bluuebunny/crossref_metadata_2025 huggingface dataset:
Local gastric and serum amoxicillin concentrations after different oral application forms
Authors: Cooreman M P , Krausgrill P , Hengels K J
Published: June 2012

The high recolonization rate after monotherapy of Helicobacter pylori-positive gastritis may be due to insufficient local drug concentrations. To investigate the role of local diffusion, we measured levels of amoxicillin, a drug with good in vitro activity against H. pylori, in the mucosa and serum. One gram of amoxicillin was given to healthy volunteers as a tablet (n = 6) or as water-dissolved, fizzing "Tab" (n = 6). Gastroscopy with biopsies from the antrum, corpus, and fundus was performed at 30, 60, and 90 min. Concentrations in the mucosa were measured after homogenization with the agar diffusion method using Bacillus subtilis as the biological indicator. Serum samples, taken basally and every 15 min, were analyzed by high-pressure liquid chromatography. Drug levels in the fundus and corpus remained far below those in the antrum for both application forms. The highest concentrations were reached after 30 min, with bactericidal levels in the antrum in two of six subjects who took the tablet form and five of six subjects who used Tabs. At 60 and 90 min, almost all values were below the MBC for 90% of the strains tested. The concentrations in serum, however, rose continuously, to reach a maximum after 75 or 90 min. These results show that incomplete elimination may be due to subbactericidal concentrations of antibiotics with high in vitro efficiency at the desired site of action in vivo and that local diffusion in the mucosa is essential for therapeutic effectiveness against H. pylori.
In vitro susceptibilities of isolates of Haemophilus ducreyi from Thailand and the United States to currently recommended and newer agents for treatment of chancroid
Authors: Knapp J S , Back A F , Babst A F , Taylor D , Rice R J
Published: June 2012

We determined the in vitro susceptibilities of 54 isolates of Haemophilus ducreyi from Thailand (29 isolates) and San Francisco (25 isolates) to penicillin G, tetracycline, amoxicillin-clavulanic acid, ceftriaxone, cefixime, erythromycin, azithromycin, ciprofloxacin, ofloxacin, and trimethoprim-sulfamethoxazole. Isolates were susceptible to < or = 0.25 microgram of ceftriaxone per ml, < or less 0.5 microgram of cefixime per ml, < or = 0.125 microgram of ciprofloxacin per ml, and < or = 0.06 microgram of ofloxacin per ml. Erythromycin was active against all isolates (MIC for 90% of isolates tested, 0.25 microgram/ml), as was azithromycin (MIC, < or = micrograms/ml). In contrast, all but one isolate were resistant to > or = 8.0 micrograms of tetracycline per ml, 11.1% of the isolates were resistant to and 40.9% of the isolates were resistant to trimethoprim-sulfamethoxazole (MIC, > or = 4/76 microgram/ml.)
Enoxacin relieves symptoms of recurrent urinary infections more rapidly than cefuroxime axetil
Authors: Brumfitt W , Hamilton-Miller J M , Walker S
Published: June 2012

In patients with a history of recurrent infections, treatment with enoxacin (200 mg/12 h for 3 days) relieved symptoms of acute urinary infection significantly more rapidly than treatment with cefuroxime axetil (125 mg/12 h for 7 days). Other parameters, including clinical and bacteriological cure rates and patients' overall opinion of their treatment, did not differ significantly between the treatments.
Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors
Authors: Byrnes V W , Sardana V V , Schleif W A , Condra J H , Waterbury J A , Wolfgang J A , Long W J , Schneider C L , Schlabach A J , Wolanski B S
Published: June 2012

The nonnucleoside reverse transcriptase (RT) inhibitors comprise a class of structurally diverse compounds that are functionally related and specific for the human immunodeficiency virus type 1 RT. Viral variants resistant to these compounds arise readily in cell culture and in treated, infected human. Therefore, the eventual clinical usefulness of the nonnucleoside inhibitors will rely on a thorough understanding of the genetic and biochemical bases for resistance. A study was performed to assess the effects of substitutions at each RT amino acid residue that influences the enzyme's susceptibility to the various nonnucleoside compounds. Single substitutions were introduced into both purified enzyme and virus. The resulting patterns of resistance were markedly distinct for each of the tested inhibitors. For instance, a > 50-fold loss of enzyme susceptibility to BI-RG-587 was engendered by any of four individual substitutions, while the same level of relative resistance to the pyridinone derivatives was mediated only by substitution at residue 181. Similarly, substitution at residue 181. Similarly, substitution at residue 106 had a noted effect on virus resistance to BI-RG-587 but not to the pyridinones. The opposite effect was mediated by a substitution at residue 179. Such knowledge of nonucleoside inhibitor resistance profiles may help in understanding the basis for resistant virus selection during clinical studies of these compounds.
Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin Structure Study Group
Authors: Tan J S , Wishnow R M , Talan D A , Duncanson F P , Norden C W
Published: June 2012

We compared the efficacy and safety of two beta-lactam-beta-lactamase inhibitor combinations, namely, piperacillin-tazobactam and ticarcillin-clavulanate, in the treatment of complicated bacterial infections of skin that required hospitalization. The study was a randomized, double-blind, comparative trial involving 20 centers. The infections were classified as (i) cellulitis with drainage, (ii) cutaneous abscess, (iii) diabetic or ischemic foot infection, and (iv) infected wounds and ulcers with drainage. The clinical response rates were comparable for the two treatment regimens (61% of the patients were cured with piperacillin-tazobactam and ticarcillin-clavulanate and improvement was seen in 15 and 16% of patients treated with piperacillin-tazobactam and ticarcillin-clavulanate, respectively). Both regimens were found to be safe and well tolerated. These data support the use of piperacillin-tazobactam for initial empiric therapy of hospitalized patients with complicated skin and skin structure infections.
Cefprozil versus penicillin V in treatment of streptococcal tonsillopharyngitis
Authors: Milatovic D , Adam D , Hamilton H , Materman E
Published: June 2012

In a randomized multicenter study, the efficacy and safety of cefprozil were compared with those of penicillin in the treatment of group A streptococcal tonsillopharyngitis in children. Of the 409 patients enrolled, 323 were evaluable for their clinical and bacteriological responses; of these 323 children, 172 received cefprozil and 151 received penicillin V. The clinical responses in patients treated with cefprozil were significantly better than those in patients who received penicillin (95.3 versus 88.1%; P = 0.023). Eradication of the original serotype of group A streptococci was achieved in 91.3% of patients treated with cefprozil and 87.4% of patients treated with penicillin, the difference not being statistically significant (P = 0.125). However, there were significantly more symptomatic patients among the bacteriological failures in the penicillin group (68.4%) than in the cefprozil group (26.7%). beta-Lactamase-producing Staphylococcus aureus was more frequently isolated from the throat flora during penicillin therapy than during cefprozil treatment. No difference in the incidence of adverse events probably related or of unknown relationship to the study drugs was observed in the two treatment groups (5.2% of those treated with cefprozil and 6.0% of those treated with penicillin). Cefprozil can be considered a safe and reliable drug for the treatment of streptococcal pharyngitis in children.
Detection of tetracyclines and efflux pump inhibitors
Authors: Rothstein D M , McGlynn M , Bernan V , McGahren J , Zaccardi J , Cekleniak N , Bertrand K P
Published: June 2012

Screening assays for the detection of tetracyclines and inhibitors of tetracycline efflux pumps are described. The tetracycline assay is based on the observation that the tetA(B) gene encoding the efflux pump of transposon Tn10 is induced by tetracycline. The Escherichia coli strain designed to detect tetracyclines contains a single copy of a tetA(B)-lacZ transcriptional fusion integrated into the chromosome and the tetR gene encoding the tetracycline repressor on a plasmid. The assay specifically detects tetracyclines of distinct structures, but not other classes of drugs. A strain capable of detecting inhibitors of the TetA(B) efflux pump contained the tetA(B)-lacZ fusion and, in addition, a tetA(B) structural gene lacking its transcriptional regulatory signals which mediated resistance to only 5 micrograms of tetracycline per ml. This strain was more refractory to induction by tetracycline because of the action of the pump. Inhibitors were detected in two ways: (i) beta-galactosidase induction in the presence of 5 ng of tetracycline per ml, a subinducing concentration, and (ii) growth inhibition in the presence of 5 micrograms of tetracycline per ml. A strain designed to detect inhibitors of the Tet(K) efflux pump from Staphylococcus aureus was constructed by substituting the tet(K) structural gene for the tetA(B) gene. Nocardamine and other siderophores were found to interfere with the action of tetracycline efflux pumps.
Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication
Authors: Kleim J P , Bender R , Billhardt U M , Meichsner C , Riess G , Rösner M , Winkler I , Paessens A
Published: June 2012

S-2720 [6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4- dihydroquinoxalin-2(1H)-thione], a quinoxaline derivative, was found to be a very potent inhibitor of both human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) activity and HIV-1 replication in tissue culture. Like other nonnucleoside RT inhibitors, S-2720 does not affect the HIV-2 RT. A S-2720-resistant virus was selected and shown to possess a mutation within the RT-coding region that has not previously been described. Notably, this mutation gives rise to a dramatic decrease in enzyme activity. S-2720, therefore, belongs to a new class of RT inhibitors that bind differently to the RT than other known nonnucleoside RT inhibitors. As no toxic effects were observed with S-2720 in mice, these quinoxaline derivatives deserve further evaluation to prove their potency as possible therapeutic agents for HIV-1 infection.
Therapy of human hydatid disease with mebendazole and albendazole
Authors: Teggi A , Lastilla M G , De Rosa F
Published: June 2012

We report our experience in the treatment with benzoimidazole carbamates (mebendazole and albendazole) of 337 patients affected by hydatid cysts with different localizations. The treated cysts showed degenerative modifications in 50.6% of the cases after mebendazole treatment and in about 80% after albendazole treatment. Relapses after therapy were observed in 30% of the cases; about 95% of the recurring cysts showed good susceptibility to a further cycle of therapy with benzoimidazole carbamates. Side effects observed with either drug were not severe and always reversible, consisting mainly of abdominal pains and increased levels of transaminases in serum. Among the factors that may influence the therapeutic results are the drug employed, the age of the cysts, the age of the patient, and the localization of the cysts and their morphological characteristics. Moreover, it can be hypothesized that each hydatid cyst has an intrinsic sensitivity to benzoimidazole carbamates.
Multicenter comparison of in vitro activities of FK-037, cefepime, ceftriaxone, ceftazidime, and cefuroxime
Authors: Washington J A , Jones R N , Gerlach E H , Murray P R , Allen S D , Knapp C C
Published: June 2012

In a multicenter study, the MICs of FK-037 for 90% of the strains tested (MIC90s) were < or = 1 microgram/ml for members of the family Enterobacteriaceae other than Citrobacter freundii, Enterobacter spp., and Serratia marcescens. Activity against Pseudomonas aeruginosa was variable, with a MIC50 and a MIC90 of 4 and 32 micrograms/ml, respectively. Relative to cefepime, however, FK-037 was less active against ceftazidime-resistant isolates of Enterobacter cloacae. The MIC90 of FK-037 for methicillin-resistant staphylococci was > 16 micrograms/ml.
Inhibition of Toxoplasma gondii protein synthesis by azithromycin
Authors: Blais J , Garneau V , Chamberland S
Published: June 2012

Azithromycin was shown to specifically inhibit the protein synthesis of Toxoplasma gondii in experimental systems by using free tachyzoites and T. gondii-infected mouse macrophages. RNA synthesis of the parasite was not affected by azithromycin. Inhibition of protein synthesis was also proportional to the relative anti-Toxoplasma activity of three macrolides.
Synthesis and virucidal activity of a water-soluble, configurationally stable, derivatized C60 fullerene
Authors: Schinazi R F , Sijbesma R , Srdanov G , Hill C L , Wudl F
Published: June 2012

The bis(monosuccinimide) derivative of p,p'-bis(2-aminoethyl)diphenyl-C60 (compound 1), prepared by the fulleroid route, is active against human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% effective concentration [EC50] averaging approximately 6 microM) in acutely or chronically infected human lymphocytes and is active in vitro against 3'-azido-3'-deoxythymidine-resistant HIV-1 (EC50, approximately 3 microM). The virucidal properties of compound 1 were confirmed by virus inactivation assays. Compound 1 was noncytotoxic up to 100 microM in peripheral blood mononuclear cells and H9, Vero, and CEM cells. In cell-free assays, whereas the fullerene showed comparable activity against HIV-1 reverse transcriptase and DNA polymerase alpha (50% inhibitory concentration of approximately 5 microM), it demonstrated selective activity against HIV-1 protease.
In vitro activity of azithromycin (CP-62,993) against Chlamydia trachomatis and Chlamydia pneumoniae
Authors: Agacfidan A , Moncada J , Schachter J
Published: June 2012

The in vitro susceptibilities of 49 strains of Chlamydia trachomatis and 3 strains of Chlamydia pneumoniae to azithromycin and tetracycline or doxycycline were determined. The MIC of azithromycin ranged from < or = 0.06 to 1.0 micrograms/ml, the MIC of tetracycline ranged from 0.03 to 0.12 micrograms/ml, and the MIC of doxycycline ranged from 0.015 to 0.06 micrograms/ml against C. trachomatis. The MIC ranges for C. pneumoniae were 0.12 to 0.25 micrograms/ml for azithromycin and 0.06 to 0.12 micrograms/ml for tetracycline. All minimal chlamydicidal concentrations were either equal to the MIC or one or two dilutions higher. No strains resistant to these antibiotics were detected. In vitro activity shows that azithromycin is highly active against C. trachomatis and C. pneumoniae.
The time of administration of 3'-azido-3'-deoxythymidine (AZT) determines its host toxicity with possible relevance to AZT chemotherapy
Authors: Zhang R , Lu Z , Diasio C R , Liu T , Soong S J
Published: June 2012

3'-Azido-3'-deoxythymidine (AZT) is the drug most widely used in the treatment of AIDS. Its major drug-related toxicity is bone marrow suppression, which limits the dose of AZT that can be used. It is essential that AZT be phosphorylated for antiviral effect. We have recently demonstrated that thymidine kinase (TK), the initial enzyme in AZT anabolism, follows a circadian pattern in rat bone marrow. The present study was undertaken to determine whether AZT toxicity is related to the time of its administration and whether the variation in toxicity is correlated with the circadian variation in TK activity. Male Sprague-Dawley rats were housed under standardized conditions of light and dark (lights on 0600 to 1800 and lights off 1800 to 0600) for 4 weeks. The animals were randomly divided into seven groups; six groups were administered AZT by intraperitoneal injection at the same dose of 750 mg/kg of body weight at various times (0400, 0800, 1200, 1600, 2000, and 2400), and one group was used as a control. AZT-related toxic effects, including bone marrow toxicity, differed significantly among the treatment groups, depending on the time of AZT administration (by analysis of variance and Cosinor analysis, P < 0.001). The least toxicity was observed in rats receiving AZT at 1600 (10 h after light onset [10 HALO], in late sleep span) and the greatest toxicity was observed in those injected at 0400 (22 HALO, in late activity span). To verify these results, we administered AZT by intraperitoneal injection at an approximately 50% lethal dose (1,500 mg/kg) to two groups of rats, one at 1200 (6 HALO, in the middle of the sleep span) and the other at 2400 (18 HALO, in the middle of the activity span). AZT lethality was significantly higher in rats receiving AZT at 2400 (18 HALO, in the middle of the activity span). Further statistical analysis demonstrated that the variation in AZT toxicity was correlated with the circadian variation in TK activity in bone marrow of the same species (peak activity at 0400 [22 HALO, in late activity span] and trough activity at 1600 [10 HALO, in late sleep span]), suggesting that the circadian variation in TK activity may be the biochemical basis for the observed circadian variation in AZT toxicity. These results may be useful in the design of improved AZT chemotherapeutic regimens.
Antileishmanial activity of sodium stibogluconate fractions
Authors: Roberts W L , Rainey P M
Published: June 2012

Sodium stibogluconate, a pentavalent antimony derivative produced by the reaction of stibonic and gluconic acids, is the drug of choice for the treatment of leishmaniasis. It has been reported to be a complex mixture rather than a single compound. We separated sodium stibogluconate into 12 fractions by anion-exchange chromatography. One fraction accounted for virtually all the leishmanicidal activity of the fractionated material against Leishmania panamensis promastigotes, with a 50% inhibitory concentration (IC50) of 12 micrograms of Sb per ml; that of unfractionated sodium stibogluconate was 154 micrograms of Sb per ml. Further analysis of this active fraction revealed that a major component was m-chlorocresol, which had been included in the sodium stibogluconate formulation as a preservative. The IC50 of pure m-chlorocresol was 1.6 micrograms/ml, a concentration equivalent to that present in unfractionated sodium stibogluconate at a concentration of 160 micrograms of Sb per ml. After ether extraction to remove m-chlorocresol, the IC50 of sodium stibogluconate was > 4,000 micrograms of Sb per ml. In contrast, when L. panamensis amastigotes were grown in macrophages, the IC50 of ether-extracted sodium stibogluconate was 10.3 micrograms of Sb per ml. The 12 fractions of ether-extracted sodium stibogluconate obtained by anion-exchange chromatography had IC50s of 10.1 to 15.4 micrograms of Sb per ml. We conclude that preservative-free sodium stibogluconate has little activity against L. panamensis promastigotes but is highly active against L. panamensis amastigotes in macrophages. This activity is associated with multiple chemical species.
Concentrations in plasma and tissue penetration of ceftriaxone and ornidazole during liver transplantation
Authors: Steib A , Jacoberger B , Von Bandel M , Beck F , Beller J P , Boudjema K , Koffel J C , Otteni J C
Published: June 2012

Plasma and epiploic fat drug concentrations and fat penetration of ceftriaxone and ornidazole given for antimicrobial prophylaxis were studied in 11 patients scheduled for liver transplantation. Ceftriaxone (1 g) and ornidazole (500 mg) were infused during 30 min after the induction of anesthesia. Arterial blood and epiploic fat samples were collected at 30, 60, and 120 min and then every 90 min following the end of the infusion until closure of the peritoneum. Blood samples were immediately centrifuged, and plasma and fat were stored at -35 degrees C until analysis. Ceftriaxone and ornidazole concentrations were determined by high-performance liquid chromatography. Surgery lasted 440 +/- 84 min and required a mean of 9.5 units of packed erythrocytes and 13 units of fresh frozen plasma. Plasma ceftriaxone concentrations decreased from 89 +/- 34 to 41 +/- 16.5 micrograms/ml from the beginning of the operation until the time of closure of the peritoneum. Corresponding levels in epiploic fat decreased from 8.7 +/- 3.3 to 4.5 +/- 3.5 micrograms/g. Ornidazole concentrations ranged, respectively, between 8.7 +/- 2.5 and 4.9 +/- 1.7 micrograms/ml in plasma samples and 4.6 +/- 1.2 and 2.5 +/- 1.1. micrograms/g in fat samples. Rates of penetration into the omentum remained at about 9% for ceftriaxone and between 50 and 70% for ornidazole. Tissue ceftriaxone concentrations were, in all cases, greater than typical MICs for 90% for Escherichia coli and Klebsiella isolates tested (MIC90S). They were insufficient in 40% of patients after 60 min with regard to the MIC90S for Staphylococcus aureus. Tissue ornidazole concentrations were not superior to MIC90S for anaerobes after 30 min in 50% of patients. These results show that a single dose of 1 g of ceftriaxone provides adequate coverage against gram-negative bacteria and that 1 g instead of 500 mg ornidazole may provide a protective effect against anaerobes during liver transplantation. Prophylaxis against S. aureus and Streptococcus faecalis requires more specific antibiotics. Prophylaxis for patients with significant blood loss or initial severe renal or hepatic failure needs further evaluation.
Attachment of an aminoglycoside, amikacin, to implantable collagen for local delivery in wounds
Authors: Boyce S T , Supp A P , Warden G D , Holder I A
Published: June 2012

Cultured skin substitutes consisting of implantable collagen (COL) and cultured human skin cells often fail clinically from destruction by microbial contamination. Hypothetically, addition of selected antimicrobial drugs to the implant may control microbial contamination and increase healing of skin wounds with these materials. As a model for drug delivery, bovine skin COL (1 mg/ml) and amikacin (AM; 46 micrograms/ml) were modified by covalent addition of biotin (B-COL and B-AM, respectively) from B-N-hydroxysuccinimide and bound together noncovalently with avidin (A). B-COL was incubated with A and then with B-peroxidase (B-P) or by serial incubation with B-AM and B-P, before P-dependent chromogen formation. Colorimetric data (n = 12 per condition) from spot tests on nitrocellulose paper were collected by transmission spectrophotometry. Specificity of drug binding in spot tests was determined by (i) serial dilution of B-COL; (ii) reactions with COL, AM, or P that had no B; (iii) removal of A; or (iv) preincubation of B-COL-A with B before incubation with B-P. Binding of B-AM was (i) dependent on the concentration of B-COL; (ii) specific to B-COL, A, and B-P (P < 0.05); and (iii) not eluted by incubation in 0.15 or 1.0 M NaCl. B-AM was found to block binding of B-P to the B-COL-A complex and to retain bacteriocidal activity against 10 clinical isolates of wound bacteria in the wet disc assay. Antimicrobial activity of B-AM was removed from solution by treatment with magnetic A and a permanent magnet. These results suggest that selected antimicrobial drugs can be biotinylated for attachments to COL-cultured cell implants without loss of pharmacologic activity. Because this chemistry utilizes a common ligand, any molar ratio of agents may be administered simultaneously and localized to the site of implantation.
Evaluation of a novel fluorescence polarization immunoassay for teicoplanin
Authors: Cox H , Whitby M , Nimmo G , Williams G
Published: June 2012

A fluorescence polarization immunoassay (FPI) for teicoplanin that uses the TDx Instrument System (Abbott, Irving, Tex.) as an automated analyzer has been developed by Innotron of Oregon Inc. and was evaluated in patients with staphylococcal infections enrolled in a clinical trial of the antibiotic. The assay proved accurate in estimating concentrations of between 5 and 100 mg/liter. The intraassay coefficient of variation was < 7.3%, while the interassay variance was < 11.6% against three commercially prepared standards at known concentrations of approximately 5, 35, and 75 mg/liter. Against routinely prepared standards at 10 concentrations between 5 and 100 mg/liter analyzed in a single run, the coefficient of variance did not exceed 4.3%. Compared with bioassay, the FPI demonstrated good correlation in terms of reliability (r = 0.909) in samples containing teicoplanin only and specificity (r = 0.916) in samples containing both teicoplanin and gentamicin. With a turnaround time of 20 min and with only 50 microliters of serum needed for estimation of the amount of drug in a sample, the FPI described here should provide a useful method of teicoplanin measurement in routine diagnostic laboratories.
Pharmacodynamic effects of extended dosing intervals of imipenem alone and in combination with amikacin against Pseudomonas aeruginosa in an in vitro model
Authors: McGrath B J , Lamp K C , Rybak M J
Published: June 2012

The pharmacodynamic effects of extended imipenem dosing intervals were studied against two strains of Pseudomonas aeruginosa (ATCC 27853 and an imipenem-resistant mutant, 27853R) in an in vitro model of infection. Imipenem was administered as monotherapy (simulated 1-g bolus every 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus every 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem administered every 8 h was equally bactericidal at 24 h compared with regimens combined with amikacin for ATCC 27853. Imipenem administered every 12 h against the sensitive strain and both imipenem monotherapy regimens against the resistant strain demonstrated regrowth at 24 h. Although both amikacin regimens administered as monotherapy resulted in rapid bacterial killing activity with respect to time to a 99.9% reduction in log10 CFU/milliliter, regrowth at 24 h was observed at levels reaching or exceeding the initial inoculum. All combination regimens resulted in no detectable growth by 24 h regardless of dosing interval for either drug or initial susceptibility to imipenem. Results from this study indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective against a sensitive strain of P. aeruginosa. Combination therapy with imipenem and once-daily or twice-daily amikacin resulted in increased killing activity against imipenem-resistant P. aeruginosa. Once-daily or twice-daily amikacin in combination therapy, regardless of P. aeruginosa susceptibility, allowed for extension of imipenem dosing intervals.
Fluconazole resistance in Candida glabrata
Authors: Hitchcock C A , Pye G W , Troke P F , Johnson E M , Warnock D W
Published: June 2012

We report a case of infection with Candida glabrata in which the organism became resistant to fluconazole and in which pre- and posttreatment isolates were available for comparison. The organism was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Fluconazole was a potent inhibitor of cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) in lysates of cells from both susceptible and resistant cultures (50% inhibitory concentration, 0.2 microM), indicating that resistance was unrelated to changes in P-450DM. Instead, it appeared to arise from a permeability barrier to fluconazole, since resistant cells were unable to take up radiolabelled drug.
Activity of a nitrofurazone matrix urinary catheter against catheter-associated uropathogens
Authors: Johnson J R , Berggren T , Conway A J
Published: June 2012

Nitrofurazone-coated urinary catheter segments inhibited 51 (75%) of 70 urinary bacterial isolates from patients with indwelling catheters. Inhibition zones correlated significantly with the nitrofurazone MIC (r2 = 0.79, P = 0.0001). All strains except the Pseudomonas spp. were inhibited by < or = 64 micrograms of nitrofurazone per ml. MICs of nitrofurazone and nitrofurantoin correlated significantly (r2 = 0.93, P = 0.0001).
Antimicrobial susceptibilities of Neisseria gonorrhoeae strains representing five distinct resistance phenotypes
Authors: Rice R J , Knapp J S
Published: June 2012

The susceptibilities of 109 strains of Neisseria gonorrhoeae to penicillin G, tetracycline, amoxicillin-clavulanic acid, cefotetan, cefoxitin, ceftriaxone, ciprofloxacin, and fleroxacin were determined. The activities of cefmetazole, cefuroxime, cefixime, and ofloxacin were also determined against 62 of these strains. Strains represented penicillin-susceptible (Pen(s)) N. gonorrhoeae; penicillinase-producing N. gonorrhoeae (PPNG) possessing 2.9-, 3.05-, 3.2-, or 4.4-MDa beta-lactamase plasmids; strains with high-level, plasmid-mediated tetracycline resistance (TRNG); strains with plasmid-mediated resistance to penicillin and tetracycline; and strains with chromosomally mediated resistance to penicillin and tetracycline (CMRNG). Ceftriaxone, cefixime, and ciprofloxacin were the most active agents tested against all strains. Pen(s), TRNG, and PPNG strains possessing a 3.2-MDa beta-lactamase plasmid were more susceptible to amoxicillin-clavulanic acid, extended- and broad-spectrum cephalosporins, and quinolones than were either PPNG strains possessing a 2.9-, a 3.05-, or a 4.4-MDa beta-lactamase plasmid or CMRNG strains.
Temporal changes of pharmacokinetics, nephrotoxicity, and subcellular distribution of tobramycin in rats
Authors: Lin L , Grenier L , Bergeron Y , Simard M , Bergeron M G , Labrecque G , Beauchamp D
Published: June 2012

The present study was designed to determine the temporal changes in tobramycin nephrotoxicity during the dark and the light periods of the day and to look for the mechanisms of such changes. Female Sprague-Dawley rats (9 to 11 weeks old) were housed in a 14-h-light-10-h-dark cycle (lights on 0600 to 2000 h). A bolus of tobramycin (60 mg/kg of body weight) was intravenously injected into a first group of 15 rats, at either 1400 or 0200 h. Six blood samples were taken from each rat, 30 to 210 min after the bolus injection. The total clearance of the drug was reduced during the rest period (1400 h) of rats compared with the activity period (0200 h) (P = 0.0007). Another group of 99 rats was given intraperitoneally a single dose of tobramycin (40 mg/kg), and renal cortices were collected 2 to 222 h after injection. The cortical drug levels were always higher in animals injected at 1400 h than in those injected at 0200 h. A last group of 32 rats was used in the studies of tobramycin (30 mg/kg/day, once daily for 10 days, intraperitoneally) nephrotoxicity and subcellular distribution. Weight gain in the rats receiving tobramycin (both 1400 and 0200 h) was significantly (P = 0.028) less than that in the controls. Nephrotoxicity, indicated by the incorporation of [3H]thymidine into cortical DNA and urinary excretion of N-acetyl-beta-D-glucosaminidase, was significantly higher in animals treated at 1400 h than in those treated at 0200 h. No difference in the subcellular distribution of tobramycin was observed. The data indicate that the reduction in the clearance of tobramycin during the rest period is in part responsible for the higher nephrotoxicity in rats.
Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain
Authors: Black P H
Published: June 2012

A bidirectional circuit exists between the central nervous system and the immune system, since activation of the immune system results in the elaboration of cytokines and inflammatory mediators; these mediators induce hypothalamic CRF, which stimulates the release of the same immunosuppressive molecules that mediate the response to stress. The brain, therefore, is likely to be involved in immune system regulation. Hypofunctioning of the HPA axis with insufficient down regulation may be involved in autoimmune or other diseases with excessive immune system activation. Hyperfunctioning of the HPA axis, which is not appropriately suppressed, has been found in a large number of patients with major depression. Evidence that stress is an important factor in both lowering resistance to infectious agents and contributing to the reactivation of latent viruses is discussed. Also discussed is the evidence that stress induces proinflammatory cytokines which may contribute to both the pathogenesis of inflammatory diseases of unknown etiology and the progression of HIV infection to AIDS by activation of HIV replication.
Effects of polyaspartic acid on pharmacokinetics of tobramycin in two strains of rat
Authors: Reinhard M K , Bekersky I , Sanders T W , Harris B J , Hottendorf G H
Published: June 2012

To provide insight into polyaspartic acid nephroprotection and differences in aminoglycoside renal toxicity between two rat strains, the single-dose pharmacokinetics of tobramycin was examined in the presence and absence of polyaspartic acid. Following a single subcutaneous 6.5-mg/kg dose of tobramycin alone, higher aminoglycoside concentrations were measured in Sprague-Dawley rats than in Fischer rats (P < 0.05). Simultaneous administration of polyaspartic acid (50 mg/kg) and tobramycin did not alter the concentrations of tobramycin in serum. The amount of tobramycin in renal tissue and the amount recovered in urine over a 24-h period were greater in both rat strains when tobramycin and polyaspartic acid were given concomitantly. In summary, polyaspartic acid did not alter the concentrations in serum achieved after a single dose of tobramycin in two different rat strains but did result in higher renal concentrations and greater urinary excretion of tobramycin.
An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy
Authors: Dietrich M , Gaus W , Kern P , Meyers W M
Published: June 2012

A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well-controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions.
Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase)
Authors: Ryan D M , Ticehurst J , Dempsey M H , Penn C R
Published: June 2012

We demonstrate the potent antiviral activity of a novel viral neuraminidase (sialidase) inhibitor, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose reduced mortality, lung consolidation, and virus titers in the lung, with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated intranasal dose required to reduce virus titers in the lungs of treated animals to 10% of that seen in untreated controls (EDAUC10 [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (EDAUC10, > 100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in terms of its in vitro activity, bioavailability, and pharmacokinetic properties and with the extracellular activity of viral sialidase.
Identification of antimicrobial peptides by using combinatorial libraries made up of unnatural amino acids
Authors: Blondelle S E , Takahashi E , Weber P A , Houghten R A
Published: June 2012

The use of water-soluble synthetic peptide combinatorial libraries permits the systematic examination of tens to hundreds of millions of peptides in existing microdilution assays. In the present study, we prepared and determined the antistaphylococcal activities of two new synthetic peptide combinatorial libraries (one N-acetylated, the other not) composed of tetrapeptides having one position defined and the remaining three positions made up of mixtures of L-, D-, and unnatural amino acids (a total of 58 different amino acids). These libraries, when used in conjunction with an iterative selection process, allowed for the development of a series of individually defined tetrapeptides with high levels of activity against Staphylococcus aureus. The activities of the final individual peptides against two additional strains of gram-positive bacteria (methicillin-resistant S. aureus and Streptococcus sanguis), a gram-negative bacterium (Escherichia coli), as well as the yeast Candida albicans were also determined. Cell viability assays showed that the identified peptides are bacteriostatic against both S. aureus and E. coli.
Potential drug targets for Mycobacterium avium defined by radiometric drug-inhibitor combination techniques
Authors: Rastogi N , Goh K S , Wright E L , Barrow W W
Published: June 2012

Previously established radiometric techniques were used to assess the effectiveness of combined antimicrobial drug-inhibitory drug (drug-inhibitor) treatment on two clinical isolates of the Mycobacterium avium complex representing three colony variants: smooth opaque (dome) (SmO), smooth transparent (SmT), and rough (Rg). All variants were identified as members of the M. avium complex; however, only the SmT colony type of strain 373 possessed characteristic serovar-specific glycopeptidolipid (GPL) antigens. MICs, determined radiometrically, of drugs with the potential to inhibit the biosynthesis of GPL antigens or other cell envelope constituents were similar for all strains. These drugs included cerulenin, N-carbamyl-DL-phenylalanine, N-carbamyl-L-isoleucine, trans-cinnamic acid, ethambutol, 1-fluoro-1-deoxy-beta-D-glucose, 2-deoxy-D-glucose, and m-fluoro-phenylalanine. The MICs of the antimicrobial drugs amikacin, sparfloxacin, and clarithromycin varied, but overall the MICs for the SmO variant were the lowest. Radiometric assessment of drug-inhibitor combinations by using established x/y determinations revealed enhanced activity when either ethambutol or cerulenin were used in combination with all antimicrobial agents for all variants except the Rg variant of strain 424, for which ethambutol was not effective. Enhanced activity with amino acid analogs was observed with the Rg colony variants of strains 373 and 424. Two potential sites for drug targeting were identified: fatty acid synthesis, for all strains assayed, and peptide biosynthesis, particularly for Rg colony variants that possess previously identified phenylalanine-containing lipopeptides as potential targets for future drug development.
In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against chlamydia
Authors: Niki Y , Kimura M , Miyashita N , Soejima R
Published: June 2012

The in vitro and in vivo activities of azithromycin against chlamydia were investigated. The MIC of azithromycin for five standard strains of different species of chlamydia and six wild-type strains of Chlamydia pneumoniae was 0.125 microgram/ml, which was superior to that of erythromycin but inferior to those of clarithromycin and minocycline. However, the therapeutic effect of a 7-day course of azithromycin at a dose of 10 mg/kg of body weight administered orally once daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 14 days after infection, which was the same as that for treatment with minocycline administered at 10 mg/kg twice daily; all erythromycin treated animals died within 10 days. When treatment was discontinued 3 days after the infection, the survival rate for mice treated with azithromycin was 90% and that for mice administered minocycline was 30%. These results suggest that azithromycin may be useful in the treatment of respiratory infections caused by intracellular pathogens, including chlamydia because of its excellent accumulation within host cells.
Antibodies against chromosomal beta-lactamase
Authors: Giwercman B , Rasmussen J W , Cioufu O , Clemmentsen I , Schumacher H , Høiby N
Published: June 2012

A murine monoclonal anti-chromosomal beta-lactamase antibody was developed and an immunoblotting technique was used to study the presence of serum and sputum antibodies against Pseudomonas aeruginosa chromosomal group 1 beta-lactamase in patients with cystic fibrosis (CF). The serum antibody response was studied with serum samples collected in 1992 from 56 CF patients in a cross-sectional study and with serum samples from 18 CF patients in a longitudinal study. Anti-beta-lactamase immunoglobulin G antibodies were present in all of the serum samples from the patients with chronic bronchopulmonary P. aeruginosa infection (CF + P) but in none of the CF patients with no or intermittent P. aeruginosa infection. Anti-beta-lactamase antibodies were present in serum from CF + P patients after six antipseudomonal courses (median) and correlated with infection with a beta-lactam-resistant strain of P. aeruginosa. The sputum antibody response and the beta-lactamase activity in sputum samples from 14 of the CF + P patients were also studied. beta-lactamase antibodies were present in 10 of these samples. P. aeruginosa strains isolated from these samples were partially derepressed, producing group 1 cephalosporinase. We found a wide range of chromosomal beta-lactamase activity in the sputum samples, with no correlation with basal or induced activity of beta-lactamase expression. The presence of anti-beta-lactamase antibodies in endobronchial sputum could be an important factor in the defense against the infection. On the other hand, immune complexes between the beta-lactamase and corresponding antibodies could play a role in the pathogenesis of bronchopulmonary injury in CF by mediating hyperimmune reactions.
Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis
Authors: Jabès D , Della Bruna C , Rossi R , Olliaro P
Published: June 2012

The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guérin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean +/- standard deviation log CFU, 0.2 +/- 0.3, compared with 5.9 +/- 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 micrograms/ml), although they were still susceptible to rifabutin. Three months of treatment with rifabutin, either daily alone or twice a week combined with isoniazid, proved to be a valid candidate for tuberculosis preventive therapy.
In vitro activity of the tribactam GV104326 against gram-positive, gram-negative, and anaerobic bacteria
Authors: Di Modugno E , Erbetti I , Ferrari L , Galassi G , Hammond S M , Xerri L
Published: June 2012

GV104326 is the first member of a new class of antibiotics (tribactams) selected for development. It combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to beta-lactamases, and complete stability to dehydropeptidases. Comparative MICs were determined for GV104326 against 415 recent clinical isolates (including beta-lactamase producers), using representative antibacterial agents (imipenem, amoxicillin-clavulanic acid, cefpirome, ciprofloxacin, gentamicin, and erythromycin). GV104326 was particularly active against gram-positive bacteria; in general, its in vitro activity was equivalent to that of imipenem, equivalent to or better than that of amoxicillin-clavulanic acid, and superior to that of cefpirome, ciprofloxacin, and erythromycin. Against gram-negative bacteria, GV104326 possessed activity similar to that of imipenem and cefpirome against enterobacteria and Haemophilus spp. but its activity was superior to that of amoxicillin-clavulanic acid. GV104326 showed excellent antianaerobe activity. GV104326 was stable to all clinically relevant beta-lactamases and was rapidly lethal to susceptible bacteria. In Escherichia coli, GV104326 bound predominantly to PBPs 1a and 2 and at low concentrations osmotically stable round forms were observed. GV104326 showed an affinity for PBPs 2 and 4 of Staphylococcus aureus.