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1.  In Vivo Selection of Rifamycin-Resistant Clostridium difficile during Rifaximin Therapy 
Antimicrobial Agents and Chemotherapy  2012;56(11):6019-6020.
We report the selection of Clostridium difficile resistant to the rifamycin class of antibiotics in a patient within 32 h of receiving rifaximin for the treatment of recurrent C. difficile diarrhea. Resistance was associated with single nucleotide substitutions within rpoB.
PMCID: PMC3486587  PMID: 22908175
2.  First Description of KPC-2-Producing Klebsiella oxytoca in Brazil 
The present work reports the detection of the first case of nosocomial Klebsiella oxytoca producing class A carbapenemase KPC-2 in Brazil. The isolate KPN106 carried a 65-kb IncW-type plasmid that harbors the blaKPC gene and Tn4401b. Moreover, we detected the presence of a class 1 integron containing a new allele, arr-8, followed by a 5′-truncated dhfrIIIc gene. In view of the recent results, we emphasize the high variability of the bacterial and genetic hosts of this resistance determinant.
PMCID: PMC3719734  PMID: 23752512
3.  Pharmacological Study of Cefoxitin as an Alternative Antibiotic Therapy to Carbapenems in Treatment of Urinary Tract Infections Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli 
Cefoxitin could be an alternative to carbapenems in extended-spectrum-beta-lactamase-producing Escherichia coli (ESBL-EC) infections. However, pharmacological and clinical data regarding cefoxitin are limited. Using a recent pharmacological model and the MICs of ESBL-EC collected from pyelonephritis, we determined the probabilities to reach four pharmacological targets: free cefoxitin concentrations above the MIC during 50% and 100% of the administration interval (T>MIC = 50% and T>MIC = 100%, respectively) and free cefoxitin concentrations above 4× MIC during 50% and 100% of the administration interval (T>4MIC = 50% and T>4MIC = 100%, respectively). Cefoxitin could be used to treat ESBL-EC pyelonephritis, but administration modalities should be optimized according to MICs in order to reach pharmacological targets.
PMCID: PMC4135984  PMID: 24777104
4.  Multidisciplinary Analysis of a Nontoxigenic Clostridium difficile Strain with Stable Resistance to Metronidazole 
Stable resistance to metronidazole in a nontoxigenic Clostridium difficile strain was investigated at both the genomic and proteomic levels. Alterations in the metabolic pathway involving the pyruvate-ferredoxin oxidoreductase were found, suggesting that reduction of metronidazole, required for its activity, may be less efficient in this strain. Proteomic studies also showed a cellular response to oxidative stress.
PMCID: PMC4135993  PMID: 24913157
5.  Complete Sequencing of IncI1 Sequence Type 2 Plasmid pJIE512b Indicates Mobilization of blaCMY-2 from an IncA/C Plasmid 
Sequencing of pJIE512b, a 92.3-kb IncI1 sequence type 2 (ST2) plasmid carrying blaCMY-2, revealed a blaCMY-2 context that appeared to have been mobilized from an IncA/C plasmid by the insertion sequence IS1294. A comparison with published plasmids suggests that blaCMY-2 has been mobilized from IncA/C to IncI1 plasmids more than once by IS1294-like elements. Alignment of pJIE512b with the only other available IncI1 ST2 plasmid revealed differences across the backbones, indicating variability within this sequence type.
PMCID: PMC4135994  PMID: 24890591
6.  Structure-Activity Relationship Study of the Plant-Derived Decapeptide OSIP108 Inhibiting Candida albicans Biofilm Formation 
We performed a structure-activity relationship study of the antibiofilm plant-derived decapeptide OSIP108. Introduction of positively charged amino acids R, H, and K resulted in an up-to-5-fold-increased antibiofilm activity against Candida albicans compared to native OSIP108, whereas replacement of R9 resulted in complete abolishment of its antibiofilm activity. By combining the most promising amino acid substitutions, we found that the double-substituted OSIP108 analogue Q6R/G7K had an 8-fold-increased antibiofilm activity.
PMCID: PMC4135999  PMID: 24913176
7.  Caspofungin at Catheter Lock Concentrations Eradicates Mature Biofilms of Candida lusitaniae and Candida guilliermondii 
The antibiofilm activities of caspofungin, anidulafungin, micafungin, and liposomal amphotericin B were studied against Candida lusitaniae, Candida guilliermondii, and a Candida albicans control strain. While anidulafungin and micafungin (0.007 to 2,048 mg/liter) showed reduced activity against biofilms of both test species, caspofungin displayed concentration-dependent antibiofilm activity, reaching complete and persistent eradication at concentrations achievable during lock therapy (512 to 2,048 mg/liter, P < 0.05). Although liposomal amphotericin B strongly inhibited mature biofilms, it possessed lower antibiofilm activity than caspofungin (P < 0.05).
PMCID: PMC4136003  PMID: 24890585
8.  Flow Cytometry-Based Analysis of Artemisinin-Resistant Plasmodium falciparum in the Ring-Stage Survival Assay 
The ring-stage survival assay (RSA) is a powerful tool for phenotyping artemisinin-resistant Plasmodium falciparum but requires experienced microscopists to count viable parasites among 10,000 erythrocytes in Giemsa-stained thin blood smears. Here we describe a rapid flow cytometric assay that accurately counts viable parasites among 250,000 erythrocytes in suspension. This method performs as well as light microscopy and can be used to standardize the collection of RSA data between research groups in laboratory and field settings.
PMCID: PMC4136004  PMID: 24867976
9.  Bordetella pertussis Lipid A Glucosamine Modification Confers Resistance to Cationic Antimicrobial Peptides and Increases Resistance to Outer Membrane Perturbation 
Bordetella pertussis, the causative agent of whooping cough, has many strategies for evading the human immune system. Lipopolysaccharide (LPS) is an important Gram-negative bacterial surface structure that activates the immune system via Toll-like receptor 4 and enables susceptibility to cationic antimicrobial peptides (CAMPs). We show modification of the lipid A region of LPS with glucosamine increased resistance to numerous CAMPs, including LL-37. Furthermore, we demonstrate that this glucosamine modification increased resistance to outer membrane perturbation.
PMCID: PMC4136009  PMID: 24867963
10.  Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals 
Genome sequencing of carbapenem-resistant Klebsiella pneumoniae isolates from regional U.S. hospitals was used to characterize strain diversity and the blaKPC genetic context. A phylogeny based on core single-nucleotide variants (SNVs) supports a division of sequence type 258 (ST258) into two distinct groups. The primary differences between the groups are in the capsular polysaccharide locus (cps) and their plasmid contents. A strict association between clade and KPC variant was found. The blaKPC gene was found on variants of two plasmid backbones. This study indicates that highly similar K. pneumoniae subpopulations coexist within the same hospitals over time.
PMCID: PMC4136011  PMID: 24913165
11.  OXA-207, a Novel OXA-24 Variant with Reduced Catalytic Efficiency against Carbapenems in Acinetobacter pittii from Spain 
A carbapenem-resistant Acinetobacter pittii strain carrying an OXA-24-like enzyme was isolated in northern Spain in 2008. Sequence analysis confirmed the presence of the novel blaOXA-207 gene flanked by the site-specific XerC/XerD-like recombination binding sites and showing a unique Gly222Val substitution compared to OXA-24. Cloning and kinetic analysis showed that OXA-207 presents a reduction in the catalytic efficiency against carbapenems and a noticeable increase for oxacillin.
PMCID: PMC4136014  PMID: 24890588
12.  Association between pncA Gene Mutations, Pyrazinamidase Activity, and Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis 
We determined MICs for, confirmed the presence of pncA mutations in, and performed pyrazinamidase testing on colonies (subclones) obtained from seven isolates that exhibited differential pyrazinamide (PZA) susceptibility. Six of the seven strains were found to exhibit characteristics resulting from the mixture of strains possessing different properties. In addition, our analysis revealed large pncA-spanning deletions (1,565 bp, 4,475 bp, and 6,258 bp) in three strains that showed high PZA resistance.
PMCID: PMC4136016  PMID: 24867972
13.  Case Report and Cohort Analysis of Drug-Induced Liver Injury Associated with Daptomycin 
A patient receiving daptomycin developed asymptomatic transaminitis and hyperbilirubinemia without concurrent multiorgan dysfunction or elevation of his creatinine kinase level. After ruling out other etiologies, the liver injury was attributed to daptomycin and was subsequently resolved. A single-center retrospective cohort analysis of baseline and follow-up liver function panels (n = 614) from all admissions from 2008 to 2013 during which daptomycin was administered did not reveal any other cases of probable or definite drug-induced liver injury associated with daptomycin.
PMCID: PMC4136030  PMID: 24820087
14.  Emergence of VIM-2 and IMP-15 Carbapenemases and Inactivation of oprD Gene in Carbapenem-Resistant Pseudomonas aeruginosa Clinical Isolates from Lebanon 
We report here the emergence of VIM-2 and IMP-15 carbapenemases in a series of clinical isolates of carbapenem-resistant Pseudomonas aeruginosa in Lebanon. We also describe the disruption of the oprD gene by either mutations or insertion sequence (IS) elements ISPa1328 and ISPre2 isoform. Our study reemphasizes a rapid dissemination of the VIM-2 carbapenemase-encoding gene in clinical isolates of P. aeruginosa in the Mediterranean basin.
PMCID: PMC4136035  PMID: 24913164
15.  SAMHD1 Has Differential Impact on the Efficacies of HIV Nucleoside Reverse Transcriptase Inhibitors 
Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI triphosphates (TPs) at significantly lower rates than dNTPs and that SAMHD1 depletion from monocytic cells affects the susceptibility of HIV-1 infections to NRTIs in complex ways that depend not only on the relative changes in dNTP and NRTI-TP concentrations but also on the NRTI activation pathways.
PMCID: PMC4136039  PMID: 24867973
16.  Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses 
We have previously shown that SSYA10-001 blocks severe acute respiratory syndrome coronavirus (SARS-CoV) replication by inhibiting SARS-CoV helicase (nsp13). Here, we show that SSYA10-001 also inhibits replication of two other coronaviruses, mouse hepatitis virus (MHV) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). A putative binding pocket for SSYA10-001 was identified and shown to be similar in SARS-CoV, MERS-CoV, and MHV helicases. These studies show that it is possible to target multiple coronaviruses through broad-spectrum inhibitors.
PMCID: PMC4136041  PMID: 24841268
17.  Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin Sensitivity In Vitro 
Reduced Plasmodium falciparum sensitivity to short-course artemisinin (ART) monotherapy manifests as a long parasite clearance half-life. We recently defined three parasite founder populations with long half-lives in Pursat, western Cambodia, where reduced ART sensitivity is prevalent. Using the ring-stage survival assay, we show that these founder populations have reduced ART sensitivity in vitro at the early ring stage of parasite development and that a genetically admixed population contains subsets of parasites with normal or reduced ART sensitivity.
PMCID: PMC4136061  PMID: 24867977
18.  Protein Binding of Rifapentine and Its 25-Desacetyl Metabolite in Patients with Pulmonary Tuberculosis 
Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower total rifapentine concentration but significantly higher free rifapentine levels in African patients of black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free rifapentine in relation to microbiological and clinical outcomes.
PMCID: PMC4136068  PMID: 24841270
19.  In Vitro and In Vivo Assessment of Dermatophyte Acquired Resistance to Efinaconazole, a Novel Triazole Antifungal 
Efinaconazole is a novel triazole antifungal drug for the topical treatment of onychomycosis, a nail infection caused mainly by dermatophytes. We assessed the potential of efinaconazole to induce resistance in dermatophytes by continuous exposure of Trichophyton rubrum strains to efinaconazole in vitro (12 passages) and in a guinea pig onychomycosis model (8 weeks). There was no evidence of efinaconazole resistance development in the tested strains under the experimental conditions used.
PMCID: PMC4136074  PMID: 24867968
20.  Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation 
Few data have been published regarding posaconazole tissue concentrations in humans. We analyzed tissue concentrations in biopsy specimens taken at autopsy from seven patients who received posaconazole prophylaxis because of graft-versus-host disease. The results were compared to plasma concentrations collected before death. Tissue concentrations suggestive of an accumulation of posaconazole were found in the heart, lung, liver, and kidney but not in the brain.
PMCID: PMC4136075  PMID: 24890587
21.  Five-Year Longitudinal Assessment (2008 to 2012) of E-101 Solution Activity against Clinical Target and Antimicrobial-Resistant Pathogens 
This study summarizes the topical E-101 solution susceptibility testing results for 760 Gram-positive and Gram-negative target pathogens collected from 75 U.S. sites between 2008 and 2012 and 103 ESKAPE pathogens. E-101 solution maintained potent activity against all bacterial species studied for each year tested, with MICs ranging from <0.008 to 0.25 μg porcine myeloperoxidase (pMPO)/ml. These results confirm that E-101 solution retains its potent broad-spectrum activity against U.S. clinical isolates and organisms with challenging resistance phenotypes.
PMCID: PMC4136076  PMID: 24841272
22.  Decreased Ceftriaxone Susceptibility in Emerging (35B and 6C) and Persisting (19A) Streptococcus pneumoniae Serotypes in the United States, 2011-2012: Ceftaroline Remains Active In Vitro among β-Lactam Agents 
Totals of 8.7% (103/1,190) and 21.0% (249/1,190) of the Streptococcus pneumoniae isolates recovered from specimens collected in the United States during the 2011-2012 AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) Surveillance Program were ceftriaxone nonsusceptible according to the CLSI (≤1 μg/ml for susceptible) and EUCAST (≤0.5 μg/ml for susceptible) criteria, respectively. Decreased susceptibility to ceftriaxone (MIC, 1 μg/ml) was frequently observed among serotypes 19A (51.4%; 128/249) and 35B (29.7%; 74/249), which were most often observed in the East South Central and South Atlantic U.S. Census regions. Ceftaroline (MIC50/90, 0.12/0.25 μg/ml) remained active (≥96.8% susceptible) when tested against these less susceptible isolates.
PMCID: PMC4136078  PMID: 24867974
23.  In Vitro Amphotericin B Susceptibility of Malassezia pachydermatis Determined by the CLSI Broth Microdilution Method and Etest Using Lipid-Enriched Media 
We determined the in vitro amphotericin B susceptibility of 60 Malassezia pachydermatis isolates by the CLSI broth microdilution method and the Etest using lipid-enriched media. All isolates were susceptible at MICs of ≤1 μg/ml, confirming the high activity of amphotericin B against this yeast species. Overall, the essential agreement between the tested methods was high (80% and 96.7% after 48 h and 72 h, respectively), and all discrepancies were regarded as nonsubstantial.
PMCID: PMC4068533  PMID: 24752258
24.  New Insights into the Bacterial RNA Polymerase Inhibitor CBR703 as a Starting Point for Optimization as an Anti-Infective Agent 
CBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents.
PMCID: PMC4068539  PMID: 24820077
25.  Phase-Variable Expression of lptA Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides 
Phosphoethanolamine (PEA) decoration of lipid A produced by Neisseria gonorrhoeae has been linked to bacterial resistance to cationic antimicrobial peptides/proteins (CAMPs) and in vivo fitness during experimental infection. We now report that the lptA gene, which encodes the PEA transferase responsible for this decoration, is in an operon and that high-frequency mutation in a polynucleotide repeat within lptA can influence gonococcal resistance to CAMPs.
PMCID: PMC4068544  PMID: 24820072

Results 1-25 (485)