bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing Aminoglycoside Therapy for Nosocomial Pneumonia Caused by Gram-Negative Bacteria
Authors: Kashuba Angela D. M. , Nafziger Anne N. , Drusano George L. , Bertino Joseph S. 
Published: October 2018

ABSTRACT

Nosocomial pneumonia is a notable cause of morbidity and mortality and leads to increases in lengths of hospital stays and institutional expenditures. Aminoglycosides are used to treat patients with these infections, but few data on the doses and schedules required to achieve optimal therapeutic outcomes exist. We analyzed aminoglycoside treatment data for 78 patients with nosocomial pneumonia to determine if optimization of aminoglycoside pharmacodynamic parameters results in a more rapid therapeutic response (defined by outcome and days to leukocyte count resolution and temperature resolution). Cox proportional hazards, Classification and Regression Tree (CART), and logistic regression analyses were applied to the data. By all analyses, the first measured maximum concentration of drug in serum (
C
max
)/MIC predicted days to temperature resolution and the second measured
C
max
/MIC predicted days to leukocyte count resolution. For days to temperature resolution and leukocyte count resolution, CART analyses produced breakpoints, with an 89% success rate at 7 days of therapy for a
C
max
/MIC of >4.7 and an 86% success rate at 7 days of therapy for a
C
max
/MIC of >4.5, respectively. Logistic regression analyses predicted a 90% probability of temperature resolution and leukocyte count resolution by day 7 if a
C
max
/MIC of ≥10 is achieved within the first 48 h of aminoglycoside therapy. Aggressive aminoglycoside dosing immediately followed by individualized pharmacokinetic monitoring would ensure that
C
max
/MIC targets are achieved early in therapy. This would increase the probability of a rapid therapeutic response for pneumonia caused by gram-negative bacteria and potentially decreasing durations of parenteral antibiotic therapy, lengths of hospitalization, and institutional expenditures, a situation in which both the patient and the institution benefit.
Esterases in Serum-Containing Growth Media Counteract Chloramphenicol Acetyltransferase Activity In Vitro
Authors: Sohaskey Charles D. , Barbour Alan G. 
Published: October 2018

ABSTRACT

The spirochete
Borrelia burgdorferi
was unexpectedly found to be as susceptible to diacetyl chloramphenicol, the product of the enzyme chloramphenicol acetyltransferase, as it was to chloramphenicol itself. The susceptibilities of
Escherichia coli
and
Bacillus subtilis
, as well as that of
B. burgdorferi
, to diacetyl chloramphenicol were then assayed in different media. All three species were susceptible to diacetyl chloramphenicol when growth media were supplemented with rabbit serum or, to a lesser extent, human serum. Susceptibility of
E. coli
and
B. subtilis
to diacetyl chloramphenicol was not observed in the absence of serum, when horse serum was used, or when the rabbit or human serum was heated first. In the presence of 10% rabbit serum, a strain of
E. coli
bearing the chloramphenicol acetyltransferase (
cat
) gene had a fourfold-lower resistance to chloramphenicol than in the absence of serum. A plate bioassay for chloramphenicol activity showed the conversion by rabbit, mouse, and human sera but not bacterial cell extracts or heated serum of diacetyl chloramphenicol to an inhibitory compound. Deacetylation of acetyl chloramphenicol by serum components was demonstrated by using fluorescent substrates and thin-layer chromatography. These studies indicate that esterases of serum can convert diacetyl chloramphenicol back to an active antibiotic, and thus, in vitro findings may not accurately reflect the level of chloramphenicol resistance by
cat
-bearing bacteria in vivo.
Influence of Renal Failure on Intestinal Clearance of Ciprofloxacin in Rats
Authors: Dautrey Sophie , Rabbaa Lydia , Laouari Denise , Lacour Bernard , Carbon Claude , Farinotti Robert 
Published: October 2018

ABSTRACT
Following intravenous doses, ciprofloxacin pharmacokinetics in control and nephrectomized rats were studied. There were no differences between control and nephrectomized rats for area under the concentration-time curve in plasma or biliary clearance. The intestinal clearance of ciprofloxacin was increased in nephrectomized rats. Intestinal elimination seems to compensate partially for the decrease in urinary excretion of ciprofloxacin in nephrectomized rats.
Multiplex Sequence Analysis Demonstrates the Competitive Growth Advantage of the A-to-G Mutants of Clarithromycin-Resistant
Helicobacter pylori
Authors: Wang Ge , Rahman M. Sayeedur , Humayun M. Zafri , Taylor Diane E. 
Published: October 2018

ABSTRACT

Clarithromycin resistance in
Helicobacter pylori
is due to point mutation within the 23S rRNA. We examined the growth rates of different types of site-directed mutants and demonstrated quantitatively the competitive growth advantage of A-to-G mutants over other types of mutants by a multiplex sequencing assay. The results provide a rational explanation of why A-to-G mutants are predominantly observed among clarithromycin-resistant clinical isolates.
Many Class I Integrons Comprise Distinct Stable Structures Occurring in Different Species of
Enterobacteriaceae
Isolated from Widespread Geographic Regions in Europe
Authors: Martinez-Freijo Pedro , Fluit Ad C. , Schmitz Franz-Joseph , Verhoef Jan , Jones Mark E. 
Published: October 2018

ABSTRACT

Three sizes of inserted regions of DNA (800, 1,000, and 1,500 bp) were shown to be common among class I integrons in unrelated clinical isolates of
Enterobacteriaceae
from different European hospitals. Sequencing showed that 800-bp inserted regions comprised identical sequences including
aacA4
, that 1,000-bp inserted regions included
aadA
, and that 1,500-bp inserted regions included
dfrI
and
aadA1
, irrespective of host species and geographic origin. In addition promoter sequences were mostly identical for each size class. These data suggest that inserted gene cassettes and promoter regions of integrons are conserved and stable, with resistance genes transferred more often as part of the entire integron structure than as individual gene cassettes.
Declining Concentrations of Dihydroartemisinin in Plasma during 5-Day Oral Treatment with Artesunate for Falciparum Malaria
Authors: Khanh Nguyen Xuan , de Vries Peter J. , Ha Le Dang , van Boxtel Chris J. , Koopmans Richard , Kager Piet A. 
Published: October 2018

ABSTRACT
Six patients with uncomplicated falciparum malaria received artesunate for 5 days. Plasma concentrations of artesunate and dihydroartemisinin were determined by high-performance liquid chromatography with electrochemical detection. The concentrations of dihydroartemisinin in plasma 2 h after a dose showed a time-dependent decline. Concentrations of artesunate in plasma especially after the last dose, were very low. Despite this, all patients responded with a fast recovery.
Fosfomycin Alters Lipopolysaccharide-Induced Inflammatory Cytokine Production in Mice
Authors: Matsumoto Tetsuya , Tateda Kazuhiro , Miyazaki Shuichi , Furuya Nobuhiko , Ohno Akira , Ishii Yoshikazu , Hirakata Yoichi , Yamaguchi Keizo 
Published: October 2018

ABSTRACTTo determine the mechanisms of immunomodulating action of fosfomycin (FOF), we examined its effect on the production of inflammatory cytokines in mice injected with lipopolysaccharide (LPS). Treatment with FOF significantly lowered the peak serum levels of tumor necrosis factor alpha and interleukin-1β, indicating that FOF alters inflammatory cytokine production after LPS stimulation.
Comparative In Vitro Activities of Amoxicillin-Clavulanate against Aerobic and Anaerobic Bacteria Isolated from Antral Puncture Specimens from Patients with Sinusitis
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni 
Published: October 2018

ABSTRACT

By an agar dilution method, the antimicrobial susceptibilities of antral sinus puncture isolates were studied. Pneumococci were generally susceptible to amoxicillin, azithromycin, and clarithromycin, but 17% of pneumococcal isolates were resistant to cefuroxime.
Haemophilus influenzae
isolates were resistant to amoxicillin and clarithromycin. β-Lactamase production occurred in 69% of
Prevotella
species. One-third of
Peptostreptococcus magnus
isolates were resistant to azithromycin and clarithromycin. Cefuroxime had limited activity against
Prevotella
species and
P. magnus
. Levofloxacin was active against most isolates except peptostreptococci. Amoxicillin-clavulanate was active against all isolates, with the MIC at which 90% of the isolates were inhibited being ≤1 μg/ml.
In Vitro Antibacterial Properties of Pexiganan, an Analog of Magainin
Authors: Ge Yigong , MacDonald Dorothy L. , Holroyd Kenneth J. , Thornsberry Clyde , Wexler Hannah , Zasloff Michael 
Published: October 2018

ABSTRACT

Pexiganan, a 22-amino-acid antimicrobial peptide, is an analog of the magainin peptides isolated from the skin of the African clawed frog. Pexiganan exhibited in vitro broad-spectrum antibacterial activity when it was tested against 3,109 clinical isolates of gram-positive and gram-negative, anaerobic and aerobic bacteria. The pexiganan MIC at which 90% of isolates are inhibited (MIC
90
) was 32 μg/ml or less for
Staphylococcus
spp.,
Streptococcus
spp.,
Enterococcus faecium
,
Corynebacterium
spp.,
Pseudomonas
spp.,
Acinetobacter
spp.,
Stenotrophomonas
spp., certain species of the family
Enterobacteriaceae
,
Bacteroides
spp.,
Peptostreptococcus
spp., and
Propionibacterium
spp. Comparison of the MICs and minimum bactericidal concentrations (MBCs) of pexiganan for 143 isolates representing 32 species demonstrated that for 92% of the isolates tested, MBCs were the same or within 1 twofold difference of the MICs, consistent with a bactericidal mechanism of action. Killing curve analysis showed that pexiganan killed
Pseudomonas aeruginosa
rapidly, with 10
6
organisms/ml eliminated within 20 min of treatment with 16 μg of pexiganan per ml. No evidence of cross-resistance to a number of other antibiotic classes was observed, as determined by the equivalence of the MIC
50
s and the MIC
90
s of pexiganan for strains resistant to oxacillin, cefazolin, cefoxitin, imipenem, ofloxacin, ciprofloxacin, gentamicin, and clindamicin versus those for strains susceptible to these antimicrobial agents. Attempts to generate resistance in several bacterial species through repeated passage with subinhibitory concentrations of pexiganan were unsuccessful. In conclusion, pexiganan exhibits properties in vitro which make it an attractive candidate for development as a topical antimicrobial agent.
9-[2-(Phosphonomethoxy)propyl]adenine (PMPA) Therapy Prolongs Survival of Infant Macaques Inoculated with Simian Immunodeficiency Virus with Reduced Susceptibility to PMPA
Authors: van Rompay Koen K. A. , Cherrington Julie M. , Marthas Marta L. , Lamy Patrick D. , Dailey Peter J. , Canfield Don R. , Tarara Ross P. , Bischofberger Norbert , Pedersen Niels C. 
Published: October 2018

ABSTRACT

Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human immunodeficiency virus infection for the study of the emergence and clinical implications of drug-resistant viral mutants. We previously demonstrated that SIV-infected infant macaques receiving prolonged treatment with 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) developed viral mutants with fivefold reduced susceptibility to PMPA in vitro and that the development of these mutants was associated with the development of a K65R mutation and additional compensatory mutations in reverse transcriptase (RT). To study directly the virulence and clinical implications of these SIV mutants, two uncloned SIV
mac
isolates with similar fivefold reduced in vitro susceptibilities to PMPA but distinct RT genotypes, SIV
mac055
(K65R, N69T, R82K A158S, S211N) and SIV
mac385
(K65R, N69S, I118V), were each inoculated intravenously into six newborn rhesus macaques; 3 weeks later, three animals of each group were started on PMPA treatment. All six untreated animals developed persistently high levels of viremia and fatal immunodeficiency within 4 months. In contrast, the six PMPA-treated animals, despite having persistently high virus levels, survived significantly longer: 5 to 9 months for the three SIV
mac055
-infected infants and ≥21 months for the three SIV
mac385
-infected infants. Virus from only one untreated animal demonstrated reversion to wild-type susceptibility and loss of the K65R mutation. In several other animals, additional RT mutations, including K64R and Y115F, were detected, but the biological role of these mutations is unclear since they did not affect the in vitro susceptibility of the virus to PMPA. In conclusion, this study demonstrates that although SIV
mac
mutants with the PMPA-selected K65R mutation in RT were highly virulent, PMPA treatment still offered strong therapeutic benefits. These results suggest that the potential emergence of HIV mutants with reduced susceptibility to PMPA in patients during prolonged PMPA therapy may not eliminate its therapeutic benefits.
Antiviral Effect of Hyperthermic Treatment in Rhinovirus Infection
Authors: Conti C. , de Marco A. , Mastromarino P. , Tomao P. , Santoro M. G. 
Published: October 2018

ABSTRACT

Human rhinoviruses (HRV) are recognized as the major etiologic agents of the common cold. Starting from the observation that local hyperthermic treatment is beneficial in patients with natural and experimental common colds, we have studied the effect of brief hyperthermic treatment (HT) on HRV replication in HeLa cells. We report that a 20-min HT at 45°C is effective in suppressing HRV multiplication by more than 90% when applied at specific stages of the virus replication cycle. Synthesis of virus proteins is not affected by HT, indicating that the target for treatment is a posttranslational event. The antiviral effect is a transient cell-mediated event and is associated with the synthesis of the 70-kDa heat shock protein hsp70. Unlike poliovirus, rhinovirus infection does not inhibit the expression of hsp70 induced by heat. The possibility that hsp70 could play a role in the control of rhinovirus replication is suggested by the fact that a different class of HSP inducers, the cyclopentenone prostaglandins PGA
1
and Δ
12
-PGJ
2
, were also effective in inhibiting HRV replication in HeLa cells. Inhibition of hsp70 expression by actinomycin D prevented the antiviral activity of prostaglandins in HRV-infected cells. These results indicate that the beneficial effect of respiratory hyperthermia may be mediated by the induction of a cytoprotective heat shock response in rhinovirus-infected cells.
The Immune Response Modifier Imiquimod Requires STAT-1 for induction of Interferon, Interferon-Stimulated Genes, and Interleukin-6
Authors: Bottrel Renata L. A. , Yang Yi-Li , Levy David E. , Tomai Mark , Reis Luiz F. L. 
Published: October 2018

ABSTRACTImiquimod is an oral inducer of interferon (IFN) and several other proinflammatory cytokines and has been successfully used topically as an antiviral agent for the treatment of genital warts. We have investigated the molecular mechanisms by which imiquimod induces the expression of IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in vivo, using mice deficient in various components of the IFN signaling system. Mice deficient in the transcription factor interferon regulatory factor 1 (IRF-1) or in the serine/threonine protein kinase PKR responded normally to imiquimod, producing high levels of circulating IFN and induction of several ISGs. On the other hand, when mice deficient in STAT-1 were treated, a 32-fold reduction in the level of circulating IFN was observed, together with a lack of induction of 2-5 oligo adenylate synthetase (2-5 OAS) and IRF-1 genes. Interestingly, there was also a lack of induction of interleukin-6 (IL-6) gene expression, although tumor necrosis factor was induced and readily detected in serum. In mice deficient in the type I IFN receptor, imiquimod induced levels of IFN similar to those in control mice, but again, neither 2-5 OAS, IRF-1, nor IL-6 genes were induced in mutant mice. Our results suggest that STAT-1 plays a critical role in the mechanism of gene activation by imiquimod. Moreover, induction of IL-6 gene expression appears to be dependent on components of the IFN signaling cascade.
Pharmacokinetics of β-
l
-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys
Authors: Martin Lee T. , Cretton-Scott Erika , Schinazi Raymond F. , Zhou Xiao-Jian , McClure Harold M. , Mathe Christophe , Gosselin Gilles , Imbach Jean-Louis , Sommadossi Jean-Pierre 
Published: October 2018

ABSTRACT

β-
l
-2′,3′-Dideoxy-5-fluorocytidine (β-
l
-FddC), a novel cytidine analog with an unnatural β-
l
sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [
3
H]β-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (
C
max
) was 29.8 ± 10.5 μM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (
t
1/2β
), and mean residence time were 0.7 ± 0.1 liters/h/kg, 1.3 ± 0.1 liters/kg, 1.8 ± 0.2 h, and 1.9 ± 0.2 h, respectively. Approximately 47% ± 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. β-
l
-FddC exhibited a
C
max
of 3.2 μM after oral administration, with a time to peak drug concentration of approximately 1.5 h and a
t
1/2
of 2.2 h. One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered β-
l
-FddC ranged from 56 to 66%.
Comparison of Activities of Broad-Spectrum β-Lactam Compounds against 1,128 Gram-Positive Cocci Recently Isolated in Cancer Treatment Centers
Authors: Diekema Daniel J. , Coffman Stacy L. , Marshall Steven A. , Beach Mondell L. , Rolston Kenneth V. I. , Jones Ronald N. 
Published: October 2018

ABSTRACT

We report the in vitro activities of broad-spectrum β-lactam antimicrobials tested against 1,128 gram-positive pathogens recently isolated from cancer patients. Cefepime and imipenem were more active than ceftazidime and ceftriaxone against these organisms. Only vancomycin demonstrated reliable activity against oxacillin-resistant staphylococci,
Enterococcus
spp., and
Corynebacterium
spp. The spectrum of gram-positive organisms against which cefepime and imipenem have activity provides an advantage over ceftazidime as empiric therapy for cancer patients, potentially reducing the need for the empiric addition of glycopeptides.
Sequences of the Genes for the TEM-20, TEM-21, TEM-22, and TEM-29 Extended-Spectrum β-Lactamases
Authors: Arlet Guillaume , Goussard Sylvie , Courvalin Patrice , Philippon Alain 
Published: October 2018

ABSTRACT

The sequences of the
bla
TEM
genes encoding TEM-20, TEM-21, TEM-22, and TEM-29 extended-spectrum β-lactamases were determined. Analysis of the deduced amino acid sequences indicated that TEM-20 and TEM-29 were derived from TEM-1 and that TEM-21 and TEM-22 were derived from TEM-2. The substitutions involved were Ser-238 and Thr-182 for TEM-20; His-164 for TEM-29; Lys-104, Arg-153, and Ser-238 for TEM-21; and Lys-104, Gly-237, and Ser-238 for TEM-22. The promoter region of the
bla
TEM-22
gene was identical to that of
bla
TEM-3
. High-level production of TEM-20 could result from a 135-bp deletion which combined the −35 region of the
Pa
promoter with the −10 region of the
P3
promoter and a G→T transition in the latter motif.
Potentiation of Isoniazid Activity againstMycobacterium tuberculosisby Melatonin
Authors: Wiid Ian , Hoal-van Helden Eileen , Hon Dinie , Lombard Carl , van Helden Paul 
Published: October 2018

ABSTRACTThe limited number of effective antituberculosis drugs available necessitates optimizing current treatments. We show that melatonin, which is synthesized in the pineal gland, can cause at least a threefold increase in the efficacy of isoniazid. This suggests that tuberculosis chemotherapy can be improved by innate molecules such as melatonin.
Pseudomonas aeruginosa
: a Survey of Resistance in 136 Hospitals in Spain
Authors: Bouza E. , Garcia-Garrote F. , Cercenado E. , Marin M. , Diaz M. S. 
Published: October 2018

ABSTRACT

We carried out a nationwide study with all of the isolates of
Pseudomonas aeruginosa
collected in a week in 136 hospitals in Spain. The data on 1,014 isolates included resistance to the following antimicrobials: piperacillin-tazobactam, 7%; meropenem, 8%; amikacin, 9%; tobramycin, 10%; piperacillin, 10%; ticarcillin, 13%; imipenem, 14%; ceftazidime, 15%; cefepime, 17%; ciprofloxacin, 23%; aztreonam, 23%; ofloxacin, 30%; gentamicin, 31%. The most frequent serotypes were O:1 (25.1%), O:4 (21.6%), and O:11 (11.3%).
In Vitro Activities of Ketolides HRM 3647 and HRM 3004, Levofloxacin, and Other Quinolones and Macrolides against
Neisseria
spp. and
Moraxella catarrhalis
Authors: Sáez-Nieto J. A. , Vázquez J. A. 
Published: October 2018

ABSTRACT

In vitro activities of the ketolides HRM 3647 and HRM 3004 against pathogenic
Neisseria gonorrhoeae
and
N. meningitidis
, saprophytic
Neisseria
isolates, and
Moraxella catarrhalis
were determined. The comparison of ketolide activities with those of the other macrolides shows a much better activity in the majority of species, with macrolide MICs at which 90% of the isolates are inhibited between 8- and 10-fold higher.
Efficacies of Albendazole Sulfoxide and Albendazole Sulfone against In Vitro-Cultivated
Echinococcus multilocularis
Metacestodes
Authors: Ingold Katrin , Bigler Peter , Thormann Wolfgang , Cavaliero Tania , Gottstein Bruno , Hemphill Andrew 
Published: October 2018

ABSTRACT

The metacestode stage of
Echinococcus multilocularis
is the causative agent of alveolar echinococcosis (AE), a parasitic disease affecting the liver, with occasional metastasis into other organs. Benzimidazole carbamate derivatives such as mebendazole and albendazole are currently used for chemotherapeutic treatment of AE. Albendazole is poorly resorbed and is metabolically converted to its main metabolite albendazole sulfoxide, which is believed to be the active component, and further to albendazole sulfone. Chemotherapy with albendazole has been shown to have a parasitostatic rather than a parasitocidal effect; it is not effective in all cases, and the recurrence rate is rather high once chemotherapy is stopped. Thus, development of new means of chemotherapy of AE is needed. This could include modifications of benzimidazoles and elucidiation of the respective biological pathways. In this study we performed in vitro drug treatment of
E. multilocularis
metacestodes with albendazole sulfoxide and albendazole sulfone. High-performance liquid chromatography analysis of vesicle fluids showed that the drugs were taken up rapidly by the parasite. Transmission electron microscopic investigation of parasite tissues and nuclear magnetic resonance spectroscopy of vesicle fluids demonstrated that albendazole sulfoxide and albendazole sulfone had similar effects with respect to parasite ultrastructure and changes in metabolites in vesicle fluids. This study shows that the in vitro cultivation model presented here provides an ideal first-round test system for screening of antiparasite drugs.