bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of metronidazole resistance in therapy of Helicobacter pylori infections
Authors: Rautelin H , Seppälä K , Renkonen O V , Vainio U , Kosunen T U
Published: June 2012

Susceptibility to metronidazole was determined by disk diffusion tests for 559 strains of Helicobacter pylori isolated from patients. The overall metronidazole resistance was 26%. In males metronidazole-resistant strains made 18% of all H. pylori strains, and in females the corresponding figure was 40% (P less than 0.001). MICs of metronidazole were determined for H. pylori strains from 86 patients undertaking triple therapy, i.e., treatment with colloidal bismuth subcitrate, amoxicillin, and metronidazole. Of the nonresponders who remained culture positive despite the therapy, 69% had strains with metronidazole MICs of greater than or equal to 32 micrograms/ml before the therapy, and all nonresponders had metronidazole-resistant strains after the therapy. Metronidazole resistance was, however, also found in 27% of responders before therapy. To find whether the MICs of metronidazole for H. pylori strains remained constant for longer periods, consecutive isolates sampled several years apart from the same patients were tested in parallel and no changes in the MICs were found. H. pylori was successfully eradicated by the triple therapy from 91% of patients with metronidazole-susceptible pretreatment strains and from 63% of patients with metronidazole-resistant strains before the therapy (P less than 0.01). Although resistance to metronidazole has a significant role in treatment failures in H. pylori infections, high eradication rates can be achieved with the use of the present triple therapy even in populations with a high overall metronidazole resistance rate.
Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B
Authors: Ellis M E , al-Hokail A A , Clink H M , Padmos M A , Ernst P , Spence D G , Tharpe W N , Hillier V F
Published: June 2012

Results of a double-blind randomized non-crossover study of rapid (45 min) versus slow (4 h) infusion of amphotericin B administered to 20 patients with proven or suspected fungal infection are reported. Toxicity was higher in the rapid infusion group than it was in the slow infusion group (mean total 7-day chill score, 173 +/- 276 versus 20 +/- 30 [P less than 0.01]; mean total 7-day dosage of meperidine required to abate rigors, 180 +/- 133 versus 58 +/- 78 mg [P less than 0.05]; and mean maximum total 7-day pulse rise, 225 +/- 64 versus 135 +/- 56 beats per min [P less than 0.02], respectively). When analyzed on a daily basis, the mean chill score, meperidine dosage, and pulse rise were also higher; and in addition, nausea and vomiting (5 of 11 patients who received a rapid infusion versus 0 of 9 patients who received a slow infusion [P less than 0.01]) appeared to be more common in those who received amphotericin B rapidly. The daily analysis approach proved that tolerance to these side effects developed with each subsequent infusion day, and by day 7 the incidence and severity were the same. This development of tolerance was significant for the mean chill score in the rapid infusion group (P less than 0.05) and for the proportion of patients with chills (P less than 0.005 for the slow infusion group; P less than 0.05 for the rapid infusion group). A decrease in creatinine clearance to greater than 51% of the baseline value was seen in two patients in each group. There were five deaths (four in the rapid infusion group, 1 in the slow infusion group) within 1 month, but none was clearly related to the amphotericin B infusion. The mean time to defervescence was similar for each group (10.8 +/- 4.1 days in the slow infusion group versus 9.9 +/- 5 days in the rapid infusion group). A rapid infusion regimen for amphotericin B cannot be recommended, at least during the first 5 to 7 days of treatment.
In vitro and in vivo activities of sparfloxacin, other quinolones, and tetracyclines against Chlamydia trachomatis
Authors: Nakata K , Maeda H , Fujii A , Arakawa S , Umezu K , Kamidono S
Published: June 2012

Sparfloxacin was more potent than other quinolones (tosufloxacin, lomefloxacin, ciprofloxacin, ofloxacin, fleroxacin, enoxacin, and norfloxacin) and as potent as minocycline and doxycycline in activity against Chlamydia trachomatis in vitro and in vivo. Sparfloxacin was more bactericidal than minocycline against C. trachomatis D/UW-3/Cx.
Susceptibilities of anaerobic bacteria isolated from animals with ovine foot rot to 28 antimicrobial agents
Authors: Piriz S , Cuenca R , Valle J , Vadillo S
Published: June 2012

The agar dilution method was used to determine the inhibitory activities of 28 antimicrobial agents against 35 strains of the genus Peptostreptococcus, 4 strains of the species Peptococcus niger, 20 strains of the species Megasphaera elsdenii, 7 strains from the species Acidaminococcus fermentans, 8 strains of the genus Clostridium, 11 strains of the genus Eubacterium, and 1 strain of the species Propionibacterium acidipropionici, all of which were isolated from 125 clinical cases of ovine foot rot between January 1987 and December 1988. The three unreidopenicillins studied proved to be the most active antimicrobial agents, with a high percentage of strains being susceptible at a concentration of 64 micrograms/ml. Penicillin G, ampicillin, and the three cephalosporins studied also had good activity. Fosfomycin showed a high degree of activity among the 116 anaerobic bacteria tested.
Effect of inoculum size on bacteriolytic activity of cefminox and four other beta-lactam antibiotics against Escherichia coli
Authors: Soriano F , Edwards R , Greenwood D
Published: June 2012

MICs and turbidimetric experiments revealed a negligible inoculum effect with two Escherichia coli strains exposed to cefminox and cefoxitin, whereas a marked inoculum effect was revealed after exposure to cefotaxime, ceftizoxime, and imipenem. The activities of the cephamycins were associated with spheroplast formation and bacteriolysis at concentrations close to the MIC, whereas the other agents induced the formation of filaments or, in the case of imipenem, rounded cells.
In vitro activities of three of the newer quinolones against anaerobic bacteria
Authors: Wexler H M , Molitoris E , Finegold S M
Published: June 2012

The antimicrobial activities of three new quinolone compounds, sparfloxacin, temafloxacin, and WIN 57273, against anaerobic bacteria were determined in three separate studies. The Wadsworth agar dilution technique using brucella-laked blood agar was used throughout. The activities of other antimicrobial agents, including ciprofloxacin, imipenem, chloramphenicol, metronidazole, cefotetan, cefoxitin, and amoxicillin-clavulanic acid, were also determined. The breakpoints of the new quinolones were 2 micrograms/ml for sparfloxacin and WIN 57273 and 4 micrograms/ml for temafloxacin. WIN 57273 displayed very good activity against anaerobes, inhibiting all strains of Bacteroides fragilis group species at 2 micrograms/ml. Only two strains of Fusobacterium species were resistant (MIC, 4 micrograms/ml). Sparfloxacin inhibited 78% of B. fragilis strains and 44% of other B. fragilis group isolates at 2 micrograms/ml. At 2 micrograms/ml, the percentages of other anaerobic species susceptible were as follows: B. gracilis, 70%; other Bacteroides species, 61%; Clostridium species, 50%; Fusobacterium species, 70%; Peptostreptococcus species, 91%; non-spore-forming gram-positive rods, 71%. Temafloxacin inhibited 91% of B. fragilis strains and 87% of other B. fragilis group species at 4 micrograms/ml. All strains of other Bacteroides species, 78% of Fusobacterium species, 80% of Clostridium species, and 90% of Peptostreptococcus species were inhibited at 4 micrograms of temafloxacin per ml.
Five versus three days of ofloxacin therapy for traveler's diarrhea: a placebo-controlled study
Authors: DuPont H L , Ericsson C D , Mathewson J J , DuPont M W
Published: June 2012

In this double-blind study with 232 patients, 300 mg of ofloxacin given orally twice daily for 5 or 3 days was compared with placebo for the treatment of acute diarrhea in U.S. students visiting Guadalajara, Mexico. The 3-day regimen of ofloxacin was found to be as effective as the 5-day regimen in producing a clinical and microbiologic cure. Clinical cures for patients who received ofloxacin for 5 days occurred in 59 of 66 (89%) subjects, whereas clinical cure occurred in 77 of 81 (95%) of those who received ofloxacin for 3 days and in 56 of 79 (71%) of those who took placebo (P = 0.0001). When the duration of diarrhea after therapy was begun was compared in subgroups, a significant (P less than 0.05) shortening of posttreatment illness occurred in comparison with that in the placebo group for the following groups: for 5 days of ofloxacin, cases of shigellosis (32 versus 98 h); for 3 days of ofloxacin, all cases (28 versus 56 h), cases of enterotoxigenic Escherichia coli diarrhea (26 versus 66 h), cases of shigellosis (24 versus 98 h), all cases of illnesses associated with a bacterial enteropathogen (28 versus 69 h), and cases of illnesses in which numerous leukocytes were found in stool by microscopy (22 versus 49 h). Microbiologic eradication rates were 75 of 78 (96%) for patients who received ofloxacin and 37 of 46 (80%) for patients who received placebo (P = 0.009). There was no significant difference in the number of adverse events reported by patients in either of the treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of sub-MICs of antibiotics on cell surface characteristics and virulence of Pasteurella multocida
Authors: Lebrun A , Caya M , Jacques M
Published: June 2012

The effects of sub-MICs of certain antibiotics, namely, penicillin G, tetracycline, and trimethoprim-sulfamethoxazole, on the cell surface characteristics and the virulences of two toxigenic isolates of Pasteurella multocida representing capsular types A and D were evaluated. Expression of proteins, in particular, outer membrane proteins and iron-regulated proteins, was not affected by exposure of bacterial cells to low concentrations of antibiotics. However, exposition of surface antigens was modified by sub-MICs of the antibiotics tested. The lipopolysaccharide profile of one isolate (capsular type D) was altered by penicillin G. Sub-MICs of penicillin G and tetracycline diminished the virulence of the capsular type A isolate and adherence to porcine tracheal rings of the capsular type D isolate. Production of dermonecrotic toxin was not affected by sub-MICs of the antibiotics tested. Our results indicate that growth of P. multocida in the presence of low concentrations of antibiotics seems to have, depending on the isolate, profound effects on cell surface characteristics, with concomitant effects on adherence or virulence. Our results also indicate that production of dermonecrotic toxin, an important virulence factor of P. multocida isolates associated with porcine atrophic rhinitis, was not affected by sub-MICs of the antibiotics studied.
Pharmacodynamic interaction between RP 59500 and gram-positive bacteria infecting fibrin clots
Authors: Turcotte A , Bergeron M G
Published: June 2012

The fibrin clot penetration and in vivo bactericidal activity of RP 59500, a new semisynthetic streptogramin, for two Staphylococcus aureus strains (one methicillin resistant and the other methicillin susceptible), two Staphylococcus epidermidis strains (one methicillin resistant and the other methicillin susceptible), and one Enterococcus faecalis strain were evaluated. The clots, inserted subcutaneously, were infected with a mean of 10(8) CFU of the pathogen per g. For each strain, groups of four rabbits received a single intravenous injection of 50 mg of RP 59500 per kg of body weight over 30 min. The mean peak level of RP 59500 in serum in the infected rabbits was 61.9 +/- 6.3 micrograms/ml. The drug was detectable in serum at a level of 0.8 micrograms/ml up to 4 h after administration. The mean peak fibrin clot drug level at 1 h was 3.3 +/- 0.1 micrograms/g. At 6 h, the level in clots was 1.2 +/- 0.1 micrograms/g. The mean half-life in serum in infected rabbits was 0.34 +/- 0.01 h, while in clots the drug exhibited a longer half-life of 3.8 +/- 0.4 h. In vivo, this new streptogramin sterilized the clots infected with the two S. aureus strains studied in less than 1 h and induced a marked reduction in colony counts of the two S. epidermidis strains studied for up to 24 h. The activity of the streptogramin against E. faecalis was limited. These results suggest that RP 59500 should be further evaluated for the treatment of infection with methicillin-resistant staphylococci.
Serum and blister fluid pharmacokinetics and bactericidal activities of ampicillin-sulbactam, cefotetan, cefoxitin, ceftizoxime, and ticarcillin-clavulanate
Authors: Jaresko G S , Barriere S L , Johnson B L
Published: June 2012

Ampicillin-sulbactam, ticarcillin-clavulanate, cefoxitin, cefotetan, and ceftizoxime are promoted for the treatment of mixed aerobic-anaerobic bacterial infections. Their activities have been compared in vitro but not in vivo. In order to assess the in vivo activities of these agents in serum and interstitial fluid, we administered single, intravenous doses of these antimicrobial agents to healthy subjects. Concentrations of the antimicrobial agents in serum and suction-induced blister fluid and bactericidal activity were measured by high-pressure liquid chromatography and the standard methodology of the National Committee for Clinical Laboratory Standards, respectively. The organisms used for bactericidal activity tests were one isolate each of Staphylococcus aureus, Klebsiella pneumoniae, and Bacteroides fragilis. Pharmacokinetic parameters in serum and blister fluid were similar to those derived in other investigations. Of note were the high and prolonged concentrations of ticarcillin and cefotetan in blister fluid, despite high-level serum protein binding. The bactericidal activities in serum and blister fluid reflected the relative in vitro activities and kinetic dispositions of the various antimicrobial agents except for the bactericidal activity of cefotetan, which was substantially lower in blister fluid than serum, despite a blister fluid:serum area under the concentration-time curve ratio of 1.5. Similarly, the activity of ticarcillin-clavulanate in blister fluid was also substantially less than would have been predicted by the blister fluid:serum ratio of the area under the concentration-time curve of 1.1, possibly because of the low concentrations of clavulanate in blister fluid. The rankings of the in vivo bactericidal activities of the five drugs were as follows: for S. aureus, ampicillin-sulbactam > ticarcillin-clavulanate > ceftizoxime > cefoxitin > cefotetan; for K. pneumoniae, ceftizoxime > cefotetan > ampicillin-sulbactam = ticarcillin-clavulanate > cefoxitin; and for B.fragilis, ticarcillin-clavulanate > cefotetan > ceftizoxime > ampicillin-sulbactam = cefoxitin.
Intravenous and oral zidovudine pharmacokinetics and coagulation effects in asymptomatic human immunodeficiency virus-infected hemophilia patients
Authors: Morse G D , Portmore A C , Marder V , Plank C , Olson J , Taylor C , Bonnez W , Reichman R C
Published: June 2012

Pharmacokinetic and coagulation studies were carried out over a 12-week period with 11 asymptomatic hemophilia patients with human immunodeficiency virus infection receiving zidovudine (ZDV). The patients received 300 mg every 4 h while awake (the accepted dose at the time of this study); consecutive 24-h intravenous (i.v.) and 12-h oral pharmacokinetic studies were conducted at weeks 1, 6, and 12. Coagulation studies were conducted at weeks 0, 4, 8, and 12. The numbers of units of factors VIII and IX and cryoprecipitate transfused during the 12-week periods before, during, and after ZDV treatment were recorded. Following i.v. and oral ZDV administration, the concentration in plasma declined rapidly over the first 4 h, and in some patients, ZDV was still detectable at 4 to 10 h. The i.v. total clearances (means +/- standard deviations) were 14.9 +/- 7.3, 11.2 +/- 3.7, and 15.1 +/- 4.7 ml/min/kg of body weight. The i.v. distribution volumes were 1.08 +/- 0.5, 1.0 +/- 0.4, and 1.65 +/- 1.4 liters/kg. The bioavailabilities were 0.54 +/- 0.22, 0.46 +/- 0.19, and 0.59 +/- 0.13 at weeks 1, 6, and 12, respectively. The pattern of ZDV-glucuronide (GZDV) disposition was similar to that of ZDV, and the peak plasma GZDV-to-ZDV ratio was higher after oral dosing, consistent with first-pass metabolism. In some individuals, up to 33% of an i.v. dose was excreted unchanged. At weeks 6 and 12, greater than 300 mg of total ZDV (GZDV plus ZDV) was recovered in the urine of some patients, suggesting tissue redistribution. Concentration in plasma after oral ZDV administration were variable, both within and between patients. The von Willebrand antigen level consistently decreased throughout the study but was not accompanied by a parallel change in ristocetin cofactor A activity, and no clinical adverse effects on coagulation were noted. This study demonstrates that ZDV can be used in hemophilia patients without worsening of their bleeding tendencies. The clinical significance of decreased ZDV clearance and the prolonged terminal elimination phase of ZDV will require further study with patients receiving chronic ZDV.
Comparison of the gentamicin resistance transposon Tn5281 with regions encoding gentamicin resistance in Enterococcus faecalis isolates from diverse geographic locations
Authors: Hodel-Christian S L , Murray B E
Published: June 2012

The genetic determinant encoding gentamicin resistance (Gmr) on the beta-lactamase encoding plasmid pBEM10 of Enterococcus faecalis HH22 is carried on a transposon, termed Tn5281, that is highly related to the staphylococcal Gmr transposons Tn4001 found in Australian isolates of Staphylococcus aureus and Tn4031 found in United States isolates of Staphylococcus epidermidis. We have now studied plasmid DNA from Gmr strains of E. faecalis isolated from diverse geographical locations (Houston, Pennsylvania, Thailand, and Chile) by using restriction endonuclease analysis and DNA-DNA hybridization to determine whether other Gmr E. faecalis carry Tn5281 or a similar type of element. We also compared these enterococci to several United States isolates of Staphylococcus aureus with nonmobile Gmr determinants. Three E. faecalis isolates (from Houston and Chile) carried Tn5281-like elements, whereas two isolates (from Houston and Pennsylvania) had restriction endonuclease and DNA-DNA hybridization patterns more similar to those of the Tn4001-IS257 hybrid found in the nonmobile Gmr determinants in United States isolates of S. aureus. A strain from Thailand had a third pattern unrelated to either Tn5281 or the nonmobile Gmr determinants present in United States isolates of S. aureus. Our results demonstrate that there is both similarity and diversity between the Gmr determinant of strains of E. faecalis isolated in diverse geographic locations.
Salicylate-inducible antibiotic resistance in Pseudomonas cepacia associated with absence of a pore-forming outer membrane protein
Authors: Burns J L , Clark D K
Published: June 2012

The most common mechanism of antibiotic resistance in multiply resistant Pseudomonas cepacia is decreased porin-mediated outer membrane permeability. In some gram-negative organisms this form of antibiotic resistance can be induced by growth in the presence of weak acids, such as salicylates, which suppress porin synthesis. To determine the effects of salicylates on outer membrane permeability of P. cepacia, a susceptible laboratory strain, 249-2, was grown in 10 mM sodium salicylate. Antibiotic susceptibility and uptake, as well as outer membrane protein patterns, were compared between strain 249-2 grown with and without salicylates. The MICs of chloramphenicol, trimethoprim, ciprofloxacin, and ceftazidime were compared between organisms grown in standard and salicylate-containing medium and are as follows: chloramphenicol, 12.5 versus 100 micrograms/ml; trimethoprim, 0.78 versus 3.125 micrograms/ml; ciprofloxacin, 0.4 versus 1.56 micrograms/ml; ceftazidime, 3.125 versus 3.125 micrograms/ml. The permeability of beta-lactam antibiotics was calculated from the rate of hydrolysis of the chromogenic cephalosporin, PADAC. There was no significant difference between strains grown in the presence and absence of salicylate. By using high-pressure liquid chromatography quantitation of loss from culture medium, the effect of 10 mM salicylate on the cellular permeability of chloramphenicol was measured in strain 249-2 by introduction of a plasmid which encodes production of chloramphenicol acetyltransferase. After 1 h of incubation, 18.5% +/- 1.54% versus 70.1% +/- 3.52%, and after 2 h, 4.20% +/- 1.65% versus 41.90% +/- 2.16% remained in supernatants from organisms grown in the absence and presence of 10 mM salicylate, respectively. Outer membrane protein pattern analysis demonstrated the absence of a protein of apparent molecular weight of 40,000 when strain 249-2 was grown in the presence of 10 mM salicylate. To determine whether this protein functioned as a porin, reconstituted membrane vesicles were constructed to assess antibiotic permeability. Vesicles constructed with this salicylate-suppressible outer membrane protein (OpcS) were permeable to chloramphenicol but not to penicillin G. These findings suggest that OpcS is a selective, antibiotic-permeable porin which can be suppressed by growth in the presence of salicylate. Further investigation will be required to determine the biochemical effects of salicylate on porin synthesis.
In vitro activity of T-3761, a new fluoroquinolone
Authors: Muratani T , Inoue M , Mitsuhashi S
Published: June 2012

The in vitro activity of T-3761, a new fluoroquinolone antimicrobial agent which has an oxazine ring structure with a cyclopropyl moiety at C-10, was compared with those of other agents against 2,854 clinical isolates. T-3761 had a broad spectrum of activity and had potent activity against gram-positive and -negative bacteria. The MICs of T-3761 against 90% of the methicillin-susceptible Staphylococcus aureus, methicillin-susceptible and -resistant Staphylococcus epidermidis, and Clostridium spp. tested were 0.39 to 6.25 micrograms/ml. Its activity was comparable to those of ciprofloxacin and ofloxacin and four- to eightfold greater than those of norfloxacin and fleroxacin, but its activity was two- to eightfold less than that of tosufloxacin. Some isolates of ciprofloxacin-resistant S. aureus (MIC of ciprofloxacin, greater than or equal to 3.13 micrograms/ml) were still susceptible to T-3761 (MIC of T-3761, less than or equal to 0.78 micrograms/ml). The MICs of T-3761 against 90% of the streptococci and enterococci tested were 3.13 to 100 micrograms/ml. Its activity was equal to or 2- or 4-fold greater than those of norfloxacin and fleroxacin, equal to or 2- or 4-fold less than those of ofloxacin and ciprofloxacin, and 4- to 16-fold less than that of tosufloxacin. The activity of T-3761 against gram-negative bacteria was usually fourfold greater than those of norfloxacin, ofloxacin, and fleroxacin. Many isolates which were resistant to nonfluoroquinolone agents, such as minocycline- or imipenem-resistant S. aureus, ceftazidime-resistant members of the family Enterobacteriaceae, gentamicin- or imipenem-resistant Pseudomonas aeruginosa, and ampicillin-resistant Haemophilus influenzae and Neisseria gonorrhoeae, were susceptible to T-3761. The MBCs of T-3761 were either equal to or twofold greater than the MICs. The number of viable cells decreased rapidly during incubation with T-3761 at one to four times the MIC. At a concentration of four times the MIC, the frequencies of appearance of spontaneous mutants resistant to T-3761 against S. aureus, Escherichia coli, Serratia marcescens, and P. aeruginosa were 2.2 x 10(-8) to less than or equal to 1.2 x 10(-9). The 50% inhibitory concentrations of T-3761 for DNA gyrases isolated from E. coli and P. aeruginosa were 0.88 and 1.9 micrograms/ml, respectively.
Mutation and mapping of genes involved in production of the antibiotic TA in Myxococcus xanthus
Authors: Varon M , Fuchs N , Monosov M , Tolchinsky S , Rosenberg E
Published: June 2012

Transposition of TnV and Tn5lac into Myxococcus xanthus yielded 8,381 kanamycin-resistant mutants that were tested for antibiotic TA production. Twenty-four of the mutants were nonproducers of TA (less than 0.4 ng/ml), and 3 produced a higher level (2.5 micrograms/ml) than the parent strain (1.5 micrograms/ml). For most of the strains, there was 100% cotransduction between kanamycin resistance and the altered TA phenotype. Southern blot analysis of restriction digests of the mutant DNA indicated that the transposons were inserted at different sites on the M. xanthus chromosome. The TA genes were mapped by cotransduction between pairs of mutants following replacement of the initial insert of one of the pair with the tetracycline resistance transposon Tn5-132. Nine of the 13 nonproducers tested were linked over a 36-kb stretch of the chromosome. There was no linkage between one of the overproducers and any of the nonproducers tested.
Effects of diclofenac on ceftriaxone pharmacokinetics in humans
Authors: Merle-Melet M , Bresler L , Lokiec F , Dopff C , Boissel P , Dureux J B
Published: June 2012

The effects of diclofenac, a nonsteroidal antiinflammatory drug, on the biliary and urinary excretion of ceftriaxone were evaluated in subjects with a T drain in the common bile duct. The kinetic study was carried out on the sixth postoperative day of treatment with ceftriaxone alone (2 g intravenously; group 1) or ceftriaxone combined with diclofenac (50 mg every 12 h orally from postoperative days 3 to 6; group 2). A significant increase in the elimination half-life of ceftriaxone was observed in group 2 patients. Diclofenac caused a significant rise in ceftriaxone biliary excretion. This increase was not sufficient to balance the significant deficit of urinary excretion of ceftriaxone.
Susceptibility of an emetine-resistant mutant of Entamoeba histolytica to multiple drugs and to channel blockers
Authors: Samuelson J C , Burke A , Courval J M
Published: June 2012

Previously a cloned emetine-resistant mutant of the protozoal parasite Entamoeba histolytica was shown to overexpress a gene for an ameba homolog of the mammalian P-glycoprotein, a plasma membrane pump that removes hydrophobic drugs from multidrug-resistant tumor cells. Three sets of experiments were performed to better characterize the multidrug-resistant phenotype of the emetine-resistant amebae. First, the emetine resistance of the mutant amebae was reversed by concentrations of calcium and sodium channel blockers effective in reversing drug resistance by multidrug-resistant tumor cells, but it was reversed only in the presence of very high concentrations of the tricyclic antidepressants. Second, the mutant amebae showed cross-resistance to antiamebic drugs used to treat luminal infection (iodoquinol and diloxanide) but were not cross-resistant to drugs used to treat invasive disease (chloroquine and metronidazole). Third, when amebae were loaded with radiolabeled emetine, the mutant parasites released the drug at approximately 1.6 times the rate of the wild-type organisms. We conclude that the emetine-resistant E. histolytica parasites have some but not all the features of the multidrug-resistant phenotype.
Comparison of the antibacterial effects of cefepime and ceftazidime against Escherichia coli in vitro and in vivo
Authors: Mattie H , Sekh B A , van Ogtrop M L , van Strijen E
Published: June 2012

The efficacies of cefepime and ceftazidime in an experimental Escherichia coli infection in granulocytopenic mice were related to their in vitro activities and their pharmacokinetic profiles. Cefepime had a higher intrinsic activity in vitro than ceftazidime, and it had a different pharmacokinetic profile, resulting in higher peak concentrations in plasma and a longer elimination half-life. To predict the antibacterial efficacy in vivo on the basis of in vitro activity and pharmacokinetics, we applied a mathematical model in which the in vitro effect is expressed as the difference in growth rate between control cultures and cultures grown in the presence of the antibiotic (ER), whereas the in vivo effect is given by the difference in the number of CFU between controls and antibiotic-treated animals (EN). The integral of ER over time, called ERt, was calculated by using in vivo concentrations. A significant linear relationship was found between EN and ERt for different doses at various times up to 4 h after administration, although the slope of this relationship was slightly but significantly less for cefepime (0.44) than for ceftazidime (0.59).
Activity of clarithromycin alone or in combination with other drugs for treatment of murine toxoplasmosis
Authors: Araujo F G , Prokocimer P , Lin T , Remington J S
Published: June 2012

The activity of the macrolide antibiotic clarithromycin was examined alone or in combination with other drugs for the treatment of acute or chronic infections with Toxoplasma gondii in mice. A dose of 300 mg of clarithromycin per kg per day administered alone for 10 days, beginning 24 hours after infection, protected 10 to 30% of mice infected with lethal inocula of tachyzoites or tissue cysts of different strains of T. gondii, including some strains isolated from patients with both AIDS and toxoplasmosis. Although clarithromycin was protective, a wide variation in its activity against different strains was observed. Survival of infected mice was increased significantly by treatment with clarithromycin in combination with pyrimethamine or with sulfadiazine. Treatment of chronically infected mice with clarithromycin at 300 mg/kg/day administered alone for 8 weeks resulted in significant reduction in the numbers of T. gondii cysts in their brains. The combination of clarithromycin and minocycline resulted in an activity against T. gondii cysts that was significantly greater than the activity of clarithromycin or minocycline administered alone. These results indicate a role for clarithromycin in the treatment of human toxoplasmosis, particularly when this antibiotic is used in combination with other drugs with activity against T. gondii.
Synergy of itraconazole with macrophages in killing Blastomyces dermatitidis
Authors: Brummer E , Bhagavathula P R , Hanson L H , Stevens D A
Published: June 2012

We examined in vitro interaction between the azole antifungal agents itraconazole and ketoconazole and macrophages and their activities against Blastomyces dermatitidis. Fungistatic and fungicidal concentrations for B. dermatitidis in vitro were assessed in a microculture system in which fungistasis was measured as inhibition of multiplication and fungicidal activity was measured as reduction of inoculum CFU. Resident peritoneal murine macrophages, which surround but do not phagocytize the fungus, were not fungicidal for B. dermatitidis isolates but were fungistatic for some isolates studied. Synergy was demonstrated when fungistatic concentrations (e.g., 0.01 micrograms/ml) of itraconazole, which limited growth 55% compared with that of controls, were cocultured with macrophages; this resulted in fungicidal activity (85% killing) against B. dermatitidis (ATCC 26199) in 72-h assays. This synergy could occur even if itraconazole was added after the macrophages had surrounded the fungus. Ketoconazole at fungistatic concentrations did not act synergistically with macrophages to kill B. dermatitidis. Lymph node lymphocytes could not substitute for macrophages in synergy with itraconazole to kill B. dermatitidis. When B. dermatitidis was separated by a filter from macrophages in Transwell cultures, fungicidal synergy with itraconazole was less efficient. Pretreatment of B. dermatitidis with itraconazole for 24 h did not render the fungus susceptible to killing by macrophages in the absence of itraconazole, whereas pretreatment of nonfungistatic macrophages with itraconazole rendered them fungistatic in a dose-dependent manner. Three other isolates were killed by otherwise fungistatic concentrations of itraconazole when the isolates were cocultured with macrophages. These findings indicate that one basis for the efficacy of itraconazole versus ketoconazole in treating blastomycosis could be synergy of a fungistatic concentration of itraconazole with macrophages in killing of B. dermatitidis.
Lesions and preferential initial localization of [S-methyl-3H]bleomycin A2 on Saccharomyces cerevisiae cell walls and membranes
Authors: Moore C W , Del Valle R , McKoy J , Pramanik A , Gordon R E
Published: June 2012

Extensive lesions were produced in cell walls of Saccharomyces cerevisiae by the bleomycin family of anticancer antibiotics (30 min to 4 h). Electron micrographs revealed that the alterations were most frequently large breaks and small interruptions or holes in cell walls, which sometimes extended into cell membranes. Large portions of cell walls were sometimes lost. Cell walls were frequently ruptured in one or more positions. More than 75% of bud scar regions in single-plane sections and all bud scars in serial sections exhibited many interruptions and breaks after 3 or 4 h of treatment. The discovery of extensive damage to cell walls was consistent with the preferential (approximately 70%) association of radiolabeled bleomycin with cell walls and perimeters of bud scar regions after short exposures (30 min). After longer exposures, the distribution of silver grains changed from a predominant association with cell walls (30 min) to an increased association with the cell cytoplasm (1 to 4 h). This correlated with increased ultrastructural damage, since damage to cell walls was generally more frequent and more severe with increasing length of treatment (30 min to 4 h) or dose (25 to 100 micrograms/ml). Although DNA lesions are believed to be the lethal properties of bleomycins, the lesions produced in cell walls are also lethal properties of the antibiotics. The distributions of lesions on cell walls suggested a generalized interaction of the antibiotic with a cell wall component. These results led us to hypothesize a mechanism of effective antifungal action for the bleomycin family of antibiotics.
In vitro demonstration of transport and delivery of antibiotics by polymorphonuclear leukocytes
Authors: Frank M O , Sullivan G W , Carper H T , Mandell G L
Published: June 2012

Several antibiotics are concentrated inside polymorphonuclear leukocytes (PMN). To investigate whether PMN could act as vehicles for delivery of antibiotics, we combined an assay measuring PMN chemotaxis under agarose with a bioassay measuring levels of antibiotic in agar. Double-layer plates were made by pouring a layer of chemotaxis agarose into tissue culture plates and then adding a thin layer of Trypticase soy agar. Neutrophils were incubated with antibiotic for 1 h and then were washed and placed in wells made in the plates. After allowing PMN to migrate under the agar toward a chemoattractant well containing formyl-methionine-leucine-phenylalanine for 3 h, Streptococcus pyogenes was streaked on top of the agar and grown overnight. PMN migration and zones of inhibition of bacterial growth were measured. Neutrophils migrated 2.51 +/- 0.16 mm toward the chemoattractant well and 1.48 +/- 0.12 mm toward the medium well; migration was not significantly affected by any of the antibiotics used. Plates with PMN incubated without antibiotic showed insignificant inhibition of bacterial growth toward chemoattractant and medium wells (0.38 +/- 0.18 and 0.14 +/- 0.12 mm, respectively; for both, P > 0.05 for difference from 0). PMN incubated with oxacillin (3 micrograms/ml), a drug not concentrated in PMN, caused a similar lack of inhibition (0.28 +/- 0.09 mm toward chemoattractant; 0.14 +/- 0.03 mm toward medium). Incubation with 30 microns of ciprofloxacin per ml resulted in inhibition that was similar in both directions (1.40 +/- 0.16 versus 1.18 +/- 0.13 mm). However, for PMN incubated with azithromycin (3 micrograms/ml), an agent highly concentrated inside phagocytes, there was a large degree of inhibition which was significantly greater in the direction of chemoattractant than in the direction of medium (3.47 +/- 0.30 versus 1.89 +/- 0.25 mm; P < 0.001), indicating that release of bioactive azithromycin by neutrophils occurred after migration. Likewise, after incubation with rifampin (10 micrograms/ml), which is also concentrated by PMN, inhibition was significantly greater in the direction of chemoattractant than in the direction of medium (1.54 +/- 0.24 versus 0.81 +/- 0.28 mm; P = 0.001). We conclude that for certain antibiotics, PMN may act as vehicles for transport and delivery of active drug to sites of infection.
In vitro susceptibilities of Actinobacillus actinomycetemcomitans to a number of antimicrobial combinations
Authors: Pavicić M J , van Winkelhoff A J , de Graaff J
Published: June 2012

The in vitro susceptibilities of Actinobacillus actinomycetemcomitans to 14 antimicrobial combinations were studied by using the checkerboard titration technique. The results, expressed as the range of the fractional inhibitory concentration indices, were as follows: for metronidazole or its hydroxymetabolite combined with cefixime, 0.2 to 0.6; for moxalactam, 0.2 to 0.6; for penicillin G, 0.3 to 0.6; for tobramycin, 0.8 to 2.0; for erythromycin, 0.8 to 1.7; for ciprofloxacin, 0.2 to 0.6; for tetracycline, 0.8 to 1.2. Our observations indicated that the beta-lactam antibiotics as well as ciprofloxacin act synergistically with both metronidazole and its hydroxymetabolite against A. actinomycetemcomitans. Synergistic interactions were independent of the individual MICs of the antibiotics tested. Erythromycin, tobramycin, and tetracycline combined with either metronidazole or its hydroxymetabolite showed additive to indifferent effects against the five strains of A. actinomycetemcomitans, with the fractional inhibitory concentration indices ranging from 0.8 to 2.0. A. actinomycetemcomitans was found to be highly susceptible to ciprofloxacin (MIC of ciprofloxacin for 90% of strains tested, 0.010 micrograms/ml) and cefixime (MIC of cefixime for 90% of strains tested, 0.8 micrograms/ml). The results indicate that in patients who are allergic to penicillin, cefixime and ciprofloxacin may be useful alternative antibiotics in combination with metronidazole for the treatment of A. actinomycetemcomitans-associated periodontitis.
3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors
Authors: Larder B A
Published: June 2012

Nonnucleoside reverse transcriptase (NNRT) inhibitors (R82913; (+)-S-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)- imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione; Cl-TIBO; and BI-RG-587, nevirapine) were used to select resistant human immunodeficiency virus type 1 (HIV-1) variants by passage in cell cultures of wild-type or 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant strains. Similar to other NNRT inhibitors, Cl-TIBO induced a single mutation (Y181 to C) in reverse transcriptase (RT) that accounted for the resistance. BI-RG-587 induced a different mutation (V106-->A) in AZT resistance backgrounds. A series of viable HIV-1 variants was constructed by site-directed mutagenesis of the RT, which harbored multiple drug resistance mutations, including Y181 to C. HIV-1 that was co-resistant to NNRT inhibitors and 2',3'-dideoxyinosine resulted when a 2',3'-dideoxyinosine resistance mutation (L74 to V) was also present in RT. By contrast, however, the Y181 to C mutation in an AZT resistance background significantly suppressed resistance to AZT, while it conferred resistance to NNRT inhibitors. However, the V106-->A substitution did not cause suppression of preexisting AZT resistance. Since certain combinations of nucleoside analogs and NNRT inhibitors might result in the development of co-resistance, careful analysis of clinical isolates obtained during combination therapy will be needed to determine the potential significance of these observations.
Pharmacokinetics of cefepime dihydrochloride arginine in subjects with renal impairment
Authors: Cronqvist J , Nilsson-Ehle I , Oqvist B , Norrby S R
Published: June 2012

In this study, the safety, tolerance, and pharmacokinetics of a single 1-g intravenous dose of cefepime (BMY-28142) were investigated. Twenty-three volunteers with various degrees of renal function were assigned to four trial groups according to glomerular filtration rates (GFR). Group IV consisted of five patients with end-stage renal disease undergoing treatment with hemodialysis. Cefepime concentrations in samples from plasma, urine, and infusion solutions were assayed with high-pressure liquid chromatography. The volume of distribution corresponded to the assumed extracellular fluid volume and did not differ significantly between the four groups. The area under the concentration-time curve increased as renal function decreased; in group II (GFR, 31 to 80 ml/[min x 1.73 m2]; n = 6), it was already three times higher than in group I (GFR, > or = 80 ml/[min x 1.73 m2]; n = 5). Mean residence time was 2.4, 6.8, 11.4, and 31.6 h for the four groups, respectively. Total clearance decreased (97.2, 34.6, 19.8, and 6.3 ml/[min x 1.73 m2]) with decreasing renal function, and a linear relationship between total plasma clearance and GFR was found with the regression equation y = 0.92x-2.0 (r = 0.991). Renal clearance was linearly correlated to GFR with the regression equation y = 0.87x-6.1 (r = 0.989), indicating that renal elimination is mainly by glomerular filtration. During hemodialysis, the extraction ratios were between 0.40 and 0.65. Dialysis clearance varied between 69.9 and 94.6 ml/(min x 1.73 m2).
Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin
Authors: O'Reilly T , Kunz S , Sande E , Zak O , Sande M A , Täuber M G
Published: June 2012

We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.
Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor
Authors: Bacchi C J , Nathan H C , Yarlett N , Goldberg B , McCann P P , Bitonti A J , Sjoerdsma A
Published: June 2012

The compound 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL73811), a potent inhibitor of S-adenosylmethionine decarboxylase, was effective in mice against six of eight clinical isolates of Trypanosoma brucei rhodesiense, the causative agent of East African sleeping sickness. In combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl), MDL73811 acted synergistically to cure seven of eight infections. MDL73811 was effective when given singly at 50 to 100 mg/kg of body weight per day for 7 days (osmotic pumps). In combination with subcurative DFMO levels (0.25 to 1.0% in drinking water for 7 days), the curative MDL73811 dose could be lowered to 25 or 50 mg/kg, depending on the isolate. Oral administration of the MDL73811-DFMO combination was also effective in an acute infection and in a long-term central nervous system model of Trypansoma brucei brucei infection. These data indicate that MDL73811 may be effective therapeutically in drug-refractory and late-stage East African trypanosomiasis.
Comparative study of penetration of lomefloxacin and ceftriaxone into transudative and exudative pleural effusion
Authors: Kimura M , Matsushima T , Nakamura J , Kobashi Y
Published: June 2012

We investigated the transpleural penetration of lomefloxacin (LFLX) and ceftriaxone (CTRX). LFLX (200 mg) was administered orally to three patients with transudative fluid and four with exudative fluid, and 2 g of CTRX was administered by drip infusion to four patients with transudative fluid and three with exudative fluid. For both groups that received LFLX and CTRX, blood samples were drawn at time zero and 1, 2, and 6 h after drug administration. Thoracocentesis of each group was performed at 6 h after drug administration. The mean ratios of concentrations in pleural fluid/maximum concentrations in serum (P/S max) of LFLX were 66% in patients with transudative fluid and 69% in patients with exudative fluid. The mean ratios of P/S max of CTRX were 9.1% in patients with transudative fluid and 13.5% in patients with exudative fluid. The P/S max ratios for the penetration of LFLX were five to six times higher than those for CTRX. In addition, there was less differentiation in concentrations of LFLX in pleural fluid between the transudative and exudative effusions than there was in the concentrations of CTRX.