The impact of multiple drug resistance (MDR) proteins on chemotherapy and drug discovery

2002 ◽  
pp. 99-131 ◽  
Author(s):  
Paul L. Skatrud
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
The Impact

scholarly journals Impact of host factors on susceptibility to antifungal agents

ADMET & DMPK ◽  
2022 ◽  
Author(s):  
Balbina Plotkin ◽  
Monika Konaklieva
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Multiple Drug Resistance ◽  
Fold Increase ◽  
Multiple Drug ◽  
Phenotypic Resistance ◽  
Microbial Response ◽  
Candida Lusitaniae ◽  
Drug Resistant Strains ◽  
The Impact

An obstacle to drug development, particularly in this era of multiple drug resistance, is the under-appreciation for the role the host environment plays in microbial response to drugs. With the rise in fungal infection and drug resistance, particularly in individuals with co-morbidities, the influence serum and its components have on antimicrobial susceptibility requires assessment. This study examined the impact of physiologically relevant glucose and insulin levels in the presence and absence of 50 % human plasma on MICs for clinical isolates of Candida lusitaniae, Candida parapsilosis, Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The addition of insulin or glucose at physiologic levels in RPMI medium alone altered the MIC in either a positive or negative fashion, depending on the organisms and drug tested, with C. glabrata most significantly altered with a 40, >32- and 46-fold increase in MIC for amphotericin B, itraconazole and miconazole, respectively. The addition of candida-antibody negative plasma also affected MIC, with the addition of glucose and insulin having a tandem effect on MIC. These findings indicate that phenotypic resistance of Candida and Cryptococcus can vary depending on the presence of insulin with glucose and plasma. This modulation of resistance may help explain treatment failures in the diabetic population and facilitate the development of stable drug-resistant strains. Furthermore, these findings indicate the need for a precision approach in the choice of drug treatment and drug development.

OP115 Effect Of Multiple Drug Resistance On Costs For Patients With Intra-Abdominal Infections in China

2017 ◽  
Vol 33 (S1) ◽  
pp. 52-52
Author(s):  
Xuemei Zhen ◽  
Yuanyuan Li ◽  
Yixi Chen ◽  
Peng Dong ◽  
Stephanie Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Multiple Drug Resistance ◽  
National Level ◽  
Multiple Drug ◽  
Real World Data ◽  
Societal Costs ◽  
Multiple Variables ◽  
Abdominal Infections ◽  
The Impact

INTRODUCTION:Multiple drug resistance (MDR) intra-abdominal infections (IAIs) are associated with noteworthy direct and societal costs. Compared to previous studies, the present one takes both resistance rate and total medical costs (TMCs) into consideration, focusing on the impact of MDR on TMCs in IAIs, as well as further estimating the additional costs at a national level.METHODS:All inpatients discharged between 1 January 2014, and 31 December 2015 from a teaching hospital were included. Due to limits in budget and the large number of inpatients, the randombetween (bottom, top) function was applied to randomly select 40 percent of patients per year. Subsequently, we manually screened out 254 patients with IAIs, according to the International Classification of Disease (tenth revision) and electronic medical records. Eventually, 101 IAIs patients were included, in which 37 were infected by non-MDR bacteria and 64 by MDR bacteria. The Kruskal-wallis non-parametric test and multiple linear regression were employed to analyze the effect of single and multiple variables on TMCs.RESULTS:Compared to patients with non-MDR infections, those with MDR were associated with significantly higher TMCs, higher antimicrobial costs, increased insurance, combination antimicrobial therapy, higher usage of antimicrobial agents, greater number of pathogens, longer length of stay, and longer intensive care unit stays. In addition, the average TMCs among patients with MDR were CNY131,801.17 (1USD was equal to CNY 6.227 in 2015), which were CNY 90,200.99 higher than those with non-MDR infections. If our results are generalizable to the whole country, the total attributable TMCs are estimated to be CNY37.06 billion, and the societal costs of CNY111.18 billion in 2015.CONCLUSIONS:This real-world data analysis demonstrated the significant excessive burden MDR infections are posing to the current Chinese healthcare system in terms of both TMCs and healthcare resource utilization. Enhanced antimicrobial stewardship in China is necessary to curb the distribution of MDR bacteria.

Genes of multidrug resistance in haematological malignancies

Biologia ◽  
2006 ◽  
Vol 61 (3) ◽  
Author(s):  
Jozef Hatok ◽  
Peter Račay ◽  
Jan Hudeček ◽  
Dušan Dobrota
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Refractory Disease ◽  
Haematological Malignancies ◽  
Reversal Agents ◽  
Lung Resistance Protein ◽  
Impact On Survival ◽  
The Impact

AbstractSince the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.

Do Multiple Drug Resistance Transporters Interfere with Cell Functioning under Normal Conditions?

2020 ◽  
Vol 85 (12-13) ◽  
pp. 1560-1569
Author(s):  
D. A. Knorre ◽  
K. V. Galkina ◽  
T. Shirokovskikh ◽  
A. Banerjee ◽  
R. Prasad
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug

scholarly journals Amelioration of the Cost of Conjugative Plasmid Carriage in Eschericha coli K12

Genetics ◽  
2003 ◽  
Vol 165 (4) ◽  
pp. 1641-1649
Author(s):  
Cecilia Dahlberg ◽  
Lin Chao
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Conjugative Plasmid ◽  
Energetic Cost ◽  
Multiple Drug ◽  
Genetic Changes ◽  
Batch Cultures ◽  
Transfer Rates ◽  
Bacterial Plasmid ◽  
The Cost

Abstract Although plasmids can provide beneficial functions to their host bacteria, they might confer a physiological or energetic cost. This study examines how natural selection may reduce the cost of carrying conjugative plasmids with drug-resistance markers in the absence of antibiotic selection. We studied two plasmids, R1 and RP4, both of which carry multiple drug resistance genes and were shown to impose an initial fitness cost on Escherichia coli. To determine if and how the cost could be reduced, we subjected plasmid-containing bacteria to 1100 generations of evolution in batch cultures. Analysis of the evolved populations revealed that plasmid loss never occurred, but that the cost was reduced through genetic changes in both the plasmids and the bacteria. Changes in the plasmids were inferred by the demonstration that evolved plasmids no longer imposed a cost on their hosts when transferred to a plasmid-free clone of the ancestral E. coli. Changes in the bacteria were shown by the lowered cost when the ancestral plasmids were introduced into evolved bacteria that had been cured of their (evolved) plasmids. Additionally, changes in the bacteria were inferred because conjugative transfer rates of evolved R1 plasmids were lower in the evolved host than in the ancestral host. Our results suggest that once a conjugative bacterial plasmid has invaded a bacterial population it will remain even if the original selection is discontinued.

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