bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suboptimal Antibiotic Dosage as a Risk Factor for Selection of Penicillin-Resistant
Streptococcus pneumoniae
: In Vitro Kinetic Model
Authors: Odenholt Inga , Gustafsson Ingegerd , Löwdin Elisabeth , Cars Otto 
Published: January 2003

ABSTRACT

Optimizing pharmacokinetic/pharmacodynamic indices of antibiotics to obtain clinical and microbiological efficacy is essential, but dosing regimens must also be tailored to minimize the risk for emergence of resistance. The aim of the present study was to investigate whether certain concentrations of benzylpenicillin are critical for the selection of resistant subpopulations. A mixed culture of
Streptococcus pneumoniae
containing ca. 90% susceptible (MIC = 0.031 mg/liter), 9% intermediate (MIC = 0.25 mg/liter), and 1% resistant (MIC = 8 mg/liter) was studied in an in vitro kinetic model. The time that concentrations exceeded the MIC (T>MIC) for the three strains in the culture was varied by different initial concentrations of benzylpenicillin. Samples for viable counts were withdrawn at different times during 24 h and seeded on blood agar plates and on selective antibiotic-containing plates. The T>MIC varied from 46 to 100% for the susceptible strain, from 6 to 100% for the intermediate strain, and from 0 to 48% for the resistant strain. Our study, which may mimic the clinical situation with carriage of a mixed population of
S. pneumoniae
with different antibiotic susceptibilities, has shown that selection of resistant bacteria may easily occur if dosing regimens are only targeted toward fully susceptible strains.
Activities of Azithromycin and Amphotericin B against
Naegleria fowleri
In Vitro and in a Mouse Model of Primary Amebic Meningoencephalitis
Authors: Goswick Shannon M. , Brenner George M. 
Published: January 2003

ABSTRACT

Inhalation of fresh water containing the free-living ameba
Naegleria fowleri
may lead to a potentially fatal infection known as primary amebic meningoencephalitis. Amphotericin B is the only agent with established clinical efficacy in the treatment of primary amebic meningoencephalitis in humans, but therapy with this drug is often associated with adverse effects on the kidneys and other organs, and not all persons treated with amphotericin B have survived. We investigated the in vitro activity and in vivo efficacy of newer therapeutic agents in an attempt to identify other useful agents for treating primary amebic meningoencephalitis. Azithromycin has shown in vitro activity against
Acanthamoeba
spp. and in vivo activity against experimental toxoplasmosis. In our study, the MIC of azithromycin against
N. fowleri
was 13.4 μM (10 μg/ml), which was 123 times greater than the MIC of amphotericin B, which was 0.108 μM (0.1 μg/ml). Azithromycin protected 100% of mice infected with
N. fowleri
at a dose of 75 mg/kg/day for 5 days, whereas amphotericin B protected only 50% of mice at a dose of 7.5 mg/kg/day for 5 days, and all control mice died during the 28-day observation period. We conclude that azithromycin has both in vitro and in vivo activity versus
N. fowleri
and may be a useful addition to therapy for primary amebic meningoencephalitis.
Activity of Tigecycline (GAR-936), a Novel Glycylcycline, against Enterococci in the Mouse Peritonitis Model
Authors: Nannini Esteban C. , Pai Suresh R. , Singh Kavindra V. , Murray Barbara E. 
Published: January 2003

ABSTRACT

A novel glycylcycline agent, tigecycline (GAR-936), was evaluated in vivo in the mouse model of peritonitis against three
Enterococcus faecalis
and four
Enterococcus faecium
isolates with different susceptibilities to vancomycin and tetracyclines, all of which were inhibited by ≤0.125 μg of tigecycline/ml. Using a single subcutaneous dose, tigecycline displayed a protective effect (50% protective dose, ≤5.7 mg/kg of body weight) against all strains tested, including two with Tn
925
(from the Tn
916
family), which contains the Tet(M) tetracycline resistance determinant, as well as VanA and VanB strains. As expected, tetracycline and minocycline were ineffective against the isolates carrying Tn
925
.
Activities of Tigecycline (GAR-936) against
Legionella pneumophila
In Vitro and in Guinea Pigs with
L. pneumophila
Pneumonia
Authors: Edelstein Paul H. , Weiss William J. , Edelstein Martha A. C. 
Published: January 2003

ABSTRACT

The activities of tigecycline (Wyeth Research) against extracellular and intracellular
Legionella pneumophila
and for the treatment of guinea pigs with
L. pneumophila
pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different
Legionella
sp. strains was 4 μg/ml versus 0.125 and 0.25 μg/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 μg/ml) against the F889 strain of
L. pneumophila
grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 μg/ml) was more active than (F889) or as active as (F2111) tigecycline (1 μg/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with
L. pneumophila
pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 μg/ml (1.2 and 1.5 μg/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 μg · h/ml, respectively. Thirteen of 16 guinea pigs with
L. pneumophila
pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 × 10
6
CFU/g (range, 2.5 × 10
4
to 3.2 × 10
6
CFU/g) versus <1 × 10
2
CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear
L. pneumophila
from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log
10
4.2 to log
10
5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular
L. pneumophila
, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.
Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin during Intermittent or Continuous Infusion in Patients with Cystic Fibrosis
Authors: Vinks Alexander A. , den Hollander Jan G. , Overbeek Shelley E. , Jelliffe Roger W. , Mouton Johan W. 
Published: January 2003

ABSTRACT

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and
R
2
values, and predictive performance was based on bias (mean weighted error [MWE]) and precision (mean weighted square error [MWSE]). A linear pharmacokinetic model could not describe combined intermittent infusion and continuous infusion data well. A good population model fit to the intermittent infusion and continuous infusion data was obtained with the constructed nonlinear models. Maximum a posteriori probability (MAP) Bayesian
R
2
values for the nonlinear models were 0.96 to 0.97. Median parameter estimates for the best nonlinear model were as follows:

K
m

, 58 ± 75 mg/liter (mean and standard deviation);
V
max
, 1,904 ± 1,009 mg/h; volume of distribution of the central compartment, 14.1 ± 3.0 liters;
k
12
, 0.63 ± 0.41 h
−1
; and
k
21
, 0.37 ± 0.19 h
−1
. The median bias (MWE) and precision (MWSE) values for MAP Bayesian estimation with the Michaelis-Menten model were 0.05 and 4.6 mg/liters, respectively. The developed nonlinear pharmacokinetic models can be used to optimize piperacillin therapy administered via continuous infusion in patients with CF and have distinct advantages over conventional linear models.
Population Pharmacokinetics of Linezolid in Patients Treated in a Compassionate-Use Program
Authors: Meagher Alison K. , Forrest Alan , Rayner Craig R. , Birmingham Mary C. , Schentag Jerome J. 
Published: January 2003

ABSTRACT

Data obtained from 318 adult patients treated under the linezolid compassionate-use protocol were used to develop a population model of the pharmacokinetics of intravenous and oral linezolid. All of the patients received 600 mg of linezolid every 12 h, intravenously and/or orally. Blood samples (2 to 10 per patient; median, 4) were obtained and assayed for linezolid by high-performance liquid chromatography. These data and patient covariates were modeled by iterative two-stage analysis, and model discrimination was done by Akaike's information criterion. Of the patient covariates considered (age, sex, ideal body weight, baseline serum albumin, hepatic or renal dysfunction, underlying malignancy, organ transplantation, surgical status, global severity of illness, site of infection, route of administration, and location of care [intensive-care unit, general floor, or outpatient]), only normalized creatinine clearance (CL
CR
) and body weight explained significant portions of the variance and were incorporated into the pharmacokinetic model. The final model included central and peripheral compartments with parallel capacity-limited (nonrenal) and first-order (renal [CL
R
]) clearances. Volumes and clearances were normalized to the ideal body weight, and CL
R
was modeled as proportional to CL
CR
. Compared to previously studied adult volunteers, intrinsic clearance was ∼60% higher and the maximum rate of metabolism was twice as high in these debilitated patients, resulting in lower area under the time-concentration curve (AUC) values (
P
< 0.001). The derived 24-h AUC, averaged over the first 7 days of treatment, ranged between 57 and 871 (median, 191) μg/ml · 24 h. Despite these variations, linezolid provided high rates of clinical cure, as well as microbiological success, in the patients treated in the compassionate-use program. The mechanism(s) of these pharmacokinetic differences is unknown and requires further mechanistic study.
Improved Pharmacokinetics and Reduced Antibody Reactivity of Lysostaphin Conjugated to Polyethylene Glycol
Authors: Walsh Scott , Shah Anjali , Mond James 
Published: January 2003

ABSTRACTLysostaphin is a 27-kDa endopeptidase that enzymatically disrupts the cell wall ofStaphylococcus aureusand is a promising candidate for treatingS. aureusblood-borne infections. It would be extremely useful to define conditions that would both increase lysostaphin's in vivo half-life to allow for more effective tissue distribution and reduce its immunogenicity. Conjugation of polyethylene glycol (PEG) to lysostaphin (PEGylation) was investigated as a means to accomplish these goals. Rather than using linear forms of PEG, branched PEGs were chosen as the initial candidates because their large spatial volumes prevent entry of the polymer into the enzyme's active sites, which could potentially reduce enzymatic function. Enzymatic activity for most PEGylated lysostaphins was reduced, but these compounds were still considerably active compared to unconjugated lysostaphin, with conjugates that had lower degrees of PEG modification having greater activity than those with higher degrees. PEGylated lysostaphin injected intravenously had a serum drug half-life of up to 24 h and resulted in much higher plasma drug concentrations than an equal dose of unconjugated lysostaphin, which had a half-life of less than 1 h. Finally, reduced binding affinity was shown for PEGylated lysostaphin in an antilysostaphin capture enzyme-linked immunosorbent assay, with some PEG-lysostaphin conjugates having binding affinities that were reduced more than 10-fold compared to unconjugated lysostaphin. These findings demonstrate that PEGylation of lysostaphin, while diminishing itsS. aureuskilling activity, results in prolonged serum drug persistence and reduced antibody binding. These features should significantly enhance lysostaphin's therapeutic value as an intravenous “antibiotic” againstS. aureus.
Prevalence of Plasmid-Mediated Quinolone Resistance
Authors: Jacoby George A. , Chow Nancy , Waites Ken B. 
Published: January 2003

ABSTRACT

Quinolone resistance encoded by the
qnr
gene and mediated by plasmid pMG252 was discovered in a clinical strain of
Klebsiella pneumoniae
that was isolated in 1994 at the University of Alabama at Birmingham Medical Center. The gene codes for a protein that protects DNA gyrase from quinolone inhibition and that belongs to the pentapeptide repeat family of proteins. The prevalence of the gene has been investigated by using PCR with
qnr
-specific primers with a sample of more than 350 gram-negative strains that originated in 18 countries and 24 states in the United States and that included many strains with plasmid-mediated AmpC or extended spectrum β-lactamase enzymes.
qnr
was found in isolates from the University of Alabama at Birmingham only during 6 months in 1994, despite the persistence of the gene for FOX-5 β-lactamase, which is linked to
qnr
on pMG252. Isolates from other locations were negative for
qnr
. The prevalence of
mcbG
in the same sample was also examined.
mcbG
encodes another member of the pentapeptide repeat family and is involved in immunity to microcin B17, which, like quinolones, targets DNA gyrase. A single clinical isolate contained
mcbG
on a transmissible R plasmid. This plasmid and one carrying the complete microcin B17 operon slightly decreased sparfloxacin susceptibility but had a much less protective effect than pMG252. Plasmid-mediated quinolone resistance was thus rare in the sample examined.
In Vivo Acquisition of Ceftriaxone Resistance in
Salmonella enterica
Serotype Anatum
Authors: Su Lin-Hui , Chiu Cheng-Hsun , Chu Chishih , Wang Mei-Hui , Chia Ju-Hsin , Wu Tsu-Lan 
Published: January 2003

ABSTRACT

The emergence of resistance to antimicrobial agents within the salmonellas is a worldwide and severe problem. A case of treatment failure due to the emergence of resistance to ceftriaxone in
Salmonella enterica
serotype Anatum was studied.
S. enterica
serotype Anatum and
Escherichia coli
, both of which are susceptible to ceftriaxone, were initially isolated from a diabetic patient hospitalized for the treatment of wound and urinary tract infections. Resistant
S. enterica
serotype Anatum and
E. coli
strains were isolated concomitantly 2 weeks after the initiation of ceftriaxone therapy. The patient eventually died of a sepsis caused by the ceftriaxone-resistant salmonella. PCR, nucleotide sequence analysis, and DNA-DNA hybridization identified a
bla
CTX-M-3
gene located on a 95.1-kb plasmid from the ceftriaxone-resistant isolates of
S. enterica
serotype Anatum and
E. coli
. The plasmid was proved to be conjugative. Molecular fingerprinting showed that the susceptible and resistant strains were genetically indistinguishable. The emergence of resistance to ceftriaxone in
S. enterica
serotype Anatum was due to the in vivo acquisition of a plasmid containing the
bla
CTX-M-3
gene and was the cause for treatment failure in this patient.
Morphological and Genetic Differences in Two Isogenic
Staphylococcus aureus
Strains with Decreased Susceptibilities to Vancomycin
Authors: Reipert Andrea , Ehlert Kerstin , Kast Thomas , Bierbaum Gabriele 
Published: January 2003

ABSTRACT

Many VISA (vancomycin intermediately resistant
Staphylococcus aureus
) strains are characterized by increased cell wall biosynthesis and decreased cross-linking of the peptide side chains, leading to accumulation of free
d
-alanyl-
d
-alanine termini in the peptidoglycan, which act as false target sites for vancomycin. A spontaneous mutant of methicillin-resistant VISA strain SA137/93A (vancomycin MIC [E-test], 8 μg/ml), called SA137/93G, showed increased resistance to vancomycin (MIC [E-test], 12 μg/ml). Analysis of the resistance profile of the mutant revealed a loss of β-lactam resistance with a concomitant increase in resistance to glycopeptides. In both strains, cell wall thickness was 1.4-fold greater than that of control isolates. However, cross-linking of the cell wall was drastically lower in SA137/93A than in SA137/93G. The sensitivity of strain SA137/93G to β-lactams was due to loss of the β-lactamase plasmid and a deletion that comprises 32.5 kb of the methicillin resistance cassette SCC
mec
, as well as 65.4 kb of chromosomal DNA. A spontaneous mutant of SA137/93G with higher sensitivity to vancomycin displayed a cell wall profile similar, in some respects, to that of an
fmhB
mutant. Results described here and elsewhere show that the only feature common to all VISA strains is a thickened cell wall, which may play a central role in the vancomycin resistance mechanism.
Mutations in
Aspergillus fumigatus
Resulting in Reduced Susceptibility to Posaconazole Appear To Be Restricted to a Single Amino Acid in the Cytochrome P450 14α-Demethylase
Authors: Mann Paul A. , Parmegiani Raulo M. , Wei Shui-Qing , Mendrick Cara A. , Li Xin , Loebenberg David , DiDomenico Beth , Hare Roberta S. , Walker Scott S. , McNicholas Paul M. 
Published: January 2003

ABSTRACT

To better understand the molecular basis of posaconazole (POS) resistance in
Aspergillus fumigatus
, resistant laboratory isolates were selected. Spontaneous mutants arose at a frequency of 1 in 10
8
and fell into two susceptibility groups, moderately resistant and highly resistant. Azole resistance in
A. fumigatus
was previously associated with decreased drug accumulation. We therefore analyzed the mutants for changes in levels of transcripts of genes encoding efflux pumps (
mdr1
and
mdr2
) and/or alterations in accumulation of [
14
C]POS. No changes in either pump expression or drug accumulation were detected. Similarly, there was no change in expression of
cyp51A
or
cyp51B
, which encode the presumed target site for POS, cytochrome P450 14α-demethylase. DNA sequencing revealed that each resistant isolate carried a single point mutation in residue 54 of
cyp51A
. Mutations at the same locus were identified in three clinical
A. fumigatus
isolates exhibiting reduced POS susceptibility but not in susceptible clinical strains. To verify that these mutations were responsible for the resistance phenotype, we introduced them into the chromosome of a POS-susceptible
A. fumigatus
strain under the control of the glyceraldehyde phosphate dehydrogenase promoter. The transformants exhibited reductions in susceptibility to POS comparable to those exhibited by the original mutants, confirming that point mutations in the
cyp51A
gene in
A. fumigatus
can confer reduced susceptibility to POS.
Biochemical Characterization of the Acquired Metallo-β-Lactamase SPM-1 fromPseudomonas aeruginosa
Authors: Murphy Tanya A. , Simm Alan M. , Toleman Mark A. , Jones Ronald N. , Walsh Timothy R. 
Published: January 2003

ABSTRACTSPM-1 is a new metallo-β-lactamase recently identified inPseudomonas aeruginosastrain 48-1997A, isolated in Sao Paulo, Brazil. Kinetic analysis demonstrated that SPM-1 has a broad hydrolytic profile across a wide range of β-lactam antibiotics. Considerable variation was observed within the penicillin, cephalosporin, and carbapenem subfamilies; however, on the whole, SPM-1 appears to preferentially hydrolyze cephalosporins. The highestkcat/Kmratios (in micromolar per second) overall were observed for this subgroup. The hydrolytic profile of SPM-1 bears the most similarity to that of the metallo-β-lactamase IMP-1, yet for the most part, SPM-1 haskcat/Kmvalues higher than those of IMP-1. Zinc chelator studies established that progressive inhibition of SPM-1 by EDTA, dipicolinic acid, and 1-10-o-phenanthroline demonstrated a biexponential pattern in which none of the chelators completely inhibited SPM-1. A homology model of SPM-1 was developed on the basis of the IMP-1 crystal structure, which showed the protein folding and active-site structure characteristic of metallo-β-lactamases and which provides an explanation for the kinetic profiles observed.
The Antifungal Protein from
Aspergillus giganteus
Causes Membrane Permeabilization
Authors: Theis T. , Wedde M. , Meyer V. , Stahl U. 
Published: January 2003

ABSTRACT

We investigated the inhibitory effects of the antifungal protein (AFP) from
Aspergillus giganteus
on the growth of several filamentous fungi. For this purpose, the MICs of AFP were determined and ranged from 0.1 μg/ml for
Fusarium oxysporum
to 200 μg/ml for
Aspergillus nidulans
. The antifungal activity of AFP was diminished in the presence of cations. We were able to show that incubation of AFP-sensitive fungi with the protein resulted in membrane permeabilization using an assay based on the uptake of the fluorescent dye SYTOX Green. No permeabilization by AFP could be detected at concentrations below the species-specific MIC. Furthermore, AFP-induced permeabilization could readily be detected after 5 min of incubation. Localization experiments with fluorescein isothiocyanate-labeled AFP and immunofluorescence staining with an AFP-specific antibody supported the observation that the protein interacts with membranes. After treatment of AFP-sensitive fungi with AFP, the protein was localized at the plasma membrane, whereas it was mainly detected inside the cells of AFP-resistant fungi. We conclude from these data that the growth-inhibitory effect of AFP is caused by permeabilization of the fungal membranes.
Genotypic Inhibitory Quotient as Predictor of Virological Response to Ritonavir-Amprenavir in Human Immunodeficiency Virus Type 1 Protease Inhibitor-Experienced Patients
Authors: Marcelin Anne-Geneviève , Lamotte Claire , Delaugerre Constance , Ktorza Nadine , Ait Mohand Hocine , Cacace Raquel , Bonmarchand Manuela , Wirden Marc , Simon Anne , Bossi Philippe , Bricaire François , Costagliola Dominique , Katlama Christine , Peytavin Gilles , Calvez Vincent 
Published: January 2003

ABSTRACTForty-nine protease inhibitor (PI)-experienced but amprenavir (APV)-naïve patients experiencing virological failure were treated with ritonavir (RTV) (100 mg twice a day [b.i.d.]) plus APV (600 mg b.i.d.). Patients responded to therapy with a median viral load decrease of −1.32 log10by week 12. The addition of low-dose RTV enhanced the minimal APV concentration in plasma (APVCmin) up to 10-fold compared with that obtained with APV (1,200 mg b.i.d.) without RTV. Baseline PI resistance mutations (L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S, I84V) identified by univariate analysis and included in a genotypic score and APVCminat week 8 were predictive of the virological response at week 12. The response to APV plus RTV was significantly reduced in patients with six or more of the resistance mutations among the ones defined above. The genotypic inhibitory quotient, calculated as the ratio of the APVCminto the number of human immunodeficiency virus type 1 protease mutations, was a better predictor than the virological or pharmacological variables used alone. This genotypic inhibitory quotient could be used in therapeutic drug monitoring to define the concentrations in plasma needed to control replication of viruses with different levels of PI resistance, as measured by the number of PI resistance mutations.