bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant
Authors: Hiemenz J. , Cagnoni P. , Simpson D. , Devine S. , Chao N. , Keirns J. , Lau W. , Facklam D. , Buell D. 
Published: March 2005

ABSTRACT
In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.
Comparison of the Pharmacodynamics of Meropenem in Patients with Ventilator-Associated Pneumonia following Administration by 3-Hour Infusion or Bolus Injection
Authors: Jaruratanasirikul Sutep , Sriwiriyajan Somchai , Punyo Jarurat 
Published: March 2005

ABSTRACT

The time that concentrations in serum are above the MIC (
T
>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of β-lactam antibiotics. The aim of this study was to demonstrate the
T
>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the
T
>MICs of 16, 8, 4, and 1 μg/ml were 28.33% ± 11.67%, 45.89% ± 22.90%, 57.00% ± 24.82%, and 74.67% ± 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the
T
>MICs of 16, 8, 4, and 1 μg/ml were 37.78% ± 20.57%, 58.11% ± 24.38%, 72.67% ± 21.97%, and 93.56% ± 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the
T
>MICs of 16, 8, 4, and 1 μg/ml were 57.89% ± 24.26%, 72.89% ± 22.40%, 85.56% ± 16.42%, and 98.56% ± 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater
T
>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 μg/ml for almost 60% of an 8-h interval.
Bactericidal and Antiendotoxic Properties of Short Cationic Peptides Derived from a Snake Venom Lys49 Phospholipase A2
Authors: Santamaría Carlos , Larios Silda , Quirós Steve , Pizarro-Cerda Javier , Gorvel Jean-Pierre , Lomonte Bruno , Moreno Edgardo 
Published: March 2005

ABSTRACTThe activities of short synthetic, nonhemolytic peptides derived from the C-terminal region of myotoxin II, a catalytically inactive phospholipase A2homologue present in the venom of the snakeBothrops asper, have been shown to reproduce the bactericidal activity of the parent protein. They combine cationic and hydrophobic-aromatic amino acids, thus functionally resembling the antimicrobial peptides of innate defenses. This study evaluated the antimicrobial and antiendotoxic properties of a 13-mer derivative peptide of the C-terminal sequence from positions 115 to 129 of myotoxin II, named pEM-2. This peptide (KKWRWWLKALAKK) showed bactericidal activity against both gram-positive and gram-negative bacteria. In comparison to previously described peptide variants derived from myotoxin II, the toxicity of pEM-2 toward eukaryotic cells in culture was significantly reduced, being similar to that of lactoferricin B but lower than that of polymyxin B. The all-denantiomer of pEM-2 [pEM-2 (d)] retained the same bactericidal potency of itsl-enantiomeric counterpart, but it showed an enhanced ability to counteract the lethal activity of an intraperitoneal lipopolysaccharide challenge in mice, which correlated with a significant reduction of the serum tumor necrosis factor alpha levels triggered by this endotoxin. Lethality induced by intraperitoneal infection of mice withEscherichia coliorSalmonella entericaserovar Typhimurium was reduced by the administration of pEM-2 (d). These results demonstrate that phospholipase A2-derived peptides may have the potential to counteract microbial infections and encourage further evaluations of their actions in vivo.
Successive Emergence of
Enterobacter aerogenes
Strains Resistant to Imipenem and Colistin in a Patient
Authors: Thiolas Aurélie , Bollet Claude , La Scola Bernard , Raoult Didier , Pagès Jean-Marie 
Published: March 2005

ABSTRACT

Enterobacter aerogenes
is an agent of hospital-acquired infection that exhibits a remarkable resistance to β-lactam antibiotics during therapy. Five successive isolates of
E. aerogenes
infecting a patient and exhibiting a multiresistance phenotype to β-lactam antibiotics and fluoroquinolones were investigated. Among these clinical strains, four presented resistant phenotypes during successive imipenem and colistin treatments. The involved resistance mechanisms exhibited by the successive isolates were associated with alterations of the outer membrane that caused a porin decrease and lipopolysaccharide modifications.
Efficacy of Caspofungin against Central Nervous System
Aspergillus fumigatus
Infection in Mice Determined by TaqMan PCR and CFU Methods
Authors: Singh Gaurav , Imai Jackie , Clemons Karl V. , Stevens David A. 
Published: March 2005

ABSTRACT

We have reported previously that prolonged caspofungin (CAS) dosing enhances survival in a murine model of central nervous system aspergillosis. In this study we determined by quantitative PCR (qPCR) and CFU enumeration whether CAS could reduce fungal burdens, prior to the deaths of untreated animals, and also assessed progressive infection in untreated mice. Mice were infected intracranially and treated for 4 days with CAS (1, 5, or 10 mg/kg of body weight/day) or amphotericin B (AMB) (3 mg/kg/day) starting 1 day postinfection. Fungal burdens in brains and kidneys of untreated controls were determined on days 1, 3, and 5 to assess progressive infection; burdens in treated animals were determined on day 5. qPCR showed higher burdens than CFU enumeration in all comparisons. In untreated animals, qPCR showed transiently increased burdens in brains, while CFU enumeration showed a decrease. qPCR showed increased burdens in kidneys, but CFU enumeration did not. Neither method indicated drug efficacy in the brain. Both methods showed AMB efficacy in the kidneys, and qPCR demonstrated CAS efficacy at all doses. Spearman correlations of qPCR and CFU determination results showed a significant correlation for most untreated groups; results correlated well for kidneys (
P
≤ 0.03) but not for brains in treated mice. Regression analyses of qPCR and CFU groups indicated different slopes for progressive infection in untreated animals but the same slopes for CAS dose-response efficacy. qPCR appeared to better reflect the progression of untreated infection. The lack of demonstration of efficacy in the brain suggests that longer dosing is necessary to cause burden reduction. These results also suggest that, when there is drug efficacy in a therapeutic study, either method appears to be useful for determining
Aspergillus fumigatus
burdens.
Susceptibility to Antibiotics and β-Lactamase Induction in Murein Hydrolase Mutants of
Escherichia coli
Authors: Korsak Dorota , Liebscher Sylvia , Vollmer Waldemar 
Published: March 2005

ABSTRACT

The antibiotic susceptibilities and capabilities to induce β-lactamases were studied in multiple
Escherichia coli
murein (peptidoglycan) hydrolase mutants.
E. coli
mutants lacking either three amidases, three amidases and one lytic transglycosylase, or six lytic transglycosylases showed higher levels of susceptibility to bacitracin, erythromycin, gallidermin, and vancomycin than the wild type. Mutant cells without three amidases lost viability in the presence of vancomycin and gallidermin, whereas the wild type was resistant to both antibiotics. β-Lactamase induction was studied after introduction of a plasmid carrying the
ampC
and
ampR
genes. Upon addition of cefoxitin to the growth medium, the wild type as well as a mutant lacking all known amidases and
dd
-endopeptidases induced β-lactamase, whereas a mutant lacking all known lytic transglycosylases was unable to induce β-lactamase, showing that lytic transglycosylase activity is essential for β-lactamase induction. Consequently, cells lacking lytic transglycosylase activity lysed in the presence of penicillin, despite the presence of the inducible β-lactamase system. We discuss the potential of murein hydrolase inhibitors for antibiotic therapy.
Scintillation Proximity Assay for Inhibitors of
Escherichia coli
MurG and, Optionally, MraY
Authors: Ravishankar Sudha , Kumar Vidya Prasanna , Chandrakala B. , Jha Ramesh K. , Solapure Suresh M. , de Sousa Sunita M. 
Published: March 2005

ABSTRACT

MurG and MraY, essential enzymes involved in the synthesis of bacterial peptidoglycan, are difficult to assay because the substrates are lipidic and hard to prepare in large quantities. Based on the use of
Escherichia coli
membranes lacking PBP1b, we report a high-throughput method to measure the activity of MurG and, optionally, MraY as well. In these membranes, incubation with the two peptidoglycan sugar precursors results in accumulation of lipid II rather than the peptidoglycan produced by wild-type membranes. MurG was assayed by addition of UDP-[
3
H]
N
-acetylglucosamine to membranes in which lipid I was preformed by incubation with UDP-
N
-acetyl-muramylpentapeptide, and the product was captured by wheat germ agglutinin scintillation proximity assay beads. In a modification of the assay, the activity of MraY was coupled to that of MurG by addition of both sugar precursors together in a single step. This allows simultaneous detection of inhibitors of either enzyme. Both assays could be performed using wild-type membranes by addition of the transglycosylase inhibitor moenomycin. Nisin and vancomycin inhibited the MurG reaction; the MraY-MurG assay was inhibited by tunicamycin as well. Inhibitors of other enzymes of peptidoglycan synthesis—penicillin G, moenomycin, and bacitracin—had no effect. Surprisingly, however, the β-lactam cephalosporin C inhibited both the MurG and MraY-MurG assays, indicating a secondary mechanism by which this drug inhibits bacterial growth. In addition, it inhibited NADH dehydrogenase in membranes, a hitherto-unreported activity. These assays can be used to screen for novel antibacterial agents.
Compensatory Adaptation to the Loss of Biological Fitness Associated with Acquisition of Fusidic Acid Resistance in
Staphylococcus aureus
Authors: Besier Silke , Ludwig Albrecht , Brade Volker , Wichelhaus Thomas A. 
Published: March 2005

ABSTRACT

Recent studies have shown that individual amino acid exchanges within elongation factor G (EF-G) cause fusidic acid resistance in
Staphylococcus aureus
. The data from the present study illustrate that the fusidic acid resistance-mediating amino acid substitutions P406L and H457Y are associated with a marked impairment of the biological fitness of
S. aureus
. In particular, strains producing EF-G derivatives with these mutations showed reduced growth, decreased plasma coagulase activity, and an impaired capability to compete with the isogenic wild-type strain. Second-site mutations within EF-G, such as A67T and S416F, that have been encountered in clinical fusidic acid-resistant isolates containing the amino acid exchanges P406L and H457Y, respectively, were shown not to contribute to resistance. Furthermore, the substitution A67T had no impact on the biological fitness in vitro. The exchange S416F, however, was found to function as a fitness-compensating mutation in
S. aureus
carrying the substitution H457Y in EF-G. In conclusion, the data presented in this report provide evidence at the molecular level that the deleterious effects of fusidic acid resistance-mediating exchanges within EF-G of
S. aureus
can be reduced considerably by specific compensating mutations in this target protein. This compensatory adaptation most likely plays a significant role in the stabilization of resistant bacteria within a given population.
Topoisomerase I Amino Acid Substitutions, Gly185Arg and Asp325Glu, Confer Camptothecin Resistance in
Leishmania donovani
Authors: Marquis Jean-François , Hardy Isabelle , Olivier Martin 
Published: March 2005

ABSTRACT

The antitumor compound camptothecin (CPT) is also recognized for its specific activity against
Leishmania donovani
topoisomerase I (Topo-I). In consequence, defining CPT resistance mechanisms represents an important strategic tool in the acquisition of a better understanding of its mode of action. In the present study, we selected a single highly resistant
L
.
donovani
strain termed LdRCPT.160 by stepwise exposure to CPT. Gene sequencing revealed two single nucleotide mutations in the LdRCPT.160
LdTOP1A
gene, resulting in two amino acid substitutions (Gly185Arg and Asp325Glu) in the protein. Moreover, these two substitutions observed in the LdTOP1A protein were correlated with a decreased Topo-I DNA relaxation activity in these resistant parasites. Nevertheless, there was no change in the
LdTOP1A
gene expression level. Interestingly, transfection studies of the LdRCPT.160
LdTOP1A
gene in its wild-type counterpart showed that it induced CPT resistance. Site-directed mutagenesis studies demonstrated that, despite a substantial level of resistance conferred by the Gly185Arg and Asp325Glu substitutions separately, both were essential to reach a high-resistance phenotype. Of interest, the amino acid substitutions observed in LdRCPT.160 LdTOP1A protein occurred near the amino acids previously predicted to interact with CPT, providing new insight into the mechanism of CPT molecular action.
A
Helicobacter pylori
TolC Efflux Pump Confers Resistance to Metronidazole
Authors: van Amsterdam Karin , Bart Aldert , van der Ende Arie 
Published: March 2005

ABSTRACT

In
Helicobacter pylori
, the contribution of efflux proteins to antibiotic resistance is not well established. As translocases that act in parallel may have overlapping substrate specificities, the loss of function of one such translocase may be compensated for by that of another translocase with no effect on susceptibilities to antibiotics. The genome of
H. pylori
26695 was assessed for the presence of putative translocases and outer membrane efflux or TolC-like proteins which could interact to form efflux systems involved in drug resistance. Twenty-seven translocases were identified, of which HP1184 was the sole representative of the multidrug and toxic compound extrusion family of translocases and which could thus have a unique substrate specificity. In addition, four TolC-like proteins (HP0605, HP0971, HP1327, and HP1489) were identified. Thus, it is feasible that inactivation of a TolC-like protein would affect the functions of multiple translocases. We aimed to determine whether efflux systems contribute to antimicrobial susceptibility by evaluation of the susceptibility profiles of an HP1184-knockout mutant, four mutants in which one of the four TolC homologs was inactivated, as well as a mutant in which both HP0605 and HP0971 were inactivated. The HP1184- and HP1489-knockout mutants both showed increased susceptibilities to ethidium bromide, while the HP0605-knockout mutant exhibited increased susceptibilities to novobiocin and sodium deoxycholate. The HP0605 and HP0971 double-knockout mutant was also more susceptible to metronidazole, in addition to being susceptible to novobiocin and sodium deoxycholate. Thus, active efflux is an eminent means of resistance to antimicrobials in
H. pylori
and resembles the situation in other bacteria.
Phenotypic Tolerance: Antibiotic Enrichment of Noninherited Resistance in Bacterial Populations
Authors: Wiuff C. , Zappala R. M. , Regoes R. R. , Garner K. N. , Baquero F. , Levin B. R. 
Published: March 2005

ABSTRACT

When growing bacteria are exposed to bactericidal concentrations of antibiotics, the sensitivity of the bacteria to the antibiotic commonly decreases with time, and substantial fractions of the bacteria survive. Using
Escherichia coli
CAB1 and antibiotics of five different classes (ampicillin, ciprofloxacin, rifampin, streptomycin, and tetracycline), we examine the details of this phenomenon and, with the aid of mathematical models, develop and explore the properties and predictions of three hypotheses that can account for this phenomenon: (i) antibiotic decay, (ii) inherited resistance, and (iii) phenotypic tolerance. Our experiments cause us to reject the first two hypotheses and provide evidence that this phenomenon can be accounted for by the antibiotic-mediated enrichment of subpopulations physiologically tolerant to but genetically susceptible to these antibiotics, phenotypic tolerance. We demonstrate that tolerant subpopulations generated by exposure to one concentration of an antibiotic are also tolerant to higher concentrations of the same antibiotic and can be tolerant to antibiotics of the other four types. Using a mathematical model, we explore the effects of phenotypic tolerance to the microbiological outcome of antibiotic treatment and demonstrate, a priori, that it can have a profound effect on the rate of clearance of the bacteria and under some conditions can prevent clearance that would be achieved in the absence of tolerance.
Efficacy of Ciprofloxacin-Releasing Bioabsorbable Osteoconductive Bone Defect Filler for Treatment of Experimental Osteomyelitis Due toStaphylococcus aureus
Authors: Koort Jyri K. , Mäkinen Tatu J. , Suokas Esa , Veiranto Minna , Jalava Jari , Knuuti Juhani , Törmälä Pertti , Aro Hannu T. 
Published: March 2005

ABSTRACTThe concept of local antibiotic delivery via biodegradable bone defect fillers with multifunctional properties for the treatment of bone infections is highly appealing. Fillers can be used to obliterate surgical dead space and to provide targeted local bactericidal concentrations in tissue for extended periods. Eventually, the osteoconductive component of the filler could guide the healing of the bone defect. The present experimental study was carried out to test this concept in a localizedStaphylococcus aureusosteomyelitis model in the rabbit (n= 31). A metaphyseal defect of the tibia was filled with a block of bone cement, followed by insertion of a bacterial inoculum. After removal of the bone cement and surgical debridement at 2 weeks, the defect was filled with a ciprofloxacin-containing (7.6% ± 0.1%, by weight) composite (treated-infection group) or with a composite without antibiotic (sham-treated group). Both a positive control group (untreated-infection group) and a negative control group were also produced. The treatment response, monitored by positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) at 3 and 6 weeks, showed rapidly decreasing amounts of [18F]FDG uptake in the treated-infection group (P= 0.001 compared with the results for the untreated-infection group at 6 weeks). The bacteriological analysis confirmed the eradication of the bone pathogen in the treated-infection group. However, three animals had culture-positive soft tissue infections. All animals in the sham-treated and untreated-infection groups had culture-positive bone infections with typical radiographic changes of osteomyelitis. Histomorphometry, peripheral quantitative computed tomography, and backscattered electron imaging of scanning electron microscopy images verified the osteoconductive properties of the bioactive glass microspheres within the composite. The median bone ciprofloxacin concentrations were 1.2 and 2.1 μg/g at two anatomic locations of the tibia. This is the first report to show the value of [18F]FDG PET for quantitative monitoring of the treatment response in bone infections. The collaborative results of bacteriologic and [18F-FDG] PET studies showed that use of the multifunctional composite was successful for eradication of theS. aureuspathogen from bone.
Expression ofccaR, Encoding the Positive Activator of Cephamycin C and Clavulanic Acid Production inStreptomyces clavuligerus, Is Dependent onbldG
Authors: Bignell Dawn R. D. , Tahlan Kapil , Colvin Kimberley R. , Jensen Susan E. , Leskiw Brenda K. 
Published: March 2005

ABSTRACTInStreptomyces coelicolor,bldGencodes a putative anti-anti-sigma factor that regulates both aerial hypha formation and antibiotic production, and a downstream transcriptionally linked open reading frame (orf3) encodes a putative anti-sigma factor protein. A cloned DNA fragment fromStreptomyces clavuligeruscontained an open reading frame that encoded a protein showing 92% identity to theS. coelicolorBldG protein and 91% identity to the BldG ortholog inStreptomyces avermitilis. Sequencing of the region downstream ofbldGinS. clavuligerusrevealed the presence of an open reading frame encoding a protein showing 72 and 69% identity to the ORF3 proteins inS. coelicolorandS. avermitilis, respectively. Northern analysis indicated that, as inS. coelicolor, theS. clavuligerus bldGgene is expressed as both a monocistronic and a polycistronic transcript, the latter including the downstreamorf3gene. High-resolution S1 nuclease mapping ofS. clavuligerus bldGtranscripts revealed the presence of threebldG-specific promoters, and analysis of expression of abldGp-egfpreporter indicated that thebldGpromoter is active at various stages of development and in both substrate and aerial hyphae. AbldGnull mutant was defective in both morphological differentiation and in the production of secondary metabolites, such as cephamycin C, clavulanic acid, and the5Sclavams. This inability to produce cephamycin C and clavulanic acid was due to the absence of the CcaR transcriptional regulator, which controls the expression of biosynthetic genes for both secondary metabolites as well as the expression of a second regulator of clavulanic acid biosynthesis, ClaR. This makesbldGthe first regulatory protein identified inS. clavuligerusthat functions upstream of CcaR and ClaR in a regulatory cascade to control secondary metabolite production.