bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells
Authors: Nagata K , Satoh H , Iwahi T , Shimoyama T , Tamura T
Published: June 2012

The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacter pylori cells; the 50% inhibitory concentrations were between 3.6 and 9.5 microM, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents N-ethylmaleimide and idoacetamide were also examined for their inhibition of the urease activity; their 50% inhibitory concentrations were 100- to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth.
Effect of oral antacids on disposition of intravenous enoxacin
Authors: Nix D E , Lebsack M E , Chapelsky M , Sedman A J , Busch J , Norman A
Published: June 2012

The effect of an intensive aluminum-magnesium hydroxide antacid regimen (Maalox TC) on the disposition of intravenous enoxacin was studied in six male and six female volunteers. A single 400-mg dose of enoxacin was administered intravenously over 30 min on two occasions separated by a 1-week washout period. Thirty milliliters of Maalox TC was administered at -8, -2.5, -0.5, 1.5, 3.5, 5.5, 7.5, 9.5, 11.5, 13.5, and 15.5 h relative to the start of one enoxacin infusion. The enoxacin dose in which antacid was coadministered was randomly selected. Fourteen plasma samples were collected over 24 h, and urine was collected in two divided intervals over 48 h. Enoxacin concentrations in plasma and urine samples were determined by high-performance liquid chromatographic assays. The intensive antacid regimen did not change the total clearance (P = 0.058) or steady-state volume of distribution (P = 0.516) for enoxacin. However, the nonrenal clearance and half-life were significantly altered (P < 0.05). The mean nonrenal clearance increased from 13.27 +/- 3.33 to 15.68 +/- 2.35 liters/h (18.2%) following the antacid regimen. This effect of antacid is unlikely to be of clinical significance. Enoxacin may be administered intravenously, but not orally, without regard to antacid treatment.
Ecology of Haemophilus influenzae and Haemophilus parainfluenzae in sputum and saliva and effects of antibiotics on their distribution in patients with lower respiratory tract infections
Authors: Foweraker J E , Cooke N J , Hawkey P M
Published: June 2012

Nine patients with lower respiratory tract infections were used to study in detail the effect of ampicillin or erythromycin on the colonization patterns of Haemophilus influenzae and Haemophilus parainfluenzae in sputum and saliva. H. influenzae was isolated from purulent sputum of eight patients before the start of treatment. Ampicillin was more effective than erythromycin at clearing H. influenzae from sputum and in decreasing purulence. By careful characterization of multiple strains, the changes in biotype distribution and antibiotic susceptibility patterns were shown. Five biotypes of H. influenzae were associated with chest infection, with type II predominating. Mixed biotype infections occurred in five patients. Most saliva contained multiple biotypes of H. parainfluenzae. Neither antibiotic selected resistant haemophili in saliva or sputum. After treatment with ampicillin, the mucoid sputum was colonized with ampicillin-susceptible H. parainfluenzae biotypes previously found in saliva. We postulate that as inflammation decreases at the bronchial mucosa, the ampicillin concentration drops, allowing ampicillin-susceptible oral H. parainfluenzae isolates to seed the residual mucoid sputum.
Anti-human immunodeficiency virus type 1 activity of an anti-CD4 immunoconjugate containing pokeweed antiviral protein
Authors: Erice A , Balfour H H , Myers D E , Leske V L , Sannerud K J , Kuebelbeck V , Irvin J D , Uckun F M
Published: June 2012

The ability of an alpha CD4-pokeweed antiviral protein (PAP) immunoconjugate to inhibit replication of human immunodeficiency virus type 1 (HIV-1) was evaluated in vitro with 22 clinical HIV-1 strains obtained from four seropositive asymptomatic individuals, three patients with AIDS-related complex, and four patients with AIDS. Fifteen isolates were from zidovudine-untreated individuals, whereas seven isolates were obtained after 24 to 104 weeks of therapy with zidovudine, alone or alternating with zalcitabine. Mean zidovudine 50% inhibitory concentrations (IC50s) were 126 nM (range, 1 to 607 nM) for isolates from zidovudine-untreated individuals and 2,498 nM (range, 14 to 6,497 nM) for strains from patients treated with antiretroviral agents. Mean alpha CD4-PAP IC50s were 48 x 10(-3) nM (range, 0.02 x 10(-3) to 212 x 10(-3) nM) for isolates from zidovudine-untreated individuals, and 16 x 10(-3) nM (range, 2 x 10(-3) to 28 x 10(-3) nM) for isolates from treated patients. Overall, higher concentrations of alpha CD4-PAP were necessary to inhibit HIV-1 strains from untreated individuals at more advanced stages of disease. Seventeen isolates were susceptible to zidovudine (mean IC50, 117 nM), and five were resistant to zidovudine (mean IC50, 3,724 nM). Mean alpha CD4-PAP IC50s were 43 x 10(-3) nM for zidovudine-susceptible isolates and 19 x 10(-3) nM for isolates resistant to zidovudine. All HIV-1 strains had IC50s greater than 0.5 nM for unconjugated PAP, the alpha CD19-PAP immunoconjugate, and monoclonal antibody alpha CD4. At concentrations as high as 5,000 nM, alphaCD4-PAP did not inhibit colony formation by normal bone marrow progenitor cells(BFU-E, CFU-GM , and CFU-GEMM) or myeloid cell lines (KG-1 and HL-60) and did not decrease cell viabilities of T-cell (Jurkat) or B-cell (FL-112 and Raji) precursor lines. Overall, alphaCD4-PAP demonstrated more potent anti-HIV-1 activity than zidovudine and inhibited replication of zidovudine-susceptible and zidovudine-resistant viruses at concentrations that were not toxic to lymphohematopoietic cell populations.
Foscarnet penetrates the blood-brain barrier: rationale for therapy of cytomegalovirus encephalitis
Authors: Hengge U R , Brockmeyer N H , Malessa R , Ravens U , Goos M
Published: June 2012

Foscarnet (phosphonoformate) is a potent virustatic drug against herpes-like viruses and is widely used in the therapy of cytomegalovirus infections in immunosuppressed patients. To obtain data on its penetration across the blood-brain barrier, we determined concentrations of foscarnet in cerebrospinal fluid and in plasma specimens from 26 patients with human immunodeficiency virus (stages 2 to 6 by Walter Reed Army Institute of Research classification) after a single infusion of 90 mg of foscarnet per kg of body weight and at steady state by electrochemical detection by high-pressure liquid chromatography. Penetration coefficients were correlated with the integrity of the blood-brain barrier. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 micrograms/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 micrograms/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 micrograms/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 micrograms/ml. The penetration coefficient was 0.05 to 0.72 (mean, 0.23 +/- 0.16). At steady state, mean foscarnet levels in plasma were 464 +/- 219 micrograms/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/- 155 micrograms/ml (1,023 mumol/liter). The penetration coefficient was 0.66 +/- 0.11. Although penetration coefficients were highly variable after a single administration and at steady state, the concentrations of foscarnet attained in cerebrospinal fluid are sufficient for complete inhibition of cytomegalovirus replication in vitro. In conclusion, we show that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain barrier and is found in the cerebrospinal fluid in virustatic concentrations. Foscarnet might be considered for additive therapy for human immunodeficiency virus encephalitis in combination with zidovudine or dideoxyinosine.
Comparative susceptibilities of 173 aerobic and anaerobic bite wound isolates to sparfloxacin, temafloxacin, clarithromycin, and older agents
Authors: Goldstein E J , Citron D M
Published: June 2012

The in vitro activities of sparfloxacin, temafloxacin, ciprofloxacin, ofloxacin, clarithromycin, erythromycin, tetracycline, cephalothin, penicillin G, and amoxicillin-clavulanic acid against 173 recent clinical bite wound isolates were determined by agar dilution. Sparfloxacin was active against all strains (MIC for 90% of strains tested, < or = 1 micrograms/ml) except for most fusobacteria and one-third of the Prevotella spp. The other fluoroquinolones had similar activities but higher MICs, especially for streptococci. Clarithromycin was more active against many isolates including Pasteurella multocida than erythromycin, with MICs of < or = 2 micrograms/ml (versus 4 micrograms/ml for erythromycin).
Ciprofloxacin for treatment of severe typhoid fever in children
Authors: Dutta P , Rasaily R , Saha M R , Mitra U , Bhattacharya S K , Bhattacharya M K , Lahiri M
Published: June 2012

Eighteen children with bacteriologically confirmed severe typhoid fever were initially treated intravenously with ciprofloxacin (10 mg/kg of body weight per day). Clinical cure with eradication of multiresistant Salmonella typhi infection was observed in 17 patients (94.4%; 95% confidence interval [CI], 84 to 100%). Children regained normal consciousness within an average of 2 days (95% CI, 1.8 to 2.2 days). The temperatures of the children returned to normal within 3.3 days (95% CI, 3.1 to 3.5 days). Complications were not observed during the hospital stay or a 3-month follow-up period. Relapse and carrier state were also not encountered during the follow-up period.
Experimental study of transplacental passage of alpha interferon by two assay techniques
Authors: Waysbort A , Giroux M , Mansat V , Teixeira M , Dumas J C , Puel J
Published: June 2012

Two methods of assaying alpha interferon (IFN-alpha) were compared during an experiment aimed at determining whether IFN-alpha crosses the human placenta. Human placentas, collected after delivery following a normal pregnancy to term, were catheterized on both sides: fetal and maternal. The IFN-alpha was introduced in known amounts in the maternal circulation and was assayed in the efferent fetal fluid. The following two detection methods were used: radioimmunoassay by competition with [125I]IFN-alpha and assay with a biological system in which IFN-alpha protected Madin-Darby bovine kidney cells from destruction by vesicular stomatitis virus. The results obtained by the two methods were in perfect agreement for the efferent fetal fluid samples. They showed the absence of placental transfer of IFN-alpha. The biological method was found to be more sensitive than radioimmunoassay for low IFN-alpha titers (< 10 IU/ml) but was less reproducible, probably owing to the use of twofold dilutions. The specificities of the two methods were similar and their practicalities were equivalent; the biological method, however, was less costly. The study illustrates the complementarity of the two methods, which were based on different principles. The agreement obtained between the two methods provides a clear confirmation of the experimental results.
Constitutively vancomycin-resistant Enterococcus faecium resistant to synergistic beta-lactam combinations
Authors: Green M , Binczewski B , Pasculle A W , Edmund M , Barbadora K , Kusne S , Shlaes D M
Published: June 2012

Vancomycin resistance among enterococci has recently been recognized. Synergy between vancomycin and penicillin has been shown in vitro for isolates of Enterococcus faecium resistant to both of these antibiotics. We describe three isolates of vancomycin-resistant E. faecium which demonstrate unique phenotypic characteristics. The isolates exhibited high-level resistance to both vancomycin and teicoplanin, consistent with the VanA phenotype. However, resistance in these isolates could not be induced or cured, and mating experiments failed to detect a transfer of resistance. The combination of vancomycin and penicillin did not significantly change the MIC of penicillin for any of the three isolates. Immunoblotting with polyclonal anti-VanB antibody showed no reaction with the cellular proteins of these strains. Probing with a vanA oligonucleotide revealed hybridization with chromosomal but not plasmid DNA. The mechanism of constitutive resistance of those strains remains unclear. A second mutational change, perhaps involving PBP 5, may explain the presence of resistance to synergistic combination penicillin-vancomycin therapy. In vitro evaluation of penicillin-vancomycin should be carried out in all clinical cases where this therapeutic regimen is being considered.
Antifungal properties in a novel series of triazino[5,6-b]indoles
Authors: Kinsman O S , Livermore D G , Smith C
Published: June 2012

GR99060 and GR99062 are representatives of a series of 1,2,4-triazino[5,6-b]indole compounds. This series possessed broad-spectrum antifungal activity in vitro. The MIC ranges of the two compounds were as follows: 0.25 to 4 micrograms/ml for Candida albicans, 0.25 to 16 micrograms/ml for Candida sp., 1 to 8 micrograms/ml for Aspergillus spp., and 0.25 to 16 micrograms/ml for Cryptococcus neoformans. GR99062 was metabolized in vitro by a mouse liver microsomal preparation, while GR99060 was stable. GR99060 was efficacious in a murine model of systemic candidiasis by oral or parenteral administration, although no clear dose-response was achieved, suggesting that other factors adversely affected the compound's in vivo activity.
Susceptibility of Mycobacterium malmoense to antibacterial drugs and drug combinations
Authors: Hoffner S E , Hjelm U , Källenius G
Published: June 2012

Mycobacterium malmoense is an opportunistic pathogen with increasingly recognized clinical importance. It is mainly isolated in northern Europe and Great Britain, most often from patients with pulmonary infections. Conventional therapy of M. malmoense infections with antituberculosis drugs is often of limited value, and there is thus a need for improved drug regimens. The potential efficacies of new alternative drugs, such as quinolones, macrolides, amikacin, and rifabutin, are still unknown, and so is the pathogen's in vitro susceptibility to most of these drugs. In this study, we used the BACTEC system for determining the pattern of resistance of clinical M. malmoense isolates to a number of antibacterial drugs as well as their possible synergistic interactions when each of them was combined with ethambutol. The majority of the strains were resistant or moderately resistant to the drug when it was tested alone at selected concentrations. However, pronounced in vitro synergism was demonstrated for combinations of ethambutol with ciprofloxacin, amikacin, and rifampin, rendering most isolates susceptible to the combined drugs. Thus, for in vitro susceptibility testing of M. malmoense, examination of the possible synergistic effects of combined drugs also can be recommended.
High specificity of cphA-encoded metallo-beta-lactamase from Aeromonas hydrophila AE036 for carbapenems and its contribution to beta-lactam resistance
Authors: Segatore B , Massidda O , Satta G , Setacci D , Amicosante G
Published: June 2012

The Aeromonas hydrophila AE036 chromosome contains a cphA gene encoding a metallo-beta-lactamase highly active against carbapenem antibiotics. This enzyme was induced in strain AE036 to the same extent by both benzylpenicillin and imipenem. When the cphA gene was inserted into plasmid pACYC184, used to transform Escherichia coli DH5 alpha, the MICs of imipenem, meropenem, and penem HRE664 for recombinant clone DH5 alpha(pAA20R), expressing the Aeromonas metallo-beta-lactamase, were significantly increased, but those of penicillins and cephalosporins were not. When the metallo-beta-lactamase purified from E. coli DH5 alpha(pAA20R) was assayed with several beta-lactam substrates, it hydrolyzed carbapenems but not penicillins or cephalosporins efficiently. These results demonstrate that this metallo-beta-lactamase possesses an unusual spectrum of activity compared with all the other class B enzymes identified so far, being active on penems and carbapenems only. This enzyme may thus contribute to the development of resistance to penems and carbapenems but not other beta-lactams.
Susceptibilities of serial Cryptococcus neoformans isolates from patients with recurrent cryptococcal meningitis to amphotericin B and fluconazole
Authors: Casadevall A , Spitzer E D , Webb D , Rinaldi M G
Published: June 2012

Amphotericin B and fluconazole susceptibilities of 13 Cryptococcus neoformans isolates from five patients with recurrent cryptococcal meningitis were determined. For each patient, serial isolates showed no increase in antibiotic resistance relative to the initial isolate. For these patients, recurrent disease was not due to drug resistance but may reflect changes in immune function and/or poor compliance.
Treatment of typhoid fever with ceftriaxone for 5 days or chloramphenicol for 14 days: a randomized clinical trial
Authors: Islam A , Butler T , Kabir I , Alam N H
Published: June 2012

To compare the therapeutic efficacy of ceftriaxone given once daily for 5 days and chloramphenicol given four times daily for 14 days, a controlled trial was carried out with 59 patients who were culture positive for Salmonella typhi. Ceftriaxone was given to 28 patients in once-daily intravenous doses of 75 mg/kg of body weight to children and 4 g to adults for 5 days; chloramphenicol was given to 31 patients at a dosage of 60 mg/kg/day until defervescence and then at 40 mg/kg/day to complete 14 days of treatment. All Salmonella isolates were susceptible to both antibiotics. Clinical cures (defervescence without complications, no relapse, and no need for further treatment) occurred in 79% of the patients treated with ceftriaxone and 90% of those treated with chloramphenicol (P = 0.37). On the third day of treatment, blood cultures were positive for S. typhi for 60% of the patients in the chloramphenicol group and 0% of the ceftriaxone group (P = 0.001). Defervescence occurred in half the patients in both groups during the first 7 days, but on days 9 to 13 after the start of treatment, nine patients in the ceftriaxone group, compared with six patients in the chloramphenicol group, remained febrile (P = 0.4). The median hematocrit and total leukocyte counts at day 14 were significantly lower for the chloramphenicol group than those for the ceftriaxone group (P = 0.01 and P = 0.02, respectively). These results indicate that the effects of therapy with ceftriaxone for typhoid fever differed from those of chloramphenicol therapy in that blood cultures became negative earlier, prolonged fever persisted in some patients, and bone marrow suppression was reduced. We conclude that a short, 5-day course of ceftriaxone is a useful alternative to conventional 14-day chloramphenicol therapy in the treatment of typhoid fever.
Effect of increased dosages of amoxicillin in treatment of experimental middle ear otitis due to penicillin-resistant Streptococcus pneumoniae
Authors: Barry B , Muffat-Joly M , Gehanno P , Pocidalo J J
Published: June 2012

A gerbil model of acute middle ear otitis was used to evaluate the efficacy of increased dosages of amoxicillin in eradicating infection induced by penicillin-resistant Streptococcus pneumoniae. Three different strains were used: (i) a serotype 23 penicillin-susceptible strain; (ii) a serotype 23 penicillin-resistant strain (MIC of penicillin, 2 micrograms/ml); and (iii) a serotype 19 highly penicillin-resistant strain (MIC of penicillin, 4 to 8 micrograms/ml). Animals were inoculated bilaterally with 10(7) CFU per ear by transbulla challenge and treated 2 to 4 h postinfection by amoxicillin administrated subcutaneously. The course of the disease was monitored bacteriologically on days 2, 4, and 8 postinfection. The three strains had a similar pathogenicity in untreated animals in terms of the duration of the disease, bacterial counts in middle ear (ME) fluid, and systemic complications. Infection due to the penicillin-susceptible strain was cured after two injections of 2.5 mg/kg of body weight. No bacteria were recovered at day 2 after two injections at 10 and 25 mg/kg with the penicillin-resistant and highly penicillin-resistant strains, respectively. Under these experimental conditions, increased does of amoxicillin consistent with MICs were able to clear ME infection. Pharmacokinetic parameters of amoxicillin in serum and ME fluid were within the clinical range at the doses used in the study.
Effect of zidovudine on preimplantation murine embryos
Authors: Toltzis P , Mourton T , Magnuson T
Published: June 2012

It previously has been demonstrated that zidovudine (AZT) is lethal to early murine embryos. The effect of the drug on pre- and postimplantation embryos was examined to delineate the timing of this toxicity and to investigate its possible mechanisms. Embryos exposed in the whole mouse during preblastocyst development were unable to proceed beyond the blastocyst stage. Similarly, when two-cell embryos harvested from unexposed females were exposed to low-concentration (1 microM) AZT in vitro over 24 h, development beyond the blastocyst stage was inhibited. In contrast, drug exposure during in vitro blastocyst and postblastocyst development resulted in little or no morphologic toxicity. Further investigation revealed that preblastocyst AZT exposure resulted in the development of blastocysts with significantly lower cell numbers than control embryos. While embryonic exposure to AZT at the blastocyst and postblastocyst stages also resulted in retarded cell division, the effects were milder than those recorded after preblastocyst exposure. These data demonstrate that the critical period of AZT toxicity toward murine embryos is between ovulation and implantation and indicate that AZT directly suppresses cell division in the preimplantation embryo.
Susceptibilities of 428 gram-positive and -negative anaerobic bacteria to Bay y3118 compared with their susceptibilities to ciprofloxacin, clindamycin, metronidazole, piperacillin, piperacillin-tazobactam, and cefoxitin
Authors: Pankuch G A , Jacobs M R , Appelbaum P C
Published: June 2012

The susceptibilities of 428 gram-negative and gram-positive anaerobes (including selected cefoxitin-resistant strains) to Bay y3118 (a new fluoroquinolone), ciprofloxacin, clindamycin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam were tested. Organisms comprised 115 Bacteroides fragilis group, 116 non-B. fragilis Bacteroides, Prevotella, and Porphyromonas spp., 40 fusobacteria, 58 peptostreptococci, 48 gram-positive non-spore-forming rods, and 51 clostridia. beta-Lactamase production was demonstrated in 87% of the gram-negative rods but in none of the gram-positive organisms. Overall, Bay y3118 was the most active agent, with all organisms inhibited at an MIC of < or = 2.0 micrograms/ml (MICs for 50% [MIC50] and 90% [MIC90] of strains tested, 0.125 and 0.5 microgram/ml, respectively). By contrast, ciprofloxacin was much less active, with only 42% of strains susceptible at a breakpoint of 2.0 micrograms/ml (MIC50, 4.0 micrograms/ml; MIC90, 16.0 micrograms/ml). Metronidazole was active against all gram-negative rods, but 7% of peptostreptococci, 83% of gram-positive non-spore-forming rods, and 4% of non-Clostridium perfringens, non-Clostridium difficile clostridia were resistant to this agent (MICs, > 16.0 micrograms/ml). Clindamycin was active against 94% of Bacteroides, Prevotella, and Porphyromonas spp., 91% of peptostreptococci, and 100% of gram-positive non-spore-forming rods, but was active against only 70% of fusobacteria and 53% of clostridia. Cefoxitin was active against > or = 90% of all groups except the B. fragilis group and non-Propionibacterium acnes gram-positive non-spore-forming rods (both 85%) and C. difficile (20%). Significant enhancement of piperacillin by tazobactam was seen in all beta-lactamase-positive strains (99% susceptible; MIC90, 8.0 micrograms/ml), and all beta-lactamase-negative strains were susceptible to piperacillin (MIC90, 8.0 micrograms/ml). Clinical studies are required to delineate the role of Bay y3118 in the treatment of anaerobic infections.
In vitro postantibiotic effect following repeated exposure to imipenem, temafloxacin, and tobramycin
Authors: McGrath B J , Marchbanks C R , Gilbert D , Dudley M N
Published: June 2012

The postantibiotic effect (PAE) following three consecutive 2-h exposures to imipenem, temafloxacin, and tobramycin was determined in Pseudomonas aeruginosa. A PAE and a bactericidal effect were consistently observed for imipenem following each cycle of drug exposure and regrowth. In contrast, the PAE increased with repeated exposure with temafloxacin (1.8 to > 5 h), but disappeared with tobramycin by the third exposure (0.9 to 0 h). These data show that the in vitro PAE may change within a strain following multiple cycles of drug exposure and bacterial regrowth.
Adverse effects of pefloxacin in irradiated C3H/HeN mice: correction with glucan therapy
Authors: Patchen M L , Brook I , Elliott T B , Jackson W E
Published: June 2012

Opportunistic bacterial infections are the predominant cause of death following myelosuppressive radiation exposure. When used alone, a variety of immunomodulators and antibiotics have been reported to reduce radiation-induced death. In these studies, the combined therapeutic effects of the immunomodulator glucan and the quinolone antibiotic pefloxacin were evaluated for survival-enhancing effects in myelosuppressed C3H/HeN mice. Mice were exposed to 7.9 Gy of whole-body 60Co radiation and treated with saline, glucan (250 mg/kg of body weight intravenously, 1 h after irradiation), pefloxacin (64 mg/kg/day orally, days 3 to 24 after irradiation), or glucan plus pefloxacin. Survival 30 days after irradiation in mice receiving these respective treatments was 25, 48, 7, and 85%. Evaluation of granulocyte-macrophage progenitor cell (GM-CFC) recovery in mice receiving these treatments revealed that, compared with recovery in saline-treated mice, glucan stimulated GM-CFC recovery, pefloxacin suppressed GM-CFC recovery, and glucan administered in combination with pefloxacin could override pefloxacin's hemopoietic suppressive effect.
Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region
Authors: Azad R F , Driver V B , Tanaka K , Crooke R M , Anderson K P
Published: June 2012

Phosphorothioate oligonucleotides complementary to mRNA of the human cytomegalovirus (HCMV) DNA polymerase gene or to RNA transcripts of the major immediate-early regions 1 and 2 (IE1 and IE2) of HCMV were evaluated for antiviral activity in a 96-well immunoassay with primary human dermal fibroblasts as host cells. Oligonucleotides complementary to RNA of the IE2 region exhibited the most potent antiviral activity. One of these oligonucleotides, ISIS 2922, was at least 30-fold more potent than the nucleoside analog, ganciclovir, with a 50% effective concentration of 0.37 microM in the 96-well immunoassay. In an infectious virus yield reduction assay, ISIS 2922 and ganciclovir reduced production of infectious virus by 2 log units at concentrations of 2.2 and 36 microM, respectively. A control oligonucleotide showed no inhibition of virus production at concentrations as high as 3 microM. ISIS 2922 reduced IE protein synthesis in HCMV-infected cells in a dose-dependent manner which correlated with antiviral activity. The antiviral activity of ISIS 2922 was not due to oligonucleotide-induced cytotoxicity since effects on cell viability or proliferation were observed only at concentrations well in excess of effective antiviral concentrations. The specificity and potency of ISIS 2922 suggest that it may be useful for the treatment of cytomegalovirus disease in humans.
Sequencing of a tet(Q) gene isolated from Bacteroides fragilis 1126
Authors: Lépine G , Lacroix J M , Walker C B , Progulske-Fox A
Published: June 2012

Recently, Tet Q, a tetracycline resistance determinant that confers resistance by a ribosome protection mechanism, was described and added to the two previously described classes, Tet M and Tet O. The first representative of this class, tetA(Q)1, was isolated from Bacteroides thetaiotaomicron DOT. We report the sequencing of a gene isolated from B. fragilis 1126 which also confers tetracycline resistance. Because of its high degree of identity (97%) with the tetA(Q)1 gene, we defined it as tetA(Q)2. MIC studies revealed that tetA(Q)2 provides a low level of resistance to tetracycline when cloned into Escherichia coli. The extensive homology between tetA(Q)1 and tetA(Q)2 supports the idea of a recent horizontal transfer of tet(Q) genes among Bacteroides spp.
Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences
Authors: Black P H
Published: June 2012

Psychoneuroimmunology is a relatively new discipline which deals with CNS-immune system interactions. The evidence for such interactions was reviewed, as was the neuroendocrinologic response to stress. Recent evidence indicates that the behavioral, nervous system, and neuroendocrine responses to stress are mediated by hypothalamic CRF, which acts on both the sympathetic nervous system and the HPA axis, resulting in increased levels of corticosteroids, catecholamines, and certain opiates, substances which are generally immunosuppressive. Concentrations of growth hormone and prolactin, which are immunoenhancing, are elevated early during the response to stress but are later suppressed. Although several other neuromediators may also be released with stress, the net effect of a variety of acute stressors is down regulation of the immune system function. In the following minireview, I consider whether stress alters the resistance of the host to infection as well as the immunomodulatory effects of released immune system mediators on the brain.
Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates
Authors: Kellam P , Larder B A
Published: June 2012

Antiviral drug susceptibility assays for clinical human immunodeficiency virus type 1 (HIV-1) isolates are required to monitor the development of drug resistance during clinical trials and antiretroviral drug therapy. First-generation phenotypic assays possess a number of drawbacks, not least the selection of unrepresentative virus populations during cocultivation. Here we describe a rapid phenotypic assay for the assessment of the susceptibility of clinical isolates to reverse transcriptase (RT) inhibitors. This procedure, called the recombinant virus assay, allows the generation of viable virus by homologous recombination of a PCR-derived pool of RT coding sequences into an RT-deleted, noninfectious proviral clone, pHIV delta BstEII. A nested PCR procedure has been optimized to allow the amplification of an RT pool from both uncultured and cocultured infected patient peripheral blood lymphocyte (PBL) DNA for subsequent use in the creation of recombinant viruses. Analysis of two patients during the course of zidovudine therapy showed that this approach produced viruses which accurately exhibited the same genotype and phenotype as that of the original infected PBL DNA. The recombinant virus assay can be performed in approximately 3 weeks without the use of donor PBLs and therefore represents a rapid, nonselective procedure for the assay of clinical isolates.
Improved medium for fluconazole susceptibility testing of Candida albicans
Authors: Rodriguez-Tudela J L , Martinez-Suarez J V
Published: June 2012

We have compared fluconazole susceptibilities of 92 clinical isolates of Candida albicans by broth microdilution in two different media: standard RPMI 1640 (RPMI) and the same medium supplemented with 18 g of glucose per liter (RPMI-glucose). Preparation of media, drugs, and inocula, as well as incubation conditions, followed the preliminary recommendations of the National Committee for Clinical Laboratory Standards (Villanova, Pa.) antifungal agent working group for broth macrodilution tests with antifungal agents, adapted to microdilution. Microtiter plates were agitated for 5 min before spectrophotometric readings were performed with an automatic plate reader set at 405 mm. The MIC endpoint was defined as an inhibitory concentration calculated from the turbidimetric data as a function of the turbidity in the drug-free control wells. The mean absorbances in the drug-free wells in RPMI and RPMI-glucose were, respectively, 0.38 (41.6% transmission) and 0.99 (10.2% transmission) (P < 0.001; Student's t test). Despite the increased growth in RPMI-glucose, 98.9% of the C. albicans strains tested for fluconazole susceptibility yielded similar MICs (+/- 1 dilution) in both media. Moreover, strains with decreased susceptibility to fluconazole displaying similar MICs in both media are easier to detect in RPMI-glucose because of the greater differences between turbidimetric readings in wells with grown or fluconazole-inhibited cultures. This objective turbidimetric method, with an easy-to-read improved medium (RPMI with glucose), together with previous experience of the National Committee for Clinical Laboratory Standards antifungal agent subcommittee, could overcome some of the present problems associated with lack of reproducibility of azole susceptibility testing.
Characterization of rifampin-resistance in pathogenic mycobacteria
Authors: Williams D L , Waguespack C , Eisenach K , Crawford J T , Portaels F , Salfinger M , Nolan C M , Abe C , Sticht-Groh V , Gillis T P
Published: June 2012

The emergence of rifampin-resistant strains of pathogenic mycobacteria has threatened the usefulness of this drug in treating mycobacterial diseases. Critical to the treatment of individuals infected with resistant strains is the rapid identification of these strains directly from clinical specimens. It has been shown that resistance to rifampin in Mycobacterium tuberculosis and Mycobacterium leprae apparently involves mutations in the rpoB gene encoding the beta-subunit of the RNA polymerases of these species. DNA sequences were obtained from a 305-bp fragment of the rpoB gene from 110 rifampin-resistant and 10 rifampin-susceptible strains of M. tuberculosis from diverse geographical regions throughout the world. In 102 of 110 rifampin-resistant strains 16 mutations affecting 13 amino acids were observed. No mutations were observed in rifampin-susceptible strains. No association was found between particular mutations in the rpoB gene and drug susceptibility patterns of multidrug-resistant M. tuberculosis strains. Drug-resistant M. tuberculosis strains from the same outbreak and exhibiting the same IS6110 DNA fingerprint and drug susceptibility pattern contained the same mutation in the rpoB gene. However, mutations are not correlated with IS6110 profiling outside of epidemics. The evolution of rifampin resistance as a consequence of mutations in the rpoB gene was documented in a patient who developed rifampin resistance during the course of treatment. Rifampin-resistant strains of M. leprae, Mycobacterium avium, and Mycobacterium africanum contained mutations in the rpoB gene similar to that documented for M. tuberculosis. This information served as the basis for developing a rapid DNA diagnostic assay (PCR-heteroduplex formation) for the detection of rifampin susceptibility of M. tuberculosis.
Pharmacokinetics of ceftriaxone in patients with typhoid fever
Authors: Acharya G , Crevoisier C , Butler T , Ho M , Tiwari M , Stoeckel K , Bradley C A
Published: June 2012

Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever.
Intracellular and extracellular penetration of azithromycin into inflammatory and noninflammatory blister fluid
Authors: Freeman C D , Nightingale C H , Nicolau D P , Belliveau P P , Banevicius M A , Quintiliani R
Published: June 2012

The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05).
In vitro activity of DU-6859a against anaerobic bacteria
Authors: Wexler H M , Molitoris E , Reeves D , Finegold S M
Published: June 2012

The activity of a new quinolone agent, DU-6859a, against 330 strains of anaerobic bacteria was determined by using the National Committee for Clinical Laboratory Standards-approved Wadsworth brucella laked blood agar method; the activity of DU-6859a was compared with those of amoxicillin-clavulanate (2:1), chloramphenicol, ciprofloxacin, clindamycin, fleroxacin, imipenem, lomefloxacin, metronidazole, sparfloxacin, and temafloxacin. DU-6859a and chloramphenicol inhibited all of the isolates at concentrations of 1 and 16 micrograms/ml, respectively; amoxicillin-clavulanate, imipenem, and metronidazole inhibited > or = 94% of the isolates at their respective breakpoints (8, 8, and 16 micrograms/ml). MICs of DU-6859a at which 90% of the strains were susceptible were 1 to 5 twofold dilutions lower than those of the other quinolones for every group of organisms. MICs of DU-6859a at which 90% of the strains were susceptible (total numbers of strains tested are in parentheses) were < or = 0.25 micrograms/ml for Bacteroides fragilis (57), other B. fragilis group species (84), Bilophila wadsworthia (15), Clostridium species (27) (including C. difficile, C. perfringens, and C. ramosum), Fusobacterium nucleatum (16), Fusobacterium mortiferum-F. varium group species (10), Peptostreptococcus species (20), non-spore-forming gram-positive rods (20), and Prevotella species (25).
Oral absorption of ofloxacin administered together with aluminum
Authors: Sánchez Navarro A , Martínez Cabarga M , Dominguez-Gil Hurlé A
Published: June 2012

A clinical study was carried out to establish the influence of aluminum on the oral absorption of ofloxacin. Ten healthy volunteers were included in a crossover study based on a Latin square design. The treatments that all volunteers received were A, consisting of 400 mg of ofloxacin, and B, consisting of 400 mg of ofloxacin plus 11 g of colloidal aluminum phosphate. The absorption constant and other ofloxacin parameters were calculated from data on levels in plasma by using model-independent calculation methods. There were no statistically significant differences between the mean values of the areas under the curve corresponding to the administration of ofloxacin alone and those of ofloxacin with aluminum. Regarding the other pharmacokinetic parameters, a significant difference between the absorption constants was found. The presence of aluminum reduces the absorption rate of this quinolone but does not modify the percentage of the absorbed dose.
Phytosterols are present in Pneumocystis carinii
Authors: Furlong S T , Samia J A , Rose R M , Fishman J A
Published: June 2012

Although originally classified as a protozoan, Pneumocystis carinii is now considered to have fungal characteristics. Drugs typically used for the treatment of fungal infections target ergosterol. Because P. carinii is an important pathogen in AIDS and other immunocompromised patients, knowledge of the sterol content of this organism may be useful as a basis for developing new treatment strategies or for improving diagnosis. P. carinii organisms were harvested from infected rat lungs and were purified by filtration. Control preparations from uninfected animals were identically prepared. Lipids were extracted from the organisms and control preparations and were separated into neutral lipid, glycolipid, and phospholipid fractions by silicic acid chromatography. The neutral lipid fraction was further treated by alkaline hydrolysis and was analyzed by reversed-phase high-pressure liquid chromatography (HPLC), gas chromatography (GC), and GC-mass spectrometry (GC-MS). As shown by HPLC, the neutral lipid fraction from infected rats contained a minimum of six peaks, while in control preparations a single peak with a retention time identical to that of cholesterol was observed. The predominant sterol in these preparations was positively identified by GC-MS as cholesterol and constituted 80 to 90% of the total. The remaining peaks had relative retention times similar to those of phytosterols by both HPLC and GC, and the similarity of these sterols to those derived from plants and fungi was confirmed by MS. Ergosterol, however, was not present. These results provide further evidence for a close phylogenetic relationship between P. carinii and fungi and suggest that these sterols could be used as targets for drug development and for improving diagnosis.
Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro
Authors: Morikawa K , Oseko F , Morikawa S , Iwamoto K
Published: June 2012

The effect of three macrolide antibiotics, midecamycin acetate, josamycin, and clarithromycin, on human T-cell function was investigated in vitro. Midecamycin acetate and josamycin suppressed the proliferative response of peripheral blood mononuclear cells stimulated by polyclonal T-cell mitogens at concentrations between 1.6 and 8 micrograms/ml. At higher concentrations (40 to 200 micrograms/ml), all these drugs showed a marked inhibitory effect. At concentrations of 1.6 to 40 micrograms/ml, these drugs suppressed interleukin-2 (IL-2) production induced by mitogen-stimulated T cells, but not the expression of IL-2 receptor (CD25), in a dose-dependent manner. Therefore, the suppressive action on T-lymphocyte proliferation seems to be based on the ability of these drugs to inhibit IL-2 production by T cells. The drug also inhibited mixed lymphocyte reaction at the same concentrations. Combined treatment with these macrolides and the known immunosuppressants such as FK506 and cyclosporin A resulted in an increased inhibition of T-cell proliferation. The immunomodulatory properties of the antibiotics may have clinical relevance for modulation of the immune response in transplant patients and in patients with inflammatory diseases.
Activities of clarithromycin, ofloxacin, and clarithromycin plus ethambutol against Mycobacterium simiae in murine model of disseminated infection
Authors: Valero G , Moreno F , Graybill J R
Published: June 2012

After 2 weeks of intravenous challenge with Mycobacterium simiae, ICR outbred mice were treated with clarithromycin, ofloxacin, or clarithromycin plus ethambutol for 4 weeks. All three therapy groups demonstrated a decrease in the level of infection in both the lungs and the spleen. There were no significant differences among the three treated groups in decreasing mycobacterial counts in the lungs; however, both ofloxacin and clarithromycin plus ethambutol were superior to clarithromycin alone in reducing the level of infection in the spleen. Results of the study suggest a potential role for these agents in the treatment of human M. simiae infection.
The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication
Authors: Neyts J , Andrei G , Snoeck R , Jähne G , Winkler I , Helsberg M , Balzarini J , De Clercq E
Published: June 2012

2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 microgram/ml), varicella-zoster virus (EC50, 0.01 to 0.02 microgram/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 microgram/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 microgram/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 microgram/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 microgram/ml), and human herpesvirus 6 (EC50, 0.0005 microgram/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 micrograms/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM degrees. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK. Compound S2242 inhibited (i) the expression of late HCHV antigens at an EC50 of 0.07 microgram/ml (0.6 microgram/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 microgram/ml (0.32 microgram/ml for ganciclovir), i.e., values that are close to the EC50S for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.