nvestigating in vitro and in vivo efficacy of antibiotic combinations with the small quinolone-like compound HT61 against pulmonary infections ...

抗菌素耐药性(AMR)的发病率在全球范围内呈上升趋势，并对与医院感染相关的几个不同的患者群体构成重大的生命威胁，特别是那些免疫功能低下的人和重症监护病房(ICU)的患者。对于与肺部感染、败血症和尿路感染(UTI)相关的常见细菌感染，全世界都观察到了对最常用抗生素的高AMR率。例如，革兰氏阴性杆菌肺炎克雷伯菌是肺炎等医院感染的主要原因，在地球上所有地区都对碳青霉烯类等B-内酰胺类抗生素产生了抗药性，一些国家报告称，由于AMR1-3的直接后果，碳青霉烯类抗生素未能对一半以上的肺炎克雷伯菌感染者提供有效的治疗。此外，铜绿假单胞菌与医院和社区获得性感染都有很大关系，其治疗在囊性纤维化(CF)中尤其成问题，因为出现了对妥布霉素耐药的铜绿假单胞菌，目前约有25%-45%的囊性纤维化患者带有MDR铜绿假单胞菌4-5。此外，多药耐药鲍曼不动杆菌在医院获得性感染中是地方性的，在过去30年里一直在全世界观察到。最后，耐多药革兰氏阳性金黄色葡萄球菌是医院感染的另一个主要原因，它导致住院时间延长，现在仅在欧盟7就有15,000名患者在住院患者中常规检测到金黄色葡萄球菌。耐多药病原体的流行增加，再加上新抗生素的短缺以及与之相关的高昂的药物开发成本和使用这些抗生素以获得经济回报的窗口较短，大大减少了可行的抗生素的供应。事实上，一些抗生素现在需要高剂量才能产生与大量不良反应相关的抗菌活性，如氨基糖苷类抗生素妥布霉素。此外，在某些情况下，耐多药病原体的流行使临床症状几乎无法治愈，从而导致生活质量下降和死亡率上升。因此，临床上迫切需要创新的抗生素治疗方法，以保持对AMR持续威胁的抵抗力。值得注意的是，尽管与革兰氏阳性感染(如MRSA)相关的感染威胁继续造成巨大的健康负担，但迫切需要关注革兰氏阴性物种，特别是世卫组织关于AMR8的全球行动计划确定的铜绿假单胞菌、肺炎克雷伯菌和鲍曼不动杆菌。抗生素与抗生素增强剂的组合有望成为多药耐药细菌感染的新治疗方案。先前的研究表明，临床批准的抗生素与抗生素增强剂的联合治疗在体外抗菌活性方面显示出显著的协同作用，但这种协同作用的临床意义还需要进一步研究9-10。我们的研究小组此前已经证明，HT61是一种小的喹诺酮类衍生化合物，对革兰氏阳性MSSA和MRSA有活性，但对革兰氏阴性铜绿假单胞菌没有活性。然而，当联合使用HT61时，其他抗菌剂如庆大霉素、新霉素和莫匹罗星对MSSA和MRSA11的体外活性都会增强。值得注意的是，我们研究小组随后的研究表明，HT61和妥布霉素对耐多药/妥布霉素铜绿假单胞菌RP73和NN212菌株具有显著的协同作用。然而，需要进一步的研究来评估HT61与与CF疗法相关的经典抗生素联合治疗的临床益处，方法是调查这种与更大范围的疾病相关铜绿假单胞菌临床分离株之间的协同作用。

The incidence of antimicrobial resistance (AMR) is increasing worldwide and poses significant life-threatening risks to several different patient populations associated with nosocomial infections, especially those of immunocompromised individuals and those in intensive care units (ICU). For common bacterial infections associated with pulmonary infections, sepsis and urinary tract infections (UTI) high rates of AMR against the most frequently used antibiotics has been observed worldwide. For example, the gram-negative pathogen K. pneumoniae, a major cause of hospital-acquired infections such as pneumonia has developed resistance to B-lactam antibiotics such as carbapenem in all regions of the planet with some countries reporting that carbapenem antibiotics failed to provide effective therapy in more than half of K. pneumonaie infected patients as a direct consequence of AMR1-3. Additionally, P. aeruginosa is heavily implicated in both hospital and community acquired infections and its treatment is particularly problematic in Cystic Fibrosis (CF), due to the emergence of tobramycin resistant P. aeruginosa with approximately 25-45% of CF patients now colonised with MDR P. aeruginosa4-5. Furthermore, MDR A. baumannii is endemic in hospital acquired infections and has been observed worldwide for the past thirty years6. Finally, MDR gram-positive S. aureus is another leading cause of nosocomial infections which contributes to prolonged hospital stays and is now routinely detected in hospital patients contributing to >15,000 patients in the European Union alone7. This increase in the prevalence of MDR pathogens combined with the shortage of new antibiotics and the associated high cost of drug development and short window of their use for financial return has significantly reduced the availability of viable antibiotics. Indeed, some antibiotics now require high doses to elicit antimicrobial activity that are associated with substantial adverse events such as the aminoglycoside antibiotic tobramycin. Furthermore, in some cases the prevalence of MDR pathogens has rendered clinical conditions virtually untreatable and therefore a concomitant decrease in quality of life and increase in mortality. There is therefore an urgent unmet clinical need for innovative approaches to antibiotic therapies which remain resilient to the ongoing threat of AMR. It is important to note that whilst the threat of infections associated with gram-positive infections such as MRSA continue to generate substantial health burdens, there is a critical need for a focus on gram-negative species, notably P. aeruginosa, K. pneumoniae and A. baumanaii as identified by the WHO's global action plan on AMR8. Antibiotic combinations with 'antibiotic enhancers' are promising candidates for novel treatment regimens for MDR bacterial infections. Previous studies demonstrated that combination therapies of clinically approved antibiotics with antibiotic enhancers exhibited significant synergism in their antimicrobial activity in vitro, however the clinical implication of this synergism requires further investigation9-10. Our research team has previously shown that HT61, a small quinolone-derived compound is active against gram-positive MSSA and MRSA but not gram-negative P. aeruginosa. However, when given in combination, HT61 augments the in vitro activities of other antimicrobial agents such as gentamicin, neomycin and mupirocin against both MSSA and MRSA11. Significantly, subsequent studies by our research group have demonstrated preliminary evidence for significant synergism between HT61 and tobramycin against the MDR/tobramycin resistant P. aeruginosa strains RP73 and NN212. However, further research is required to evaluate the clinical benefit of the HT61 combination therapies with classical antibiotics associated with CF therapies through the investigation of this phenomenon of synergism against a larger panel of disease relevant clinical isolates of P.aeruginosa.