Epidemiology and Pathogenesis of Acute Inflammation - Essay Example

? Clinical Science Number and of (e.g., June Clinical Science Epidemiology and Pathogenesis of Acute Inflammation Caused by Bacterial Infections An acute inflammatory response is the body’s initial and immediate response to an injury or an infection (Kumar et al. 2004; Prescott 2002). It is the body’s first line of defence against possible danger. Signs of acute inflammation include warmth, redness, swelling, pain and loss of function (calor, rubor, tumor, dolor, and functio laesa) (Prescott 2002). Acute inflammation is marked by a series of coordinated immune responses and has several causes that include microbial infection (bacterial, viral), hypersensitive reaction, and tissue damage or injury (Underwood 2004). In case of bacterial infections, acute inflammation is induced by exotoxins and endotoxins associated with the bacteria (Underwood 2004). The inflammatory response is activated by the body to clear the bacterial pathogen and to repair damages caused by the pathogen (Kumar et al. 2004). Common types of acute inflammations associated with bacterial infections include meningitis (inflammation of the meninges), Pneumonia (inflammation in lungs), pleurisy (inflammation of the pleura), pericarditis (inflammation of the pericardium), colitis (inflammation of the colon), cholecystisis (inflammation of the gall bladder), cystisis (inflammation of the urinary bladder), osteomyelitis (inflammation of the bone), cellulitis (inflammation of the subcutaneous tissues), and arthritis (inflammation of the joints) (Sen et al. 2010). Infection along with systemic inflammation results in sepsis, which has a very frequent rate of incidence, with more than 750,000 cases reported in 1995 in the US alone (Kumar et al. 2004). Acute inflammation of the lungs, also called pneumonia, is often associated with pneumococci, while Bacillus cereus, Staphylococcus aureus, and Enterococcus faecalis are often associated with acute ocular inflammation (Niederkorn 2007). Cellulitis, acute inflammation of the dermis and subcutaneous tissue, is often associated with bacterial infections caused by Pasteurella multocida, Clostridium species, staphylococci, and Corynebacterium pseudotuberculosis (Quinn et al. 2011). Examples of acute inflammation include boils and abscesses, pneumonia, middle ear infections, and meningitis, and are usually caused by Neisseria meningitidis, Streptococcus pyogenes, and Staphylococcus aureus (MacPherson & Austyn 2012). Acute inflammation caused by bacterial infection is typified by local pain, vasodilation, and oedema, apart from systemic symptoms such as anorexia and fever (MacPherson & Austyn 2012). It is characterised by a vascular phase and a cellular phase (Porth 2010). In the vascular phase, vasoconstriction occurs momentarily, followed by rapid vasodilation at the site of infection (Porth 2010). Increased redness and heat is felt at the site of vasodilation due to increased blood flow in the capillaries. Vascular permeability is also increased resulting in the release of exudate into the extravascular spaces (Porth 2010). The exudate is protein-rich and the loss of this protein rich fluid from the capillaries causes a reduction in the osmotic pressure within the capillaries. It is also accompanied with an increase in the osmotic pressure of the interstitial space. This sequence of events clubbed with an increase in capillary pressure causes an outpouring of fluid into the tissue space. This results in swelling, impaired function and pain at the site of infection. The cellular phase of acute inflammatory response is initiated when inflammatory mediators are released by the injured or infected cells (Prescott 2002). These mediators activate the endothelium of surrounding capillaries. Capillaries have a group of cell adhesion molecules called selectins in their walls. These selectins, specifically P- and E- selectins attract neutrophils towards the endothelium. As these neutrophils approach the endothelium, inflammatory mediators released by the capillaries activate adhesion receptors, also called integrins, on the neutrophils. These integrins then adhere to the adhesion molecules such as ICAM-1 and VCAM-1 on the endothelium (Prescott 2002). This results in the firm attachment of the neutrophils to the endothelium, which then penetrate it and enter the interstitial tissue fluid. From this fluid, the neutrophils migrate to the site of infection or injury and attack the bacterial pathogen or any other cause of infection or tissue damage. The infection site attracts leukocytes and neutrophils by releasing chemotaxins. Bacterial exotoxins, endotoxins, and substances released from the injured or infected tissues act as chemotaxins. Following the neutrophils, other leukocytes such as macrophages, monocytes and lymphocytes also arrive at the site of injury through chemotaxis. During these two phases of acute inflammation, the release of inflammatory mediators also causes a rise in the acidity of the extracellular fluid, which in turn activates kallikrein, an extracellular enzyme (Prescott 2002). This enzyme results in the splitting of bradykinin from its precursor molecule. Bradykinin attaches to the wall of the capillaries and opens the cell-cell junctions, enabling the release of leukocytes into the tissues. It also binds and activates the mast cells of surrounding connective tissue (Prescott 2002). The activation of mast cells occurs when there is an influx of calcium ions into the cells, causing their degranulation and subsequent release of histamine and other mediators. Histamine further widens the junctions in the walls of the capillaries to facilitate the outflow of bradykinin, leukocytes, etc, causing oedema. Bradykinin stimulates prostaglandin production, which causes swelling of the infected area. Prostaglandins are also responsible for the sensation of pain at the infected site. A fibrin clot develops at the infected site to keep the infection localised. Acute inflammatory response in bacterial infections results in neutralisation and elimination of the pathogen. Prescott (2002) summarises the entire inflammatory response into a series of four events. Firstly, there is vasodilation and increased blood flow resulting in an influx of leukocytes and antimicrobial factors that destroy the offending pathogen. Secondly, there is a rise in temperature, which not only stimulates the immune response but also inhibits growth of the pathogen. Thirdly, a fibrin clot is formed which limits further spreading of the pathogen by keeping it localised. Lastly, phagocytes that accumulate at the inflamed area destroy the pathogen through phagocytosis. Pharmacokinetic and Pharmacodynamic Properties of Broad-Spectrum Antibiotics used in the Treatment of Bacterial Infections The study of pharmacokinetic properties of a drug deals with the investigation of how it is distributed in the body and how it is subsequently eliminated, while the study of pharmacodynamic properties of a drug deals with the investigation of how the activity of the drug is related to its concentration (Cars 1997). In case of antibiotics, pharmacokinetics refer to the variations in antibiotic concentration in tissue and serum overtime, and pharmacodynamics refer to the biological effects of the antibiotic, especially how it kills or inhibits the growth of the pathogen (Burgess 1999). The incidence of sub-optimal or sub-lethal concentrations of antibiotics in serum or tissues is one of the most important causes of drug resistance. Therefore, the “optimization” of the use of antibiotics is vital so as to prevent drug resistance and to ensure appropriate treatment of bacterial infections (Bambeke et al. 2006, p. 218). This has led to the emergence of “pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics” as an entirely new discipline in pharmacology (Bambeke et al. 2006, p. 218). Amsden, Ballow and Bertino (cited in Bambeke et al. 2006) define this discipline as the “discipline that strives to understand the relationships between drug concentrations and effects, both desirable (eg, bacterial killing) and undesirable (eg, side effects)” (p. 218). The pharmacokinetic and pharmacodynamic properties of antibiotics are interrelated. Intensive pharmacokinetic and pharmacodynamic studies of antibiotics are essential in order to design appropriate dosage regimens that minimise the chances of sub-lethal antibiotic concentrations to prevent the emergence of drug resistant bacteria (Burgess 1999). Broad-spectrum antibiotics are divided into two groups, namely concentration dependent drugs and concentration independent drugs, based on their pharmacodynamic properties (Burgess 1999). Fluoroquinolones and aminoglycosides are concentration dependant drugs, while ?-lacatams are concentration independent drugs. The post antibiotic effect of concentration-dependant drugs is generally more prolonged, especially in case of infections caused by gram-negative bacteria (Tozer & Rowland 2006; Burgess 1999). The higher the concentration of concentration-dependant drugs (fluoroquinolones and aminoglycosides), the higher and faster is the bactericidal activity (Tozer and Rowland 2006). The concentration-independent drugs (?-lacatams) are also referred to as time-dependant drugs because rather than the peak concentrations, the extent of time in which the drug concentration is maintained above the MIC (minimal inhibitory concentration) of the bacteria is an important consideration for treatment of infection (Burgess 1999). Therefore, for best therapeutic activity, ?-lacatam drugs have to be administered frequently so that free serum levels of the drug continuously stay above the MIC (Cars 1996). Furthermore, as the post-antibiotic effect of ?-lacatams is short, their frequent administration is warranted for enhanced therapeutic efficacy (Tozer and Rowland 2006). Bambeke et al. (2006) identify three important pharmacokinetic/pharmacodynamic (PK/PD) parameters of antibiotics. The first PK/PD parameter is the time at which the peak drug concentration is higher than the pathogen’s MIC (t>MIC). According to this parameter, the bactericidal activity of the drug is dependent on its dosage, half-life, and frequency of administration. This parameter applies to ?-lacatams as already discussed above. The second PK/PD parameter links the peak drug concentration in the serum with the MIC (Cmax/MIC). According to this parameter, bactericidal activity depends on the unit dose of the drug and its volume of distribution in the tissues. This parameter applies to most concentration-dependant drugs such as aminoglycosides and fluorquinolones. The third PK/PD parameter is a combination of the above two types of effects and is given by the “area under the concentration-time curve” (AUC/MIC) (Bambeke et al. 2006, p. 218). According to this parameter, bactericidal activity is dependent on both concentration and time, and is negatively related with drug clearance. This parameter also applies to aminoglycosides and fluoroquinolones. For aminoglycosides, the peak drug concentrations need to be maintained at least 10 to 12 times higher than the MIC (Burgess 1999). In case of fluoroquinolones, high peak concentrations are not attained in clinical settings owing to their toxic side effects. Therefore, for fluoroquinolones, “area under the inhibitory curve” (AUIC), which is the ratio of AUC to MIC, is the governing parameter (Burgess 1999). The AUIC is usually maintained 125 times higher than the MIC (Burgess 1999). The three parameters listed above are more applicable to extracellular infections because they depend on the drug concentrations in the serum. In case of intracellular infections, the application of these three parameters is limited and further exploration of PK/PD properties is underway (Bambeke et al. 2006). Prevention of Infections through Ayurvedic Medicine Ayurveda is a holistic, ancient medical system developed in India around 5000 BC (Fritts et al. 2008). ‘Ayurveda’, meaning “Science of life”, aims at maintaining health by creating a balance between the spirit, mind, and body (Fritts et al. 2008). As described by the two main Ayurvedic texts, Carak samhita and Sushruta samhita, Ayurvedic medicine is subdivided into eight branches that deal with obstetrics, pediatrics, head and neck disease, internal medicine, toxicology, surgery, psychiatry, rejuvenation, elderly care, and sexual vitality (Fritt et al. 2008). It emphasises more on the patient’s constitution rather than the illness itself, and treatment and prevention is done by employing herbs, yoga, dietary and lifestyle changes. Ayurvedic medicine is believed to be very efficient in preventing microbial infections. Although the Ayurvedic approach allows the use of modern drugs for treatment or prevention of infections in case of emergencies, it places more emphasis on the use of traditional herbs and extracts that balance an individual’s health and help in preventing or fighting infection (Treadway 1998). Modern Ayurvedic practice also allows the use of allopathic medicine such as vaccines, along with the use of traditional Ayurvedic prophylactics (Devaraj 2003). Many Indian plants used in Ayurvedic medicine practice have proven anti-microbial activity. Some of these plants include Azadirachta indica (neem/lilac), Boerhaavia diffusa (Hogweed), Piper longum (long pepper), Tinospora cordifolia (moonseed), and Emblica officinalis (amla) (Najam, Singh and Verma 2008; Treadway 1998). The allopathic approach to prevention of infections contends the use of antibiotics to defend against microbes as they are considered the main cause of infection. On the other hand, Ayurveda does not identify microbes as the main cause of infection. It rather considers microbial infection as a symptom of the imbalance in doshas or body elements, which results in a weakening of the immune system (Treadway 1998). Therefore, for the prevention of infections, maintenance of the balance is of the highest priority. For the maintenance or restoration of this balance, herbal extracts, lifestyle and dietary recommendations are employed. The herbal medicine used for prevention of infections is usually a combination of herbs that not only prevent overgrowth of microbes but also boost the organ systems that carry out detoxification and immune related functions (Treadway 1998). Thus, Ayurvedic medicine promotes the body’s resistance to disease and is primarily a prophylactic medical practice (Agarwal & Singh 1999). Innumerable studies have investigated the anti-microbial and therapeutic properties of herbs used in traditional Ayurvedic medicine. In spite of the persistence of this ancient medical system for many centuries, modern medical practitioners are of divided opinion as to its safety and efficacy. Many evidence-based studies have proven the benefits of Ayurvedic medicine but opponents contend that these studies lack appropriate design or have other limitations. Najam, Singh and Verma (2008) reviewed studies on the Ayurvedic practice of using Clerodendrum aculeatum and Boerhaavia diffusa extracts for prevention of viral infections and carcinogenesis. Studies have shown that proteins and alkaloids in these plants possess diuretic, anti-inflammatory, anti-viral and anti-cancer properties. Trials on extracts of Andrographis paniculata that are believed to prevent upper respiratory tract infections have shown that the ethanolic extract of this plant possesses anti-inflammatory, immunomodulatory, anti-allergic, and antipyretic activity (Premila 2006). In another study, Chauhan (2004) investigated the scientific basis for the therapeutic effects of panchgavya (cowpathy), a common practice in Ayurveda. This practice employs five cow products namely milk, ghee, curd, dung and urine. The study found that cow urine promoted blastogenesis of B and T lymphocytes, apart from augmenting the titres of IgM, IgA and IgG antibodies in mice. Furthermore, cow urine is also found to promote macrophage phagocytic activity and the secretion of interleukins 1 and 2. These immunomodulatory properties have been attributed to its efficacy in prevention of microbial infections. A study that investigated the efficacy of extracts of Azadirachta indica (neem) found them to possess antiviral activity (Treadway 1998). Neem extracts are also found to be useful in prevention of skin infections. Zingiber officinale (ginger), another common ingredient of Ayurvedic herbal extracts is used for the prevention and treatment of colds. It is also used as a digestive aid and carminative. Studies on Tinospora cordifolia have shown that it possesses immunomodulatory activity (Treadway 1998). Six compounds that are responsible for this activity were identified in the study. Agarwal and Singh (1999) have listed many evidence-based studies on the immunomodulatory and infection preventing activity of herbs used in Ayurvedic medicine. While sufficient scientific evidence is available to prove the efficacy of Ayurvedic practice in preventing infections, several investigators have believe otherwise. For instance, Fritts et al. (2008) reviewed studies on the efficacy of traditional Indian medicinal systems including Ayurveda in preventing and curing AIDS. They concluded that there is a “dearth of high-quality data” supporting the efficacy and safety of the therapies used in these medicinal practices. Similarly, Martin and Ernst (2003), who reviewed studies on herbal medicines used for the treatment of bacterial infections concluded that the “clinical efficacy of none of the herbal medicines (evaluated in the review) has so far been demonstrated beyond doubt” and that “this area seems to merit further study through rigorous clinical trials” (p. 241). They further argue that most of the studies are methodologically weak. Therefore, while further investigations and clinical trials are underway, the fact that Ayurveda, a medical practice that has survived for thousands of years, has been successful in preventing and combating infections cannot be completely undermined. References Agarwal, SS & Singh, VK 1999, ‘Immunomodulators: A review of studies on Indian Medicinal plants and synthetic peptides’, PINSA, vol. B65, no. 3, pp. 179-204. 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