Bicarbonate-Mediated Enhancement of Beta-Lactam-MRSA Killing: Mechanisms and Clinical Translatability
Bicarbonate-Mediated Enhancement of Beta-Lactam-MRSA Killing: Mechanisms and Clinical Translatability
批准号:
10626037
负责人:
YAN Q. XIONG
金额:
$32.81万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-01 至 2024-05-31
关键词:
AddressAntibiotic ResistanceAntibioticsBacteremiaBacteriaBicarbonatesBindingBlood CirculationBlood VesselsCathetersCefazolinCell WallChemicalsClinicalClinical TrialsCoagulaseCollectionCommunitiesDataDoseDrug SensitizationDrug resistanceEndocarditisEventExhibitsFoundationsFutureGenesGeneticGenotypeGenus staphylococcusHemodialysisHospitalsHost DefenseHumanIn VitroInfectionJointsLaboratoriesLibrariesMediatingMethicillinMethicillin ResistanceMethodsModelingMusNafcillinNebraskaOrganOutcomeOxacillinPathway interactionsPenicillin ResistancePenicillin-Binding ProteinsPeptidesPhenotypePlayPopulation AnalysisPredispositionRefractoryRegimenResearchResistanceSepsisSerumSkinStaphylococcus aureusStaphylococcus aureus infectionSupplementationSyndromeTestingTherapeuticTimeTissuesantimicrobial peptidebeta-Lactam Resistancebeta-Lactamsbonecardiac devicecathelicidin antimicrobial peptideclinical translationdesignin vitro testingin vivoin vivo Modelmethicillin resistant Staphylococcus aureusmutantneutrophilpathogenprototyperesistant strainsmall moleculestandard of caretranscriptome sequencing
中文摘要
摘要
耐甲氧西林金黄色葡萄球菌(MRSA)是两种侵袭性感染的主要原因
社区获得的和医院相关的环境。根据标准,MRSA菌株具有内在耐药性
对β-内酰胺类抗生素的体外药敏试验。与此相反,甲氧西林敏感的S.金黄色葡萄球菌(MSSA)
菌株仍然对许多标准护理β-内酰胺(例如苯唑西林;萘夫西林;头孢唑啉)高度敏感。
不推荐β-内酰胺类药物治疗MRSA感染:i)MRSA β-内酰胺MIC高于
当前CLSI“折点”; ii)它们与青霉素结合蛋白(PBP)2a(主要
MRSA菌株中负责细胞壁合成和分裂的PBP); iii)使细胞壁饱和所需的β-内酰胺水平
PBP 2a超过用标准临床剂量方案实现的人血清水平;和
实验性MRSA感染(例如,心内膜炎)与β-内酰胺类药物的联合使用通常无效。
几个实验室最近表明,标准MIC测试介质的重碳酸盐稀释可以
在体外使一些(但不是全部)MRSA菌株对β-内酰胺和宿主防御肽(例如,LL-37从
嗜中性粒细胞;皮肤)。此外,在体外表现出“碳酸氢盐响应性”表型的MRSA菌株(即,
在标准培养基中β-内酰胺耐药,但在含碳酸氢盐培养基中敏感)有效地
在鼠菌血症模型中用选定的β-内酰胺根除。我们使用四个放大这些观察结果
原型MRSA菌株(LAC-USA-300; COL [USA 100] ; MW-2 [USA 400]; BMC 1001 [USA 300],
证明了以下关键结果:i)所有菌株在体外标准(MHB)中对以下两种都具有抗性:
苯唑西林(OX)和头孢唑啉(CFZ);两种菌株在碳酸氢盐-
补充MHB,变得对两种β-内酰胺高度敏感,而两种没有; ii)两种碳酸氢盐-
在群体分析中,响应菌株为异型,而另外两个菌株为同型(AUC
> 0.9); iii)两种碳酸氢盐响应性菌株均被OX和
CFZ在实验性心内膜炎(IE),而两个碳酸氢盐无反应菌株是难治性;
和iv)碳酸氢盐影响mecA-pbp 2a和sarA-sigB遗传途径。
目前的建议将调查:i)碳酸氢盐反应表型的范围在体外,
β-内酰胺类抗生素在临床MRSA菌株的较大集合中的应用; ii)此类抗生素的整体大规模可翻译性
侵袭性MRSA感染(IE)的相关体内模型的体外指标;和iii)潜在的机制
MRSA中的碳酸氢盐反应性。该提案可为关键临床试验奠定基础
利用碳酸氢盐评估改良MRSA对β-内酰胺类体外试验的可预测性
补充标准培养基。这项研究具有从根本上改变
目前MRSA对β-内酰胺类抗生素的体外药敏试验方法。
英文摘要
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of invasive infections in both
community-acquired and hospital-associated contexts. MRSA strains are intrinsically resistant by standard
in vitro susceptibility testing to β-lactam antibiotics. In contrast, methicillin-susceptible S. aureus (MSSA)
strains remain highly susceptible to many standard-of-care β-lactams (e.g. oxacillin; nafcillin; cefazolin).
β-lactams are not recommended for treating MRSA infections: i) MRSA β-lactam MICs are above
current CLSI “breakpoints”; ii) they bind relatively poorly to penicillin-binding protein (PBP) 2a (predominant
PBP in MRSA strains responsible for cell wall synthesis and division); iii) β-lactam levels required to saturate
PBP 2a exceed human serum levels achieved with standard clinical dose-regimens; and iv) treatment of
experimental MRSA infections (e.g., endocarditis) with β-lactams are generally ineffective.
Several labs recently showed that bicarbonate supplemention of standard MIC testing media can
“sensitize” some (but not all) MRSA strains in vitro to β-lactams and host defense peptides (e.g., LL-37 from
neutrophils; skin). Further, MRSA strains exhibiting a “bicarbonate- responsive” phenotype in vitro (i.e.,
β-lactam-resistant in standard media, but susceptible in bicarbonate-containing media) were effectively
eradicated in murine bacteremia models with selected β-lactams. We amplified these observations using four
prototype MRSA strains (LAC-USA-300; COL [USA 100] ; MW-2 [USA 400]; BMC1001 [USA 300] which
demonstrated the following key outcomes: i) all strains were resistant in vitro in standard (MHB) to both
oxacillin (OX) and cefazolin (CFZ); two strains exhibited a bicarbonate-responsive phenotype in bicarbonate-
supplemented MHB, becoming highly susceptible to both β-lactams, while two did not; ii) two bicarbonate-
responsive strains were heterotypic on population analyses, while the other two strains were homotypic (AUCs
> 0.9); iii) both bicarbonate-responsive strains were effectively cleared from all target organs by both OX and
CFZ in experimental endocarditis (IE), while two bicarbonate-nonresponsive strains were refractory to therapy;
and iv) bicarbonate impacted both the mecA-pbp2a and sarA-sigB genetic pathways.
The current proposal will investigate: i) the scope of the bicarbonate-responsive phenotype in vitro to
β-lactams among a larger collection of clinical MRSA strains; ii) the overall large-scale translatability of such
in vitro metrics to a relevant in vivo model of invasive MRSA infection (IE); and iii) the mechanism(s) underlying
bicarbonate-responsiveness in MRSA. This proposal could lay the foundation for pivotal clinical trial(s)
assessing predictability of modified in vitro testing of MRSA to β-lactams, utilizing bicarbonate
supplementation of standard media. This research has the overarching potential to fundamentally transform
current MRSA in vitro susceptibility testing methods for β-lactams.
期刊论文(5)
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会议论文
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批准号:10543433
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项目类别:
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资助金额:$45.08万
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财政年份:2019
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负责人:YAN Q. XIONG
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依托单位:
The role of purine biosynthesis and stringent response in persistent MRSA endovascular infections
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批准号:10307524
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项目类别:
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资助金额:$45.08万
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财政年份:2019
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负责人:YAN Q. XIONG
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依托单位:
Early agr Activation is a Key Pathogenic Signature in Persistent MRSA Bacteremia
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批准号:8416324
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项目类别:
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资助金额:$20.66万
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财政年份:2012
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负责人:YAN Q. XIONG
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依托单位:
Early agr Activation is a Key Pathogenic Signature in Persistent MRSA Bacteremia
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批准号:8224120
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项目类别:
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资助金额:$18.3万
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财政年份:2012
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负责人:YAN Q. XIONG
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依托单位:
海外基金