassium, calcium, and magnesium were calculated for each period. Urinary beta-2-microglobulin excretion was also assessed. Analysis of variance was done. We observed no variation in clearances of creatinine or inulin or in urinary electrolyte output. PAH clearance was significantly decreased during apalcillin infusion. Apalcillin appeared to compete with PAH for proximal tubular secretion but induced no further renal dysfunction.
Dispersal in Campylobacter spp. of aphA-3, a kanamycin resistance determinant from gram-positive cocci
Authors: Papadopoulou B , Courvalin P
Published: June 2012

DNA annealing studies indicated that kanamycin resistance in Campylobacter strains from various geographical areas is encoded by a gene structurally related to aphA-3 of gram-positive cocci. This finding confirms the transfer of genetic material between gram-positive and gram-negative bacteria under natural conditions.
Antibacterial properties of (2,3)-alpha- and (2,3)-beta-methylene analogs of penicillin G
Authors: Christenson J G , Pruess D L , Talbot M K , Keith D D
Published: June 2012

The penam nucleus can assume two conformations; these are designated open and closed. The synthetic (2,3)-alpha- and (2,3)-beta-methylenepenams can be regarded as analogs of the open and closed conformations, respectively. It has been shown that the beta-methylenepenams are essentially inactive, suggesting that the closed conformation of penams is also inactive. In this study, we investigated a series of beta-lactams, all of which contained phenylacetamido side chains: penicillin G, the (2,3)-alpha- and (2,3)-beta-methylenepenams, and the 3-acetoxymethyl- and 3-methylcephalosporins. The alpha-methylenepenam and penicillin G were the most active compounds, while the beta-methylene isomer was only poorly active. Results with permeability mutants suggested that the alpha-methylene compound penetrated the outer membrane somewhat more readily than penicillin G did. The intrinsic potency of the alpha-methylenepenam appeared to be similar to that of penicillin G, on the basis of their affinities for penicillin-binding proteins and their abilities to inhibit peptidoglycan synthesis in ether-permeabilized Escherichia coli, while the beta-methylene analog had very poor intrinsic potency. The alpha-methylene analog was about 10-fold more efficient (Vmax/Km) than penicillin G as a substrate for the cephalosporinases from Enterobacter cloacae and Proteus vulgaris, but it was about 40-fold less efficient with penicillinase from Staphylococcus aureus. These results strongly support the hypothesis that the active conformation of penams is the open conformation and suggest that the position in space of the carboxyl group relative to the beta-lactam carbonyl is an important determinant of cephalosporinlike character, as distinct from penicillinlike character.
Simple assay of beta-lactamase with agar medium containing a chromogenic cephalosporin, pyridinium-2-azo-p-dimethylaniline chromophore (PADAC)
Authors: Kobayashi S , Arai S , Hayashi S , Sakaguchi T
Published: June 2012

A new beta-lactamase assay method with agar plates containing pyridinium-2-azo-p-dimethylaniline chromophore (PADAC) (50 microM), a beta-lactamase-labile, chromogenic cephalosporin, was examined. On the PADAC plates inoculated with beta-lactamase-producing gram-negative bacteria (10(4) CFU per spot) and incubated at 37 degrees C, a yellow zone showing hydrolysis of PADAC by beta-lactamase was formed around the colony. The zone diameter increased with incubation time. Examination with Enterobacter cloacae GN7471 revealed that beta-lactamase activity was present in the agar around the colony, decreasing exponentially with increasing distance from the colonial margin; this suggests that the PADAC hydrolysis zone is formed by an extracellular enzyme. At 18 h, significant correlations were obtained between the zone diameters of the 10 species (clinical isolates) examined and their periplasmic beta-lactamase activities determined spectrophotometrically. The addition of clavulanic acid (0.5 to 10 micrograms/ml) inhibited zone formation on the PADAC plates inoculated with type IIIa, Va, Vb, PSE-1, and Ic beta-lactamase producers. When the clinical isolates were tested on plates with clavulanic acid (2 micrograms/ml), inhibition was observed in 41 to 58% of the Escherichia coli, Serratia marcescens, and Pseudomonas aeruginosa isolates and in all isolates of Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus vulgaris. Thus, the use of the inhibitor made it possible to detect penicillinase or type Ic cephalosporinase producers. These results proved that the PADAC plate might be a useful tool permitting easy, semiquantitative determination of beta-lactamase activity.
Comparison of two bromovinyl nucleoside analogs, 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil and E-5-(2-bromovinyl)-2'-deoxyuridine, with acyclovir in inhibition of Epstein-Barr virus replication
Authors: Lin J C , Machida H
Published: June 2012

The effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), a new antiviral drug, on Epstein-Barr virus (EBV) was studied and compared with those of E-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) and acyclovir (ACV). BV-araU effectively inhibited EBV replication both in superinfected Raji cells and in virus producer P3HR-1(LS) cells, as determined by density gradient centrifugation, in situ cytohybridization with an EBV DNA probe, and cRNA-DNA hybridization. The 50% effective doses for viral DNA replication were 0.26, 0.06, and 0.3 microM for BV-araU, BVdU, and ACV, respectively. The relative efficacy on the basis of the in vitro therapeutic index was BVdU (6,500) greater than BV-araU (1,500) greater than ACV (850). Synthesis of EBV-induced polypeptides with molecular weights of 145,000 and 140,000 was inhibited by these drugs. Kinetic analysis of reversibility of inhibition of EBV DNA replication after removal of the drugs indicated that BV-araU, like BVdU, has a more prolonged inhibitory effect than ACV. These results indicate that the 2' OH group in the arabinosyl configuration of BV-araU results in marked reduction in anti-EBV activity while slightly diminishing cytotoxicity.
Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect
Authors: Ikeda Y , Nishino T
Published: June 2012

Fifteen beta-lactam antibiotics were divided into four classes based on their antibacterial actions and beta-lactamase-inducing activities in Proteus vulgaris. One of these groups, which included cefmenoxime, ceftriaxone, cefuzonam, and cefotaxime, showed a clear paradoxical antibacterial activity against P. vulgaris. This group showed growth-inhibitory activity at relatively low concentrations, up to certain limits. These cephalosporins have, as a common moiety, an aminothiazolyl-oxyimino group in the 7-acyl side chain and have high beta-lactamase-inducing activities and low stabilities against the beta-lactamase. In a mutant strain incapable of inducing beta-lactamase, however, the paradoxical antibacterial activity was not observed. These findings suggest that beta-lactamase plays an essential role in the paradoxical antibacterial effect in P. vulgaris. We conclude that the induction of a large amount of beta-lactamase and the low stability against beta-lactamase may account for the paradoxical antibacterial activity in P. vulgaris.
In vitro susceptibilities of Nocardia species to newer antimicrobial agents
Authors: Berkey P , Moore D , Rolston K
Published: June 2012

The in vitro activities of various quinolones, two newer cephalosporins, and imipenem against 23 strains of Nocardia asteroides, 4 strains of Nocardia brasiliensis, and 4 strains of Nocardia caviae were determined by an agar dilution method. PD-117558, a newer carboxyquinolone, and imipenem were the most active agents tested, inhibiting 90% of N. asteroides isolates at an MIC of 2 micrograms/ml. Of the 23 strains of N. asteroides, 15 were susceptible to cefpirome and 10 were susceptible to ciprofloxacin. The N. brasiliensis and N. caviae strains were very susceptible to PD-117558 (MIC, less than or equal to 1 microgram/ml), moderately susceptible to ciprofloxacin, and resistant to most of the other tested drugs.
In vitro cleavable-complex assay to monitor antimicrobial potency of quinolones
Authors: Walton L , Elwell L P
Published: June 2012

Seven quinolones were evaluated to determine whether their ability to generate the DNA gyrase-mediated cleavable complex correlated with their ability to inhibit the catalytic activity of purified DNA gyrase and inhibit the growth of Escherichia coli. The rank order of potency of these drugs in the cleavable-complex assay was essentially the same as in the DNA supercoiling-inhibition assay. It required 2- to 10-fold-lower drug concentrations to generate the cleavable complex than to inhibit E. coli DNA gyrase. With the newer fluoroquinolones, a 25- to 100-fold-greater concentration was required for DNA gyrase inhibition than for cell growth inhibition, suggesting a more subtle interaction between these inhibitors and DNA gyrase than mere enzyme inhibition.
Effects of ribonucleotide reductase inhibition on pyrimidine deoxynucleotide metabolism in acyclovir-treated cells infected with herpes simplex virus type 1
Authors: Karlsson A , Harmenberg J
Published: June 2012

The pyrimidine metabolism of fibroblasts infected with herpes simplex virus type 1 was studied. Herpes simplex virus type 1 infection increased the dTTP pool and thymidylate synthetase activity but reduced thymidine excretion. Addition of acyclovir to infected cells increased thymidine excretion, the dTTP pool, and thymidylate synthetase activity. Addition of a virus-specific ribonucleotide reductase inhibitor (A723U) decreased all three. The synergy between the two compounds is discussed.
Rapid determination of amphotericin B levels in serum by high-performance liquid chromatography without interference by bilirubin
Authors: Hosotsubo H , Takezawa J , Taenaka N , Hosotsubo K , Yoshiya I
Published: June 2012

A high-performance liquid chromatographic method for the determination of amphotericin B concentrations in human serum without bilirubin interference was developed and compared with a microbiological assay. The high-performance liquid chromatographic assay utilized a reversed-phase trimethyl silica column, simple sample preparation, and visible detection. Reproducibility studies yielded coefficient-of-variation ranges from 1.02 to 2.11% for within-day precision and 2.88 to 4.32% for between-day precision. The correlation coefficient with the microbiological assay was 0.984 for amphotericin B.
Effects of cyclophosphamide and a metabolite, acrolein, on Naegleria fowleri in vitro and in vivo
Authors: Zhang L , Marciano-Cabral F , Bradley S G
Published: June 2012

Mice challenged intranasally with Naegleria fowleri died of primary amoebic meningoencephalitis. Mice given 30 mg of cyclophosphamide per kg of body weight daily for 10 days starting 2 days before challenge were protected. Neither cyclophosphamide nor serum from cyclophosphamide-treated mice inhibited N. fowleri in vitro. A metabolic product of cyclophosphamide, acrolein, inhibited growth and enflagellation of N. fowleri. Acrolein at 40 microM was amoebicidal. Acrolein injured starved cells and amoebae at 5 degrees C and growing N. fowleri.