bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models
Authors: Andes D. , Craig W. A.
Published: December 2005

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10
6.8
to 10
8.4
CFU/thigh of strains of
Streptococcus pneumoniae
ATCC 10813 or
Staphylococcus aureus
ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with
S. pneumoniae
strain ATCC 10813 and −1.5 to 10.7 h with
S. aureus
strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10
6.1
to 10
7.8
CFU/thigh of four isolates of
S. aureus
(three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of
S. pneumoniae
(one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 μg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs ± standard deviations (SDs) for
S. pneumoniae
and
S. aureus
isolates were 14 ± 10 and 31 ± 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.
AsnB Is Involved in Natural Resistance of
Mycobacterium smegmatis
to Multiple Drugs
Authors: Ren Huiping , Liu Jun
Published: December 2005

Mycobacteria are naturally resistant to most common antibiotics and chemotherapeutic agents. The underlying molecular mechanisms are not fully understood. In this paper, we describe a hypersensitive mutant of
Mycobacterium smegmatis
, MS 2-39, which was isolated by screening for transposon insertion mutants of
M. smegmatis
mc
2
155 that exhibit increased sensitivity to rifampin, erythromycin, or novobiocin. The mutant MS 2-39 exhibited increased sensitivity to all three of the above mentioned antibiotics as well as fusidic acid, but its sensitivity to other antibiotics, including isoniazid, ethambutol, streptomycin, chloramphenicol, norfloxacin, tetracycline, and β-lactams, remained unchanged. Uptake experiment with hydrophobic agents and cell wall lipid analysis suggest that the mutant cell wall is normal. The transposon insertion was localized within the
asnB
gene, which is predicted to encode a glutamine-dependent asparagine synthetase. Transformation of the mutant with wild-type
asnB
of mc
2
155 or
asnB
of
Mycobacterium tuberculosis
complemented the drug sensitivity phenotype. These results suggest that AsnB plays a role in the natural resistance of mycobacteria.
Resistance to Erythromycin and Telithromycin in
Streptococcus pyogenes
Isolates Obtained between 1999 and 2002 from Greek Children with Tonsillopharyngitis: Phenotypic and Genotypic Analysis
Authors: Grivea Ioanna N. , Al-Lahham Adnan , Katopodis George D. , Syrogiannopoulos George A. , Reinert Ralf René
Published: December 2005

Since the late 1990s, the prevalence of erythromycin-resistant
Streptococcus pyogenes
has significantly increased in several European countries. Between January 1999 and December 2002, 1,577 isolates of
S. pyogenes
were recovered from children with tonsillopharyngitis living in various areas of Western Greece. Erythromycin resistance was observed in 379 (24%) of the 1,577 isolates. All erythromycin-resistant strains along with 153 randomly selected erythromycin-susceptible
S. pyogenes
isolates were tested for their antimicrobial susceptibility, resistance phenotypes, and genotypes. Representative isolates underwent
emm
gene sequence typing. Isolates with reduced susceptibility to telithromycin (MIC, ≥2 μg/ml) were studied for multilocus sequence type, L22, L4, and 23S rRNA mutations. Of the total 379 erythromycin-resistant isolates, 193 (50.9%) harbored the
mef
(A) gene, 163 (43%)
erm
(A), 1 (0.3%)
mef
(A) plus
erm
(A), and 22 (5.8%) the
erm
(B) gene. Among the erythromycin-susceptible isolates,
emm
1 (25%),
emm
2 (12.5%), and
emm
77 (12.5%) predominated. Furthermore, among the erythromycin-resistant isolates,
emm
4 (30.6%),
emm
28 (22.2%), and
emm
77 (12.5%) prevailed. Resistance to telithromycin was observed in 22 (5.8%) of the erythromycin-resistant isolates. Sixteen (72.7%) of the 22 isolates appeared to be clonally related, since all of them belonged to
emm
type 28 and multilocus sequence type 52. One of the well-known mutations (T2166C) in 23S rRNA, as well as a new one (T2136C), was detected in erythromycin- and telithromycin-resistant isolates. High incidence of macrolide resistance and clonal spread of telithromycin resistance were the characteristics of the Greek
S. pyogenes
isolates obtained from 1999 to 2002.
Topical Voriconazole as a Novel Treatment for Fungal Keratitis
Authors: Sponsel William , Chen Nancy , Dang Demi , Paris Gianmarco , Graybill John , Najvar Laura K. , Zhou Lei , Lam Kwok-Wai , Glickman Randolph , Scribbick Frank
Published: December 2005

Paecilomyces lilacinus
is a fungal pathogen which is generally resistant to amphotericin B and certain other antifungals and is an uncommon cause of devastating fungal keratitis. In the present studies, we evaluated topical voriconazole as therapy for
P. lilacinus
keratitis in rabbits. Thirty eyes of 15 rabbits were studied. In five animals, the uninfected left eye was treated twice daily with voriconazole (drug control, uninfected eye). In these same animals, the right eye was infected with
P. lilacinus
but not treated with voriconazole (infection control eye). By day 5, the infection controls had lesions of >2.4 mm in diameter, with conjunctivitis and severe hypopyon, and were sacrificed. In the other 10 rabbits (voriconazole treatment), the right eyes were infected with
P. lilacinus
and treated with voriconazole beginning on day 3 after infection. Voriconazole therapy caused lesions to decrease during 8 days of therapy, after which rabbits were sacrificed (11 days postinfection). Hyphal masses were present in the control infected eyes and absent in treated infected eyes. Voriconazole was detected in all tissues of treated eyes. Topical voriconazole is effective treatment for
P. lilacinus
experimental keratitis, and it penetrates more deeply than the corneal tissue.
Global Transcriptome Analysis of the Responses of a Fluoroquinolone-Resistant
Streptococcus pneumoniae
Mutant and Its Parent to Ciprofloxacin
Authors: Marrer Estelle , Satoh A. Tatsuo , Johnson Margaret M. , Piddock Laura J. V. , Page Malcolm G. P.
Published: December 2005

Streptococcus pneumoniae
M22 is a multidrug-resistant mutant selected after exposure of capsulated wild-type
S. pneumoniae
NCTC 7465 (strain M4) to ciprofloxacin. DNA microarray analysis comparing the gene expression profiles of strain M22 with those of strain M4 showed that strain M22 constitutively expressed 22 genes at levels higher than those observed in strain M4 under all conditions studied. These included the genes encoding the enzymes involved in branched-chain amino acid biosynthesis and two genes (
patA
and
patB
) with sequences suggestive of ABC transporter proteins. Expression of the
patA
and
patB
genes was induced by ciprofloxacin in both strains, but in strain M4 it only reached the levels observed in strain M22 after long incubation with high concentrations of ciprofloxacin. The altered expression profile observed with strain M22 suggested that the mutation or mutations acquired during resistance selection bring the cell into a state in which the expression of critical genes is preemptively altered to correct for the potential effects of ciprofloxacin on gene expression in the parent strain.
Single-Ascending-Dose Pharmacokinetics and Safety of the Novel Broad-Spectrum Antifungal Triazole BAL4815 after Intravenous Infusions (50, 100, and 200 Milligrams) and Oral Administrations (100, 200, and 400 Milligrams) of Its Prodrug, BAL8557, in Healthy Volunteers
Authors: Schmitt-Hoffmann Anne , Roos Brigitte , Heep Markus , Schleimer Michael , Weidekamm Erhard , Brown Tom , Roehrle Michael , Beglinger Christoph
Published: December 2005

BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.
Multiple-Dose Pharmacokinetics and Safety of the New Antifungal Triazole BAL4815 after Intravenous Infusion and Oral Administration of Its Prodrug, BAL8557, in Healthy Volunteers
Authors: Schmitt-Hoffmann Anne , Roos Brigitte , Maares Jürgen , Heep Markus , Spickerman Jochen , Weidekamm Erhard , Brown Tom , Roehrle Michael
Published: December 2005

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (
C
max
) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study,
C
max
values of 2.56 and 2.55 μg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-β-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.
Pentamidine Is Active in a Neutropenic Murine Model of Acute Invasive Pulmonary Fusariosis
Authors: Lionakis Michail S. , Chamilos Georgios , Lewis Russell E. , Wiederhold Nathan P. , Raad Issam I. , Samonis George , Kontoyiannis Dimitrios P.
Published: December 2005

We studied the efficacy of pentamidine (PNT) as prophylaxis or early treatment in acute pulmonary fusariosis in neutropenic mice. PNT-preexposed mice had significantly improved survival and reduced fungal burden compared to amphotericin B-preexposed and untreated mice. PNT-treated mice had increased survival but no difference in fungal burden versus untreated mice.
Molecular Genetic and Structural Modeling Studies of
Staphylococcus aureus
RNA Polymerase and the Fitness of Rifampin Resistance Genotypes in Relation to Clinical Prevalence
Authors: O'Neill A. J. , Huovinen T. , Fishwick C. W. G. , Chopra I.
Published: December 2005

The adaptive and further evolutionary responses of
Staphylococcus aureus
to selection pressure with the antibiotic rifampin have not been explored in detail. We now present a detailed analysis of these systems. The use of rifampin for the chemotherapy of infections caused by
S. aureus
has resulted in the selection of mutants with alterations within the β subunit of the target enzyme, RNA polymerase. Using a new collection of strains, we have identified numerous novel mutations in the β subunits of both clinical and in vitro-derived resistant strains and established that additional, undefined mechanisms contribute to expression of rifampin resistance in clinical isolates of
S. aureus
. The fitness costs associated with rifampin resistance genotypes were found to have a significant influence on their clinical prevalence, with the most common clinical genotype (H
481
N, S
529
L) exhibiting no fitness cost in vitro. Intragenic mutations which compensate for the fitness costs associated with rifampin resistance in clinical strains of
S. aureus
were identified for the first time. Structural explanations for rifampin resistance and the loss of fitness were obtained by molecular modeling of mutated RNA polymerase enzymes.
Quinolone Efflux Pumps Play a Central Role in Emergence of Fluoroquinolone Resistance in
Streptococcus pneumoniae
Authors: Jumbe Nelson L. , Louie Arnold , Miller Michael H. , Liu Weiguo , Deziel Mark R. , Tam Vincent H. , Bachhawat Reetu , Drusano George L.
Published: December 2005

The preferential use of older antimicrobial agents is, in general, sound public health policy and is meant to maintain susceptibility to newer agents. In the case of fluoroquinolones, however, this strategy is flawed and may actually hasten the spread of
Streptococcus pneumoniae
strains resistant to newer members of the class. In a mouse thigh infection model, we were unable to isolate clones of pneumococci resistant to the newer fluoroquinolone levofloxacin at 2 × or 4 × the baseline MIC. An initial exposure in vivo to the older agent, ciprofloxacin, allowed straightforward selection of clones resistant to levofloxacin in a subsequent experiment. The original ciprofloxacin exposure generated clones without changes in the
parC
/
E
and
gyrA
/
B
quinolone target sites almost exclusively but did allow overexpression of a reserpine-responsive pump. While this caused only minimal change in the levofloxacin MIC (0.6 mg/liter to 0.8 mg/liter), it allowed a major change in the mutational frequency to resistance for levofloxacin (<1/10
8.5
to approximately 1/10
4.5
), which allowed levofloxacin-resistant clones to be isolated in a subsequent in vivo experiment. The reason underlying ciprofloxacin's propensity to select for pump-overexpressed clones is likely related to its hydrophilicity. To preserve the susceptibility of
Streptococcus pneumoniae
to newer members of the class of quinolones, use of ciprofloxacin for community-acquired respiratory infections should be minimized.
Computer-Aided Design of Agents That Inhibit the
cep
Quorum-Sensing System of
Burkholderia cenocepacia
Authors: Riedel Kathrin , Köthe Manuela , Kramer Bernd , Saeb Wael , Gotschlich Astrid , Ammendola Aldo , Eberl Leo
Published: December 2005

Recent research has provided evidence that interference with bacterial cell-to-cell signaling is a promising strategy for the development of novel antimicrobial agents. Here we report on the computer-aided design of novel compounds that specifically inhibit an
N
-acyl-homoserine lactone-dependent communication system that is widespread among members of the genus
Burkholderia
. This genus comprises more than 30 species, many of which are important pathogens of animals and humans. Over the past few years, several
Burkholderia
species, most notably
Burkholderia cenocepacia
, have emerged as important opportunistic pathogens causing severe pulmonary deterioration in persons with cystic fibrosis. As efficient treatment of
Burkholderia
infections is hampered by the inherent resistance of the organisms to a large range of antibiotics, novel strategies for battling these pathogens need to be developed. Here we show that compounds targeting the
B. cenocepacia
signaling system efficiently inhibit the expression of virulence factors and attenuate the pathogenicity of the organism.
Distinct Antifungal Mechanisms: β-Defensins RequireCandida albicansSsa1 Protein, while Trk1p Mediates Activity of Cysteine-Free Cationic Peptides
Authors: Vylkova Slavena , Li Xuewei S. , Berner Jennifer C. , Edgerton Mira
Published: December 2005

Salivary histatin 5 (Hst 5) kills the fungal pathogenCandida albicansvia a multistep process which includes binding to Ssa1/2 proteins on the cell surface and requires the TRK1 potassium transporter. Hst 5-induced membrane permeability to propidium iodide (PI) was nearly abolished in strain CaTK1 (TRK1/trk1), suggesting that Hst 5-induced influx of PI is via Trk1p. To explore the functional role of Trk1p in the mechanism of other antifungal peptides, we evaluated candidacidal activity and PI uptake in wild-type strain CaTK2 (TRK1/TRK1) and strain CaTK1 following treatment with lactoferricin 11 (LFcn 11), bactenecin 16 (BN 16), and virion-associated protein VPR 12. Strain CaTK1 was resistant to killing with these peptides (VPR 12 > LFcn 11 > BN 16), showing the requirement of Trk1p for fungicidal activity. In contrast, human neutrophil defensin 1 (HNP-1), human β-defensin 2 (hBD-2), and hBD-3 effects on viability of and membrane permeability to PI were not different between mutant and wild-type strains, clearly showing that their candidacidal mechanism does not involve Trk1p as a functional effector. To test whether defensins require binding toCandidasurface Ssa1/2 proteins for their activity, we measured the killing effectiveness inSSA1/2mutant strains. Both hBD-2 and hBD-3, but not HNP-1, exhibited reduced killing ofssa1Δ andssa2Δ strains compared to the wild type, showing that Ssa1 and Ssa2 proteins are required for their fungicidal activity. These results demonstrate that (i) Trk1p mediates candidacidal activities of cysteine-free peptides, but not of defensins, and (ii) hBD-2 and hBD-3, but not HNP-1, require Ssa1/2p for antifungal activity.
VraSR Two-Component Regulatory System and Its Role in Induction of
pbp2
and
vraSR
Expression by Cell Wall Antimicrobials in
Staphylococcus aureus
Authors: Yin Shaohui , Daum Robert S. , Boyle-Vavra Susan
Published: December 2005

The VraS/VraR two-component system (VraSR) regulates transcriptional induction of penicillin-binding protein 2 (encoded by
pbp2
) by vancomycin in
Staphylococcus aureus
. We have now defined the
vraSR
operon and determined that its induction by β-lactams as well as by vancomycin is autoregulated. Induction of the
pbp2
and
vraSR
operons by β-lactams and related compounds within 1 hour after exposure to the antimicrobials was dependent on
vraS
. However, when a disk diffusion assay that can detect induction of genes over an extended time period was used, induction of the
pbp2
operon was mediated by some β-lactams, including oxacillin; this induction was independent of
vraS
.
Microdialysis Study of Imipenem Distribution in the Intraperitoneal Fluid of Rats with or without Experimental Peritonitis
Authors: Lefeuvre Sandrine , Marchand Sandrine , Lamarche Isabelle , Mimoz Olivier , Couet William
Published: December 2005

The purpose of this study was to extend the use of microdialysis to the investigation of antibiotic distribution into the intraperitoneal fluid of rats with or without peritonitis. Microdialysis probes were inserted into the jugular vein and peritoneal cavity of control rats or rats with intra-abdominal sepsis (
n
= 8 in each group) induced by cecal ligation and punctures. Imipenem (IPM) probe recoveries were determined in each rat by retrodialysis by drug. IPM was infused intravenously at a dose of 30 mg · kg
−1
over 30 min, microdialysis samples were collected for 120 min, and IPM concentrations were determined by high-performance liquid chromatography. Intraperitoneal infection had no statistically significant effect on IPM clearance (11.9 ± 2.3 ml · min
−1
· kg
−1
in control rats versus 10.9 ± 2.1 ml · min
−1
· kg
−1
in rats with peritonitis) or the volume of distribution (296 ± 47 ml · kg
−1
in control rats versus 310 ± 49 ml · kg
−1
in rats with peritonitis). IPM concentration profiles in intraperitoneal fluid and blood were virtually superimposed in control rats, whereas in infected animals, the mean intraperitoneal IPM concentrations were apparently slightly lower than corresponding blood levels. However, the areas under the concentration-versus-time curve estimated in intraperitoneal fluid and blood were not significantly different in both groups, with the corresponding ratios close to unity (1.01 ± 0.19 and 0.89 ± 0.28 in control rats and rats with peritonitis, respectively). In conclusion, IPM distribution in intraperitoneal fluid is rapid and complete both in control rats and in rats with peritonitis.
5-Nitroimidazole Drugs Effective against Metronidazole-Resistant
Trichomonas vaginalis
and
Giardia duodenalis
Authors: Upcroft Jacqueline A. , Dunn Linda A. , Wright Janelle M. , Benakli Kamel , Upcroft Peter , Vanelle Patrice
Published: December 2005

Metronidazole (Mz)-resistant
Giardia
and
Trichomonas
were inhibited by 1 of 30 new 5-nitroimidazole drugs. Another five drugs were effective against some but not all of the Mz-resistant parasites. This study provides the incentive for the continued design of 5-nitroimidazole drugs to bypass cross-resistance among established 5-nitromidazole antiparasitic drugs.
The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors
Authors: Parkin Neil T. , Gupta Soumi , Chappey Colombe , Petropoulos Christos J.
Published: December 2005

Genotypic patterns associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in the absence of well-characterized resistance mutations were identified using a database (n> 47,000) of phenotype-genotype data. Among samples with no known NNRTI mutations, the most resistant samples contained K101P (n= 35) or a combination of K103R and V179D (n= 41). Site-directed mutagenesis confirmed the importance of these mutations.
bla
IMP-9
and Its Association with Large Plasmids Carried by
Pseudomonas aeruginosa
Isolates from the People's Republic of China
Authors: Xiong Jianhui , Hynes Michael F. , Ye Huifen , Chen Huiling , Yang Yinmei , M'Zali Fatima , Hawkey Peter M.
Published: December 2005

A novel plasmid-mediated metallo-β-lactamase (IMP-9) is described in seven isolates of
Pseudomonas aeruginosa
from Guangzhou, China, isolated in 2000. The gene was carried on a large (∼450-kb) IncP-2 conjugative plasmid. This is the first report of carriage of
bla
IMP
genes on such large plasmids.
Lethal Action of Quinolones against a Temperature-Sensitive
dnaB
Replication Mutant of
Escherichia coli
Authors: Zhao Xilin , Malik Muhammad , Chan Nymph , Drlica-Wagner Alex , Wang Jian-Ying , Li Xinying , Drlica Karl
Published: December 2005

Inhibition of DNA replication in an
Escherichia coli dnaB-22
mutant failed to block quinolone-mediated lethality. Inhibition of protein synthesis by chloramphenicol inhibited nalidixic acid lethality and, to a lesser extent, ciprofloxacin lethality in both
dnaB-22
and wild-type cells. Thus, major features of quinolone-mediated lethality do not depend on ongoing replication.
Norfloxacin Blood-Brain Barrier Transport in Rats Is Not Affected by Probenecid Coadministration
Authors: Marchand Sandrine , Forsell Anna , Chenel Marylore , Comets Emmanuelle , Lamarche Isabelle , Couet William
Published: December 2005

The effect of probenecid (PRO) on norfloxacin (NOR) blood-brain barrier transport was investigated with rats by microdialysis. Maximum brain drug concentrations were rapidly attained, and the brain penetration factor was close to 5% in the absence and presence of PRO. In conclusion, PRO has no effect on NOR blood-brain barrier transport.
Multicenter Antimicrobial Susceptibility Survey of Gram-Negative Bacteria Isolated from Patients with Community-Acquired Infections in the People's Republic of China
Authors: Ling Thomas K. W. , Xiong Jianhui , Yu Yunsong , Lee Ching Ching , Ye Huifen , Hawkey Peter M.
Published: December 2005

A survey of 2,099 gram-negative bacilli from community infections at seven centers in the People's Republic of China is reported. The rates of resistance of 1,615 isolates of the family
Enterobacteriaceae
were as follows: 40.8% for ciprofloxacin, 32.2% for gentamicin, 0% for imipenem or ertapenem, and 14.7% for cefotaxime. The rates of extended-spectrum β-lactamase production were 16% for
Escherichia coli
and 17% for
Klebsiella
.
Comparative In Vitro Activities of Retapamulin (SB-275833) against 141 Clinical Isolates of
Propionibacterium
spp., Including 117
P. acnes
Isolates
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Warren Yumi A. , Tyrrell Kerin L. , Fernandez Helen T.
Published: December 2005

Using the NCCLS agar dilution method, we studied the in vitro activity of retapamulin (SB-275833) against 141 clinical isolates of
Propionibacterium
species, including seven multiresistant strains, and found retapamulin to be the most active agent among those tested with MICs of ≤1 μg/ml against all isolates.
Ciprofloxacin-Resistant
Salmonella enterica
Serovar Typhimurium Strains Are Difficult To Select in the Absence of AcrB and TolC
Authors: Ricci Vito , Tzakas Peter , Buckley Anthony , Coldham Nick C. , Piddock Laura J. V.
Published: December 2005

It has been proposed that lack of a functional efflux system(s) will lead to a lower frequency of selection of resistance to fluoroquinolones and other antibiotics. We constructed five strains of
Salmonella enterica
serovar Typhimurium SL1344 that lacked efflux gene components of resistance nodulation cell division pumps (
acrB
,
acrD
,
acrF
,
acrBacrF
, and
tolC
) plus three strains that lack genes that effect efflux gene expression (
marA
,
soxS
, and
ramA
) and a hypermutable strain (
mutS
::
aph
). Strains were exposed to ciprofloxacin at 2× the MIC in agar, in the presence and absence of Phe-Arg-β-naphthylamide, an efflux pump inhibitor. Mutants were selected from all strains except those lacking
acrB
,
tolC
, or
acrBacrF
. For strains from which mutants were selected, there were no significant differences between the frequencies of resistance. Except for mutants of the
ramA
::
aph
strain, two phenotypes arose: resistance to quinolones only and multiple antibiotic resistance (MAR).
ramA
::
aph
mutants were resistant to quinolones only, suggesting a role for
ramA
in MAR in
S. enterica
serovar Typhimurium. Phe-Arg-β-naphthylamide (20 μg/ml) had no effect on the frequencies of resistance or ciprofloxacin MICs. In conclusion, functional AcrB and TolC in
S. enterica
serovar Typhimurium are important for the selection of ciprofloxacin-resistant mutants.
Arginine or Nitrate Enhances Antibiotic Susceptibility of
Pseudomonas aeruginosa
in Biofilms
Authors: Borriello Giorgia , Richards Lee , Ehrlich Garth D. , Stewart Philip S.
Published: December 2005

Arginine enhanced the killing of
Pseudomonas aeruginosa
by ciprofloxacin and tobramycin under anaerobic, but not aerobic, growth conditions. Arginine or nitrate also enhanced the killing by these antibiotics in mature biofilms, reducing viable cell counts by a factor of 10 to 100 beyond that achieved by antibiotics alone.
Different Modes of Action of Naphthyridones in Gram-Positive and Gram-Negative Bacteria
Authors: Buurman Ed T. , Johnson Kenneth D. , Kelly Roxanne K. , MacCormack Kathy
Published: December 2005

Naphthyridones that were recently described as a class of translation inhibitors in gram-positive bacteria mediate their mode of action via GyrA in
Haemophilus influenzae
and
Escherichia coli
. These are the first examples of compounds in which modes of action in different bacterial pathogens are mediated through widely different targets.
Bloodstream Infections with Metallo-β-Lactamase-Producing
Pseudomonas aeruginosa
: Epidemiology, Microbiology, and Clinical Outcomes
Authors: Marra Alexandre R. , Pereira Carlos Alberto P. , Gales Ana Cristina , Menezes Liana C. , Cal Ruy Guilherme R. , de Souza José Marconi A. , Edmond Michael B. , Faro Cynthia , Wey Sérgio B.
Published: December 2005

Pseudomonas aeruginosa
strains that produce metallo-β-lactamases (MBLs) are becoming increasingly prevalent. We evaluated the epidemiological and microbiological characteristics of monomicrobial bloodstream infections caused by MBL-producing
P. aeruginosa
isolates, as well as the clinical outcomes in patients with these infections.
Dexamethasone Attenuates Staphylococcal Enterotoxin B-Induced Hypothermic Response and Protects Mice from Superantigen-Induced Toxic Shock
Authors: Krakauer Teresa , Buckley Marilyn
Published: December 2005

The superantigenic staphylococcal enterotoxins are important virulence factors and contribute to various diseases, including food poisoning and toxic shock. Dexamethasone, an anti-inflammatory agent, attenuated staphylococcal enterotoxin B (SEB)-induced hypothermia and serum proinflammatory cytokines and improved survival from 0% to 86% in a lethal mouse model of SEB-mediated shock.
Rifampin Augments Cytokine-Induced Nitric Oxide Production in Human Alveolar Epithelial Cells
Authors: Yuhas Yael , Berent Eva , Ovadiah Hila , Azoulay Inbar , Ashkenazi Shai
Published: December 2005

Rifampin increased nitric oxide production and inducible nitric oxide synthase expression in alveolar cells stimulated with cytokines. Nitric oxide concentrations after induction with cytokines, cytokines with 10 μg/ml rifampin, and cytokines with 50 μg/ml rifampin were 3.2, 4.5, and 8.8 μM, respectively (
P
< 0.02 versus cytokines alone). This indicates that rifampin modulates the immune response.
Multidrug-Resistant
Pseudomonas aeruginosa
: Risk Factors and Clinical Impact
Authors: Aloush Valerie , Navon-Venezia Shiri , Seigman-Igra Yardena , Cabili Shaltiel , Carmeli Yehuda
Published: December 2005

Pseudomonas aeruginosa
, a leading nosocomial pathogen, may become multidrug resistant (MDR). Its rate of occurrence, the individual risk factors among affected patients, and the clinical impact of infection are undetermined. We conducted an epidemiologic evaluation and molecular typing using pulsed-field gel electrophoresis (PFGE) of 36 isolates for 82 patients with MDR
P. aeruginosa
and 82 controls matched by ward, length of hospital stay, and calendar time. A matched case-control study identified individual risk factors for having MDR
P. aeruginosa
, and a retrospective matched-cohort study examined clinical outcomes of such infections. The 36 isolates belonged to 12 PFGE clones. Two clones dominated, with one originating in an intensive care unit (ICU). Cases and controls had similar demographic characteristics and numbers of comorbid conditions. A multivariate model identified ICU stay, being bedridden, having high invasive devices scores, and being treated with broad-spectrum cephalosporins and with aminoglycosides as significant risk factors for isolating MDR
P. aeruginosa
. Having a malignant disease was a protective factor (odds ratio [OR] = 0.2;
P
= 0.03). MDR
P. aeruginosa
was associated with severe outcomes compared to controls, including increased mortality (OR = 4.4;
P
= 0.04), hospital stay (hazard ratio, 2;
P
= 0.001), and requirement for procedures (OR = 5.4;
P
= 0.001). The survivors functioned more poorly at discharge than the controls, and more of the survivors were discharged to rehabilitation centers or chronic care facilities. The epidemiology of MDR
P. aeruginosa
is complex. Critically ill patients that require intensive care and are treated with multiple antibiotic agents are at high risk. MDR
P. aeruginosa
infections are associated with severe adverse clinical outcomes.
High Prevalence of Antimicrobial Resistance among
Shigella
Isolates in the United States Tested by the National Antimicrobial Resistance Monitoring System from 1999 to 2002
Authors: Sivapalasingam Sumathi , Nelson Jennifer M. , Joyce Kevin , Hoekstra Mike , Angulo Frederick J. , Mintz Eric D.
Published: December 2005

Shigella
spp. infect approximately 450,000 persons annually in the United States, resulting in over 6,000 hospitalizations. Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th
Shigella
isolate from 16 state or local public health laboratories for susceptibility to 15 antimicrobial agents. From 1999 to 2002, NARMS tested 1,604 isolates. Among 1,598 isolates identified to species level, 1,278 (80%) were
Shigella sonnei
, 295 (18%) were
Shigella flexneri
, 18 (1%) were
Shigella boydii
, and 7 (0.4%) were
Shigella dysenteriae
. Overall, 1,251 (78%) were resistant to ampicillin and 744 (46%) were resistant to trimethoprim-sulfamethoxazole (TMP-SMX). Prevalence of TMP-SMX- or ampicillin- and TMP-SMX-resistant
Shigella sonnei
isolates varied by geographic region, with lower rates in the South and Midwest regions (TMP-SMX resistance, 27% and 30%, respectively; ampicillin and TMP-SMX resistance, 25% and 22%, respectively) and higher rates in the East and West regions (TMP-SMX resistance, 66% and 80%, respectively; ampicillin and TMP-SMX resistance, 54% and 65%, respectively). Nineteen isolates (1%) were resistant to nalidixic acid (1% of
S. sonnei
and 2% of
S. flexneri
isolates); 12 (63%) of these isolates had decreased susceptibility to ciprofloxacin. One
S. flexneri
isolate was resistant to ciprofloxacin. All isolates were susceptible to ceftriaxone. Since 1986, resistance to ampicillin and TMP-SMX has dramatically increased.
Shigella
isolates in the United States remain susceptible to ciprofloxacin and ceftriaxone.
Multiple Combination Bactericidal Testing of Staphylococcal Biofilms from Implant-Associated Infections
Authors: Saginur Raphael , StDenis Melissa , Ferris Wendy , Aaron Shawn D. , Chan Francis , Lee Craig , Ramotar Karam
Published: December 2005

Standardized susceptibility testing fails to predict in vivo resistance of device-related infections to antimicrobials. We assessed agents and combinations of antimicrobials against clinical isolates of
Staphylococcus epidermidis
and
S. aureus
(methicillin-resistant
S. aureus
and methicillin-sensitive
S. aureus
) retrieved from device-associated infections. Isolates were grown planktonically and as biofilms. Biofilm cultures of the organisms were found to be much more resistant to inhibitory and bactericidal effects of single and combination antibiotics than planktonic cultures (
P
< 0.001). Rifampin was the most common constituent of antibiotic combinations active against staphylococcal biofilms. Other frequently effective antimicrobials were vancomycin and fusidic acid. Susceptibility testing involving biofilm-associated bacteria suggests new options for combination antibiotic therapy.
Comparison of Censored Regression and Standard Regression Analyses for Modeling Relationships between Antimicrobial Susceptibility and Patient- and Institution-Specific Variables
Authors: Hammel Jeffrey P. , Bhavnani Sujata M. , Jones Ronald N. , Forrest Alan , Ambrose Paul G.
Published: December 2005

In order to identify patients likely to be infected with resistant bacterial pathogens, analytic methods such as standard regression (SR) may be applied to surveillance data to determine patient- and institution-specific factors predictive of an increased MIC. However, the censored nature of MIC data (e.g., MIC ≤ 0.5 mg/liter or MIC > 8 mg/liter) imposes certain limitations on the use of SR. In order to investigate the nature of these limitations, simulations were performed to compare a regression tailored for censored data (censored regression [CR]) and one tailored for an SR. By using a model relating piperacillin-tazobactam MICs against
Enterobacter
spp. to patient age and hospital bed capacity, 200 simulations of 500 isolates were performed. Various MIC censoring patterns were imposed by using 26 left- or right-censored (
L
,
R
) pairs (i.e., MICs ≤ 2 mg/liter

L

[2

L

] or MICs > 2 mg/liter

R

[2

R

], respectively). Data were fit by CR and SR for which censored MICs were either (i) excluded, (ii) replaced by 2

L

or 2

R

, or (iii) replaced by 2

L
− 1

or 2

R
+ 1

. Total censoring for the 26 pairs ranged from 7 to 86%. By CR, deviations of average parameter estimates from the true parameter values were <0.10 log
2
(mg/liter) for all parameters for each of the 26 pairs. By SR, these deviations were >0.10 log
2
(mg/liter) for at least 18 of the 26 pairs for all but one parameter. Two-standard-error confidence intervals for individual parameters contained as little as 0% of cases for all SR approaches but ≥91.5% of cases for the CR approach. When censored MIC data are modeled, CR may reduce or eliminate biased parameter estimates obtained by SR.
Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers
Authors: Grunder Gabriela , Zysset-Aschmann Yvonne , Vollenweider Florence , Maier Thomas , Krähenbühl Stephan , Drewe Juergen
Published: December 2005

Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (
C
max
) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to
C
max
, lag time, volume of distribution [
V
/
F
], and clearance [CL/
F
]). However, a significant sex difference was observed for AUC,
C
max
,
V/F
, and CL/
F
; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.
In Vitro and In Vivo Interactions between Miltefosine and Other Antileishmanial Drugs
Authors: Seifert Karin , Croft Simon L.
Published: December 2005

The interaction of miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo. In vitro interactions were indifferent for miltefosine combined with amphotericin B (mean sums of fractional inhibitory concentrations [mean ∑FICs] ranging from 1.22 to 1.51 at the 50% effective concentration [EC
50
] level and 1.08 to 1.38 at the EC
90
level), sitamaquine (mean ∑FICs from 1.33 to 1.38 and 1.0 to 1.02, respectively), and paromomycin (mean ∑FICs from 0.79 to 0.93 at the EC
50
and 0.77 to 1.35 at the EC
90
level). Some synergy was observed for miltefosine combined with sodium stibogluconate (mean ∑FICs from 0.61 to 0.75 at EC
50
and 0.49 to 0.97 at EC
90
). Different interactions were found in vivo, where the highest potentiation of miltefosine activity was achieved with amphotericin B (activity enhancement index [AEI] of up to 11.3). No significant interaction was observed when miltefosine was combined with sodium stibogluconate (AEI of up to 2.38). The potentiation of miltefosine in vivo was also achieved with the combination of miltefosine and paromomycin (AEI of up to 7.22).
Resistance ofLeishmania donovanito Sodium Stibogluconate Is Related to the Expression of Host and Parasite γ-Glutamylcysteine Synthetase
Authors: Carter K. C. , Hutchison S. , Henriquez F. L. , Légaré D. , Ouellette M. , Roberts C. W. , Mullen A. B.
Published: December 2005

Sequencing studies showed that the γ-glutamylcysteine synthetase (γ-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S)Leishmania donovanistrains were identical, indicating that SSG resistance was related to quantitative differences in γ-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host γ-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of γ-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection against oxidative stress and facilitating SSG efflux. However a similar differential effect on host and parasite γ-GCS expression was not obtained when using tissues from infected mice. In this case γ-GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on γ-GCS expression. Consistent with the proposed mechanism from in vitro studies, increasing tissue GSH levels in the presence of SSG by cotreatment ofL. donovani-infected mice with SSG solution and GSH incorporated into nonionic surfactant vesicles was more effective in reducing liver, spleen, and bone marrow parasite burdens than monotherapy with SSG. Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels byL. donovani.
Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole
Authors: Chamilos Georgios , Lewis Russell E. , Kontoyiannis Dimitrios P.
Published: December 2005

Zygomycetes are emerging opportunistic molds resistant to most conventional antifungals. We evaluated the in vitro activity of lovastatin (LOV), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, against seven clinical isolates of
Zygomycetes
by using standard microdilution methods in three different media, disk diffusion testing, and viability dye staining. To further study the in vivo efficacy of LOV against zygomycetes, we developed a
Drosophila melanogaster
model of zygomycosis. In different experiments, groups of Toll-deficient (
Tl
) flies fed LOV-containing food were subsequently injected with two representative
Zygomycetes
isolates (
Mucor
and
Rhizopus
spp.). Finally, we examined the effects of LOV on voriconazole (VRC) activity against zygomycetes in vitro by checkerboard dilution, Epsilometer test-based methods, and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining and in vivo in
Tl
flies fed food containing LOV plus VRC and infected with zygomycetes. LOV exhibited significant, medium, and strain-independent fungicidal activity against all
Zygomycetes
isolates in vitro by all testing methods (MIC
50
, 48.0 μg/ml; 50% minimal fungicidal concentration, 56.0 μg/ml; 50% effective concentration, 29.4 μg/ml [6.6 to 38.9 μg/ml]).
Tl
flies fed LOV-containing food and infected with
Mucor
had a significantly better 6-day survival rate than did infected
Tl
flies fed regular food (
P
 = 0.0005). LOV displayed in vitro synergy with VRC against all
Zygomycetes
isolates (fractional inhibitory concentration index, 0.104 to 0.290) by all methods used. LOV also displayed synergy with VRC in the
Drosophila
model of zygomycosis (
P
< 0.01). LOV is significantly active against zygomycetes and synergizes with triazoles inherently resistant to them, such as VRC. The clinical significance of these findings needs to be further explored.
DIFFERENT LEARNING METHODOLOGIES FOR VISION-BASED NAVIGATION BEHAVIORS
Authors: CICIRELLI G. , D'ORAZIO T. , DISTANTE A.
Published: December 2005

In this work the complex behavior of localizing a mobile vehicle with respect to the door of the environment and then reaching the door has been developed. The robot uses visual information to detect and recognize the door and to determine its state with respect to it. This complex task has been divided into two separate behaviors: door-recognition and door-reaching. A supervised methodology based on learning by components has been applied for recognizing the door. Learning by components allows to recognize the door also in difficult situations such as partial occlusions and besides, it makes recognition independent of viewpoint variations and scale changes. An unsupervised methodology based on reinforcement learning has been used for the door-reaching behavior, instead. The image of the door gives information about the relative position of the vehicle with respect to the door. Then the Q-learning algorithm is used to generate the optimal state-action associations. The problem of defining the state and the action sets has been addressed with the aim of producing smooth paths, of reducing the effects of visual errors during real navigation, and of keeping low the computational cost during the learning phase. A novel way to obtain a continuous action set has been introduced: it uses a fuzzy model to evaluate the system state. Experimental results in real environment show both the robustness of the door-recognition behavior and the generality of the door-reaching behavior.