Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
Respiratory tract infections
- M. Emmerson
It has been traditional to subdivide the respiratory tract into upper and lower regions, above and below the epiglottis, and to talk of upper respiratory tract infection and lower respiratory tract infection separately. To a large extent this is reasonable; the upper respiratory tract has a rich and varied microbial population at all times, whereas in most healthy people the lower respiratory tract, protected by ciliated epithelium, mucus, and macrophages, is virtually free from microbes.
Similarly, fairly well-recognized collections of symptoms and signs have been held to define illnesses which can be diagnosed with variable confidence. These include the common cold, pharyngitis, tonsillitis, otitis media, croup, bronchitis, bronchiolitis, and pneumonia, as well as specific infections such as influenza, diphtheria, and whooping cough.
Some bacteria and viruses can, however, play a part in several of these conditions, and there is considerable overlap between lower and upper tract disease. Fever, excess serous and mucous secretion in the nose and paranasal sinuses, inflammation of the throat and respiratory passages, stimulation of the cough reflex, loss of ciliary activity, shedding of superficial mucosa, spasm of bronchial smooth muscle, and collapse of alveoli can all be found in many respiratory infections. Between them they give rise to the runny noses, headache, earache, cough, sputum production, malaise, and chest pain which, in different combinations, make up the varying clinical pictures of acute respiratory disease.
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 probably help, and may be vital. It is often difficult to recognize when bacteria may be involved. Secondary bacterial infection is often, but not always, present in otitis media, sinusitis, and pneumonia, and few would withhold antibiotics for these conditions. Other conditions such as pharyngitis (sore throat) and croup are more controversial.
Upper respiratory tract infection
This is one of the commonest problems seen in general medical practice and one of the most controversial. The most important causal organism is Streptococcus pyogenes, which has been said, in different surveys, to cause less than 20 per cent or more than 50 per cent of all sore throats. Viruses (particularly the adenoviruses) account for most of the others.
Streptococcal sore throat is important because it may lead to serious complications. It is not possible on clinical findings alone to distinguish between streptococcal and non-streptococcal sore throat, and rapid tests for the detection of β-haemolytic streptococci in throat swabs are not sufficiently reliable for routine use. The question is, therefore, whether to take a throat swab for culture before starting specific treatment or to treat all sore throats as though they were streptococcal, without culture.
The aims of treatment are:
- to prevent non-suppurative sequelae (rheumatic fever and acute glomerulonephritis)
- to prevent suppurative complications such as sinusitis, peritonsillar abscess, otitis media, cervical adenitis, and pneumonia
- to decrease the spread of infection by removing the source
- to shorten the course of the disease.
Antibiotic treatment of streptococcal sore throat will prevent subsequent rheumatic fever, which may follow in 0.4–2.8 per cent of untreated cases, even if treatment is delayed for up to 9 days after onset. Patients who have had an attack of rheumatic fever should be treated with continuous oral penicillin for several years, to prevent a recurrence. There is no convincing evidence that acute nephritis can be prevented by treating a streptococcal sore throat. Suppurative complications are also markedly decreased by prompt treatment, as is spread of infection to contacts. Treatment probably shortens the duration of the sore throat, but not by much. Controlled studies are unconvincing. On balance, since little is lost by delaying the start of treatment by 24 h, where adequate bacteriological facilities are available it is worthwhile treating with antibiotics only those sore throats shown to be streptococcal by culture. In the absence of bacteriological guidance it is reasonable to err on the side of caution and to treat as though all were streptococcal. There is, however, room for discretion and many general practitioners are guided more by the severity of the disease and the social circumstances of their patients than by any consideration of the presumed aetiology.
The antibiotic of choice is either penicillin or, for penicillin-hypersensitive patients, erythromycin, and there is evidence that these should be given for at
least 10 days to eradicate the organism. Ampicillin should not be used, as it 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. For those patients with recurrent streptococcal throats, co-amoxiclav or cefaclor appear to eradicate the organism better than oral penicillin.
At present uncommon in Britain, and indeed everywhere that an effective vaccination policy is practised, diphtheria is nevertheless important in the differential diagnosis of sore throat. Diagnosis must be made on clinical grounds—the severity of the illness, the presence of a diphtheritic membranous exudate—as treatment of the acute illness with antitoxin is life saving and must be started before bacteriological confirmation can be completed. Penicillin and erythromycin (or other macrolides) are effective in eradicating the organism, but nose and throat cultures should be repeated 2–3 weeks after treatment to detect patients who continue to harbour the organism. Most of these will be cleared by a repeat course of antibiotic.
Noisy difficult breathing, hoarseness, and stridor are common signs of acute laryngo-tracheo-bronchitis in children in winter. This distressing condition is usually viral in origin; parainfluenza viruses, the respiratory syncytial virus, and adenoviruses are particularly common causes. Treatment is supportive; the condition is usually self limiting and resolves in 2–4 days if uncomplicated. Endotracheal intubation or tracheostomy may be needed to relieve respiratory obstruction.
This 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 airway obstruction with dramatic suddenness. It is this complication which makes acute epiglottitis such a life-threatening condition. Treatment is as much concerned with maintaining the airway as with controlling the infection, but, as soon as the condition is suspected, treatment should be started with parenteral cefotaxime or, if that is not readily available, intramuscular ampicillin or intravenous chloramphenicol. Some strains of H. influenzae are resistant to chloramphenicol or ampicillin (occasionally both) and these cannot be used with full confidence. It is hoped that introduction of the H. influenzae type b conjugate vaccine will lead to a decrease in the incidence of acute epiglottitis.
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.
Acute otitis media and sinusitis
Mild catarrhal inflammation spreading up the eustachian tubes and into the paranasal sinuses is a common accompaniment of most viral upper respiratory infections, and often resolves without chemotherapy as the cold subsides. More severe illness, with toothache, facial pain and tenderness, and a purulent nasal discharge, or earache, pain on moving the pinna, and a red bulging eardrum, indicates bacterial infection and demands antibiotic treatment.
Acute sinusitis and acute otitis media are both caused predominantly by H. influenzae and Streptococcus pneumoniae. Staphylococci, Str. pyogenes, and α-haemolytic streptococci are less often involved. The antibiotic of choice is amoxycillin; erythromycin and co-amoxiclav are logical alternatives and may be necessary if β-lactamase-producing H. influenzae is involved. The optimal duration of therapy is unknown, but 10 days is conventional. Supportive measures such as elevation of the head of the bed, humidification, analgesics, and decongestants may be helpful. Patients with acute fulminating infection which fails to resolve rapidly should be referred to an ENT surgeon for possible surgical drainage.
Acute bacterial parotitis
As a rule, bacteria reach the parotid gland by retrograde passage from the mouth. The infection is usually unilateral and used to be a common complication of abdominal surgery. Today, good control of post-operative fluid balance, prompt blood replacement, and attention to oral hygiene have made post-operative parotitis a rarity, and the condition is now more often seen in debilitating medical disease, as a result of a dry infected mouth. Occasional cases may follow obstruction of the parotid duct by calculus or a foreign body, or even occur as an embolic complication of septicaemia.
Treatment consists of correction of dehydration, oral toilet, and antibiotics. As the infection is usually due to Staph. aureus, the antibiotic of choice is flucloxacillin. Surgical drainage may be necessary if these measures fall to bring prompt relief.
Infection in the mouth
Almost all acute suppurative mouth infections originate in the teeth, and are usually the result of dental caries and periodontal disease. Both of these are
caused by the metabolism of sugars by oral bacteria, mainly streptococci. The sugars are converted into dextrans and mucopolysaccharides which accumulate as dental plaque, localizing the bacteria to the tooth surface and gingival margins, and allowing acid production to attack the tooth substance.
When plaque develops under the gingival margin and the periodontal membrane is broken, particles of food accumulate and become infected. The gums retract and become inflamed, and chronic gingivitis results. Acute infection may punctuate the course of chronic periodontal disease, but is usually localized as an acute dental abscess.
The bacteria usually involved are streptococci, mainly of the α-haemolytic and non-haemolytic varieties, and when antibiotic treatment is indicated, penicillin and erythromycin are both effective. The mainstay of treatment and prevention is, however, proper mouth hygiene, dental care, and attention to diet. Soft sugary foods cause dental disease; crisp abrasive fibrous foods prevent it.
This is an acute ulcerative gingivitis accompanied by, and probably caused by, proliferation of normal mouth microbes, including a spirochaete (Treponema vincenti), fusiform bacilli, and other oral anaerobes. The main symptoms are bleeding gums, soreness of the mouth, a bad taste, and offensive breath. The disease always occurs in a mouth already ravaged by pre-existing gingivitis and poor oral hygiene. There is extensive gingival ulceration, and contact ulcers may form on the sides of the tongue and the cheek. Occasionally, the infection may spread to cause an acute ulcerative tonsillitis and pharyngitis, a condition known as Vincent's angina.
Vincent's infection responds rapidly to penicillin or metronidazole. When the condition has subsided proper attention should be given to dental care and the correction of underlying mouth disease. Acute ulcerative gingivitis may be an early sign of serious haematological diseases, such as acute leukaemia or agran-ulocytosis, and these should be excluded.
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 infection is acquired by the infant 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 is almost always indicative of serious underlying disease, among which endocrine disturbances such as diabetes mellitus, severe blood dyscrasias, and disseminated malignancy are prominent; it may herald the onset
of AIDS. The condition may complicate treatment with broad-spectrum antibiotics or steroids. A less sinister, but more common manifestation of oral candida infection is the chronic atrophic candidosis which may plague people wearing ill-fitting dentures. In all these conditions one of the oral polyene or azole derivatives may be used to control the candida, but treatment is essentially that appropriate to the underlying condition.
This is another condition closely associated with poor oral hygiene, gingivitis, dental decay, and especially tooth extraction, in which a normal mouth organism, Actinomyces israelii, gains access to already unhealthy tissues and causes a subacute or chronic suppurative infection.
- israeliiis an anaerobic Gram-positive bacillus which shows true branching. On the rare occasions on which it invades tissues it causes an intense poly-morphonuclear neutrophil reaction. The most usual mode of infection is through a tooth socket after extraction. Within 1–6 weeks after extraction, the patient notices a small swelling over the mandible. This enlarges and, if untreated, the infection spreads to form an abscess cavity, with extension to involve overlying skin and the formation of one or more sinuses. The pus characteristically contains ‘sulphur granules’, which are colonies of the actinomycete, and the diagnosis is confirmed by culture. Usually, medical advice is sought before the abscess points. Incision, drainage, and treatment with penicillin will control the infection, but the antibiotic needs to be given for 2–3 months to avoid relapse. Fusidic acid, clindamycin, erythromycin, and tetracycline are also active against actinomyces, but prolonged treatment is necessary to effect cure.
Lower respiratory tract infection
Most cases of acute bronchitis in a previously healthy adult are caused by viruses, although some may be caused by Mycoplasma pneumoniae. The illness is characterized by chest tightness, wheeze, breathlessness, and cough. Usually mild, it can be severe in the very young, the very old, the debilitated, and in acute exacerbations of chronic bronchitis. If mild, treatment is symptomatic and antibiotics are rarely indicated, especially when the sputum remains mucoid. Purulent sputum or severe illness makes secondary bacterial infection likely, and the most probable offending organisms are Str. pneumoniae, Moraxella catarrhalis, and H. influenzae, for which cefuroxime and erythromycin are appropriate. The possibility of M. pneumoniae infection makes erythromycin or a tetracycline a logical initial choice of antibiotic.
This term covers a very wide range of diseases, from the irritating, trivial, but persistent cough with some sputum most days in winter and little else, to advanced chronic obstructive airways disease with severe disability and constant respiratory distress. This makes the role of antibiotics in the management of chronic bronchitis particularly difficult to assess. The aim of treatment has been to control acute exacerbations when they occur; long-term prophylaxis has been used for patients with advanced illness and constantly purulent sputum. It now seems clear that those patients who regularly suffer frequent acute exacerbations throughout winter do benefit from long-term antibiotic treatment throughout the winter months, but that for most patients prompt early treatment of acute exacerbations as they occur is just as good. Tetracyclines, ampicillin, amoxycillin, and co-trimoxazole can all be used, and there is little to choose between them. Patient preference and experience of side-effects often decide which is used. A supply of the chosen drug is given at the beginning of winter and the patient instructed to start taking it as soon as symptoms dictate. Patients who do not respond to the chosen antibiotic may benefit from a course of co-amoxiclav or ciprofloxacin.
Any interference with the defences of the respiratory tract or the normal drainage of the lung may predispose to pneumonia. Such interference may be caused by antecedent upper respiratory infection such as a common cold, and many patients with pneumonia give a history of such an infection. At any time, but usually within a week of the onset of the cold, the patient rapidly becomes more ill, with a rise in temperature, cough, at first dry and painful, but later productive of viscid purulent or blood-stained sputum, pleuritic pain, and rapid respiration. The diagnosis is made by finding clinical or radiological evidence of consolidation.
Most pneumonias are caused by infective agents, although chemical or allergic pneumonias do occur. The consolidation may be confined to part or the whole of one or more lobes of the lungs—lobar pneumonia—or may be patchily distributed in a lobular pattern throughout the lung fields—bronchopneumonia.
The pneumococcus is by far the commonest cause of lobar pneumonia in previously healthy children and adults, and is also prominent in pneumonias following acute exacerbations of chronic bronchitis, together with H. influenzae, and occasionally staphylococci, klebsiellae, and a variety of upper respiratory organisms. Nevertheless, lobar pneumonia is not always pneumococcal; any anatomical type of pneumonia can on occasion be caused by almost any respiratory pathogen. Patients with pneumonia require treatment before the results of bacterial investigation are known, and it is seldom possible to be sure of the cause before starting therapy.
In the previously healthy child or relatively young adult it is reasonable to assume that the infection is pneumococcal and to start treatment with high-dose penicillin by injection; if there is a possibility of infection by penicillin-resistant pneumococci then cefotaxime or ceftriaxone should be given. Alternatively, a combination of ampicillin and erythromycin can be used. This covers not only pneumococci and H. influenzae, but also L. pneumophila (see below) and M. pneumoniae, a fairly common cause of atypical pneumonia which occurs in epidemic waves and often affects young adults in schools, colleges, or army camps.
Pneumonia is the leading cause of mortality resulting from infection acquired in hospital. The incidence of nosocomial pneumonia in intensive care units ranges from 10 to 65 per cent, with case fatalities of 13–55 per cent. It is often associated with mechanical ventilation. The micro-organisms isolated from tracheal aspirates are primarily Gram-negative bacilli, which may be antibiotic resistant. The source of these is primarily exogenous, but they may be secondarily acquired from stomach or oropharyngeal aspirates. Since tracheal aspirates are poor indicators of ventilator-associated pneumonia, protected bronchoscopic techniques are recommended to confirm the diagnosis. The initial use of cefuroxime or cefo-taxime can be modified following appropriate culture results from the laboratory.
Legionella pneumophila has proved to be a surprisingly frequent cause of lobar pneumonia, accounting for 10 per cent or more of cases in some series. It can occur in explosive outbreaks, but is more commonly sporadic, and, contrary to popular belief, is far more often relatively mild and self limiting than fulminating and lethal. More than half the cases diagnosed in the UK are found retrospectively by antibody studies on follow-up after recovery from the acute illness. Erythromycin is the antibiotic of choice, and is usually given together with rifampicin in proven cases of severe Legionella pneumonia.
This serious infection is uncommon except during epidemics of influenza. It is an occasional complication of viral pneumonia at any age, but is especially dangerous in infancy. Any such patient who becomes rapidly and gravely ill with pneumonia should be treated with high-dose antistaphylococcal therapy. Flucloxacillin and fusidic acid are commonly used in the UK.
Patients developing pneumonia as a complication of some other serious underlying disease are at special risk of infection with unusual organisms. Hospital staphylococci and a variety of Gram-negative organisms, including Klebsiella
and Pseudomonas, are important. Speculative treatment with a combination of an aminoglycoside (e.g. gentamicin) and an expanded-spectrum cephalosporin (e.g. cefotaxime) is indicated while an attempt is made to isolate a significant organism from sputum, blood, pleural fluid, lung puncture, trans-tracheal aspirate, or broncho-alveolar lavage.
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. Appropriate treatment is discussed inChapter 29.
It must be stressed that, in the treatment of all severe pneumonias, general medical and nursing care and physiotherapy are as important as antibiotic administration. Close monitoring of blood gases, prompt relief of hypoxia, a readiness to resort to mechanical ventilation early, the correction of dehydration, and the relief of pain are all of great importance in the management of this condition.
The commonest cause of empyema (purulent pleural effusion) is extension of infection from the lung, but infection can also result from penetrating chest wounds, as a complication of thoracic surgery or by extension upwards from a sub-phrenic abscess. The commonest infecting organisms are Staph. aureus, Str. pneumoniae, Str. pyogenes, anaerobic streptococci, Bacteroides, and other anaerobic bacteria. Mixed infections are frequent, and even when bulk pus from the empyema is cultured the causal organism may not be isolated in up to a quarter of cases, usually because of prior antibiotic treatment. Treatment is by drainage of pus and administration of antibiotics. Initial treatment with penicillin and metronidazole can be modified when the results of examination of the aspirated pus become known, but chemotherapy must in any case be continued for several weeks, or until the empyema cavity is satisfactorily obliterated. A regimen of high-dose penicillin or flucloxacillin and metronidazole should also be used in the treatment of aspiration pneumonia and lung abscess, in which a similar range of organisms may be involved.
The susceptibility of patients with cystic fibrosis to pulmonary infection is well recognized and is often the cause of early death. 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. These are difficult to treat, but clinical improvement, without eradication of the organism, is often achieved with a combination of ceftazidime and gentamicin given in high doses intravenously.
Oral ciprofloxacin may also be useful, and, although resistance may supervene, sensitivity often returns during inter-treatment periods.
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.
Other respiratory infections
The treatment of tuberculosis is considered in Chapter 26; influenza and other respiratory viral infections are dealt with in Chapter 28.