Skin and Soft tissue infections

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Respiratory tract infections

Respiratory Tract Infections

Respiratory Tract Infections

Respiratory infections are caused by viruses, or bacteria, or both. If the illness is entirely viral in origin, an antibiotic will not help. If there is a bacterial component, antibiotic treatment will sometimes help, and may be vital. It is often difficult to recognize when bacteria may be involved in respiratory infection as secondary bacterial infection may complicate viral respiratory infections. However, the key question in the decision about treatment with antimicrobials is: do the benefits to the patient outweigh the risks? It is not necessary to prescribe antimicrobials for all bacterial respiratory infections.

When considering the role of antimicrobial chemotherapy it is important to reflect on the epidemiology of infection in the twentieth century (Fig. 1). There are two striking features: the doubling of mortality in 1918, caused by the influenza pandemic; and the steep decline in mortality through the first half of the century, before the arrival of antimicrobial chemotherapy or vaccines. The introduction of antimicrobial chemotherapy did accelerate the decline in mortality from some respiratory infections (e.g. otitis media, pneumonia, and tuberculosis) but had no impact on others (e.g. bronchitis). Two conclusions can be drawn from Fig. 19.1 first, it is clear why there is so much concern about the possibility of an influenza pandemic given the massive impact on mortality of the 1918 pandemic. Second, antimicrobial chemotherapy has not had the dramatic effect on mortality from infections that is popularly attributed to it. The major impact in the first half of the twentieth century came from improvements in public health, which is why death from all infections still increases with increasing socio-economic deprivation in the twenty-first century. Antimicrobial chemotherapy is just one component of an overall strategy to prevent and treat infections.

Fig. 1 Infectious diseases mortality in the USA during the twentieth century. Reproduced from Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. Journal of the American Medical Association 1999; 28: 61-66 with permission from American Medical Association.

Upper respiratory tract infection

Sore throat

This is one of the commonest acute problems seen in general medical practice, with an incidence of 100 cases per 1000 inhabitants per year, although only a minority of these will present to a doctor. It is commoner in females than men. Symptoms include: sore throat with anorexia, lethargy, and systemic illness. On examination there may be inflamed tonsils or pharynx, a purulent exudate on tonsils, fever, and anterior cervical lymphadenopathy.

Sore throat may be part of the early symptom complex of many upper respiratory viral infections, in which case cough is a common additional feature. Occasionally, it may be a presenting symptom of acute epiglottitis or other serious upper airway disease.

There is no evidence that bacterial sore throats are more severe or long-lasting than viral ones. The most commonly identified organism is Streptococcus pyogenes, the group A β-haemolytic streptococcus. Most other cases are caused by adenoviruses. There is no reliable way to distinguish between bacterial and viral causes based on symptoms and signs.

The gold standard for diagnosis of streptococcal infection in the throat includes a positive anti-streptolysin O (ASO) titre in addition to culture of Str. pyogenes from the throat. There is a high asymptomatic carrier rate for the organism (up to 40%) and it is common to culture it from sore throats when there is no serological evidence of infection. Moreover a negative culture does not rule out Str. pyogenes as a cause of sore throat. Neither culture of throat swabs nor rapid tests based on detection of streptococcal antigen are helpful in most cases.

Most people with sore throat manage the condition successfully without seeing a doctor. Paracetamol is an effective analgesic, with less risk of adverse effects than non-steroidal anti-inflammatory drugs. Aspirin should be avoided in children because of the risk of Reye's syndrome. The immediate benefits from antimicrobial chemotherapy are actually very meagre. Symptoms usually persist for 5-7 days with or without antibiotics, which only shorten illness by 24 h. The same control of symptoms can probably be achieved with paracetamol.

Streptococcal sore throat is important because it may lead to serious complications, particularly rheumatic fever, which is still prevalent in many countries. Evidence about the effectiveness of antibiotics for preventing nonsuppurative and suppurative complications comes from studies on military personnel living in overcrowded barracks in the late 1940s and early 1950s. This evidence has little relevance to management of sore throat in modern communities, at least in the developed world, where rheumatic fever is now very uncommon. Similarly experience with the use of antibiotics to prevent cross-infection in sore throat comes mainly from army barracks and other closed institutions. It is very unlikely (and unproven) that trying to eradicate Str. pyogenes with routine antibiotic therapy for sore throat will produce any measurable health gain in the general public in Western countries, whereas it is likely that this would increase the prevalence of antimicrobial resistance.

A patient information leaflet may be of value in the management of acute sore throat and may assist in managing future episodes at home without general practitioner involvement. Patients who are skeptical about withholding antibiotics can be given a prescription with the suggestion that they do not use it unless their symptoms persist for more than 3 days. Only about 30% of patients who are given delayed prescriptions go to the pharmacy to get their antibiotics.

If antibiotics are to be prescribed the drugs of choice are penicillin V or a macrolide, and these should be given for at least 10 days to eradicate the organism and prevent recurrence. Glandular fever commonly causes symptoms and signs that are indistinguishable from streptococcal throat infection (including a very impressive purulent exudate on the tonsils). Ampicillin, amoxicillin, and co-amoxiclav should not be used, as they will cause a rash if the sore throat is the herald of glandular fever. Tetracyclines are also inappropriate because of the high incidence of resistance among streptococci.

Other infections that may present with sore throat

Croup

Noisy difficult breathing, hoarseness, and stridor are common signs of croup, a distressing condition that is usually viral in origin. Treatment is supportive; the condition is usually self-limiting and resolves in 2-4 days if uncomplicated, but severe cases may require endotracheal intubation or tracheostomy. Acute epiglottitis is a much less common, but much more dangerous, cause of croup caused by infection with Haemophilus influenzae type b; it can occur in adults as well as in children. There is systemic illness as well as local respiratory difficulty, and the swollen oedematous epiglottis can cause complete airways obstruction with dramatic suddenness. It is this complication that makes acute epiglottitis such a life-threatening condition. Treatment is as much concerned with maintaining the airways as with controlling the infection.

If breathing difficulty is present in a patient with croup, urgent referral to hospital is mandatory and attempts to examine the throat should be avoided.

Diphtheria

Although rare in countries with effective vaccination policies, diphtheria is still prevalent in many parts of the world. Diagnosis is made on clinical grounds, notably the presence of a characteristic membranous exudate on the tonsils and pharynx. Treatment with antitoxin should be given immediately without waiting for laboratory confirmation. Antibiotics have no part to play in treating the infection, but penicillin or erythromycin is effective in eradicating the infection to prevent spread.

Thrush

Oral thrush, infection of the mucous membrane with the yeast Candida albicans, is predominantly a neonatal infection. Candida is a common vaginal commensal, especially in pregnancy, and the infant acquires infection during passage through the birth canal. It presents in the first few days of life as white curdy patches on cheeks, lips, palate, and tongue. Treatment is with local nystatin.

In adults, oral thrush may follow treatment with antibacterials or corticosteroids. However, it may be indicative of serious underlying disease, such as diabetes or immunodeficiency. In all these conditions one of the oral polyene or azole derivatives may be used to control the candida.

Acute otitis media

Three-quarters of cases of acute otitis media occur in children; one in four children will have an episode during their first 10 years of life. Acute otitis media should be distinguished from otitis media with effusion, commonly referred to as glue ear; as many as 80% of children suffer this infection at least once before the age of 4.

Acute otitis media is an inflammation of the middle ear of rapid onset presenting with local symptoms (earache, rubbing or tugging of the affected ear) and systemic signs (fever, irritability, disturbed sleeping). It is often preceded by other upper respiratory symptoms such as cough or rhinorrhoea. On examination a middle ear effusion may be present but in addition the drum looks opaque and may be bulging.

The condition is caused predominantly by H. influenzae and Streptococcus pneumoniae. Staphylococci, Str. pyogenes, and α-haemolytic streptococci are less often involved. However, acute otitis media should not be treated routinely with antibiotics. As with sore throat, antibiotics only have a small impact on the duration of acute symptoms, which can be controlled equally effective with paracetamol. If an antibiotic is to be prescribed a 5-day course is sufficient; the antibiotic of choice is amoxicillin; erythromycin and coamoxiclav are logical alternatives and may be necessary if β-lactamase-producing H. influenzae is involved. Decongestants, antihistamines, and mucolytics are not effective. As with sore throat, patient information leaflets and delayed antibiotic prescriptions are effective strategies for reducing the unnecessary use of antibiotics.

Glue ear is an inflammation of the middle ear with accumulation of fluid in the middle ear but without symptoms or signs of acute inflammation. It is often asymptomatic and earache is uncommon. On examination a middle ear effusion is present but with a normal looking ear drum. Antibiotics should not be given.

Acute sinusitis

Acute sinusitis presents with pain originating in the maxillary, frontal, ethmoid, or sphenoid sinuses, with the maxillary sinus being by far the commonest. Onset of facial pain is often preceded by non-specific symptoms of upper respiratory inflammation and there may be systemic signs of inflammation. The bacterial causes of acute sinusitis are the same as acute otitis media. If X-ray or culture confirms the clinical diagnosis then antibiotics can substantially reduce the duration of symptoms. However, neither of these investigations is routinely available in primary care.

Culture of the sinuses requires percutaneous sinus puncture and aspiration, which is not a procedure that most general practitioners are trained to do (or that many patients would consent to). Unfortunately antibiotic treatment of patients with symptoms suggestive of sinusitis but without confirmation by X-ray or culture is no more effective than symptomatic relief.

As with acute otitis media antibiotics for acute sinusitis should be reserved for the more severe cases. Penicillin V or amoxicillin are as effective as newer antibiotics. The recommended duration of treatment is 10 days in the absence of evidence that shorter courses are as effective.

Lower respiratory tract infections

Acute cough is the most common symptom of lower respiratory infection, whether as a new symptom or as an exacerbation of chronic symptoms. Cough is not a universal feature: some patients with pneumonia present with pleuritic chest pain or with symptoms of systemic inflammatory response (fever, malaise, headache, or myalgia) without cough. The most important diagnosis to make is pneumonia because it can be life threatening and its outcome can be improved with antimicrobial chemotherapy. However, it is not possible to distinguish reliably between pneumonia and other causes of lower respiratory tract infection from clinical history and signs. Consequently, in primary care management must be based on an assessment of severity of illness and need for referral to hospital.

Epidemiology

The incidence of lower respiratory tract infection in the UK is between 40 and 90 cases per 1000 population per year, being commoner in the very young and old and in the winter months. In the UK there is about a four-fold higher incidence in the most deprived communities in comparison with the most affluent communities.

Mortality is highest in the elderly. The 30-day mortality associated with lower respiratory tract infection in people over 65 years old is 10%. However, many of these elderly people die ‘with’ rather than ‘of’ the infection. Bronchopneumonia is often recorded as the immediate cause of death in people with chronic, life-threatening diseases. Mortality from ‘pneumonia’ has actually increased in developed countries since the introduction of antibiotics, but more people are living longer and most of this mortality is from bronchopneumonia.

Most people with lower respiratory infections manage their own symptoms without seeking medical attention. Of 1 million people with lower respiratory tract infection only 300 000 will see a primary care physician. Of these 1 in 4 (70 000) will be treated with antibiotics, although only about 1 in 10 (7000 people) will have a diagnosis of pneumonia. From the original 300 000 people who presented to a primary care physician only about 200 (0.7%) will be admitted to hospital with pneumonia.

Management in primary care

The key to management of lower respiratory tract infection in primary care is to distinguish between patients who have severe infection that should be referred to hospital and the majority (99%) who can be managed safely at home. There are four questions to address:

• Has the patient been previously well or is there underlying chronic respiratory or other disease?
• Has there been the development or deterioration in either dyspnoea or sputum purulence?
• Are there any new localizing physical signs in the chest to suggest pneumonia?
• Are any features of severity present (Box 19.1).

The answers to these questions distinguish between four broad populations of people with lower respiratory tract infection. These will be discussed starting with the most severe (but least common).

Box 19.1 Features of severity of lower respiratory tract infection that can be easily assessed in primary care (items in bold are most important)

• Raised respiratory rate (>30/min)
• Low blood pressure (<90mmHg systolic and or <60mmHg diastolic)
• Confusion of recent onset
• Age>50 years
• Coexisting disease present (e.g. severe chronic obstructive pulmonary disease, cardiac failure, cerebrovascular, neoplastic, renal or liver disease)
• Very high or very low temperature (<35°C or >40°C)
• Tachycardia (>125/min)

Patients with features indicating severe infection

Referral to hospital should be considered in patients who exhibit one or more of the features of severity , especially if they are over the age of 50. This applies whether or not the patient has additional physical signs indicating pneumonia because the absence of these signs is not a reliable method for excluding pneumonia. The final decision should be based on clinical judgement that includes social factors. Even a relatively well patient who lives in poor social circumstances or in an isolated rural area with no home support may require referral to hospital. Conversely patients who are 65 years old and have signs of pneumonia can be managed safely at home if they have sufficient social support.

Suspected community-acquired pneumonia without features of severity

These patients have new focal signs in the chest (crackles or altered breath sounds), but are not severely ill. In the absence of chest X-ray (not available in many primary care settings) pneumonia can be diagnosed from symptoms of an acute lower respiratory infection (cough or dyspnoea or pleuritic chest pain) with at least one systemic symptom of infection (fever or tachycardia) and new focal signs on chest examination. However, only 50% of those with all of these features will actually have an abnormal chest X-ray.

Below the age of 45 very few patients with pneumonia also have chronic obstructive pulmonary disease. Between the ages of 45 and 64 the proportion is up to 10% and rises to 20% between the ages of 75 and 84. Pneumonia in these patients is more likely to be associated with severity criteria.

A wide variety of organisms can cause pneumonia, including viruses. The commonest bacterial cause is Str. pneumoniae, which accounts for about 70-80% of cases in which a bacterial pathogen is identified. Atypical bacteria (Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae, Chlamydophila psittaci, Legionella pneumophila, and Coxiella burnetii) collectively account for 10-20% of cases and the remainder are caused by H. influenzae or Staphylococcus aureus. The latter is particularly associated with secondary bacterial infection following influenza.

With current technology neither sputum culture nor blood tests such as C-reactive protein or white cell count provide sufficient added value to the diagnosis to justify routine use. Sputum culture may be recommended in areas with a high prevalence of penicillin-resistant pneumococci.

Pneumonia is a life-threatening illness. None the less, patients with no features of severity can be managed safely at home with oral amoxicillin, a macrolide, or a tetracycline. There is no need to give combination therapy. A macrolide or tetracycline may be preferred if there are clinical features suggesting infection with one of the atypical bacteria (e.g. prominent upper respiratory symptoms, headache, or symptom duration for >1 week) particularly in younger patients or during an epidemic year for M. pneumoniae.

Patients with underlying chronic respiratory disease

These patients often have no new signs in the chest other than dyspnoea and sputum purulence. In the absence of signs of severity or of pneumonia the diagnosis is an acute exacerbation of the underlying condition. The likely bacterial pathogens are H. influenzae, Str. pneumoniae, and Moraxella catarrhalis. The development of green (purulent) sputum is a good indicator of a high bacterial load in the sputum. However, even in these patients antibacterial treatment has only a slight impact on the course of an acute exacerbation, shortening an illness of 5-7 days by no more than 1 day. Antibacterial treatment does not benefit patients with acute exacerbations of chronic obstructive pulmonary disease who do not have purulent sputum. The prevalence of resistance to aminopenicillins in H. influenzae is 10-30% and is much higher in Mor. catarrhalis. Despite this the clinical effectiveness of amoxicillin is just as good as co-amoxiclav or fluoroquinolones, probably because of the modest benefit from any antibacterial treatment. For the same reason routine sputum culture is not recommended and should be reserved for patients with symptoms that persist despite treatment with amoxicillin. A macrolide or tetracycline is appropriate for patients who are allergic to penicillin, or who have not responded to amoxicillin treatment. Fluoroquinolones should not be used empirically in the management of exacerbations of respiratory disease in primary care.

Non-pneumonic lower respiratory infection (acute bronchitis)

Most patients with no signs in the chest, who have been previously well and do not have other features of severity, have non-pneumonic infection, most of which are caused by viruses. A few cases are caused by M. pneumoniae, Bordetella pertussis, C. pneumoniae, Str. pneumoniae, or H. influenzae. Patients will have an illness lasting several days with or without antibiotics, which should not be prescribed unless patients have signs in the chest or features of severity (Box 19.1). Sputum purulence alone is not an indication for antibiotics in a previously well patient with no chest signs. As with sore throat and acute otitis media, patient information leaflets and delayed prescriptions are effective strategies for reducing unnecessary antibiotic treatment.

Pertussis (whooping cough)

Antibiotics are notoriously ineffective in controlling the distressing cough of pertussis; nevertheless, erythromycin has been shown to eradicate the organism from the respiratory tract and can also be used for the protection of susceptible close contacts. Vaccination is the only reliable way of preventing and controlling this early childhood infectious disease.

Cystic fibrosis

The susceptibility of patients with cystic fibrosis to pulmonary infection is well recognized and is often the cause of early death. Most lung infections in patients with cystic fibrosis are managed in the community, usually by outreach teams from secondary care. One of the striking features of chest infections in cystic fibrosis is that relatively few pathogens are involved. Early in the disease the organisms implicated are frequently Staph. aureus or H. influenzae, or both. As patients progress through adolescence to adulthood, these pathogens are replaced by Pseudomonas aeruginosa. Major problems arise when Ps. aeruginosa is replaced by Stenotrophomonas maltophilia or Burkholderia cepacia; these organisms are often resistant to many antibiotics and treatment should be guided by laboratory findings. The selection of antibiotics in patients with cystic fibrosis should be determined by the specialist services that manage the patient.

Management in hospital

Community-acquired pneumonia

In hospital the clinical diagnosis can be confirmed with a chest X-ray, although it should be recognized that its sensitivity is not 100%. The gold standard for diagnosis of bacterial pneumonia is culture of bacteria from lung tissues or a needle aspirate from the lung but these tests are too dangerous to use in routine clinical practice. The point is that some patients with pneumonia can have a normal chest X-ray at presentation, so if the clinical features strongly suggest pneumonia it is reasonable to treat and repeat the chest X-ray after 24-48 h.

The severity criteria for community-acquired pneumonia are based on assessments of confusion, urea concentration, respiratory rate, and blood pressure for those 65 years of age and older (CURB-65 score; Table .1). It is similar to but importantly different from the classification of severity of sepsis. The CURB-65 score is specifically designed to be used in patients who present to hospital in order to identify low-risk patients who do not need to be admitted to hospital, whereas the classification of sepsis is intended to be used for any patient with infection (community or hospital acquired) to identify patients who are deteriorating and require more intensive therapy. The CURB-65 score identifies low-risk patients more accurately than the sepsis severity score. There are more complex pneumonia-specific scores (for example the pneumonia severity index used in North America) but these are no more accurate than CURB-65.

Table .1 The CURB-65 severity score for patients presenting to hospital with community acquired pneumonia and the mortality range measured in two prospective cohort studies. CURB-65: score one point for each of: Confusion; urea >7mmol/l; respiratory rate ≥30/min; low systolic (<90mm Hg) or diastolic (≤60mm Hg) blood pressure); age ≥65 years
Risk CURB-65 score 30-day mortality Low risk 0-1 0-1% Intermediate 2 8-9% High risk >2 22-23% All patients Not applicable 9-10% Data from Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377-382.

Between 30 and 50% of patients who present to hospital with community-acquired pneumonia are found to be in the CURB-65 low-risk group. However, about half of these patients have other reasons for admission. Some will have co-morbidities that require inpatient management. In particular, patients with chronic obstructive pulmonary disease and pneumonia could be in respiratory failure and yet have a CURB-65 score of 0 (if they have a respiratory rate <30/min, which is likely if they have Type 2 respiratory failure). In addition to medical reasons for admission some patients will have poor social circumstances or insufficient support to be managed at home.

The management of patients admitted to hospital should be determined by their CURB-65 score. Low-risk patients who are admitted for other reasons can be managed in the same way as low-risk patients in the community, with either amoxicillin, a macrolide, or a tetracycline. Some guidelines do recommend that all patients admitted to hospital with pneumonia should receive antibiotics for pneumonia caused by atypical bacteria but several clinical trials shows that treatment with an aminopenicillin alone is just as effective for patients with low or intermediate risk pneumonia.

At the other end of the scale, patients at high risk should be treated with intravenous antibiotics that are effective against the full range of pathogens that may cause community-acquired pneumonia. Possible regimens include co-amoxiclav or cefuroxime plus a macrolide, or a fluoroquinolone with good activity against Str. pneumoniae (e.g. levofloxacin). The patient must receive the antibiotic(s) immediately and certainly within 4h of admission as later administration is associated with increased mortality. If patients are admitted through an Accident and Emergency Department they must receive their first dose of antibiotics there before transfer to the ward. If they are admitted direct to a ward the first dose must be clearly written for immediate administration, not left until the next drug round. In addition to intravenous antibiotics patients with severe pneumonia must have their oxygen requirements assessed by pulse oximetry or blood gas measurement within 4h of admission and receive high flow oxygen (5 litres per minute) if they are hypoxic. Adequate fluid replacement is also essential. Patients should be referred to a high dependency or intensive care unit if their vital signs do not improve rapidly. When young patients die from community-acquired pneumonia it is usually because of failure to recognize the need for intensive care.

The management of patients at intermediate risk falls between these two extremes and is a matter for clinical judgement. If in doubt it would be wise to treat as severe pneumonia while waiting for senior review.

Hospital-acquired pneumonia

Pneumonia is the leading cause of mortality resulting from infection acquired in hospital. The incidence of hospital-acquired pneumonia in intensive care units ranges from 10 to 65%, with case fatalities of 13-55%. It is often associated with mechanical ventilation. The risk of hospital-acquired pneumonia can be substantially reduced by using non-invasive methods for respiratory support instead of ventilation and by having clear care protocols for protecting host defences against respiratory infection during mechanical ventilation. Chemoprophylaxis plays a role through the use of selective decontamination of the digestive tract, which reduces the numbers of Gram-negative bacilli and hence the risk of infection.

The micro-organisms causing pneumonia within 5 days of admission are quite different from those seen in disease with a later onset. The bacteria responsible for early onset pneumonia are Str. pneumoniae, H. influenzae, Staph. aureus, and only rarely enteric Gram-negative bacilli. In contrast late onset infection is almost always caused by Gram-negative bacteria, mainly enterobacteria but also Ps. aeruginosa and Acinetobacter spp.

Methicillin-resistant Staph. aureus (MRSA) is becoming increasingly common in some units. Since tracheal aspirates are poor indicators of the cause of ventilator-associated pneumonia, bronchoalveolar lavage is recommended to confirm the diagnosis.

Empirical treatment for early onset pneumonia in patients who have not received antibiotics should be with co-amoxiclav or cefuroxime. Treatment of patients who have already received antibiotics or have late onset disease should be with a broad-spectrum cephalosporin such as cefotaxime, a fluoroquinolone or piperacillin plus tazobactam. Combination therapy is no more effective than monotherapy. Subsequent treatment should be directed by the results of broncho-alveolar lavage.

Other respiratory tract infections

Pneumonia developing in association with neutropenia following treatment with cytotoxic drugs, or in patients with immunosuppression, including those suffering from AIDS, may be due to Pneumocystis carinii, other fungi, or viruses

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Control of the Spread of Resistance

Control of the Spread of Resistance

The 60-year period during which antibiotics have been available has seen dramatic changes in the disease burden caused by infections. Outcomes from infections such as pneumococcal pneumonia, tuberculosis, and streptococcal puerperal sepsis, that used to cause considerable morbidity and mortality, are now frequently benign, at least in developed countries. We can also prevent much infection by using antibiotics during high-risk procedures, notably in the peri-operative period. The immense social, economic, and health benefits that are due to antibiotic use are, however, increasingly overshadowed by the issue of resistance. Indeed, the emergence and spread of multiresistant strains (sometimes referred to emotively as ‘superbugs’) have raised the spectrum of untreatable infection. The reality is that such instances remain extremely rare. However, resistance does limit antibiotic choice available to prescribers, sometimes meaning that less effective, more toxic or more expensive drugs have to be used. For example, the antibiotics needed to treat multiresistant forms of tuberculosis are over 100 times more expensive than the first-line drugs used to treat disease caused by fully susceptible strains. Such excess costs mean that some infections can no longer be treated in poor communities where resistance to first-line drugs is widespread. Furthermore, significant slowing in the development of genuinely new antibiotics (i.e. those with novel modes of action to which cross-resistance to older agents does not occur) has increased the potential for this threat to become a reality that once again compromises patient outcome.

In 1945 during his Nobel Prize acceptance speech Sir Alexander Fleming said ‘It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.’ This warning was evident less than a decade after the introduction of penicillin, when a particular penicillin-resistant Staphylococcus aureus strain started to cause outbreaks of postoperative and perinatal infection in hospitals across the world. Poor hospital cleaning, increasing dependence on antibiotics and changing healthcare practices were blamed. Unfortunately, these issues are again topical, with frequent media headlines about ‘superbugs’ and their spread.

Compared with most other drugs of similar potency, antibiotics are remarkably safe, and they are also remarkably effective. This has inevitably led to liberal, even lavish use, and concern has frequently been expressed that excessive and inappropriate use of these agents is the chief cause of the widespread emergence of resistant organisms. Misuse of most drugs tends to have consequences only for the individual patient. Unfortunately, inappropriate antibiotic use can have adverse consequences for both the individual and for wider populations. Below Figure shows the disturbing relationship between the prescribing of penicillin-like antibiotics in multiple populations and the respective prevalence of pneumococcal strains with reduced susceptibility (or frank resistance) to penicillin. Of course, many of the antibiotics prescribed would not have been specifically for pneumococcal infection. This is, therefore, evidence of the selective pressure for resistance emergence in (respiratory tract) flora and subsequent spread of bacteria within populations. Such effects have been referred to as the collateral damage associated with antibiotic therapy.

Availability of antibiotics

Most developed countries have tightly regulated systems for the control of the manufacture, importation, distribution, sale, supply and description of medicinal products, including antibiotics, for human and veterinary use. In the global market for medicines, licensing authorities will increasingly be required to ensure that there is a consistency of approach to medicines availability. Currently there are many examples of inconsistencies in the availability and recommendations for use of antibiotics throughout both the developed and developing world. The availability of antibiotics, notably newer more expensive agents is an issue in poorer countries. Pharmaceutical companies have a part to play in helping to ensure that antimicrobial agents, including critical antimalarial, antituberculosis, and antiretroviral drugs are priced and advertised appropriately in these markets.

While the sale and distribution of antibiotics are fairly tightly controlled in rich, developed countries, the marketing of these agents is much less restricted in the poorer, and numerically much larger, developing world. Paradoxically, the use of antibiotics in the developing countries needs to be extended, not restricted, if standards of health are to be brought up to those of the developed world. A key issue here is unregulated ‘over the counter’ availability of antibiotics. Controversy persists about striking a balance between making effective medicines available in a timely fashion to those who need them, against the potential detrimental effects of uncontrolled or indiscriminate use. This argument is most pertinent in the case of antimicrobial drugs, as there is no other example in therapeutics in which local misuse of an efficacious agent can lead to a general diminution in its effectiveness. It was no great surprise that chloramphenicol-resistant typhoid bacilli first emerged in South America and penicillin-resistant gonococci in south-east Asia, where unrestricted availability of antibiotics is commonplace. In some countries antibiotics can still be purchased easily as single tablets resulting in inappropriate use, suboptimal dosing and the consequent encouragement of resistance.

Correlation between antimicrobial use (outpatient prescribing of penicillins) and resistance (prevalence of penicillin-non-susceptible Str. pneumoniae) in 19 countries in Europe. Reprinted from: Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005; 365: 579-587 with permission from Elsevier.

In the UK fluconazole and aciclovir have been available for over-the-counter purchase without the need for a prescription for more than a decade. There is no convincing evidence that this availability additional to prescribed courses has increased the emergence of resistance to these agents in the target pathogens—Candida albicans and herpes simplex virus—for which they are commonly used. This may, however, reflect inherent properties of these drugs uncommonly to select for resistant variants. There is pressure to extend the availability of over-the-counter antibiotics to include drugs such as trimethoprim for use in urinary tract infections. It will be important to monitor any such changes closely to determine the benefits and drawbacks of any such deregulation of antibiotics. A related issue is the extension of capacity to prescribe antibiotics (and other drugs) to other healthcare professionals, including pharmacists and nurses. Such extended roles clearly need to be underpinned by appropriate training and education, and the availability of carefully constructed guidelines (see below).

Inappropriate antibiotic use

Attention has repeatedly been drawn to the worldwide public health problem of the spread and persistence of drug-resistant organisms, and there have been frequent calls for regulation to curb the unnecessary use and misuse of antimicrobial drugs in some countries. The following practices have been clearly identified as contributing to the present situation:

• Inappropriate prescribing of antibiotics; e.g. for ailments for which they are ineffective, such as for sore throats where 80% of infective cases are caused by viruses.
• Incorrect dose or duration of use; e.g. in uncomplicated urinary tract infection more than 3 days of antibiotic treatment does not increase the chance of success, but does increase the risk of selection of resistance bacteria in the gut flora and adverse drug effects.
• Excessive use of antibiotic prophylaxis; e.g. for most types of surgery there is no value in giving more than one dose of antibiotic(s). Excess antibiotic doses may encourage resistance emergence or side effects including antibiotic-associated diarrhoea.
• Antibiotic use without prescription; e.g. the uncontrolled availability of antibiotics ‘over the counter’, which can result in unnecessary use or intermittent, suboptimal dosing. The increasing availability of antibiotics through the internet may exacerbate this risk. In some countries, poorly formulated or manufactured, counterfeited or expired antibiotics are sold and used for self-medication or prophylaxis.
• Animal/agricultural use of antibiotics; e.g. using clinically useful antibiotics as growth promoters in animal feeds and on agricultural crops (see below).

Antibiotics use in animals

More than half of all antibiotics produced worldwide are used in animals, primarily as part of the food production chain. Two aspects of this use are particularly concerning. First, there is a large overlap between the types of antibiotics given to animals and those used to treat infection in man. Secondly, large quantities of antibiotics are used not to treat overt infection but instead as animal growth promoters to increase weight gain and therefore market value of animals. Combining these two issues, it is not surprising therefore that there is mounting evidence of resistant bacteria developing in animals and either infecting human beings or acting as a source of resistance genes for human pathogens. For example, avoparcin use in animals is linked to the development of resistance to glycopeptides in animal strains of enterococci and possibly also in human strains. Avoparcin was banned as a growth promoter in Denmark in 1995, at which point about 80% of Danish broiler chickens were colonized with vancomycin-resistant enterococci; the current prevalence is less than 5%. Similarly, fluoroquinolone use in animals has been clearly associated with the increase in prevalence of fluoroquinolone resistance in salmonella and campylobacter strains that infect man. Notably, a multiresistant Salmonella enterica serotype Typhimurium strain (DT104) has spread in animals, foods and, subsequently, in human beings.

All use of antimicrobial agents for growth promotion is now banned in the European Union. There is some concern that the therapeutic use of antibiotics in animals may increase as use of antibiotic growth promoters is curtailed, but this is unlikely to have the same negative consequences as seen with unrestricted use of antibiotics in animals.

Antibiotic prescribing in the community and hospital

The European Union, the US Food and Drug Administration and the World Health Organization have initiated national and regional campaigns aimed at professionals and the public to reduce the unnecessary prescribing of antibiotics. Efforts have been concentrated on prescribing in the community, not least because this accounts for 80% of all human use of antimicrobial drugs. Principles such as not prescribing antibiotics for viral sore throats, or simple coughs and colds, and avoiding the use of new and more expensive antibiotics (e.g. quinolones and cephalosporins) when standard and less expensive antibiotics remain effective have been emphasized. Prescribing of antibiotics started to fall in England in 1995-1996. The decrease subsequently stabilized, with a slight rise in 2003-2004.

It is not clear whether this decrease in prescribing has been driven by reduced incidence of infections (such as respiratory tract infections), reduced consultation rates, or because general practitioners are following prescribing guidance for infections more closely. However, prescribing of paediatric antibiotic preparations fell by almost 50%—a much greater reduction than that seen for the whole population. This suggests that public (parental) expectation, and hence pressure, for the doctor to prescribe an antibiotic following a consultation may be decreasing.

Trends in prescribing of antibacterial drugs in general practice in England. Reproduced from: National Health Service Business Services Authority prescription pricing division website.

It is estimated that up to 50% of antibiotic usage in hospitals is inappropriate. Interventions to improve antibiotic prescribing for hospital inpatients can be successful, and importantly may reduce antimicrobial resistance or hospital-acquired infections, such as Clostridium difficile infection. A key issue is choosing the most appropriate control methods for a given setting and ensuring that they are sustainable. The scope of measures that can be used to reduce inappropriate antibiotic prescribing is too large to consider in detail here, but can generally be grouped into educational or restrictive approaches or a combination of the two.

Appropriate antibiotic use

The World Health Organization advocates the following 12 key interventions to promote more rational use of medicines in general; all are applicable to antibiotic use:

1. Establishment of a multidisciplinary national body to coordinate policies on medicine use.
2. Use of clinical guidelines.
3. Development and use of national essential medicines list.
4. Establishment of drug and therapeutics committees in districts and hospitals.
5. Inclusion of problem-based pharmacotherapy training in undergraduate curricula.
6. Continuing in-service medical education as a licensure requirement.
7. Supervision, audit, and feedback.
8. Use of independent information on medicines.
9. Public education about medicines.
10. Avoidance of perverse financial incentives.
11. Use of appropriate and enforced regulation.
12. Sufficient government expenditure to ensure availability of medicines and staff.

In addition to these measures, good antimicrobial prescribing needs to be informed by timely and accurate information on the likely infecting pathogens. Delays in diagnosis occur through poor or non-existing sampling techniques, delay in transport, slow and laborious laboratory techniques, and unsatisfactory reporting methods. A major problem in dealing with patients in whom an infection is suspected is distinguishing between infection and colonization. Patients with an undiagnosed fever may well be colonized with potentially pathogenic micro-organisms, but may not be infected. The distinction is not always obvious, and under these circumstances it is understandable for a clinician to prescribe antibiotics. It is not rational, however, to treat patients merely because they have a raised temperature. Good practice dictates that all relevant samples for culture should ideally be collected before treatment, unless this requirement could compromise outcome (for example, in patients with suspected meningitis where prompt antibiotic therapy may be life saving). The initial choice of antimicrobial therapy will depend on the most likely infecting organism, the severity of the illness, and the type of patient. If the identity of the organism is known then treatment can be specific and a single, narrow-spectrum antibiotic used. If the infecting organism can be targeted then broad-spectrum antibiotics do not need to be used, thus leaving much of the body's normal flora undisturbed.

Initial (often empirical) antibiotic therapy is based on good surveillance and prompt guidance informed by accessible policies (see Chapter 18) or from infection specialists. Crucially, antibiotic prescriptions should be reviewed regularly to determine whether the drug or route of administration is still appropriate. Oral antibiotics tend to be considerably cheaper than intravenous alternatives and of course do not require an access device that itself may be a source of infection. For these reasons, intravenous antibiotics should be reviewed after 48-72 h and switched to an ‘equivalent’ oral formulation, provided oral absorption is satisfactory and the oral antibiotic has the requisite pharmacokinetic characteristics. New microbiological or other information (e.g. fever defervescence for at least 24 h, marked clinical improvement; low C-reactive protein) should prompt a review of therapy and consideration of whether a switch to oral antibiotic(s), a narrow spectrum intravenous alternative, or cessation of antibiotics (no infection present) is appropriate. Laboratory reports should contain information on a restricted number of antibiotic susceptibilities.

Antibiotic policies and resistance surveillance

Even in relatively straightforward clinical situations there are often several equally effective agents that might be used. Choice may then be determined by a locally agreed set of guidelines for the rational use of antibiotics. The antibiotic formulary is a locally agreed list of available antibiotics, usually including some degree of restriction on particular agents. Guidance on the most appropriate use of antibiotics should not be too restrictive, should reflect local needs, and should be formulated with the agreement of the local users. Advice should of course facilitate the most effective treatment for the individual patient, but should take into account the potential consequences for the wider population.

The best antibiotic policies are grounded in good microbiology laboratory surveillance, which is required to detect important change in bacterial resistance. Clinicians need to be aware of the local and changing patterns of infection and antibiotic resistance in their locality. Information about new agents, together with an assessment of their likely place in therapy, should be available. There are a number of caveats to pathogen and antibiotic surveillance data in general. Bias inherent in the way samples or pathogens are collected is a common problem. For example, uncomplicated urinary tract and respiratory tract infections are usually treated empirically and indeed without samples being submitted. General practitioners tend to reserve the submission of urine or sputum samples for those cases that have complicated courses or where recurrence of symptoms occurs. Thus, antibiotic treatment policies based entirely on the results of such samples and pathogens will tend to be skewed towards more antibiotic-resistant pathogens, and in turn may recommend unnecessarily broad spectrum or newer antibiotics. Such issues can be overcome by using sentinel (sometimes also called spotter) practices that submit samples from patients with ‘normal’ infections, usually for set periods of the year.

Antibiotic rotation

The selective pressure that results from relying on one or a few antibiotics has led some to explore whether antibiotic rotation (also called antibiotic cycling), particularly in the intensive care unit, can reduce or delay the emergence of resistance. However, this theory has several important unanswered issues: how often should antibiotics be rotated? Is the optimum period of usage the same for all antimicrobial drugs? Which antibiotics and classes should be rotated and in what order? What are the practicalities of ensuring compliance with a rotational policy? Current consensus is that routine antibiotic rotation should not be implemented. Indeed, several studies have been unable to demonstrate a reduction in the prevalence of resistance while antibiotic rotation was being used, and some have found that resistance actually increased during some parts of the cycle. Ironically, diverse antimicrobial prescribing may be associated with reduced emergence of resistance. This should not be interpreted as an argument for entirely unrestricted prescribing, as this is likely to be associated with suboptimal therapy for some patients.

Monitoring antibiotic policies

Blind faith in a restrictive antibiotic policy is not the answer to control of antibiotic usage since bacterial resistance patterns change over time owing to selective pressure. Periodic antibiotic audit should be mandatory in all areas where prescribing occurs. This should not be viewed as a policing exercise, so implying a threat to the clinician's freedom to prescribe, but instead should serve as a need to justify selection of antimicrobial agents in the light of critical analysis. Monitoring antibiotic usage should provide ward, unit, and hospital-wide information on prescribing patterns. This should prove useful for trend analysis and allow discrepancies to be identified. Such information lends itself to detailed scrutiny to differentiate between rational, questionable, and irrational antibiotic usage. Clinical efficacy and adverse events can be evaluated. Correlations between antibiotic usage and antimicrobial resistance should be sought, and changes can be made. A ‘defined daily dose’ for each antibiotic can be used as a standard unit of measurement, and can be useful to identify qualitative as well as quantitative variability in prescribing.

The next stage on from monitoring antibiotic usage is antibiotic audit, thereby closing the audit loop (See The Table Below).

Control of the transmission of antibiotic-resistant bacteria

It is essential that an active infection control programme is also in place, so that patients harbouring multiresistant bacteria are appropriately nursed, managed, and treated. While a full account of the optimal infection control procedure to minimize the risk of pathogen transmission is not appropriate here, some important principles are worth emphasizing. Isolation of patients and ensuring scrupulous hand hygiene, such as with alcohol-based hand rubs, can reduce the risk of transmission and the spread of pathogens. Much has been written about hospital cleanliness and the risk of hospital infection, notably the spread of antibiotic-resistant bacteria such as methicillin-resistant Staph. aureus (MRSA), but the lack of data to substantiate a link between these is stark. The great majority of infections acquired during healthcare arise because of poor hand hygiene. Compliance with hand hygiene policies should therefore be monitored. Although the need to isolate a patient may conflict with other pressures on healthcare delivery, this should not prevent infection control teams implementing this fundamental way of minimizing pathogen dissemination risk where appropriate. Patients may be isolated in single rooms or cohort-isolated in groups of beds or on dedicated units.

Audit of antibiotic prescribing

Much infection control practice is based on empiricism, and policies are frequently based on experience rather than controlled trial data. This does not mean that such policies are optional! There is ample evidence that when infection control measures are strictly enforced, the incidence of infection with resistant organisms can be reduced. Effective ways of preventing cross-infection with and spread of antibiotic-resistant pathogens still need to be defined and refined. Crucially, these approaches may need to differ depending on whether a particular antibiotic-resistant pathogen has already become established (endemic) or is rare (sporadic). A good analogy is plugging the holes in a leaking dyke: eventually more than fingers are needed to sustain the barrier. Controversy still exists about the true control benefit of screening for specific potential pathogens such as MRSA. The role and benefit of new rapid screening methods, usually based on DNA detection, remain to be determined. Alternative approaches include targeted prophylaxis against such pathogens in patients undergoing high-risk procedures such as surgery.

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