*4.9. Hoechst 33342 Staining Analysis*

Treated cells were then washed, harvested, and then fixated using ethanol. After incubation for 20 min, 10 μM Hoechst 33342 staining was added following another 20 min incubation in room temperature. Observation was perform using a fluorescence microscope (Leica DMI6000 B, Wetzlar, Germany).


**Abstract**

This chapter deals with the reuse and recycling of tropical natural fibers and their potential valorization in construction materials in a context of circular economy and sustainable development. These fibers constitute large volumes of fibrous waste resulting from various agro-food industries worldwide. Depending on their intrinsic qualities and properties (physical and mechanical), they can be reused as reinforcing material in cementitious mixes (hardened mixes) or mixes with soils (raw mixes) and molded into a prismatic brick-like shape. These bricks constitute construction materials that have mechanical and other characteristics. A whole methodology specific to the development of such materials and their optimization is presented. It includes the preparation, characterization, cutting of the fibers to the desired length and the making of the mixtures. This is followed by optimization (fibers distribution), control and quality of the fiber-reinforced material. Two examples illustrate the application of this methodology: a reinforced mortar based on coconut fibers (hardened cementitious mix) and a green brick based on sediment and oil palm fibers.

**Keywords:** natural fibers, recycling, sustainability, waste management, building materials


**Author details**

Umberto D'Alessandro

Address all correspondence to<EMAIL_ADDRESS>
Medical Research Council Unit, The Gambia and London School of Hygiene and Tropical Medicine, Fajara, The Gambia


**4.3 Vitreoschisis or second membrane identification**

Often the posterior vitreous gel splits into an anterior and a posterior leaflet [22]. One may be easily mistaken by looking at the posterior leaflet as the edge of the hyaloid near the FVP and start pulling it. It is important to identify the anterior leaflet that extends beyond the FVP sometimes as thin flimsy glistening membrane onto the surface of TRD/adjacent retina and start separating it from the retina. Once this is identified using a pic or a needle and separated, it is easier to get the right plane for further dissection. If not correctly identified, one can have multiple iatrogenic breaks, since the anterior leaflet of posterior hyaloid (also known as second membrane) is still adherent to underlying retina. Though the aetiology is uncertain, some authors believe that the split may be caused due to the bleeding from the vascular epicentres (Video 3; https:// cdn.intechopen.com/public/chapter\_videos/241965/VIDEO\_3.mov).

In rare circumstances, where the hyaloid is very densely adherent extending till periphery, with flat broad and dense fibrovascular proliferations, one of the authors (Dr. MPS) have tried intravitreal autologous serum injection 24 hours prior to the surgery for induction of PVD with a successful outcome. In the event of any iatrogenic break in the periphery or near the vitreous base better, one can also support with BB/SB to avoid transmitted tractions from the vitreous base.

Hybrid vitrectomy: Some surgeons prefer hybrid vitrectomy using 23G trocar cannulas and 25G or 27G cutters for better membrane delamination. This has the advantage of higher cut-rate and the port site being closer to the tip of cutter helps in easier grasp of membranes [23]. Newer cutters (27G) with very high cutting rates with low vaccum can allow precise cutting in close proximity to the retina with reduced risk of breaks [24].


**6. Conclusion**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

anodal stimulation increasing glutamate release probability.

substantial cost increase for an otherwise cheap intervention.

trans-cutaneously rather than effects on cortical neurons [103].

**5.7 Less explored effects of electric currents and future research avenues**

Imposed electric fields may have a wider biological effects. For instance tDCS could influence glia [89, 104]. Future work should consider these largely unexplored effects so as to provide a more comprehensive mechanistic basis for weak

prevent hyperactivity or hypoactivity [95].

Human spectroscopy studies have demonstrated that anodal tDCS causes a local gamma aminobutyric acid (GABA) reduction [91] whereas cathodal stimulation leads to decreased glutamatergic neuronal activity. Currently the suggested mechanism of tDCS is thought to include presynaptic modulation of neurons, with the stimulation effects related to synaptic inputs rather than solely action potential generation [92, 93]. Evidence from animal studies of DCS also suggests presynaptic effects, with cathodal stimulation reducing the probability of glutamate release and

To explain the longer term effects of tDCS, anodal tDCS had been initially assumed to induce long term potentiation (LTP)-like effects whereas cathodal tDCS thought to induce long term depression (LDP)-like effects. However this is now thought to be overly simplistic. Some of the variability in effects of anodal and cathodal stimulation has been explained by mechanisms of homeostatic plasticity [94] formalized in the Bienenstock-Cooper-Munro (BCM) rule of bidirectional synaptic plasticity [95]. These mechanisms are proposed to occur within neural networks to

Importantly recently it has also been highlighted that polarization of the cell membrane must be dependent on the orientation of the neuron to the extracellular current vector [96]. Further evidence of the importance of axonal orientation has been provided by animal studies with evidence from rat hippocampus suggests that effects of electrical current vary dependent on the orientation of axons [97]. The significance of axonal orientation in the effects of DCS could have wider implications as to how develop tDCS methods. Diffusion magnetic resonance imaging (dMRI) enables an assessment of the structural connectivity and integrity of tracts. It has been suggested that tractography achieved from dMRI may be beneficial for optimal electrode positioning in clinical instances where there has been disruption in fibre tracts due to disease [98] or that dMRI may aid understanding of the effects of neuromodulation at a cellular level [99]. Imaging techniques may also offer a means of individualizing interventions, but they would have the disadvantage of a

Transcranial alternating current (tACS) of the primary motor cortex (M1) has been shown in the past to be effective in modulating sensory thresholds for tactile sensation and visual phenomena [100] and offers potential for pain modulation [101]. tACS involves weak alternating currents being applied through the skull via electrodes on the scalp with montages similar to those used with tDCS. tACS can be applied in a wide frequency range, with the effect of each frequency range still to be explored. There is evidence of gamma and alpha oscillations being associated with pain processing and perception. Despite its potential only a limited number of studies have used tACS although alpha range stimulation has been found beneficial for pain relief [102]. Studies combining tACS with fMRI, neurophysiology or QST may help address the optimum tACS frequency for pain relief. The mechanistic effects of tACS are less well understood than tDCS and interestingly there has been the suggestion that tACS effects could be a result of stimulation of peripheral nerves

**200**

**5.6 tACS**

Pain is a complex sensation associated with the activity of multiple cortical and sub-cortical regions in the brain. The overall pain percept must result from the interplay between multiple ascending pathways that convey nociceptive input from the peripheral with descending pathways that act to modulate nociceptive input. The mechanisms for the formation of chronic pain are uncertain; though it is known that there are both peripheral, spinal cord and central mechanisms underlying the formation of chronic pain. Non-invasive neuromodulation through tDCS presents a particularly interesting treatment intervention for pain as recent evidence also suggests that its mechanism of action is not only the modulation of neuronal activity but that the technique also influences the neuro-immune response. However, for appropriate translation of tDCS to a clinical setting there remains the need for research for both increased mechanistic understanding as well as studies how the level of electric stimulation applied can be accurately targeted and tailored to individuals and different disease groups.


*2.1. Geomechanical Modeling*

Many researchers [33–43] find a notably high influence of fine fractions (<50 μm) on the well operation (mainly plugging screens), as a result, the material associated with the formation of sand arches was worked out, but significant results were not achieved in by analyzing the literature (except for the connection of the aforementioned arches with the process of the natural decrease in the number of suspended particles in the first few days of well operation).

Some investigations look at the use of chemical compositions for the selective retention of fine fractions; however, no field test results have been conducted [14,15,44–48].

Interdependences were investigated within the framework of a field with high viscosity oil, currently under development between the following parameters: the number of suspended particles, the influence of the sand production process on the operation of

individual wells and the study of the effectiveness of screens of certain standard sizes and structures [49,50]. It was found that with different production rates and water-cuts, the interdependence of the number of suspended particles on certain parameters may or may not be observed, as, for example, with the flow rate: its increase or decrease does not affect the number of suspended particles in the fluid flow, which is unexpected (since the fluid flow with a higher speed should entrain more rock particles from the formation). It was found that for wells with a liquid flow rate of <100 m3/day, there is a significant dependence for the number of suspended particles on water cut (for wells with a flow rate >100 m3/day, there is no dependence). The effect of water cut on the process of formation destruction has been noted numerous times, which is some confirmation of the fact that phase flow is one of the key parameters that should be taken into account when working with a poorly cemented reservoir.

The authors analyzed the operating experience of one of the facilities and constructed a distribution of the well stock, categorizing wells as either "complicated" or "uncomplicated" according to the following criteria: flow rates (Figure 2), water cut (Figure 3) and target bottomhole pressure (Figure 4). It can be seen from the graphs that operational complications (failures due to erosive wear or clogging with mechanical inclusions of downhole pumping equipment are mostly observed in the well stock with a flow rate of less than 100 m3/day and a water cut of less than 50%).

Coupling of wells is not always applicable due to the differentials in the tubing diameter, equipment and other factors, which influence the sanding process. The number of wells for consideration for the first category (0–50 m3/day) is three times fewer than the second. Making conclusions based on the beforementioned data seems questionable since a two-time increase in liquid flow rate leads to a rise in sanding. Nevertheless, a further increase in flow rate does not lead to complications in the well.

It is worth noting that many authors have found during their investigations that the amount of sand carried out increases along with an increase in water cut. Nevertheless, the graph above does not show this effect, since when the water cut is above 50%, there are no complicated wells at all.

**Figure 2.** Distribution of sand-prone well stock by fluid flow rate.

**Figure 3.** Distribution of sand-prone well stock by water cut.

**Figure 4.** Distribution of sand-prone well stock by bottomhole pressure.

With a decrease in bottomhole pressure (on average, a higher depression of the reservoir), a dependence of a higher level of sanding and complication can be observed.

This phenomenon is associated with the low bearing capacity of the flow and with high viscosity of the oil, which is explained by the lower sedimentation rate of the sand particles. Well operation is carried out according to the target bottomhole pressure control program, which is determined by the requirements of rational oilfield.

The trend towards lower drawdowns in the bottomhole formation zone is confirmed by the analysis of Figure 4, where it can be seen that the least number of failures and complications in the well stock with a target bottomhole pressure of more than 9 MPa, with the initial formation pressure—10.6 MPa.

Thus, the main issue of scientific and practical interest is the prediction of the onset of reservoir destruction and further determination of the critical bottomhole pressure (which leads to the production of sand together with the formation fluid) and, ultimately, to finding the optimal dynamics of bottomhole pressure lowering. There are two basic ways to solve this issue—practical modeling (laboratory tests) via sand retention tests (SRT) and Prepack tests and mathematical modeling. Physical modeling gives good results and provides a lot of information; however, preparing these experiments is time consuming, especially with bulk modeling included.

A literature review [16–19] makes it possible to recommend geomechanical modeling as a tool for assessing the stability of the bottomhole formation zone during operation in the conditions of weakly consolidated sandstones. The stability model is adapted to the data of caliper, imager, mini-frac and modular dynamic tests (MDT) studies. The model-building sequence for one-dimensional geomechanical modeling for PK formations is shown in Figure 5.

**Figure 5.** General scheme of geomechanical modeling. BSL—Broadband sonic logging, LOT—fractest, MDT—stress-test with bottomhole tester.

The 1D model of stability of the bottomhole formation zone according to the criteria of Mogi–Coulomb and Mohr–Coulomb is based on the current parameters of the formation and according to the data of the well operation:

The bottomhole pressure and the angular position around the circumference of the wellbore are the specified parameters in this model. Detailed algorithm for this modeling procedure is presented in [9].

The results of the calculations of the 1D model are used to determine the admissible value of depression, at which the fracture of the bottomhole formation zone will not occur. The next stage is a calculation of the optimal step for lowering the bottomhole pressure to value, when the well is brought to the target operating mode (at analogous fields— 0.3–0.5 MPa/day). A significant advantage of the proposed approach is the ability to assess the critical depression value even in the absence of core studies of the mechanical properties of the rock.

As a result, the following geomechanical modeling algorithm was developed:


136 Clostridium Difficile - A Comprehensive Overview Clostridium Difficile - A Comprehensive Overview

Mild CDI 1st line

Severe CDI 1st line

**Severity Preference Medications**

Alternate (PO) Alternate (IV)

Alternate (IV)

**Table 2.** Treatment modalities for *Clostridium difficile* infections.

hours

Relapsed CDI 1st line Treatment based on severity as above

Regardless of the type of medication, early treatment has been supported as the most effective pharmacologic treatment. A study by Zahar et al. conducted in three French ICUs has demonstrated that early treatment of ICU-acquired *C. difficile* infection results in mortality rates consistent with a control population of other ICU patients that have developed diarrhea that is not *C. difficile* infection associated. Treatment was initiated within 24 hours of onset and consisted of either metronidazole or oral vancomycin. The study involved 5,260 patients with an incidence of ICU-acquired diarrhea of 9.7%. All those with diarrhea were tested for *C. difficile* infection and 13.5% of those tested had confirmed toxin A or B by EIA and further confirmation by culture. None of the positive cultures produced any of the hypervirulent NAP1/027 strains seen in North American outbreaks. Overall mortality of ICU-acquired *C. difficile* infection was not independently associated with higher mortality rates compared to other patients with diarrhea in the ICU when matched for severity of illness, comorbidities, or complications occurring in the ICU. However, both the overall hospital stay and ICU stay was prolonged in the ICU-acquired *C. difficile* infection patients when compared to ICU patients as a whole (median 4 vs. 20 days) and ICU patients with diarrhea not associated with *C. difficile* infection (median 17 vs. 20 days). Despite these prolonged median stays, analysis did not demonstrate a statistically significant difference in length of stay with an estimated increase in overall ICU stay of 6.3 days ± 4.3, p = 0.14 compared to other ICU patients with diarrhea [83].

Microbial therapy with fecal transplantation can be accomplished with instillation of liquid preparations of stool from healthy donors. This method has proven successful for treating recurrent *C. difficile* infection in 70–100% of cases [84]. Probiotics may prevent attachment of *C. difficile* to epithelial cells and can reduce the incidence of *C. difficile* infection. *Saccharomyces boulardii* in particular has proven to be effective [49] whereas the use of *Lactobacillus* with conventional antibiotic therapy has shown mixed results including some studies showing no benefit in the treatment of *C. difficile* infection in several randomized controlled trials [85–88].

Use of anion exchange resins, such as cholestyramine and colestipol, with the hope of binding *C. difficile* cytotoxins in the treatment of *C. difficile* infection, has not only been shown to be effective [89, 90], but also carries the theoretical risk of binding intraluminal vancomycin, thus resulting in subtherapeutic vancomycin levels [91]. Intravenous immunoglobulins have been suggested for treatment of *C. difficile* infection but due to an insufficient evidence base and conflicting data, its use cannot be generally recommended until further studies have been conducted [92, 93]. Subtotal colectomy should be considered if there is no response to medical therapy within 3–4 days or if the patient remains seriously ill to avoid complications such as colonic perforation and sepsis [7].

## **7. Treatment failure and relapse**

Patient characteristics that predispose to metronidazole failure include low serum albumin, continued exposure to the inciting antibiotic, and residence in the ICU [94, 95]. Particularly worrisome and concerning is the finding that relapsing or recurrent infections occur in up to 30% of patients treated for *C. difficile* infection whether the initial treatment was metronidazole or vancomycin [96]. This could be due to reinfection with the same endogenous strain or from a different strain acquired exogenously. Patients that had an initial infection followed by reinfection have a 50–65% chance of further repeated episodes. A metaanalysis by Garey et al. found that reexposure to antimicrobials, gastric acid suppression, and older age are all associated with an increased risk of recurrent *C. difficile* infection [97]. Patients that have three or more episodes of *C. difficile* infection, considered to be multiple *C. difficile* infection recurrence, are best treated with a tapered regimen of oral vancomycin. The initial dose of vancomycin administered is at the usual 125 mg by mouth four times a day for 10–14 days but then one dose per day is removed one week at a time until the patient is taking one dose every 2–3 days. The rationale for this regimen is that as the doses are spaced out, the colonic flora has time to regenerate [48].

There is some evidence to support that plant based diets may reduce the number of pathobionts such as *C. difficile* and increase the number of protective species such as Lactobacillus [100–103]. Altered flora with resulting altered bile metabolism within the gut by flora favored by plant-based diets have implications in colonocyte protection [102]. Intestinal microbiota are able to produce short chain fatty acids (SCFA), such as acetate, propionate, and butyrate, through metabolism of dietary fiber. These SCFA have been shown to be colonocyte protective. A strong positive correlation has been found between *Faecalibacterium prausnitzii* and butyrate production in the gastrointestinal tract, suggesting that this species may be associated with higher fiber intake and reduced risk, not only for *C. difficile* infection, but also for other common comorbidities in the elderly including cardiovascular disease, colon cancer, diabetes, and obesity [104]. A move toward a diet that decreases risk for contracting *C. difficile* infection should be encouraged, not only in the elderly, but also generally, because of the broad implications.

*Clostridium difficile* in the ICU

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Disinfectant products based on quaternary ammonium compounds, commonly used to clean patient rooms, are not sporicidal. Therefore, using sporicidal hypochlorite-based disinfectants on surfaces is recommended. However, use of antisporicidal agents outside an outbreak

Hand hygiene is the most important preventive measure to reduce transmission of *C. difficile* spores. Soap and water has been demonstrated to be superior to alcohol based hand rubs and other forms of hand sanitation with regard to transmission by healthcare workers [21, 107]. Hospital hygiene hand protocols should be followed assiduously at all times. Other precautions that should be utilized include isolation of the patient, barrier precautions, and use of chlorine based chemical wipes [107]. These precautions should not be lifted based on stool studies as there are no diagnostic methods to determine response to treatment. Rather, the decision should be made on clinical signs and symptoms with resolution of diarrhea, fevers, and leukocytosis. A strong antibiotic stewardship program is essential to limit the use of antibiotics that may cause *C. difficile* infection and is generally a good principle to follow. It has been demonstrated that up to 25% of antibiotic administration is not indicated, even in the ICU [108].

Diarrhea is a common problem in the ICU affecting up to 40% of patients admitted. Severely burned patients may have an incidence of greater than 90% [109, 110]. Enteral tube feeding is the most common cause of diarrhea in the ICU; other causes include hypoalbuminemia, intestinal ischemia, and medications. *C. difficile* infection is the most common infectious cause of diarrhea in the ICU [111, 112]. The severity of *C. difficile* infection is increasing which is possibly related to the emergence of more virulent strains such as the BI/NAP1/027 strain, prompting more admissions to the ICU for management of *C. difficile* infection related complications [113].

is not associated with lower rates of *C. difficile* infection [105, 106].

**10.** *Clostridium difficile* **infection in the intensive care unit**

**9. Prevention of hospital spread**

## **8. Generating optimal colonic flora for risk reduction**

There is an urgent need for alternative means of preventing and treating *C. difficile* infection in high-risk individuals. Metagenomics have improved our understanding of the "colonization resistance barrier" and how this could be optimized. The "colonization resistance barrier" in the normal healthy colon consists of high microbial diversity, substrate/area competition, immune response modulation and short-chain fatty acid (SCFA) production [16, 98]. These factors are often missing in the elderly. Decreased pH, oxidation-reduction potentials, and higher concentrations of short-chain fatty acids have been suggested to inhibit *C. difficile* growth and toxin production throughout *in vitro* and *in vivo* studies. There is, therefore, evidence in support of a colonization resistance barrier against *C. difficile* infection [16, 98].

For instance, *in vitro, Bifidobacterium longum* and *Bifidobacterium breve* have been show to significantly reduce the growth of the toxigenic strain *C. difficile* LMG21717 [99]. In a randomized, placebo-controlled, double-blind trial at a long-term elderly care facility, the effectiveness of a *Lactobacillus casei* strain Shirota (LcS) infused beverage was demonstrated by altering *Clostridium* infection rates among the residents. Daily consumption of the beverage resulted in a significantly lower incidence of fever and improved bowel movements. When compared to a resident control group drinking a placebo beverage, stool studies from the experimental LcS group showed significantly higher number of both *Bifidobacterium* and *Lactobacillus* (p < 0.01), significantly lower number of destructive bacteria such as *C. difficile* (p < 0.05), and a higher fecal acetic acid concentration. This study was also conducted among the facility's staff and a significant difference in the intestinal microbiota, fecal acetic acid, and pH was also observed between the LcS and placebo groups [100].

There is some evidence to support that plant based diets may reduce the number of pathobionts such as *C. difficile* and increase the number of protective species such as Lactobacillus [100–103]. Altered flora with resulting altered bile metabolism within the gut by flora favored by plant-based diets have implications in colonocyte protection [102]. Intestinal microbiota are able to produce short chain fatty acids (SCFA), such as acetate, propionate, and butyrate, through metabolism of dietary fiber. These SCFA have been shown to be colonocyte protective. A strong positive correlation has been found between *Faecalibacterium prausnitzii* and butyrate production in the gastrointestinal tract, suggesting that this species may be associated with higher fiber intake and reduced risk, not only for *C. difficile* infection, but also for other common comorbidities in the elderly including cardiovascular disease, colon cancer, diabetes, and obesity [104]. A move toward a diet that decreases risk for contracting *C. difficile* infection should be encouraged, not only in the elderly, but also generally, because of the broad implications.

## **9. Prevention of hospital spread**

**7. Treatment failure and relapse**

138 Clostridium Difficile - A Comprehensive Overview Clostridium Difficile - A Comprehensive Overview

flora has time to regenerate [48].

**8. Generating optimal colonic flora for risk reduction**

observed between the LcS and placebo groups [100].

Patient characteristics that predispose to metronidazole failure include low serum albumin, continued exposure to the inciting antibiotic, and residence in the ICU [94, 95]. Particularly worrisome and concerning is the finding that relapsing or recurrent infections occur in up to 30% of patients treated for *C. difficile* infection whether the initial treatment was metronidazole or vancomycin [96]. This could be due to reinfection with the same endogenous strain or from a different strain acquired exogenously. Patients that had an initial infection followed by reinfection have a 50–65% chance of further repeated episodes. A metaanalysis by Garey et al. found that reexposure to antimicrobials, gastric acid suppression, and older age are all associated with an increased risk of recurrent *C. difficile* infection [97]. Patients that have three or more episodes of *C. difficile* infection, considered to be multiple *C. difficile* infection recurrence, are best treated with a tapered regimen of oral vancomycin. The initial dose of vancomycin administered is at the usual 125 mg by mouth four times a day for 10–14 days but then one dose per day is removed one week at a time until the patient is taking one dose every 2–3 days. The rationale for this regimen is that as the doses are spaced out, the colonic

There is an urgent need for alternative means of preventing and treating *C. difficile* infection in high-risk individuals. Metagenomics have improved our understanding of the "colonization resistance barrier" and how this could be optimized. The "colonization resistance barrier" in the normal healthy colon consists of high microbial diversity, substrate/area competition, immune response modulation and short-chain fatty acid (SCFA) production [16, 98]. These factors are often missing in the elderly. Decreased pH, oxidation-reduction potentials, and higher concentrations of short-chain fatty acids have been suggested to inhibit *C. difficile* growth and toxin production throughout *in vitro* and *in vivo* studies. There is, therefore, evidence in support of a colonization resistance barrier against *C. difficile* infection [16, 98].

For instance, *in vitro, Bifidobacterium longum* and *Bifidobacterium breve* have been show to significantly reduce the growth of the toxigenic strain *C. difficile* LMG21717 [99]. In a randomized, placebo-controlled, double-blind trial at a long-term elderly care facility, the effectiveness of a *Lactobacillus casei* strain Shirota (LcS) infused beverage was demonstrated by altering *Clostridium* infection rates among the residents. Daily consumption of the beverage resulted in a significantly lower incidence of fever and improved bowel movements. When compared to a resident control group drinking a placebo beverage, stool studies from the experimental LcS group showed significantly higher number of both *Bifidobacterium* and *Lactobacillus* (p < 0.01), significantly lower number of destructive bacteria such as *C. difficile* (p < 0.05), and a higher fecal acetic acid concentration. This study was also conducted among the facility's staff and a significant difference in the intestinal microbiota, fecal acetic acid, and pH was also Disinfectant products based on quaternary ammonium compounds, commonly used to clean patient rooms, are not sporicidal. Therefore, using sporicidal hypochlorite-based disinfectants on surfaces is recommended. However, use of antisporicidal agents outside an outbreak is not associated with lower rates of *C. difficile* infection [105, 106].

Hand hygiene is the most important preventive measure to reduce transmission of *C. difficile* spores. Soap and water has been demonstrated to be superior to alcohol based hand rubs and other forms of hand sanitation with regard to transmission by healthcare workers [21, 107]. Hospital hygiene hand protocols should be followed assiduously at all times. Other precautions that should be utilized include isolation of the patient, barrier precautions, and use of chlorine based chemical wipes [107]. These precautions should not be lifted based on stool studies as there are no diagnostic methods to determine response to treatment. Rather, the decision should be made on clinical signs and symptoms with resolution of diarrhea, fevers, and leukocytosis. A strong antibiotic stewardship program is essential to limit the use of antibiotics that may cause *C. difficile* infection and is generally a good principle to follow. It has been demonstrated that up to 25% of antibiotic administration is not indicated, even in the ICU [108].

## **10.** *Clostridium difficile* **infection in the intensive care unit**

Diarrhea is a common problem in the ICU affecting up to 40% of patients admitted. Severely burned patients may have an incidence of greater than 90% [109, 110]. Enteral tube feeding is the most common cause of diarrhea in the ICU; other causes include hypoalbuminemia, intestinal ischemia, and medications. *C. difficile* infection is the most common infectious cause of diarrhea in the ICU [111, 112]. The severity of *C. difficile* infection is increasing which is possibly related to the emergence of more virulent strains such as the BI/NAP1/027 strain, prompting more admissions to the ICU for management of *C. difficile* infection related complications [113].

In a systematic review and metaanalysis of 22 published studies from 1983 to 2015 that included 80,835 ICU patients, the effects of *C. difficile* infection on morbidity and mortality were investigated. Karanika et al. found that prevalence of *C. difficile* infection among ICU patients was 2% but 5-fold greater in those patients with diarrhea (11%). Those patients that were diagnosed with *C. difficile* infection had a 25% incidence of the severe form of the disease and diagnosed with pseudomembranous colitis. ICU mortality was not significantly different between the group with *C. difficile* infection and the non*C. difficile* infection group based on seven studies that enrolled a combined 12,165 patients. However, the overall hospital mortality between those same groups was significantly increased in the *C. difficile* infection group with 32% mortality compared to 24% (p = 0.03). Similarly, length of ICU and hospital stay among *C. difficile* infection patients was longer when compared to non*C. difficile* infection patients. Based on five studies with over 10,000 patients, *C. difficile* infection patients had an average ICU stay of 24 days and overall hospital stay of 50 days compared to 19 days and 30 days, respectively, for the non*C. difficile* infection group (p = 0.001) [114].

thought to be synergistic with the production of toxin A and B. Strain BI/NAP1/027 was found to be highly resistant to fluoroquinolone classes of antibiotics and was also found to produce 16-fold higher concentrations of toxin A and 23-fold higher concentrations of toxin B than less virulent toxinotype 0 strains. The binary toxin has been associated with more severe diarrhea when combined with toxin A and B. When produced alone, binary toxin does not appear to produce disease [3, 10] but does appear to be a marker of both *C. difficile* infection severity and recurrence [120]. The emergence is generally believed to be related to fluoroquinolone

*Clostridium difficile* in the ICU

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*C. difficile* is a very diverse group of toxin producing organisms. Newer technologies have allowed the identification of numerous toxinotypes and ribotypes with varying virulence factors and toxin production. Multiple lineages contain hypervirulent strains. The large degree of horizontal gene transfer through transposons, bacteriophages, and homologous recombination has dispersed genetic material and pathogenic properties among different

The increased prevalence of ribotypes 027, 017, and 078 may be solely due to population expansion over the last decade or due to a nosocomial enrichment of the proper environment and conditions for the expansion and transference of these virulent strains. The sudden rise may also be related to the delay in purifying selection pressures seen in the more recently diverging lineages. However, a more likely explanation for increasing incidence is the right combination of elderly patients in a contaminated environment with antibiotic and acid suppression medications. Given the high incidence of colonized guts in the hospitalized pediatric population (70%), the hospitalized adult population (25%), the animal kingdom (40%), and

The high virulence, along with a highly mobile genome capable of antibiotic resistance, has prompted further research in the development of vaccinations. Sanofi-Aventis is currently undergoing trials with a vaccine containing formalin-inactivated toxins A and B. To date, 100 healthy subjects have been exposed to the vaccine without any serious side

The hardiness of *C. difficile* spores and the ease with which this bacterium alters its genome has allowed it to flourish and survive among a variety of hosts and reservoirs. More virulent strains are a real possibility given the mobility of code sequencing regions within the genome. As the population continues to age and makes an increasingly stronger presence throughout the healthcare system, especially in the ICU, *C. difficile* will continue to plague patients and healthcare providers until further measures are discovered to control transmission. The increased burden will stress the current resources and facilities financially, geographically, and the pool of available care takers. To date, the best treatment modalities include eliminating the implicated antibiotics, early initiation of oral vancomycin and metronidazole, and

exposure though not to the particular type of fluoroquinolone [121, 122].

the natural environment (50%), reducing exposure is near impossible [14].

strict infection-control engineering to prevent the initial infection.

**12. Conclusions**

strains.

effects [123].

Even though only 3% of patients with *C. difficile* infection require subtotal colectomy for fulminant *C. difficile* colitis, 20% of ICU patients with severe *C. difficile* infection will still require partial colectomy or diversion [115, 116]. Colectomy in this setting is associated with a 50% mortality [90]. Mortality rates are lower when surgical intervention is undertaken within 48 hours of lack of response to medical therapy [117]. During NAP1/027 outbreaks, patients with age >65 years, leukocytosis and elevated lactate appear to benefit the most from early colectomy [118].

In a series of 29 patients with severe or severe/complicated *C. difficile* infection refractory to oral vancomycin ± rectal vancomycin and intravenous metronidazole therapy who underwent fecal microbiota transplantation (FMT) plus continued vancomycin, overall treatment response was 93% (27/29), including 100% (10/10) for severe *C. difficile* infection and 89% (17/19) for severe/complicated *C. difficile* infection. A single FMT was performed in 62%, two FMTs were performed in 31%, and three FMTs in 7% of patients. Continued use of non *C. difficile* infection antibiotics predicted repeat FMT. Thirty-day all-cause mortality after FMT was 7%. Of the two patients who died within 30 days, one underwent colectomy and succumbed to sepsis; the other died from septic shock related to *C. difficile* infection [84]. Further research into the use of FMT combined with continued vancomycin is needed.

## **11. Modern outbreaks**

In 2003, a major outbreak of *C. difficile* occurred in Quebec, Canada and was identified as ribotype 027, strain BI/NAP1. This strain has been identified in >50% of all isolates from hospitals in Europe and North America [4, 10, 20]. Prior to the 2003 outbreak, this strain only accounted for 14 of over 6000 (<0.02%) typed strains collected from U.S. cases during the period of 1984 to 1993. Following the 2003 outbreak in Canada, 96 of 187 (51%) strains tested positive for 027 in eight U.S. outbreaks [119].

The BI/NAP1/027 strain belongs to a hypervirulent group of strains along with types 001, 017, and 078. In particular, the binary toxin produced by 027 was not seen previously. It is thought to be synergistic with the production of toxin A and B. Strain BI/NAP1/027 was found to be highly resistant to fluoroquinolone classes of antibiotics and was also found to produce 16-fold higher concentrations of toxin A and 23-fold higher concentrations of toxin B than less virulent toxinotype 0 strains. The binary toxin has been associated with more severe diarrhea when combined with toxin A and B. When produced alone, binary toxin does not appear to produce disease [3, 10] but does appear to be a marker of both *C. difficile* infection severity and recurrence [120]. The emergence is generally believed to be related to fluoroquinolone exposure though not to the particular type of fluoroquinolone [121, 122].

## **12. Conclusions**

In a systematic review and metaanalysis of 22 published studies from 1983 to 2015 that included 80,835 ICU patients, the effects of *C. difficile* infection on morbidity and mortality were investigated. Karanika et al. found that prevalence of *C. difficile* infection among ICU patients was 2% but 5-fold greater in those patients with diarrhea (11%). Those patients that were diagnosed with *C. difficile* infection had a 25% incidence of the severe form of the disease and diagnosed with pseudomembranous colitis. ICU mortality was not significantly different between the group with *C. difficile* infection and the non*C. difficile* infection group based on seven studies that enrolled a combined 12,165 patients. However, the overall hospital mortality between those same groups was significantly increased in the *C. difficile* infection group with 32% mortality compared to 24% (p = 0.03). Similarly, length of ICU and hospital stay among *C. difficile* infection patients was longer when compared to non*C. difficile* infection patients. Based on five studies with over 10,000 patients, *C. difficile* infection patients had an average ICU stay of 24 days and overall hospital stay of 50 days compared to 19 days and 30

Even though only 3% of patients with *C. difficile* infection require subtotal colectomy for fulminant *C. difficile* colitis, 20% of ICU patients with severe *C. difficile* infection will still require partial colectomy or diversion [115, 116]. Colectomy in this setting is associated with a 50% mortality [90]. Mortality rates are lower when surgical intervention is undertaken within 48 hours of lack of response to medical therapy [117]. During NAP1/027 outbreaks, patients with age >65 years, leukocytosis and elevated lactate appear to benefit the most from early colectomy [118]. In a series of 29 patients with severe or severe/complicated *C. difficile* infection refractory to oral vancomycin ± rectal vancomycin and intravenous metronidazole therapy who underwent fecal microbiota transplantation (FMT) plus continued vancomycin, overall treatment response was 93% (27/29), including 100% (10/10) for severe *C. difficile* infection and 89% (17/19) for severe/complicated *C. difficile* infection. A single FMT was performed in 62%, two FMTs were performed in 31%, and three FMTs in 7% of patients. Continued use of non *C. difficile* infection antibiotics predicted repeat FMT. Thirty-day all-cause mortality after FMT was 7%. Of the two patients who died within 30 days, one underwent colectomy and succumbed to sepsis; the other died from septic shock related to *C. difficile* infection [84]. Further research

In 2003, a major outbreak of *C. difficile* occurred in Quebec, Canada and was identified as ribotype 027, strain BI/NAP1. This strain has been identified in >50% of all isolates from hospitals in Europe and North America [4, 10, 20]. Prior to the 2003 outbreak, this strain only accounted for 14 of over 6000 (<0.02%) typed strains collected from U.S. cases during the period of 1984 to 1993. Following the 2003 outbreak in Canada, 96 of 187 (51%) strains tested positive for 027

The BI/NAP1/027 strain belongs to a hypervirulent group of strains along with types 001, 017, and 078. In particular, the binary toxin produced by 027 was not seen previously. It is

days, respectively, for the non*C. difficile* infection group (p = 0.001) [114].

into the use of FMT combined with continued vancomycin is needed.

**11. Modern outbreaks**

140 Clostridium Difficile - A Comprehensive Overview Clostridium Difficile - A Comprehensive Overview

in eight U.S. outbreaks [119].

*C. difficile* is a very diverse group of toxin producing organisms. Newer technologies have allowed the identification of numerous toxinotypes and ribotypes with varying virulence factors and toxin production. Multiple lineages contain hypervirulent strains. The large degree of horizontal gene transfer through transposons, bacteriophages, and homologous recombination has dispersed genetic material and pathogenic properties among different strains.

The increased prevalence of ribotypes 027, 017, and 078 may be solely due to population expansion over the last decade or due to a nosocomial enrichment of the proper environment and conditions for the expansion and transference of these virulent strains. The sudden rise may also be related to the delay in purifying selection pressures seen in the more recently diverging lineages. However, a more likely explanation for increasing incidence is the right combination of elderly patients in a contaminated environment with antibiotic and acid suppression medications. Given the high incidence of colonized guts in the hospitalized pediatric population (70%), the hospitalized adult population (25%), the animal kingdom (40%), and the natural environment (50%), reducing exposure is near impossible [14].

The high virulence, along with a highly mobile genome capable of antibiotic resistance, has prompted further research in the development of vaccinations. Sanofi-Aventis is currently undergoing trials with a vaccine containing formalin-inactivated toxins A and B. To date, 100 healthy subjects have been exposed to the vaccine without any serious side effects [123].

The hardiness of *C. difficile* spores and the ease with which this bacterium alters its genome has allowed it to flourish and survive among a variety of hosts and reservoirs. More virulent strains are a real possibility given the mobility of code sequencing regions within the genome. As the population continues to age and makes an increasingly stronger presence throughout the healthcare system, especially in the ICU, *C. difficile* will continue to plague patients and healthcare providers until further measures are discovered to control transmission. The increased burden will stress the current resources and facilities financially, geographically, and the pool of available care takers. To date, the best treatment modalities include eliminating the implicated antibiotics, early initiation of oral vancomycin and metronidazole, and strict infection-control engineering to prevent the initial infection.

## **Author details**

William C. Sherman, Chris Lewis, Jong O. Lee and David N. Herndon\*

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Surgery, University of Texas Medical Branch – Galveston, Galveston, Texas, United States of America

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## *Edited by Shymaa Enany*

Clostridium difficile bacteria could be found everywhere around us: in the air, water, and soil and in the feces of humans and animals.  Many people have the bacteria in their intestines and never have any symptoms. Still, it can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon. The chance of developing a C. difficile infection increases with the usage of high doses of antibiotics over a prolonged period; thus, it is most often spread in the healthcare facilities between workers, patients, and residents. Each year in the United States, almost a half million people get sick from C. difficile, and approximately 29,000 patients died within 30 days of its initial diagnosis. Nowadays, C. difficile infections have become more frequent, severe, and difficult to treat. Therefore, the early diagnosis and the suitable treatment have become a real demand. In this book, we present the experience of worldwide specialists on the diagnosis and the treatment of C. difficile infections along with its lights and shadows.

Clostridium Difficile - A Comprehensive Overview

Clostridium Difficile

A Comprehensive Overview

*Edited by Shymaa Enany*

Photo by Jezperklauzen / iStock