bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro antifungal activities of amphotericin B and liposome-encapsulated amphotericin B
Authors: Hopfer R L , Mills K , Mehta R , Lopez-Berestein G , Fainstein V , Juliano R L
Published: June 2012

The in vitro activities of liposome-encapsulated amphotericin B and free amphotericin B against Candida albicans 336 were comparable. Amphotericin B concentrations 12-fold and greater than 50-fold higher were required to kill the same organism when cholesterol and ergosterol were incorporated into the liposomes. The addition of cholesterol to liposomes caused a significant increase in the minimal fungicidal concentration of amphotericin B in 7 of 19 other yeast strains tested, whereas ergosterol caused an increase in 18 of the 19 strains.
In vitro activity of ticarcillin plus clavulanic acid against 632 clinical isolates
Authors: Fuchs P C , Barry A L , Thornsberry C , Jones R N
Published: June 2012

A total of 632 clinical bacterial isolates were tested for susceptibility to twofold dilutions of ticarcillin alone and in combination with 1, 2, and 4 micrograms of clavulanic acid (CA) (Timentin) per ml by a reference microdilution method. With the addition of CA, ticarcillin MICs were reduced eightfold or greater with 54 of 59 (92%) strains of the family Enterobacteriaceae with ticarcillin MICs of greater than or equal to 64 micrograms/ml. The inhibitory effect of CA on pseudomonads was minimal. Ticarcillin MICs for beta-lactamase-producing Haemophilus influenzae, Neisseria gonorrhoeae, and most Staphylococcus aureus were reduced to less than or equal to 0.5 micrograms/ml when CA was added. For dilution susceptibility testing of ticarcillin-clavulanic acid, dilutions of ticarcillin combined with 2 micrograms of CA per ml is suggested.
Antagonism by chloramphenicol of broad-spectrum beta-lactam antibiotics against Klebsiella pneumoniae
Authors: Brown T H , Alford R H
Published: June 2012

Chloramphenicol combined with cefotaxime, moxalactam, cefoperazone, aztreonam, or imipenem was tested in vitro against clinical isolates of Klebsiella pneumoniae. By time-kill cultures (killing curves), chloramphenicol interfered with activity of all five beta-lactams. When chloramphenicol was added before the beta-lactams, the action of cefotaxime, moxalactam, or cefoperazone against all isolates was antagonized at all times tested. The action of aztreonam was antagonized against four of six isolates. With imipenem, antagonism occurred against half of the isolates at some time during 24 h when chloramphenicol was added simultaneously, provided that a sufficient inoculum of K. pneumoniae was employed. Generally, less antagonism resulted when chloramphenicol was added after the cephalosporins. Interference of bactericidal activity of three new cephalosporins by chloramphenicol has potential clinical relevance to the therapy of gram-negative bacillary meningitis. The lesser antagonism of aztreonam and imipenem by chloramphenicol is of uncertain clinical relevance but indicates that this in vitro phenomenon may apply to a wide range of beta-lactam antibiotics.
Pharmacokinetics of vancomycin in patients with various degrees of renal function
Authors: Matzke G R , McGory R W , Halstenson C E , Keane W F
Published: June 2012

The pharmacokinetics of vancomycin were characterized in 56 patients with different degrees of renal function after an intravenous dose of 18.4 +/- 4.7 mg kg-1 (mean +/- standard deviation). Seven subjects had a creatinine clearance (CLCR) of greater than 60 ml min-1 (group I), 13 had a CLCR of 10 to 60 ml min-1 (group II), and 36 had a CLCR of less than 10 ml min-1 (group III). Serial serum samples (range, 3 to 8) were collected during the 168 h after drug administration. The serum concentration-time profile in all patients demonstrated monoexponential decay. The mean half-lives were 9.1, 32.3, and 146.7 h in groups I, II, and III, respectively. A significant decline in serum clearance (CLS) was also noted (62.7 to 28.3 to 4.87 ml min-1 in groups I, II, and III, respectively). The steady-state volume of distribution varied from 0.72 to 0.90 liter kg-1. There was no significant relationship between the steady-state volume of distribution and CLCR. The observed relationship between CLS and CLCR (CLS = 3.66 + 0.689 CLCR; r = 0.8807) can be utilized to devise dosage schedules for patients with any degree of renal impairment. This relationship was utilized to develop a nomogram for initial and maintenance dosing of vancomycin.
Inhibition and killing of Candida albicans in vitro by five imidazoles in clinical use
Authors: Lefler E , Stevens D A
Published: June 2012

Five imidazoles (clotrimazole, econazole, ketoconazole, miconazole, and tioconazole) in clinical use were compared for their ability to inhibit and kill Candida albicans. Eleven isolates were obtained from patients before therapy. By spectrophotometric determination of 50% growth inhibition, all isolates were inhibited at low concentrations, with clotrimazole slightly less active than the other four drugs. By the conventional MIC determination, tioconazole was more active than all of the others (P less than 0.01) except clotrimazole. In killing (minimum fungicidal concentration [MFC] assay), tioconazole was the most active by several analyses. Studies of the kinetics of killing indicated that the drugs studied could kill under conditions used for the MFC determination and that tioconazole and ketoconazole could kill particularly rapidly. If the drug was washed from the cells before subculturing, concentrations above the MFC were required to kill, but tioconazole could produce a lethal lesion in all cells virtually instantaneously. These findings are pertinent to MFC and killing kinetics methodology and to the observation of drug persistence after topical application. The results differ from some previous in vitro comparisons made with different methods. They are relevant to conclusions about drug mechanisms based on their abilities to inhibit and to kill, and they underscore the need to study various assay methods and fungal species.
Evaluation of Sch 29,482 in the eradication of Neisseria meningitidis from nasopharyngeal carriers
Authors: Pugsley M P , Dworzack D L , Sanders C C , Sanders W E
Published: June 2012

Fifty-eight chronic carriers of Neisseria meningitidis were given 250 mg of Sch 29,482 or placebo orally every 6 h for 4 days. Although 22 of 29 subjects taking Sch 29,482 became culture negative while taking the drug, only five were culture negative 2 weeks posttherapy. There were no significant adverse reactions.
Evaluation of lithium as an inhibitory agent of herpes simplex virus in cell cultures and during reactivation of latent infection in rabbits
Authors: Trousdale M D , Gordon Y J , Peters A C , Gropen T I , Nelson E , Nesburn A B
Published: June 2012

Lithium carbonate inhibited plaque formation of herpes simplex virus types 1 and 2 in rabbit kidney and Vero cells (50% effective dose, 435.5 to 490 micrograms/ml). Plasma lithium levels of 67 to 134 micrograms/ml were achieved by oral therapy in rabbits. However, neither ocular virus shedding nor virus-positive trigeminal ganglia were reduced after intentional reactivation of latent herpes simplex virus infection.
Antibiotic resistance of degraded strains of Bordetella pertussis
Authors: Bannatyne R M , Cheung R
Published: June 2012

The susceptibilities to erythromycin, rifampin, polymyxin B, ampicillin, tetracycline, gentamicin, fusidic acid, trimethoprim, and spectinomycin of five virulent phase I strains of Bordetella pertussis and their degraded phase IV descendants were compared. Increases in MICs of 2- to 16-fold were observed for erythromycin, rifampin, tetracycline, fusidic acid, trimethoprim, and spectinomycin for four of the five degraded strains.
Comparison of azlocillin, ceftizoxime, cefoxitin, and amikacin alone and in combination against Pseudomonas aeruginosa in a neutropenic-site rabbit model
Authors: Peterson L R , Gerding D N , Moody J A , Fasching C E
Published: June 2012

The efficacy of beta-lactam antibiotics and amikacin alone and in various combinations against Pseudomonas aeruginosa was studied in a rabbit model simulating a closed-space infection in a locally neutropenic site. Six strains of P. aeruginosa were studied in semipermeable chambers placed subcutaneously in rabbits. Therapy was begun 4 h after inoculation of 5 X 10(4) CFU of bacteria per ml of pooled rabbit serum into the chambers. Antibiotics were administered intramuscularly every 6 h for 16 doses. Quantitative bacteriology was measured at the start of therapy and at 20, 44, and 92 h thereafter. Antibiotic concentrations were measured in blood and chamber fluid. Results were compared with in vitro tests of susceptibility and synergy. No single-agent therapy eradicated any of the six test organisms. Azlocillin (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated five of six organisms by 92 h, and ceftizoxime (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated three of six test strains. Azlocillin plus ceftizoxime (each 100 mg/kg per dose) failed to eliminate any of the six strains. To eliminate P. aeruginosa in this model, two drugs were required, with one being an aminoglycoside. In vitro susceptibility tests of synergy were predictive of successful therapy whenever the antibiotic concentrations (free and total) at the infection site exceeded the MBC for both the aminoglycoside alone and the beta-lactam when tested in combination with amikacin.
Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis
Authors: Reed M D , Stern R C , Yamashita T S , Ackers I , Myers C M , Blumer J L
Published: June 2012

The single-dose pharmacokinetics of cefsulodin were evaluated in 12 patients with cystic fibrosis. Each patient received 3 g of cefsulodin intravenously over 30 min. Multiple plasma and urine samples were obtained during the 6-h study period for the determination of cefsulodin. Pharmacokinetic parameters were determined by model-independent methods. Mean values for t1/2, Vss, and CLp were 1.53 h, 0.242 liters/kg, and 117.3 ml/min per 1.73 m2, respectively. Six-hour urine recovery revealed 73.2% of the administered dose with a corresponding cefsulodin urinary clearance of 75.1 ml/min. These pharmacokinetic data in patients with cystic fibrosis appear consistent with data reported for unaffected individuals.
Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid
Authors: Barry A L , Jones R N , Thornsberry C , Ayers L W , Gerlach E H , Sommers H M
Published: June 2012

In vitro studies were performed comparing ciprofloxacin (Bay o 9867) and norfloxacin with three related organic acids. Ciprofloxacin was two to eight times more active than norfloxacin against 658 bacterial isolates representing 30 species. For all species tested, ciprofloxacin MICs for 90% inhibition were less than or equal to 2.0 micrograms ml. Additional tests with 5,994 isolates detected only 37 (0.6%) strains resistant to 2.0 micrograms of ciprofloxacin per ml and 106 (1.8%) resistant to 1.0 micrograms/ml. Only 6 (0.1%) of the 5,994 strains were resistant to 16 micrograms of norfloxacin per ml, and 129 (2.1%) were resistant to 4.0 micrograms/ml. The majority of resistant strains were streptococci or Pseudomonas spp. Resistance among the Enterobacteriaceae was extremely rare (i.e., greater than 99.8% susceptible to both drugs.
Treatment of experimental cutaneous leishmaniasis with liposome-intercalated amphotericin B
Authors: Panosian C B , Barza M , Szoka F , Wyler D J
Published: June 2012

The therapeutic efficacy of a liposomal preparation of amphotericin B was evaluated in two murine models of cutaneous leishmaniasis. No significant decrease in tissue parasite density was observed in C57BL/6 mice after systemic treatment instituted seven days after footpad inoculation with Leishmania tropica; in contrast, BALB/c mice showed a modest response.
Comparison of the in vitro activities of ofloxacin and tetracycline against Chlamydia trachomatis as assessed by indirect immunofluorescence
Authors: Bailey J M , Heppleston C , Richmond S J
Published: June 2012

The in vitro activity of ofloxacin (DL8280), a new pyridone carboxylic acid, against Chlamydia trachomatis serotype E was assessed by growth of chlamydia in cycloheximide-treated McCoy cells. Chlamydia-infected monolayers were exposed to the drug for 48 and 96 h and for 48 h followed by 48 h of further incubation after withdrawal of ofloxacin. Inclusions were visualized by indirect immunofluorescence, and the effect of the drug was assessed both by inclusion development and by the number of inclusion-forming units generated in the monolayers. The action of ofloxacin was completely lethal when monolayers were exposed to a concentration of 1 microgram/ml throughout one chlamydial developmental cycle. In contrast, tetracycline, when examined by similar techniques, inhibited inclusion development at a concentration of 0.3 micrograms/ml, but was only lethal at 2.4 micrograms/ml. Ofloxacin may prove to be a useful new antichlamydial agent.
Aztreonam concentrations in human prostatic tissue
Authors: Madsen P O , Dhruv R , Friedhoff L T
Published: June 2012

The concentrations of aztreonam in human prostatic tissue specimens obtained by transurethral resection were measured in nine patients after the intramuscular administration of a single 1-g dose. The average concentration of aztreonam was 7.8 microgram/g of prostate between 50 and 180 min after dosage. The average ratio of the drug concentration in prostate to that in serum was 0.25. The concentrations of aztreonam achieved were significantly higher than the MICs for most members of the family Enterobacteriaceae implicated in chronic prostatitis.
Comparative activities of aztreonam and cefotaxime against Escherichia coli and Bacteroides spp. in pure and mixed cultures
Authors: Soriano F , Ponte M C
Published: June 2012

The activities of aztreonam and cefotaxime against one Escherichia coli strain and three Bacteroides strains have been studied by using pure and mixed cultures of aerobic and anaerobic bacteria. A fixed concentration (8 micrograms/ml) of cefotaxime or aztreonam killed E. coli that was exposed in pure culture, but the pressure of Bacteroides spp. in the same system deteriorated cefotaxime, allowing the full growth of E. coli after 24 h. On the other hand, the presence of Bacteroides spp. produced less deterioration of aztreonam, which reduced the initial E. coli inoculum. This observation could be useful in clinical practice when treating mixed aerobic and anaerobic infections.
Inoculum effect of new beta-lactam antibiotics on Pseudomonas aeruginosa
Authors: Eng R H , Smith S M , Cherubin C
Published: June 2012

The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the antibiotics were divided into three groups based upon the observations. The group 1 antibiotics (cefotaxime, moxalactam, cefoperazone, azlocillin, piperacillin, and aztreonam) demonstrated a large inoculum effect, were poorly bactericidal, produced aberrant, elongated bacilli, and did not inhibit the increase in turbidity of high inocula during an 18-h incubation. The group 2 antibiotics (ceftazidime and ticarcillin) were slowly bactericidal, caused minimal formation of aberrant, elongated bacilli, and slowly decreased the turbidity of high inocula. The group 3 antibiotics (imipenem and gentamicin) were bactericidal, did not cause the formation of elongated bacilli, and decreased the turbidity of high inocula rapidly. Data are presented which suggest that the inoculum effect seen with the group 1 beta-lactam antibiotics is related to (i) the poor intrinsic antibactericidal activity of these antibiotics for P. aeruginosa at the inocula tested and (ii) failure of these antibiotics to inhibit the formation of aberrant and filamentous bacilli, which can result in increased bacterial mass and turbidity.
Single- and multiple-dose pharmacokinetics of pipemidic acid in normal human volunteers
Authors: Klinge E , Männistö P T , Mäntylä R , Mattila J , Hänninen U
Published: June 2012

The pharmacokinetic profile of pipemidic acid was studied in two groups of young healthy volunteers by using a new, sensitive, high-pressure liquid chromatography procedure for quantitation of pipemidic acid in biological fluids. After oral or intravenous administration, the disposition of pipemidic acid may be described as a one- or a two-compartment open model, respectively. Oral bioavailability was 93.1 +/- 11% (mean +/- standard error). After administration of a 100-mg tablet, 13.4 +/- 2.7% was bound to serum proteins at the time of peak drug concentration in serum. Excretion of pipemidic acid in saliva was negligible, the saliva/serum ratio being about 0.32. At steady state after the twice-daily administration of a 500-mg tablet, which is a recommended dosage regimen, a peak drug concentration in serum of 4.3 +/- 0.5 micrograms/ml was attained in 1.2 +/- 0.1 h. The apparent volume of distribution was 1.9 +/- 0.2 liters/kg, and the elimination half-life was 3.4 +/- 0.2 h. The renal clearance was 4.3 +/- 0.7 ml/min per kg, and the total clearance was 6.3 +/- 0.5 ml/min per kg. Despite a considerable water load, the minimum concentration in urine at the end of a dosing interval averaged 100 micrograms/ml, which widely exceeds the known MIC of pipemidic acid against bacteria commonly causing urinary tract infections.
Enhanced killing of Candida albicans by cultured peritoneal exudate cells treated with SM-1213, a synthetic immunomodulator
Authors: Morrison C J , Gordon P , Hashimoto T
Published: June 2012

The effect of SM-1213 [1,2-O-isopropylidene-3-O-3'-(N', N'-dimethylamino-n-propyl)-D-glucofuranose] on the candidastatic and candidacidal capacity of guinea pig peritoneal exudate cells was investigated. Phagocytes treated with SM-1213 demonstrated an enhanced ability to inhibit intracellular hyphal formation and elongation of Candida albicans cells as well as to reduce the percentage of viable cells remaining after phagocytosis. Significant drug-induced anticandidal effects were also observed when peritoneal exudate cells were preincubated with SM-1213 and washed before infection with C. albicans. SM-1213 had no direct anticandidal effect against the yeast or hyphal form of the fungus, suggesting that the observed candidastatic and candidacidal effect of this drug was due to the enhancement of antimicrobial functions of phagocytes.
In vitro activities of enoxacin and 17 other antimicrobial agents against multiply resistant, gram-negative bacteria
Authors: Rudrik J T , Cavalieri S J , Britt E M
Published: June 2012

Enoxacin (CI-919) was evaluated for activity against 120 multiply resistant clinical isolates of the family Enterobacteriaceae and Pseudomonas aeruginosa. The MIC of enoxacin for 95% of the strains tested was less than or equal to 2 micrograms/ml. Approximately 90% of the isolates were susceptible to enoxacin, norfloxacin, ceftazidime, moxalactam, cefotaxime, cefoperazone, and amikacin. Marked resistance to the other seven antimicrobial agents tested was observed.
Disposition of [14C]aztreonam in rats, dogs, and monkeys
Authors: Kripalani K J , Singhvi S M , Weinstein S H , Everett D W , Bathala M S , Dean A V , Ita C E , Lawrence L , Meeker F S , Shaw J M
Published: June 2012

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.
New polymeric biocides: synthesis and antibacterial activities of polycations with pendant biguanide groups
Authors: Ikeda T , Yamaguchi H , Tazuke S
Published: June 2012

Acrylate monomers with pendant biguanide groups were successfully synthesized, and their homopolymers and copolymers were prepared with acrylamide. These cationic disinfectants of polymeric forms exhibited high antibacterial activity against gram-positive bacteria, whereas they were less active against gram-negative bacteria. It was found that the activity of the polymeric disinfectants was much higher than that of the monomeric species, and the difference in activity between the polymers and the monomers was discussed on the basis of their contributions to each elementary process of the lethal action.
Therapeutic relevance of penicillin-induced hypersensitivity of Staphylococcus aureus to killing by polymorphonuclear leukocytes
Authors: Lam C , Georgopoulos A , Laber G , Schütze E
Published: June 2012

There is an overwhelming body of evidence that certain Staphylococcus aureus strains become more sensitive to killing by polymorphonuclear leukocytes after their growth in media containing subinhibitory concentrations of penicillin. However, it is not clear to what extent this phenomenon contributes to the curative effect of penicillin in vivo. To explore its therapeutic relevance, we evaluated the interaction of staphylococci pretreated with penicillin in vitro with leukocytes in cell-proof diffusion chambers (porosity, 0.22 micron) implanted subcutaneously in rabbits. Under this in vivo environment, staphylococci pretreated with penicillin remained hypersensitive to leukocyte killing as under in vitro conditions. Furthermore, when the staphylococci were mixed with the leukocytes in chambers implanted intraperitoneally in mice which subsequently received intravenously a suboptimal dose of penicillin, they also became hypersensitive to leukocytic killing. However, because the staphylococcal growth rate was considerably reduced in vivo, the degree of penicillin-induced sensitivity to leukocytic killing was smaller than that obtained in test tube cultures; nevertheless, the enhanced killing was significant. Additional support that the curative effect of penicillin partly depends on its synergistic action with the leukocytes was provided by the relative decrease in virulence of staphylococci pretreated with penicillin in mice in which the cellular host defenses were already recruited at the focus of inoculation. These observations indicate that penicillin-induced hypersensitivity of staphylococci to leukocytic killing is not only an in vitro phenomenon, but an effect which has therapeutic relevance.
Topical treatment of cutaneous herpes simplex virus infection in hairless mice with (E)-5-(2-bromovinyl)-2'-deoxyuridine and related compounds
Authors: de Clercq E
Published: June 2012

(E)-5-(2-Bromovinyl)-2'-deoxyuridine (bromovinyldeoxyuridine) was found to suppress the development of herpetic skin lesions and the paralysis and mortality associated therewith in hairless mice inoculated intracutaneously with herpes simplex virus type 1. This protective effect was achieved with bromovinyldeoxyuridine applied topically at 1, 3, or 10% in either dimethylsulfoxide (DMSO), Beeler base, Tween-glycerol-water, 5% Azone (1-dodecylazacycloheptan-2-one) in water, or 5% Azone in DMSO. The optimal vehicle was 5% Azone in DMSO, in which bromovinyldeoxyuridine was effective even at a concentration as low as 0.3%. In its protective activity against cutaneous herpes simplex virus type 1 infection in hairless mice, bromovinyldeoxyuridine was clearly superior to other established antiherpes compounds such as 5-iodo-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, arabinosyl thymine, and arabinosyl (E)-5-(2-bromovinyl) uracil when formulated at 10% in DMSO or Azone-DMSO. However, no activity was noted with any of these drug formulations against cutaneous herpes simplex virus type 2 infection. In contrast, acycloguanosine (acyclovir) proved quite effective in the topical treatment of cutaneous herpes simplex virus type 2 infection when used at 10% in DMSO or at 5% in propylene glycol.
Comparative pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime in rats, dogs, and rhesus monkeys
Authors: Matsui H , Komiya M , Ikeda C , Tachibana A
Published: June 2012

The pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime were studied in rats, dogs, and rhesus monkeys (only YM-13115 and ceftriaxone were studied in rhesus monkeys). The plasma half-lives in rats were 48 min for YM-13115, 34 min for ceftriaxone, and 14 min for ceftazidime. In dogs, they were 21.9 min for YM-13115, 50.7 min for ceftriaxone, and 49.0 min for ceftazidime. In monkeys, they were 5.30 h for YM-13115 and 3.40 h for ceftriaxone. The 24-h urinary recoveries in rats were 26.7% of the dose for YM-13115, 32.0% for ceftriaxone, and 97.1% for ceftazidime. In dogs, they were 13.3% for YM-13115, 62.5% for ceftriaxone, and 86.3% for ceftazidime. In monkeys, they were 22.5% for YM-13115 and 29.3% for ceftriaxone. The 24-h biliary recoveries in rats were 72.2% for YM-13115, 61.8% for ceftriaxone, and 0.63% for ceftazidime.
Pharmacokinetics of intravenously administered ciprofloxacin
Authors: Wise R , Lockley R M , Webberly M , Dent J
Published: June 2012

A 100-mg dose of ciprofloxacin was given as an intravenous bolus injection to each of six healthy volunteers, after which the levels of this agent were measured in serum, blister fluid, and urine. After administration, distribution of ciprofloxacin was very rapid, and the mean distribution volume was very large (177 liters). The mean terminal serum half-life was 4.0 h. The agent penetrated blister fluid rapidly, with the mean maximum level being 0.53 micrograms/ml at 30 min, after which time the blister levels exceeded those in serum. The 48-h urinary recovery of ciprofloxacin was about 80%.
Serum bactericidal activity of aztreonam, cefoperazone, and amikacin, alone or in combination, against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa
Authors: Van Laethem Y , Husson M , Klastersky J
Published: June 2012

Serum samples from volunteers receiving (per kilogram) 20 mg of aztreonam, 20 mg of cefoperazone, 7.5 mg of amikacin, 20 mg of cefoperazone plus 20 mg of aztreonam, or 20 mg of aztreonam plus 7.5 mg of amikacin were evaluated for bactericidal activity against Escherichia coli, Klebsiella pneumonia, Serratia marcescens, and Pseudomonas aeruginosa. Serum bactericidal activities were similar for aztreonam alone or in combination but were lower for amikacin and cefoperazone alone, especially against S. marcescens and P. aeruginosa. Killing studies, performed with serum samples diluted 1:8, demonstrated a high killing rate for aztreonam plus amikacin, especially against P. aeruginosa.
Moxalactam penetration into normal heart valve, cardiac vegetations, and myocardium in relation to protein binding and physiological distribution spaces
Authors: Fitzpatrick B C , Gengo F M , Schentag J J
Published: June 2012

Rabbits with catheters implanted in the left ventricle were given a single dose of moxalactam and sacrificed at various times thereafter for measurement of the concentration of this antimicrobial agent in serum, heart muscle, and various heart valves. Penetration into both extravascular sites was rapid; steady state was achieved within 5 min after the dose. Moxalactam showed essentially complete penetration into valve lesions, whereas concentrations in heart muscle were only 20% of those in serum. The physiological distribution of moxalactam in heart muscle was beyond the inulin space, but substantially lower than total body water. This myocardial distribution ratio was not predicted by the serum-free fraction or blood trapped in tissues alone, but was in good agreement with that of extracellular fluid plus blood trapped in tissues. The moxalactam distribution profile was most compatible with that of drugs which are excluded from cells but readily distributed throughout extracellular fluids. This explains its nearly complete penetration into heart valves as well as its incomplete penetration into heart muscle, since the two sites differ in their relative proportions of cells and extracellular fluid spaces.
Characterization of non-beta-lactamase-mediated ampicillin resistance in Haemophilus influenzae
Authors: Mendelman P M , Chaffin D O , Stull T L , Rubens C E , Mack K D , Smith A L
Published: June 2012

Ampicillin resistance in Haemophilus influenzae is most often due to the plasmid-mediated production of TEM beta-lactamase. We studied four strains with high-level ampicillin resistance (MIC of 32 micrograms/ml with an inoculum of 10(5) CFU on solid media) which did not produce detectable beta-lactamase activity with two different detection methods. Two of the four strains contained extrachromosomal DNA by agarose gel electrophoresis. Conjugation failed to transfer ampicillin resistance; in contrast, transformation yielded ampicillin-resistant transformants in three of the four strains. These transformants did not contain detectable extrachromosomal DNA. In addition, mobilization of the resistance determinant by transformation to, or conjugation with, recombination-deficient strains was unsuccessful. DNA-DNA hybridization experiments revealed no homology of the DNA of these strains with two R plasmids (one coding for ampicillin resistance, the other for chloramphenicol and tetracycline resistance). We conclude that the genetic basis of the non-beta-lactamase ampicillin resistance in these strains appears to be chromosomally mediated. We investigated the mechanism of resistance in these strains. Enzymatic modification of penicillin was not detected by autoradiography of a thin-layer chromatogram of cell sonic extracts of three ampicillin-resistant transformant strains incubated with [14C]penicillin. To assess changes in permeability of the cell envelope, a plasmid coding for beta-lactamase was conjugated into these strains, and the hydrolysis of penicillin by intact cells and cell sonic extracts was compared. Only one of three transformant strains had significantly diminished permeability. Outer membrane proteins of these strains analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed apparent differences in comparison with the isogenic ampicillin-susceptible recipient strain. Autofluorography of a sodium dodecyl sulfate-polyacrylamide gel electrophoresis of Sarkosyl-solubilized crude membrane (the putative inner membranes) from these ampicillin-resistant transformant strains incubated with [3H]penicillin compared with the isogenic ampicillin-susceptible recipient strain revealed reduced binding to PBP 3 and 6, 3 and 4, or 4. In addition, affinity binding studies revealed decreased affinity of PBP 4 for ampicillin of all four transformants tested. We conclude that the major mechanism of resistance in these strains is altered penicillin-binding proteins; however, other mechanisms, including permeability, may also play a role.
In vitro activities of ureidopenicillins alone and in combination with amikacin and three cephalosporin antibiotics
Authors: Moody J A , Peterson L R , Gerding D N
Published: June 2012

The MIC and MBC activity of mezlocillin alone and in combination with two concentrations of ceftizoxime, moxalactam, and amikacin and a single concentration of cefoxitin was studied in a broth microdilution partial checkerboard against 472 strains of aerobic gram-negative and gram-positive bacteria. Azlocillin was tested alone and in the same combinations against Pseudomonas aeruginosa. Of the gram-negative bacilli tested, 38% were gentamicin resistant. Antagonism (less than or equal to a fourfold ureidopenicillin MIC increase) was observed frequently with combinations of ureidopenicillins plus cefoxitin and sporadically with ureidopenicillins plus ceftizoxime or moxalactam. Partial synergism (less than or equal to a fourfold ureidopenicillin MIC decrease) was evident with both combinations of ureidopenicillins plus amikacin and ureidopenicillins plus ceftizoxime or moxalactam, the percentage being dependent upon the individual species and combinations.
In vitro comparison of amifloxacin and six other antibiotics against aminoglycoside-resistant Pseudomonas aeruginosa
Authors: Thompson K D , O'Keefe J P , Tatarowicz W A
Published: June 2012

The in vitro activity of the synthetic fluoroquinolone amifloxacin was compared with those of six other antibiotics: ampicillin, aztreonam, cefotaxime, cephalexin, cinoxacin, and gentamicin. Amifloxacin had the lowest 50% MIC of any of the antibiotics tested against aminoglycoside-resistant Pseudomonas aeruginosa, 4 micrograms/ml.
Rapid high-pressure liquid chromatographic method for analysis of phenoxymethylpenicillin in human serum
Authors: Lindberg R L , Huupponen R K , Huovinen P
Published: June 2012

A selective high-pressure liquid chromatographic method for the determination of phenoxymethylpenicillin in human serum is described. The technique is based on the single extraction of the drug from acidified serum with diethyl ether. Chloramphenicol is used as internal standard. The chromatographic system consists of a reversed-phase C-18 column; the mobile phase is acetonitrile-0.01 M potassium acetate buffer (20:80 [vol/vol]; pH 6.5). The method can accurately measure serum penicillin concentrations down to 30 micrograms/liter with 500 microliter of sample. The coefficient of variation for intraassay variability of penicillin is between 1.5 and 4.9% in the range of 0.125 to 16.00 mg/liter. The extraction efficiency is 78.5 +/- 6.8% (+/- standard deviation; n = 9), and the calibration graph is linear in the concentration range studied. Pharmacokinetic data, obtained with the present method from seven healthy volunteers, are presented.
Purification and characterization of the Lactobacillus acidophilus bacteriocin lactacin B
Authors: Barefoot S F , Klaenhammer T R
Published: June 2012

Parameters for production and purification of a bacteriocin produced by Lactobacillus acidophilus N2 are described. Production of lactacin B was pH dependent, with maximum activity detected in broth cultures maintained at pH 6. Lactacin B was purified by ion-exchange chromatography, ultrafiltration, and successive gel filtrations in the presence of 8 M urea and then 0.1% sodium dodecyl sulfate. The molecular weight of lactacin B was ca. 6,000 to 6,500, and the purified compound showed maximum absorbance at 211 nm. The activity of purified lactacin B was bactericidal to sensitive cells and restricted to members of the family Lactobacilliaceae, L. leichmannii, L. bulgaricus, L. helveticus, and L. lactis. Characteristics identified for lactacin B indicated that it was a peptide and confirmed its identity as a bacteriocin.
Affinity of temocillin for Escherichia coli K-12 penicillin-binding proteins
Authors: Labia R , Baron P , Masson J M , Hill G , Cole M
Published: June 2012

Temocillin is a 6 alpha-methoxy penicillin which shows poor affinity for the penicillin-binding proteins (PBPs) of Escherichia coli K-12 when tested by competition with [14C]penicillin G or [125I]penicillin X. When the reaction conditions for the radiolabeled penicillin used in this procedure were modified by lowering the temperature (2 degrees C) and reducing the incubation time (3 min), temocillin showed a much higher affinity for PBP-3 and improved affinity for the other PBPs, with the exception of PBP-2. Direct labeling procedures with [14C]temocillin also showed that the compound had affinity for PBPs 1a and 3. These results are more consistent with the effects of temocillin on the morphology of E. coli than the poor affinity values obtained by the classical competitive procedure. Reasons for the disparity between these assay systems are discussed.
Alterations in human fecal flora, including ingrowth of Clostridium difficile, related to cefoxitin therapy
Authors: Mulligan M E , Citron D , Gabay E , Kirby B D , George W L , Finegold S M
Published: June 2012

To evaluate the effects of parenteral cefoxitin therapy on human fecal flora, we cultured fecal specimens obtained from six patients before, during, and after therapy and used standard methods to identify and quantify all microorganisms. The major changes (observed in at least three patients) included the acquisition or proliferation of group D Streptococcus species, coagulase-negative Staphylococcus species, cefoxitin-resistant members of the family Enterobacteriaceae, Pseudomonas species, and various species of the Bacteroides fragilis group. The most striking finding was ingrowth of Clostridium difficile, noted in five of the six patients. There was concomitant eradication or decrease of cefoxitin-susceptible Enterobacteriaceae family members, Bacteroides species other than the B. fragilis group, Clostridium species other than C. difficile, and Lactobacillus species. These marked alterations of fecal flora may have important clinical consequences.
Comparative penetration of cefonicid and cefazolin into the atrial appendage and pericardial fluid of patients undergoing open-heart surgery
Authors: Dudley M N , Nightingale C H , Drezner A D , Low H B , Quintiliani R
Published: June 2012

The penetration of cefonicid and cefazolin into cardiac tissue was compared after a single 30-mg/kg dose in 30 patients undergoing aortocoronary artery bypass graft surgery. Samples of the right atrial appendage, pericardial fluid, and serum were obtained at various times and assayed for drug content. The concentrations of cefonicid in serum and the atrial appendage were at least twice those observed for cefazolin at a given time after a dose. The mean (+/- standard deviation) atrial appendage-serum ratio was 0.47 +/- 0.14 for cefonicid and 0.34 +/- 0.06 for cefazolin (P less than 0.005). Pericardial fluid concentrations of cefonicid were slightly lower than those observed in patients receiving cefazolin (P greater than 0.05). A single intravenous dose of cefonicid provides high and sustained concentrations in serum and cardiac tissue and thus may be useful in antibiotic prophylaxis of certain surgical procedures; however, further study of the efficacy of this agent in the prevention and treatment of infections associated with Staphylococcus spp. is needed.
Correlation of the effect of beta-lactamase inhibitors on the beta-lactamase in growing cultures of gram-negative bacteria with their effect on the isolated beta-lactamase
Authors: Easton C J , Knowles J R
Published: June 2012

The effectiveness of clavulanic acid, sulbactam, quinacillin sulfone, and the carbapenems MM13902 and MM4550 as inhibitors of TEM-2 beta-lactamase in growing cultures of gram-negative bacteria has been studied. Each of these beta-lactams inhibited the enzyme in intact cells, and the nature of the inhibition correlated with studies on the purified enzyme. The potency of these compounds as inhibitors of the beta-lactamase in vivo can be correlated with the amounts hydrolyzed by the purified enzyme under saturating conditions during the inhibition of the enzyme in vitro.
Comparison of the pharmacokinetics of ceftazidime and moxalactam and their microbiological correlates in volunteers
Authors: Drusano G L , Standiford H C , Fitzpatrick B , Leslie J , Tangtatsawasdi P , Ryan P , Tatem B , Moody M R , Schimpff S C
Published: June 2012

We compared ceftazidime with moxalactam, a commonly utilized, currently available drug. The microbiological activities of ceftazidime and moxalactam were studied. In addition, single-dose pharmacokinetics and serum bactericidal activity 1 and 6 h after a 2.0-g, 30-min infusion of each drug were determined in a crossover study in human volunteers. In vitro, both drugs had MICs for 90% of the isolates of less than 1.0 microgram/ml against the common members of the family Enterobacteriaceae and of 8.0 micrograms/ml against Staphylococcus aureus. Against Pseudomonas aeruginosa ceftazidime was more active than moxalactam, the respective MICs for 90% of the isolates being 8 and 128 micrograms/ml. Mean half-lives were 1.75 (+/- 0.21) h for ceftazidime and 2.5 (+/- 0.38) h for moxalactam. The serum bactericidal titers for both compounds against Escherichia coli and Klebsiella pneumoniae were high. Titers against S. aureus 6 h after infusion were negative. The mean (geometric) serum bactericidal titer of ceftazidime against 31 strains of P. aeruginosa (1:44) was higher than that of moxalactam (1:3.4).
Activity of apalcillin against Pseudomonas aeruginosa
Authors: Hollick G E , Gundrum J , Venezia R A
Published: June 2012

The in vitro activity of apalcillin was tested against 107 clinical isolates of Pseudomonas aeruginosa, and the results were compared to those for piperacillin, mezlocillin, azlocillin, and carbenicillin. MIC analysis showed that 97% of the isolates were susceptible to piperacillin, 97% were susceptible to apalcillin, 93% were susceptible to azlocillin, 87% were susceptible to mezlocillin, and 84% were susceptible to carbenicillin.
Protection by D-amino acids against growth inhibition and lysis caused by beta-lactam antibiotics
Authors: Tuomanen E , Tomasz A
Published: June 2012

D-Isomers of several amino acids completely protected growing cultures of Escherichia coli against all antibacterial effects of beta-lactam antibiotics up to approximately two to three times the MICs of the antibiotics. L-Isomers of amino acids were ineffective. Protection depended on the concentration and time of addition of the D-amino acids. This appears to be the first demonstration of natural products capable of reversing the antibacterial effects of beta-lactam antibiotics.
Treatment of typhoid fever with cefamandole
Authors: Uwaydah M , Nassar N T , Harakeh H , Vartivarian S , Talhouk A , Kantarjian H
Published: June 2012

Cefamandole therapy was evaluated in nine patients with typhoid fever. Six patients, including all five who received the antibiotic by continuous intravenous drip (8.0 g daily), were cured. Dosage schedules resulting in maintenance of antibiotic concentrations in serum high above the MIC seemed to correlate well with treatment success.
Comparative pharmacokinetics of Sch 28191 and amphotericin B in mice, rats, dogs, and cynomolgus monkeys
Authors: Kim H , Loebenberg D , Marco A , Symchowicz S , Lin C
Published: June 2012

The pharmacokinetics of Sch 28191, the N-D-ornithyl methyl ester of amphotericin B, and amphotericin B were studied in mice, rats, dogs, and cynomolgus monkeys after an intravenous dose of 0.6 mg/kg was administered. The decline in the concentrations of Sch 28191 and amphotericin B in serum appeared to be biphasic in nature. The half-life at the distribution phase and the half-life at the elimination phase of Sch 28191 were similar to those of amphotericin B in all animals studied. The half-life at the distribution phase in serum was 0.9 to 1.5 h in all animals studied. The half-lives at the elimination phase in serum were 25 to 28 h in mice, 16 to 18 h in rats, 44 to 47 h in dogs, and 35 h in cynomolgus monkeys. The areas under the serum concentration-time curves of Sch 28191 were five- to eightfold larger than those of amphotericin B in rats, dogs, and cynomolgus monkeys but were only slightly larger than those of amphotericin B in mice. In dogs, the urinary excretion (over 9 days) of unchanged drug accounted for 23% of the Sch 28191 dose and 25% of the amphotericin B dose. The concentrations of Sch 28191 in serum were also studied after the intravenous administration of 0.3, 0.6, or 1.25 mg/kg to dogs. The serum concentration-time curves were parallel for these doses. There was a linear relationship between the areas under the concentration-time curves and the doses, indicating dose proportionality.
Interferon aerosol suppression of vesicular stomatitis virus replication in the lungs of infected mice
Authors: Wyde P R , Wilson S Z , Sun C S , Knight V
Published: June 2012

Mice were inoculated intranasally with vesicular stomatitis virus 16 to 22 h after being exposed to small-particle aerosols of saline, natural mouse alpha interferon, recombinant human alpha interferon A, or hybrid recombinant human alpha interferon A/D bgl for 2, 4, or 8 h. Compared with comparably inoculated, untreated mice, significantly reduced levels of vesicular stomatitis virus were observed in the lungs of animals treated with any interferon preparation for 8 h and in groups treated with mouse alpha interferon or hybrid recombinant human alpha interferon A/D bgl for 4 h. No significant reductions in lung virus titers were observed in any group treated with interferon for 2 h or in any of the groups treated with saline.
Use of the fluorescent probe 1-N-phenylnaphthylamine to study the interactions of aminoglycoside antibiotics with the outer membrane of Pseudomonas aeruginosa
Authors: Loh B , Grant C , Hancock R E
Published: June 2012

The mode of interaction of the polycationic aminoglycoside antibiotics with the surface of Pseudomonas aeruginosa cells was studied with the hydrophobic fluorescent probe 1-N-phenylnaphthylamine (NPN). The addition of the aminoglycoside gentamicin to intact cells in the presence of NPN led to a shift in the fluorescence emission maximum from 460 to 420 nm. At the same time the NPN fluorescence intensity increased fourfold. Gentamicin caused no such effects when added to outer membrane vesicles, suggesting that the increased fluorescence resulted from the interaction of gentamicin with intact cells. Gentamicin-promoted NPN uptake was inhibited by the divalent cations Mg2+ and Ca2+, but occurred in the absence of gentamicin transport across the inner membrane. Low concentrations of gentamicin (2 micrograms/ml) caused NPN fluorescence to increase over a period of 4 min in a sigmoidal fashion. At higher concentrations (50 micrograms/ml) the increase occurred within a few seconds. The final fluorescence intensity was almost independent of the gentamicin concentration. A centrifugation technique was used to demonstrate that gentamicin caused actual uptake of NPN from the supernatant. The initial rate of NPN uptake varied according to the gentamicin concentration in a sigmoidal fashion. Similar data were obtained for seven other aminoglycoside antibiotics. The data, when reanalyzed as a Hill plot, gave a series of lines with a mean slope (the Hill number) of 2.26 +/- 0.26, suggesting that the interaction of aminoglycosides with the cell surface to permeabilize it to NPN involved at least three sites and demonstrated positive cooperativity. There was a statistically significant relationship between the pseudoassociation constant K, from the Hill plots and the minimal inhibitory concentrations for the eight antibiotics. These results are consistent with the concept that aminoglycosides interact as a divalent cation binding site on the P. aeruginosa outer membrane and permeabilize it to the hydrophobic prove NPN.