The widespread use of NAIs during the 2009 pandemic brought its own problems. Resistance to oseltamavir emerged (Gulland, 2009), and some argued that the cure was worse than the disease (Strong et al., 2009). Further, a Cochrane review (Jefferson et al., 2009) found no good evidence that oseltamivir prevents secondary complications such as pneumonia, one of the main justifications for its widespread use in pandemic influenza. However, the relatively benign course of the 2009 pandemic should not provide false reassurance as to the risks associated with future pandemics.

Sore throat (pharyngitis)

Acute epiglottitis

Acute epiglottitis is a rapidly progressive cellulitis of the epiglottis and adjacent structures. Local swelling has the potential to cause rapid-onset airway obstruction, so the condition is a medical emergency. Previously, almost all childhood cases and a high proportion of adult cases were caused by Haemophilus influenzae type b (Hib), with the rest being caused by other organisms such as pneumococci, streptococci and staphylococci. With the advent of routine vaccination against H. influenzae type b in October 1992, this disease has become uncommon.

The typical patient is a child between 2 and 4 years old with fever and difficulty speaking and breathing. The patient may drool because of impaired swallowing. The diagnosis is made clinically and the initial management is concentrated upon establishing or maintaining an airway. This takes priority over all other diagnostic and therapeutic manoeuvres. Thereafter, the diagnosis may be confirmed by visualisation of the epiglottis, typically described as ‘cherry-red’. Microbiological confirmation may be obtained by culturing the epiglottis and the blood, but not until the airway is secure.

In view of the high prevalence of amoxicillin resistance among encapsulated H. influenzae, the treatment of choice is a cephalosporin. It is customary to use a third-generation cephalosporin such as cefotaxime or ceftriaxone, but there is no reason why the infection should not respond to a second-generation agent such as cefuroxime. If a sensitive organism is recovered, high-dose parenteral amoxicillin may be substituted.

Otitis media

Causative organisms

Inflammation of the middle ear (otitis media) is a common condition seen most frequently in children under 3 years of age. Most cases are due to bacteria, although viruses such as influenza virus and rhinoviruses have been implicated in a sizeable minority. S. pneumoniae and H. influenzae are the two most commonly encountered bacterial pathogens. Moraxella catarrhalis and S. pyogenes account for a smaller proportion of cases, perhaps 10%, and other bacteria are seen only rarely.

Clinical features

Classically, otitis media presents with ear pain, which may be severe. If the drum perforates, the pain is relieved and a purulent discharge may follow. There may be a degree of hearing impairment plus non-speciﬁc symptoms such as fever or vomiting. Complications include mastoiditis (which is now rare), meningitis and, particularly in the case of H. influenzae infection, septicaemia and disseminated infection. With the advent of routine vaccination against H. influenzae type b, these complications have become uncommon.

Diagnosis

The diagnosis of otitis media is essentially made clinically and laboratory investigations have little role to play. Unless the drum is perforated, there is little sense in sending a swab of the external auditory canal, the results of which are likely to be unhelpful or misleading. For this reason, a causative organism is rarely isolated and treatment has to be given empirically.

Treatment

There has been much debate about whether or not antibiotics should be used for the initial treatment of acute otitis media. A meta-analysis combined seven clinical trials involving 2202 children and concluded that, although antibiotics confer a modest reduction in pain at 2–7 days, they do not reduce the incidence of short-term complications such as hearing problems and they do cause side effects (Glasziou et al., 2004). The benefit of antibiotic treatment may be greater in children under two than in older children (Damoiseaux et al., 2000), but in any case about 80% of cases treated without antibiotics will resolve spontaneously within 3 days. If antibiotic treatment is to be given, it should be effective against the three main bacterial pathogens: S. pneumoniae, H. influenzae and S. pyogenes. The streptococci are usually sensitive to penicillins, but these are much less active against H. influenzae, so the broader spectrum agents amoxicillin or ampicillin are preferred. These drugs have identical antibacterial activity, but amoxicillin is recommended for oral treatment since it is better absorbed from the gastro-intestinal tract. Patients with penicillin allergy may be treated with a later-generation cephalosporin (see later).

About 20% of H. influenzae strains are resistant to amoxicillin due to production of β-lactamase, so if there is no response to amoxicillin, an alternative agent should be chosen. Both erythromycin and the earlier oral cephalosporins such as cefalexin are insufficiently active against H. influenzae and should not be used. Alternatives include co-amoxiclav (a combination of amoxicillin and the β-lactamase inhibitor clavulanic acid) or an orally active later-generation cephalosporin such as cefixime. Cefuroxime axetil, while active in vitro, is poorly absorbed and often causes diarrhoea.

Pneumococcal conjugate vaccines, which are currently given routinely in the childhood vaccination schedule, may reduce the incidence of acute otitis media, although a recent review (Jansen et al., 2009) found only modest benefit. No benefit was found for influenza vaccination (Hoberman et al., 2003). Long-term antibiotic prophylaxis might have a role in some children (Leach and Morris, 2006), but any benefit has to be balanced against the risks.

Acute sinusitis

Causative organisms

Normally, the paranasal sinuses are sterile but they can become infected following damage to the mucous membrane which lines them. This usually occurs following a viral URTI but is sometimes associated with the presence of dental disease. Acute sinusitis is usually caused by the same organisms which cause otitis media, but occasionally other organisms such as S. aureus, viridans streptococci (a term used to describe α-haemolytic streptococci other than S. pneumoniae) and anaerobes may be found. Viruses are occasionally found in conjunction with the bacteria.

Clinical features

The main feature of acute sinusitis is facial pain and tenderness, often accompanied by headache and a purulent nasal discharge. Complications include frontal bone osteomyelitis, meningitis and brain abscess. The condition may become chronic with persistent low-grade pain and nasal discharge, sometimes with acute exacerbations.

Diagnosis

As with otitis media, this is a clinical diagnosis and obtaining specimens for bacteriological examination is not usually practicable. In patients with chronic sinusitis, therapeutic sinus washouts may yield specimens for microbiological culture.

Treatment

Since the causative organisms are the same as those found in otitis media, the same recommendations for treatment apply. Proximity to the mouth means that anaerobes are implicated quite frequently in acute sinusitis, particularly if associated with dental disease, and in such cases, the addition of metronidazole may be worthwhile. Amoxicillin/clavulanate (co-amoxiclav) has also demonstrated effectiveness. Doxycycline has proved popular due to its broad spectrum of activity and once-daily dosage.

Lower respiratory infections

Acute bronchitis and acute exacerbations of COPD

Bronchitis means inflammation of the bronchi. It is important to distinguish between acute bronchitis, which is usually, if not always, infective, and chronic bronchitis, which is a chronic inflammatory condition characterised by thickened, oedematous bronchial mucosa with mucus gland hypertrophy and usually caused by smoking. Chronic bronchitis often co-exists with emphysema, both of which lead to airflow limitation and the clinical syndrome of COPD.

The importance of chronic bronchitis is that it renders the patient more susceptible to acute infections and more likely to suffer respiratory compromise as a result. These acute exacerbations of COPD are a frequent cause of morbidity and admission to hospital. An exacerbation is defined as ‘a sustained worsening of the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset’ (NICE, 2004). Common symptoms include worsening breathlessness, cough, increased sputum production and change in sputum colour. It is important to remember that not all acute exacerbations of COPD have an infective aetiology since atmospheric pollutants are sometimes implicated.

Causative organisms

In otherwise healthy patients, the causes of acute bronchitis include viruses such as rhinovirus, coronavirus, adenovirus and influenza virus, and bacteria such as Bordetella pertussis, Mycoplasma pneumoniae and Chlamydophila pneumoniae (formerly Chlamydia pneumoniae). The role of bacteria such as S. pneumoniae and H. influenzae is uncertain because these organisms are nasopharyngeal commensals and their isolation can be misleading, but there is a presumption that they account for at least a proportion of infections.

In patients with acute exacerbations of chronic bronchitis, sputum culture frequently yields potential pathogens such as S. pneumoniae, H. influenzae and M. catarrhalis. However, these organisms are also found in the sputum at much the same frequencies between exacerbations, so it is unclear to what extent (if at all) they play a pathogenic role. A considerable proportion of acute exacerbations is associated with viral infections such as colds or influenza, or might even be non-infective.

Clinical features

The characteristic feature of acute bronchitis is a cough productive of purulent sputum, that is, phlegm that is yellow or green, the colour reflecting the presence of pus cells, sometimes with wheezing and breathlessness. In patients with pre-existing lung disease, the lack of reserve may lead to respiratory compromise, which in turn may exacerbate, or be exacerbated by, cardiac failure. Sometimes, the condition progresses to frank bronchopneumonia (see later), although the dividing line between a severe exacerbation of COPD and bronchopneumonia is often unclear.

Diagnosis

The diagnosis of acute bronchitis or acute exacerbation of COPD is made clinically and does not depend on the results of investigations. If antibiotics are to be given, a sputum sample should be sent for bacteriology, as this will allow antibiotic sensitivity tests to be performed on potential pathogens. However, the decision to treat should not be based on the results of sputum culture alone.

Treatment

Younger patients without pre-existing respiratory disease are likely to recover rapidly and might not require specific treatment. For more severe cases, including exacerbations of COPD, the two main arms of treatment are airflow optimisation and antibiotic therapy. Airflow optimisation consists of physiotherapy to aid expectoration of secretions, adjunctive oxygen if appropriate, bronchodilators and sometimes short-course corticosteroids. In severe cases, a period of artificial ventilation may be required, an intervention which has become more common with the advent of non-invasive ventilation techniques.

Despite the reservation that many cases are non-infective, current guidelines recommend that antibiotics are prescribed when an exacerbation is associated with more purulent sputum (NICE, 2004). There is no unequivocal evidence that one antibiotic is better than another, so recommendations for empiric treatment are based generally upon spectrum, side effects and cost. Most authorities favour either a tetracycline such as doxycycline or an aminopenicillin such as amoxicillin, since these agents cover most strains of S. pneumoniae and H. influenzae. Some people argue in favour of co-amoxiclav, which covers β-lactamase producing strains of H. influenzae and M. catarrhalis that are therefore resistant to amoxicillin, but this agent is more expensive and has a greater incidence of side effects. For penicillin-allergic patients for whom tetracyclines are contraindicated, neither the macrolide erythromycin nor the earlier oral cephalosporins such as cefalexin or cefradine are sufficiently active against H. influenzae for empiric use. However, both clarithromycin and newer oral cephalosporins such as cefixime are active against haemophili while retaining activity against pneumococci.

The following recommendations can be made for the empiric antibiotic treatment of acute bronchitis and exacerbations of COPD. If a plausible pathogen is isolated, treatment can be modified accordingly.

First-line agents

• Doxycycline

• Amoxicillin

Second-line agents

• Co-amoxiclav

• Clarithromycin

• Ceﬁxime

A number of other drugs are promoted for the treatment of COPD exacerbations. Of these, azithromycin is not recommended, as it is less active than clarithromycin against S. pneumoniae. The activity of ciprofloxacin against S. pneumoniae is insufficient to justify its use as monotherapy against pneumococcal infections (although it has useful activity against H. influenzae and M. catarrhalis), and levofloxacin (which is the active isomer of ofloxacin) does not seem to offer any great microbiological advantage. Moxifloxacin is a quinolone that retains activity against Gram-negative organisms such as Haemophilus and Moraxella but has greater activity against Gram-positives such as S. pneumoniae. It has been favourably compared to standard treatment in exacerbations of COPD (Wilson et al., 2004). However, its use has been limited by the high incidence of Clostridium difficile infection (CDI) associated with quinolone use, and rarely the development of life-threatening hepatic toxicity.

Bronchiolitis

Bronchiolitis is characterised by inflammatory changes in the small bronchi and bronchioles, but not by consolidation. It is particularly recognised as a disease of infants in the first year of life, in whom a small degree of airway narrowing can have a dramatic effect on airflow, but the causal organisms are equally capable of infecting adults, who may then act as reservoirs of infection. Most cases are caused by respiratory syncytial virus (RSV), which occurs in annual winter epidemics, but hMPV, parainfluenzaviruses, rhinoviruses, adenoviruses and occasionally M. pneumoniae have also been implicated.

Bronchiolitis is characterised by a prodrome of fever and coryzal symptoms which progresses to wheezing, respiratory distress and hypoxia of varying degrees. Aetiological confirmation may be made by immunofluorescence and/or viral culture of respiratory secretions, although increasingly the diagnosis of respiratory syncytial virus is made using rapid antigen detection tests.

The treatment of bronchiolitis is mainly supportive and consists of oxygen, adequate hydration and ventilatory assistance if required. Severe cases of respiratory syncytial virus disease may be treated with ribavirin, a synthetic nucleoside administered by nebuliser. There is limited evidence for its efficacy and it is currently only recommended for use in immunocompromised patients to reduce the duration of viral shedding (Yanney and Vyas, 2008).

Babies born earlier than 35 weeks of gestation or those less than 6 months of age at the onset of the respiratory syncytial virus season are at high risk of the disease. Likewise, infants under two years of age with chronic lung disease or severe immunodeficiency, or under 6 months of age with congenital heart disease are similarly at high risk, and all are candidates for prophylactic treatment with palivizumab. This is a humanised monoclonal antibody used for passive immunisation against respiratory syncytial virus (JCVI, 2005). There is currently no vaccine against RSV.

Pneumonia

Pneumonia is defined as inflammation of the lung parenchyma, that is, of the alveoli rather than the bronchi or bronchioles, of infective origin and characterised by consolidation. Consolidation is a pathological process in which the alveoli are filled with a mixture of inflammatory exudate, bacteria and white blood cells that on chest X-ray appear as an opaque shadow in the normally clear lungs.

A wide range of organisms can cause pneumonia, so it is useful to apply some kind of classification system, at least until the aetiology of a particular case has been determined. Pneumonia is often classified clinically into lobar pneumonia, bronchopneumonia or atypical pneumonia, but this does not correlate entirely with the bacteriological cause and in any case the distinctions are often blurred. It is more practical to classify pneumonia according to the nature of its acquisition, the usual terms being community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP).

Community-acquired pneumonia

Causative organisms

The causes of CAP are summarised in Table 35.1. The most common vegetative bacterial causes are S. pneumoniae, the pneumococcus, which can cause both lobar and bronchopneumonia, and non-capsulate strains of H. influenzae which usually give rise to bronchopneumonia.

Table 35.1 Causes of community-acquired pneumonia

Organism	Comments
Streptococcus pneumoniae	Classically causes lobar pneumonia, bronchopneumonia now common
Haemophilus influenzae	Cause of bronchopneumonia, usually non-capsulate strains
Staphylococcus aureus	Severe pneumonia with abscess formation, typically following influenza
Klebsiella pneumoniae	Friedlander’s bacillus, causing an uncommon but severe necrotising pneumonia
Legionella pneumophila	Particularly serogroup 1; causes Legionnaire’s disease, usually acquired from aquatic environmental sources
Mycoplasma pneumoniae	Cause of acute pneumonia in young people, respiratory symptoms often overshadowed by systemic upset
Chlamydophila pneumoniae	Mild but prolonged illness usually seen in older people, respiratory symptoms often overshadowed by systemic upset
Chlamydophila psittaci	Causes psittacosis, a respiratory and multisystem disease acquired from infected birds
Coxiella burnetii	Causes Q fever, a respiratory and multisystem disease acquired from animals such as sheep
Viruses	Several viruses can cause pneumonia in adults, including influenza, parainfluenza and varicella zoster viruses

The so-called atypical pneumonias are a heterogeneous group of diseases which nevertheless have several clinical features in common and which are clinically distinct from the classic picture of pneumococcal pneumonia. Aetiological agents include Legionella pneumophila, M. pneumoniae, C. pneumoniae, Chlamydophila psittaci, Coxiella burnetii and viruses. L. pneumophila is the cause of Legionnaire’s disease which occurs sporadically and in outbreaks often associated with contaminated air-conditioning or water systems. From 2002 to 2008, there were 300–600 new cases a year reported in England and Wales. Legionnaire’s disease may be rapidly progressive with very extensive consolidation and consequent respiratory failure.

Viral infections should not be forgotten as causes of pneumonia, although in practice it is unusual to make a definitive early diagnosis, so most cases are treated with antibacterials. Influenza can cause a primary viral pneumonia as well as be complicated by secondary bacterial (particularly staphylococcal) pneumonia, chickenpox can be complicated by primary varicella pneumonia particularly in adults, and cytomegalovirus is capable of causing a variety of infections, including pneumonia, in patients with compromised cell-mediated immunity.

Clinical features

Pneumococcal lobar pneumonia presents with a cough, initially dry but later producing purulent or blood-stained, rust-coloured sputum, together with dyspnoea, fever and pleuritic chest pain. The peripheral white blood cell count is usually raised and the patient may be bacteraemic. The chest X-ray shows consolidation confined to one or more lobes (or segments of lobes) of the lungs. This classic picture is now quite rare perhaps because the early use of antibiotics modifies the natural history of the disease. Bronchopneumonia presents more non-specifically with productive cough and breathlessness, and patchy consolidation on the chest X-ray usually in the bases of both lungs. This disease is very common and is typically seen in patients with severe COPD or in those who are frail and terminally ill. In fact, pneumonia has been described as the old man’s friend because it is a relatively painless cause of death.

The atypical pneumonias are characterised clinically by fever, systemic symptoms and a dry cough, radiologically by widespread patchy consolidation in both lungs and biochemically by abnormalities in liver enzymes and perhaps evidence of inappropriate antidiuretic hormone secretion, evident as a low plasma sodium.

Despite the differences described, clinical features alone are not usually sufficient to make a confident bacteriological diagnosis, a fact that has major implications for the empirical treatment of pneumonia.

Diagnosis

Sputum culture is the mainstay of diagnosis for pneumonia caused by pneumococci and H. influenzae. Sputum microscopy is unreliable because oropharyngeal contaminants are often indistinguishable from pathogens. The success of sputum culture is very dependent upon the quality of the specimen, which may be inadequate either because the patient is unable to expectorate or because the nature of the disease is such that sputum production is not a major feature. A more sensitive (although more invasive) technique is to perform bronchoscopy and bronchoalveolar lavage. Lavage fluid, being uncontaminated by mouth flora, is suitable for microscopy as well as culture.

In pneumococcal disease, blood cultures are frequently positive and national guidance (Lim et al., 2009) suggests that laboratories should also offer plasma and urine testing for pneumococcal antigen. Legionella infection may be diagnosed by culture (if appropriate media are used) or by urinary antigen testing, but culture of Mycoplasma and Chlamydophila species is beyond the scope of most routine diagnostic laboratories. Viruses may be detected by immunofluorescence, by viral culture or by polymerase chain reaction (PCR), but timely diagnosis requires a good specimen such as bronchoalveolar lavage fluid. In practice, the aetiology of atypical pneumonia is usually determined serologically (for instance, by acute and convalescent antibody testing), if at all.

Targeted treatment

The treatment of choice for pneumococcal pneumonia is benzylpenicillin or amoxicillin. Erythromycin monotherapy may be used in penicillin-allergic patients, but resistance rates are rising, macrolides are bacteriostatic rather than bactericidal and the comparative efficacy of this approach is not known. There is retrospective evidence that combination therapy using both a β-lactam and a macrolide can reduce mortality in patients whose pneumonia is complicated by pneumococcal bacteraemia (Martinez et al., 2003).

Pneumococci with reduced susceptibility to penicillin are becoming increasingly common, particularly in continental Europe and the USA. In the UK, about 5–10% of strains express ‘intermediate susceptibility’ (minimum inhibitory concentration; MIC 0.1–1 mg/L), but high-level resistance (MIC >1 mg/L) remains uncommon. Intermediate susceptibility may result in treatment failure in conditions such as otitis media or meningitis, infections at sites where antibiotic penetration is reduced, but antibiotic penetration into the lungs is sufficiently good that penicillin and amoxicillin remain effective for pneumonia. Strains expressing high-level resistance are unlikely to respond to penicillins, however. Such strains are often co-resistant to macrolides and other first-line agents, and may require treatment with a later-generation cephalosporin or a glycopeptide.

The sensitivity of H. influenzae to antibiotics has been discussed above. Amoxicillin is the agent of choice, with co-amoxiclav, parenteral cefuroxime, cefixime or ciprofloxacin as alternatives. Erythromycin is poorly active, but the newer macrolide clarithromycin and the azalide azithromycin possess more activity.

M. pneumoniae does not possess a cell wall and is therefore not susceptible to β-lactam agents. A tetracycline or a macrolide are suitable alternatives. Tetracyclines are also effective against C. pneumoniae, C. psittaci and C. burnetii, but erythromycin is probably less effective. Quinolones are also highly active against these organisms.

Staphylococcal pneumonia is usually treated with flucloxacillin plus a second agent such as rifampicin or fusidic acid, although there is no good clinical evidence that combination treatment is better than a single agent. MRSA (meticillin-resistant S. aureus) pneumonia is being seen more commonly in the community as well as in hospital. Strains of S. aureus expressing Panton-Valentine Leukocidin, an exotoxin, are capable of causing a severe necrotising pneumonia and if clinically suspected should warrant urgent critical care and specialist microbiological input.

Treatment recommendations for Legionnaire’s disease are based on a retrospective review of the famous Philadelphia outbreak of 1976 (Fraser et al., 1977), in which two deaths occurred among the 18 patients who were given erythromycin, compared to 16 deaths in 71 patients treated with penicillin or amoxicillin. This observation accords with the facts that Legionella is an intracellular pathogen and that macrolides penetrate more efficiently than β-lactams into cells. Azithromycin is probably the most effective of the macrolide/azalide derivatives, but clinical evidence to confirm this is lacking. Other agents with proven clinical efficacy and good intracellular activity against Legionella include rifampicin and quinolones. There have been no randomised controlled clinical trials, nor are there likely to be. Guidance, based on observation studies, suggests non-severe cases should be treated with an oral fluoroquinolone (with a macrolide as an alternative), and severe cases treated with a combination of a fluoroquinolone plus either a macrolide or rifampicin, de-escalating to a fluoroquinolone as the sole agent after the first few days (Lim et al., 2009). Treatment is not recommended for the non-pneumonic form of legionellosis (Pontiac fever) which presents as a self-limiting flu-like illness.

Empiric treatment

All of the foregoing recommendations presuppose that the infecting organism is known before treatment is commenced. In practice, this is rarely the case and therapy will initially be empirical or best-guess in nature (Table 35.2). The most authoritative recommendations for the initial treatment of CAP are those produced by the British Thoracic Society (Lim et al., 2009). For mild disease, these recommend treatment with amoxicillin, providing activity against pneumococci and most strains of H. influenzae, with doxycycline or clarithromycin being the preferred alternatives in penicillin-allergic patients. However, for moderate or severe disease requiring admission to hospital, they take the view that, until the aetiology is known, treatment should cover both ‘typical’ causes (such as S. pneumoniae and H. influenza) and atypical causes (such as M. pneumoniae, Chlamydophila species and Legionella). For patients with moderate or severe CAP, the guidelines therefore recommend a combination of a β-lactam drug plus a macrolide, the exact choice of agent and route being decided according to the clinical severity of the infection. In practice, this is usually interpreted as amoxicillin plus a macrolide for less severe disease, and co-amoxiclav plus a macrolide (or cefuroxime plus a macrolide) for more severe disease. Severity is assessed according to clinical parameters and outcome predicted by use of one of a number of assessment tools such as CURB-65, based on the onset of Confusion, the serum Urea, the Respiratory rate, the Blood pressure and age >65 years.

Table 35.2 Treatment of community-acquired pneumonia

Scenario	Typical regimen	Comments
Mild to moderate pneumonia, organism unknown	Amoxicillin plus a macrolide	Amoxicillin covers S. pneumoniae and most H. influenzae while macrolide provides cover against atypical pathogens. It is debatable whether clinical outcomes are improved by using antibiotics active against atypical pathogens in all-cause non-severe community-acquired pneumonia
Severe pneumonia, organism unknown	Co-amoxiclav plus a macrolide Cefuroxime plus a macrolide in penicillin allergy	Co-amoxiclav and cefuroxime provide cover against S. aureus, coliforms and β-lactamase producing haemophili while retaining the pneumococcal cover of amoxicillin
Pneumococcal pneumonia	Penicillin or amoxicillin or a macrolide	High-level penicillin resistance remains uncommon in the UK.
H. influenzae	Non-β-lactamase producing: amoxicillin β-lactamase producing: cefuroxime or co-amoxiclav	Also sensitive to quinolones
Staphylococcal pneumonia	Non-MRSA: flucloxacillin +/– a second agent such as rifampicin or fusidic acid MRSA: requires microbiology input, options include linezolid or glycopeptides	Isolation of S. aureus from sputum may reflect contamination with oropharyngeal commensals and should be interpreted cautiously. MRSA pneumonia may also be treated with linezolid
Mycoplasma pneumoniae	Macrolide or tetracycline	Treat for 14 days
Chlamydophila spp.	Tetracycline preferred	Treat for 14 days
Legionella spp.	A fluoroquinolone such as ciprofloxacin. A macrolide such as clarithromycin is an alternative if intolerant.	Addition of a macrolide or rifampicin in severe cases

Moxifloxacin, a newer fluoroquinolone, is licensed in the UK for treatment of non-severe pneumonia where other antibiotics cannot be used. Currently, it is licensed only in oral form.

Pressure to treat pneumonia (much of which is pneumococcal and would respond to penicillin) with broad-spectrum empiric regimens, in particular, with cephalosporins and fluoroquinolones, has been cited as a factor in the rising incidence of Clostridium difﬁcile and MRSA infections. The treatment of pneumonia illustrates many of the dilemmas and conflicting priorities of modern antimicrobial prescribing.

Hospital-acquired (nosocomial) pneumonia

Causative organisms

The most frequent causes of HAP are Gram-negative bacilli (Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp.) and S. aureus, including MRSA (Box 35.1). However, it is important to remember that pneumococcal pneumonia may develop in hospitalised patients and also that hospital water supplies have been implicated in outbreaks and sporadic cases of Legionella infection. Further, it must be recognised that the common Gram-negative causes of nosocomial pneumonia will vary between hospitals and even between different units within the same hospital. This is especially true of ventilator-associated pneumonia, which for obvious reasons is usually acquired on intensive care units where broad-spectrum antibiotics are frequently used, and where there may be a particular ‘resident flora’ with an established antibiotic resistance pattern.

Clinical features

Nosocomial pneumonia accounts for 10–15% of all hospital-acquired infections, usually presenting with sepsis and/or respiratory failure. Up to 50% of cases are acquired on intensive care units. Predisposing features include stroke, mechanical ventilation, chronic lung disease, recent surgery and previous antibiotic exposure.

Diagnosis

Sputum is commonly sent for culture but is sometimes unhelpful as it may be contaminated by mouth flora. If the patient has received antibiotics, the normal mouth flora is often replaced by resistant organisms such as staphylococci or Gram-negative bacilli, making the interpretation of culture results difficult. Bronchoalveolar lavage is often more helpful. Blood cultures may be positive.

Treatment

The range of organisms causing nosocomial pneumonia is very large, so broad-spectrum empiric therapy is indicated. The choice of antibiotics will be influenced by preceding antibiotic therapy, the duration of hospital admission and above all by the individual unit’s experience with hospital bacteria. The combinations shown in Table 35.3 have all been used at some time and all have advantages and disadvantages. Several of the combinations include an aminoglycoside, and this may not be desirable in all patients. Single-agent therapy is attractive for ease of administration, and agents such as piperacillin-tazobactam and meropenem have suitably broad spectra that include activity against P. aeruginosa. Currently licensed β-lactam agents are inactive against MRSA infections; in such cases specialist management advice is required.

Table 35.3 Treatment regimens for hospital-acquired pneumonia (HAP)

Regimen	Comments
Co-amoxiclav	Good activity against community-associated pathogens, many Enterobacteriaceae and S. aureus. Recommended for early-onset HAP (within 5 days of admission) in antibiotic naïve patients without other risk factors
Ureidopenicillin plus aminoglycoside (e.g. piperacillin plus gentamicin)	Good activity against Gram-negative bacilli such as P. aeruginosa and also against pneumococci. Combination of piperacillin with the β-lactamase inhibitor tazobactam, currently the only ureidopenicillin product marketed in the UK, extends the spectrum to include S. aureus (not MRSA), anaerobes and some strains of E. coli, Klebsiella, etc. that are resistant to piperacillin alone. Piperacillin-tazobactam can also be used reliably as monotherapy
Cephalosporin plus an aminoglycoside (e.g. cefuroxime plus gentamicin)	Good activity against Gram-negative bacilli such as E. coli, Klebsiella, and Gram-positive organisms, but poor against P. aeruginosa and anaerobes
Clindamycin plus aminoglycoside	Good activity against Gram-positive organisms and anaerobes but much less so against Gram-negatives. Favoured in the USA where metronidazole is unpopular for the treatment of anaerobic infections
Ciprofloxacin plus glycopeptide (vancomycin or teicoplanin)	Ciprofloxacin provides good activity against most Gram-negative bacilli including P. aeruginosa. Glycopeptide provides activity against S. aureus (including MRSA) and pneumococci, although its penetration into the respiratory tract is relatively poor
Meropenem (monotherapy)	Broad-spectrum agent including activity against Extended Spectrum Beta Lactamase (ESBL) producing Enterobacteriaceae. Not active against MRSA. Ertapenem does not cover Pseudomonas spp. or Acinetobacter spp. so is unsuitable
Linezolid combinations	It is increasingly necessary to cover MRSA in empiric or targeted treatment of hospital-acquired pneumonia. Traditional options include glycopeptides and, where the prevailing strains are sensitive, aminoglycosides, but there are concerns about penetration into the lung. Linezolid, an oxazolidinone, provides reliable activity
Aztreonam combinations	Good activity against gram-negative bacilli Including Pseudomonas but offers no activity against anaerobic or Gram-positive organisms. Expensive. A β-lactam agent that can be used safely in patients with history of severe penicillin allergy
Temocillin	Excellent activity against Gram-negative organisms including ESBL-producing Enterobacteriaceae. No activity against Gram-positive organisms and Pseudomonas
Ceftazidime (monotherapy)	Very active against Gram-negative bacilli including Pseudomonas but less so against Gram-positive organisms and anaerobes. Due to the high incidence of Clostridium difficile infection and selection of multi-resistant organisms associated with its use, this agent has largely been superseded by other newer agents

In all cases, a macrolide would be added if Legionnaire’s disease was suspected and, if not already covered by the regimen, metronidazole would be required for suspected anaerobic infection.

Prevention

General strategies for minimising the incidence of HAP include early postoperative mobilisation, analgesia, physiotherapy and promotion of rational antibiotic prescribing. The Department of Health’s Saving Lives programme makes specific recommendations for the prevention of ventilator-associated pneumonia (DoH, 2007), including head of bed elevation, sedation holding to reduce the duration of mechanical ventilation and good general hygiene of tubing management and suction.

Another strategy proposed for the prevention of ventilator-associated pneumonia is selective decontamination of the digestive tract (SDD), based on the premise that the infecting organisms initially colonise the patient’s oropharynx or intestinal tract (Kallett and Quinn, 2005). By administering non-absorbable antibiotics such as an aminoglycoside or colistin to the gut, and applying a paste containing these agents to the oropharynx, it is proposed that the potential causative organisms will be eradicated and the incidence of pneumonia thereby reduced. In some centres, an antifungal agent such as amphotericin B is added; others also advocate addition of a systemic broad-spectrum agent such as cefotaxime.

The role of selective decontamination of the digestive tract remains controversial. Recent guidelines (Masterton et al., 2008) recommend its consideration in patients in whom mechanical ventilation is anticipated for more than 48 h. Whether any benefits really outweigh the risks is unclear.

Another suggestion is prophylactic administration of aerosolised antibiotics to ventilated patients (and perhaps other patients at risk). Agents suitable for aerosolised delivery and with the appropriate antimicrobial spectrum include aminoglycosides (particularly tobramycin) and the polymyxin drug colistin. There are no published data available at present and therefore this approach cannot be universally recommended.

Aspiration pneumonia

One further condition which may be seen either in hospital or in the community is aspiration pneumonia, initiated by inhalation of stomach contents contaminated by bacteria from the mouth. Risk factors include alcohol, hypnotic drugs and general anaesthesia, all of these being factors that may make a patient vomit while unconscious. Gastric acid is very destructive to lung tissue and leads to severe tissue necrosis. Damaged tissue is then prone to secondary infection often with abscess formation. Anaerobic bacteria are particularly implicated, but these are often accompanied by aerobic organisms such as viridans streptococci. Treatment with metronidazole plus amoxicillin is usually adequate, but broader spectrum drugs may be used if there are reasons to suspect Gram-negative involvement, for instance, if the patient has been in hospital or previously exposed to antibiotics.

Severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-associated coronavirus or SARS CoV). Clinically it causes pneumonitis, presenting with a flu-like prodrome and progressing to dyspnoea, dry cough and often adult respiratory distress syndrome, requiring ventilatory support. Treatment is largely supportive. It was first described in 2003 (Drosten et al., 2003) after a large outbreak originating in China spread throughout the Americas, Europe and Asia. The outbreak terminated in that year, with only small numbers of cases occurring since. Many experts predict that SARS will re-emerge.

Cystic ﬁbrosis

Cystic ﬁbrosis (CF) is an inherited, autosomal recessive disease which at the cellular level is due to a defect in the transport of ions in and out of cells. This leads to changes in the consistency and chemical composition of exocrine secretions, which in the lungs is manifest by the production of very sticky, tenacious mucus which is difficult to clear by mucociliary action. The production of such mucus leads to airway obstruction with resulting infection. Repeated episodes of infection lead eventually to bronchiectasis and permanent lung damage, which in turn predisposes the patient to further infection.

Infecting organisms

In infants and young children, S. aureus is the most common pathogen. H. influenzae is sometimes encountered, but from the age of about 5 years onwards P. aeruginosa is seen with increasing frequency until, by the age of 18, most patients are chronically infected with this organism, which once present is never completely eradicated. An important feature of those P. aeruginosa strains which infect patients with cystic fibrosis is their production of large amounts of alginate, a polymer of mannuronic and glucuronic acid. This seems to be a virulence factor for the organism in that it inhibits opsonisation and phagocytosis and enables the bacteria to adhere to the bronchial epithelium, thus inhibiting clearance. It does not confer additional antibiotic resistance. Strains which produce large amounts of alginate have a wet, slimy appearance on laboratory culture media and are termed ‘mucoid’ strains.

Occasionally, other Gram-negative bacteria are seen, such as Escherichia coli, which interestingly may also produce alginate in these patients, a characteristic which is otherwise very rare, or Stenotrophomonas maltophilia. Many centres worldwide have also experienced problems with members of the Burkholderia cepacia complex, which previously were known as plant pathogens. The most frequent culprits are B. cenocepacia (formerly B. cepacia genomovar III) and B. multivorans (formerly B. cepacia genomovar II). These organisms are often exceptionally resistant to antibiotics, and their acquisition may be associated with rapidly progressive respiratory failure. Patients colonised with P. aeruginosa and B. cepacia complex should be isolated to prevent transmission to other CF patients.

Clinical features

CF is characterised by persistent cough and copious sputum production. Many patients are chronically breathless. At times, acute exacerbations occur in which there is fever, increased cough with purulent sputum and increased dyspnoea. Systemic sepsis, however, is very rare. Eventually, chronic pulmonary infection leads to respiratory insufficiency, cardiac failure and death.

Treatment

Although this section will concentrate on antibiotic therapy, it should not be forgotten that other means of treatment such as physiotherapy play a vital part, while lung transplantation can be life saving. Even regarding antibiotics, there are fundamental questions that remain to be addressed; for instance, it is not known whether it is best to give antibiotics according to a planned, regular schedule or in response to exacerbations, and practice varies.

The treatment of infection in a child with cystic fibrosis will probably be directed against staphylococci, for which the usual anti-staphylococcal antibiotics such as flucloxacillin or erythromycin can be used. Once the patient is colonised by P. aeruginosa, treatment depends on early and vigorous therapy with antipseudomonal antibiotics (see Table 35.4). At first isolation of P. aeruginosa, eradication is attempted with oral ciprofloxacin and a nebulised antibiotic such as colistin. For chronically colonised patients, regular prophylactic intravenous treatment is given with a β-lactam/aminoglycoside combination such as ceftazidime plus tobramycin. Agents such as meropenem or a quinolone are usually reserved for treatment failures or when resistant organisms are encountered. The prolonged use of ceftazidime or ciprofloxacin alone should be avoided if possible since strains of P. aeruginosa and some other Gram-negative bacilli may become resistant to these agents while the patient is receiving treatment. Other treatment modalities are emerging: in a multi-centre, randomised controlled trial, long-term low-dose azithromycin was associated with improvements in lung function in patients chronically infected with P. aeruginosa (Saiman et al., 2003).

Table 35.4 Antipseudomonal antibiotics

Antibiotic	Comment
Ticarcillin	One of the first β-lactam agents effective against Pseudomonas but now considered insufficiently active. In combination with the β-lactamase inhibitor clavulanic acid, it may be active against some otherwise resistant strains
Ureidopenicillins	Piperacillin, formulated in combination with the β-lactamase inhibitor tazobactam, is the only one of these agents now available in the UK
Monobactams	Aztreonam offers good activity against Gram-negative organisms but no activity against Gram-positive organisms
Cephalosporins	Ceftazidime is the most active antipseudomonal cephalosporin and is very active against other Gram-negative bacilli. It has rather lower activity against Gram-positive bacteria. Pseudomonas may develop resistance during treatment
Aminoglycosides	Gentamicin and tobramycin have very similar activity against Pseudomonas; tobramycin is perhaps slightly more active. Netilmicin is less active, while amikacin may be active against some gentamicin-resistant strains
Quinolones	Ciprofloxacin can be given orally and parenterally but as with ceftazidime, resistance can develop while the patient is on treatment. Other quinolones such as ofloxacin, its L-isomer levofloxacin, and moxifloxacin have better Gram-positive spectrum but concomitantly less activity against Pseudomonas
Polymyxins	These peptide antibiotics are considered too toxic for systemic use in all but the most desperate cases, but colistin (polymyxin E) can be given by inhalation
Carbapenems	Broad-spectrum agents with good Gram-negative activity. Imipenem was the first of these drugs, but CNS toxicity and its requirement for combination with the renal dipeptidase inhibitor cilastatin have largely led to its replacement by meropenem. Doripenem is a newer carbapenem with similar activity to meropenem. Ertapenem has poor activity against P. aeruginosa

Interestingly, patients with cystic fibrosis have a more rapid clearance of some antibiotics than other patients. This is particularly noticeable with the aminoglycosides and larger doses are often required to achieve satisfactory plasma levels.

Children with cystic fibrosis are admitted to hospital very frequently, sometimes for long periods of time, and it is not surprising that some of these children develop an intense dislike of hospitals. This has encouraged the use of long-term indwelling central venous cannulae to allow administration of intravenous antibiotics at home by the parents. Ciprofloxacin can be given orally and offers the possibility of treatment for less severe exacerbations at home, perhaps after a brief time in hospital for parenteral therapy.

B. cepacia is often very difficult to treat and strains may be resistant to all available antibiotics. Under these circumstances, combination therapy is often used.

There is some evidence that in vitro resistance in some Gram- negative organisms such as P. aeruginosa and B. cepacia complex does not correlate with treatment failure in the patient.

The use of inhaled (usually nebulised) antibiotics as an adjunct to parenteral therapy has attracted attention, both for treatment of acute exacerbations and for longer-term use in an attempt to reduce the Pseudomonas load. Agents which have been administered in this way include colistin, tobramycin and other aminoglycosides, carbenicillin and ceftazidime. The best evidence that long-term administration can be beneficial comes from a large multi-centre trial of nebulised tobramycin (Moss, 2001) in which 520 patients were randomised to receive once-daily nebulised tobramycin or placebo in on–off cycles for 24 weeks, followed by open-label tobramycin to complete 2 years of study. Nebulised tobramycin was safe and well tolerated and was associated with a reduction in hospitalisation and improvements in lung function. This was at the expense of a degree of tobramycin resistance, although this did not seem to be clinically significant.

Respiratory infection in the immunocompromised

The increased use of immunosuppressive agents, and to a lesser extent, the spread of HIV infection, has led to increasing numbers of immunocompromised individuals. Respiratory tract infections, in general, and pneumonia, in particular, are frequent complications. Morbidity and mortality are high; so rapid recognition, accurate diagnosis and correct treatment are of prime importance. Diagnosis may be complicated by the sheer number of potential pathogens, the problem of distinguishing infection from non-infective conditions such as malignant infiltration or radiation pneumonitis, and non-specific or delayed presentation. The nature, duration and severity of the underlying immune defect, together with specific epidemiologic or environmental factors, influence the risk of infection by different organisms. These are summarised briefly in Table 35.5. Common therapeutic problems are summarised in Table 35.6.

Table 35.5 Basic causes, defects and infections in immunocompromised individuals

Table 35.6 Common therapeutic problems

Problem	Comments
No pathogens isolated on sputum culture	Possibilities include an inadequate specimen such as saliva, non-infected or sterilised sputum, or a pathogen that cannot be cultured on routine media such as Chlamydophila pneumoniae or Mycobacterium tuberculosis. Pneumococci are susceptible to autolysis and may fail to grow even from a well-taken specimen, particularly if transport to the laboratory is delayed
Staphylococcus aureus isolated (including MRSA)	S. aureus pneumonia is a severe disease with characteristic clinical features, often associated with bacteraemia. However, the organism is frequently isolated from the sputum of patients with bronchitis or bronchopneumonia. In these instances, it usually reflects contamination of the specimen with oropharyngeal commensals although some patients undoubtedly have a clinical infection requiring anti-staphylococcal antibiotics
Candida spp. isolated	Unless there are reasons to suspect Candida pneumonia (as a consequence of neutropenia, for example), the isolation of yeasts is likely to reflect oropharyngeal contamination of the specimen. Yeasts can be carried commensally in the mouth, particularly in the presence of dentures, but a search for clinically apparent mucocutaneous candidiasis should be made
Aspergillus spp. isolated	Invasive aspergillosis, allergic bronchopulmonary aspergillosis and aspergilloma should be considered. Alternatively, the finding might reflect inconsequential oropharyngeal carriage
Penicillin-resistant pneumococci isolated	Respiratory infections caused by strains with low-level resistance (MIC 0.1–1 mg/L) may be treated with penicillins. Strains with high-level resistance should be treated according to their sensitivity profile, for example, using a later-generation cephalosporin or a macrolide
Coliforms isolated	Significance depends on the clinical context: unlikely to be responsible for community-acquired infection unless there is bronchiectasis, but may be relevant to hospital-acquired infections particularly if present in pure culture
Failure of a chest infection to respond to antibiotics	Consider poor compliance, inadequate dosage, viral or otherwise insensitive aetiology. Remember that β-lactam drugs are ineffective against Chlamydophila, Mycoplasma and Legionella infections
Sore throat, no pathogens isolated	Consider viral aetiology, particularly glandular fever in teenagers and young adults
Persistent illness following treatment for pneumococcal pneumonia	Consider the possibility of an empyema (pus in the pleural space), a condition which usually requires surgical drainage