bluuebunny/crossref_metadata_2025 huggingface dataset:
Ciprofloxacin concentrations and impact of the colon microflora in patients undergoing colorectal surgery
Authors: Brismar B , Edlund C , Malmborg A S , Nord C E
Published: June 2012

Ciprofloxacin was given perorally in two doses of 750 mg each with a 12-h interval starting 24 h prior to surgery, 400 mg of ciprofloxacin was given intravenously at the induction of anesthesia, and 400 mg of ciprofloxacin was given 12 h later to 21 patients undergoing elective colorectal surgery. The maximum concentrations in serum (mean value +/- standard deviation, 11.1 +/- 7.8 mg/liter) during surgery were reached 30 min after ciprofloxacin was administered. The ciprofloxacin concentrations in the intestinal mucosa samples were 2.7 to 37.8 mg/kg of tissue weight, and the concentrations in the fecal samples were less than 0.1 to 858 mg/kg. The aerobic and anaerobic bacteria in the fecal flora were suppressed markedly during the prophylaxis period. No postoperative infections occurred.
In vitro activities of combinations of aztreonam, ciprofloxacin, and ceftazidime against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from patients with cystic fibrosis
Authors: Bosso J A , Saxon B A , Matsen J M
Published: June 2012

The in vitro activities of two-drug combinations of aztreonam, ciprofloxacin, and ceftazidime were studied in 96 clinical isolates of Pseudomonas aeruginosa and in 20 clinical isolates of Pseudomonas cepacia from cystic fibrosis patients. Some synergy was observed with each combination used against P. aeruginosa, but synergy was rare when the combinations were used against P. cepacia.
Selective toxicity of alkanolamines
Authors: Sandin M , Allenmark S , Edebo L
Published: June 2012

The antimicrobial effects of diethanolamine, dimethylamino-methyl-propanol, and butylethanolamine are greatly enhanced at high pH. Their antimicrobial activities are closely correlated with their uncharged forms, indicating that diffusion through cell membrane(s) is rate limiting for the antimicrobial action. Since these compounds are selectively toxic at high pH, they are appropriate antimicrobial agents for use in alkaline metalworking fluids.
Inoculum effect on growth-delay time of oxacillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis exposed to cefamandole, cefazolin, and cefuroxime
Authors: Yourassowsky E , van der Linden M P , Crokaert F
Published: June 2012

Cephalosporins have been recommended as prophylactic antibiotics in patients undergoing cardiovascular surgery. The major function of these antibiotics is to protect patients against Staphylococcus aureus and Staphylococcus epidermidis infections. The lowest inoculum amount responsible for infection during surgery is unknown but is probably low. To determine the comparative activities of cefazolin, cefuroxime, and cefamandole against S. aureus and S. epidermidis for prophylactic purposes, we selected five strains of S. aureus and S. epidermidis that presented homogeneous resistances to oxacillin. A continuously monitored turbidimetric method was used to evaluate cultures with variable inoculum sizes ranging from 10(6) to 1 CFU/ml and exposed to cefazolin, cefuroxime, and cefamandole at concentrations of 0.5, 1, 2, 4, 8, 16, and 32 micrograms/ml. Growth was defined as an increase of 0.1 optical density unit. The relationship between the time required for growth, the antibiotic concentration, and the initial bacterial density showed that cefamandole was more active than cefazolin, which, in turn, was revealed to be more active than cefuroxime against S. aureus and S. epidermidis.
Effects of dosage, peak and trough concentrations in serum, protein binding, and bactericidal rate on efficacy of teicoplanin in a rabbit model of endocarditis
Authors: Chambers H F , Kennedy S
Published: June 2012

The effect of dosage and the relative importance of peak and trough concentrations in serum for efficacy of teicoplanin were examined in a rabbit model of aortic valve endocarditis. Concentrations of teicoplanin in serum exceeded the MIC by several hundredfold, yet teicoplanin was less rapidly bactericidal than penicillin both in vitro and for endocarditis caused by a strain of Streptococcus sanguis. Because teicoplanin was 90% protein bound in rabbit serum, low free-drug concentrations probably resulted in less activity in vivo than in vitro. Because teicoplanin has a relatively low bactericidal rate and a high degree of protein binding, a sustained concentration in serum several times greater than the MIC may be important for efficacy in vivo. An intravenous regimen with relatively high peak concentrations in serum was less effective than an intramuscular regimen for endocarditis caused by a strain of Staphylococcus aureus, indicating that high peaks are unlikely to be an important determinant of efficacy. The therapeutically more relevant concentration in serum may be the trough.
Treatment of murine coccidioidal meningitis with SCH39304
Authors: Defaveri J , Sun S H , Graybill J R
Published: June 2012

The triazole SCH39304 was compared with itraconazole and fluconazole for treatment of murine coccidioidal meningitis. Mice were treated for 30 days with 1, 5, 10, or 30 mg of each drug per kg of body weight. Survival and brain tissue counts were measured. At equivalent doses, SCH39304 was more effective than the other triazoles.
Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) on experimental infections in mice with herpes simplex virus type 1 strains of different degrees of virulence
Authors: Machida H , Takezawa J
Published: June 2012

In vivo antiherpesvirus effects of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) were tested in two mouse model infections with herpes simplex virus type 1 (HSV-1) strains which showed different degrees of virulence in mice. Successful efficacies of oral and intraperitoneal (i.p.) treatments with brovavir were demonstrated in both intracerebral and i.p. infections with the HSV-1 WT-51 strain of moderate virulence. However, only weak or modest effects of brovavir were observed against the two model infections with a highly virulent strain, HSV-1 VR-3. Brovavir was not effective in reducing mortality of mice infected i.p. with HSV-1 KOS, which exhibited the highest virulence in mice among HSV-1 strains used when inoculated i.p. However, the drug had a significant effect on intracerebral infection with the KOS strain. Efficacies of oral treatment with brovavir were almost equal to those of i.p. administration in the model infections. After intracerebral inoculation, the VR-3 strain grew in brains of mice at a higher rate than the WT-51 strain. By oral treatment with 50 mg of brovavir per kg twice daily, replication of the WT-51 strain in the brains was markedly suppressed and was eliminated after transient elevation of the titer. Growth of the VR-3 strain in the brains was simply delayed by the drug treatment. Thus, the antiviral efficacy of brovavir in mice was affected by the degree of virulence of the challenge virus strain used for infection.
Biological characterization of a new radioactive labeling reagent for bacterial penicillin-binding proteins
Authors: Preston D A , Wu C Y , Blaszczak L C , Seitz D E , Halligan N G
Published: June 2012

Radiolabeled penicillin G is widely used as the imaging agent in penicillin-binding protein (PBP) assays. The disadvantages of most forms of labeled penicillin G are instability on storage and the long exposure times usually required for autoradiography or fluorography of electrophoretic gels. We investigated the utility of radioiodinated penicillin V as an alternative reagent. Radioiodination of p-(trimethylstannyl)penicillin V with [125I]Na, using a modification of the chloramine-T method, is simple, high yielding, and site specific. We demonstrated the general equivalence of commercially obtained [3H]penicillin G and locally synthesized [125I]penicillin V (IPV) in their recognition of bacterial PBPs. Profiles of PBPs in membranes from Bacteroides fragilis, Escherichia coli, Providencia rettgeri, Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium labeled with IPV or [3H]penicillin G were virtually identical. Use of IPV as the imaging agent in competition experiments for determination of the affinities of various beta-lactam antibiotics for the PBPs of E. coli yielded results similar to those obtained in experiments with [3H]penicillin G. Dried electrophoretic gels from typical PBP experiments, using IPV at 37.3 Ci/mmol and 30 micrograms/ml, exposed X-ray film in 8 to 24 h. The stability of IPV on storage at 4 degrees C was inversely proportional to specific activity. At 37.3 Ci/mmol and 60 micrograms/ml, IPV retained useful activity for at least 60 days at 4 degrees C. IPV represents a practical and stable reagent for rapid PBP assays.
Suppression of both antimony-susceptible and antimony-resistant Leishmania donovani by a bis(benzyl)polyamine analog
Authors: Baumann R J , Hanson W L , McCann P P , Sjoerdsma A , Bitonti A J
Published: June 2012

It was recently demonstrated that a bis(benzyl)polyamine analog (MDL 27695; N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane) possessed potent antimalarial activity in vitro and in vivo (A. J. Bitonti, J. A. Dumont, T. L. Bush, M. L. Edwards, D. M. Stemerick, P. P. McCann, and A. Sjoerdsma, Proc. Natl. Acad. Sci. USA 86:651-655, 1989). We now report that MDL 27695 also has potent antileishmanial activity, eliminating 77 to 100% of Leishmania donovani amastigotes from mouse peritoneal macrophages in vitro at 1 microM. Administration of 15 mg of MDL 27695 per kg three times per day for 5 days to L. donovani-infected mice suppressed parasite burdens in liver, spleen, and bone marrow by 83 to 96, 90, and 87%, respectively, and by 99.9% in livers of mice given the same dose two times per day for 10 days. Liver parasites were suppressed 74% in L. donovani-infected hamsters treated three times per day for 4 days with 5 mg of MDL 27695 per kg. The 50% effective doses for MDL 27695 were 2.5 mg/kg in mice and about 1 mg/kg in hamsters. In hamsters, MDL 27695 was equally effective against both antimony-susceptible and antimony-resistant L. donovani, suggesting a different mechanism of action for the two types of drugs. Coadministration of N1,N4-bis(butadienyl)-butanediamine (MDL 72527) to mice to inhibit host polyamine oxidase, and hence the formation of oxidative metabolites of MDL 27695, did not affect the antileishmanial activity of MDL 27695. Thus, the mechanism of action of MDL 27695 does not appear to be related to its oxidation to toxic metabolites but may involve interference with DNA and RNA syntheses as found previously in Plasmodium falciparum (Bitonti et al., Proc. Natl. Acad. Sci. USA 86:651-655, 1989).
Comparison of vancomycin- and teicoplanin-induced histamine release and "red man syndrome"
Authors: Sahai J , Healy D P , Shelton M J , Miller J S , Ruberg S J , Polk R
Published: June 2012

Twelve healthy adult males participated in a double-blind, randomized, two-way crossover study to determine histamine release and the frequency and severity of "red man syndrome" (RMS) following intravenous administration of vancomycin (15 mg/kg of body weight over 60 min) and teicoplanin (15 mg/kg over 30 min). Concentrations of vancomycin and teicoplanin in serum and concentrations of histamine in plasma were measured at baseline and during and after each infusion. Erythema and pruritus were classified a priori as mild, moderate, or severe. The extent of erythema was determined by the use of a burn chart, and pruritus was assessed by the subject with a rank scale. Global severity of RMS was determined by summation of the individual scores for pruritus and erythema. Baseline areas under the concentration-time curve for histamine were not significantly different for the vancomycin and teicoplanin treatments. Vancomycin caused RMS in 11 of 12 subjects (9 severe and 2 moderate cases) and was associated with a significant increase in plasma histamine (46.7 +/- 31.3 ng.min/ml, P less than 0.05). In contrast, teicoplanin did not cause RMS or elicit significant histamine release (8.7 +/- 13.2 ng.min/ml). Peak concentrations of vancomycin and teicoplanin in serum were 58.8 +/- 8.4 and 148.0 +/- 31.8 micrograms/ml, respectively (P less than 0.05). Assuming equal efficacy, these data suggest that teicoplanin may be a safe alternative agent in subjects experiencing severe RMS due to vancomycin; however, further studies in the clinical setting are needed.
In vitro and in vivo effects of doxycycline on Toxoplasma gondii
Authors: Chang H R , Comte R , Pechère J C
Published: June 2012

We investigated the effects of doxycycline on Toxoplasma gondii infections in vitro and in vivo. Resident peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to doxycycline at different concentrations. The antitoxoplasmic activity of doxycycline was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. The concentration of doxycycline that inhibited 50% of the radioactive uptake was calculated to be 6.4 micrograms/ml (95% confidence limits, 5.07 to 8.06 micrograms/ml); the concentration of doxycycline that inhibited 90% of the radioactive uptake was 14 micrograms/ml. Tetracycline was ineffective up to 40 micrograms/ml. Furthermore, microscopic examination of the infected macrophages after treatment with doxycycline confirmed the inhibition of intracellular growth of T. gondii. Mice acutely infected by the intraperitoneal route with 5 x 10(3) tachyzoites of T. gondii were protected against death with a dose of 300 mg of doxycycline per kg (body weight) administered by the oral route for 10 days, starting 24 h after challenge. When mice were infected with 10(5) tachyzoites of T. gondii and treated 12 days starting 2 h after challenge, the protection and the cure rates were, respectively, 100 and 0% after doxycycline alone (300 mg/kg per day), 0 and 0% after pyrimethamine alone (12.5 mg/kg per day), and 100 and 60% after the combination of these two drugs at the same dosages given above. These results suggest that doxycycline may prove to be useful in the treatment of toxoplasmic infections.
Lysis and aberrant morphology of Bacillus subtilis cells caused by surfactants and their relation to autolysin activity
Authors: Tsuchido T , Svarachorn A , Soga H , Takano M
Published: June 2012

The surfactants tested in this study lysed Bacillus subtilis 168 cells at the logarithmic growth phase. Results obtained with inhibitors and a mutant that had defective autolytic enzymes suggested that cell lysis resulted from the deregulation of autolysin activity. The addition of surfactants at sublytic concentrations produced twisted cells, filamented cells, or both. Autolysins extracted with 5 M LiCl from the cell wall fraction and lysozyme added to cells that were treated with surfactants restored the apparently normal cell rod morphology, suggesting that surfactants interfere with the role of autolysins in normal construction of the cell envelope. The rates of cellular autolysis and autolysin activity remaining in growing cells after exposure to a surfactant at a sublytic concentration decreased, although the rate of turnover of cell wall peptidoglycan was the same as that of control cells. Surfactants were suggested to interact with the regulatory system of autolysins and, thus, to affect the activities of autolysins in B. subtilis cells and to cause either morphological changes or cell autolysis, depending on the concentration of surfactants.
Azole susceptibility and hyphal formation in a cytochrome P-450-deficient mutant of Candida albicans
Authors: Lees N D , Broughton M C , Sanglard D , Bard M
Published: June 2012

A cytochrome P-450-deficient mutant of Candida albicans, strain D10, was employed to study the mode of action of imidazole antifungal agents. This mutant accumulates exclusively 14-alpha-methylsterols, resulting in a sterol profile which mimics that of azole-treated wild-type strains. Since the widely accepted primary effect of imidazoles is the inhibition of cytochrome P-450-mediated demethylation of the ergosterol precursor lanosterol, strain D10 and its wild-type revertant, strain D10R, were grown in the presence of concentrations of clotrimazole, miconazole, and ketoconazole known to inhibit demethylation. The growth of strain D10 was unaffected by these antifungal agents, while that of strain D10R was significantly reduced. At higher azole concentrations (which are known to exert a direct, disruptive action on the cell membrane), the growth of both strains was immediately and completely inhibited by clotrimazole and miconazole. Ketoconazole was membrane disruptive only for strain D10; this is the first report of a direct membrane effect for this drug. Because hyphal formation has been implicated in the pathogenesis of C. albicans and because it has been shown to be inhibited by azoles, the hypha-forming capability of strain D10 was examined. Strain D10 was shown to be seriously defective in hyphal formation, suggesting that this function may be dependent on the 14-alpha-demethylation of lanosterol. The results of this study suggest that inhibition of lanosterol demethylation per se is neither fungicidal nor fungistatic, although the growth rate is reduced. In addition, the substitution of 14-alpha-methylsterols for ergosterol results in defective hyphal formation and in a cell that is more susceptible to membrane-active agents such as ketoconazole.
Pentoxifylline modulates meningeal inflammation in experimental bacterial meningitis
Authors: Sáez-Llorens X , Ramilo O , Mustafa M M , Mertsola J , de Alba C , Hansen E , McCracken G H
Published: June 2012

Pentoxifylline has been shown to decrease endotoxin-induced tumor necrosis factor alpha production and reverse the inflammatory actions of interleukin-1 (IL-1) and tumor necrosis factor on leukocyte function. Because of the potential role of this cytokine-leukocyte interaction in the pathogenesis of bacterial meningitis, we investigated the ability of pentoxifylline to modulate meningeal inflammation in the rabbit meningitis model. Pentoxifylline treatment (initially an intravenous injection of 20 mg/kg followed by 6 mg/kg per h) started 20 min before intracisternal injection of 20 ng of Haemophilus influenzae type b lipooligosaccharide (endotoxin) reduced significantly concentrations in cerebrospinal fluid of leukocytes (P less than 0.0001), protein (P less than 0.001), and lactate (P less than 0.001) during the 9-h infusion compared with values in intravenous-saline-treated rabbits. When pentoxifylline was given 1 h after H. influenzae type b endotoxin, the mean peak lactate and leukocyte concentrations in cerebrospinal fluid were significantly lower than those in control animals. Pentoxifylline also significantly decreased lactate and protein concentrations (P less than 0.05) and tended to diminish leukocyte counts (P = 0.08) compared with results in control animals after antibiotic-induced release of endotoxin in animals with H. influenzae meningitis. In this regard, dexamethasone was superior to pentoxifylline and no synergism was observed when the drugs were combined. Additionally, pentoxifylline attenuated meningeal inflammatory changes induced by intracisternal inoculation of 10 ng of rabbit recombinant IL-1 beta compared with results in either dexamethasone- or saline-treated animals. We conclude that pentoxifylline is effective in this animal model in modulating the meningeal inflammatory response following intracisternal inoculation of H. influenzae type b endotoxin or organisms or rabbit recombinant IL-1beta.
Enzyme immunoconjugates utilizing glucose oxidase and myeloperoxidase are cytotoxic to Candida tropicalis
Authors: Casentini-Borocz D , Bringman T
Published: June 2012

A dual-enzyme immunoconjugate system was evaluated for its cytotoxic effect on Candida tropicalis. Glucose oxidase, which generates hydrogen peroxide in the presence of glucose and oxygen and myeloperoxidase, which catalyzes the oxidation of halides in the presence of hydrogen peroxide, were each conjugated to a C. tropicalis-specific monoclonal antibody. Neither the glucose oxidase nor the myeloperoxidase conjugates exhibited any significant cytotoxic effect by themselves. A combination of glucose oxidase conjugate (3.2 ng/ml) and myeloperoxidase conjugate (12.8 ng/ml) in the presence of 5 mg of glucose per ml, 150 mM chloride, and 50 microM iodide was cytotoxic to C. tropicalis, killing 99.9% of the treated sample. Flow cytometry was used to characterize the binding of the conjugates to yeast cells and demonstrated that the binding of both conjugates to the yeast cell surface is required for cytotoxicity. In addition, the concentrations of conjugates required for a cytotoxic effect were below the concentrations required to saturate all of the yeast cell surface antibody-binding sites.
Multicenter prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks
Authors: Cisneros J M , Viciana P , Colmenero J , Pachón J , Martinez C , Alarcón A
Published: June 2012

The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of doxcycline plus streptomycin for 2 of those weeks was analyzed by a multicenter prospective study of 139 patients. Subjects with central nervous system involvement, endocarditis, or spondylitis were excluded from the study. All but 5 of the 139 patients completed the full treatment schedule and became afebrile in the first week of therapy. Four patients suffered relapses during the follow-up period. Of the five patients who did not complete the treatment, two left because of adverse secondary effects (1.4%), another two left for noncomplicance with the treatment (1.4%), and the remaining patient was considered a therapeutic failure because his symptoms persisted after the first week of therapy (0.7%). We concluded that the combination of doxycycline and streptomycin is an effective treatment for the types of brucellosis included in our study.
Percentages and distributions of teicoplanin- and vancomycin-resistant strains among coagulase-negative staphylococci
Authors: Goldstein F W , Coutrot A , Sieffer A , Acar J F
Published: June 2012

The activities of teicoplanin and vancomycin against 362 coagulase-negative staphylococci were determined by an agar dilution method. At the 4- and 32-micrograms/ml breakpoint levels of the National Committee for Clinical Laboratory Standards, 23.2% of the strains were intermediate and 1.7% were resistant to teicoplanin, in contrast to less than 0.3% intermediate to vancomycin. Resistant strains belonged to the species Staphylococcus epidermidis (74%) and S. haemolyticus (19%).
Further characterization of borderline methicillin-resistant Staphylococcus aureus and analysis of penicillin-binding proteins
Authors: Montanari M P , Tonin E , Biavasco F , Varaldo P E
Published: June 2012

Eighty-nine Staphylococcus aureus strains were grouped according to their susceptibility or resistance to methicillin and oxacillin. The role of beta-lactamase in borderline methicillin resistance was confirmed by tests with beta-lactamase inhibitors, particularly when salt-supplemented medium was used. A penicillin-binding protein assay indicated that borderline methicillin-resistant S. aureus strains do not produce PBP 2a.
In vitro antibacterial spectrum of E1040 compared with those of cefpirome and ceftazidime and disk diffusion interpretive criteria for E1040
Authors: Fuchs P C , Jones R N , Barry A L
Published: June 2012

E1040 is a new parenteral cephalosporin which was tested against 690 clinical isolates and compared with cefpirome and ceftazidime. E1040 had the best activity of the three drugs against Pseudomonas aeruginosa, inhibiting 89% of strains at 8.0 micrograms/ml. E1040 demonstrated good activity against members of the family Enterobacteriaceae, including cefpirome-resistant and ceftazidime-resistant strains. E1040 also had good activity against streptococci but much poorer activity against enterococci and staphylococci. When E1040 broth microdilution and disk diffusion susceptibility test results were compared, the 30-micrograms disk was recommended, with the following tentative interpretive criteria: susceptible, greater than or equal to 18 mm (MIC, less than or equal to 8.0 micrograms/ml); intermediate, 15 to 17 mm (MIC, 16 micrograms/ml); and resistant, less than or equal to 14 mm (MIC, greater than or equal to 32 micrograms/ml).
Steady-state pharmacokinetics of fleroxacin in patients with skin and skin structure infections
Authors: Heim-Duthoy K , Peltier G , Awni W
Published: June 2012

Steady-state pharmacokinetics of oral fleroxacin were studied in six males who had skin or skin structure infections and who were receiving 400 mg of fleroxacin once a day. Blood samples (n = 10) and total urine output were collected during a 24-h dosing interval. Fleroxacin concentrations in serum and urine were determined by high-performance liquid chromatography. The maximum concentration in serum and the time to achieve that maximum were 6.2 +/- 2.2 micrograms/ml and 0.94 +/- 0.62 h, respectively. The absorption half-life, alpha half-life, beta half-life, apparent steady-state volume of distribution, apparent total body clearance, and renal clearance were 0.56 +/- 0.37 h, 0.78 +/- 0.51 h, 10.56 +/- 1.40 h, 0.85 +/- 0.31 liters/kg, 129.2 +/- 19.6 ml/min, and 53.3 +/- 16.7 ml/min, respectively. Fleroxacin disposition in this patient population was similar to that in noninfected volunteers with normal renal function.
Crossover assessment of serum bactericidal activity and pharmacokinetics of five broad-spectrum cephalosporins in the elderly
Authors: Deeter R G , Weinstein M P , Swanson K A , Gross J S , Bailey L C
Published: June 2012

To better define the pharmacokinetics and serum bactericidal activity (SBA) of the expanded-spectrum cephalosporins in the elderly, we administered single 2-g intravenous infusions of cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime to six healthy volunteers over the age of 65 years. Serum was collected over 24 h, and concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were determined for each drug. SBA was measured against representative strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Pseudomonas aeruginosa. All agents tested had excellent SBAs against E. coli and K. pneumoniae, often for a longer duration than would be expected on the basis of conventional dosing regimens. Ceftazidime had the greatest SBA against E. aerogenes and was the only agent with a substantial SBA against P. aeruginosa. Although ceftizoxime had the greatest SBA against S. aureus, none of these cephalosporins had substantial antistaphylococcal SBAs. Pharmacokinetic analysis revealed that cefoperazone and ceftriaxone had markedly different concentration-time profiles in the elderly volunteers than would have been expected on the basis of existing data from younger volunteers. For older patients, dosing guidelines for these two agents may need to be altered.
Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients
Authors: Krüger H U , Schuler U , Proksch B , Göbel M , Ehninger G
Published: June 2012

The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination.
Inhibition of Pneumocystis carinii dihydropteroate synthetase by sulfa drugs
Authors: Merali S , Zhang Y , Sloan D , Meshnick S
Published: June 2012

A new reversed-phase high-pressure liquid chromatography assay procedure for dihydropteroate synthetase (DHPS) that involves the elution of the enzyme incubation solution with a series of three solvents of decreasing polarity (ammonium phosphate buffer, 10% methanol, and 50% methanol) was designed. By this procedure DHPS was detected in Escherichia coli and Pneumocystis carinii with specific activities of 450 and 14 U/mg, respectively. A comparison of the effects of five sulfa drugs on P. carinii DHPS activity revealed that dapsone is the most potent of these drugs.
Inhibitory effects of atropine, protamine, and their combination on hepatitis A virus replication in PLC/PRF/5 cells
Authors: Biziagos E , Crance J M , Passagot J , Deloince R
Published: June 2012

Atropine, protamine, and the combination of these drugs were tested for their effects on hepatitis A virus (HAV) replication in cell culture. PLC/PRF/5 hepatoma cells were treated simultaneously with nontoxic concentrations of these drugs and inoculated with HAV strain CF 53 at several multiplicities of infection. The yields of infectious HAV after 4 and 15 days were markedly reduced by each drug, especially at the lowest multiplicity of infection. The activities of each drug were irreversible. Atropine was active when it was added as late as 2 h after inoculation with HAV. An anti-HAV effect was also induced by treating cells with atropine prior to inoculation. Protamine was active as late as 6 h postinoculation. The combination of atropine and protamine resulted in an enhanced anti-HAV effect. We concluded that these drugs affect undetermined, but separate, steps in the HAV replication cycle.
Assessment of cefazolin and cefuroxime tissue penetration by using a continuous intravenous infusion
Authors: Connors J E , DiPiro J T , Hayter R G , Hooker K D , Stanfield J A , Young T R
Published: June 2012

A continuous intravenous infusion was used to assess the tissue penetration of cefazolin (14 subjects) and cefuroxime (15 subjects) in orthopedic surgery patients. Subjects were randomly assigned to receive a continuous intravenous infusion of cefazolin (mean, 178.6 mg/h) or cefuroxime (mean, 330.0 mg/h) at a rate estimated to achieve a target steady-state total concentration of 50 micrograms/ml in serum. The infusion was initiated 12 to 14 h before surgery, and blood and muscle tissue samples were collected intraoperatively at the times of incision and wound closure. Although there was a significant difference between the free concentrations of cefazolin (at incision, 9.3 micrograms/ml; at closure, 9.2 micrograms/ml) and cefuroxime in serum (at incision, 26.9 micrograms/ml; at closure, 31.8 micrograms/ml), there was no difference in the total concentrations in muscle at either surgical incision (cefazolin, 6.1 micrograms/g; cefuroxime, 5.6 micrograms/g) or wound closure (cefazolin, 7.7 micrograms/g; cefuroxime, 7.4 micrograms/g). There was a significant correlation between the pooled free serum and total muscle concentrations for cefazolin (P = 0.001); however, there was no correlation between these variables with the pooled cefuroxime data (P = 0.403). These findings indicate that the free drug concentration in serum alone is not consistently predictive of the total concentration of cephalosporin in muscle.
Oral temafloxacin versus vancomycin for therapy of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus
Authors: Hessen M T , Pitsakis P G , Kaye D
Published: June 2012

We compared oral temafloxacin, a new fluoroquinolone agent, with vancomycin, each with and without rifampin, in the therapy of rats with aortic valve endocarditis caused by a clinical isolate of methicillin-resistant Staphylococcus aureus. The temafloxacin, vancomycin, and rifampin MICs and MBCs were 0.78 and 1.56, 1.56 and 3.13, and less than 0.024 and 0.78 microgram/ml, respectively. The animals were classified into the following six treatment groups: vancomycin (60 mg/kg) +/- rifampin (6 mg/kg) each intramuscularly every 12 h for 5 days; temafloxacin (100 mg/kg) orally +/- rifampin (6 mg/kg) intramuscularly every 12 h for 5 days; rifampin (6 mg/kg) intramuscularly every 12 h for 5 days; and untreated controls. All regimens with either vancomycin or temafloxacin resulted in improved survival over controls, but only temafloxacin regimens resulted in a significant reduction in bacterial counts in vegetations. These data support further investigation of the efficacy of temafloxacin in treating serious infections caused by methicillin-resistant S. aureus.
Eradication of Helicobacter mustelae from the ferret stomach: an animal model of Helicobacter (Campylobacter) pylori chemotherapy
Authors: Otto G , Fox J G , Wu P Y , Taylor N S
Published: June 2012

Colonization of the ferret stomach by Helicobacter mustelae has been suggested as a possible animal model for Helicobacter pylori-associated gastroduodenal disease of humans. Our study was designed to determine whether antimicrobial chemotherapy could eradicate H. mustelae from ferrets. Triple antimicrobial therapy combining amoxicillin, metronidazole, and bismuth subsalicylate was successful in eradicating the organism from 5 of 7 (71%) adult ferrets. Despite apparent in vitro susceptibility, neither chloramphenicol monotherapy nor a polytherapeutic regimen combining tetracycline, metronidazole, and bismuth subsalicylate proved effective in the eradication of H. mustelae. Several strains isolated after unsuccessful polytherapy showed markedly increased resistance to metronidazole. These preliminary findings are similar to results of H. pylori treatment trials with humans and suggest that the ferret may be a useful model for evaluating and comparing potential antimicrobial modalities for the eradication of H. pylori.
6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile inhibits poliovirus uncoating
Authors: González M E , Almela M J , Yacout M , Carrasco L
Published: June 2012

We investigated the mode of action of 6-(3,4-dichlorophenoxy-3-(ethylthio)-2-pyridincarbonitrile against poliovirus. This agent effectively blocked the synthesis of poliovirus proteins and RNA when it was added at the beginning of infection. Poliovirus attachment and internalization into HeLa cells were not inhibited in the presence of the compound; poliovirus uncoating was the target of its activity.
In vitro activities of irloxacin and E-3846, two new quinolones
Authors: García-Rodríguez J A , García Sánchez J E , Muñoz Bellido J L , Trujillano I
Published: June 2012

Irloxacin and E-3846 are two new fluorinated quinolones. We evaluated the activities of these antimicrobial agents, ciprofloxacin, ofloxacin, enoxacin, pefloxacin, norfloxacin, and nalidixic acid against 1,161 bacterial strains. Ciprofloxacin was the most active quinolone. Irloxacin did not show great activity. The activity of E-3846 against gram-negative bacteria was similar to those of ofloxacin and pefloxacin, and E-3846 was the most active quinolone against gram-positive bacteria and anaerobes.
Influence of temperature on degradation kinetics of ceftriaxone in diluted and undiluted human serum
Authors: Esteban M J , Cantón E , Rius F
Published: June 2012

The stability of ceftriaxone in undiluted human serum and in human serum diluted 1/20 in 0.1 M phosphate buffer (pH 6.0) was measured at -70, -40, -20, 4, and 37 degrees C. Ceftriaxone in diluted human serum contained at least 90% of the initial activity after 3 months of storage at -20, -40, and -70 degrees C; unbuffered human serum contained 82.41, 84.92, and 88.96% of the initial activity, respectively. Ceftriaxone in unbuffered human serum and in diluted human serum showed 80.33 and 86.25% of the initial activity, respectively, after 55 days at 4 degrees C. After 120 h at 37 degrees C, this antibiotic in unbuffered human serum contained 33.08% of the initial activity, whereas samples of diluted human serum contained more than 60%. Consequently, the stability of antibiotic in human serum diluted 1/20 in 0.1 M phosphate buffer (pH 6.0) is increased.
Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli
Authors: Yoshida H , Bogaki M , Nakamura M , Nakamura S
Published: June 2012

Nucleotide sequence analysis of the gyrA genes of 10 spontaneous quinolone-resistant gyrA mutants of Escherichia coli KL16, including four mutants examined previously, disclosed that quinolone resistance was caused by a point mutation within the region between amino acids 67 and 106, especially in the vicinity of amino acid 83, of the GyrA protein.
Influence of plasma exchange pheresis on plasma elimination of ceftriaxone
Authors: Bakken J S , Cavalieri S J , Gangeness D
Published: June 2012

The plasma elimination rates of serial 2-g intravenous injections of ceftriaxone were studied in a patient who also was treated with therapeutic plasma exchange pheresis. Plasmapheresis had negligible influence on the total clearance of ceftriaxone.
Open trial of cefepime (BMY 28142) for infections in hospitalized patients
Authors: Oster S , Edelstein H , Cassano K , McCabe R
Published: June 2012

The safety and efficacy of cefepime, a new broad-spectrum, semisynthetic parenteral cephem antibiotic, were evaluated in an open trial at a single hospital. Seventy patients were treated with cefepime: 44 had lower respiratory tract infections, 4 had urinary tract infections, and 22 had skin or soft tissue infections. Of 65 clinically evaluable patients, 64 (98%) had satisfactory responses. No mortality or superinfections occurred. Of 57 respiratory and urinary tract pathogens, 54 (95%) were eradicated and 3 (5%) persisted after therapy. Five bacteremias (two with Streptococcus pneumoniae and one each with Staphylococcus aureus, Proteus mirabilis, and a coagulase-negative staphylococcus) were eradicated. MICs ranged from 1 to 8 micrograms/ml for 13 S. aureus and 9 Pseudomonas aeruginosa isolates and were less than or equal to 0.125 micrograms/ml for 10 streptococcal isolates. Adverse effects occurred in two patients: transient diarrhea and Clostridium difficile toxin in the stool in one patient and loose bowel movements and increased transaminases in the other patient. Cefepime appeared to be well tolerated in humans and was effective against a wide range of isolates, including S. aureus and P. aeruginosa.
Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers
Authors: Cook J A , Silverman M H , Schelling D J , Nix D E , Schentag J J , Brown R R , Stroshane R M
Published: June 2012

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.
Comparative toxicities of amphotericin B and its monomethyl ester derivative on glial cells in culture
Authors: Racis S P , Plescia O J , Geller H M , Schaffner C P
Published: June 2012

Amphotericin B (AmB) is a potent antifungal polyene macrolide antibiotic and is the drug of choice for the treatment of deep-seated mycotic infections. Its use is limited, owing to its nephrotoxicity, and it must be dispersed in deoxycholate for parenteral administration. In contrast, AME (the monomethyl derivative of AmB) is water dispersible, is appreciably less cytotoxic than AmB toward a variety of cell types, and is reportedly active against the acquired immunodeficiency syndrome virus (human immunodeficiency virus type 1). The latter activity has generated interest in AME as an antiviral drug. However, AME is perceived to be neurotoxic, based on the outcome of a human clinical trial of AME as an antifungal drug. AmB is not regarded as neurotoxic, presumably because any neurotoxicity in vivo is precluded by its nephrotoxicity. It was important, therefore, to determine the potential for neurotoxicity of the two agents in comparative tests, assessing the effects of their direct action against neural cells in culture. Rat cortical cells, comprising astrocytes and oligodendrocytes, were used. AME was at least 10 times less toxic than AmB and equally less toxic against several other nonneural cell types also included in these tests. Equally important, AmB disrupted the myelin sheath in these cultures, and it inhibited its generation. AME did not, even at a concentration 10 times greater than the toxic concentration of AmB. AmB is, therefore, potentially more neurotoxic than AME, contrary to current perception. AME is effective as an antifungal and antiviral drug at a concentration far below its toxic concentration for neural cells. Also, AME does not cross the blood-brain barrier appreciably, so that a therapeutic level in blood can be expected without encountering neurotoxicity.
Comparison of in vitro antimicrobial susceptibilities of Mycobacterium avium-M. intracellulare strains from patients with acquired immunodeficiency syndrome (AIDS), patients without AIDS, and animal sources
Authors: Byrne S K , Geddes G L , Isaac-Renton J L , Black W A
Published: June 2012

Difloxacin, A-56620, cefazolin, cefotaxime, ceftizoxime, cephapirin, SK&F 88070, and spectinomycin were used to compare the in vitro susceptibilities of Mycobacterium avium-M. intracellular isolates from patients with acquired immunodeficiency syndrome (AIDS), patients without AIDS, and diseased animals. Against the isolates from humans without AIDS, the quinolone compounds difloxacin and A-56620 were found to be the most effective, each inhibiting 50% of strains at a concentration of 2 micrograms/ml. The remaining antimicrobial agents had MICs for 50% of strains tested of at least 32 micrograms/ml. Statistically significant differences were observed in the antibiogram patterns among the M. avium-M. intracellulare strains from each of the three sources.
In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism
Authors: Queen S A , Jagt D L , Reyes P
Published: June 2012

A unique metabolic feature of malaria parasites is their restricted ability to synthesize nucleotides. These parasites are unable to synthesize the purine ring and must therefore obtain preformed purine bases and nucleosides from the host cell, the erythrocyte. On the other hand, pyrimidines must be synthesized de novo because of the inability of the parasites to salvage preformed pyrimidines. Thus, one would anticipate that the blockage of purine salvage or pyrimidine de novo synthesis should adversely affect parasite growth. This premise was tested in vitro with a total of 64 compounds, mostly purine and pyrimidine analogs, known to inhibit one or more steps of nucleotide synthesis. Of the 64 compounds, 22 produced a 50% inhibition of the growth of the human malaria parasite Plasmodium falciparum at a concentration of 50 microM or less. Inhibition of the growth of chloroquine-resistant clones of P. falciparum did not differ significantly from that of the growth of chloroquine-susceptible clones. Two of the compounds which effectively inhibited parasite growth, 6-mercaptopurine and 6-thioguanine, were found to be potent competitive inhibitors of a key purine-salvaging enzyme (hypoxanthine-guanine-xanthine phosphoribosyltransferase) of the parasite.
Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations
Authors: Oldfield E C , Garst P D , Hostettler C , White M , Samuelson D
Published: June 2012

We conducted a randomized, double-blind trial of 1- versus 4-h infusions of amphotericin B to determine whether there was any difference in infusion-related toxicity. A total of 128 maintenance infusions in 12 patients were studied; 62 were randomized to 1-h infusions (group A) and 66 were randomized to 4-h infusions (group B). We found no significant differences between patients in groups A and B in mean temperature, pulse, or systolic or diastolic blood pressure measured during the infusions. At a significant level of 0.05, the power to detect a mean difference in temperature of 2 degrees C, a pulse difference of 20 beats per min, a decrease in diastolic blood pressure of 10 mm Hg, or a decrease in systolic blood pressure of 20 mm Hg was 0.95. Rigors and chills were noted in 15 of 62 (24.1%) infusions in group A patients and 12 of 66 (18.1%) infusions in group B patients (P = 0.40). Meperidine was required because of severe persistent rigors in 6 of 62 (9.6%) infusions in group A patients and 6 of 66 (8.9%) infusions in group B patients (P = 0.91). An increase in temperature was noted in five (8%) of the group A infusions and seven (10.6%) of the group B infusions (P = 0.63). The mean time to onset of rigors, an increase in temperature, and an increase in pulse occurred significantly earlier in group A than in group B patients (P = 0.02 for all comparisons). We conclude that there is no difference in the incidence or severity of the infusion-related toxicity of amphotericin B with a 1-h infusion rate compared with a 4-h infusion rate. However, the onset of infusion-related toxicity occurs significantly earlier with a 1-h infusion.