bluuebunny/crossref_metadata_2025 huggingface dataset:
Posttherapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs
Authors: Harrison C J , Miller R L , Bernstein D I
Published: June 2012

Imiquimod, an immunomodulator with no direct in vitro antiviral activity, has in vivo anti-herpesvirus activity by inducing interferon and enhancing other only partially defined immune responses. Imiquimod treatment of primary genital herpes simplex virus (HSV) infection in guinea pigs reduces the level of genital disease by 90%. We further investigated its utility as suppressive therapy of recurrent disease in animals that had recently recovered from primary genital HSV-2 disease. Imiquimod administered intravaginally once per day for 5 days reduced the number of recurrences only during treatment, while a 21-day regimen reduced the number of recurrences for 8 weeks. For the entire 10 weeks of observation, overall numbers of recurrences were reduced 67% by the 21-day imiquimod treatment (P < 0.0001). Latent HSV in ganglia was not affected by either regimen. Increased circulating alpha interferon activity was observed during therapy with both regimens. Interferon levels rapidly returned to baseline with cessation of treatment. Posttreatment, 5-day imiquimod treatment did not provide clinical benefit or enhancement of cell-mediated or cytokine responses. Twenty-one-day imiquimod treatment reduced both the number of clinical recurrences and levels of HSV antibody for 5 to 6 weeks posttreatment compared with the placebo. Additionally, 21-day imiquimod treatment enhanced HSV antigen-specific interleukin 2 production and proliferative responses by mononuclear cells (P < 0.001) for 4 weeks after treatment. Twenty-one-day imiquimod therapy suppressed recurrent HSV genital disease during and for weeks after therapy, enhanced memory-dependent cytokine and T-cell responses, and reduced the level of antibody responses.
Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence
Authors: Katiyar S K , Gordon V R , McLaughlin G L , Edlind T D
Published: June 2012

Benzimidazoles have been widely used since the 1960s as anthelmintic agents in veterinary and human medicine and as antifungal agents in agriculture. More recently, selected benzimidazole derivatives were shown to be active in vitro against two protozoan parasites, Trichomonas vaginalis and Giardia lamblia, and clinical studies with AIDS patients have suggested that microsporidia are susceptible as well. Here, we first present in vitro susceptibility data for T. vaginalis and G. lamblia using an expanded set of benzimidazole derivatives. Both parasites were highly susceptible to four derivatives, including mebendazole, flubendazole, and fenbendazole (50% inhibitory concentrations of 0.005 to 0.16 microgram/ml). These derivatives also had lethal activity that was time dependent: 90% of T. vaginalis cells failed to recover following a 20-h exposure to mebendazole at 0.17 microgram/ml. G. lamblia, but not T. vaginalis, was highly susceptible to five additional derivatives. Next, we examined in vitro activity of benzimidazoles against additional protozoan parasites: little or no activity was observed against Entamoeba histolytica, Leishmania major, and Acanthamoeba polyphaga. Since the microtubule protein beta-tubulin has been identified as the benzimidazole target in helminths and fungi, potential correlations between benzimidazole activity and beta-tubulin sequence were examined. This analysis included partial sequences (residues 108 to 259) from the organisms mentioned above, as well as the microsporidia Encephalitozoon hellem and Encephalitozoon cuniculi and the sporozoan Cryptosporidium parvum. beta-tubulin residues Glu-198 and, in particular, Phe-200 are strong predictors of benzimidazole susceptibility; both are present in Encephalitozoon spp. but absent in C. parvum.
Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers
Authors: Bowsher R R , Compton J A , Kirkwood J A , Place G D , Jones C D , Mabry T E , Hyslop D L , Hatcher B L , DeSante K A
Published: June 2012

Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.
Nucleotide sequence of a plasmid-mediated cephalosporinase gene (blaLAT-1) found in Klebsiella pneumoniae
Authors: Tzouvelekis L S , Tzelepi E , Mentis A F
Published: June 2012

The nucleotide sequence of the gene encoding a novel cephalosporinase (LAT-1), carried by a non-self-transferable plasmid from Klebsiella pneumoniae, has been determined. It was found that the sequence shares a high degree of homology with the Citrobacter freundii OS60 ampC structural gene.
Penetration of cefprozil into middle ear fluid of patients with otitis media
Authors: Shyu W C , Haddad J , Reilly J , Khan W N , Campbell D A , Tsai Y , Barbhaiya R H
Published: June 2012

Penetration of cefprozil into the middle ear fluid was investigated in patients with chronic otitis media. A total of 89 patients ranging from 7 months to 11 years old participated in the study. The middle ear fluid was removed by ventilation tubes inserted through the tympanic membrane at times ranging from 0.38 to 5.97 h after oral administration of a single dose of 15 or 20 mg/kg of body weight. A blood sample was also collected as soon as the middle ear fluid was removed. Plasma samples were analyzed for the concentration of cefprozil by a high-performance liquid chromatographic assay. Middle ear fluid samples were analyzed for the concentration of cefprozil by a microbiological assay. The concentrations of cefprozil in plasma ranged from 0.38 to 15.97 micrograms/ml at the 15-mg/kg dose level and from 1.28 to 21.47 micrograms/ml at the 20-mg/kg dose level. The corresponding middle ear fluid concentrations of cefprozil ranged from 0.06 to 4.44 micrograms/ml and from 0.17 to 8.67 micrograms/ml, respectively. Cefprozil penetrates well into middle ear fluid in patients with chronic otitis media.
Evaluation of effects of altered gastric pH on absorption of dapsone in healthy volunteers
Authors: Breen G A , Brocavich J M , Etzel J V , Shah V , Schaefer P , Forlenza S
Published: June 2012

A prospective, randomized, crossover study was performed with seven healthy volunteers to address the effect of increased gastric pH on dapsone absorption. Subjects were randomized to receive a single 100-mg dose of dapsone or a single 100-mg dose of dapsone in addition to 30 ml of a high potency antacid 1 h before dapsone administration and hourly thereafter for a total of 10 doses. Dapsone concentrations in serum were measured periodically for 48 h. No statistical differences between the two regimens were noted when mean dapsone maximal initial concentrations, times to peak, and areas under the curve were compared. These data suggest that an increase in gastric pH has little or no effect on the absorption of dapsone in healthy subjects.
Nucleotide sequence of the gyrA gene and characterization of ciprofloxacin-resistant mutants of Helicobacter pylori
Authors: Moore R A , Beckthold B , Wong S , Kureishi A , Bryan L E
Published: June 2012

PCR was used to amplify a 238-bp region from Helicobacter pylori which corresponded to the quinolone resistance-determining region in Escherichia coli. The gyrA gene of H. pylori was cloned and sequenced. An open reading frame of 2,478 nucleotides coded for a polypeptide of 826 amino acids with a calculated molecular mass of 92,508 Da. The amino acid sequence showed an overall 52% identity with other bacterial gyrA genes but was most closely related to the gyrA subunit of Campylobacter jejuni (76.5% identity). Sequencing of the amplification product from ciprofloxacin-resistant mutants of H. pylori revealed four classes of mutations with substitutions at amino acid 87 (Asn-->Lys), amino acid 88 (Ala-->Val), and amino acid 91 (Asp-->Gly, -->Asn, or -->Tyr) and a double substitution at amino acids 91 and 97 (Ala-->Val). Ciprofloxacin-susceptible strains of H. pylori could be transformed to ciprofloxacin resistance by using the amplified fragment from resistant strains as donor DNA. Of the 11 ciprofloxacin-resistant mutants examined, only one did not have an alteration within the quinolone resistance-determining region, suggesting that, in H. pylori, resistance to quinolones is primarily a result of alterations in gyrA.
Immediate zidovudine treatment protects simian immunodeficiency virus-infected newborn macaques against rapid onset of AIDS
Authors: Van Rompay K K , Otsyula M G , Marthas M L , Miller C J , McChesney M B , Pedersen N C
Published: June 2012

Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a practical animal model of pediatric AIDS. Intravenous inoculation of rhesus newborns with uncloned SIVmac resulted in a high virus load, no antiviral immune responses, severe immunodeficiency, and a high mortality rate within 3 months. In contrast, immediate oral zidovudine (AZT) treatment of SIV-inoculated rhesus newborns either prevented infection or resulted in reduced virus load, enhanced antiviral immune responses, a low frequency of AZT-resistant virus isolates, and delayed disease progression with negligible toxicity. These results suggest that early chronic AZT treatment of human immunodeficiency virus-exposed newborns may have benefits that outweigh its potential side effects.
Single amino acid replacements at positions altered in naturally occurring extended-spectrum TEM beta-lactamases
Authors: Blazquez J , Morosini M I , Negri M C , Gonzalez-Leiza M , Baquero F
Published: June 2012

By directed mutagenesis, we constructed a set of seven TEM-1 derivatives containing single replacements in each one of the amino acids substituted in naturally occurring extended-spectrum TEM beta-lactamases. The exact contribution of each mutation to the resistance phenotype was determined. In addition, mutant enzyme production and stabilities were studied. Five of seven mutations determined to some extent variations in cephalosporin and/or monobactam activity. Dramatic changes in the hydrolysis of ceftazidime and aztreonam occurred when a serine was at position 164. Changes at positions 104, 238, and 240 showed more leaky variation in activity towards cephalosporins and aztreonam. Replacements at positions 237 and 265 caused no variation in susceptibility to cephalosporins. Interestingly, the change from Gln to Lys at position 39 found in TEM-2, classically considered a neutral change, slightly but consistently increased the MIC of ceftazidime and aztreonam. The in vitro construction of mutations appearing in naturally occurring TEM-beta-lactamases, studied in the same genetic context, may help to understand the evolution of extended-spectrum beta-lactamases.
Comparative study of mupirocin and oral co-trimoxazole plus topical fusidic acid in eradication of nasal carriage of methicillin-resistant Staphylococcus aureus
Authors: Parras F , Guerrero M C , Bouza E , Blázquez M J , Moreno S , Menarguez M C , Cercenado E
Published: June 2012

Mupirocin is a topically applied drug that is very active in the eradication of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). However, studies designed to compare mupirocin treatment with other antimicrobial regimens are lacking. We therefore conducted an open, prospective, randomized, controlled trial to compare the efficacy and safety of mupirocin versus those of oral co-trimoxazole plus topical fusidic acid (both regimens with a clorhexidine scrub bath) for the eradication of MRSA from nasal and extranasal carriers of MRSA. The eradication rates with mupirocin and co-trimoxazole plus fusidic acid at 2, 7, 14, 21, 28, and 90 days were 93 and of 93, 100 and 100, 97 and 94, 100 and 92, 96 and 95, and 78 and 71%, respectively, for nasal carriage. At 7, 14, and 28 days the eradication rates for extranasal carriage by the two regimens were 23 and 74, 83 and 76, and 45 and 69%, respectively. The efficacies and safety of both regimens were similar. The MRSA isolates were not resistant to the study drugs either at the baseline or at follow-up. These results suggest that mupirocin and co-trimoxazole plus fusidic acid, both used in conjunction with a chlorhexidine soap bath, are equally effective and safe for the eradication of MRSA from nasal and extranasal MRSA carriers. Mupirocin was easier to use but was more expensive.
Randomized, double-blind comparison of single-dose regimens of rufloxacin and pefloxacin for acute uncomplicated cystitis in women. French Multicenter Urinary Tract Infection-Rufloxacin Group
Authors: Jardin A , Cesana M
Published: June 2012

In a double-blind, randomized, multicenter study, 463 adult women with symptomatic acute uncomplicated cystitis were treated orally with either a 400-mg single dose of rufloxacin (n = 226) or an 800-mg single dose of pefloxacin (n = 237). Escherichia coli (78%) and Proteus mirabilis (7%) were the most common isolates from 350 patients with significant pretreatment bacteriuria (uropathogens, > or = 10(5) CFU/ml). In the intention-to-treat analysis of patients with significant pretreatment bacteriuria, 343 patients were assessed for bacteriological outcome and 345 were assessed for clinical outcome. The bacteriological cure rate was 88% in the rufloxacin group and 84% in the pefloxacin group (95% confidence interval [CI] for difference in proportions, -4 to 12%), while the clinical resolution rate was 85 and 84%, respectively (95% CI, -8 to 9%). The per-protocol analysis demonstrated that among the 264 assessable patients, the bacteriological cure rate obtained with rufloxacin at 4 weeks of follow-up was comparable to that with pefloxacin (91 versus 85%; 95% CI, -3 to 15%). Among 295 clinically assessable patients, the clinical resolution rate at 4 weeks of follow-up was 89% in the rufloxacin group and 88% in the pefloxacin group (95% CI, -6 to 10%). Potentially drug-related adverse events occurred in 19% of the rufloxacin patients and in 18% of the pefloxacin patients. A single oral dose of 400 mg of rufloxacin is as effective and safe as a single oral dose of 800 mg of pefloxacin for the treatment of acute uncomplicated cystitis in women.
Amikacin levels in bronchial secretions of 10 pneumonia patients with respiratory support treated once daily versus twice daily
Authors: Santré C , Georges H , Jacquier J M , Leroy O , Beuscart C , Buguin D , Beaucaire G
Published: June 2012

In this study, concentrations of amikacin in blood and bronchial secretions of 10 patients with mechanical ventilation for acute respiratory failure due to pneumonia were measured. One-half of the patients received amikacin twice daily, and the others received once-daily administration. Concentrations in bronchial secretions of the patients treated twice daily ranged from 3 to 4 mg/liter, i.e., they were similar to those in previously published reports. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion, and they reached 4.8 +/- 2.6 mg/liter on day 1 and 4.0 +/- 2.7 mg/liter on day 3. For the patients treated with amikacin once daily, concentrations in bronchial secretions were more than twofold higher, above 8 mg/liter for 12 h. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion and reached 13.6 +/- 9.3 mg/liter on day 1 and 10.4 +/- 3.5 mg/liter on day 3. These concentrations are higher than the MICs for less sensitive bacterial strains, such as Acinetobacter spp. and Pseudomonas aeruginosa.
Antimicrobial susceptibilities of Stomatococcus mucilaginosus and of Micrococcus spp
Authors: von Eiff C , Herrmann M , Peters G
Published: June 2012

The in vitro susceptibilities of 63 isolates of Stomatococcus mucilaginosus and of 188 isolates of Micrococcus spp. to 18 antimicrobial agents were determined by the agar dilution method. Many beta-lactams, imipenem, rifampin, and the glycopeptides were shown to be active in vitro against Stomatococcus and Micrococcus isolates, whereas the activities of antibiotics such as some aminoglycosides, erythromycin, and fosfomycin against an important number of these microorganisms are limited.
Mutations in katG gene sequences in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis are rare
Authors: Pretorius G S , van Helden P D , Sirgel F , Eisenach K D , Victor T C
Published: June 2012

In this study, a battery of oligonucleotides was directed toward the katG gene and PCR-single-stranded conformation polymorphism (SSCP) analysis was used to search for katG gene deviations in clinical isolates of Mycobacterium tuberculosis from different geographical regions. Since a complete deletion of the katG gene was not found, it is suggested that deletion is not a major mechanism of isoniazid (isonicotinic acid hydrazide; INH) resistance in these isolates. However, 7 of 39 isolates (4 of 25 from South Africa and 3 of 14 from other geographical regions) showed mobility shifts by SSCP analysis, suggesting aberrations in the katG gene. Direct sequence analysis confirmed that the mobility shifts were due to Thr-275-->Ala (Thr275Ala), Arg409Ala, Arg463Leu, and Asp695Ala mutations and a 12-bp deletion in the 5' region of the katG gene. Mutations at codons 275, 463, and 695 created altered restriction sites for HhaI, MspI, and HaeIII, respectively, and sequence results, supported by restriction fragment length polymorphism analysis, suggested that the PCR-SSCP procedure is a good indicator of mutations in PCR-amplified fragments. Identical mutations at codons 463 and 275 were found in isolates from different geographical regions. This may suggest a common evolutionary event, but one of the control isolates (susceptible to INH [3%; n = 30]) also had a mutation at codon 463. The results suggest that variations in the katG coding gene sequences of INH-resistant isolates of M. tuberculosis are infrequent and that defects in other regions of the M. tuberculosis genome are of equal or greater importance in contributing to the acquisition of resistance to INH.
Antimicrobial activity of CS-940, a new trifluorinated quinolone
Authors: Biedenbach D J , Sutton L D , Jones R N
Published: June 2012

The antimicrobial activity of CS-940, a new trifluorinated quinolone drug, was tested against 761 clinical isolates. CS-940 activity against members of the family Enterobacteriaceae was most similar to that of ciprofloxacin and ofloxacin, with a large range of MICs inhibiting 90% of isolates tested (MIC90S) of 0.015 to 16 micrograms/ml (median MIC90, 0.06 micrograms/ml). CS-940 had greater activity than ciprofloxacin or ofloxacin when they were tested against Acinetobacter spp. (MIC90S, 0.03 micrograms/ml) and Stenotrophomonas (Xanthomonas) maltophilia (MIC90S, 2 micrograms/ml). CS-940 demonstrated a high degree of potency against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. (MIC90S, < or = 0.06 micrograms/ml). CS-940 was two- to eightfold more active than ciprofloxacin or ofloxacin against oxacillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, and coagulase-negative Staphylococcus spp. CS-940 was also very active against Streptococcus spp. and enterococci, for which MIC90S were < or = 2 micrograms/ml; for Enterococcus faecium, however, the MIC90 was 4 micrograms/ml. CS-940 was generally less active than a comparison investigational fluoroquinolone, clinafloxacin. This compound appears promising by in vitro test analysis and warrants further in vivo trials.
Antimicrobial and mercury resistance in aerobic gram-negative bacilli in fecal flora among persons with and without dental amalgam fillings
Authors: Osterblad M , Leistevuo J , Leistevuo T , Järvinen H , Pyy L , Tenovuo J , Huovinen P
Published: June 2012

Antimicrobial resistance is more widespread than can be accounted for as being a consequence of the selection pressure caused by the use of antibiotics alone. In this study, we tested the hypothesis that a high mercury content in feces might select for mercury-resistant bacteria and thus for antimicrobial resistance linked to mercury resistance. Three subject groups with different exposures to dental amalgam fillings were compared. None of the subjects had taken antimicrobial agents during the three preceding months or longer. The group exposed to dental amalgam (n = 92) had 13 times more mercury in feces than the group that had never been exposed to amalgam (n = 43) and the group whose amalgam fillings had been removed (n = 56). No significant differences in either mercury resistance or antibiotic resistance in the fecal aerobic gram-negative flora of these subject groups were seen. The following antimicrobial resistance frequencies were detected with a replica plating method: > or = 1% resistance was seen in 40% of the subjects for ampicillin, 14% of the subjects for cefuroxime, 6% of the subjects for nalidixic acid, 14% of the subjects for trimethoprim, 19% of the subjects for sulfamethoxazole, and 25% of the subjects for tetracycline. The amount of mercury in feces derived from amalgam was not selective for any resistance factors in aerobic gram-negative bacteria, but antimicrobial resistance was widespread even among healthy subjects with no recent exposure to antibiotics.
Detection of human cytomegalovirus mutations associated with ganciclovir resistance in cerebrospinal fluid of AIDS patients with central nervous system disease
Authors: Wolf D G , Lee D J , Spector S A
Published: June 2012

To examine the involvement of ganciclovir-resistant strains in the development of central nervous system (CNS) disease caused by human cytomegalovirus (HCMV), 14 AIDS patients with CNS disease caused by HCMV were studied for the presence of HCMV strains with UL97 gene mutations associated with ganciclovir resistance by using amplification and direct sequencing of HCMV DNA in cerebrospinal fluid (CSF). The CSF of all seven patients who had not received ganciclovir prior to the development of CNS disease and four patients who had been receiving the drug for 3 to 8 months contained wild-type UL97 sequences. The CSF of three patients who had received ganciclovir for 12 to 30 months contained HCMV strains with nucleotide changes leading to single-amino-acid substitutions within conserved UL97 sites implicated in nucleotide binding (position 460) and substrate recognition (position 591). Patients containing mutant and wild-type strains revealed a similar spectrum of clinical and histopathologic manifestations. These findings indicate that CNS disease in AIDS patients receiving prolonged ganciclovir therapy can be caused by ganciclovir-resistant HCMV strains. Direct genotypic analysis of HCMV DNA within CSF should help to identify ganciclovir-resistant virus and to guide anti-HCMV therapy.
Killing activity of cefpirome against penicillin-resistant Streptococcus pneumoniae isolates from patients with meningitis in a pharmacodynamic model simulating the cerebrospinal fluid concentration profile
Authors: Fitoussi F , Doit C , Sandin A , Pechinot A , Kazmierczack A , Geslin P , Bingen E
Published: June 2012

An in vitro pharmacodynamic model was used to determine the killing kinetics of cefpirome against 20 Streptococcus pneumoniae strains (penicillin G MICs, > 0.125 to 2 micrograms/ml) isolated from patients with meningitis. The concentration of cefpirome was adjusted dynamically to simulate the median concentration profile obtained in the cerebrospinal fluid of adults after the infusion of a single dose of 2 g. The cefpirome MIC at which 90% of isolates are inhibited was 0.5 microgram/ml. Bactericidal activity was observed at 6 h, with mean killing of 3.51 +/- 0.34 log10 CFU/ml for all strains for which the cefpirome MIC was < 0.5 microgram/ml. In contrast, for strains for which the cefpirome MIC was > or = 0.5 microgram/ml, killing was significantly less (P < 0.05), with a mean reduction of only 2.86 +/- 0.57 log10 CFU/ml.
Successful treatment of cryptococcal meningitis with amphotericin B colloidal dispersion: report of four cases
Authors: Valero G , Graybill J R
Published: June 2012

Four patients with cryptococcal meningitis were treated with amphotericin B colloidal dispersion because of nephrotoxicity from prior treatment with conventional amphotericin B. The limited experience presented here suggests that amphotericin B colloidal dispersion is efficacious for the treatment of cryptococcal meningitis, despite being undetectable in cerebrospinal fluid, and offers a potential therapeutic alternative for patients who cannot tolerate conventional amphotericin B.
Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy
Authors: Gakunju D M , Mberu E K , Dossaji S F , Gray A I , Waigh R D , Waterman P G , Watkins W M
Published: June 2012

Bioassay-guided fractionation of extracts of Toddalia asiatica, a plant used by the Pokot tribe of Kenya to treat fevers, has yielded the alkaloid nitidine as the major antimalarial component. Fractions containing nitidine have in vitro 50% inhibitory concentrations against Plasmodium falciparum in the range of 9 to 108 ng/ml for a range of chloroquine-susceptible and -resistant strains. The results show a lack of cross-resistance between chloroquine and nitidine.
Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines
Authors: Vennerstrom J L , Makler M T , Angerhofer C K , Williams J A
Published: June 2012

In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue. Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquine-susceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.
Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans
Authors: Soul-Lawton J , Seaber E , On N , Wootton R , Rolan P , Posner J
Published: June 2012

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma = 0.19 microM), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 45% in urine and 475 in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.
Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates
Authors: Blaney S M , Daniel M J , Harker A J , Godwin K , Balis F M
Published: June 2012

2'-Deoxy-3'-thiacytidine is a dideoxycytidine analog with a sulfur in place of the 3' carbon of the ribose. There are two enantiomeric forms of the compound, both of which inhibit human immunodeficiency virus type 1 and 2 replication in vitro. However, the (-) enantiomer (lamivudine) appears to be significantly less cytotoxic to uninfected lymphocytes than is the (+) enantiomer. Lamivudine has entered initial clinical trials, and the present study was designed to describe the pharmacokinetic behavior of this compound in both plasma and cerebrospinal fluid (CSF) of primates. Lamivudine was administered as an intravenous bolus dose of 20 mg/kg for 24 h for administration. Urine samples were also obtained from two animals. The same dose of the racemate (BCH-189) was administered to one animal. The drug was quantitated in CSF and plasma with a reverse-phase high-pressure liquid chromatography technique. Elimination of lamivudine from plasma was biexponential, with a mean alpha phase half-life of 5.4 min, a mean beta phase half-life of 84 min, and a total clearance of 6.1 liters/h. The total clearance of the same dose of BCH-189 in a single animal was 11.0 liters/h. In two animals from which urine was obtained for 12 h postadministration, 32 and 59% of the drug was recovered unchanged. The deamination product of lamivudine was not detected. The CSF/plasma ratio of lamivudine was significantly higher when the drug was measured in the lumbar CSF (mean, 0.41) than when it was measured in the ventricular CSF (mean, 0.079). The measured CSF/plasma ratio for ventricular CSF is equivalent to that of other dideoxycytidine analogs, confirming the importance of the nucleobase in determining the degree of CSF penetration. The difference in lamivudine exposure in ventricular and lumbar CSF suggests that there is a transport mechanism for efflux of cytidine analogs from ventricular CSF.
In vitro antimicrobial effect against Streptococcus pneumoniae of adding rifampin to penicillin, ceftriaxone, or 1-ofloxacin
Authors: Giron K P , Gross M E , Musher D M , Williams T W , Tharappel R A
Published: June 2012

Adding rifampin to penicillin or l-ofloxacin diminished the rate at which these antibiotics killed 21 clinical isolates isolates of Streptococcus pneumoniae in vitro. A less pronounced inhibitory effect was observed when rifampin was added to ceftriaxone. Synergy was not observed for any bacterial isolate. The in vitro demonstration of indifference or antagonism using these antibiotic combinations argues against the empirical addition of rifampin to beta-lactams or fluoroquinolones in treating serious pneumococcal infections.
Comparative in vitro activities of LY191145, a new glycopeptide, and vancomycin against Staphylococcus aureus and Staphylococcus-infected fibrin clots
Authors: Kang S L , Rybak M J
Published: June 2012

Bactericidal activities of LY191145, an investigational glycopeptide, and vancomycin against Staphylococcus aureus were evaluated. Only LY191145 at a concentration 16-fold greater than the MIC was able to achieve 99.9% killing against methicillin-susceptible S. aureus (ATCC 25923; 8.0 h). Both agents demonstrated 99.9% killing against methicillin-resistant clinical isolate S. aureus MRSA67 over 24 h at concentrations 4-, 8-, and 16-fold greater than the MIC, but bacteria were killed at a more rapid rate by LY191145 (1.63 versus 5.02 h; P < 0.001). Against strain ATCC 25923- and MRSA67-infected fibrin clots, total reductions by LY191145 and vancomycin over 72 h were not statistically significantly different at a concentration 16 times the MIC (1.12 +/- 0.31 and 1.23 +/- 0.13 and 1.40 +/- 0.17 and 1.36 +/- 0.37 CFU/g; respectively). Increasing the drug concentration to 50 times the MIC did not alter the values significantly, and there was no statistically significant difference between the two agents. Overall, LY191145 exhibited more rapid bactericidal activity than vancomycin against S. aureus, and a concentration 16-fold greater than the MIC appears to be optimal.
Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin
Authors: Conte J E , Golden J A , Duncan S , McKenna E , Zurlinden E
Published: June 2012

The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean +/- standard deviation) of ELF were 1.9 +/- 2.0 ml and 1.5 +/- 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 +/- 73.0 micrograms/ml at 8 h to 11.9 +/- 3.6 micrograms/ml at 24 h) and alveolar cells (range, 505.8 +/- 293.1 micrograms/ml at 4 h to 17.0 +/- 34.0 micrograms/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 +/- microgram/ml in ELF and 0 to 0.8 +/- 1.3 microgram/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments in unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.
Subinhibitory concentrations of cefpodoxime alter membrane protein expression of Actinobacillus actinomycetemcomitans and enhance its susceptibility to killing by neutrophils
Authors: Baker P J , Busby W F , Wilson M E
Published: June 2012

The aim of the present study was to determine the effect of the antibiotic cefpodoxime on the gram-negative periodontopathic microorganism Actinobacillus actinomycetemcomitans and its interaction with elements of the host immune system. Growth of A. actinomycetemcomitans in subinhibitory concentrations of cefpodoxime induced morphological changes in the bacteria, causing the organisms to grow as filaments rather than coccobacilli. Growth in cefpodoxime did not render these bacteria susceptible to killing by serum, nor did it abrogate the requirement for serum opsonins to support the bactericidal activity of neutrophils. Cefpodoxime enhanced the susceptibility of A. actinomycetemcomitans to the bactericidal activity of neutrophils. In the presence of suitable opsonins, neutrophils were able to kill four times as many cefpodoxime-induced A. actinomycetemcomitans filaments as untreated A. actinomycetemcomitans CFU. This effect was due to antibiotic actions on the bacterium and not on the neutrophil. At inhibitory concentrations, the bactericidal activities of cefpodoxime and neutrophils were additive, and cefpodoxime did not interfere with the normal functioning of the neutrophils. Concomitant with these morphological and functional changes, the expression of two outer membrane proteins (66 and 29 kDa) and one inner membrane protein (57 kDa) was decreased in A. actinomycetemcomitans grown in cefpodoxime. The concentration range over which cefpodoxime is effective against A. actinomycetemcomitans in vivo may be extended by the ability of subinhibitory concentrations to enhance the susceptibility of this organism to host immune defenses.
Right-sided endocarditis caused by Staphylococcus aureus in drug abusers
Authors: Fortún J , Pérez-Molina J A , Añón M T , Martínez-Beltrán J , Loza E , Guerrero A
Published: June 2012

A prospective, open, and randomized study of right-sided endocarditis caused by Staphylococcus aureus in drug abuse patients is reported. The following parenteral treatments were compared. Group A patients were treated with 2 g of cloxacillin every 4 h and 1.5 mg of gentamicin per kg of body weight every 8 h for 2 weeks. Group B patients were treated with teicoplanin at 10 mg/kg/12 h on the 1st to 3rd days, 6 mg/kg/12 h on the 4th to 7th days, and 7 mg/kg/24 h on the 8th days. Drug abusers with bacteremia caused by S. aureus and suggestive signs of endocarditis were included. Clinical failures were observed in one patient in group A and in four of six patients in group B. Three patients in group B developed breakthrough bacteremia with teicoplanin-susceptible strains on days +6, +14, and +19. Serum teicoplanin levels and serum bactericidal titers showed a decrease in the 2nd week, when dosages received were 7 mg/kg/day. In conclusion, in treatment of right-sided endocarditis caused by S. aureus in drug abusers with teicoplanin, the use of dosages of 7 mg/kg/day is not recommended even if patients have received dosages of 12 mg/kg/day during the 1st week.
Polymyxin B stimulates production of complement components and cytokines in human monocytes
Authors: Høgåsen A K , Abrahamsen T G
Published: June 2012

Polymyxin B (PmB), an agent often used to neutralize the effects of bacterial lipopolysaccharide (LPS), was shown to exert a dose-dependent stimulatory effect on the biosynthesis of C3, factor B, interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in human monocytes. A low dose of PmB (1 to 5 micrograms/ml) efficiently suppressed the LPS-induced (1 or 100 ng/ml) production of IL-6, GM-CSF, and factor B, but not the C3 production induced by 100 ng of LPS per ml. A reduced level of GM-CSF may have contributed to the persisting high C3 concentrations and the apparent lack of LPS inhibition in the latter situation, since GM-CSF is an inhibitor of monocyte C3 biosynthesis.
Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B
Authors: Sugar A M , Hitchcock C A , Troke P F , Picard M
Published: June 2012

A study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems, combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and, consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.
Mechanism of tonB-dependent transport of KP-736, a 1,5-dihydroxy-4-pyridone-substituted cephalosporin, into Escherichia coli K-12 cells
Authors: Tatsumi Y , Maejima T , Mitsuhashi S
Published: June 2012

The mechanism of transport of KP-736, a novel cephalosporin with a 1,5-dihydroxy-4-pyridone moiety at the C-7 position, into the Escherichia coli K-12 cell was investigated by determining the susceptibilities of iron transport mutants to KP-736. The tonB mutant showed a higher degree of resistance to KP-736, indicating that KP-736 was incorporated into E. coli cells via the tonB-dependent iron transport system. The product of the exbB gene was also necessary for the maximal antibacterial potency of KP-736. Cir-lacking and Fiu-lacking mutants showed a moderate level of resistance to KP-736. However, mutants lacking any one of the proteins FepA, FecA, FhuA, and FhuE did not show any increased resistance to KP-736. Two types of spontaneous mutants (e.g., KT1004 and KT1011) could be isolated from cir and fiu mutants by selection for KP-736 resistance and showed the same level of resistance to KP-736 as a tonB mutant. KT1004 showed tonB phenotypes, resistance to phage phi 80, and loss of FecA, whereas KT1011 did not. KT1011 lost the ability to express both Cir and Fiu proteins. These results indicate that the Cir and Fiu outer membrane proteins are involved specifically in the tonB-dependent transport process of KP-736. Against OmpF- and OmpC-deficient transformants producing various groups of beta-lactamases, KP-736 was more effective than the other cephalosporins tested.
Safety and bioequivalency of three formulations of respiratory syncytial virus-enriched immunoglobulin
Authors: Groothuis J R , Simoes E A , Lehr M V , Kramer A A , Hemming V G , Rodriguez W J , Arrobio J , Welliver R C , Siber G R
Published: June 2012

Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We compared LYO, LYO-VI, and a more convenient liquid RSVIG (LIQ-VI) in 30 preterm infants (median age, 7 months; median weight, 5.4 kg). Infants were randomized to receive LYO (n = 10), LYO-VI (n = 10), or LIQ-VI (n = 10) in monthly infusions of 750 mg/kg of body weight per dose (December to March). Children were monitored closely for adverse reactions to RSVIG and for RSV illness.
Mechanism of enhanced antipseudomonal activity of BO-2727, a new injectable 1-beta-methyl carbapenem
Authors: Hazumi N , Fuse A , Matsuda K , Hashizume T , Sanada M
Published: June 2012

The mechanism of the enhanced activity of BO-2727 against imipenem-resistant Pseudomonas aeruginosa was studied by using a set of four isogenic strains derived from beta-lactamase-deficient P. aeruginosa PAO4089 (blaJ blaP). Complementation of the blaJ and blaP mutations conferred greater resistance to biapenem, panipenem, and imipenem than to BO-2727 and meropenem, most notably in the outer membrane protein D2-deficient strain. The higher levels of resistance to biapenem, panipenem, and imipenem can be explained by the slow but significant hydrolysis by beta-lactamase, whereas the reduced levels of resistance to BO-2727 and meropenem would be attributable to their stability in the presence of high levels of beta-lactamase and the fact that they cause only low induction of beta-lactamase. It is also noted that the activity of BO-2727 against the beta-lactamase-deficient strain was less affected by the loss of the D2 porin than was that of meropenem, indicating that BO-2727 in comparison with meropenem can overcome an intrinsic resistance caused by the loss of D2. Moreover, comparative in vitro resistance studies have shown that BO-2727 and meropenem selected fewer resistant cells than other carbapenems. In conclusion, BO-2727 exhibited improved activity against imipenem-resistant P. aeruginosa, probably because of its ability to overcome loss of the D2 porin and beta-lactamase hydrolysis.
In vitro activity and killing effect of DX-8739, a new carbapenem, compared with those of meropenem and imipenem against multiresistant Pseudomonas aeruginosa
Authors: Giamarellos-Bourboulis E J , Grecka P , Giamarellou H
Published: June 2012

DX-8739 is a new dehydropeptidase I-stable carbapenem. In order to evaluate its activity in comparison with those of meropenem and imipenem, 147 multiresistant Pseudomonas aeruginosa isolates acquired nosocomially were simultaneously exposed to the actions of the three carbapenems in vitro, whereas to compare their killing effects on 14 strains, 56 killing curve studies were performed. Overall DX-8739 was found to possess inhibitory activity as well as bactericidal activity statistically superior to those of meropenem and imipenem. At a concentration of 4 micrograms/ml, 106 strains (72.1%) were found to be imipenem resistant; 33 and 27.4% of these strains were inhibited by DX-8739 and meropenem, respectively, a statistically significant difference (P < 0.05). DX-8739 was also shown to possess intrinsic activity in vitro superior to those of meropenem and imipenem against the imipenem-susceptible population of strains. However, no statistically significant difference regarding the comparative killing activities of the three studied carbapenems was observed. Following exposure to carbapenem for 24 h, 33.3, 44.4, and 70% of the strains which survived became resistant to DX-8739, meropenem, and imipenem, respectively. The reported results demonstrate the significant activity of DX-8739 against multiresistant P. aeruginosa strains acquired nosocomially. The mechanism of action of DX-8739 on P. aeruginosa is unknown, and various hypotheses that might explain its in vitro superiority over meropenem and imipenem are proposed.