bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo activities of Q-35, a new fluoroquinolone, against Mycoplasma pneumoniae
Authors: Gohara Y , Arai S , Akashi A , Kuwano K , Tseng C C , Matsubara S , Matumoto M , Furudera T
Published: June 2012

The in vitro potency and in vivo efficacy of Q-35, a new fluoroquinolone, against Mycoplasma pneumoniae were investigated by pharmacokinetic studies with M. pneumoniae-infected hamsters. By using fluoroquinolones, macrolides, and tetracyclines as references, Q-35 was found to possess the greatest mycoplasmacidal activity. The MIC for 90% of strains tested (MIC90) and the MIC50 were 0.78 and 0.39 microgram/ml, respectively, and the MBC for 90% of strains tested (MBC90) and the MBC50 were 3.13 and 0.78 microgram/ml, respectively. The MBC50-to-MIC50 ratio for Q-35 was 2. Furthermore, only Q-35 continued to be effective against 19 strains of erythromycin-resistant mutants of M. pneumoniae. The efficacies of fluoroquinolones against M. pneumoniae were also investigated by using an experimental hamster pneumonia model to measure the CFU of M. pneumoniae in the lungs. Q-35 and ofloxacin were efficacious following oral administration of 200 mg/kg/day for 5 days, initiated 24 h after infection, while ciprofloxacin was not active. Continuous administration of Q-35 for 10 days significantly reduced numbers of viable M. pneumoniae in the lungs. These results suggest that both Q-35 and ofloxacin are effective in the early phase of infection and, moreover, that Q-35 is also effective in the middle stage of infection, when progressive lung alterations and continuous increases in mycoplasmal growth occur. Peak levels of Q-35 in sera and lungs after oral administration were higher than those of ciprofloxacin but lower than those of ofloxacin. On the basis of these results, Q-35 appears to be a promising antimicrobial agent in chemotherapy of mycoplasmal infection.
Quinolones in treatment of human brucellosis: comparative trial of ofloxacin-rifampin versus doxycycline-rifampin
Authors: Akova M , Uzun O , Akalin H E , Hayran M , Unal S , Gür D
Published: June 2012

Quinolones have been reported to be active against Brucella species in vitro. In this prospective randomized study, the efficacy and safety of the combination of ofloxacin plus rifampin were compared with the efficacy and safety of doxycycline plus rifampin, both combinations administered for a 6-week period in treatment of brucellosis. Sixty-one patients were enrolled in the study, and 49 had blood or bone marrow cultures positive for Brucella melitensis. Thirty patients received 200 mg of doxycycline plus 600 mg of rifampin once daily, and 31 patients were treated with 400 mg of ofloxacin plus 600 mg of rifampin once daily for 6 weeks. Nine patients in each group had complications of the disease. There was one therapeutic failure in the ofloxacin-rifampin treatment group, and one patient from each group relapsed (3.3% of those in the doxycycline-rifampin treatment group versus 3.2% of those in the ofloxacin-rifampin treatment group). Gastric discomfort was the major side effect observed in 13 patients (43.3%) who received doxycycline plus rifampin, whereas only 2 patients (6.5%) treated with ofloxacin plus rifampin complained of gastric irritation. These results suggest that the combination of ofloxacin plus rifampin administered for 6 weeks is as effective as doxycycline plus rifampin given for the same period, regardless of the presence of complications of the disease.
Comparative pharmacokinetics and serum bactericidal activities of SCE-2787 and ceftazidime
Authors: Paulfeuerborn W , Müller H J , Borner K , Koeppe P , Lode H
Published: June 2012

Ceftazidime and the new SCE-2787 are parenteral cephalosporins with a broad antimicrobial spectrum. Pharmacokinetics, serum bactericidal activities, and side effects were investigated in a randomized crossover study. A total of 12 healthy volunteers received a 20-min infusion of 1.5 g of SCE-2787 or 2.0 g of ceftazidime. Serum and urine concentrations were determined by the bioassay method and by high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) drug concentrations in serum at the end of infusion of SCE-2787 and ceftazidime were 124.4 +/- 23.8 and 233.1 +/- 54.1 mg/liter, respectively. The urine recovery of SCE-2787 was 87.8% +/- 5.5% of dose in 24 h and for ceftazidime was 85.8% +/- 6.3% of dose in 24 h. Metabolites of SCE-2787 could not be detected by HPLC in serum or urine. Pharmacokinetic parameters were calculated both with a noncompartmental analysis and on the basis of an open two-compartment model (drugs are administered into and eliminated from a central compartment only. However, reversible drug distribution from the central space occurs simultaneously into one peripheral space). The area under the concentration time curve from 0 h to infinity of SCE-2787 was 197.9 +/- 25.4 mg.h/liter, and that of ceftazidime was 334.2 +/- 40.0 mg.h/liter. SCE-2787 had a mean terminal half-life in the elimination phase of 109.0 +/- 15.3 min, while that of ceftazidime was 99.0 +/- 13.4 min. The volume of distribution at steady state of SCE-2787 was 17.1 +/- 1.6 liters/70 kg, and that of ceftazidime was 122.9 +/- 1.3 liters/70 kg. The mean residence time of SCE-2787 was 136.4 +/- 15.4 min, and that of ceftazidime was 122.9 +/- 12.7 min. The renal clearance per. 1.73 m2 of SCE-2787 was 103.1 +/- 12.3 ml/min, and that of ceftazidime was 80.6 +/- 13.2 ml/min. The serum bactericidal activities were measured with the microdilution method of Stratton and Reller (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. One hour after administration, we measured mean reciprocal bactericidal titers of SCE-2787 and ceftazidime, respectively, against Escherichia coli of 388 and 243, against Klebsiella pneumoniae of 395 and 138, against Pseudomonas aeruginosa of 13.0 and 12.7, and against Staphylococcus aureus of 32.2 and 4.0. No severe side effects were observed in this single drug administration.
Efficacy of micronized halofantrine in semi-immune patients with acute uncomplicated falciparum malaria in Cameroon
Authors: Fadat G , Louis F J , Louis J P , Le Bras J
Published: June 2012

Fifty subjects with acute uncomplicated falciparum malaria were treated orally with a new micronized formulation of halofantrine. The dose given corresponded to one-half the normal dose for the standard formulation. Parasitemia cleared in all subjects within 78 h. There was recrudescence of falciparum malaria in seven subjects after day 14. The mean +/- standard deviation clearance times of parasitemia and fever were 49.0 +/- 14.2 and 24.3 +/- 13.2 h, respectively. Other clinical symptoms related to malaria cleared within the first 3 days. Pruritus occurred in two subjects, back pain occurred in one subject, and diarrhea occurred in one subject; all of these symptoms were mild. Hematological and biochemical indices were not adversely affected by treatment except in five subjects in whom minor and transitory increases in aspartate aminotransferase and alanine aminotransferase were observed. Micronized halofantrine appears to be a safe, well-tolerated, and effective treatment for acute falciparum malaria in semiimmune patients.
Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the northeastern Thai-Cambodian border
Authors: Smithuis F M , van Woensel J B , Nordlander E , Vantha W S , ter Kuile F O
Published: June 2012

In 1991 and 1992, a prospective randomized trial was conducted on the northern Thai-Cambodian border. That trial compared the efficacy and tolerance of two mefloquine regimens for the treatment of uncomplicated Plasmodium falciparum malaria in an area with multi-drug-resistant P. falciparum. The resolution of fever and other symptoms was faster with high-dose mefloquine (25 mg/kg of body weight [M25 group; n = 68]) than with the conventional 15-mg/kg dose (M15 group; n = 71). There were no early treatment failures (days 7 to 9) in the M25 group, but there were 5 (7%) treatment failures in the M15 group (P = 0.03). The incidences of treatment failures by day 28 were 40% with the M15 group and 11% with the M25 group (P = 0.0004). By day 42, these values had risen to 50 and 27%, respectively (P = 0.01). The risk of treatment failure was highest in children (relative risk, 2.1; 95% confidence interval, 1.3 to 3.4) and patients with posttreatment diarrhea (relative risk, 2.0; 95% confidence interval, 1.3 to 3.1). Over half of the recrudescences in the M25 group occurred between days 28 and 42, whereas 17% of the recrudescences in the M15 group occurred between days 28 and 42 (P = 0.02). Thus, the sensitivity of assessment was significantly increased with longer follow-up. Treatment failure was associated with a delayed parasite clearance and an inadequate hematological recovery. Upper gastrointestinal side effects and dizziness were significantly more common in the M25 group, but overall, the high dose was relatively well tolerated, in particular by children. An increase in the dose to 25 mg/kg can prolong the therapeutic use of mefloquine in areas with multi-drug-resistant P.falciparum malaria where high-grade resistance to mefloquine is still rare.
Bleomycin increases amikacin and streptomycin resistance in Escherichia coli harboring transposon Tn5
Authors: Blazquez J , Martinez J L , Baquero F
Published: June 2012

The antitumor antibiotic bleomycin acts as a transcriptional inducer of the neo-ble-str operon of the transposon Tn5, increasing the resistance level to streptomycin and amikacin in Tn5-containing Escherichia coli. The mechanism may involve a recA-independent induction mediated by DNA damage.
Sequence analysis of PER-1 extended-spectrum beta-lactamase from Pseudomonas aeruginosa and comparison with class A beta-lactamases
Authors: Nordmann P , Naas T
Published: June 2012

We have determined the nucleotide sequence (EMBL accession number, Z 21957) of the cloned chromosomal PER-1 extended-spectrum beta-lactamase gene from a Pseudomonas aeruginosa RNL-1 clinical isolate, blaPER-1 corresponds to a 924-bp open reading frame which encodes a polypeptide of 308 amino acids. This open reading frame is preceded by a -10 and a -35 region consistent with a putative P. aeruginosa promoter. Primer extension analysis of the PER-1 mRNA start revealed that this promoter was active in P. aeruginosa but not in Escherichia coli, in which PER-1 expression was driven by vector promoter sequences. N-terminal sequencing identified the PER-1 26-amino-acid leader peptide and enabled us to calculate the molecular mass (30.8 kDa) of the PER-1 mature form. Analysis of the percent GC content of blaPER-1 and of its 5' upstream sequences, as well as the codon usage for blaPER-1, indicated that blaPER-1 may have been inserted into P. aeruginosa genomic DNA from a nonpseudomonad bacterium. The PER-1 gene showed very low homology with other beta-lactamase genes at the DNA level. By using computer methods, assessment of the extent of identity between PER-1 and 10 beta-lactamase amino acid sequences indicated that PER-1 is a class A beta-lactamase. PER-1 shares around 27% amino acid identity with the sequenced extended-spectrum beta-lactamases of the TEM-SHV series and MEN-1 from Enterobacteriaceae species. The use of parsimony methods showed that PER-1 is not more closely related to gram-negative than to gram-positive bacterial class A beta-lactamases. Surprisingly, among class A beta-lactamases, PER-1 was most closely related to the recently reported CFXA from Bacteroides vulgatus, with which it shared 40% amino acid identity. This work indicates that non-Enterobacteriaceae species such as P. aeruginosa may possess class A extended-spectrum beta-lactamase genes possibly resulting from intergeneric DNA transfer.
In vitro susceptibilities of rapidly growing mycobacteria to newer antimicrobial agents
Authors: Khardori N , Nguyen H , Rosenbaum B , Rolston K , Bodey G P
Published: June 2012

The in vitro antimicrobial susceptibilities of 42 isolates of rapidly growing mycobacteria (Mycobacterium fortuitum, M. chelonae, and Mycobacterium species [other than M. fortuitum and M. chelonae]) to nine quinolones, including newer agents, two new aminoglycosides, and an aminocyclitol (trospectomycin) were determined by a broth microdilution method. The new quinolones, PD 117596, PD 127391, and PD 117558, showed excellent in vitro activities against M. fortuitum (MICs for 90% of isolates [MIC90s], 0.06, 0.06, and 0.12 microgram/ml, respectively). The MIC90 of ciprofloxacin for M. fortuitum was 0.5 microgram/ml. Only 14 to 28% of isolates of M. chelonae were susceptible to various quinolones. Most isolates of all three species were susceptible to the new aminoglycosides SCH 21420 and SCH 22591. The MIC90s of trospectomycin were 8 micrograms/ml for M. chelonae, 32 micrograms/ml for Mycobacterium species, and > 64 micrograms/ml for M. fortuitum.
Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate beta enantiomers of cytidine analogs
Authors: Faraj A , Agrofoglio L A , Wakefield J K , McPherson S , Morrow C D , Gosselin G , Mathe C , Imbach J L , Schinazi R F , Sommadossi J P
Published: June 2012

(-)-beta-L-2',3'-Dideoxycytidine (L-ddC) and (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (L-FddC) have been reported to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in vitro. In the present study, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (L-FddCTP) were demonstrated to competitively inhibit HIV-1 reverse transcriptase (RT), with inhibition constants (KiS) of 2 and 1.6 microM, respectively, when a poly(rI).oligo(dC)10-15 template primer was used; in comparison Ki values for beta-D-2',3'-dideoxycytidine 5'-triphosphate (D-ddCTP) and beta-D-2',3'-dideoxy-5-fluorocytidine 5'-triphosphate (D-FddCTP) were 1.1 and 1.4 microM, respectively. Use of the mutant RT at position 184 (substitution of methionine to valine [M184V]), which is associated with resistance to beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), resulted in significant increases (50- to 60-fold) in Ki values for L-ddCTP and L-FddCTP, whereas the elevation in Ki values for D-ddCTP and D-FddCTP was moderate (2-fold). L-ddCTP and L-FddCTP did not inhibit human DNA polymerases alpha and beta up to 100 microM. In contrast, D-ddCTP and D-FddCTP inhibited human DNA polymerase beta, with Ki values of 0.5 and 2.5 microM, respectively. By using sequencing analysis, L-ddCTP and L-FddCTP exhibited DNA chain-terminating activities toward the parental HIV-1 RT, whereas they were not a substrate for the mutant M184V HIV-1 RT.L-ddC and L-FddC did not inhibit the mitochondrial DNA content of human cells up to a concentration of 10 microM, whereas D-ddC and D-FddC decreased the mitochondrial DNA content by 90% at concentrations of 1 and 10 microM, respectively. All of these results suggest that further development of L-ddC, and L-FddC in particular, is warranted as a possible anti-HIV candidate.
Susceptibilities of 123 strains of Xanthomonas maltophilia to eight beta-lactams (including beta-lactam-beta-lactamase inhibitor combinations) and ciprofloxacin tested by five methods
Authors: Pankuch G A , Jacobs M R , Rittenhouse S F , Appelbaum P C
Published: June 2012

This study evaluated the susceptibility of 123 Xanthomonas maltophilia strains to ticarcillin, ticarcillin-clavulanate, ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, imipenem, and ciprofloxacin by Kirby-Bauer disk, E test, and Sensititre dehydrated microdilution MIC and conventional agar dilution MIC methodology. Intermediate susceptibility breakpoints for members of the family Enterobacteriaceae were used. When results were analyzed as MICs for 50 and 90% of the strains tested and percentages of strains susceptible at the breakpoint, good correlation between the methods was observed, with ticarcillin-clavulanate clearly the most active beta-lactam by all four methods. However, when the various methods were compared with the agar dilution methodology by regression analysis, poor r2 values (0.3 to 0.7) were obtained for compounds with sufficient on-scale values to permit analysis. When the number of strains with log2 ratios of reference agar dilution MICs to test MICs of +3 to -3 were analyzed, correlation was also poor, with many major and very major discrepancies for all methods tested. Results obtained with time-kill studies of nine strains with discrepant ticarcillin-clavulanate MICs appeared to correlate best when compared at 24 h with agar dilution MICs. The concentration of ticarcillin-clavulanate required to reduce the colony count by > or = 2 log10 reduction values for eight of nine strains compared with that for growth controls was < or = 16.0/2.0 micrograms/ml at 6 h and ranged from 16.0/2.0 micrograms/ml to 128.0/2.0 micrograms/ml at 24 h. The susceptibility method of choice for X. maltophilia has not yet been standardized, but time-kill studies correlated best with agar dilution MICs.
Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites
Authors: Akahane K , Kimura Y , Tsutomi Y , Hayakawa I
Published: June 2012

The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)3- chain between norfloxacin and BPAA (flexible structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA.
Evaluation of OPC-17116 against important pathogens that cause respiratory tract infections
Authors: Wakebe H , Imada T , Yoneda H , Mukai F , Ohguro K , Ohmori K , Tamaoka H , Yabuuchi Y
Published: June 2012

The antibacterial activity of OPC-17116, a new fluoroquinolone antibacterial agent, against important pathogens that cause respiratory tract infections was evaluated in vitro and in vivo and compared with those of ciprofloxacin, ofloxacin, and norfloxacin. The pharmacokinetic profiles of OPC-17116 were studied in both mice and rats given the drug orally at doses of 50 and 40 mg/kg of body weight, respectively. OPC-17116 showed a high degree of distribution in the lung tissues of both species, with maximum concentrations of 29.6 and 32.0 micrograms/g, respectively. Furthermore, the drug concentrations in lung tissue were about 10 to 15 times greater than the concentrations in plasma. OPC-17116 showed potent antibacterial activity against such pathogens as Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, and Moraxella catarrhalis. The MICs of this compound for 90% of these organisms except methicillin-resistant S. aureus and P. aeruginosa ranged from < or = 0.006 to 0.78 microgram/ml. The in vitro antibacterial activity of OPC-17116 was reflected by the efficacy of a single oral dose against systemic bacterial infections in mice. OPC-17116 showed a superior effect against gram-positive bacteria, H. influenzae, and M. catarrhalis. In comparison with the other reference compounds, the efficacy of OPC-17116 was less than that of ciprofloxacin against K. pneumoniae and P. aeruginosa. OPC-17116 showed a greater therapeutic effect than the other drugs against experimental acute pneumonia caused by these organisms in mice or rats. This excellent therapeutic effect against respiratory tract infections may be a result of its high level of distribution in lung tissue.
Pharmacokinetics and distribution in tissue of FK-037, a new parenteral cephalosporin
Authors: Wise R , Andrews J M , O'Neill P , Jolley A , Fowler C , Rogge M C
Published: June 2012

A single 1-g or 2-g intravenous dose of the cephalosporin FK-037 was given over 30 min in a cross-over-designed study, to each of six healthy male volunteers, and the concentrations of the drug were measured in plasma and cantharides-induced blister fluid over the subsequent 12 h. Urine was collected over 24 h. After a washout period of 6 weeks, during which the blisters healed, the study was repeated at the other dose level. Following the 1-g dose, the mean peak concentration in plasma was 83.8 micrograms/ml, and after the 2-g dose it was 142.6 micrograms/ml. The mean peak concentrations in the inflammatory fluid were 37.9 and 63.3 micrograms/ml, respectively. The mean elimination half-lives from plasma and inflammatory fluid were 2.0 and 2.5 h, respectively, after 1 g and 2.0 h and 3.7 h, respectively, after 2 g. The amounts of penetration into inflammatory fluid (as assessed by ratios of areas under the concentration-time curves) were 109.9 and 110.5% following doses of 1 and 2 g, respectively. The proportions of the administered drug recovered in the urine by 24 h were 87.6 and 85.7%, respectively. Our results indicate that FK-037 should prove to be efficacious in the treatment of a wide range of systemic infections.
In vitro model to assess effect of antimicrobial agents on Encephalitozoon cuniculi
Authors: Beauvais B , Sarfati C , Challier S , Derouin F
Published: June 2012

We have developed a new micromethod to study the effect of drugs on microsporidia, using MRC5 fibroblasts infected by 10(5) spores of Encephalitozoon cuniculi. After 3 days of incubation with various concentrations of drugs, parasitic foci were counted in stained cultures. The inhibition of microsporidial growth exceeding 90% with albendazole (0.005 microgram/ml), fumagillin (0.001 microgram/ml), 5-fluorouracil (3 micrograms/ml), and sparfloxacin (30 micrograms/ml) was observed. Chloroquine, pefloxacin, azithromycin, and rifabutin were partially effective, at high concentrations. Arprinocid, metronidazole, minocycline, doxycycline, itraconazole, and difluoromethylornithine were not evaluable, since concentrations that inhibited microsporidia were also toxic for fibroblasts. Pyrimethamine, piritrexim, sulfonamides, paromomycin, roxithromycin, atovaquone, and flucytosine were ineffective. Our results confirm that albendazole and fumagillin have marked activity against E. cuniculi and show the antimicrosporidial activity of 5-fluorouracil and sparfloxacin. These data may form the basis for treatment of Encephalitozoon hellem and Septata intestinalis infections and represent an attempt to identify drugs effective against Enterocytozoon bieneusi.
Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux
Authors: Leonard P J , Rathod P K , Golin J
Published: June 2012

The yeast (Saccharomyces cerevisiae) PDR5 gene product encodes a 160-kDa protein related to the large ABC family of transporters, including the human MDR1 multidrug resistance p-glycoprotein. Loss of function mutations in PDR5 result in chloramphenicol hypersensitivity. A pdr5::Tn5 loss of function mutant exhibits a markedly impaired efflux of chloramphenicol compared with that of an isogenic PDR5 (wild-type) control.
In vitro activity of a new antifungal triazole, D0870, against Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus
Authors: Barchiesi F , Colombo A L , McGough D A , Fothergill A W , Rinaldi M G
Published: June 2012

We investigated the in vitro activity of a new antifungal triazole, D0870, against 100 Candida albicans isolates from the oral cavities of patients infected with human immunodeficiency virus by using a broth macrodilution method following the recommendations provided by the National Committee for Clinical Laboratory Standards (document M27-P). All of the isolates were chosen from C. albicans isolates already tested for fluconazole susceptibility by the procedure of the National Committee for Clinical Laboratory Standards. Fifty isolates were considered fluconazole susceptible (MICs, < or = 4 micrograms/ml), and 50 isolates were considered fluconazole resistant (MICs, > or = 8 micrograms/ml). The in vitro data demonstrated that D0870 had good activity against isolates tested; for 90% of all strains of C. albicans, MICs were 0.5 micrograms/ml. However, the D0870 MICs for the fluconazole-susceptible isolates were lower than those for the fluconazole-resistant isolates; MICs for 50 and 90% of the isolates tested were < or = 0.0078 and 0.06 micrograms/ml, respectively, for fluconazole-susceptible isolates and 0.25 and 2 micrograms/ml, respectively, for fluconazole-resistant isolates (P < 0.001). Our data suggest that this new triazole could represent a valid alternative in the treatment of oral candidiasis in human immunodeficiency virus-infected patients.
Ultrasonic enhancement of antibiotic action on gram-negative bacteria
Authors: Pitt W G , McBride M O , Lunceford J K , Roper R J , Sagers R D
Published: June 2012

The effect of gentamicin upon planktonic cultures of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, and Staphylococcus aureus was measured with and without application of 67-kHz ultrasonic stimulation. The ultrasound was applied at levels that had no inhibitory or bactericidal activity against the bacteria. Measurements of the MIC and bactericidal activity of gentamicin against planktonic cultures of P. aeruginosa and E. coli demonstrated that simultaneous application of 67-kHz ultrasound enhanced the effectiveness of the antibiotic. A synergistic effect was observed and bacterial viability was reduced several orders of magnitude when gentamicin concentrations and ultrasonic levels which by themselves did not reduce viability were combined. As the age of the culture increased, the bacteria became more resistant to the effect of the antibiotic alone. Application of ultrasound appeared to reverse this resistance. The ultrasonic treatment-enhanced activity was evident with cultures of P. aeruginosa and E. coli but was not observed with cultures of gram-positive S. epidermidis and S. aureus. These results may have application in the treatment of bacterial biofilm infections on implant devices, which infections are usually more resistant to antibiotic therapy.
Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women
Authors: Elhanan G , Tabenkin H , Yahalom R , Raz R
Published: June 2012

A randomized study was conducted to assess the clinical and microbiological efficacies of a single 3-g dose of fosfomycin trometamol for the treatment of uncomplicated lower urinary tract infections in women compared with a 5-day regimen of cephalexin at 0.5 g four times daily. One hundred twelve women, all of whom had documented infections with bacteria sensitive to both antibiotics, were included. Fifty-eight women received fosfomycin trometamol, and 54 women received cephalexin. The two groups did not differ in age, severity, or duration of current urinary tract infection, menstrual status, sexual activity, or use of contraceptives. Ninety percent of pathogens in the fosfomycin trometamol group and 81% in the cephalexin group were Escherichia coli (the difference is not significant [NS]). A clinical evaluation at the 5-day follow-up showed that 91% of the women in each group were free of symptoms, while five women in each group were considered therapy failures and were treated by another antibiotic course. A microbiological evaluation at the 5-day follow-up showed a 91% eradication rate in the fosfomycin trometamol group and an 83% eradication rate in the cephalexin group (NS). At the 1-month follow-up, a clinical evaluation demonstrated prolonged resolution in 86 and 78%, respectively, of the participating women (NS). A microbiological evaluation at 1 month demonstrated prolonged eradication in 47 (81%) women treated with fosfomycin trometamol and in 37 (68%) women treated with cephalexin (NS). Three and six women, respectively, had relapsed. No adverse reactions were reported by the fosfomycin trometamol-treated women, while three women treated with cephalexin reported mild adverse reactions but completed the study period. Fosfomycin trometamol in a single 3-g dose is as effective as a 5-day regimen of cephalexin for the treatment of uncomplicated lower urinary tract infection in women.
Antimicrobial resistance of Shigella isolates causing traveler's diarrhea
Authors: Vila J , Gascon J , Abdalla S , Gomez J , Marco F , Moreno A , Corachan M , Jimenez de Anta T
Published: June 2012

Shigella isolates were identified as a cause of traveler's diarrhea in 67 (10%) of 675 patients and were tested for resistance to seven antimicrobial agents in a comparative study with those causing nontraveler's diarrhea in Spain. Ampicillin and chloramphenicol resistance was more frequent in Shigella flexneri (60 and 46%, respectively) than in Shigella sonnei (32 and 18%, respectively) and in travel-related isolates (P < 0.05 and 0.04, respectively). Of S. sonnei isolates from patients with traveler's diarrhea, 73 and 54% showed tetracycline and trimethoprim-sulfamethoxazole resistance, respectively, compared with only 8% of isolates from patients without a history of travel to developing countries (P < 0.007 and P < 0.0002). Low-level resistance to cephalosporins was found, whereas quinolone-resistant strains were not detected among travel-related Shigella isolates. Thus, quinolones may be an effective alternative therapy for travel-related shigellosis.
Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus
Authors: Frick L W , Lambe C U , St John L , Taylor L C , Nelson D J
Published: June 2012

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.
Pharmacokinetic and pharmacodynamic activities of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar
Authors: Hyatt J M , Nix D E , Schentag J J
Published: June 2012

The serum bactericidal activity of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar (0.4 microgram/ml) was assessed with serum ultrafiltrates from five healthy volunteers receiving ciprofloxacin at 400 mg intravenously every 8 h. In addition, human serum was supplemented with ciprofloxacin to achieve a mean steady-state concentration (Css) that might be achieved in patients with renal failure, with total clearances of 3 to 4 liters/h (elimination rate constant, 0.08 h-1). The area under the inhibitory titer curve from 0 to 24 h (AUIC24) and the area under the bactericidal titer curve from 0 to 24 h (AUBC24) were both measured and predicted as the area under the concentration-time curve from 0 to 24 h (AUC24)/MIC and AUC24/MBC, respectively. We previously demonstrated that a breakpoint AUC24/MIC of 125 for ciprofloxacin had a significantly higher probability of treatment success than lower values, with 250 to 500 being optimal. Volunteer sera (mean Css, 1.55 to 2.48 micrograms/ml) achieved AUC24/MICs of 90 to 145. Supplemented serum (mean Css, 6.00 to 7.42 micrograms/ml) achieved AUC24/MICs of 350 to 450. Correlation coefficients for measured and predicted values of AUC24/MIC and AUC24/MBC were 0.826 and 0.941, respectively. The mean percent errors were not significantly different from zero for either AUIC24 or AUBC24 values (P > 0.1, P > 0.4). Time-kill curve studies were performed with low (1.55 to 2.48 micrograms/ml), intermediate (6.00 to 7.42 micrograms/ml), and high (15 to 25 micrograms/ml) concentrations of ciprofloxacin for the three organisms. At low concentrations (3 to 6 times the MIC) AUC24/MICs were <125 for two of five volunteers and the killing rates were considerably more rapid for P. aeruginosa than for S. pneumoniae or S.aureus. Intermediate concentrations (15 to 18 times the MIC) achieved optimal AUC24/MICs, and the killing rates were similar for the three organisms. A paradoxical decrease in the killing rate was seen at high concentrations (35 to 60 times the MIC). At clinically achievable concentrations, ciprofloxacin killed P. aeruginosa more rapidly than it did either S. pneumoniae or S. aureus.
Pharmacokinetics of the triazole antifungal agent genaconazole in healthy men after oral and intravenous administration
Authors: Mojaverian P , Radwanski E , Affrime M B , Cayen M N , Lin C C
Published: June 2012

The pharmacokinetics of genaconazole, a potent new difluorophenyl-triazole antifungal agent, was studied in 12 healthy male volunteers following a single oral or intravenous administration of the drug. In a randomized two-way crossover design, each volunteer received either two 50-mg genaconazole tablets orally or a parenteral preparation containing 100 mg of genaconazole given as a 30-min intravenous infusion. Both dosage regimens were well tolerated. Blood and urine samples were collected up to 10 days after drug administration. Concentrations of genaconazole in plasma and urine were determined by a specific high-performance liquid chromatography assay with a limit of quantitation of 0.1 microgram/ml. Pharmacokinetic evaluation following oral and intravenous doses indicated that mean values for the area under the concentration-time curve from 0 h to infinity (137 and 136 micrograms.h/ml), half-life (50 and 49 h), volume of distribution (52 and 52 liters), and clearance (12 and 12 ml/min) were independent of the route of drug administration. The oral and intravenous administrations of genaconazole yielded virtually superimposable plasma concentration-time curves, resulting in an absolute bioavailability of 100%. Amounts of unchanged genaconazole found in urine samples from 0 to 240 h after oral and intravenous doses were comparable, and urinary excretion accounted for 76 and 78% of the administered dose, respectively. Renal clearances for the two routes of administration were also similar, and renal clearance accounted for over 80% of the total body clearance. The 100% absolute bioavailability of genaconazole regardless of the route of administration provides greater dosing flexibility in various clinical settings than currently exists.
Quantification, qualification, and microbial killing efficiencies of antimicrobial chlorine-based substances produced by iontophoresis
Authors: Davis C P , Shirtliff M E , Trieff N M , Hoskins S L , Warren M M
Published: June 2012

The dependence of microbial killing on chloride ions present in solutions undergoing iontophoresis is addressed. A 400-microA current was applied to vials containing synthetic urine or saline, and the production of chlorine-based substances (CBSs) was detected by the N,N-diethyl-p-phenylene diamine colorimetric method. It was found that as the time of current application increased, the total concentration of CBSs also increased. The iontophoretic current converted (through oxidation) chloride ions present in the solutions into CBSs such as free chlorine, chlorine dioxide, chlorite, monochloramine, and dichloramine (the last two were produced by iontophoresis only when nitrogenous substances were present in the solution). Two of the CBSs (free Cl and ClO2), when they were separately added back to microbial suspensions (approximately 3 x 10(5) CFU/ml) at the same concentrations at which they were detected in either 0.46% (wt/vol) NaCl solution or synthetic urine iontophoresed for 4 h at 400 microA, reduced or eliminated bacterial genera and a fungus. However, when free Cl and ClO2 were jointly added back to microbial suspensions, bacterial and fungal killing was synergistic and more rapid and complete than when these chlorine-based biocides were added separately. Therefore, iontophoresis of solutions containing chloride ions produces chlorine-based biocides that are responsible for the antimicrobial effect of iontophoresis.
Extended-spectrum beta-lactamases in clinical isolates of Enterobacter gergoviae and Escherichia coli in China
Authors: Cheng Y , Chen M
Published: June 2012

Resistance to ceftazidime, detected in isolates of Escherichia coli 5518 and Enterobacter gergoviae 3773 from our hospital, was transferred, together with resistance to aminoglycosides, trimethoprim, sulfonamide, and other beta-lactam antibiotics, by conjugation to E. coli JP559. Both E. coli transconjugants were resistant to ampicillin, all cephalosporins, and aztreonam but remained susceptible to cefoxitin and imipenem. The enzymes of the two transconjugant strains readily hydrolyzed cephalosporins in a spectrophotometric assay. Hybridization results suggested that the extended-spectrum beta-lactamase produced by E. coli 5518 was a non-TEM, non-SHV enzyme, the origin of which is currently unknown. The beta-lactamase produced by E. gergoviae 3773 was of the SHV type and was further proved to be SHV-2 by DNA sequencing. Thus, extended-spectrum beta-lactamases are occurring in China as well as in other parts of the world.
Effects of antifungal agent combinations administered simultaneously and sequentially against Aspergillus fumigatus
Authors: Maesaki S , Kohno S , Kaku M , Koga H , Hara K
Published: June 2012

The in vitro effects of antifungal agent combinations administered simultaneously and sequentially against 15 strains of Aspergillus fumigatus were tested by the yeast-malt broth method. The synergistic effect of the combination of amphotericin B (AMPH) and miconazole was observed in nine strains (60%). However, the combinations of AMPH and fluconazole, AMPH and ketoconazole, and AMPH and itraconazole administered simultaneously showed antagonistic effects against three (20%), five (34%), and four (26%) strains, respectively. The effects of combinations of azole antifungal agents administered simultaneously were indifferent or antagonistic against A. fumigatus. In experiments measuring the effects of sequentially administered antifungal agents, however, pretreatment with AMPH and then azole antifungal agents exhibited better in vitro efficacy than that found in experiments measuring the effects of simultaneously administered AMPH and azole compounds.
Characterization of the PNT1 pentamidine resistance gene of Saccharomyces cerevisiae
Authors: Ludewig G , Staben C
Published: June 2012

The Saccharomyces cerevisiae PNT1 gene was isolated and characterized. When present in high copy number in S. cerevisiae, PNT1 confers resistance to the anti-Pneumocystis carinii drug pentamidine. The PNT1 gene encodes a previously uncharacterized polypeptide of 409 amino acids. The predicted gene product is a very basic (pI 9.9) polypeptide with one potential membrane-associated region. PNT1 is located on chromosome XVR of S. cerevisiae. It is transcribed at a very low level. Overexpression of the gene increases resistance to the cytostatic and mitochondrial DNA-damaging effects of pentamidine and related cationic compounds. Disruption of the gene leads to slightly increased levels of susceptibility to pentamidine and some related compounds.
New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs
Authors: Pauwels R , Andries K , Debyser Z , Kukla M J , Schols D , Breslin H J , Woestenborghs R , Desmyter J , Janssen M A , De Clercq E
Published: June 2012

Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces.
In vitro and in vivo antimycobacterial activities of a new quinolone, DU-6859a
Authors: Saito H , Tomioka H , Sato K , Dekio S
Published: June 2012

A new fluoroquinolone, DU-6859a, was studied for its in vitro and in vivo antimycobacterial activities. MIC determination by the agar dilution method with 7H11 medium revealed that DU-6859a had MICs at which 90% of M. kansasii (0.78 microgram/ml), M. marinum (1.56 micrograms/ml), M. scrofulaceum (1.56 micrograms/ml), M. fortuitum (0.39 microgram/ml), M. chelonae subsp. abscessus (6.25 micrograms/ml), and M. chelonae subsp. chelonae (1.56 micrograms/ml) were inhibited were 4 to 32 times lower than those of ofloxacin and sparfloxacin. The MICs of DU-6859a at which 90% of M. tuberculosis (0.2 microgram/ml) and M. avium-M. intracellulare complex (12.5 micrograms/ml each) were inhibited were comparable to those of sparfloxacin but were four- to eightfold lower than those of ofloxacin. Thus, DU-6859a possessed more potent in vitro activity than sparfloxacin and ofloxacin against most mycobacterial species. DU-6859a exerted significant efficacy against infections caused by M. intracellulare and M. chelonae subsp. abscessus induced in mice when it was given at a dose of 1 mg per mouse (ca. 50 mg/kg of body weight) in terms of reducing the frequency of occurrence and the degree of gross pulmonary or renal lesions and bacterial loads in the lungs, spleens, or kidneys. The efficacy of DU-6859a was greater than that of ofloxacin and was more pronounced against M. chelonae infections than against M. intracellulare infections.
In vitro and ex vivo effects of cyclosporin A on phagocytic host defenses against Aspergillus fumigatus
Authors: Roilides E , Robinson T , Sein T , Pizzo P A , Walsh T J
Published: June 2012

Because cyclosporin A (CsA) is extensively used as an immunosuppressive agent, its effects on phagocytic defenses against Aspergillus fumigatus were studied in vitro and ex vivo. After incubation with 10 to 250 ng of CsA per ml at 37 degrees C for 60 min, polymorphonuclear leukocytes (PMNs) exhibited unaltered superoxide anion (O2-) production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, whereas > or = 500 ng/ml significantly suppressed it (P < 0.01). Moreover, at < 250 ng of CsA per ml, PMNs exhibited no change in their capacity to damage unopsonized hyphae of A. fumigatus compared with controls, whereas at > or = 250 ng/ml, CsA suppressed the function (P < 0.01). Although neither CsA (250 ng/ml) nor hydrocortisone (10 micrograms/ml) suppressed PMN O2- production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, combination of the two agents reduced the function compared with that at the baseline (P < 0.05). Incubation of monocytes with 100 ng of CsA per ml for 1 or 2 days suppressed their antihyphal activity. No essential change in phagocytic activity of monocyte-derived macrophages (MDMs) against A. fumigatus conidia, tested as the percentage of phagocytosing MDMs and average number of MDM-associated conidia, was detected after 2 or 4 days of incubation with 10 to 1,000 ng of CsA per ml. Furthermore, in rabbits treated with CsA (up to 20 mg/kg of body weight per day intravenously for 7 days), neither O2- production and hyphal damage caused by PMNs or monocytes against hyphae nor phagocytosis of conidia by pulmonary alveolar macrophages was significantly suppressed. Thus, these results demonstrated that CsA within therapeutically relevant concentrations does not suppress antifungal activity of phagocytes except that of circulating monocytes. However, it may induce significant immunosuppression of phagocytes' antifungal function at relatively high concentrations in vitro, especially when combined with corticosteroids.