bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum and Cerebrospinal Fluid Pharmacokinetics of Intravenous and Oral Lamivudine in Human Immunodeficiency Virus-Infected Children
Authors: Mueller Brigitta U. , Lewis Linda L. , Yuen Geoffrey J. , Farley Maureen , Keller Amy , Church Joseph A. , Goldsmith Jonathan C. , Venzon David J. , Rubin Marc , Pizzo Philip A. , Balis Frank M. 
Published: October 2018

ABSTRACT

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (± standard deviation) in the children was 0.53 ± 0.19 liter/kg/h (229 ± 77 ml/min/m
2
of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 ± 0.18 and 2.2 ± 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% ± 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 μM for ≥8 h of 24 h on the twice daily oral dosing schedule with doses of ≥2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.
Bacteriological Efficacies of Three Macrolides Compared with Those of Amoxicillin-Clavulanate against
Streptococcus pneumoniae
and
Haemophilus influenzae
Authors: Berry Valerie , Thorburn Christine E. , Knott Sarah J. , Woodnutt Gary 
Published: October 2018

ABSTRACT

Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against
Streptococcus pneumoniae
and
Haemophilus influenzae
, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable
S. pneumoniae
slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against
H. influenzae
, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against
S. pneumoniae
, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (
P
< 0.01). Against
H. influenzae
, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (
P
< 0.01). Azithromycin demonstrated significant in vivo activity (
P
< 0.05) but was significantly less effective than amoxicillin-clavulanate (
P
< 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against
H. influenzae
, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.
In Vitro Inhibition of Hepadnavirus Polymerases by the Triphosphates of BMS-200475 and Lobucavir
Authors: Seifer Maria , Hamatake Robert K. , Colonno Richard J. , Standring David N. 
Published: October 2018

ABSTRACT
The guanosine analogs BMS-200475 and lobucavir have previously been shown to effectively suppress propagation of the human hepatitis B virus (HBV) and woodchuck hepatitis virus (WHV) in 2.2.15 liver cells and in the woodchuck animal model system, respectively. This repression was presumed to occur via inhibition of the viral polymerase (Pol) by the triphosphate (TP) forms of BMS-200475 and lobucavir which are both produced in mammalian cells. To determine the exact mode of action, BMS-200475–TP and lobucavir-TP, along with several other guanosine analog-TPs and lamivudine-TP were tested against the HBV, WHV, and duck hepatitis B virus (DHBV) polymerases in vitro. Estimates of the 50% inhibitory concentrations revealed that BMS-200475–TP and lobucavir-TP inhibited HBV, WHV, and DHBV Pol comparably and were superior to the other nucleoside-TPs tested. More importantly, both analogs blocked the three distinct phases of hepadnaviral replication: priming, reverse transcription, and DNA-dependent DNA synthesis. These data suggest that the modest potency of lobucavir in 2.2.15 cells may be the result of poor phosphorylation in vivo. Kinetic studies revealed that BMS-200475–TP and lobucavir-TP competitively inhibit HBV Pol and WHV Pol with respect to the natural dGTP substrate and that both drugs appear to bind to Pol with very high affinities. Endogenous sequencing reactions conducted in replicative HBV nucleocapsids suggested that BMS-200475–TP and lobucavir-TP are nonobligate chain terminators that stall Pol at sites that are distinct yet characteristically two to three residues downstream from dG incorporation sites.
Efficacy of the Carbocyclic 2′-Deoxyguanosine Nucleoside BMS-200475 in the Woodchuck Model of Hepatitis B Virus Infection
Authors: Genovesi E. V. , Lamb L. , Medina I. , Taylor D. , Seifer M. , Innaimo S. , Colonno R. J. , Standring D. N. , Clark J. M. 
Published: October 2018

ABSTRACT

Daily oral treatment with the cyclopentyl 2′-deoxyguanosine nucleoside BMS-200475 at doses ranging from 0.02 to 0.5 mg/kg of body weight for 1 to 3 months effectively reduced the level of woodchuck hepatitis virus (WHV) viremia in chronically infected woodchucks as measured by reductions in serum WHV DNA levels and endogenous hepadnaviral polymerase activity. Within 4 weeks of daily therapy with 0.5 or 0.1 mg of BMS-200475 per kg, endogenous viral polymerase levels in serum were reduced about 1,000-fold compared to pretreatment levels. Serum WHV DNA levels determined by a dot blot hybridization technique were comparably decreased in these treated animals. In the 3-month study, the sera of animals that had undetectable levels of WHV DNA by the dot blot technique were further analyzed by a highly sensitive semiquantitative PCR assay. The results indicate that BMS-200475 therapy reduced mean WHV titers by 10
7
- to 10
8
-fold, down to levels as low as 10
2
to 10
3
virions/ml of serum. Southern blot hybridization analysis of liver biopsy samples taken from animals during and after BMS-200475 treatment showed remarkable reductions in the levels of WHV DNA replicative intermediates and in the levels of covalently closed circular viral DNA. WHV viremia in BMS-200475-treated WHV carriers eventually returned to pretreatment levels after therapy was stopped. These results indicate that BMS-200475 should be evaluated in clinical trials for the therapy of chronic human hepatitis B virus infections.
ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease
Authors: Sham Hing L. , Kempf Dale J. , Molla Akhteruzammen , Marsh Kennan C. , Kumar Gondi N. , Chen Chih-Ming , Kati Warren , Stewart Kent , Lal Ritu , Hsu Ann , Betebenner David , Korneyeva Marina , Vasavanonda Sudthida , McDonald Edith , Saldivar Ayda , Wideburg Norm , Chen Xiaoqi , Niu Ping , Park Chang , Jayanti Venkata , Grabowski Brian , Granneman G. Richard , Sun Eugene , Japour Anthony J. , Leonard John M. , Plattner Jacob J. , Norbeck Daniel W. 
Published: October 2018

ABSTRACT

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (

K
i

= 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC
50
], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC
50
, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC
50
in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC
50
for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.
An
Escherichia coli
Expression Assay and Screen for Human Immunodeficiency Virus Protease Variants with Decreased Susceptibility to Indinavir
Authors: Melnick Laurence , Yang Shiow-Shong , Rossi Rick , Zepp Charlie , Heefner Donald 
Published: October 2018

ABSTRACT

We have developed a recombinant
Escherichia coli
screening system for the rapid detection and identification of amino acid substitutions in the human immunodeficiency virus (HIV) protease associated with decreased susceptibility to the protease inhibitor indinavir (MK-639; Merck & Co.). The assay depends upon the correct processing of a segment of the HIV-1 HXB2
gag-pol
polyprotein followed by detection of HIV reverse transcriptase activity by a highly sensitive, colorimetric enzyme-linked immunosorbent assay. The highly sensitive system detects the contributions of single substitutions such as I84V, L90M, and L63P. The combination of single substitutions further decreases the sensitivity to indinavir. We constructed a library of HIV protease variant genes containing dispersed mutations and, using the
E. coli
recombinant system, screened for mutants with decreased indinavir sensitivity. The discovered HIV protease variants contain amino acid substitutions commonly associated with indinavir resistance in clinical isolates, including the substitutions L90M, L63P, I64V, V82A, L24I, and I54T. One substitution, W6R, is also frequently found by the screen and has not been reported elsewhere. Of a total of 12,000 isolates that were screened, 12 protease variants with decreased sensitivity to indinavir were found. The L63P substitution, which is also associated with indinavir resistance, increases the stability of the isolated protease relative to that of the native HXB2 protease. The rapidity, sensitivity, and accuracy of this screen also make it useful for screening for novel inhibitors. We have found the approach described here to be useful for the detection of amino acid substitutions in HIV protease that have been associated with drug resistance as well as for the screening of novel compounds for inhibitory activity.
In Vitro Activities of Ketolide HMR 3647, Macrolides, and Clindamycin against Coryneform Bacteria
Authors: Martínez-Martínez Luis , Pascual Alvaro , Suárez Ana Isabel , Perea Evelio J. 
Published: October 2018

ABSTRACT

The in vitro activity of ketolide HMR 3647 against coryneform bacteria isolated from clinical samples was evaluated. Except against
Corynebacterium jeikeium
and
C. urealyticum
, HMR 3647 showed high activity against
Corynebacterium
spp., being more active than 14- and 16-membered macrolides, azithromycin, or clindamycin. HMR 3647 also had high in vitro activity against
Brevibacterium
spp. and
Listeria monocytogenes
.
In Vitro Susceptibilities of the Microsporidia
Encephalitozoon cuniculi
,
Encephalitozoon hellem
, and
Encephalitozoon intestinalis
to Albendazole and Its Sulfoxide and Sulfone Metabolites
Authors: Ridoux Olivier , Drancourt Michel 
Published: October 2018

ABSTRACT

In vitro comparisons demonstrated that the efficacy of albendazole, albendazole-sulfoxide, and albendazole-sulfone against pathogenic
Encephalitozoon
species was proportional to the degree of oxidation at a concentration of >10
−3
μg/ml. Furthermore, at a concentration of <10
−2
μg/ml, benzimidazoles were more effective against
Encephalitozoon cuniculi
and
Encephalitozoon hellem
than against
Encephalitozoon intestinalis
.
Efficacies of Cefepime, Ceftazidime, and Imipenem Alone or in Combination with Amikacin in Rats with Experimental Pneumonia Due to Ceftazidime-Susceptible or -Resistant
Enterobacter cloacae
Strains
Authors: Mimoz Olivier , Jacolot Anne , Leotard Sophie , Hidri Nadia , Samii Kamran , Nordmann Patrice , Petitjean Olivier 
Published: October 2018

ABSTRACT

The antibacterial activities of human regimens of cefepime, ceftazidime, and imipenem alone or in combination with amikacin against an isogenic pair of
Enterobacter cloacae
strains (wild type and its corresponding derepressed cephalosporinase mutant) were compared by using our nonlethal model of pneumonia with 180 immunocompetent rats. Compared with untreated animals, all β-lactam-treated rats, except those inoculated with the mutant isolate and receiving ceftazidime, had significantly lower bacterial counts in their lungs 60 h after the onset of therapy. Although the combination of a β-lactam and amikacin was more bactericidal than each corresponding antimicrobial agent alone, true synergy was noted only with cefepime and imipenem against the constitutive derepressed strain.
Amphotericin B Colloidal Dispersion Combined with Flucytosine with or without Fluconazole for Treatment of Murine Cryptococcal Meningitis
Authors: Diamond DeAnn M. , Bauer Madeline , Daniel Barbra E. , Leal Mary Ann E. , Johnson Debra , Williams Byron K. , Thomas Ann M. , Ding James C. , Najvar Laura , Graybill J. Richard , Larsen Robert A. 
Published: October 2018

ABSTRACT

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by
Cryptococcus neoformans
compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of
C. neoformans
. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (
P
< 0.00001) and to achieve the maximum antifungal effect (
P
< 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.
The Gene Encoding the Low-Affinity Penicillin-Binding Protein 3r in
Enterococcus hirae
S185R Is Borne on a Plasmid Carrying Other Antibiotic Resistance Determinants
Authors: Raze Dominique , Dardenne Olivier , Hallut Séverine , Martinez-Bueno Manuel , Coyette Jacques , Ghuysen Jean-Marie 
Published: October 2018

ABSTRACT

Two plasmid-derived
Nco
I DNA fragments of 14 and 4.5 kb, respectively, have been isolated from the multidrug-resistant strain
Enterococcus hirae
S185R and analyzed. The 14-kb fragment contains two inverted (
L
and
R
) IS
1216
insertion modules of the ISS
1
family. These modules define a Tn
5466
transposon-like structure that contains one copy of the methylase-encoding
ermAM
conferring erythromycin resistance and one copy of the adenylyl-transferase-encoding
aadE
conferring streptomycin resistance. Immediately on the left side of IS
1216L
there occurs a copy of
pbp3r
encoding the low-affinity penicillin-binding protein (PBP) PBP3r, itself preceded by a
psr
-like gene (
psr3r
) that controls the synthesis of PBP3r.
ermAM
,
aadE
, and the transposase gene (
tnp
) of IS
1216R
have the same polarities, and these are opposite those of
psr3r
,
pbp3r
, and the
tnp
gene of IS
1216L
. The 4.5-kb fragment is a copy of the 4.5-kb sequence at the 5′ end of the 14-kb fragment, although it is not a restriction product of the 14-kb fragment. It contains three genes with the same polarity:
psr3r
,
pbp3r
, and
tnp
in an IS
1216
element. Because of the very high degree of identity (99%) with the chromosomal
psrfm
and
pbp5fm
genes of
Enterococcus faecium
D63R, it is proposed that both the
psr3r
and
pbp3r
genes were transferred from an
E. faecium
strain and inserted in a plasmid of
E. hirae. E. hirae
is the first known bacterial species in which a low-affinity PBP-encoding gene has been found to be plasmid borne.
Rifampin Increases Cytokine-Induced Expression of the CD1b Molecule in Human Peripheral Blood Monocytes
Authors: Tentori L. , Graziani G. , Porcelli S. A. , Sugita M. , Brenner M. B. , Madaio R. , Bonmassar E. , Giuliani A. , Aquino A. 
Published: October 2018

ABSTRACT

In recent years, it has been shown that a nonclassical, major histocompatibility complex-independent system (i.e., CD1-restricted T-cell responses) is involved in T-cell immunity against nonpeptide antigens. The CD1 system appears to function by presenting microbial lipid antigens to specific T cells, and the antigens so far identified include several known constituents of mycobacterial cell walls. Among the four known human CD1 isoforms, the CD1b protein is the best characterized with regard to its antigen-presenting function. Expression of CD1b is upregulated on human blood monocytes upon exposure to granulocyte/macrophage-colony stimulating factor, alone or in combination with interleukin-4 (IL-4) (S. A. Porcelli, Adv. Immunol. 59:1–98, 1995). Rifampin (RFP) and its derivatives are widely used for chemoprophylaxis or chemotherapy against
Mycobacterium tuberculosis
. However, this agent was found to reduce the mitogen responsiveness of human B and T lymphocytes, chemotaxis, and delayed-type hypersensitivity. The present study extends the immunopharmacological profile of RFP by examining its effects on CD1b expression by human peripheral blood monocytes exposed to GM-CSF plus IL-4. The results showed that clinically attainable concentrations (i.e., 2 or 10 μg/ml for 24 h) of the agent produced a marked increase in CD1b expression on the plasma membrane, as evaluated by fluorescence-activated cell sorter analysis, whereas it had no effect on cytosolic fractions, as indicated by Western blot analysis. This was found to be the result of increased CD1b gene expression, as shown by Northern blot analysis of CD1b mRNA. These results suggest that RFP could be of potential value in augmenting the CD1b-restricted antigen recognition system, thereby enhancing protective cellular immunity to
M. tuberculosis.
Reduced Clinical Efficacy of Pazufloxacin against Gonorrhea Due to High Prevalence of Quinolone-Resistant Isolates with the GyrA Mutation
Authors: Tanaka Masatoshi , Matsumoto Tetsuro , Sakumoto Misao , Takahashi Koichi , Saika Takeshi , Kabayashi Intetsu , Kumazawa Joichi , Group The Pazufloxacin Std 
Published: October 2018

ABSTRACT

Forty-two men with gonococcal urethritis were treated with an oral dosage of 200 mg of pazufloxacin, a new fluoroquinolone, three times daily for 3 days. Only 28 of the 42 men (66.7%) had negative culture results for
Neisseria gonorrhoeae
during follow-up. Of the 42 isolates, 41 could be recultured for antibiotic susceptibility testing and DNA sequencing. In 26 of the 41 isolates (63.4%), GyrA mutations with or without ParC mutations were identified. Among the 26 isolates, 23 contained a single GyrA mutation, 1 contained two GyrA mutations, and 2 contained three mutations including double GyrA and single ParC mutations. A single Ser-91-to-Phe mutation, which was detected in 14 of the 26 isolates, was the most common GyrA mutation, followed by an Ala-75 to Ser mutation and an Asp-95 to Asn or Gly mutation in GyrA. All three isolates with two or three mutations contained the Ser-91-to-Phe GyrA mutation. Eleven of the 14 isolates with the single Ser-91-to-Phe mutation within GyrA and all 3 isolates with two or three mutations persisted after pazufloxacin treatment. On the other hand, all 15 wild-type and 9 mutant isolates with a substitution at codon Ala-75 or Asp-95 were eradicated. The mean MIC of pazufloxacin for mutants with the single Ser-91-to-Phe mutation in GyrA was 66-fold higher than that for the wild type. The results obtained in this study suggest that a high prevalence of fluoroquinolone-resistant gonococcal isolates with the Ser-91-to-Phe mutation in GyrA reduced the efficacy of pazufloxacin as treatment for gonococcal urethritis.
Antibiotic Treatment of Experimental Pneumonic Plague in Mice
Authors: Byrne William R. , Welkos Susan L. , Pitt M. Louise , Davis Kelly J. , Brueckner Ralf P. , Ezzell John W. , Nelson Gene O. , Vaccaro Joseph R. , Battersby Luann C. , Friedlander Arthur M. 
Published: October 2018

ABSTRACT

A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized
Yersinia pestis
organisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia.