bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing
Authors: Hardin T C , Sharkey P K , Lam Y F , Wallace J E , Rinaldi M G , Graybill J R
Published: June 2012

The pharmacokinetics of SCH-39304, an investigational, orally active, broad-spectrum antifungal agent, were evaluated in 17 adult, human immunodeficiency virus-positive males. Patients were studied on days 1 and 16 and were divided into the following three treatment groups: (i) patients with culture-proven oropharyngeal candidiasis who were not receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 6); (ii) patients with culture-proven oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 5); and (iii) patients with or without oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 200 mg of SCH-39304 daily (n = 6). All patients received a single daily dose of the study medication for 16 days. Plasma samples for SCH-39304 concentration measurement were collected for 6 h following the initial dose and for 504 h following the day 16 dose. Urine was collected for 24 h following SCH-39304 administration on days 1 and 16. All samples were assayed for SCH-39304 by gas chromatography. Wide intersubject variations in SCH-39304 plasma concentration-versus-time profiles were observed on each study day. Absorption appeared to be slow, with mean day 1 peak plasma SCH-39304 concentrations of 1.2 micrograms/ml at 2.1 h (50 mg) and 3.9 micrograms/ml at 4.0 h (200 mg) after drug administration. Mean peak plasma SCH-39304 concentrations on day 16 were 7.6 micrograms/ml at 4.3 h (50 mg) and 17.2 micrograms/ml at 3.2 h (200 mg) after drug administration. Mean elimination half-lives on day 16 for the 50- and 200-mg daily dosages were 100 and 89 h, respectively. SCH-39304 was cleared primarily unchanged in the urine. Mean areas under the plasma concentration-versus-time curve (from 0 to 24 h) on day 16 reflect a lower than expected increase with the 200-mg/day regimen (314.5 microgram.h/ml) compared with that for the 50-mg/day regimen (139.9 microgram.h/ml), suggesting the potential for reduced bioavailability at higher dosages. No significant effect of concurrent zidovudine therapy on the kinetics of SCH-39304 was observed.
Optimal dosing of trimethoprim-sulfamethoxazole when used with loperamide to treat traveler's diarrhea
Authors: Ericsson C D , Nicholls-Vasquez I , DuPont H L , Mathewson J J
Published: June 2012

To explore the optimal dosing regimen for trimethoprim-sulfamethoxazole (TMP-SMX) when used in combination with loperamide to treat traveler's diarrhea, 190 U.S. adults with acute diarrhea were enrolled in a double-blind, randomized trial in Guadalajara, Mexico. All patients received loperamide (4-mg loading dose; 2 mg after each loose stool, not to exceed 16 mg/day for 3 days) and were randomized to receive a 3-day course of TMP-SMX (160:800 mg twice daily for six doses) (group A), a single large dose of TMP-SMX (320:1,600 mg) (group B), or a large loading dose (320:1,600 mg) followed by standard doses for 3 days (160:800 mg twice daily for five doses) (group C). Patients in group C responded best (P < 0.01), with 75% of subjects recovered from diarrhea in 12 h compared with 34 h (group A) and 33 h (group B). Similar differences in favor of group C were noted in the subset of patients who presented with moderate to severe diarrhea. On average, patients in group C took significantly (P < 0.05) less loperamide (1.2 mg) after the 4-mg loading dose compared with patients in group A (2.4 mg) or group B (2.0 mg). We conclude that the most efficacious treatment of traveler's diarrhea in the interior of Mexico is to take loperamide in usual doses to control symptoms in combination with a single large dose of TMP-SMX, which should then be continued for 3 days in standard doses.
Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement of its extracellular and intracellular activities by ethambutol
Authors: Rastogi N , Goh K S , Labrousse V
Published: June 2012

Radiometric MICs of clarithromycin, a new macrolide drug, were determined against five mycobactin-dependent strains of Mycobacterium paratuberculosis (including two Crohn's disease clinical isolates) and compared with those of other drugs which included rifampin, ethambutol, amikacin, ofloxacin, ciprofloxacin, and sparfloxacin. Among the drugs screened, clarithromycin was the drug for which MICs were lowest against the five strains tested. As MICs were significantly below the reported Cmax levels (about 4 micrograms/ml), the intracellular activity of clarithromycin against the type strain of M. paratuberculosis maintained in cultured macrophages was screened. Clarithromycin was able to kill the initial inoculum by more than 1 log within 7 days, and this activity was further potentiated by ethambutol. Extracellular drug combination screened by using sublethal concentrations of the drugs showed that ethambutol was able to enhance clarithromycin activity in three out of four M. paratuberculosis strains instead of only one out of four strains (or none in the case of ofloxacin) when associated with other drugs. These results suggest that clarithromycin may be fruitful to treat human disease in which M. paratuberculosis may be etiologically involved.
Comparison of enterococcal and staphylococcal beta-lactamase-encoding fragments
Authors: Smith M C , Murray B E
Published: June 2012

A restriction map of a 13.5-kb EcoRI fragment encoding beta-lactamase from a plasmid isolated from enterococcal strain PA was prepared and found to differ markedly from the published maps of beta-lactamase-encoding EcoRI fragments of two staphylococcal plasmids and the plasmid from enterococcal strain HH22. This comparison also showed that one of two contiguous EcoRV fragments that encompass the beta-lactamase gene differs in size in the PA strain from that found in the other strains. However, restriction sites in the beta-lactamase structural gene (blaZ) were identical in all four plasmids. Further studies compared the beta-lactamase genes of four clinical enterococcal isolates from various geographic locations with those described above. Isolates from Virginia and Florida generated EcoRV fragments identical to those from the plasmid from strain PA, while isolates from Lebanon and Argentina showed EcoRV fragments analogous to those from HH22 and the staphylococci studied. Although there is evidence suggesting that some of these beta-lactamase-producing enterococcal isolates represent a single strain, this study indicates that there is significant variation in the plasmids that encode beta-lactamase.
Relationship of pharmacokinetics and drug distribution in tissue to increased safety of amphotericin B colloidal dispersion in dogs
Authors: Fielding R M , Singer A W , Wang L H , Babbar S , Guo L S
Published: June 2012

The safety, pharmacokinetics, and distribution in tissue of an amphotericin B (AmB)-cholesteryl sulfate colloidal dispersion (ABCD) were compared with those of micellar amphotericin B-deoxycholate (m-AmB). Dogs received 14 daily injections of ABCD (0.6 to 10 mg/kg of body weight per day) or m-AmB (0.6 mg/kg/day). Safety was evaluated by monitoring body weight, hematology, clinical chemistry, and urinalysis during the study and by microscopic examination of tissues at the time of necropsy (day 16). AmB concentrations in plasma were measured in some groups on days 1, 7, and 14 and in necropsy tissue samples. ABCD produced a spectrum of toxic effects in the kidneys, gut, and liver similar to those of m-AmB, but ABCD was eightfold safer than m-AmB. The highest tolerated dose of ABCD (5.0 mg/kg/day) produced effects similar to those of m-AmB (0.6 mg/kg/day). ABCD produced lower concentrations in plasma than an equal dose of m-AmB did. Clearances on days 7 and 14 were higher for ABCD (304 and 295 ml/h.kg) than they were for m-AmB (67 and 53 ml/h.kg). Concentrations in plasma reached steady state after ABCD administration, but they increased after repeated dosing with m-AmB. Diurnal fluctuations in AmB concentrations in plasma were observed 4 to 8 h after the time of dosing. ABCD resulted in lower AmB concentrations in tissue than m-AmB did, except in the reticuloendothelial system. Up to 90% of AmB administered as ABCD was recovered from the liver and spleen on day 16. Reduced drug levels in the kidneys and gut correlated with reduced indications of toxicity in these organs after ABCD administration. Although ABCD increased concentrations of AmB in the reticuloendothelial system, increased toxicity was not observed in these organs.
Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers
Authors: Woodworth J R , Nyhart E H , Brier G L , Wolny J D , Black H R
Published: June 2012

Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Daptomycin was administered as a single 14C-labeled dose (1.0 mg/kg of body weight) and as single doses between 0.5 and 6.0 mg/kg. All doses were intravenous. Antibacterial activity was determined from doses of 2.0, 3.0, 4.0, and 6.0 mg/kg against two strains of Staphylococcus aureus (one methicillin resistant) and one Enterococcus strain. After administration of 14C-labeled daptomycin, recovery of 14C in urine and feces accounted for 83% of the administered dose, with the greatest fraction (78%) appearing in the urine. Specific analysis for daptomycin in both urine and plasma indicated that metabolic products were present in urine, but total 14C in plasma consisted of daptomycin only. Doses between 0.5 and 6 mg/kg were linear, with a limited total body clearance (0.13 to 0.21 ml/min/kg) and a small volume of distribution (0.10 to 0.15 liter/kg). The small volume of distribution may be a factor of the high plasma protein binding (90 to 95%). Renal clearance made up 34 to 54% of total body clearance. Daptomycin demonstrated in vivo antibacterial activity against all three test strains, with the greatest activity observed against methicillin-resistant S. aureus. The predicted MIC for all three strains was approximately 13 micrograms/ml, corresponding to total (bound plus unbound) drug. On the basis of the drug's pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective.
In vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against the cyst form of Toxoplasma gondii
Authors: Araujo F G , Huskinson-Mark J , Gutteridge W E , Remington J S
Published: June 2012

The in vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against the cyst form of Toxoplasma gondii were evaluated. In vitro treatment (100 micrograms of 566C80 per ml for 3 days) of cysts isolated from brains of mice infected for 1, 2, 3, 4, or 9 months resulted in loss of viability of the cysts and did not reveal any influence of the duration of in vivo infection on sensitivity to the drug. In vivo experiments to determine the effect of prolonged treatment with 200 mg of 566C80 per kg of body weight per day on cysts in brains of CBA/Ca mice infected with strain ME49 revealed a steady and significant decline in the numbers of cysts compared with the numbers in untreated controls. Histopathology of brains from control mice revealed inflammatory infiltrates around capillaries and in the parenchymas and meninges which were consistently less evident in the brains of treated mice. In addition, cysts were rarely observed in treated mice, whereas extensive inflammation and large numbers of cysts were found throughout the entire brain in control mice infected for the same period. The reduction in the numbers of cysts was evident as early as day 5 of treatment but was more marked at 8 weeks of treatment. The numbers of cysts in the brains of Swiss Webster mice infected for 3 or 6 months also significantly decreased following treatment for 15 or 30 days with the same dose of 566C80. Our results indicate that 566C80 has excellent activity against cysts of T. gondii both in vivo and in vitro and that sensitivity of the cysts to 566C80 is not affected by the duration of the infection in vivo.
Prevention of indigenous infection of mice with Escherichia coli by nonspecific immunostimulation
Authors: Nomoto K , Yokokura T , Mitsuyama M , Yoshikai Y , Nomoto K
Published: June 2012

We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an intestinal infection with indigenous Escherichia coli induced by the drug (K. Nomoto, T. Yokokura, Y. Yoshikai, M. Mitsuyama, and K. Nomoto, Can J. Microbiol. 37:244-247, 1991). In the present study we demonstrate that nonspecific immunostimulation is effective in the protection of mice from the lethal indigenous infection induced by 5-FU. Intravenous or subcutaneous injection of a preparation of heat-killed Lactobacillus casei YIT 9018, a potent nonspecific immunostimulant, into BALB/c mice reduced the lethal toxicity of 5-FU at doses ranging from 338 to 800 mg/kg of body weight if YIT 9018 was injected 7 to 40 days before administration of 5-FU. Systemic infection with E. coli developed in all of the 5-FU-treated control mice 7 days or more after administration of 5-FU in large doses and was accompanied by overgrowth of the bacteria in the intestinal tract. Pretreatment of mice with YIT 9018 resulted in a decreased occurrence of systemic infection with E. coli to levels of 0 to 20% and no significant changes in the population levels of E. coli in the intestinal tract during the 14 days after administration of 5-FU. The levels of leukopenia in the spleen and peripheral blood were lower, and recovery of granulocyte-macrophage precursor cells in the spleen and femur began earlier in the treated animals than in the 5-FU-treated controls. Intravenous transfusion of syngeneic normal bone marrow cells or spleen cells into the mice at an early period after administration of 5-FU diminished markedly the occurrence of the lethal indigenous infection, suggestion that an earlier recovery from chemotherapy-induced myelosuppression is important in the mechanisms of protection of the host from the infection.
Anticoccidial activities of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine and other alpha 2 adrenergic agonists
Authors: McFarland J W , Ricketts A P , Newcomb D M , Shively J E , Glazer E A
Published: June 2012

Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among alpha 2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional alpha 2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, alpha 1 agonists and alpha antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate alpha 2 adrenoceptor. alpha 2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.
Pharmacokinetics of temafloxacin in humans after multiple oral doses
Authors: Granneman G R , Carpentier P , Morrison P J , Pernet A G
Published: June 2012

The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects.
Use of a predictor panel for development of a new disk for diffusion tests with cefoperazone-sulbactam
Authors: Bradford P A , Sanders C C
Published: June 2012

The proper disk mass for diffusion susceptibility tests with cefoperazone-sulbactam was determined by using a predictor panel of clinical isolates that included staphylococci and gram-negative bacteria intrinsically susceptible, intrinsically resistant, and of various susceptibilities because of the production of different types and amounts of beta-lactamase. A primary panel of 24 isolates was used to screen various disk masses of cefoperazone and sulbactam in disk diffusion susceptibility tests. Regression analyses were performed for each combination by comparing MICs to zone diameters. Analysis of each component demonstrated that decreasing the disk mass of cefoperazone shifted the regression line to the left while decreasing the disk mass of sulbactam diminished the slope of the line. Ten candidate disks that adequately separated susceptible and resistant strains among the primary panel were identified, and these 10 disks, along with the previously proposed 75/30-micrograms disk, were then tested against an expanded panel of 265 isolates. Results indicated that a 30/20-micrograms cefoperazone-sulbactam disk provided the best separation between susceptible and resistant strains when interpretive criteria of less than or equal to 15 mm for resistance, 16 to 19 mm for moderate susceptibility, and greater than or equal to 20 mm for susceptibility were used. They also identified discrepancies between agar and broth microdilution MICs of sufficient size to warrant separate interpretive criteria for the two methods. Overall, the use of a predictor panel to develop interpretive criteria for susceptibility tests appeared to be a very useful approach, especially when antibiotics designed to be used against drug-resistant organisms are involved.
Use of norfloxacin to study colonization ability of Escherichia coli in in vivo and in vitro models of the porcine gut
Authors: Nielsen E M , Schlundt J
Published: June 2012

The colonization resistance conveyed by the intestinal microbiota can prevent colonization of the intestinal system by new strains. In this study, this resistance was partly circumvented by use of the antimicrobial drug norfloxacin. The colonization abilities of two closely related Escherichia coli strains, which were resistant to nalidixic acid and rifampin, respectively, were investigated in minipigs and a two-stage continuous-flow in vitro gut model. Whereas both strains were unable to colonize the intact enteric system in vivo and in vitro, a 3-day norfloxacin treatment modified both systems to allow colonization by the nalidixic acid-resistant strain but not the rifampin-resistant strain. The results indicate the usefulness of norfloxacin to circumvent the normal colonization resistance while keeping a fairly normal microbiota in the gut. The results also indicate that it could be possible to construct in vitro gut models which could distinguish between strains with different gut colonization abilities. Both of these possibilities could come to be used in the study of the colonization and effects in the gut of new bacterial strains, i.e., genetically modified microorganisms.
The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein
Authors: Neyfakh A A
Published: June 2012

The Bacillus subtilis multidrug efflux transporter Bmr demonstrates 44% amino acid sequence identity with a product of the Staphylococcus aureus gene norA, which is responsible for clinically relevant resistance to fluoroquinolones. We show here that overexpression of bmr in B. subtilis provides strong resistance to fluoroquinolones that can be reversed by reserpine, an inhibitor of Bmr.
Bactericidal titers of loracarbef (LY 163892) in serum and killing rates in volunteers receiving 400 versus 200 milligrams
Authors: Van der Auwera P
Published: June 2012

In a randomized crossover trial, six volunteers received 200- and 400-mg doses of loracarbef (LY 163892), a new oral cephalosporin. Mean +/- standard error of the mean concentrations in serum obtained after 1.5 and 3 h were 13.2 +/- 2.8 and 4.3 +/- 0.7 mg/liter, respectively, after the 400-mg dose and 6.9 +/- 1.0 and 1.7 +/- 0.2 mg/liter, respectively, after the 200-mg dose. Bactericidal reciprocal titers measured against respiratory pathogens in serum suggested that loracarbef would be highly effective against Streptococcus pneumoniae and Streptococcus pyogenes (median titers, 8 to 128 at 1.5 h and less than 2 to 32 at 3 h) and beta-lactamase-negative Haemophilus influenzae (median titers, 4 at 1.5 h and 2 to 4 at 3 h). Other species (Branhamella catarrhalis, Streptococcus anginosus, Staphylococcus aureus) were associated with lower bactericidal titers. Killing curves performed against 12 strains demonstrated that the bioactivity of loracarbef (measured by the reduction in the area under the control growth curve) was significantly correlated with the concentration/MIC ratio, whereas the initial rate of killing was not, once the concentration was greater than the MIC. Our results suggest that administration of 400 mg of loracarbef every 8 h might be associated with more favorable pharmacodynamic parameters against target bacteria.
In vitro toxicological evaluation of ISIS 1082, a phosphorothioate oligonucleotide inhibitor of herpes simplex virus
Authors: Crooke R M , Hoke G D , Shoemaker J E
Published: June 2012

ISIS 1082, a phosphorothioate oligonucleotide targeted to a translation initiation codon of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) virion capsid protein UL13 inhibits in vitro viral replication. To better understand the pharmacological properties of ISIS 1082, we examined its effects in nonvirally infected HeLa cells by using a number of cytotoxicity assays. Our data indicate that ISIS 1082 had no effect on HeLa cell viability as measured by cellular proliferation and clonogenic assays at concentrations as high as 100 microM. Additionally, DNA, RNA, and protein synthesis were only inhibited by 25% in cells treated with 100 microM ISIS 1082. The effects of ISIS 1082 on DNA synthesis were compared with those of acyclovir and trifluorothymidine, two clinically used antiherpetic agents. Acyclovir displayed effects similar to that of ISIS 1082. However, trifluorothymidine, which has been reported to be a potential mutagen and teratogen, significantly altered DNA replication at concentrations from 1 to 100 microM. Isolated HeLa DNA polymerases were inhibited by the compound, with a 50% inhibitory concentration of 2 microM. The in vitro antiviral (K. Draper and V. Brown-Driver, submitted for publication; K.G. Draper and V. Brown-Driver, Antiviral Res. Suppl. 1:106, 1991) and cytotoxicity studies suggest that ISIS 1082 is a selective, nontoxic, antiherpetic therapeutic agent.
Correlation of various in vitro testing methods with clinical outcomes in patients with Bacteroides fragilis group infections treated with cefoxitin: a retrospective analysis
Authors: Snydman D R , Cuchural G J , McDermott L , Gill M
Published: June 2012

There is limited information regarding the correlation of anaerobic susceptibility testing and outcome in the treatment of Bacteroides fragilis infections. We retrospectively analyzed the clinical outcomes of B. fragilis infections in patients treated with cefoxitin; the analysis was blinded for susceptibility results. Isolates of B. fragilis were tested by multiple agar dilution methods, disk elution, and commercial broth microdilution methods. Of 19 patients analyzed, 11 were cured and 8 were treatment failures. No significant differences existed between the groups with respect to age, sex distribution, weight, APACHE II score, dose of cefoxitin, or bacteremia. Failure was associated with a longer cefoxitin dosing interval (P = 0.019), a longer duration of hospitalization (P = 0.038), and decreased duration of cefoxitin treatment (P = 0.05). Four agar dilution systems (brucella plus blood, Wilkins-Chalgren, Wilkins-Chalgren plus blood, brain heart infusion plus blood) and two broth systems (Wilkins-Chalgren microdilution and a commercial system [Micromedia; Beckman, Carlsbad, Calif.]) all demonstrated lower geometric mean MICs for isolates from the group of patients that could be cured. Only the commercial broth microdilution medium (Micromedia) demonstrated a significantly reduced geometric mean MIC (P = 0.056). By using a logistic regression analysis, the shorter cefoxitin dosing interval (P = 0.0004) and the lower geometric mean MIC (P = 0.0088) in the commercial broth microdilution system were shown to be independent predictors of treatment success. These data suggest that the time that the concentration of cefoxitin is over the MIC for B. fragilis may be an important predictor of treatment success.
Effects of cefetamet (Ro 15-8074) on Treponema pallidum and experimental syphilis
Authors: Fitzgerald T J
Published: June 2012

Cefetamet pivoxil (Ro 15-8075) is a newly developed, expanded-spectrum cephalosporin that is orally active. In vitro, the active form, cefetamet (Ro 15-8074), at a concentration of 0.05 micrograms/ml killed and lysed Treponema pallidum. Rabbit serum did not diminish its effectiveness. The antibiotic rapidly entered the circulation following intramuscular injection into rabbits, attaining its highest levels of 24 to 37 micrograms/ml within 10 to 30 min. Animals were infected intradermally with T. pallidum and then treated with different doses of cefetamet. Accelerated healing was detected following treatment with 15 and 30 mg/kg of body weight. The antibiotic was also effective in killing organisms that had disseminated to distant tissues. In three separate sets of experiments, rabbits were infected with treponemes and then treated with cefetamet intramuscularly at 1, 15, or 30 mg/kg as follows: (i) after lesions had just become clinically apparent, (ii) after lesions were enlarged and well developed, or (iii) prior to the appearance of clinical lesions. Antibiotic effectiveness was determined by sacrificing the animals 1 week after antibiotic treatment and examining splenic tissue for residual, disseminated treponemes. Cefetamet was treponemicidal in all three situations. Maximum effects occurred when the antibiotic was injected before lesions had become clinically apparent (incubation period). These results suggest that cefetamet pivoxil might be useful for treating syphilitic infections.
Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice
Authors: Sundelof J G , Hajdu R , Cleare W J , Onishi J , Kropp H
Published: June 2012

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was less than 4% for both compounds.
Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys
Authors: Rodríguez C A , Smith D E
Published: June 2012

The effects of variations in renal perfusate flow on the excretion of cefonicid was examined in isolated perfused rat kidneys. Cefonicid, an expanded-spectrum cephalosporin, is primarily eliminated by active tubular secretion and is neither metabolized nor reabsorbed in the isolated kidney. We used angiotensin II (AII), a strong vasoconstrictor hormone of the afferent and the efferent arterioles in the kidney, to determine whether the renal and secretion clearances, as well as the excretion ratio (ER = CLR/[fu x GFR], where CLR is renal clearance, fu is the unbound fraction, and GFR is glomerular filtration rate), of this low-extraction compound can be altered by a decreased perfusion flow. Control studies were performed in the absence (n = 5) and presence (n = 4) of AII; cefonicid studies were performed in the absence (n = 4) and presence (n = 5) of AII. AII (1 to 4 ng/min) and cefonicid (5 to 10 micrograms/min) were infused into the perfusate. Cefonicid was assayed by high-performance liquid chromatography, and its protein binding was determined by ultrafiltration. AII decreased the perfusate flow rate and increased the renal vascular resistance and filtration fraction of the isolated kidney in the presence and absence of cefonicid. The glomerular filtration rate remained unchanged among the groups. The fractional excretion of glucose was low and steady, indicating a well-preserved tubular function. Although the unbound fraction was unchanged between treatments, the renal and secretion clearances and the excretion ratio of cefonicid were reduced by about 40% in the presence of AII (excretion ratios, 10.3 without AII versus 6.03 with AII). These results suggest that the altered clearance parameters of cefonicid are the result of a flow-induced change in the intrinsic secretory transport of the drug.
In vitro activity of E1040 against imipenem-resistant Pseudomonas aeruginosa strains
Authors: Watanabe M , Inoue E , Katsu K , Iyobe S , Mitsuhashi S
Published: June 2012

E1040 showed the most potent activity (MIC for 90% of strains, 6.25 micrograms/ml) among beta-lactams tested against 70 strains of imipenem-resistant Pseudomonas aeruginosa. Two strains showed high-level resistance to E1040; one strain produced a type II oxyiminocephalosporin-hydrolyzing beta-lactamase (group 3), and the other produced an enzyme similar to a type II penicillinase (OXA-1). Both beta-lactamases contributed to resistance to E1040.
Iron transport-mediated antibacterial activity of and development of resistance to hydroxamate and catechol siderophore-carbacephalosporin conjugates
Authors: Minnick A A , McKee J A , Dolence E K , Miller M J
Published: June 2012

Peptides containing residues of N5-acetyl-N5-hydroxy-L-ornithine were evaluated as potential artificial siderophores of beta-lactam-hypersusceptible Escherichia coli X580. Only those peptides which were capable of forming a hexadentate complex around ferric iron, which is analogous to the natural siderophore ferrichrome, were able to reverse the growth inhibition effects of the ferric iron chelator ethylenediamine di(o-hydroxyphenylacetic acid). A synthetic bis(catechol) spermidine derivative, similar to the natural siderophores enterobactin and agrobactin, also exhibited siderophore activity with this strain. Conjugation of the N5-acetyl-N5-hydroxy-L-ornithine tripeptide and the bis(catechol) siderophore to the potent carbacephalosporin loracarbef and closely related analogs provided compounds which exhibited antibacterial activity against E. coli X580. As was observed with the naturally occurring albomycins, the initial bactericidal effect was followed by the appearance of survivors that were resistant to the test compound. An enhanced killing effect was observed when the parent was incubated simultaneously with hydroxamate and catechol siderophore-antibiotic conjugates. Natural and synthetic siderophore growth promotion experiments with survivors resistant to the conjugates strongly suggested that disabled ferrichrome and enterobactin-catechol assimilation mechanisms may be responsible for the observed resistance. One isolated survivor was postulated to be a tonB mutant. The antibacterial activities of the described siderophore-carbacephalosporin conjugates appear to be related to an iron transport assimilation mechanism and would not have been detected during routine MIC testing procedures.
In vitro activity of Ro 23-9424, a dual-action antibacterial agent, against bacterial isolates from cancer patients compared with those of other agents
Authors: Rolston K V , Nguyen H T , Ho D H , LeBlanc B , Bodey G P
Published: June 2012

The in vitro activity of Ro 23-9424 against bacterial isolates from patients with cancer was compared with those of fleroxacin, ciprofloxacin, cefoperazone, and ceftazidime. Ro 23-9424 inhibited the majority of the members of the family Enterobacteriaceae and all Aeromonas isolates at a concentration of less than or equal to 1.0 micrograms/ml. It was also active against Acinetobacter spp. and Haemophilus influenzae, including beta-lactamase-producing strains. The MIC for 90% of isolates (MIC90) of Pseudomonas aeruginosa was 16.0 micrograms/ml. All group A and B streptococci were inhibited by less than or equal to 0.25 micrograms/ml, and 90% of group G streptococci and Streptococcus pneumoniae were inhibited by 1.0 micrograms/ml. All methicillin-susceptible strains of Staphylococcus aureus and 60% of methicillin-resistant strains were susceptible to 2.0 micrograms of Ro 23-9424 per ml, whereas the MIC90 for Staphylococcus epidermidis and Staphylococcus hominis isolates was 4.0 micrograms/ml. Staphylococcus haemolyticus and Enterococcus spp. were less susceptible; MIC90s for them were 16.0 and 32.0 micrograms/ml. Ro 23-9424 has a broad antibacterial spectrum and potential utility for therapy of infections in cancer patients.
A pneumococcal clinical isolate with high-level resistance to cefotaxime and ceftriaxone
Authors: Figueiredo A M , Connor J D , Severin A , Vaz Pato M V , Tomasz A
Published: June 2012

A beta-lactam-resistant serotype 23F Streptococcus pneumoniae clinical isolate from the cerebrospinal fluid of a pediatric patient from California is unusual in that the MICs of cefotaxime and ceftriaxone (2.5 micrograms/ml each) are higher than that of benzylpenicillin (0.3 micrograms/ml); the isolate also has patterns of penicillin-binding proteins and of cell wall peptides which are atypical compared with those of previously examined penicillin-resistant pneumococci.
Susceptibility of Pseudomonas species to the novel antibiotics mureidomycins
Authors: Isono F , Kodama K , Inukai M
Published: June 2012

Strains of Pseudomonas aeruginosa, including imipenem- or ofloxacin-resistant clinical isolates, and some other species in the genus Pseudomonas were inhibited by novel antibiotics of the mureidomycin (MRD) group. On the other hand, almost all other gram-positive and gram-negative bacteria were resistant to MRDs, though the antibiotics potently inhibited the in vitro peptidoglycan synthesis of Escherichia coli and P. aeruginosa. All of the strains in the genus Pseudomonas that were inhibited by less than or equal to 200 micrograms of MRDs per ml were classified into the rRNA groups I and III, and none of the tested strains of rRNA group I were resistant to MRDs, suggesting that these two groups are closely related to each other evolutionary. Among group I strains, P. aeruginosa, P. mendocina, P. stutzeri, and P. alcaligenes were more susceptible than the others, suggesting a closer relationship among these species.
Discriminative criteria for Neisseria meningitidis isolates that are moderately susceptible to penicillin and ampicillin
Authors: Campos J , Trujillo G , Seuba T , Rodriguez A
Published: June 2012

The prevalence of Neisseria meningitidis isolates that are moderately susceptible to penicillin and ampicillin has increased very quickly in Spain; the current prevalences in our hospital are 48.4 and 55.6%, respectively. We studied the reliability of the disk diffusion method for discriminating between fully susceptible (MIC, less than or equal to 0.06 microgram/ml) and moderately susceptible (MICs, 0.12 to 1.0 microgram/ml) isolates. Thirty-eight isolates (12 Pen(s) Amp(s), 18 Penr Ampr, and 8 Pen(s) Ampr) were assayed by the disk diffusion and plate dilution methods by use of disks of 1, 2, 5, and 10 U of penicillin, 2 and 10 micrograms of ampicillin, and 1 microgram of oxacillin on Mueller-Hinton agar with or without 5% sheep blood. Breakpoints were generated, and their discriminative values were determined with a collection of 195 meningococcal strains isolated consecutively from cerebrospinal fluid or blood. None of the strains produced beta-lactamase. Penicillin- and ampicillin-susceptible strains (MIC, less than or equal to 0.06 microgram/ml) had oxacillin inhibition zones of greater than or equal to 11 mm on blood agar. Moderate susceptibility to ampicillin and penicillin was suggested by an inhibition zone of less than or equal to 10 mm around the 1-microgram disk and an inhibition zone of less than or equal to 26 mm around the 2-U penicillin disk. We conclude that discrimination between fully susceptible and moderately susceptible populations of N. meningitidis can be accomplished by the disk diffusion method by use of Mueller-Hinton agar plus 5% sheep blood with the 1-microgram oxacillin disk (which is especially suited for screening methods) and the 2-U penicillin disk. The lack of an oxacillin inhibition zone indicates moderate susceptibility to either penicillin or ampicillin or both.
Levels of pyrimethamine in sera and cerebrospinal and ventricular fluids from infants treated for congenital toxoplasmosis. Toxoplasmosis Study Group
Authors: McLeod R , Mack D , Foss R , Boyer K , Withers S , Levin S , Hubbell J
Published: June 2012

Pyrimethamine levels in sera, cerebrospinal fluid (CSF), and ventricular fluid were measured by using reversed-phase high-pressure liquid chromatography. The specimens were from 37 infants receiving pyrimethamine for treatment of suspect or proven congenital toxoplasmosis. Pyrimethamine half-life in serum was 64 +/- 12 h when determined by study of terminal-phase kinetics of samples obtained from nine babies. This half-life was significantly different (P = 0.008) from the pyrimethamine half-life (33 +/- 12 h) determined by terminal-phase kinetics for two babies of the same age taking phenobarbital. Serum pyrimethamine levels at various intervals after dosages of pyrimethamine were also lower for infants receiving phenobarbital. Levels measured in sera from babies taking the same dose of pyrimethamine throughout their first year of life did not appear to vary significantly over time or at different ages (P greater than 0.05). Mean +/- standard deviation serum levels 4 h after a pyrimethamine dose were 1.297 +/- 0.54 micrograms/ml for babies taking 1 mg of pyrimethamine per kg of body weight daily and 0.7 +/- 0.26 microgram/ml for babies taking 1 mg/kg each Monday, Wednesday, and Friday. Levels in CSF were approximately 10 to 25% of concomitant levels in serum. Serum folate levels for infants who took 0.64 to 1.7 mg leukovorin per kg ranged from 33 to 663 ng/ml. To determine whether the levels of pyrimethamine in serum and CSF of treated infants were in a range that affected the most virulent, rapidly replicating, and standard laboratory strain of Toxoplasma gondii, effects of various concentrations of pyrimethamine and sulfadiazine on replication of T. gondii in vitro were assessed. The levels of the antimicrobial agents effective in vitro were in the range of levels of pyrimethamine achieved in sera and CSF. Although folinic acid could inhibit the therapeutic effect of pyrimethamine and sulfadiazine in vitro, inhibition was noted only at levels (> or = 4,800 ng/ml) that were considerably higher than the folate levels found in the treated infants' sera.
Nucleotide sequence of the ampC-ampR region from the chromosome of Yersinia enterocolitica
Authors: Seoane A , Francia M V , García Lobo J M
Published: June 2012

The nucleotide sequence of a 3.1-kb region from the chromosome of the Yersinia enterocolitica O:5b strain IP97 containing the gene for an inducible chromosomal cephalosporinase has been determined. The cephalosporinase gene was homologous to other enterobacterial chromosomal cephalosporinase genes, and it was accompanied by a gene homologous to the regulatory ampR gene. The arrangement of genes in the Y. enterocolitica ampCR unit was identical to that in the Enterobacter cloacae and Citrobacter freundii ampCR units.
Vancomycin is not an essential component of the initial empiric treatment regimen for febrile neutropenic patients receiving ceftazidime: a randomized prospective study
Authors: Ramphal R , Bolger M , Oblon D J , Sherertz R J , Malone J D , Rand K H , Gilliom M , Shands J W , Kramer B S
Published: June 2012

The use of vancomycin as part of the initial antibiotic therapy of febrile neutropenic patients has become a controversial issue. Some studies support its incorporation in the initial regimen, and others suggest that vancomycin can be added later. We examined this issue in a prospective, randomized trial. We randomized 127 febrile neutropenic patients to receive either ceftazidime alone or ceftazidime plus vancomycin as the initial empiric antibiotic treatment. We added vancomycin to the ceftazidime arm of the study when fever persisted after 96 h of monotherapy, when new fever occurred after this time, or when a moderately ceftazidime-resistant gram-positive bacterium was isolated. Each of these regimens had similar initial response rates, similar durations of initial fever, similar frequencies of new fever during therapy, similar microbiological cure rates, similar superinfection rates, and similar survival rates. We observed more renal and cutaneous toxicities in patients receiving vancomycin and ceftazidime as initial therapy. We conclude that ceftazidime is appropriate as initial therapy for febrile neutropenic patients and that the addition of vancomycin is appropriate when fever persists after 4 days of monotherapy or when fever recurs following an initial response.
Susceptibility testing of bacteria recovered from patients with peritonitis complicating continuous ambulatory peritoneal dialysis
Authors: Ludlam H , Johnston L , Hopkins P
Published: June 2012

Antagonism of antibiotic activity by peritoneal dialysate has been postulated to be a cause of failure of treatment of peritonitis complicating continuous ambulatory peritoneal dialysis. We evaluated by a case-control study whether unexpected treatment failure could be attributed to such antagonism. Bacteria isolated from 34 patient episodes of peritonitis treated with the same regimen of ciprofloxacin monotherapy were studied. Ciprofloxacin was significantly less active in dialysate than in Iso-Sensitest broth (IB). The median MIC in IB was 0.5 microgram/ml, increasing to 2.0 micrograms/ml for both fresh dialysate (FD) (P = 0.003) and pooled dialysis effluent (PDE) (P = 0.03); the median MBC in IB was 8.0 micrograms/ml, increasing to 128.0 micrograms/ml in FD (P = 0.0002) and 64.0 micrograms/ml in PDE (P = 0.02). However, no significant differences were found in the results for patients suffering unexpected treatment failure (relapse of peritonitis) compared with the results for patients whose infection resolved without sequel. In IB the median MICs for relapsers and nonrelapsers were 1.0 and 0.5 microgram/ml, respectively (P = 0.88); median MBCs were 32.0 and 4.0 micrograms/ml (P = 0.19). In FD median MICs for relapsers and nonrelapsers were 2.0 and 1.0 micrograms/ml (P = 0.06); median MBCs were 128.0 micrograms/ml for both groups (P = 0.84). In PDE the median MICs were 2.0 micrograms/ml for both groups (P = 0.78); median MBCs were 256.0 and 64.0 micrograms/ml (P = 0.17). We therefore found no evidence to suggest that antagonism of antibiotic activity by dialysate is a cause of treatment failure or that conventional methods for laboratory susceptibility testing in peritonitis complicating continuous ambulatory peritoneal dialysis should be abandoned in favor of testing in media containing dialysate.
Pharmacokinetics and bactericidal rates of daptomycin and vancomycin in intravenous drug abusers being treated for gram-positive endocarditis and bacteremia
Authors: Rybak M J , Bailey E M , Lamp K C , Kaatz G W
Published: June 2012

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic parameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval after intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1- and 6-h serum samples by using four isolates of Staphylococcus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enrolled in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were higher than reported in healthy volunteers. Although not statistically different, D clearance was 22% higher than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50% for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis.3+