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L Lincoln

Publications and source records attributed to L Lincoln.

8 recordsLinked to original sources
PubMed2006

Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans.

Numerous factors have been theorized to affect the development of antimicrobial resistance, including those specific to the host, the organism, the environment, the drug, and the drug prescriber. One variable under the control of the prescriber is the drug dosing regimen. Dosing regimens can vary in dose level, dosing interval, and treatment duration. The current studies examined the relationships between antimicrobial dosing regimens and resistance development by use of an in vivo model. A murine model of systemic Candida albicans infection was used to examine resistance emergence during exposure to the triazole antifungal fluconazole. Data from this experimental model demonstrated that the more frequently administered dosing prevented selection of the isogenic resistant cell populations. Conversely, dosing regimens producing prolonged sub-MIC effects appeared to contribute to the outgrowth of isogenic resistant strains. The association between dosing and resistance emergence observed in the current investigation is disparate from that described for antimicrobial compounds with cidal killing characteristics. The inhibitory or static antimicrobial activity of the triazole compounds may explain these differences.

Animals↗
PubMed2006

In vivo fluconazole pharmacodynamics and resistance development in a previously susceptible Candida albicans population examined by microbiologic and transcriptional profiling.

Antimicrobial drug resistance can limit the ability to effectively treat patients. Numerous factors have been proposed to impact the development of antimicrobial resistance, including those specific to the drug and the dosing regimen. The field of investigation that examines the relationship between dosing regimen and outcome is termed antimicrobial pharmacokinetics and pharmacodynamics. Our prior in vivo investigations examined the relationship between fluconazole pharmacodynamics and the modulation of isogenic resistant and susceptible Candida albicans populations in a mixed-inoculum design (1). The goal of the current studies was to examine the impact of fluconazole pharmacodynamics on resistance emergence from a susceptible parent population over time using a murine systemic-candidiasis model. Both microbiologic and transcriptional endpoints were examined during the evolution of cell populations. As in our previous investigation, the more frequently administered dosing regimen prevented the emergence of a resistant cell phenotype. Conversely, dosing regimens that produced prolonged sub-MIC concentrations were associated with resistance development. The studies also demonstrated a striking relationship between fluconazole pharmacodynamic exposures and the mRNA abundance of drug resistance-associated efflux pumps. Global transcriptional profiling of cell populations during the progressive emergence of a resistance phenotype provides insight into the mechanisms underlying this complex physiologic process.

Animals↗
PubMed2006

Time course of microbiologic outcome and gene expression in Candida albicans during and following in vitro and in vivo exposure to fluconazole.

Pharmacodynamics (PD) considers the relationship between drug exposure and effect. The two factors that have been used to distinguish the PD behaviors of antimicrobials are the impact of concentration on the extent of organism killing and the duration of persistent microbiologic suppression (postantibiotic effect). The goals of these studies were (i) to examine the relationship between antimicrobial PD and gene expression and (ii) to gain insight into the mechanism of fluconazole effects persisting following exposure. Microarrays were used to estimate the transcriptional response of Candida albicans to a supra-MIC F exposure over time in vitro. Fluconazole at four times the MIC was added to a log-phase C. albicans culture, and cells were collected to determine viable growth and for microarray analyses. We identified differential expression of 18% of all genes for at least one of the time points. More genes were upregulated (n=1,053 [16%]) than downregulated (174 [3%]). Of genes with known function that were upregulated during exposure, most were related to plasma membrane/cell wall synthesis (18%), stress responses (7%), and metabolism (6%). The categories of downregulated genes during exposure included protein synthesis (15%), DNA synthesis/repair (7%), and transport (7%) genes. The majority of genes identified at the postexposure time points were from the protein (17%) and DNA (7%) synthesis categories. In subsequent studies, three genes (CDR1, CDR2, and ERG11) were examined in greater detail (more concentration and time points) following fluconazole exposure in vitro and in vivo. Expression levels from the in vitro and in vivo studies were congruent. CDR1 and CDR2 transcripts were reduced during in vitro fluconazole exposure and during supra-MIC exposure in vivo. However, in the postexposure period, the mRNA abundance of both pumps increased. ERG11 expression increased during exposure and fell in the postexposure period. The expression of the three genes responded in a dose-dependent manner. In sum, the microarray data obtained during and following fluconazole exposure identified genes both known and unknown to be affected by this drug class. The expanded in vitro and in vivo expression data set underscores the importance of considering the time course of exposure in pharmacogenomic investigations.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Development of a burn rehabilitation unit: impact on burn center length of stay and functional outcome.

In 1995 we initiated the development of a specialized burn rehabilitation unit within an acute rehabilitation hospital, geographically separated from our burn center. The purpose was to allow an earlier initiation of an intensive rehabilitation program while still maintaining optimal burn wound care and nutritional support. The unit was directed by a burn center nurse coordinator who spent 50% of the time in the burn center and 50% in the rehabilitation unit training and supervising care. By 1996 the unit was able to manage open wounds, including skin substitutes of as much as 18% total body surface area, with 2- to 3-day returns to the center for wound coverage (2.5 +/- 0.5 procedures/patient). Our length of stay in 1996 for burns requiring inpatient rehabilitation (mean size 54% +/- 7% total body surface area) decreased by 21 +/- 5 days with respect to those in 1994 and 1995, with no increased morbidity. This length of stay was also significantly shorter (24%) than that predicted by the American Burn Association Registry formula. In addition, the rehabilitation unit length of stay required to restore the same degree of function according to a standardized measurement was significantly shorter (by 9 +/- 3 days) than for patients referred to other rehabilitation facilities in 1996. We conclude that the benefits of a burn rehabilitation unit include not only a decreased burn center length of stay but also a more rapid restoration of function.

Adult↗