Microecology

To understand the microecology (pathophysiology) of a virus within a macroecosystem, some small indications might be obtained from the organ, tissue, and even specific cell predilection of a virus.

From: Viral Ecology , 2000

The Developing Intestinal Microbiome

Josef Neu, , ... Volker Mai , in Avery's Diseases of the Newborn (Ninth Edition), 2012

Nutrition And The Developing Intestinal Microbiome

A more specific understanding of the neonatal intestinal microecology as it relates to inflammatory mechanisms may lead to measures that can prevent diseases. In the premature infant, the reliance on parenteral nutrition while providing few or no enteral nutrients may be highly significant in the promotion of intestinal inflammation, because the presence of enteral nutrients can prevent gut-derived inflammation (Kudsk, 2002). Whether this is partially due to stimulation of commensal bacterial growth is speculative. Several in vitro studies have shown that probiotics (live, heat-killed, and DNA from probiotic bacteria) can downregulate intestinal IL-8 production (Bai et al, 2004; Jijon et al, 2004; Li et al, 2009; Lopez et al, 2008; Ma et al, 2004; Rachmilewicz et al, 2004; Zhang et al, 2005) induced by proinflammatory stimuli such as LPS.

Human milk contains a wide array of biologically active components. The growth of pathogenic bacteria and viruses is known to be inhibited by proteins such as lactoferrin, secretory IgA, and peptides formed from human milk during digestion (Lonnerdal, 2004). Human milk is an important factor in the initiation, development, and composition of the neonatal gut microbiota. It has been found to be a significant source of lactic acid bacteria that appear to be of endogenous origin and not contaminants from the breast skin (Martin and Walker, 2006; Perez et al, 2007). The lactobacillus isolated from milk of healthy mothers is phylogenetically related to strains commonly used in commercial probiotic products and shares characteristics such as survival in GI tract conditions, production of antimicrobial compounds, adherence to intestinal cells, production of biogenic amines, and patterns of antibiotic resistance. Among the numerous substances present in human milk, some of the oligosaccharides have a prebiotic effect, stimulating the development of bifidobacteria in the colon (Coppa et al, 2004). Breastfed infants, unlike those who are formula fed, have an intestinal ecosystem characterized by a strong prevalence of bifidobacteria and lactobacilli (Bourlioux et al, 2003; Saavedra, 2001). Human milk can be considered a synbiotic (Coppa et al, 2004), because it contains live beneficial bacteria (probiotics) as well as nutrients that can enhance their growth (prebiotics).

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Microbiota of the Intestine: Probiotics

M. Gueimonde , S. Salminen , in Encyclopedia of Human Nutrition (Third Edition), 2013

Intestinal Microecology and Cancer

A number of studies have focused on the impact of probiotics on intestinal microecology and cancer. L. acidophilus, L. casei Shirota strain, and LGG have been shown to have inhibitory effects on chemically induced tumors in animals. Some specific strains of probiotic bacteria are able to bind carcinogens and to downregulate some microbial carcinogenic enzymatic activities. This phenomenon may then reduce carcinogen production and exert a beneficial effect in the colon, the urinary tract, and the bladder.

The most interesting documentation is that concerning on L. casei Shirota. There have been several mechanistic studies on the effects of the strain reporting decreased mutagen excretion, and some human clinical studies have been conducted using this strain. In clinical and multicentre studies carried out in Japan, prophylactic effects of oral administration of L. casei Shirota on the recurrence of superficial bladder cancer have been reported. Recently, a large Japanese case control study has been conducted on the habitual intake of lactic acid bacteria and risk reduction of bladder cancer. Results suggested that the habitual intake of fermented milk with the strain reduces the risk of bladder cancer in the Japanese population. More studies, and especially human studies also in other countries, are needed before the establishment of firm conclusions.

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Biofilm Formation Under In Vitro Conditions

Claudia Trappetti , Marco R. Oggioni , in Streptococcus Pneumoniae, 2015

Pneumococcal Biofilm Models

Bacteria living in biofilms are phenotypically distinct from their planktonic counterparts, and so far much of our understanding of biofilm physiology and micro-ecology originates from experiments using in vitro biofilm models. Various in vitro models have been developed for pneumococcal biofilm growth. The first published biofilm model was a Sorbarod biofilm [11]. A Sorbarod consists of a paper sleeve containing compacted cellulose fibers placed in a silicone tube and connected via a plastic adaptor to a sterile glass tube. This simple model of biofilm was used to establish a continuous bacterial culture for over 12   h and to test its susceptibility to various antibiotics. This model system also allowed the finding that capsule-off mutations are selected in biofilms [12].

The continuous-flow reactor, established in 2004, is one of the most popular biofilm model systems. This "open" system, which allows continual replenishment of fresh nutrients, permits the formation of biofilm under a wide range of flow rates and nutrient conditions over extended periods of incubation [13,14]. This model is commonly used to study the development of mature biofilms and assess changes in the growth environment or specific genetic mutations to the structure of mature biofilms, detachment from biofilms, spatial and temporal gene expression, and, most importantly, the distribution of extracellular polymeric substances. Still, in vitro biofilms cannot be considered universally valid as an in vitro model for disease. The group of Carlos Orihuela clearly showed that using a continuous-flow-through line model, sessile bacteria were highly attenuated in experimental invasive disease models, possibly suggesting a better correlation to bacteria during colonization [15].

In addition to these systems, two static microtiter models were set up exploiting either high inocula in poor media [6,16] or low inocula in rich media [4,17] using plastic supports. This technique simplifies biofilm formation and quantification, allowing analyses of high numbers of laboratory samples. The use of plastic supports permits the study of early biofilm stages up to 24   h; however, if the growth medium is replenished daily, biofilms can also be maintained for up to 3–4 days. Moscoso et al. determined that the optimal conditions for biofilm formation of S. pneumoniae on abiotic surfaces were obtained when polyvinyl chloride plates were used [16]. In addition, they found that either a chemically defined (Cden or CDM) or semisynthetic (C) medium supported strong biofilm formation, whereas growth in a complex medium, such as CAT or Todd–Hewitt broth, resulted in weak biofilms. In C medium, the number of adherent cells reached a maximum after 8   h of incubation at 34°C. Oggioni et al. performed a biofilm time course experiment using the rich tryptic soy broth (TSB) media, where low-inoculum bacteria were grown on flat-bottom polystyrene tissue culture plates in the presence or absence of pneumococcal competence-stimulating peptide (CSP) at various concentrations (0–300   ng/mL). After the initial background attachment of a few cells upon inoculation, pneumococci attached quite abruptly to the solid support during the late exponential phase of growth. The stability of biofilm in this model was found to be dependent on a functional competence system, which, in response to exogenous CSP added to the medium, allowed for the formation of stable biofilms; this was also observed at 24   h [4]. CSP concentration for biofilm formation showed a narrow optimum condition in a range similar to that of inducing maximal competence in planktonic cells. The biofilm-competence dependence was not confirmed for microtiter models based on a more steady state of growth as continuous culture biofilm or the microtiter model in poor medium [18]. In vitro biofilm formation using microtiter plates was more recently evaluated at 6, 12, 18, and 24   h of incubation in TSB media in presence of glucose. The authors found that biofilm growth was also independent of exogenously added stimulating peptide and medium replacement. Instead, the best results were obtained after 18   h in the presence of 1% glucose. The authors proposed a correlation of the findings with the clinical biofilm disease common in hyperglycemic patients, where high concentrations of glucose in the blood can worsen systemic bacterial infection [19]. More solid are investigations that link distinct aspects of in vitro biofilms to disease and that describe lack of correlation to invasive disease potential [20,21].

Lately, Marks et al. emphasized the importance of using epithelial cells as a support for streptococcal biofilm formation, providing a better platform for bacteria to form a more mature and structured biofilm. Fixed tissue cultures are able to maintain the adhesive ability of the cells, and streptococcal biofilm formed on this substrate shares the same morphology and architecture with biofilm formed in the nasopharynx of infected mice. Moreover, biofilms formed on epithelial cells have the ability to initiate faster attachment than the glass support; after 6   h a specialized architecture matrix-like formation could be detected [22].

Selection of the appropriate in vitro biofilm model system depends not only on the preferences of the investigators and the resources available, but most importantly on the issues to be investigated. The primary advantage of the microtiter plates method is that its relatively high throughput capacity enables screens for mutants defective in attachment and evaluation of the effects of different treatments or compounds on attachment or biofilm formation. However, this method is less well suited to studies of biofilm structure or of antimicrobial resistance properties. On the other hand, flow cells are capable of creating a uniform and constant environment for in vitro purposes. Furthermore, the regulatory processes of biofilm elaboration are cyclical and dynamic, and the external stimuli, normally present in the host, trigger alterations in the expression of a subset of genes required for biofilm formation; thus, the current state of technology is still a distant representation of the dynamics of the host environment in vivo.

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Macroecology and Microecology of Viruses of Terrestrial Mammals

CHARLES H. CALISHER , FRANK J. FENNER , in Viral Ecology, 2000

IV. EFFECTS OF VIRUSES ON VERTEBRATE AND ARTHROPOD POPULATIONS

If viruses have evolved as "renegade genes" in certain cells, it would be no mystery as to why they are so well adapted to those cells and to the general milieu in which those cells are found, their microecology. If viruses arose extracellularly, or at least not from the cells in which they are found, and have simply adapted as parasites of those cells, again it is no wonder they are found there. Whether by parallel evolution or coevolution in which, respectively, the virus and host happen to evolve together or evolve interdependently, the fact of virus evolution is clear.

Pathogen evolution likely has been influenced by the internal (and by inference the external) environment of the vector, certainly the arthropod vector in the case of arboviruses. Whether obvious or not, mammalian biology must be influenced by the presence of a virus, whether as a pathogen or nonpathogen (e.g., mammalian host behavior, body temperature, antibody production, or for vaccine use).

Arthropod hosts may be preferred sites for arboviruses to evolve. Persistent infection is common in competent arthropods, and such persistence is conducive to the accumulation of intramolecular genomic alterations and the accumulation of spontaneous mutations (Beaty et al., 1997). It would seem likely that the longer a virus–host relationship occurs, the less incompatible the relationship.

Most virus infections of mammals lead to subclinical infections. This seems to be the case with virus infections of arthropods, but even slight changes due to virus infection can have significant consequences. For example, virus infection may alter the capacity of the arthropod to transmit the virus, and such infections may affect arthropod feeding behavior, survival, and fertility (Platt et al., 1997).

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Induction and modulation of inflammatory networks by bacterial protein toxins

Steffen Backert , ... Brigitte König , in The Comprehensive Sourcebook of Bacterial Protein Toxins (Third Edition), 2006

Microecology

As long as gene therapy is not yet available, antimicrobial treatment must be optimized, along with measures for the prevention of early infection and the transmission of the pathogens among CF patients. These measures largely rely on the knowledge of the microbial status of the CF patient at all times. CF is dominated by the presence of microbial biofilm formation; the expression and release of microbial pathogenicity factors and toxins are modulated by the cooperative interaction of the microorganisms. Molecular biological methods seem to be appropriate for a more precise analysis of microbial pathogenicity.

Recently, we described the so called T-RFLP method (Terminal Restriction Fragment Length P olymorphisms) for the complete qualitative and quantitative analysis of the respiratory microecology ( Trotha et al., 2002). The method allows us to track static and dynamic changes in the microbial communities under antibiotic therapy; thus, a better knowledge of interactions between commensal and/or pathogenic microbes with each other and with the human host is obtained. We used model microbial communities consisting of CF relevant microorganisms, e.g., P. aeruginosa, S. aureus, Klebsiella pneumoniae, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxydans, and Mycobacterium abscessus. Fifty-one sputum samples from 15 patients suffering from cystic fibrosis at different stages of disease and antibiotic therapy were analyzed. Our extended studies showed the changes in the microbial pattern after antibiotic treatment (Figure 54.7). This technique will also allow us to determine the fluctuating pattern of microbial communities, the formation of biofilms, as well as of the regulation of bacterial toxin production. In this regard, the virulence of S. aureus is dependent on the temporal expression of a diverse array of virulence factors, including both cell-associated products, such as protein A, collagen- and fibronectin-binding protein, and secreted products including lipases, proteases, alpha-, beta-hemolysin, and the respective superantigens. We studied to what extent P. aeruginosa is able to modulate the expression of staphylococcal SAGs, e.g., enterotoxin A. Both microorganisms were co-cultured over various times, and the expression pattern of staphylococcal SEA-specific mRNA was analyzed, representative for the classical superantigens. We have clearly shown that the presence of P. aeruginosa at increasing concentrations down-regulated the SEA-mRNA expression of S. aureus prior to a decrease of the colony-forming units of S. aureus (Figure 54.8).

FIGURE 54.7. Therapy-related changes in the T-RFLP pattern of CF sputum samples.

The T-RFLP pattern in the sputum samples from one individual CF patient at the beginning of antibiotic therapy and at 3, 9, and 14 days after the onset of antibiotic therapy was determined. The 155 bp peak for P. aeruginosa, as well as the peaks for the Clostridium and Streptococcus ssp. clusters, are decreasing during antibiotic therapy. The 98 bp internal quantification standard is not influenced by the antibiotic therapy

FIGURE 54.8. Pseudomonas aeruginosa—Staphylococcus aureus interaction.

S. aureus bacteria were cultivated in the absence or in the presence of P. aeruginosa PAO1 (10:1; 3:1) in a total volume of 10ml for up to 6h in Lydia broth medium at 37°C with gentle agitation. After the indicated time intervals, a) the colony forming units of S. aureus as well as of P. aeruginosa were determined; b) total RNA was prepared and the staphylococcal enterotoxin A specific (SEA) mRNA copies were determined by quantitative real-time RT-PCR. Values represent SEA-specific mRNA copies per ml culture.

At present, we focus on multimicrobial cultures by applying chemostat procedures for biomodeling purposes. Mathematical models will predict the microbial disease status, the pathogenicity profile of the relevant microorganisms, and the efficacy of treatment in CF patients, but also in other infectious diseases. Thus, toxin-mediated cellular and cell-biological events can be exactly quantitated and evaluated in the future.

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Gastrointestinal Microbiology in the Normal Host☆

Menghui Zhang , ... Liping Zhao , in Encyclopedia of Microbiology (Fourth Edition), 2019

Succession of Flora in Infants

The GI tract is sterile at birth and the colonization of GI microbiota undergoes dramatic changes in composition during the first year of life. Facultative aerobes (Enterobacteriaceae, Enterococcus, and Streptococcus) first colonize the neonatal gut at birth due to the presence of abundant oxygen in the gut, but once the oxygen is used up by these facultative aerobes, obligate anaerobic genera (Bifidobacterium, Bacteroides and Clostridium, etc.) take the place and predominate in the suckling period (Vael and Desager, 2009). The composition of gut microbes is less complex but more dissimilar among newborns (Backhed et al., 2015). During the weaning process, supplying solid foods causes a significant shift in the infant gut micro-ecology (Fanaro and Vigi, 2008), and finally a gut microbiota broadly similar to that of adults is established by the age of 1 year (Palmer et al., 2007).

Delivery mode, feeding type and mothers' gut microbiota affect the composition of the newborns' gut microbiota. Compared to babies delivered by C-section who receive the skin, mouth and environmental bacteria randomly as the seeds for their gut microbiota, the babies delivered vaginally get the first inoculum for their gut microbiota from the bacteria present in the birth canal of the mothers, so babies delivered naturally develop healthier gut microbiota with important microbes such as Bacteroides and Bifidobacterium (Backhed et al., 2015; Dominguez-Bello et al., 2010).

Breast milk is an ideal source for the babies' commensal microbiota and continuous promoter for beneficial gut bacteria since it contains both probiotics derived from the mothers' intestine and prebiotic oligosaccharides that promote the growth of beneficial probiotics (e.g., Bifidobacterium) (Martin et al., 2003, 2012; Coppa et al., 2006). The gut microbiota of breast-fed infants is dominated by Bifidobacterium, which is considered protective for infant health (Rivero-Urgell and Santamaria-Orleans, 2001). In contrast, the gut of formula-fed infants, who have a higher incidence of infections, is colonized by an adult-type gut microflora in which Bacteroides, Clostridium, Bifidobacterium, Lactobacillus, Gram-positive cocci, coliforms, and other groups are all predominantly represented (Gad, 2007). The weaning process is the major driving force of the succession of gut microbiota in infants, resulting in the enrichment of Roseburia, Clostridium, Anaerostipes etc. However, such compositional and functional shift of gut microbiota does not happen even though solid food has been introduced to infants, until the breast-feeding is entirely stopped. The breast-feeding has been shown to be associated with the adult microbiota community type and may influence the life-long profiles of metabolic and immune systems (Ding and Schloss, 2014).

The gut microbiota established in first years of life plays a fundamental role in the host health not only in infancy but also in childhood and adulthood by affecting the digestion and nutrition, modulating the maturation of the immune system, resisting pathogens, influencing the energy storage and obesity, and even affecting the behavior of host through the metabolism of vitamins, iron, and amino acids that are essential for the development of neuro and brain (Vael and Desager, 2009; Fanaro and Vigi, 2008; Hsiao et al., 2013; Diaz Heijtz et al., 2011).

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Application of Intestinal Flora in the Study of TCM Formulae

Xianpeng Zu , ... Weidong Zhang , in Systems Biology and its Application in TCM Formulas Research, 2018

5.4.2.3 Other TCM Preparations

The Shenfu injection can protect the rat intestinal mucosa barrier in acute necrotizing pancreatitis through inhibiting the expression of NF-κB in the intestine and reducing the generation of proinflammatory regulators (i.e., TNF-α, ICAM-1, and iNOS). 65 Zhao 66 established a rat model of severe acute pancreatitis (SAP) by retrograde injection of 3.5% sodium taurocholate through the cholangio-pancreatic duct. Using this model, this group found that Qingyi particles can reduce pancreatic injury and the permeability of the intestinal mucosa as well as protect the intestinal mucosal barrier of rats with SAP.

Mutualistic and symbiotic intestinal microorganisms and their hosts have been involved in coevolution processes for millennia. These microorganisms continuously exchange material and information with the host, resulting in the formation of an interdependent and tightly controlled intestinal microecosystem. With the development of methods to examine interplay between this microecology and modern Chinese medicine, there is growing recognition of the close relationship between the intestinal flora and the corresponding health or illness of the host. Once the dynamic equilibrium of the intestinal microecosystem is broken, the intestinal flora will lose balance and allow the entry of pathogenic disease-associated organisms. The traditional medicines of China have gradually gained worldwide acceptance because of their reduced incidence of adverse reactions and lack of drug resistance or tolerance with long-term use. The theory of TCM emphasizes understanding the human body at the integral level and carrying out treatment based on physiological syndromes with treatments guided to a holistic approach to medicine in order to prevent and treat disease. The intestinal flora, the biggest microecosystem in the superorganism of the human body, has been found to have an inevitable connection with TCM. Therefore some scholars have suggested that the intestinal flora may be the potential target for many of the effects of TCM on disease.

The recent rapid development of various omics technologies, such as transcriptomics, proteomics, metabolomics, and metagenomics provides great convenience for researchers to study the interactions of effective TCM ingredients and intestinal flora. It is estimated that 99% of nature's bacteria cannot be readily cultured in vitro. However, metagenome sequencing techniques can not only acquire the composition and genetic functioning information of the flora but also identify specific bacteria associated with diseases. 67 Metabolomic technologies can help reveal the close relationships between the intestinal flora and the TCM metabolism, find potential metabolic markers, and identify key functional bacteria required for the TCM metabolism. These methods can provide valuable clues to increase our understanding of the mechanistic basis action of TCM at the multiingredient, multitarget, and multilevels. However, metagenomics analysis does not easily distinguish between those genes that are expressed and nonexpressed genes. Therefore, the application of transcriptomics and proteomics becomes necessary to provide additional context. Eventually, the combined use of multiple "omics" technologies will be needed to further clarify the material basis of TCM's efficacy and distinguish the potential role(s) of the intestinal bacteria-mediated molecular mechanisms associated with TCM use (Fig. 5.7).

Fig. 5.7. Research strategies for studying the mechanism of action of TCM based on multiomics techniques.

The intestinal flora is composed of a large number of microorganisms that are indispensable to the human body; it dramatically affects or may even determine the efficacy and toxicity of TCM. Components in TCM formulae function, at least in part, by regulating the balance of the intestinal microecosystem. In-depth research on the interactions of TCM with the intestinal bacteria will contribute to our appreciation of the metabolism, absorption, and toxic effects following oral TCM administration as well as help us clarify the functional material basis of TCM mechanisms. Such research can also guide the development of intestinal flora-oriented personalized medicine preparations and rationally designed clinical medication combinations, thus providing new research ideas and methods for modern TCM research and new drug development.

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Infections in the Immunocompromised Host

J. Peter Donnelly , ... Walter J.F.M. van der Velden , in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015

Skin

Healthy skin provides an effective barrier against invasion by microorganisms, mainly by remaining intact. Desquamation helps limit the opportunities for transient organisms to establish residence. Normally, very little water is present on the skin surface. Colonization with organisms sensitive to desiccation, such as gram-negative bacilli, is not favored. The skin also forms an acid mantle with a pH of 5.0 to 6.0, and its surface temperature is on average approximately 5° C lower than the core body temperature. 19 Besides containing secretory IgA, sweat also possesses sufficient salt to create a high osmotic pressure. Organisms that can withstand these conditions and compete successfully for binding sites and nutrients include staphylococci, corynebacteria, and the lipophilic yeast Malassezia furfur. 19 These organisms further modulate the microecology of the skin by releasing fatty acids from sebaceous secretions to produce a hydrophobic milieu as well as lactic and propionic acids, which help maintain a low pH. Many of the bacteria also elaborate bacteriocins that inhibit other microorganisms.

The composition of the skin microflora is influenced by general factors including climate, body location, age, sex, race, and occupation, as well as by the use of soaps, detergents, and disinfectants. Antibiotics secreted in sweat disturb the balance within the commensal microbiota and leave the surface vulnerable to colonization by exogenous gram-negative bacilli. Antibiotics also exert selective pressure on the skin microbiota and cause resistance to emerge, as has been observed during treatment with ciprofloxacin. 20 Moreover, ciprofloxacin is excreted in sweat and induces resistance among skin staphylococci within a few days of exposure. 21,22 β-Lactam antibiotics, including ceftazidime, ceftriaxone, cefuroxime, benzyl penicillin, and phenoxymethylpenicillin (penicillin V), can also be found in sweat, which might explain the ready selection of resistant staphylococci. 23 Chemotherapy and irradiation can cause radical changes in healthy skin that cause hair loss, dryness, and loss of sweat production.

Needle punctures and catheters provide a ready means of access for microorganisms through the stratum corneum and into the bloodstream. When the skin is broken, the release of fibronectin is thought to assist colonization with Staphylococcus aureus, whereas other changes facilitate colonization with gram-negative bacilli such as Acinetobacter baumannii and enteric bacteria. Abraded skin can lead to local infection, which can be a reservoir that promotes further spread to entry sites of intravenous catheters. When the balance is lost between host defenses and commensal microbiota around hair follicles, the follicles can become inflamed and necrotic and form a potential nidus of infection. Clinical infection therefore results from breaks in the skin, loss of local immunity, and disturbances within the resident microbiota.

Vascular devices have gained widespread acceptance as a relatively safe form of long-term venous access, but regular use is associated with a marked increase in the incidence of bacteremia with coagulase-negative staphylococci, which frequently colonize the catheter lumen (see Chapter 302). 24,25 These staphylococci are commonly resistant to aminoglycosides, trimethoprim-sulfamethoxazole, and penicillinase-resistant penicillins and may also be resistant to fluoroquinolones. 26 Unless the catheter ends in an implanted port, skin commensal microbiota have potential access into the bloodstream. The hub is the most likely source of contamination leading to catheter colonization, 27 and the risk increases with use. 28 Infections related to the external surface of the catheter (exit site infections and tunnel infections) can result in serious soft tissue infection, most notably by S. aureus. Exit site infections occur much less frequently than does intraluminal con­tamination. The latter may be caused by a variety of bacteria, many of which have relatively low virulence. Once established, these infections can be very difficult to treat without removing the device, particularly those caused by Bacillus spp., Candida spp., and Pseudomonas aeruginosa. 29-32,33

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Hepatic Encephalopathy

A.S. Basile , K.D. Mullen , in Encyclopedia of Neuroscience, 2009

Therapy

Therapeutic strategies for allaying the manifestations of HE may focus on the target organ, the CNS, and the gut. Current, standard therapeutic regimens are directed at reducing ammonia production and absorption from the gut. Restricting oral protein consumption in order to reduce a source of ammonia was a primary treatment for decades, but is now discouraged because it aggravates lean body wasting in cirrhosis. Another approach to reducing gut ammonia production from dietary sources is to prescribe less encephalopathogenic, vegetable-based protein diets. Nonabsorbable antibiotics and cathartics (lactulose and lactitol) have also been used to reduce ammonia production and absorption. In addition to its antibiotic actions, neomycin may reduce ammonia production by inhibiting intestinal glutaminase. Bacterial overgrowth in the small intestine and other disturbances of the microecology of indigenous gut flora are common in cirrhosis, and may impact toxin/ammonia production. The ammonia-lowering actions of lactulose/lactitol may be due in part to their effects on gut flora. However, despite their widespread use, controlled trials have indicated that lactulose/lactitol and neomycin therapies are not superior to placebo in the treatment of HE. The utility of these agents in the treatment of HE is currently being reassessed using randomized, placebo-controlled trials. Similarly, the efficacy of modulating intestinal flora, such as through the administration of Enterobacter faecium SF 68, in treating HE is receiving renewed interest.

Another mode of therapy is to enhance the excretion of waste nitrogen from the body in patients with liver failure. Sodium benzoate, phenylacetate, and l-ornithine-l-aspartate (LOLA) promote this process through a variety of mechanisms. LOLA may improve HE by lowering ammonia levels and suppressing ammonia-induced neurotoxicity by stimulating urea cycle function. Moreover, LOLA is more effective than placebo in clinical trials.

Other therapies for HE shown to be effective in placebo-controlled trials include acarbose and the centrally acting benzodiazepine receptor antagonist, flumazenil. There are a number of anecdotal reports of the efficacy of flumazenil in treating patients suffering from HE. It has been claimed that the reversal of coma by flumazenil in these reports reflects the abuse of benzodiazepines by patients with liver disease. However, these claims do not take into account that endogenous benzodiazepine receptor ligands have been found in multiple animal models of HE. Moreover, a number of placebo-controlled trials of the efficacy of flumazenil in controlled patient populations have been conducted. Typically, low doses (1–5   mg) of flumazenil reverse HE in 30% of patients within 0.5–5   min of administration. In a meta-analysis of 12 randomized trials, eight with cross-over design, flumazenil was associated with a significant improvement of HE (30%) compared to placebo (7%), particularly in a subpopulation of patients with low-grade encephalopathy. While no follow-up therapy was employed in these studies, long-term suppression of HE has been reported with chronic oral administration of flumazenil (25   mg). Development of a long-acting, orally available form of a benzodiazepine antagonist should enhance the use of this therapy for HE.

Finally, can the evidence implicating ammonia in the enhancement of GABAergic neurotransmission be used to develop therapeutic modalities for treating HE? An agent that can reverse ammonia's enhancement of GABA and benzodiazepine receptor function with minimal convulsant activity would be desirable. Such an agent may be an antagonist of the neurosteroid-binding site on the GABAA receptor complex, such as pregnenolone. As previously noted, ammonia enhances the binding of [3H]flunitrazepam. Performing these assays in the presence of pregnenolone sulfate completely abolished the ability of ammonia to enhance the binding of [3H]flunitrazepam. Similar effects were seen on ligand binding to the GABA site on the GABAA receptor complex. These preliminary observations suggest a potential use for neurosteroid antagonists in reversing some of the psychomotor symptoms of HE. Interestingly, present therapeutic protocols aimed at reducing ammonia levels by restricting dietary intake and modifying colonies of enteric bacteria may also reduce the synthesis or uptake of benzodiazepine receptor ligands or their precursors.

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The Potential Use of Bacteriophage Therapy as a Treatment Option in a Post-Antibiotic Era

R.R. Bragg , ... L. Meyburgh , in Antibiotic Resistance, 2016

Advantages of Phage Therapy Over Antibiotic Treatment

One of the key features of phages to be used in therapy is the specificity with which they infect bacterial cells, to such an extent that certain phages only attack specific strains within a species. 25 This contrasts the mode of operation observed in antibiotics, which work broadly against either Gram-negative or Gram-positive bacteria, regardless of pathogenicity. This can often lead to gaps in the host microecology, which promotes colonization by other potentially more pathogenic bacteria, causing secondary infections. The narrow host range displayed by phages can be advantageous, as beneficial bacteria are not disturbed during administration. Specificity is mainly determined by the ability of phage receptors to recognize host target proteins involved in adsorption during initial stages of infection.

In addition, the specificity of phages means that they show negligible toxicity toward host cells, other than some rare, reversible allergic reactions. In 1987, researchers reported a less than 3% occurrence of allergic reaction to phage administration in a group of 138 human patients 26 ; however, these allergic reactions were fully reversible. By contrast, several antibiotics can cause multiple side effects, including fatal allergies and permanent tissue damage, particularly when applied in high doses. 27 Phages also have the added advantage of remaining in the environment in a dormant state until their hosts are available for replication.

The vascular dissemination of intravenously administered phages has been demonstrated, 28 which is ideal when treating localized infections in different parts of the body. This is an obvious advantage over certain antibiotics, which only reach specific organs during treatment. Phages have also been effective in penetrating biofilms layer by layer as they infect, lyse, and proliferate, as opposed to antibiotics that are not able to infiltrate biofilms effectively. 29 Phage therapy has proved effective in the elimination of membrane biofouling caused by antibiotic-resistant Delftia tsuruhatensis biofilms in a prototype lab-scale membrane bioreactor, demonstrating the potential to solve the problem of membrane biofouling in full-scale wastewater treatment plants, as well as pathogenic biofilms on medical devices. 30

Phage therapy has more longevity potential than antibiotics, due to lower occurrences of resistant strains, since bacteria have 10-fold less probability of becoming resistant to phages than to antibiotics. 24 It has been hypothesized that phages naturally evolved alongside their host bacteria. 31 Therefore, if a bacterium develops resistance to a phage, the phage could adapt through mutation and evolve to once again infect the resistant bacterium, as opposed to antibiotics that obviously cannot adapt. In addition, there is likely to be a number of other phages capable of infecting a bacterium that developed resistance to one phage, since phages are ubiquitous in the biosphere—estimated at about 1031 phages 31 —making them readily available for discovery in common and accessible environments. 32 For example, sewerage is an abundant source of phages specific to enteric bacteria, like E. coli phages shown in Fig. 15.3. In contrast, the available number of approved antibiotic compounds available is limited, and the development and especially the approval of new antibiotics are very long processes.

Figure 15.3. E. coli phages BSP (isolated from sewage water in Bloemfontein, Free State, RSA).

Phage therapy is potentially a more sustainable treatment option since phages are self-managing in the sense that they will proliferate as long as there are host cells in an environment. This is in contrast to the need to maintain antibiotic pressure long enough to prevent bacteria from becoming resistant. In addition, phages will remain in the environment in a state of dormancy until their hosts are available for replication.

The safety of phage therapy in immunocompromised individuals has been demonstrated. 33 It has been proposed that phage therapy might be less efficient in immunocompromised patients due to the development of resistance by bacteria, based on the observation of resistant mutants emerging after exposure to phages in certain cases. 17 In immunocompetent individuals, phage-resistant bacteria can be cleared by the immune system following the eradication of phage-sensitive bacteria, whereas these remaining bacteria will be less efficiently cleared in hosts with impaired immunity. 34 Despite these arguments, it has been showed that immunodeficiency could be advantageous to phage therapy owing to the delayed clearance of virions from the body. The half-life of phage T7 in B-cell-deficient mice was shown to be significantly prolonged in comparison to immunocompetent mice. 35

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