bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activities of meropenem, PD 127391, PD 131628, ceftazidime, chloramphenicol, co-trimoxazole, and ciprofloxacin against Pseudomonas cepacia
Authors: Lewin C , Doherty C , Govan J
Published: June 2012

In a study of 110 Pseudomonas cepacia isolates from patients without cystic fibrosis, the in vitro potencies of three new compounds, meropenem, PD 127391, and PD 131628, were comparable to those of ceftazidime and ciprofloxacin and exceeded those of chloramphenicol and co-trimoxazole. The MICs of ceftazidime, ciprofloxacin, meropenem, and the PD compounds for 90% of strains tested were < or = 4 micrograms/ml, whereas they were 32 micrograms/ml for chloramphenicol and co-trimoxazole. Data for 20 isolates from patients with cystic fibrosis indicated that the isolates were less susceptible to all seven antibiotics tested, with the most active compounds being meropenem and PD 127391.
In vitro antimicrobial production of beta-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferase by and susceptibility of clinical isolates of Acinetobacter baumannii
Authors: Vila J , Marcos A , Marco F , Abdalla S , Vergara Y , Reig R , Gomez-Lus R , Jimenez de Anta T
Published: June 2012

Antimicrobial susceptibility testing was performed on 54 epidemiologically unrelated clinical isolates of Acinetobacter baumannii by using a standard agar dilution technique. On the basis of the in vitro activities, imipenem and doxycycline were the most active agents, whereas amikacin, isepamicin, and the new fluorquinolones ciprofloxacin and ofloxacin presented moderate activity. Cephalosporinase activity was found in 98% of the strains, whereas lactamases of TEM type 1 and one with a pI of 7 to 7.5 were present in 16 and 11% of the strains, respectively. Resistance to aminoglycosides was explained by the production of the three classes of aminoglycoside-modifying enzymes, with predominance of aminoglycoside-3'-phosphotransferase VI in 28% of the strains.
Susceptibilities of beta-lactamase-producing and -nonproducing ampicillin-resistant strains of Haemophilus influenzae to ceftibuten, cefaclor, cefuroxime, cefixime, cefotaxime, and amoxicillin-clavulanic acid
Authors: Barry A L , Fuchs P C , Pfaller M A
Published: June 2012

In in vitro studies we evaluated the susceptibilities of beta-lactamase-producing and -nonproducing, ampicillin-resistant strains of Haemophilus influenzae and compared them with those of ampicillin-susceptible strains. Ampicillin, amoxicillin-clavulanic acid, ceftibuten, cefaclor, cefuroxime, cefixime, and cefotaxime were evaluated by broth microdilution tests and disk diffusion tests. The disk diffusion tests accurately categorized beta-lactamase-producing strains and ampicillin-susceptible strains as being susceptible to the study drugs other than ampicillin. Ampicillin-resistant, beta-lactamase-nonproducing strains were relatively resistant to all seven study drugs, but the disk diffusion test did not always predict that resistance. The clinical relevance of the decreased susceptibility to various agents remains unclear, but to be conservative, all ampicillin-resistant, beta-lactamase-nonproducing strains might be assumed to be resistant to other beta-lactams. After excluding that small group of isolates, reliable susceptibility test results were obtained with lots of Haemophilus Test Medium that met quality assurance criteria.
A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives
Authors: Sullivan V , Biron K K , Talarico C , Stanat S C , Davis M , Pozzi L M , Coen D M
Published: June 2012

Ganciclovir-resistant mutant 759rD100 derived from human cytomegalovirus strain AD169 contains two resistance mutations, one of which is in the UL97 gene and results in decreased ganciclovir phosphorylation in infected cells [V. Sullivan, C. L. Talarico, S. C. Stanat, M. Davis, D. M. Coen, and K. K. Biron, Nature (London) 358:162-164, 1992]. In the present study, we mapped the second mutation to a 4.1-kb DNA fragment containing the DNA polymerase gene and showed that it confers ganciclovir resistance without impairing phosphorylation. Sequence analysis of the 4.1-kb region revealed a single nucleotide change that resulted in a glycine-to-alanine substitution at position 987 within conserved region V of the DNA polymerase. Recombinant viruses constructed to contain the DNA polymerase mutation but not the phosphorylation defect displayed intermediate resistance (4- to 6-fold) to ganciclovir relative to the original mutant 759rD100 (22-fold); the recombinant viruses also displayed resistance to ganciclovir cyclic phosphate (7-fold), 1-(dihydroxy-2-propoxymethyl)-cytosine (12-fold), and the phosphonylmethoxyalkyl derivatives (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (8- to 10-fold). However, the recombinant viruses remained susceptible to certain related compounds. These results imply that the human cytomegalovirus DNA polymerase is a selective target for the antiviral activities of ganciclovir, certain of its derivatives and phosphonomethoxyalkyl derivatives; support a role for region V in substrate recognition; and suggest the possibility of clinical resistance of human cytomegalovirus to these compounds because of polymerase mutations.
Antiretroviral activities of protease inhibitors against murine leukemia virus and simian immunodeficiency virus in tissue culture
Authors: Black P L , Downs M B , Lewis M G , Ussery M A , Dreyer G B , Petteway S R , Lambert D M
Published: June 2012

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polyproteins in cultures of human immunodeficiency virus type 1 (HIV-1)-infected T lymphocytes and, as a result, inhibit the infectivity of HIV-1 for such cultures. The ability of HIV-1 protease inhibitors to suppress replication of the C-type retrovirus Rauscher murine leukemia virus (R-MuLV) and the HIV-related lentivirus simian immunodeficiency virus (SIV) was examined in plaque reduction assays and syncytium reduction assays, respectively. Three of seven compounds examined blocked production of infectious R-MuLV, with 50% inhibitory concentrations of < or = 1 microM. Little or no cellular cytotoxicity was detectable at concentrations up to 100 microM. The same compounds which inhibited the infectivity of HIV-1 also produced activity against SIV and R-MuLV. Electron microscopic examination revealed the presence of many virions with atypical morphologies in cultures treated with the active compounds. Morphometric analysis demonstrated that the active compounds reduced the number of membrane-associated virus particles. These results demonstrate that synthetic peptide analog inhibitors of retroviral proteases significantly inhibit proteolytic processing of the gag polyproteins of R-MuLV and SIV and inhibit the replication of these retroviruses. These results are similar to those for inhibition of HIV-1 infectivity by these compounds, and thus, R-MuLV and SIV might be suitable models for the in vivo evaluation of the antiretroviral activities of these protease inhibitors.
Cloning of a Streptomyces clavuligerus DNA fragment encoding the cephalosporin 7 alpha-hydroxylase and its expression in Streptomyces lividans
Authors: Xiao X , Hintermann G , Häusler A , Barker P J , Foor F , Demain A L , Piret J
Published: June 2012

A 26-mer DNA probe was designed from N-terminal sequence data for the cephalosporin 7 alpha-hydroxylase (CH) of Streptomyces clavuligerus NRRL 3585 and used to screen a DNA library from this organism. The library was constructed in the lambda GEM-11 phage system. After plaque purification and reprobing, positive recombinant phages were chosen for further analysis. Characterization of the cloned DNA by restriction mapping and Southern hybridization showed that a 1.5-kb SalI fragment hybridized to the probe. Polymerase chain reaction assays using this fragment as a template and the probe as a primer indicated that the fragment carries the entire putative CH gene (cmcI). This was confirmed through the expression of CH enzymatic activity when the fragment was introduced into Streptomyces lividans. A putative beta-lactamase activity was detected in S. lividans.
Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis
Authors: Stein G E , Mummaw N
Published: June 2012

Itraconazole is a new orally active triazole antifungal agent with enhanced activity against Candida species. In the clinical trial described in this paper, we compared the efficacy and safety of itraconazole capsules with those of clotrimazole vaginal tablets and placebo oral capsules for women with acute vulvovaginal candidiasis. Ninety-five patients were randomized in a 2:1:1 fashion to receive itraconazole (200 mg/day), clotrimazole (200 mg/day), or placebo (two capsules per day) for 3 consecutive days. Clinical success rates (cure and improvement) were similar for women who received itraconazole (96%) and clotrimazole (100%) 1 week posttreatment. These response rates were statistically superior to those obtained with placebo treatment (77%, P < 0.05). Negative mycological cultures were found in 95, 73, and 32% of the patients treated with clotrimazole, itraconazole, and placebo, respectively (P < 0.005) [active treatments versus placebo]). By 4 weeks posttreatment, the clinical failure rate for itraconazole was less than that observed for clotrimazole (17 versus 30%), but this difference did not reach statistical significance (P > 0.05; beta = 0.81). Mycological response rates for itraconazole and clotrimazole were also similar. No patients enrolled in this study discontinued treatment because of an adverse event. Minor side effects were reported by 35, 4, and 41% of patients who received itraconazole, clotrimazole, and placebo, respectively. The most common side effects associated with itraconazole therapy were nausea and headache. In summary, itraconazole was found to be as effective and safe as clotrimazole in women with acute candida vaginitis. Moreover, oral therapy was highly favored over intravaginal treatment in our survey of patients.
Analysis of the aac(3)-VIa gene encoding a novel 3-N-acetyltransferase
Authors: Rather P N , Mann P A , Mierzwa R , Hare R S , Miller G H , Shaw K J
Published: June 2012

Biochemical analysis (G. A. Papanicolaou, R. S. Hare, R. Mierzwa, and G. H. Miller, abstr. 152, Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother., 1989) demonstrated the presence of a novel 3-N-acetyltransferase in Enterobacter cloacae 88020217. This organism was resistant to gentamicin, and the MIC of 2'-N-ethylnetilmicin for it was fourfold lower than that of 6'-N-ethylnetilmicin, a resistance pattern which suggested 2'-acetylating activity. However, high-pressure liquid chromatography analysis demonstrated that the enzyme acetylated sisomicin in the 3 position. We have cloned the structural gene for this enzyme from a large (> 70-kb) conjugative plasmid present in E. cloacae. Subcloning experiments have localized the aac(3)-VIa gene to a 2.1-kb Sau3A fragment. The deduced AAC(3)-VIa protein showed 48% amino acid identity to the AAC(3)-IIa protein and 39% identity to the AAC(3)-VII protein. Examination of the 5'-flanking sequences demonstrated that the aac(3)-VIa gene was located 167 bp downstream of the aadA1 gene and was present in an integron. In addition, the aac(3)-VIa gene is also downstream of a 59-base element often seen in an integron environment. Primer extension analysis has identified a promoter for the aac(3)-VIa gene downstream of both the aadA1 gene and a 59-base element.
Antimicrobial activity of DV-7751a, a new fluoroquinolone
Authors: Tanaka M , Hoshino K , Ishida H , Sato K , Hayakawa I , Osada Y
Published: June 2012

We compared the in vitro antibacterial activity of DV-7751a against gram-positive and -negative bacteria with those of quinolones currently available. MICs for 90% of the strains tested (MIC90s) against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis were 0.20, 0.39, 0.20, and 0.78 micrograms/ml, respectively. Moreover, MIC50s for DV-7751a against ofloxacin-resistant methicillin-resistant S. aureus were 4-, 8-, 16-, 32-, and 64-fold lower than those for tosufloxacin and sparfloxacin, levofloxacin, ofloxacin and fleroxacin, ciprofloxacin, and lomefloxacin, respectively. DV-7751a inhibited the growth of all strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Peptostreptococcus spp. at 0.39, 0.39, and 0.78 micrograms/ml, respectively, and was 4- to > 16-fold more active against enterococci at the MIC90 level than the other quinolones tested. The activity of DV-7751a against Pseudomonas aeruginosa was roughly comparable to those of levofloxacin and sparfloxacin at the MIC90 level and was two- to fourfold less than that of ciprofloxacin. DV-7751a showed activity comparable to those of levofloxacin and ciprofloxacin against the other glucose-nonfermenting bacteria Haemophilus influenzae, Neisseria gonorrhoeae, and Moraxella catarrhalis (MIC90s of 0.025, 0.20, and 0.10 micrograms/ml, respectively). DV-7751a activity was not affected by medium, inoculum size, or the addition of human serum but was decreased under acidic conditions and in human urine, as were the other quinolones tested. Time-kill curve studies demonstrated the rapid bactericidal action of DV-7751a against S. aureus, S. pneumoniae, Escherichia coli, and P. aeruginosa. The frequency of spontaneous resistance to DV-7751a was less than or equal to those of the reference drugs. DV-7751a inhibited the supercoiling activity of DNA gyrases from S. aureus, E. coli, and P. aeruginosa at concentrations comparable to those of levofloxacin and sparfloxacin.
Effects of standard breakfast on pharmacokinetics of oral zidovudine in patients with AIDS
Authors: Ruhnke M , Bauer F E , Seifert M , Trautmann M , Hille H , Koeppe P
Published: June 2012

The influence of a standard breakfast on the single-dose pharmacokinetics of zidovudine (AZT) after oral administration of 100 and 250 mg of AZT was studied in 27 subjects with advanced human immunodeficiency virus infection (Centers for Disease Control stage IV). Concentrations of AZT and the 5'-glucuronide metabolite (GAZT) in serum and urine were measured by a high-pressure liquid chromatographic method. Pharmacokinetic analysis was done by an open one-compartment model as well as noncompartmentally. The results were summarized as medians with 50% confidence ranges because of the high degree of interindividual variability. Peak levels in plasma were moderately reduced after administration of 100 mg AZT in the nonfasting group (1.79 mumol/liter in the fasting group [F], 1.12 mumol/liter in the group that received breakfast [B]) and were markedly reduced after administration of 250 mg AZT (6.51 mumol/liter [F], 1.79 mumol/liter [B]). The terminal half-life in plasma was prolonged almost twofold after breakfast with 100 and 250 mg of AZT (100 mg, 36.4 min [F] and 51.6 min [B]; 250 mg, 35.3 min [F] and 63.6 min [B]). Recoveries (AZT and GAZT) in urine varied with both dosages, reflecting more a problem of accounting for the metabolite GAZT in urine than a relevant difference (100 mg, 115% [F] and 76.5% [B]; 250 mg, 71% [F] and 99.4% [B]). Our data suggest that absorption of AZT in human immunodeficiency virus-infected subjects is extremely variable, with a high degree of interindividual differences. Furthermore, breakfast had a marked influence on the absorption of AZT, suggesting that the drug should be taken in a fasting state.
Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide
Authors: Tanaka M , Kurata T , Fujisawa C , Ohshima Y , Aoki H , Okazaki O , Hakusui H
Published: June 2012

The mechanisms of reduction in absorption of levofloxacin (LVFX) by coadministration of aluminum hydroxide were studied. The partition coefficient of LVFX (0.1 mM) between chloroform and phosphate buffer (pH 5.0) was reduced by 60 to 70% with the addition of metal ions such as Cu2+, Al3+, and Fe2+ (0.8 mM), which indicated the formation of LVFX-metal ion chelates. However, there was no significant difference in absorption from rat intestine between the synthetic LVFX-Al3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, Al(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20% of the control in the in situ ligated loop experiment, in which partial precipitation of aluminum hydroxide was observed in the dosing solution. Data for adsorption of LVFX and ofloxacin (OFLX) from aqueous solution by aluminum hydroxide were shown to fit Langmuir plots, and the adsorptive capacities (rmax) and the K values were 7.0 mg/g and 1.77 x 10(4) M-1 for LVFX and 7.4 mg/g and 1.42 x 10(4) M-1 for OFLX, respectively. The rate of adsorption of several quinolones (50 microM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.0%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) approximately LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) approximately OFLX (20.9%) approximately ENX (18.3%) > NFLX (11.9%). These results strongly suggest that adsorption of quinolones by aluminum hydroxide reprecipitated in the small intestine would play an important role in the reduced bioavailability of quinolones after coadministration with aluminum-containing antacids.
High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase
Authors: Boucher C A , Cammack N , Schipper P , Schuurman R , Rouse P , Wainberg M A , Cameron J M
Published: June 2012

Passage of human immunodeficiency virus type 1 in the presence of increasing 2'-deoxy-3'-thiacytidine (3TC) concentrations results in high-level (> 100-fold) 3TC-resistant viruses. All 3TC-resistant viruses possess a substitution at the second codon (from a methionine into an isoleucine) at position 184 within the highly conserved motif (YMDD) of human immunodeficiency virus type 1 reverse transcriptase. 3TC-resistant viruses were cross-resistant to the (-) enantiomer of the fluorinated derivative of BCH-189 but remained susceptible to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. The susceptibilities of the 3TC-resistant viruses to the (+) enantiomers of BCH-189 and the fluorinated derivative of BCH-189 demonstrate an enantiomeric specificity for viruses selected under these conditions. Introduction of an isoleucine substitution at codon 184 into a background of two known 3'-azido-3'-deoxythymidine resistance mutations (amino acids 41 and 215) restored the susceptibility of this virus to 3'-azido-3'-deoxythymidine.
Inhibition of host cell invasion and intracellular replication of Trypanosoma cruzi by N,N'-bis(benzyl)-substituted polyamine analogs
Authors: Majumder S , Kierszenbaum F
Published: June 2012

We studied the effects of two N,N'-bis(benzyl)-substituted polyamine analogs on the capacities of Trypanosoma cruzi to invade and multiply within a mammalian host cell. At concentrations as low as 1 microM, these compounds reduced significantly the infectivity of the parasite for rat heart myoblasts in a time-dependent manner. Pretreatment of virulent T. cruzi trypomastigotes, but not myoblast pretreatment, reduced the level of infectivity. The inhibitory effects started to subside 3 h after removal of the drugs and were no longer detectable after 4 h. A significant decrease in the rate of intracellular amastigote multiplication was also seen when the drugs were added to myoblast cultures which had been previously infected with untreated T. cruzi. These results show that N,N'-bis(benzyl)-substituted polyamine analogs meet the two most important criteria for potential chemotherapeutic agents against T. cruzi infection, namely, inhibition of both host cell invasion and intracellular replication by this parasite.
Antibacterial activities of OPC-17116, ofloxacin, and ciprofloxacin against 200 isolates of Neisseria gonorrhoeae
Authors: Zenilman J M , Neumann T , Patton M , Reichart C
Published: June 2012

OPC-17116 is a new fluoroquinolone with potent activity against aerobic and anaerobic organisms. We evaluated the susceptibilities of 200 clinical gonococcal isolates including organisms with plasmid and chromosomally mediated resistance to beta-lactams and tetracycline. The antibiotics studied included OPC-17116, ofloxacin, ciprofloxacin, penicillin, tetracycline, erythromycin, azithromycin, and ceftriaxone. All isolates tested were susceptible to the quinolone class of antibiotics. The MICs of ciprofloxacin, ofloxacin, and OPC-17116 for 90% of isolates tested were 0.004, 0.03, and 0.004 micrograms/ml, respectively. For organisms with chromosomally mediated resistance to penicillin and tetracycline, geometric mean MICs of all antibiotics including the quinolones were increased.
Efficacy of itraconazole solution in a rabbit model of invasive aspergillosis
Authors: Patterson T F , Fothergill A W , Rinaldi M G
Published: June 2012

The efficacy of an itraconazole-cyclodextrin solution against Aspergillus fumigatus was assessed in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral itraconazole solution at dosages of 20 and 40 mg/kg/day improved survival as compared with that of controls. Itraconazole (40 mg/kg/day) not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues and was as effective as amphotericin B in these studies. The higher dose of itraconazole produced higher levels in serum, which correlated with improved efficacy of the drug. This itraconazole-cyclodextrin solution was well absorbed and was effective in the treatment of experimental invasive aspergillosis; it demonstrates the potential of this class of agents in improving therapy for invasive aspergillosis.
In vitro and in vivo antifungal activities of D0870, a new triazole agent
Authors: Yamada H , Tsuda T , Watanabe T , Ohashi M , Murakami K , Mochizuki H
Published: June 2012

In vitro and in vivo antifungal activities of D0870 were evaluated in comparison with those of fluconazole. D0870, which is the R-enantiomer of ICI195,739, was found to be the mycologically active enantiomer by comparing the activities of D0870 with those of M16355 (S-enantiomer of ICI195,739). D0870 showed a broad spectrum of antifungal activity and MICs and minimum antibiotic concentrations 4- to 2,000-fold lower in synthetic amino acid medium (fungal) agar than those of fluconazole for various fungi. Although MICs of D0870 were affected by variation of the test conditions, such as type of medium, inoculum size of fungi, supplementation with fetal bovine serum, and pH of medium, they were consistently much lower than those of fluconazole under any condition. In vivo activities of D0870 in the systemic infection models with Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in normal mice and in the mice immunosuppressed with cyclophosphamide or cortisone acetate were 2- to 7-fold and 3- to 89-fold greater than those of fluconazole, respectively. In these infection models in immunosuppressed mice, the therapeutic efficacy of D0870 was almost equivalent to that in normal mice, whereas the efficacy of fluconazole was 2- to 50-fold lower than that in normal mice.
Experimental visceral leishmaniasis: role of trans-aconitic acid in combined chemotherapy
Authors: Kar S , Kar K , Bhattacharya P K , Ghosh D K
Published: June 2012

We previously reported the effectiveness of trans-aconitic acid (TAA) as an antileishmanial compound. Inhibitory effects of TAA along with other antileishmanial compounds on transformation and in vitro multiplication in macrophage cultures of Leishmania donovani have been assessed. The efficacy of TAA in combined chemotherapy of experimental visceral leishmaniasis has also been evaluated along with those of commonly used antileishmanial compounds such as sodium stibogluconate, pentamidine, and allopurinol. TAA (2 mM) inhibited transformation of L. donovani amastigotes to promastigotes by 95.2%, whereas in combination with pentamidine (5 micrograms/ml), allopurinol (10 micrograms/ml), and sodium stibogluconate (50 micrograms of Sb per ml), it inhibited transformation by about 100, 99, and 98.5%, respectively. Sodium stibogluconate (20 micrograms of Sb per ml), pentamidine (2 micrograms/ml), and allopurinol (5 micrograms/ml) suppressed the amastigote burden in peritoneal macrophage cultures from BALB/c mice by 32.6, 56.1, and 46.3%, respectively. When these three drugs were used along with TAA (5 mM), the parasite loads were reduced by 100, 100, and 88.1%, respectively. TAA (5 mM) alone suppressed the amastigote burden by 59.5%. In experimental visceral leishmaniasis in hamsters (1-month model), TAA at a dose of 200 mg/kg of body weight per day suppressed the spleen parasite load by 73.5%, and TAA in combination with sodium stibogluconate (50 mg of Sb per kg per day), pentamidine (8 mg/kg/day), and allopurinol (15 mg/kg/day) inhibited the spleen parasite load by 98, 98.9, and 97%, respectively. Individually, these three drugs inhibited the parasite load by 35, 20, and 22%, respectively. TAA (400 mg/kg/day) inhibited the spleen parasite load by 99.8%, but an inhibitory effect of approximately 100% was noted when TAA was supplemented with an antileishmanial drug. TAA was administered in experimental animals through oral, intraperitoneal, and intramuscular routes; the intramuscular route was most effective.
Fusidic acid alone or in combination with vancomycin for therapy of experimental endocarditis due to methicillin-resistant Staphylococcus aureus
Authors: Fantin B , Leclercq R , Duval J , Carbon C
Published: June 2012

The usefulness of fusidic acid, alone or combined with vancomycin, was investigated for the therapy of experimental endocarditis caused in rabbits by a methicillin-resistant strain of Staphylococcus aureus. In vitro killing curves showed an indifferent interaction between the two antibiotics. In vivo, vancomycin alone was as effective as a vancomycin-fusidic acid combination (P < 0.05 versus control animals). No resistance to fusidic acid emerged during combination therapy. Fusidic acid alone was not effective. Resistance emerged in 5 of 12 animals treated with fusidic acid alone and was responsible for antibacterial failure. Fusidic acid alone was effective (P < 0.001) and did not select resistant strains if therapy was started when animals retained a smaller inoculum. We concluded that the vancomycin-fusidic acid combination exhibited no advantage over vancomycin alone in this model.
Bactericidal activity of the fluoroquinolone WIN 57273 against high-level gentamicin-resistant Enterococcus faecalis
Authors: Noskin G A , Mehl P , Warren J R
Published: June 2012

The fluoroquinolone WIN 57273 showed identical bactericidal activities (MBC for 90% of the strains = 0.25 micrograms/ml) for bacteremic strains of Enterococcus faecalis with and without high-level gentamicin resistance. WIN 57273 was bactericidal in time-kill measurements with highly gentamicin-resistant, ciprofloxacin-susceptible strains of E. faecalis. However, WIN 57273 was indifferent with penicillin for gentamicin-resistant E. faecalis and was not bactericidal for ciprofloxacin-resistant E. faecalis.
Activities of potential therapeutic and prophylactic antibiotics against blood culture isolates of viridans group streptococci from neutropenic patients receiving ciprofloxacin
Authors: McWhinney P H , Patel S , Whiley R A , Hardie J M , Gillespie S H , Kibbler C C
Published: June 2012

All 47 sequential blood culture isolates of viridans group streptococci obtained from febrile neutropenic patients receiving quinolone prophylaxis were susceptible to vancomycin, teicoplanin, and imipenem. Resistance to benzylpenicillin (MIC for 50% of isolates [MIC50], 0.125 microgram/ml) and ceftazidime (MIC50, 4 micrograms/ml) was common. Most isolates were susceptible to amoxicillin, co-amoxiclav (amoxicillin-clavulanic acid at a 2:1 ratio by weight), azlocillin, clarithromycin, and erythromycin, with azithromycin showing comparable activity. The MIC90 of sparfloxacin was 1 microgram/ml; those for ciprofloxacin and ofloxacin were > 16 and 16 micrograms/ml, respectively.
Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania
Authors: Chen M , Christensen S B , Blom J , Lemmich E , Nadelmann L , Fich K , Theander T G , Kharazmi A
Published: June 2012

Licochalcone A, an oxygenated chalcone isolated from the roots of Chinese licorice plant, inhibited the growth of both Leishmania major and Leishmania donovani promastigotes and amastigotes. The structure of the licochalcone A was established by mass and nuclear magnetic resonance spectroscopies and by synthesis, and its purity was verified by high-pressure liquid chromatography. The 50% inhibition of growth of logarithmic- and stationary-phase promastigotes of L. major, as measured by [3H]thymidine uptake, were 4 and 2.5 micrograms/ml, respectively. The growth of L. major promastigotes was totally inhibited after a 20-h incubation period with licochalcone A at 5 micrograms/ml. At a concentration of 0.5 microgram/ml, licochalcone A markedly reduced the infection rate of human peripheral blood monocyte-derived macrophages and U937 cells with L. major promastigotes and exhibited a strong intracellular killing of the parasite. These data show that intracellular Leishmania amastigotes are more susceptible than promastigotes to licochalcone A. Results of studies on the site of action of licochalcone A indicate that the target organelle appears to be the parasite mitochondria. These findings demonstrate that licochalcone A in concentrations that are nontoxic to host cells exhibits a strong antileishmanial activity and that appropriate substituted chalcones might be a new class of antileishmanial drugs.
Use of a predictor panel to evaluate susceptibility test methods proposed for piperacillin-tazobactam
Authors: Bradford P A , Sanders C C
Published: June 2012

A predictor panel of clinical isolates that produce a variety of types and amounts of beta-lactamases was used to assess the accuracy of dilution and disk diffusion susceptibility tests for piperacillin-tazobactam. Combinations of piperacillin-tazobactam with a fixed ratio of 8:1 and with tazobactam held constant at 4 micrograms/ml were examined in dilution tests performed in agar. In addition, disks containing 100 and 10 micrograms of piperacillin and tazobactam, respectively, were examined in diffusion tests. Three very major discrepancies between MICs determined with an 8:1 ratio and MICs determined with tazobactam held constant at 4 micrograms/ml were noted. These involved strains that appeared to be susceptible in tests with the 8:1 ratio but resistant when tazobactam was held constant at 4 micrograms/ml. However, the differences were only twofold. Error rate-bounded analysis with the disk containing 100 and 10 micrograms of piperacillin and tazobactam, respectively, revealed low error rates, regardless of whether MICs were determined with an 8:1 ratio or tazobactam held constant at 4 micrograms/ml. Thus, a predictor panel was useful in the identification of accurate susceptibility test for piperacillin-tazobactam.
Limitations of plasmid complementation test for determination of quinolone resistance due to changes in the gyrase A protein and identification of conditional quinolone resistance locus
Authors: Soussy C J , Wolfson J S , Ng E Y , Hooper D C
Published: June 2012

Plasmid pJSW101 derived from pUC19 and carrying the wild-type gyrA gene was found to be unstable in HM72, a quinolone-resistant (QR) clinical isolate of Escherichia coli, and resulted in no change in quinolone MICs. MICs determined in the presence of ampicillin to ensure plasmid presence, however, resulted in complementation. HM72 was proved to have a gyrA mutation based on the DNA sequence of a 418-bp fragment of gyrA. DNA sequencing identified a common mutation encoding Leu-83 as the cause of QR. To identify loci other than gyrA and nfxB contributing to QR in KF111b, zgh-3075::Tn10 (67 min) in CAG12152 was transduced into KF111b. Sixteen percent of the transductants had a fourfold decrease in norfloxacin MIC, indicating the presence of a locus, nfxD, which contributes to QR. Outcross of nfxD from DH151 (gyrA nfxB nfxD zgh-3075::Tn10) resulted in 8% of the KF130 gyrA, 2% of the EN226-3 gyrA, and none of the KL16 (wild-type) transductants, with a four- to eightfold increase in norfloxacin MIC. In the presence of ampicillin, the resistance of a gyrA nfxD double mutant, DH161 nfxD gyrA (from EN226-3), was fully complemented by gyrA+. Thus, gyrA+ plasmid complementation tests for QR may be falsely negative with plasmid instability, a difficulty which may be circumvented by maintenance of plasmid selection. In addition, if nfxD-like mutations occur in gyrA clinical isolates, a positive test may overestimate the level of resistance attributable to gyrA alone.
A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential
Authors: Corbett A H , Guerry P , Pflieger P , Osheroff N
Published: June 2012

Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryotic cells have been described. Many of these compounds contain aromatic substituents in their C-7 ring positions. To determine whether pyrimido[1,6-a]benzimidazoles, a class of drugs modeled on quinolones, also display activity toward eukaryotic systems, the effects of Ro 46-7864 and Ro 47-3359 on Drosophila melanogaster topoisomerase II and Kc cells were characterized. While the former drug contains an aliphatic group (4-N-methylpiperazine) at the ring position equivalent to C-7 in quinolones, the latter compound contains an aromatic substituent (2,6-dimethylpyridine). Both pyrimido[1,6-a]benzimidazoles inhibited DNA relaxation catalyzed by the type II enzyme. However, only Ro 47-3359 enhanced topoisomerase II-mediated DNA cleavage and was toxic to Kc cells. At a concentration of 100 microM, this drug approximately doubled the levels of DNA breakage in vitro and killed > 50% of the initial cell population of cultures. These results strongly suggest that selected pyrimido[1,6-a]benzimidazoles may function as topoisomerase II-targeted drugs with cytotoxic potential.
Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition
Authors: Bell C A , Dykstra C C , Naiman N A , Cory M , Fairley T A , Tidwell R R
Published: June 2012

Nine dicationically substituted bis-benzimidazoles were examined for their in vitro activities against Giardia lamblia WB (ATCC 30957). The potential mechanisms of action of these compounds were evaluated by investigating the relationship among in vitro antigiardial activity and the affinity of the molecules for DNA and their ability to inhibit the activity of giardial topoisomerase II. Each compound demonstrated antigiardial activity, as measured by assessing the incorporation of [methyl-3H]thymidine by giardial trophozoites exposed to the test agents. Three compounds exhibited excellent in vitro antigiardial activities, with 50% inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCl and metronidazole. Putative mechanisms of action for these compounds were suggested by the strong correlation observed among in vitro antigiardial activity and the affinity of the molecules for natural and synthetic DNA and their ability to inhibit the relaxation activity of giardial topoisomerase II. A strong correlation between the DNA binding affinity of these compounds and their inhibition of giardial topoisomerase II activity was also observed.
Influence of local radiotherapy on penetration of fluconazole into human saliva
Authors: Oliary J , Tod M , Louchahi K , Petitjean O , Frachet B , Le Gros V , Brion N
Published: June 2012

The pharmacokinetics of fluconazole (50 mg, single oral dose) in saliva and plasma were determined for five healthy subjects and five patients who underwent radiotherapy (dose, > 45 Gy over a 6-week period) in the salivary gland area and suffered from oropharyngeal candidiasis. Saliva was collected after electrical stimulation. Fluconazole was measured by liquid chromatography. From healthy volunteers and patients, saliva and plasma were sampled from 0 to 24 h. Although fluconazole penetration kinetics were significantly slowed down in irradiated patients, saliva concentrations of fluconazole were higher than those in the plasma, except at 1 h. In the postdistribution phase, the saliva/plasma concentration ratio was in the range of 1.2 to 1.4, and there was no significant difference between healthy subjects and patients. The saliva concentration of fluconazole was over 1 mg/liter throughout the entire interval 2 to 24 h after drug intake. From these results, the clinical efficacy of fluconazole for oropharyngeal candidiasis is not expected to be less than that in subjects with normal salivary glands, provided that salivary secretion remains.
Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration
Authors: de Lalla F , Novelli A , Pellizzer G , Milocchi F , Viola R , Rigon A , Stecca C , Dal Pizzol V , Fallani S , Periti P
Published: June 2012

Twenty-four patients undergoing monolateral or bilateral total knee replacement (TKR) procedures were randomized to receive teicoplanin (T) either systemically or regionally. Subjects scheduled for systemic prophylaxis and undergoing monolateral (six patients) or bilateral (five patients) TKR received a single 800-mg dose of T in 100 ml of saline as a 5-min infusion into a forearm vein 2.5 h before surgery. For regional prophylaxis, patients undergoing monolateral surgery (eight subjects) received 400 mg of T in 100 ml of saline as a 5-min infusion into a foot vein of the leg to be operated on immediately after the tourniquet was inflated. For the five patients scheduled for bilateral operation and regional prophylaxis, the administration of T was also repeated for the second knee operation. The tourniquet, as the standard TKR surgical technique, was inflated to 400 mm Hg (c. 50 kPa) in all 24 patients immediately before the beginning of surgery and kept in place for the duration of the operation. Samples of serum, bone, skin, synovia, and subcutaneous tissue were collected at timed intervals during surgery. They were microbiologically assayed for T by using Bacillus subtilis as the test organism. Overall, the mean T concentrations obtained with regional route prophylaxis were found to be 2 to 10 times higher than those achieved following systemic prophylaxis. Moreover, peak levels in different tissues after regional prophylaxis were significantly higher (P < 0.05). None of the patients experienced adverse effects due to regional or systemic T administration; no prosthetic or wound infections were observed in the follow-up period (from 12 to 26 months).
Bactericidal activities of synthetic human leukocyte cathepsin G-derived antibiotic peptides and congeners against Actinobacillus actinomycetemcomitans and Capnocytophaga sputigena
Authors: Miyasaki K T , Bodeau A L , Pohl J , Shafer W M
Published: June 2012

Actinobacillus actinomycetemcomitans and Capnocytophaga spp. are gram-negative bacteria implicated in the etiology of periodontal disease (particularly in individuals with neutrophil defects) and life-threatening systemic infections. They are resistant to many antibiotics of microbial origin but are sensitive to the nonoxidative microbicidal action of neutrophils. These organisms are susceptible to the microbicidal effect of cathepsin G but are killed by two distinct mechanisms. The purpose of this study was to assess their sensitivity to the antibiotic effects of IIGGR and HPQYNQR, antimicrobial peptides derived from human neutrophil cathepsin G. The efficacies of the synthetic peptides IIGGR and HPQYNQR were tested by single-dose screening, dose-response, and kinetic assays against three representative strains (each) of A. actinomycetemcomitans and Capnocytophaga spp. and one strain of Eikenella corrodens. Strains of A. actinomycetemcomitans were sensitive to IIGGR and HPQYNQR at equal concentrations (wt/vol), whereas strains of Capnocytophaga and E. corrodens were more sensitive to IIGGR than to HPQYNQR. These differential antibiotic effects occurred over both time and dose ranges too narrow to be of therapeutic significance but are consistent with the premise that cathepsin G kills these oral bacteria by two distinct mechanisms. Except for IVGGR, congeners of IIGGR, including AIGGR, IAGGR, IIAGR, IIGAR, IIGGA, IQGGR, ILGGR, and I-norleucyl-GGR (InLGGR), were microbicidal at 500 micrograms/ml. IIGGR-amide exhibited no antibiotic activity. The D-enantiomer of IIGGR, DIDIGGDR, was as potent as IIGGR itself. APQYNQR exhibited antibiotic activity but somewhat less than HPQYNQR. We conclude that charge distribution, but not chirality or net charge, is an important determinant in the antibiotic efficacy of IIGGR. Moreover, peptide antibiotics derived from cathepsin G may have therapeutic value against periodontal gram-negative, facultative bacteria.
Transient carbapenem resistance induced by salicylate in Pseudomonas aeruginosa associated with suppression of outer membrane protein D2 synthesis
Authors: Sumita Y , Fukasawa M
Published: June 2012

Pseudomonas aeruginosa PAO1 showed increased phenotypic resistance to imipenem, panipenem, and biapenem specifically in the presence of salicylate. The antipseudomonal activity of carbapenems was reduced in proportion to the concentration of salicylate. This resistance was transient and nonheritable. The synthesis of the outer membrane protein D2 (OprD or OprD2) in P. aeruginosa PAO1 was inhibited by 4 to 32 mM salicylate in the bacterial growth medium, whereas no changes in any other outer membrane proteins were observed. These results indicate that salicylate suppresses the synthesis of OprD and therefore reduces the antipseudomonal activity of carbapenems. Under these conditions, one carbapenem--meropenem--is still active against P. aeruginosa, which indicates that meropenem can pass through the outer membrane via both the D2 channel and another undefined route(s).
Efficacy of intravenous itraconazole against experimental pulmonary aspergillosis
Authors: Miyazaki H M , Kohno S , Miyazaki Y , Mitsutake K , Tomono K , Kaku M , Koga H , Hara K
Published: June 2012

The efficacy of intravenous itraconazole solubilized in hydroxypropyl-beta-cyclodextrin was assessed in a rat model of Aspergillus fumigatus pneumonia. Immunosuppressed rats were infected by intratracheal inoculation of A. fumigatus conidia. Intravenous administration of various doses of itraconazole was started immediately after infection and continued once a day for 7 days. A 10-mg dose of intravenous itraconazole per kg was as effective on survival as 1 mg of amphotericin B per kg daily (a survival rate of 100% in 28 days), while treatment with 1 mg/kg did not increase the survival rate. The 50% lethal dose of intravenous itraconazole given to immunosuppressed and uninfected rats for 7 days was 24.5 mg/kg/day. A microbiological assay to estimate accumulation in tissue after five daily intravenous administrations of itraconazole at 10 mg/kg showed that itraconazole and its active metabolites were present in the lungs for at least 6 h, reaching the MIC as previously described (B. Dupont and E. Drouchet, Rev. Infect. Dis. 9(Suppl. 1):71-76, 1987; A. Espinel-Ingroff, S. Shadomy, and R. J. Gebhart, Antimicrob. Agents Chemother. 26:5-9, 1984). Intravenous itraconazole was considered to be worth evaluating in clinical trials of aspergillosis.
In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis
Authors: Ashtekar D R , Costa-Perira R , Nagrajan K , Vishvanathan N , Bhatt A D , Rittel W
Published: June 2012

CGI 17341 (2-ethyl-5-nitro-2,3-dihydro[2-1b]imidazo-oxazole) is a novel orally active representative of the 5-nitroimidazole series of antimicrobial agents. At concentrations ranging from 0.1 to 0.3 micrograms/ml, CGI 17341 inhibited the drug-susceptible and multi-drug-resistant strains of Mycobacterium tuberculosis. CGI 17341 had no cross-resistance with isoniazid, rifampin, streptomycin, or ethambutol. While the in vitro activity of CGI 17341 against M. tuberculosis was comparable to those of isoniazid and rifampin, it was superior to those of streptomycin, ciprofloxacin or norfloxacin, and oxazolidinone DuP 721. The MIC of CGI 17341 was not affected when the pH of the medium was decreased from 6.8 to 5.6, while four- to sixfold increases in the MICs of ciprofloxacin and isoniazid were observed. In mice infected with M. tuberculosis, the 50% effective dose for CGI 17341 was 7.7 mg/kg of body weight (95% confidence limits, 3.5 and 10.27) when administered on days 11 and 12 postinfection. CGI 17341 gave a dose-dependent (r = 0.995) and significant increase in the survival time. Our data indicate that the 5-nitroimidazole CGI 17341 is a promising and novel antituberculosis compound with potent in vitro and in vivo activities. Further investigations on this compound are warranted.
Uptake and intracellular activity of fluconazole in human polymorphonuclear leukocytes
Authors: Pascual A , García I , Conejo C , Perea E J
Published: June 2012

The penetration of fluconazole into human polymorphonuclear leukocytes (PMNs) and tissue culture epithelial cells (McCoy) was evaluated. At different extracellular concentrations (0.5 to 10 mg/liter), fluconazole reached cell-associated concentrations greater than the extracellular ones in either human PMNs (intracellular concentration to extracellular concentration ratio, > or = 2.2) or McCoy cells (intracellular concentration to extracellular concentration ratio, > or = 1.3). The uptake of fluconazole by PMNs was rapid and reversible but was not energy dependent. The intracellular penetration of fluconazole was not affected by environmental pH or temperature. Ingestion of opsonized zymosan and opsonized Candida albicans did not significantly increase the amount of PMN-associated fluconazole. At therapeutic extracellular concentrations, the intracellular activity of fluconazole against C. albicans in PMNs was significantly lower than that of amphotericin B. It was concluded that fluconazole reaches high intracellular concentrations within PMNs but shows moderate activity against intracellular C. albicans in vitro.