Antimicrobial resistance

Antimicrobial resistance - Microorganisms have evolved in the presence of antibiotics, which are antimicrobial agents produced naturally by bacteria and fungi. They have therefore developed multiple resistance mechanisms (categorised in Fig. 6.14) to all classes of antimicrobial agent (antibiotics and their derivatives). Resistance may be an innate property of a microorganism (intrinsic resistance) or may be acquired, by either spontaneous mutation or horizontal transfer of genetic material from another organism. For some agents, e.g. penicillins, a degree of resistance occurs in vivo when the bacterial load is high and the molecular target for the antimicrobial is down-regulated (an ‘inoculum effect’).

Antimicrobial Resistance

Antimicrobial Resistance

The mecA gene encodes a low-affinity penicillin-binding protein, which confers resistance to meticillin and other penicillinase-resistant penicillins in Staph. aureus. It is common for plasmids to encode resistance to multiple antimicrobials, which may be transferred horizontally. Extended spectrum â-lactamases (ESBL) are encoded on plasmids, which are transferred relatively easily between bacteria including Enterobacteriaceae. Plasmid-mediated carbapenemases have been detected in strains of Klebsiella pneumoniae. Glycopeptide resistance in enterococci is also transferred on mobile genetic elements. Strains of MRSA have been described that exhibit intermediate resistance to glycopeptides, through the development of a relatively impermeable cell wall (GISA).

Factors implicated in the emergence of antimicrobialresistance include the inappropriate use of antibiotics when not indicated (e.g. in viral infections) inadequate dosage or treatment duration, excessive use of broad- spectrum agents, and use of antimicrobials as growth-promoters in agriculture. However any antimicrobial use exerts a selection pressure that favours the development of resistance. Combination antimicrobial therapy may reduce the emergence of resistance. This is recommended in treatment of patients infected with HIV, which is highly prone to spontaneous mutation (p. 406). 

Despite use of combination therapy for M. tuberculosis, multidrug-resistant TB (MDR-TB, resistant to isoniazid and rifampicin) and extremely drug-resistant TB (XDR-TB,  resistant to isoniazid and rifampicin, any fluoroquinolone, and at least one injectable antimicrobial antituberculous agent) have been reported worldwide and are increasing in incidence (p. 693).

Characteristics of successful pathogens

Characteristics of successful pathogens - Successful pathogens have a number of attributes. They compete with host cells and colonising flora by various methods including sequestration of nutrients, use of metabolic pathways not used by competing bacteria, or production of bacteriocins (small antimicrobial peptides proteins that kill closely related bacteria). Motility enables pathogens to reach their site of infection, often in sterile sites that colonising bacteria do not reach, such as the distal airway. Many microorganisms, including viruses, use ‘adhesins’ to attach to host cells at the site of infection. Other pathogens can invade through tissues.

Five pathogens were selected for testing in the prototype POCT
instrument: (a) Streptococcus Pneumonia, (b) Pseudomonas,
(c) Cadida, (d) Staphylococcus aureus, and (e) Escherichia coli.
Infections with any of these pathogens can lead to sepsis.
If a patient does not receive medical intervention within hours,
 death is imminent.

Pathogens

Pathogens may produce toxins, microbial molecules that cause adverse effects on host cells either at the site of infection or remotely following carriage through the blood stream. Endotoxin is a cell wall component released mainly following bacterial cell damage and has generalised inflammatory effects. Exotoxins are proteins released by living bacteria, which often have specific effects on target organs (Box 6.3.) Intracellular pathogens, including viruses, bacteria (e.g. Salmonella spp., Listeria monocytogenes and Mycobacterium tuberculosis), parasites (e.g. Leishmania spp.) and fungi (e.g. Histoplasma capsulatum), have the capacity to survive in intracellular environments, including after phagocytosis by macrophages. Pathogenic bacteria express different arrays of genes, depending on environmental stress (pH, iron starvation, O2 starvation etc.) and anatomical location. In quorum sensing, bacteria communicate with one another to adapt their replication or metabolism according to local population density. Bacteria and fungi may respond to the presence of an artificial surface (e.g. prosthetic device, venous catheter) by forming a biofilm, which is a population of organisms encased in a matrix of extracellular molecules. Biofilm-associated organisms are highly resistant to antimicrobial agents.

Genetic diversity enhances the pathogenic capacity of bacteria. Some virulence factor genes are found on plasmids or in phages and are exchanged between different strains or species. The ability to acquire genes from the gene pool of all strains of the species (the ‘bacterial supragenome’) increases diversity and the potential for pathogenicity. Viruses exploit their rapid reproduction and potential to exchange nucleic acid with host cells to enhance diversity. Once a strain acquires a particularly effective combination of virulence genes, it may become an epidemic strain, accounting for a large subset of infections in a particular region. This phenomenon accounts for influenza pandemics.

Drugs

Drugs - A huge investment has been made by the pharmaceutical industry in finding drugs for obesity. The side-effect profile has limited the use of many agents, but a few drugs are currently licensed (Box 5.28). There is no role for diuretics, or for thyroxine therapy without biochemical evidence of hypothyroidism.

Orlistat is Drug Obesity

Anti-obesity Drug Reductil Faces a Ban in Europe

Orlistat inhibits pancreatic and gastric lipases andthereby decreases the hydrolysis of ingested triglycerides, reducing dietary fat absorption by ∼30%. The drug is not absorbed and adverse side-effects relate to the effect of the resultant fat malabsorption on the gut: namely, loose stools, oily spotting, faecal urgency, flatus and the potential for malabsorption of fat-soluble vitamins. Orlistat is taken with each of the three main meals of the day and the dose can be adjusted (60–120 mg) to minimise side-effects. Its efficacy is shown in Box 5.29 and Figure 5.13; these effects may be explained because patients taking orlistat adhere better to low-fat diets in order to avoid unpleasant gastrointestinal side-effects. Sibutramine reduces food intake through β1- adrenoceptor and 5-HT 2A/2C (5hydroxytryptamine,serotonin) receptor agonist activity in the central nervous system. 

Weight loss with sibutramine is 3–5 kg better than placebo with 6 months’ therapy and is associated with an improvement in lipid profile (see Box 5.29).Side-effects include dry mouth, constipation and insomnia. Unfortunately, noradrenergic effects of the drug can increase heart rate and blood pressure; these effects are especially undesirable in obese patients. Sibutramine is thus usually second choice after orlistat and cannot be used in those with hypertension or cardiovascular disease. There is insufficient evidence to recommend coprescription of orlistat and sibutramine.

Rimonabant is a cannabinoid receptor antagonist which acts in the hypothalamus to reduce appetite and may also have beneficial effects in peripheral tissues. Its efficacy in patients with obesity and type 2 diabetes is similar to orlistat (see Box 5.29), including reducing HbA1c by ∼1%. However, rimonabant may exacerbate or induce depression and has been associated with a small increased risk of suicide, which has prevented it being licensed in the US and has limited its use in Europe. Drug therapy is usually reserved for patients with high risk of complications from obesity (see Fig. 5.12), and its optimum timing and duration are controversial.

Although life-long therapy is advocated for many drugs which reduce risk on the basis of relatively short-term research trials (e.g. drugs for hypertension and osteoporosis), patients who continue to take antiobesity drugs tend to regain weight with time (see Fig. 5.13). This, together with finite health-care resources, has led to the recommendation in some guidelines that anti-obesity drugs are used in the short term to maximise the weight loss achieved with low-calorie diets (so that inevitable regain of weight starts from a lower baseline), but are not used in the long-term maintenance of weight.

Weight loss diets

Weight loss diets - In overweight people, adherence to the lifestyle advice above may gradually induce weight loss. In obese patients, more active intervention is usually required to lose weight before conversion to ‘weight maintenance’ advice above. A significant industry has developed in marketing diets for weight loss. These vary substantially in their balance of macronutrients (Box 5.27), but there is little evidence that they vary in their medium-term (1 year) efficacy.

eat vegetables regularly can lower weight

fitness weight loss

They all involve a reduction of daily total energy intake of ∼2.5 MJ (600 kcal) from the patient’s normal consumption. The goal is to lose ∼0.5 kg/week. Weight loss is highly variable, with patient compliance being the major determinant of success. There is some evidence that weight loss diets are most effective in their early weeks, and that compliance is improved by novelty of the diet; this provides some justification for switching to a different dietary regime when weight loss slows on the first diet. Vitamin supplementation is wise in those diets in which macronutrient balance is markedly disturbed.

Eat fruit for diet

In some patients more rapid weight loss is required, e.g. in preparation for surgery. There is no role for starvation diets, which risk profound loss of muscle mass and the development of arrhythmias (and even sudden death) secondary to elevated free fatty acids, ketosis and deranged electrolytes. Very low calorie diets (VLCDs) are recommended for short-term rapid weight loss, producing losses of 1.5–2.5 kg/week compared to 0.5 kg/ week on conventional regimes, but require the supervision of an experienced physician and nutritionist. The composition of the diet should ensure a minimum of 50 g of protein each day for men and 40 g for women to minimise muscle degradation. Energy content should be a minimum of 1.65 MJ (400 kcal) for women of height < 1.73 m, and 2.1 MJ (500 kcal) for all men and for women taller than 1.73 m. Side-effects are a problem in the early stages and include orthostatic hypotension, headache, diarrhoea and nausea.

Drugs A huge investment has been made by the pharmaceutical industry in finding drugs for obesity. The side-effect profile has limited the use of many agents, but a few drugs are currently licensed (Box 5.28). There is no role for diuretics, or for thyroxine therapy without biochemical evidence of hypothyroidism. Orlistat inhibits pancreatic and gastric lipases and thereby decreases the hydrolysis of ingested triglycerides, reducing dietary fat absorption by ∼30%. The drug is not absorbed and adverse side-effects relate to the effect of the resultant fat malabsorption on the gut: namely, loose stools, oily spotting, faecal urgency, flatus and the potential for malabsorption of fat-soluble vitamins.

Orlistat is taken with each of the three main meals of the day and the dose can be adjusted (60–120 mg) to minimise side-effects. Its efficacy is shown in Box 5.29 and Figure 5.13; these effects may be explained because patients taking orlistat adhere better to low-fat diets in order to avoid unpleasant gastrointestinal side-effects.

Smoking

Smoking - Smoking tobacco dramatically increases the risk of developing many diseases. It is responsible for a substantial majority of cases of lung cancer and chronic obstructive pulmonary disease, and most smokers die either from these respiratory diseases or from ischaemic heart disease. Smoking also causes cancers of the upper respiratory and gastrointestinal tracts, pancreas, bladder and kidney, and increases risks of peripheral vascular disease, stroke and peptic ulceration. Maternal smoking is an important cause of fetal growth retardation. 

Smoking can damage your health

Stop Smoking

Moreover, there is increasing evidence that passive (or ‘secondhand’) smoking has adverse effects on cardiovascular and respiratory health. When the ill-health effects of smoking were first discovered, doctors imagined that warning people about the dangers of smoking would result in them giving up. However, it also took increased taxation of tobacco, banning of advertising and support for smoking cessation to maintain a decline in smoking rates. In several European countries (including the UK), this has culminated in a complete ban on smoking in all public places—legislation that only became possible as the public became convinced of the dangers of secondhand smoke.  However, smoking rates remain high in many poorer areas and are increasing amongst young women. In many developing countries tobacco companies have found new markets and rates are rising. World-wide, there are ∼1 billion smokers, and 3 million die prematurely each year as a result of their habit.

In reality, there is a complex hierarchy of systems that interact to cause smokers to initiate and maintain their habit. At the molecular and cellular levels, nicotine acts on the nervous system to create dependence, so that smokers experience unpleasant effects when they attempt to quit. So, even if they know it is harmful, the role of addiction in maintaining the habit is important. Influences at the personal and social level are just as important. Many individuals bolster their denial of the harmful effects of smoking by focusing on someone they knew personally who smoked until he or she was very old and died peacefully in bed. Such strong counterexamples help smokers to maintain internal beliefs that comfort them when presented with statistical evidence.

Weaning from respiratory support

Weaning from respiratory support - This is the process of progressively reducing and eventually removing all external ventilatory support and associated apparatus. The majority of patients require mechanical ventilatory support for only a few daysand do not need weaning; simple trials of spontaneous breathing via the endotracheal tube will usually indicate whether the patient can be successfully extubated or not. In contrast, patients who have required long-termventilatory support for severe lung disease, such as ARDS, may initially be unable to sustain even a modest degree of respiratory work because of residual decreased lung compliance and hence increased work of breathing, compounded by respiratory muscle weakness. These patients require weaning until respiratory muscle strength improves to the point that all support can be discontinued. 

Evidence-based guildines for weaning and discountinuing ventilatory support

Weaning techniques involve the patient breathing spontaneously for increasing periods of the day and a gradual reduction in the level of ventilatory support. This often involves graduation to partial support modesand then non-invasive modes of ventilatory support. The process of identifying patients able to progress to spontaneous breathing and extubation is carried out.

According to a ‘weaning protocol’. This entails deciding whether a patient can be safely subjected to a spontaneous breathing trial (Box 8.22). If the patient meets these criteria, he/she undergoes the breathing trial for 2–5 minutes. The ratio of the respiratory rate to tidal volume is calculated. If it is < 105 breaths/min/L, the patient continues the trial for a further 30-minute to 2-hour period before extubation. In the event of failure (increased respiratory rate; decreased tidal volume), gradual weaning of ventilation continues using synchronised intermittent mandatory ventilation (SIMV), pressure support ventilation (PSV) or intermittent periods of spontaneous breathing. Non-invasive ventilation via a facemask can allow earlier extubation in certain groups, such as patients with COPD,

with weaning continuing after removal of the endotracheal tube. Despite the development of objective tests and indices of the patient’s ability to sustain spontaneous ventilation, the decision to extubate and the speed of weaning from mechanical ventilation still rely largely on clinical judgement.

Allostatic Load

Allostatic Load - As selye noted, the initial respon se of the body to stressful  circumstances may be arousal, but over time this response may give way to exhaustion, leading to comulative damage to to the organism, Building on these ideas, researchers have developed the concept allostatic load (McEwen & Stellar, 1993). This concept refers to the fact that physiological systems within the body fluctuate to meer demands from stress, a state called allostasis. Over time, allostatic load builds up, which in defined as the physiological costs of chronic exposure to fluctuating or heightened neural or neuroendocrineresponse that results from repeated or chronic.

Mornington Peninsula Chiropractors

Allostatic Load

This buildup of allostatic load that is, the longterm costs of chronic or repeated stress can  be assessed by a number of indicators (T. E. Seeman, Singer, Horwitz & McEwen, 1997). These include decreases in cellmediated immunity, the inability to shut off cortisol in response to stress, lowered heart rate variability, elevated  epinephrine levels, a high waist to hip ratio, volume of the hippocampus (which is believed to decrease with repeated stimulation of the HPA), problems with memory (an indirect measure of hippocampal functioning), high plasma fibrinogen, and elevated blood pressure. Many of these changes occur normally with age, so to the extent that they occur early, allostatic load may be thought of as accelerated aging of the organism in response to stress. Over time, this kind of wear and tear can lead to illness. These effects may be exacerbated by the poor health habits practiced by people under chronic stress. The damage due to chronic stress. The damage due to chronic or repeated stress is only  made worse if people also cope with stress via higher fat diet, less frequent exercise, and smoking, all of which stress can encourage (Ng & Jeffery, 2003).

The physiology of stress and, in particular, the recent research on the cumulative adverse effects off stress are important because they suggest the pathways by which stress exerts adverse on the body ultimately contributing to the likelihood of desease. The relationship of stress, both short and long term, to both acute disorders such as infection, and chronic disease is now so well etabilished that stress is implicated in most deseases, either  in their etiology, their course, or both. We explorer these processes more fully when we address different disease such as heart desease and hypertension in chapter 13 and cancer and arthritis in chapter 14. At this point, suffice it to say, stress is one of the major risk factors for desease that humans encounter.