Causative organisms

Pharyngitis is a common condition. In most cases, it never comes to medical attention and is treated with simple therapy directed at symptom relief. Many cases are not due to infection at all but are caused by other factors such as smoking. Where infection is the cause, most cases are viral and form part of the cold-and-flu spectrum. Epstein–Barr virus (EBV), which causes glandular fever (infectious mononucleosis), is a less common but important cause of sore throat since it may be confused with streptococcal infection.

The only common bacterial cause of sore throat is Streptococcus pyogenes, the Lancefield group A β-haemolytic streptococcus. Infrequent causes include β-haemolytic streptococci of groups C and G, Arcanobacterium haemolyticum, Neisseria gonorrhoeae and mycoplasmas. Corynebacterium diphtheriae, the cause of diphtheria, is rare in the UK but should be borne in mind when investigating travellers returning from parts of the world where diphtheria is common. C. ulcerans is as common a cause of clinical diphtheria in the UK as C. diphtheriae but usually runs a more benign course.

Clinical features

The presenting complaint is sore throat, often associated with fever and the usual symptoms of the common cold. It is standard teaching that sore throats of different aetiology cannot be distinguished clinically. Nevertheless, more severe cases are more likely to be caused by EBV or S. pyogenes, and in these patients, there may be marked inflammation of the pharynx with a whitish exudate on the tonsils, plus enlarged and tender cervical lymph nodes.

Group A streptococcal infection has a number of potential complications. Pharyngeal infection may occasionally give rise to disseminated infection elsewhere, but this is rare. More frequent accompaniments are otitis media, peritonsillar abscess and sinusitis. These should be distinguished from the non-suppurative complications of streptococcal infection, rheumatic fever and glomerulonephritis, which are mediated immunologically. Occasional cases are still seen in the UK and remain important causes of renal and cardiac disease in developing countries. Scarlet fever, a toxin-mediated manifestation of streptococcal infection, is associated with a macular rash and sometimes considerable systemic illness.

In the UK, there has been a recent increase in rates of group A streptococcal infection. This includes invasive group A streptococcal infection (iGAS), associated with infection in normally sterile sites such as blood or tissue. The most common serotypes seen in England and Wales are emm 1, 3, and 89; emm 3 infections are associated with higher case fatality rates. The cause of the upsurge is unknown but may represent a natural periodic increase or alternatively excess transmission associated with high rates of influenza in 2008 (Lamagni et al., 2009).

Diagnosis

In most cases of pharyngitis, a bacteriological diagnosis cannot be made and thereby these are presumed to be viral in origin. The aim of any diagnostic procedure is to distinguish the streptococcal sore throat, which is amenable to antibiotic treatment, from viral infections, which are not. If a definite bacterial diagnosis is required, a throat swab should be taken for culture and, unless the details of a particular case prompt a search for more unusual organisms, culture techniques are directed towards detecting β-haemolytic streptococci. If bacterial culture is negative and glandular fever is suspected, blood should be taken for serological confirmation using either the non-specific ‘monospot test’ for atypical lymphocytes or specific tests for antibodies to EBV. Other viruses may be diagnosed by viral culture or serology, but this does not usually contribute to management. Rapid bedside tests are available that detect group A streptococcal antigens in the throat, but there are concerns about their sensitivity and specificity and they have not been widely introduced in the UK.

Treatment

Treatment of viral sore throat is directed at symptomatic relief, for example with rest, antipyretics and aspirin gargles. Streptococcal sore throat is usually treated with antibiotics although the extent to which they shorten the duration of symptoms and reduce the incidence of suppurative complications is modest (Del Mar et al., 2004). Antibiotic treatment also reduces the incidence of non-suppurative complications so is likely to be of greater benefit where these are common. There is also an argument that treating to eradicate streptococcal carriage might reduce the risk of relapse or later streptococcal infection at other sites.

Broadly, there are three treatment strategies:

There is no correct approach and each has its advocates, although the problem of resistance has led to increasing pressure on prescribers to restrict empirical antibiotic use particularly for conditions such as pharyngitis that are frequently viral. The prevailing view is that antibiotics should not be routinely prescribed except where there is a high risk of severe infection, for instance, in immunocompromised patients (NICE, 2010).

Antibiotics effective against S. pyogenes include penicillins, cephalosporins and macrolides. Resistance to penicillins and cephalosporins has not (yet) been described in group A streptococci, although about 4% of isolates are resistant to erythromycin. Even against sensitive strains, macrolides such as erythromycin are demonstrably less effective than β-lactams.

Penicillins such as benzylpenicillin (penicillin G) or phenoxymethylpenicillin (penicillin V) have traditionally been regarded as the treatment of choice for streptococcal sore throat, but there is now convincing evidence that cephalosporins are more effective in terms of both clinical response and eradication of the organism from the oropharynx. This was summarised in a large meta-analysis of 40 studies in which 10-day courses of oral cephalosporins and penicillins were compared in the management of children with streptococcal pharyngitis (Casey and Pichichero, 2004). Bacteriological and clinical cure significantly favoured cephalosporins over penicillins, perhaps because penicillins are hydrolysed by β-lactamases produced by organisms such as anaerobes naturally resident in the oropharynx, whereas cephalosporins are not. The 10-day course length became accepted following earlier studies that compared the effect of different durations of penicillin treatment on bacteriological colonisation, but a recent systematic review (Atamimi et al., 2009) found comparable efficacy with shorter courses of newer antibiotics such as azithromycin.

However, despite the therapeutic superiority, it remains debatable whether the extra expense of cephalosporins is justified. Cefalexin is the preferred cephalosporin. Penicillin or amoxicillin is the preferred penicillin, with the proviso that amoxicillin and other aminopenicillins should not be used unless EBV infection is unlikely, since for reasons that are not understood, these drugs often cause skin rashes if used in this condition.

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.

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.

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.

Second-line agents

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