bluuebunny/crossref_metadata_2025_split huggingface dataset:
Class A Carbapenemase FPH-1 from Francisella philomiragia
Authors: Toth Marta , Vakulenko Viktoria , Antunes Nuno T. , Frase Hilary , Vakulenko Sergei B. 
Published: March 2012

ABSTRACT

FPH-1 is a new class A carbapenemase from
Francisella philomiragia
. It produces high-level resistance to penicillins and the narrow-spectrum cephalosporin cephalothin and hydrolyzes these β-lactam antibiotics with catalytic efficiencies of 10
6
to 10
7
M
−1
s
−1
. When expressed in
Escherichia coli
, the enzyme confers resistance to clavulanic acid, tazobactam, and sulbactam and has

K
i

values of 7.5, 4, and 220 μM, respectively, against these inhibitors. FPH-1 increases the MIC of the monobactam aztreonam 256-fold and the MIC of the broad-spectrum cephalosporin ceftazidime 128-fold, while the MIC of cefoxitin remains unchanged. MICs of the carbapenem antibiotics imipenem, meropenem, doripenem, and ertapenem are elevated 8-, 8-, 16-, and 64-fold, respectively, against an
E. coli
JM83 strain producing the FPH-1 carbapenemase. The catalytic efficiencies of the enzyme against carbapenems are in the range of 10
4
to 10
5
M
−1
s
−1
. FPH-1 is 77% identical to the FTU-1 β-lactamase from
Francisella tularensis
and has low amino acid sequence identity with other class A β-lactamases. Together with FTU-1, FPH-1 constitutes a new branch of the prolific and ever-expanding class A β-lactamase tree.
NDM-1-Producing Klebsiella pneumoniae Resistant to Colistin in a French Community Patient without History of Foreign Travel
Authors: Arpin Corinne , Noury Patrick , Boraud Delphine , Coulange Laure , Manetti Alain , André Catherine , M'Zali Fatima , Quentin Claudine 
Published: March 2012

ABSTRACT

A carbapenem-resistant
Klebsiella pneumoniae
strain, Kp5196, was responsible for an uncomplicated cystitis in a patient living at home and without history of foreign travel. This isolate produced the metallocarbapenemase NDM-1 and was resistant to all antibiotics except tetracyclines and colistin. The
K. pneumoniae
strain belonged to sequence type ST15, and
bla
NDM-1
was carried by a nontypeable conjugative plasmid. Two months later, a similar ST15 isolate, Kp5241, was present in the patient but was additionally colistin resistant.
Dissemination of pCT-Like IncK Plasmids Harboring CTX-M-14 Extended-Spectrum β-Lactamase among Clinical Escherichia coli Isolates in the United Kingdom
Authors: Dhanji Hiran , Khan Parmina , Cottell Jennifer L. , Piddock Laura J. V. , Zhang Jiancheng , Livermore David M. , Woodford Neil 
Published: March 2012

ABSTRACT

IncK plasmids encoding CTX-M-14 extended-spectrum β-lactamase (ESBL) and highly related to plasmid pCT were detected in 13 of 67 (19%) human clinical isolates of
Escherichia coli
with a group 9 CTX-M-type ESBL from the United Kingdom and in 2 quality assurance isolates. None of these
E. coli
strains was related to the cattle strain from which pCT was originally characterized.
Scaling Adult Doses of Antifungal and Antibacterial Agents to Children
Authors: Dawson Thomas H. 
Published: March 2012

ABSTRACTMy general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined fromin vitromeasurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents.
Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method
Authors: Moreira da Silva Rodrigo , Oliveira Líliam Teixeira , Silva Barcellos Neila Márcia , de Souza Jacqueline , de Lana Marta 
Published: March 2012

ABSTRACT

A combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (
C
max
) and an increase of 2.66-fold in the volume of distribution (
V
) and 7.5-fold in the elimination half-life (
t
1/2β
) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC

0-
t

), area under the curve extrapolated to infinity (AUC
0-∞
), time to maximum concentration of drug in serum (
T
max
), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against
Trypanosoma cruzi in vivo
.
Safety and Tolerability of Voriconazole in Patients with Baseline Renal Insufficiency and Candidemia
Authors: Oude Lashof A. M. L. , Sobel J. D. , Ruhnke M. , Pappas P. G. , Viscoli C. , Schlamm H. T. , Rex J. H. , Kullberg B. J. 
Published: March 2012

ABSTRACT
Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.
Multidrug-Resistant Proteus mirabilis Bloodstream Infections: Risk Factors and Outcomes
Authors: Tumbarello Mario , Trecarichi Enrico Maria , Fiori Barbara , Losito Angela Raffaella , D'Inzeo Tiziana , Campana Lara , Ruggeri Alberto , Di Meco Eugenia , Liberto Elvira , Fadda Giovanni , Cauda Roberto , Spanu Teresa 
Published: March 2012

ABSTRACT

Our aims were to identify (i) risk factors associated with the acquisition of multidrug-resistant (MDR, to 3 or more classes of antimicrobials)
Proteus mirabilis
isolates responsible for bloodstream infections (BSIs) and (ii) the impact on mortality of such infections. Risk factors for acquiring MDR
P. mirabilis
BSIs were investigated in a case-case-control study; those associated with mortality were assessed by comparing survivors and nonsurvivors in a cohort study. The population consisted of 99 adult inpatients with
P. mirabilis
BSIs identified by our laboratory over an 11-year period (1999 to 2009), 36 (33.3%) of which were caused by MDR strains, and the overall 21-day mortality rate was 30.3%. Acquisition of an MDR strain was independently associated with admission from a long-term care facility (odds ratio [OR], 9.78; 95% confidence interval [CI], 1.94 to 49.16), previous therapy with fluoroquinolones (OR, 5.52; 95% CI, 1.30 to 23.43) or oxyimino-cephalosporins (OR, 4.72; 95% CI, 1.31 to 16.99), urinary catheterization (OR, 3.89; 95% CI, 1.50 to 10.09), and previous hospitalization (OR, 2.68; 95% CI, 10.4 to 6.89). Patients with MDR
P. mirabilis
BSIs received inadequate initial antimicrobial therapy (IIAT, i.e., treatment with drugs to which the isolate displayed
in vitro
resistance) more frequently than those with non-MDR infections; they also had increased mortality and (for survivors) longer post-BSI-onset hospital stays. In multivariate regression analysis, 21-day mortality was associated with septic shock at BSI onset (OR, 12.97; 95% CI, 32.2 to 52.23),
P. mirabilis
isolates that were MDR (OR, 6.62; 95% CI, 16.4 to 26.68), and IIAT (OR, 9.85; 95% CI, 26.7 to 36.25), the only modifiable risk factor of the 3. These findings can potentially improve clinicians' ability to identify
P. mirabilis
BSIs likely to be MDR, thereby reducing the risk of IIAT—a major risk factor for mortality in these cases—and facilitating the prompt implementation of appropriate infection control measures.
Involvement of the Lon Protease in the SOS Response Triggered by Ciprofloxacin in Pseudomonas aeruginosa PAO1
Authors: Breidenstein Elena B. M. , Bains Manjeet , Hancock Robert E. W. 
Published: March 2012

ABSTRACT

Pseudomonas aeruginosa
PAO1
lon
mutants have phenotypes of deficiencies in cell division, swarming, twitching, and biofilm formation as well as a phenotype of ciprofloxacin supersusceptibility. In this study, we demonstrated that a
lon
mutant was also supersensitive to the DNA-damaging agent UV light. To understand the influence of
lon
in causing these phenotypes, global gene expression was characterized by performing microarrays on the
lon
mutant and the PAO1 wild type grown in the presence of subinhibitory concentrations of ciprofloxacin. This revealed major differences in the expression of genes involved in the SOS response and DNA repair. Real-time quantitative PCR confirmed that these genes were highly upregulated upon ciprofloxacin exposure in the wild type but were significantly less induced in the
lon
mutant, indicating that Lon modulates the SOS response and consequentially ciprofloxacin susceptibility. As the known Lon target SulA is a member of the SOS response regulon, the influence of mutating or overexpressing this gene, and the negative regulator of the SOS response, LexA, was examined. Overexpression of
lexA
had no effect on the Lon-related phenotypes, but
sulA
overexpression recapitulated certain
lon
mutant phenotypes, including altered motility and cell division, indicating that Lon regulates these phenotypes through SulA. However,
sulA
overexpression did not affect ciprofloxacin susceptibility or biofilm formation, indicating that these properties were independently determined. Lon protease was also demonstrated to strongly influence RecA protein accumulation in the presence of ciprofloxacin. A model of DNA repair involving the Lon protease is proposed.
Efficacy of Ceftobiprole Medocaril against Enterococcus faecalis in a Murine Urinary Tract Infection Model
Authors: Singh Kavindra V. , Murray Barbara E. 
Published: March 2012

ABSTRACT

We evaluated ceftobiprole against the well-characterized
Enterococcus faecalis
strain OG1RF (with and without the β-lactamase [Bla] plasmid pBEM10) in a murine urinary tract infection (UTI) model. Ceftobiprole was equally effective for Bla
+
and Bla
−
OG1 strains, while ampicillin was moderately to markedly (depending on the inoculum) less effective against Bla
+
than Bla
−
OG1 strains. These data illustrate an
in vivo
effect on ampicillin of Bla production by
E. faecalis
and the stability and efficacy of ceftobiprole in experimental UTI.
Broad Phenotypic Cross-Resistance to Elvitegravir in HIV-Infected Patients Failing on Raltegravir-Containing Regimens
Authors: Garrido Carolina , Villacian Jorge , Zahonero Natalia , Pattery Theresa , Garcia Federico , Gutierrez Felix , Caballero Estrella , Van Houtte Margriet , Soriano Vincent , de Mendoza Carmen 
Published: March 2012

ABSTRACTThe failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV-infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance testing (Antivirogram v2.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2.5 (interquartile range [IQR], 2.1 to 3.1). Fourteen samples from patients with RAL failures showed diminished RAL susceptibility, with a median FC of 38.5 (IQR, 10.8 to 103.2). Primary integrase resistance mutations were found in 11 of these samples, displaying a median FC of 68.5 (IQR, 23.5 to 134.3). The remaining 3 samples showed a median FC of 2.5 (IQR, 2 to 2.7). EVG susceptibility was diminished in 19/40 samples from patients with RAL failures (median FC, 7.71 [IQR, 2.48 to 99.93]). Cross-resistance between RAL and EVG was high (R2= 0.8;P< 0.001), with drug susceptibility being more frequently reduced for EVG than for RAL (44.3% versus 24.6%;P= 0.035). Susceptibility to RAL and EVG is rarely affected in the absence of primary integrase resistance mutations. There is broad cross-resistance between RAL and EVG, which should preclude their sequential use. Resistance to EVG seems to be more frequent and might be more influenced by integrase variability.
The Aminopeptidase Inhibitor CHR-2863 Is an Orally Bioavailable Inhibitor of Murine Malaria
Authors: Skinner-Adams Tina S. , Peatey Christopher L. , Anderson Karen , Trenholme Katharine R. , Krige David , Brown Christopher L. , Stack Colin , Nsangou Desire M. M. , Mathews Rency T. , Thivierge Karine , Dalton John P. , Gardiner Donald L. 
Published: March 2012

ABSTRACT
Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an ever-increasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria.
Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses
Authors: Miller Benjamin , Hershberger Ellie , Benziger David , Trinh MyMy , Friedland Ian 
Published: March 2012

ABSTRACT
The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.
The Relative Contributions of Physical Structure and Cell Density to the Antibiotic Susceptibility of Bacteria in Biofilms
Authors: Kirby Amy E. , Garner Kimberly , Levin Bruce R. 
Published: March 2012

ABSTRACT

For many bacterial infections, noninherited mechanisms of resistance are responsible for extending the term of treatment and in some cases precluding its success. Among the most important of these noninherited mechanisms of resistance is the ability of bacteria to form biofilms. There is compelling evidence that bacteria within biofilms are more refractory to antibiotics than are planktonic cells. Not so clear, however, is the extent to which this resistance can be attributed to the structure of biofilms rather than the physiology and density of bacteria within them. To explore the contribution of the structure of biofilms to resistance in a quantitative way, we developed an assay that compares the antibiotic sensitivity of bacteria in biofilms to cells mechanically released from these structures. Our method, which we apply to
Escherichia coli
and
Staphylococcus aureus
each with antibiotics of five classes, controls for the density and physiological state of the treated bacteria. For most of the antibiotics tested, the bacteria in biofilms were no more resistant than the corresponding populations of planktonic cells of similar density. Our results, however, suggest that killing by gentamicin, streptomycin, and colistin is profoundly inhibited by the structure of biofilms; these drugs are substantially more effective in killing bacteria released from biofilms than cells within these structures.
Nasopharyngeal Colonization Elicits Antibody Responses to Staphylococcal and Pneumococcal Proteins That Are Not Associated with a Reduced Risk of Subsequent Carriage
Authors: Prevaes Sabine M. P. J. , van Wamel Willem J. B. , de Vogel Corné P. , Veenhoven Reinier H. , van Gils Elske J. M. , van Belkum Alex , Sanders Elisabeth A. M. , Bogaert Debby 
Published: March 2012

ABSTRACT

Knowledge of the immunological correlates of
Staphylococcus aureus
and
Streptococcus pneumoniae
colonization is required for the search for future protein vaccines. We evaluated natural antibody levels against pneumococcal and staphylococcal proteins in relation to previous bacterial colonization with both pathogens. In a randomized controlled trial, nasopharyngeal samples were obtained from children at 1.5, 6, 12, 18, and 24 months and cultured for
S. aureus
and
S. pneumoniae
. Approximately 50% of the children were PCV7 vaccinated. Serum IgG against 18 pneumococcal and 40 staphylococcal proteins was semiquantified by Luminex technology from 111 12 month olds and 158 24 month olds. Previous culture-proven
S. aureus
colonization was associated with higher IgG levels against 6/40 staphylococcal proteins (ClfB, ClfA, Efb, CHIPS, LukD, and LukF [
P
≤ 0.001]) compared to noncarriers. Previous pneumococcal colonization was associated with increased IgG levels against 12/18 pneumococcal proteins compared to noncarriers (
P
≤ 0.003). Increasing age was associated with higher levels of antibodies to most pneumococcal proteins and lower levels of antibodies to over half the staphylococcal proteins, reflecting natural colonization dynamics. Anti-
S. pneumoniae
and anti-
S. aureus
protein antibodies at the age of 12 months were not negatively correlated with subsequent colonization with the homologous species in the following year and did not differ between PCV7-vaccinated and nonvaccinated children. Colonization with
S. aureus
and
S. pneumoniae
induces serum IgG against many proteins, predominantly proteins with immune-modulating functions, irrespective of PCV7 vaccination. None of them appeared to be protective against new acquisition with both pathogens, possibly due to the polymorphic nature of those proteins in the circulating bacterial population.