bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Strategies Using Cefpirome and Ceftazidime for Empiric Treatment of Pneumonia in Intensive Care Patients
Authors: Wolff M. 
Published: October 2018

ABSTRACT
In an international, multicenter, open-label, randomized comparative study, adult patients in intensive care units were enrolled to receive cefpirome intravenously at 2 g twice daily or ceftazidime intravenously at 2 g three times daily for the empiric treatment of pneumonia. Randomization was performed after a double stratification according to the investigator’s initial choice of monotherapy or combination therapy and then on the basis of the severity of disease. The primary endpoint was the clinical response at the end of treatment in the intent-to-treat population. Data for all patients were reviewed by a blinded observer. Of the 400 enrolled patients, 201 received cefpirome (monotherapy, 56%) and 199 received ceftazidime (monotherapy, 51%). Pneumonia was hospital acquired for 75% of the patients. Clinical failures rates were 34 versus 36% (odds ratio = 0.922; upper bound of 90% confidence interval = 1.301) in the intent-to-treat analysis for cefpirome and ceftazidime, respectively. For the cefpirome and ceftazidime groups, there were 35 versus 30% clinical failures among monotherapy-stratified patients, respectively, and 34 versus 42% clinical failures among combination therapy-stratified patients, respectively. The rates of clinical failures in the per-protocol analysis were 38 and 42%, respectively. In the population of patients evaluable for bacteriologic efficacy, eradication or presumed eradication was obtained for 71% (172 of 241) and 70% (162 of 230) of the pathogens isolated from the patients receiving cefpirome and ceftazidime, respectively. The mortality rates within 2 weeks after the end of treatment were similar (cefpirome group, 31%; ceftazidime group, 26%), as were the percentages of patients with at least one treatment-related adverse event (17 and 19%, respectively). An empiric treatment strategy with cefpirome at 2 g twice daily is equivalent in terms of efficacy and tolerance to ceftazidime at 2 g three times daily for the treatment of pneumonia in patients in intensive care units.
In Vitro and In Vivo Antibacterial Activities of S-4661, a New Carbapenem
Authors: Tsuji Masakatsu , Ishii Yoshikazu , Ohno Akira , Miyazaki Shuichi , Yamaguchi Keizo 
Published: October 2018

ABSTRACT

The in vitro and in vivo antibacterial activities of S-4661, a new 1β-methylcarbapenem, were compared with those of imipenem, meropenem, biapenem, cefpirome, and ceftazidime. The activity of S-4661 against methicillin-susceptible staphylococci and streptococci was comparable to that of imipenem, with an MIC at which 90% of the strains tested were inhibited (MIC
90
) equal to 0.5 μg/ml or less. S-4661 was highly active against members of the family
Enterobacteriaceae
,
Haemophilus influenzae
, and
Moraxella catarrhalis
, with MIC
90
s ranging from 0.032 to 0.5 μg/ml. Against imipenem-resistant
Pseudomonas aeruginosa
, S-4661 was the most active among test agents (MIC
90
, 8 μg/ml). Furthermore, S-4661 displayed a high degree of activity against many ceftazidime-, ciprofloxacin-, and gentamicin-resistant isolates of
P. aeruginosa
. The in vivo efficacy of S-4661 against experimentally induced infections in mice caused by gram-positive and gram-negative bacteria, including penicillin-resistant
Streptococcus pneumoniae
and drug-resistant
P. aeruginosa
, reflected its potent in vitro activity and high levels in plasma in mice. We conclude that S-4661 is a promising new carbapenem for the treatment of infections caused by gram-positive and -negative bacteria, including penicillin-resistant
S. pneumoniae
and drug-resistant
P. aeruginosa.
Characterization of In40 of
Enterobacter aerogenes
BM2688, a Class 1 Integron with Two New Gene Cassettes,
cmlA2
and
qacF
Authors: Ploy Marie-Cécile , Courvalin Patrice , Lambert Thierry 
Published: October 2018

ABSTRACT

Enterobacter aerogenes
BM2688, which is resistant to multiple antibiotics, and its aminoglycoside-susceptible derivative BM2688-1 were isolated from the same clinical sample. Strain BM2688 harbored plasmid pIP833, which carries a class 1 integron, In40, containing (in addition to
qacEΔ1
and
sul1
, which are characteristic of class 1 integrons) four gene cassettes:
aac(6′)-Ib
,
qacF
,
cmlA2
, and
oxa-9
. The
cmlA2
gene had 83.7% identity with the previously described nonenzymatic chloramphenicol resistance
cmlA1
gene. The
qacF
gene conferred resistance to quaternary ammonium compounds and displayed a high degree of similarity with
qacE
(67.8% identity) which, however, has been found as part of a cassette with a very different 59-base element. The
oxa-9
gene was not expressed due to a lack of promoter sequences. Study of the antibiotic-susceptible derivative BM2688-1 indicated that a 3,148-bp deletion between the 3′ end of the
aac(6′)-Ib
gene and the 3′ conserved segment of In40 was responsible for the loss of resistance. The occurrence of this DNA rearrangement, which did not involve homologous sequences, suggests that the In40 integrase could promote recombination at secondary sites.
Accumulation of Amphotericin B in Human Macrophages Enhances Activity againstAspergillus fumigatusConidia: Quantification of Conidial Kill at the Single-Cell Level
Authors: Jahn Bernhard , Rampp Albert , Dick Christian , Jahn Andreas , Palmer Michael , Bhakdi Sucharit 
Published: October 2018

ABSTRACTA cytofluorometric assay that allowed assessment of damage to phagocytosedAspergillus fumigatusconidia at the single-cell level was developed. After ingestion by monocyte-derived macrophages (MDMs), conidia were reisolated by treatment of the cells with streptolysin O, a pore-forming toxin with lytic properties on mammalian cells but not on fungi. The counts obtained by staining of damaged conidia with propidium iodide and quantification by cytofluorometry correlated with colony counts. By the use of this method, we demonstrate that MDMs differentiated in vitro by low-dose granulocyte-macrophage colony-stimulating factor and gamma interferon have only a limited capacity to damageAspergillusconidia in vitro. The killing rate 12 h after phagocytosis was found to be only 10 to 15%. However, intracellular loading of the phagocytes with amphotericin B (AmB) dose dependently enhanced the anticonidial activity. Preincubation of macrophages with only 1 μg of AmB per ml resulted in an uptake of 18 fg of AmB/cell, leading to killing rates of 50 to 60%. The experimental protocol provides a new tool for the rapid quantification of anticonidial activity againstA. fumigatusin vitro. Intracellular accumulation of AmB may represent an important factor underlying the efficacy of this antifungal drug in the prophylaxis and treatment ofAspergillusinfections.
Characterization of Mutations in therpoBGene That Confer Rifampin Resistance inStaphylococcus aureus
Authors: Aubry-Damon Hélène , Soussy Claude-James , Courvalin Patrice 
Published: October 2018

ABSTRACTMutations in the rifampin resistance-determining (Rif) regions of therpoBgene ofStaphylococcus aureusmutants obtained during therapy or in vitro were analyzed by gene amplification and sequencing. Each of the resistant clinical isolates, including five nonrelated clones and two strains isolated from the same patient, and of the 10 in vitro mutants had a single base pair change that resulted in an amino acid substitution in the β subunit of RNA polymerase. Eight mutational changes at seven positions were found in cluster I of the central Rif region. Certain substitutions (His481/Tyr and Asp471/Tyr [S. aureuscoordinates]) were present in several mutants. Substitutions Gln468/Arg, His481/Tyr, and Arg484/His, which conferred high-level rifampin resistance, were identical or in the same codon as those described in other bacterial genera, whereas Asp550/Gly has not been reported previously. Substitutions at codon 477 conferred high- or low-level resistance, depending on the nature of the new amino acid. The levels of resistance of in vivo and one-step in vitro mutants carrying identical mutations were similar, suggesting that no other resistance mechanism was present in the clinical isolates. On the basis of these data and the population distribution of more than 4,000 clinicalS. aureusisolates, we propose ≤0.5 and ≥8 μg/ml as new breakpoints for the clinical categorization of this species relative to rifampin.
Pharmacodynamics of Gatifloxacin in Cerebrospinal Fluid in Experimental Cephalosporin-Resistant Pneumococcal Meningitis
Authors: Lutsar Irja , Friedland Ian R. , Wubbel Loretta , McCoig Cynthia C. , Jafri Hasan S. , Ng Winston , Ghaffar Faryal , McCracken George H. 
Published: October 2018

ABSTRACT

The purpose of this study was to evaluate the cerebrospinal fluid (CSF) pharmacodynamics of a new fluoroquinolone, gatifloxacin (AM-1155), in experimental pneumococcal meningitis. The penetration of gatifloxacin into CSF, calculated as the percentage of the area under the concentration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. Gatifloxacin showed linear pharmacokinetics in CSF, and 1 h after intravenous dosages of 7.5, 15, or 30 mg/kg of body weight, peak CSF concentrations were 0.46 ± 0.08 (mean ± standard deviation), 0.94 ± 0.16, and 1.84 ± 0.5 μg/ml, respectively. The elimination half-life of gatifloxacin in CSF was 3.8 to 5.6 h (compared with 2.7 to 3.2 h in blood). There was a significant interrelationship among the highest measured values of gatifloxacin in blood and CSF/minimal bactericidal concentration (
C
peak
/MBC), the time antibiotic concentrations exceeded the MBC (
T
> MBC), and AUC/MBC (
r
= 0.94); in single-dose experiments, each correlated significantly with the bacterial killing rate. Divided-dose regimens, resulting in greater
T
> MBC values but lower
C
peak
/MBC ratios, were more effective in terms of bacterial clearance compared with corresponding single-dose regimens. Gatifloxacin therapy was as effective as currently recommended regimens (e.g., a combination of ceftriaxone and vancomycin) against this highly cephalosporin-resistant pneumococcal strain. The bactericidal activity of gatifloxacin in CSF was closely related to the AUC/MBC ratio, but maximal activity was achieved only when drug concentrations exceeded the MBC for the entire dosing interval.
Antiparasitic Effects of the Intra-Golgi Transport Inhibitor Megalomicin
Authors: Bonay Pedro , Durán-Chica Isabel , Fresno Manuel , Alarcón Balbino , Alcina Antonio 
Published: October 2018

ABSTRACT

The macrolide antibiotic megalomicin (MGM) has been shown to inhibit vesicular transport between the medial- and trans-Golgi, resulting in the undersialylation of cellular proteins (P. Bonay, S. Munro, M. Fresno, and B. Alarcón, J. Biol. Chem. 271:3719–3726, 1996). Due to the effects of MGM on the Golgi and on the replication of enveloped viruses, we decided to test whether it has any antiparasitic activity. The results showed that MGM has potent activity against the epimastigote stage of
Trypanosoma cruzi
, producing a 50% inhibitory concentration (IC
50
) of 0.2 μg/ml. Furthermore, MGM was also active against the intracellular replicative, amastigote form of
T. cruzi
, completely preventing its replication in infected murine LLC/MK2 macrophages at a dose of 5 μg/ml. Although less potent, MGM was also active against
Trypanosoma brucei
epimastigotes (IC
50
, 2 μg/ml) and
Leishmania donovani
and
Leishmania major
promastigotes (IC
50
, 3 and 8 μg/ml, respectively). MGM also blocked intracellular replication of the asexual stage of
Plasmodium falciparum
-infected erythrocytes at 1 μg/ml. Finally, MGM was active in an in vivo model, resulting in the complete protection of BALB/c mice from death caused by acute
T. brucei
infection and significantly reducing the parasitemia. These results suggest that MGM is a potential drug for the treatment of veterinary and human parasitic diseases.
In Vivo Efficacy of ABT-255 against Drug-Sensitive and -Resistant
Mycobacterium tuberculosis
Strains
Authors: Oleksijew Andy , Meulbroek Jon , Ewing Patty , Jarvis Ken , Mitten Mike , Paige Lenette , Tovcimak Ann , Nukkula Mike , Chu Daniel , Alder Jeffrey D. 
Published: October 2018

ABSTRACT

Current therapy for pulmonary tuberculosis involves 6 months of treatment with isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin for reliable treatment efficacy. The long treatment period increases the probability of noncompliance, leading to the generation of multidrug-resistant isolates of
Mycobacterium tuberculosis
. A treatment option that significantly shortened the course of therapy, or a new class of antibacterial effective against drug-resistant
M. tuberculosis
would be of value. ABT-255 is a novel 2-pyridone antibacterial agent which demonstrates in vitro potency and in vivo efficacy against drug-susceptible and drug-resistant
M. tuberculosis
strains. By the Alamar blue reduction technique, the MIC of ABT-255 against susceptible strains of
M. tuberculosis
ranged from 0.016 to 0.031 μg/ml. The MIC of ABT-255 against rifampin- or ethambutol-resistant
M. tuberculosis
isolates was 0.031 μg/ml. In a murine model of pulmonary tuberculosis, 4 weeks of oral ABT-255 therapy produced a 2- to 5-log
10
reduction in viable drug-susceptible
M. tuberculosis
counts from lung tissue. Against drug-resistant strains of
M. tuberculosis
, ABT-255 produced a 2- to 3-log
10
reduction in viable bacterial counts from lung tissue. ABT-255 is a promising new antibacterial agent with activity against
M. tuberculosis
.
Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits
Authors: Groll Andreas H. , Sein Tin , Petraitis Vidas , Petraitiene Ruta , Callender Diana , Gonzalez Corina E. , Giri Neelam , Bacher John , Piscitelli Stephen , Walsh Thomas J. 
Published: October 2018

ABSTRACT

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (
C
max
) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC
0–24
) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (
P
< 0.005 to
P
< 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC
0–24
below the values obtained at 50 mg/kg (
P
< 0.01) and after single-dose administration of the same dosage (
P
< 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.
Antitrypanosomal Activity of a New Triazine Derivative, SIPI 1029, In Vitro and in Model Infections
Authors: Bacchi Cyrus J. , Vargas Marcus , Rattendi Donna , Goldberg Burt , Zhou Weicheng 
Published: October 2018

ABSTRACT

A recently developed diaminotriazine derivative [
O
,
O
′-bis(1,2-dihydro-2,2-tetramethylene-4,6-diamino-
S
-triazin-1-yl)-1,6-hexanediol dihydrochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems. In vitro, SIPI 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of
Trypanosoma brucei brucei
and
Trypanosoma brucei rhodesiense
at 0.15 to 2.15 nM (50% inhibitory concentrations). In in vivo mouse laboratory models of
T. b. rhodesiense
clinical isolate infections, SIPI 1029 was curative for 12 of 13 isolates at ≤10 mg/kg of body weight/day for 3 days. In eight infections, a single dose was ≥60% curative, and in six of these, a dose of ≤5 mg/kg was sufficient for ≥60% cure rates. A number of these isolates were resistant to the standard trypanocide melarsoprol (Arsobal) and/or the diamidines diminazene aceturate (Berenil) and pentamidine. SIPI 1029 was also curative in combination with
dl
-α-difluoromethylornithine (Ornidyl) in a
T. b. brucei
central nervous system model infection. Some evidence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 or 3 days in which deaths were observed in 6 of 65 animals given this dosage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.
A New Approach for Early Assessment of the Epileptogenic Potential of Quinolones
Authors: Delon Annie , Pariat Claudine , Courtois Philippe , Bouquet Serge , Couet William 
Published: October 2018

ABSTRACT
The epileptogenic potential of pefloxacin and norfloxacin, two quinolone antibiotics, was investigated in vivo in three different animal species by measuring drug concentrations in cerebrospinal fluid (CSF), which is part of the biophase, at the onset of convulsions. Interestingly, the pefloxacin-to-norfloxacin concentration ratios in CSF were virtually constant across the species (7.0, 6.6, and 6.0 in mice, rats, and rabbits, respectively), suggesting that this approach could be used to predict the relative epileptogenic potential of quinolones in humans.
In Vitro Susceptibilities of
Chlamydia pneumoniae
Strains Recovered from Atherosclerotic Coronary Arteries
Authors: Gieffers Jens , Solbach Werner , Maass Matthias 
Published: October 2018

ABSTRACT

Chlamydia pneumoniae
strains have been recovered from arteriosclerotic coronary arteries, but their antibiotic susceptibility profiles have not yet been examined. We report in vitro susceptibility data for five cardiovascular
C. pneumoniae
isolates. These strains did not differ significantly from respiratory strains in their patterns of susceptibility to azithromycin, erythromycin, roxithromycin, ofloxacin, doxycycline, rifampin, and penicillin G. Roxithromycin was the most active macrolide, and rifampin was the most effective drug overall.
PMX-622 (Polymyxin B-Dextran 70) Does Not Alter In Vitro Activities of 11 Antimicrobial Agents
Authors: Fuchs Peter C. , Barry Arthur L. , Brown Steven D. 
Published: October 2018

ABSTRACT
Because of its capacity to neutralize the lethality of gram-negative bacterial endotoxic lipopolysaccharides, PMX-622 (polymyxin B bound to dextran 70) is being developed for possible adjunctive therapy of gram-negative sepsis. In this study, it was determined that the in vitro antimicrobial activity of PMX-622 was minimal and that it does not interfere with the in vitro antimicrobial activity of 11 antibiotics commonly used to treat gram-negative infections.
Gonococcal Resistance to β-Lactams and Tetracycline Involves Mutation in Loop 3 of the Porin Encoded at the
penB
Locus
Authors: Gill M. J. , Simjee S. , Al-Hattawi K. , Robertson B. D. , Easmon C. S. F. , Ison C. A. 
Published: October 2018

ABSTRACT

penB
is a chromosomal mutation that confers resistance to β-lactams and tetracyclines and reduced susceptibility to quinolones in
Neisseria gonorrhoeae
. It is linked to the porin gene (
por
) and requires the increased expression of an efflux pump due to
mtr
. Transformation of a susceptible gonococcus (strain H1) with chromosomal DNA from strain FA140 (
penA mtr penB
; porin serovar IB1) and conjugal transfer of a β-lactamase-expressing plasmid was used to produce isogenic strains for determination of equilibrium periplasmic penicillin concentrations by the method of Zimmermann and Rosselet (W. Zimmermann and A. Rosselet, Antimicrob. Agents Chemother. 12:368–372, 1977). In transformants with the Mtr and PenB phenotypes, equilibrium concentrations of penicillin were reduced. DNA sequence analysis of
por
from isogenic
penB
and
penB
+
transformants revealed 14 sequence differences; nine of these differences resulted in amino acid changes. Three amino acid changes were found in the putative gonococcal equivalent of the pore-constricting loop 3 of
Escherichia coli
OmpF. Two of these changes (Gly-101–Ala-102→Asp-Asp) result in an increased negative charge at this position in
por
loop 3. PCR products comprising the complete
por
gene from strain FA140 were transformed into strain H1-2 (
penA mtr
; porin serovar IB-3), with the resulting transformants having the antibiotic susceptibility phenotype associated with
penB. penB
-like mutations were found in loop 3 of clinical isolates of gonococci with chromosomally mediated resistance to penicillin. We conclude that
penB
is a mutation in loop 3 of
por
that reduces porin permeability to hydrophilic antibiotics and plays an important role in the development of chromosomally mediated resistance to penicillin and tetracycline in gonococci.
Pharmacodynamics of (−)-β-2′,3′-Dideoxy-3′-Thiacytidine in Chronically Virus-Infected Woodchucks Compared to Its Pharmacodynamics in Humans
Authors: Hurwitz Selwyn J. , Tennant Bud C. , Korba Brent E. , Gerin John L. , Schinazi Raymond F. 
Published: October 2018

ABSTRACT
The pharmacodynamics of (−)-β-2′,3′-dideoxy-3′-thiacytidine (3TC) was studied in chronically woodchuck hepatitis virus-infected woodchucks and compared to that in previous studies in hepatitis B virus (HBV)-infected humans. Net depletion rates of serum virus DNA in woodchucks receiving 3TC were modeled as a sum of an exponentially declining virus input and a first-order elimination. Preceding shoulders and pseudo-first-order virus half-lives in serum ranged from 1 to 7 days and were dose dependent. Higher plasma 3TC concentrations were needed in woodchucks for virus depletion similar to that attained in humans. Human HBV depletion curves from a previous clinical study with 3TC (≥100 mg per day) were described by a biexponential relationship. The average half-life value in humans, normalized to fraction of area under the serum virus load-time curve, was similar to the average half-life value observed in woodchucks given the highest 3TC dose (2.4 and 2.0 days, respectively). On cessation of therapy, virus load rebounds in woodchucks were dose dependent and resembled posttherapy virus “flares” reported to occur in humans. The estimates of drug exposures that could lead to optimal antiviral effects presented indicate that 3TC should not be underdosed and compliance should be monitored. The study of chronically infected woodchucks may prove useful for optimizing drug regimens for hepadnavirus infections.