多黏菌素的研究进展与临床应用

随着多耐药革兰阴性杆菌不断出现,这类超级细菌对目前除多黏菌素之外其他抗菌药物全部耐药,使临床医师重新关注多黏菌素的应用.目前仅有多黏菌素B和多黏菌素E(黏菌素)用于临床.最近研究与应用较多的为黏菌素.因此,临床医师需要熟悉黏菌素的使用,最大限度提高疗效、降低耐药性的产生和避免不良反应.     

Discovery of a potential MCR-1 inhibitor that reverses polymyxin activity against clinical mcr-1-positive Enterobacteriaceae

The recent emergence of the plasmid-mediated colistin resistance gene mcr-1 poses a substantial clinical threat to the severe infections caused by CRE (Carbapenem Resistant Enterobacteriaceae), as the treatment failure of the mcr-1-positive CRE “Superbug” most likely occurs by using the combination of carbapenem and polymixins. Therefore, our study aims to seek a potent MCR-1 inhibitor to fight this infection. A checkerboard MIC (Minimum Inhibitory Concentration) assay, time-killing assay, MPNP (Modified rapid polymyxin Nordmann/Poirel) test, combined disk test and molecular modelling analysis were performed on different mcr-1-positive strains to confirm the synergistic effects of the combination of colistin and osthole (OST). And a thigh mouse infection model was also used to evaluate such synergies. We identified that OST regained the bactericidal activity of polymyxins (FIC (Fractional Inhibitory Concentration) index?=?0.11±0.04 ? 0.29±0.10) against mcr-1-positive Enterobacteriaceae including Escherichia coli and Klebsiella pneumoniae. The in-vitro time-killing assays showed that either OST or polymyxins failed to eradicate mcr-1-positive Enterobacteriaceae, but the combination eliminated mcr-1-positive Enterobacteriaceae by 3–7-h post-inoculation. The mouse infection model demonstrated that the combination therapy significantly reduced the bacterial load in the thighs following subcutaneous administration. Our results established that OST is a promising natural compound that could be used to extend the life of polymyxins and to tackle the inevitability of serious infections caused by polymyxin-resistant bacteria.     

Convulsions and apnoea in a patient infected with New Delhi metallo-β-lactamase-1 Escherichia coli treated with colistin

There has been a resurgence of interest in the use of colistin for the treatment of multidrug-resistant Gram-negative bacterial infections. A more favorable infection outcome is observed when colistin is used in combination with carbapenems. We present a patient with severe New Delhi metallo-β-lactamase-1 Escherichia coli infection who developed convulsions rapidly followed by acute respiratory muscle weakness and apnoea during treatment with colistin and meropenem. Chromatographic assay showed a "trough" colistin level that was approximately fourfold higher than previously reported maximum steady-state colistin plasma levels in critically ill patients. The patient's renal clearance never necessitated dose adjustments, suggesting that the observed high plasma colistin level might be due to impaired non renal elimination. Although meropenem itself has very low neurotoxic potential, its concomitant use with colistin may have elicited colistin neurotoxicity.     

黏菌素E杀灭钉螺效果的初步研究

目的观察黏菌素E对钉螺的杀灭效果。方法采用室内浸杀法、喷洒法观察黏菌素E 对湖北钉螺的杀螺效果,通过鱼毒试验观察黏菌素E对鱼的毒性作用。结果药物浓度为5．0、1．0 g／L时,分别浸杀24、48 h和72 h,各组钉螺的死亡率均为100％;药物浓度为0．5 g／L时,浸杀24、 48 h和72 h,钉螺死亡率分别为95．00％、100．00％和100．00％;药物浓度为0．1 g／L时,浸杀24、48 h和72 h,钉螺死亡率分别为90．00％、95．00％和100．00％;药物浓度为0．01 g／L,浸杀24、48 h和 72 h,钉螺死亡率分别为70．00％、86．00％和100．00％。分别用35、70、140 mg／m2黏菌素E进行喷洒灭螺,钉螺死亡率分别为60．00％、100．00％和100．00％。鱼毒试验显示黏菌素E对鱼的毒性为弱毒性。结论黏菌素E是一种有效的灭螺药物,有进一步研究的价值。     

Successful treatment with intravenous colistin for sinusitis, orbital cellulites, and pneumonia caused by multidrug-resistant metallo-beta-lactamase-producing Pseudomonas aeruginosa in a patient with acute myeloid leukemia

The incidence of multidrug-resistant Pseudomonas aeruginosa (MDRPA) and metallo-beta-lactamase (MBL)-producing P. aeruginosa has increased worldwide. The treatment options are limited for infectious diseases caused by these two organisms. The use of colistin has been of recent interest in cases involving both types. We report the case of a 74-year-old man with acute myeloid leukemia who was successfully treated with intravenous colistin for maxillary sinusitis and orbital cellulites due to MBL-producing MDRPA during neutropenia, and then for pneumonia caused by the bacteria after the recovery of neutrophil counts.     

Amikacin and colistin for treatment of Acinetobacter baumannii meningitis

We report a case of a 52-year-old man with post-surgical meningitis due to a multi-drug resistant Acinetobacter baumannii. Despite therapy with intravenous amikacin and imipenem the meningitis progressed. Upon institution of combination therapy with amikacin by the intravenous and intrathecal (IT) routes, and intravenous colistin the patient experienced successful clinical and microbiological outcomes.     

Successful management of nosocomial ventriculitis and meningitis caused by extensively drug-resistant Acinetobacter baumannii in Austria

Nosocomial infections caused by the Gram-negative coccobacillus Acinetobacter baumannii have substantially increased over recent years. Because Acinetobacter is a genus with a tendency to quickly develop resistance to multiple antimicrobial agents, therapy is often complicated, requiring the return to previously used drugs. The authors report a case of meningitis due to extensively drug-resistant A baumannii in an Austrian patient who had undergone neurosurgery in northern Italy. The case illustrates the limits of therapeutic options in central nervous system infections caused by extensively drug-resistant pathogens.     

Extremely drug-resistant NDM-9-producing ST147 Klebsiella pneumoniae causing infections in Italy,May 2020

A large outbreak of New Delhi metallo-beta-lactamase (NDM)-1-producing Klebsiella pneumoniae sequence type (ST) 147 occurred in Tuscany, Italy in 2018–2019. In 2020, ST147 NDM-9-producing K. pneumoniae were detected at the University Hospital of Pisa, Tuscany, in two critically ill patients; one developed bacteraemia. Genomic and phylogenetic analyses suggest relatedness of 2018–2019 and 2020 strains, with a change from NDM-1 to NDM-9 in the latter and evolution by colistin, tigecycline and fosfomycin resistance acquisition.     

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg + colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg + colistin groups compared to the baseline (p = 0.013 and p = 0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p = 0.005), the creatinine value in the colistin group was significantly higher than the Mg + colistin group (p = 0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p < 0.001). The Mg + colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p = 0.035), renal affected area (p < 0.001), and SQS (p = 0.001) than the Mg + colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.