Antibiotic treatment in developing countries

In developing countries the main goal of treatment is to reduce the risk of death as cheaply as possible.11 52 53 Table 2 shows the antibiotic treatment suggested by the WHO for severe and very severe paediatric CAP cases diagnosed in the Third World.11 The recommended first-line drugs for severe cases are benzylpenicillin, amoxicillin and chloramphenicol, whereas ampicillin or amoxicillin plus gentamicin are recommended in the case of very severe CAP.11 The choice of an alternative regimen, the duration of therapy and hospitalisation, and the possibility of continuing antibiotic administration orally at home are all conditioned by the evolution of the disease, the development of complications and the presence of risk factors.11 54

It is clear that this approach causes a number of problems due to the risk of nosocomial morbidities and greater healthcare costs, which is why various studies have investigated whether it is possible to treat severe CAP orally at home without significantly increasing the number of treatment failures or the risks of complications and death.53 55–59 Unfortunately, only a few of these are sufficiently adequate methodologically to allow firm conclusions.55–59 Nevertheless, despite their differences in terms of the antibiotics used and efficacy criteria, they all indicate that there is no significant difference between oral and parenteral therapy in the rates of treatment failure or clinical success at the end of therapy and the end of follow-up (table 3). However, these studies do not take into consideration the relative benefits and harms of oral antibiotics in children with CAP associated with bacterial confirmation, radiographic lobar consolidation or progression to empyema, which means that oral antibiotic therapy cannot be systematically prescribed in all cases of severe CAP. Consequently, the therapeutic approach suggested by the WHO remains the best compromise between the lowest risk of failure and the greatest simplicity of therapy.

One possible further simplification leading to a significant reduction in the duration of hospitalisation could theoretically be based on data concerning the predictors of a treatment response. In this regard, the proportion of children with pneumonia who fail to respond adequately to conventional antibiotic and supportive treatment varies from 9% to 21%, regardless of the antibiotic used,60 and it has been demonstrated that data derived from a patient's history and first examination—such as younger age, previous use of antibiotics, breastfeeding, living in an overcrowded home, higher respiratory rate and immunisation status—are independent predictors of possible treatment failure.57 61

When available, blood oxygen saturation offers substantial advantages in identifying possible treatment failures. Studies from Indonesia, Kenya, Zambia and Gambia have found that the risk of death is 1.4–4.6 times higher in children with hypoxia at baseline than in those without.53 61–67 Chest radiography, which enables identification of the characteristics that correlate more with a bacterial or more with a viral aetiology, is often not available in developing countries.2 4 5 On the other hand, a pulse oximeter is significantly easier to use than chest radiographic equipment, less expensive, easier to calibrate and easier to maintain and repair.53 Consequently, its use (together with the consideration of clinical data) would seem to be the best way of deciding, after a brief period of observation, whether a child risks failure on oral antibiotic treatment or can be safely managed at home. Unlike in developed countries, fever and laboratory examinations are generally not used in developing countries for CAP assessment.2 4 5

Antibiotic treatment in developed countries

In industrialised countries the initial treatment of severe CAP includes hospitalisation and the intravenous administration of antibiotics.7 16 22 68–70 The choice of antibiotic mainly depends on the patient's age, and a single drug active against the most probable infecting agent has long been suggested.7 16 22 68–70 However, the recent demonstration that atypical bacteria can play a role in causing severe CAP has led some experts to suggest using a combination of a beta-lactam and macrolide antibiotic in all children aged >3 months.16 22 Table 4 summarises the current therapeutic approach to severe CAP in developed countries recommended by a large group of experts. It appears clear that age is the most important factor to determine aetiology. Although viral aetiology plays a major role in children aged <2 years while in older children bacteria (especially atypical bacteria) are more common, the large overlap in clinical, laboratory and radiographic findings between the different aetiologies supports the systematic use of antibiotics in severe CAP.22

The global pandemic of antibiotic resistance of the isolated pathogens commonly found in children with respiratory disease has had a marginal impact on the antimicrobial management of severe and complicated paediatric CAP.22 This is because, although S pneumoniae strains have progressively developed multiple resistance mechanisms over the last 20–30 years and resistant strains (including some with multidrug resistance) have spread to several regions of the world,71 72 it has been found that the risk of failure after treatment with penicillins and cephalosporins is not significantly different from that usually found in adults and children with CAP due to antibiotic-sensitive S pneumoniae strains.73–78 Moreover, in most of the cases of failure, it was difficult to define whether the negative result was a true bacteriological failure due to the resistance of the infecting organism or a clinical failure due to other concomitant factors.73–78 The success of treatment with beta-lactam antibiotics, even in the presence of resistant strains, can be easily explained on the basis of the pharmacokinetic and pharmacodynamic principles predicting probable clinical success.79 80

The question of the resistance of S pneumoniae to macrolides is more important22 because the risk of the failure of macrolide monotherapy in cases of bacteraemic CAP has been clearly documented.81 82 This explains why macrolide monotherapy is not suggested for the initial treatment of severe paediatric CAP and, when macrolides are prescribed, why they are always used in combination with beta-lactams in order to cover atypical bacteria (which have only rarely shown resistance to macrolides).22 68

Finally, in each antibiotic class the choice has to be restricted to the drug that is most active against the possible infecting agents and has the best tolerability and safety profile, the narrowest spectrum of activity and the lowest cost.1–3 7 22 34 Once a clinical improvement has been demonstrated, patients who can tolerate oral medications and do not have diarrhoea should be switched to oral therapy in order to reduce patient discomfort, favour hospital discharge and limit healthcare costs. The total duration of treatment is usually 10–14 days. In the case of complications, broader spectrum antibiotics (eg, piperacillin plus a beta-lactam inhibitor or a carbapenem combined with vancomycin) are recommended for longer periods (3–6 weeks).

Parapneumonic effusion

The rates of parapneumonic effusion have been increasing in the USA and Europe over recent years, and it is now encountered in approximately 40% of all patients with bacterial pneumonias.19 83–85 Some authors have suggested that the use of PCV-7 may be involved as a result of the so-called ‘replacement phenomenon’19 41–43 83–85—that is, by reducing the circulation of the strains included in the vaccine, PCV-7 favours diseases due to non-vaccine serotypes, including the serotypes 1, 3, 5, 7F and 19A that are frequently associated with empyema. However, this hypothesis requires confirmation because the effect of serotype replacement on invasive disease rates in children has so far been marginal,86 87 and it has been shown that the increasing incidence of infections due to serotypes such as 19A is independent of the use of PCV-7.88 In most cases of empyema, fluid volume is minimal and the fluid is not contaminated and contains only marginal amounts of fibrin and cells.19 However, in the presence of bacteria (about 20–30% of cases), fluid volume tends to increase and its composition changes, with progression to the fibrinopurulent and organisation phase.11 In case of CAP, the fluid is caused by changes in local factors and is represented by exudate (ie, it differs from transudate because it is characterised by one of the following: ratio of pleural fluid protein to serum protein >0.5; ratio of pleural fluid lactate dehydrogenase (LDH) to serum LDH >0.6; pleural fluid LDH >0.7 times the normal upper limit for serum).

The aim of treating parapneumonic effusion is to sterilise the pleural fluid and restore normal lung function. Once again, the choice of antibiotic is different in developing and developed countries. The WHO recommends the administration of chloramphemicol 25 mg/kg intramuscularly or intravenously every 8 h until the child has improved, and then the same drug orally for a total of 4 weeks.11 In the case of documented infection due to S aureus, the WHO suggests cloxacillin 50 mg/kg intramuscularly or intravenously every 6 h together with gentamicin 7.5 mg/kg intramuscularly or intravenously once a day until the child has improved, and then oral oxacillin four times a day for a total of 3 weeks.11

In the developed world, because S pneumoniae is the most frequent cause of empyema,19 83 84 86 primary therapy is based on high intravenous doses of an antibiotic capable of assuring good pneumococcal coverage.7 16 22 As there is no correlation between the development of empyema and the presence of S pneumoniae resistance to antibiotics,89 the recommended antibiotic is the same as that suggested for severe cases. In the case of necrotising pneumonia, progressive disease or underlying immunodeficiency, broader spectrum drugs combined with an antistaphylococcal antibiotic are indicated in very young children. The duration of administration has not been codified, but most authors suggest intravenous therapy for 1 week after the resolution of fever followed by oral therapy for a further 1–4 weeks.90

Regardless of age, the drainage of pleural fluid is not indicated unless its ultrasonographically-detected volume exceeds 1 cm.86 90 If the volume is higher, drainage is useful to confirm the diagnosis by excluding other causes of pleural effusion, define the quality of the fluid, identify the infecting organism and reduce respiratory symptoms, thus accelerating disease resolution. Theoretically, the fluid can be drained in four ways: thoracocentesis, by means of a chest tube (with or without fibrinolysis) or surgical debridement.90–93 A single tap can be used when ultrasound indicates that the fluid volume marginally exceeds 1 cm and lateral decubitus radiography shows that it is freely flowing in the pleural space,90–93 but when the volume is greater or the fluid becomes loculated, it is necessary to use repeated taps or insert a drain.90–93 Although non-randomised studies have shown that the two procedures are comparable, many authors prefer drain insertion because repeated punctures are more traumatic.90–93

Fibrinolytic medication is advocated when the pleural fluid becomes organised.86 90 93 94 However, the efficacy of fibrinolytic agents is debated and the most recent data seem to suggest that they do not significantly reduce the duration of fever, chest tube drainage or hospitalisation, and that surgery may still be necessary regardless of the stage of the disease.95

Data concerning the efficacy of video-assisted thoracoscopic surgery (VATS) are also controversial. Avansino et al found that the patients who underwent primary surgery experienced less mortality and required shorter periods of hospitalisation, tube thoracostomy and antibiotic therapy.96 On the other hand, Sonnappa et al found that VATS and tube thoracostomy with intrapleural urokinase were substantially equivalent in terms of failure rates and median post-intervention hospitalisation.97

On the basis of these data, it seems that the stepwise algorithm for pleural empyema suggested by Proesmans and De Boeck can be considered acceptable.90 This considers antibiotics alone whenever the pleural fluid volume is <1 cm; if this is not the case, intercostal tube drainage should be used, with the addition of fibrinolytics when the fluid seems to be organised. VATS is only considered as a salvage procedure in cases where the previous therapies fail.

Finally, children with parapneumonic effusion should be carefully observed for signs and symptoms of haemodynamic deterioration due to pericardial effusion.90 98 99 Although the amount of pericardial fluid is usually very small and does not give rise to symptoms, pericardiocentesis is sometimes needed.

Necrotising pneumonia and pneumatoceles

During the course of bacterial CAP, necrotising pneumonia and pneumatoceles develop as a result of localised bronchiolar and alveolar necrosis.100 Although bacteria such as S pneumoniae, H influenzae, Klebsiella pneumoniae and Escherichia coli may be involved, the main cause is S aureus,100 which means that an intravenous antistaphylococcal drug should be immediately administered once the diagnosis has been made. The choice of drug depends on the incidence of the methicillin resistance of S aureus in the area in which the case occurs: if this is more than 20%, vancomycin should be used.

The duration of intravenous antibiotic administration has not been codified, but it is reasonable to assume that it should be continued until the child shows signs of improvement, and then be followed by oral administration for a total antibiotic course of at least 3 weeks.

Most pneumatoceles spontaneously disappear and the radiographic alterations within the first 2 months, although this may take as long as 6 months. Complicated cases should continue to be followed up, including those with more than 50% involvement of the hemithorax and severe atelectasis, and the development of broncopleural fistulae with tension.100 When these occur, image-guided catheter drainage is indicated and, if this fails, surgical excision is the only solution.100 101

Lung abscesses

Lung abscesses occur as a result of the acute destruction of the pulmonary parenchyma, usually due to bacteria gaining access from the oropharynx,102 103 although less frequently they are caused by an underlying bronchial process, the evolution of CAP or a septic embolus.

Anaerobic bacteria (Prevotella, Fusobacterium, Peptostreptococcus and Bacteroides) are the most frequent agents recovered from lung abscesses and account for 70–90% of all isolates.104 105 S aureus is most frequently found when there is associated empyema,106 107 and facultative pathogens include α-haemolytic streptococci, Enterobacteriaceae, S pyogenes and S pneumoniae.108 109

Evolution to a lung abscess is often insidious. Approximately half of such patients have cough and fever and produce sputum, and chest pain and haemoptysis may also occur. However, putrid breath is occasionally the sole or predominant manifestation.102 103 The diagnosis is based on the chest radiographic finding of an air-fluid level indicating a cavity at least 2 cm with a defined wall.110 However, chest x-rays are initially non-diagnostic in about one-fifth of cases.110 CT scanning is a useful means of defining the extent of the disease, any underlying anomalies and the presence of a foreign body. Ultrasonography may also be useful for follow-up purposes.110

The mainstay of treatment is prolonged antibiotic therapy.111 112 Most experts advocate a 2–3-week course of parenteral antibiotics followed by a course of oral antibiotics to complete a total of 4–6 weeks. The chosen antibiotics should provide aerobic and anaerobic coverage (ie, a penicillinase-resistant agent active against S aureus and clindamycin or piperacillin plus a beta-lactam inhibitor or meropenem).111 112 If Gram-negative bacteria are suspected or isolated, an aminoglycoside should be added.111 112

Between 80% and 90% of all lung abscesses resolve with the use of antibiotic therapy alone. Most children become asymptomatic within 7–10 days, although the fever may persist for as long as 3 weeks.111 112 In the case of severely ill patients or those who fail to improve after 7–10 days of appropriate antimicrobial therapy, surgical intervention should be considered. Minimally invasive and often CT-guided percutaneous aspiration techniques are increasingly being used, but drainage may also be necessary if the abscess is >4 cm in diameter and causes a mediastinal shift or leads to ventilator dependency.113 In rare complicated cases, thoracotomy with lobectomy and/or decortications may be necessary.113

Oxygen

Oxygen administration is considered essential in the treatment of severe CAP in both developing and developed countries, although there are some minor differences in target oxygen saturation (Sao₂) levels. The WHO suggests giving oxygen to children with severe CAP and severely low chest indrawing or a respiratory rate of ≥70 breaths/min, and to all children with very severe CAP.11 Oxygen administration is recommended until the signs of hypoxia disappear or, if pulse oximetry is available, until Sao₂ remains stable at >90%. The BTS guidelines indicate oxygen administration in all cases of severe CAP and suggest maintaining Sao₂ levels of >92%.7

There are greater differences in the methods used to deliver oxygen because the WHO recommends nasal prongs or a nasal or nasopharyngeal catheter and stresses the fact that a face or head mask is not indicated,11 whereas the BTS guidelines suggest using nasal cannulae, a head box and face mask, while highlighting the fact that there is no strong evidence indicating that any of these methods is more effective than the others.7 On the other hand, feeding is easier with nasal cannulae, although they do not allow the delivery of oxygen flow rates of >2 l/min.

Fluid therapy

As children with severe CAP are usually unable to maintain their fluid intake because of breathlessness or fatigue,114–116 nasogastric or intravenous fluid therapy is mandatory. Nasogastric tube feeds can impair respiratory conditions in neonates and younger children with narrow nasal passages,114 so these and patients affected by vomiting should preferably undergo intravenous fluid infusion if possible. Fluid intake should be calculated taking into account possible dehydration and the greater liquid losses due to the increased respiratory rate and fever. However, fluid balance and serum electrolyte concentrations should be monitored daily because inappropriate antidiuretic hormone secretion is relatively common in severely ill children and, in such cases, the volume and type of fluid infusion should be carefully monitored.115 116

Physiotherapy

Chest physiotherapy is widely used in paediatric practice (particularly in the industrialised world) because it is thought to be beneficial in evacuating inflammatory exudates and tracheobronchial secretions, removing airway obstructions, reducing airway resistance, enhancing gas exchange and reducing the work of breathing.117 118 However, its real usefulness is debatable because there is no scientific evidence that it modifies the course of CAP, even in severe cases or in the presence of complications.119–122 Although not completely exhaustive because there are a number of types of chest physiotherapy whose efficacy may be different (ie, chest percussion and vibrations, the use of oscillating devices and the use positive expiratory pressure), these findings further support the recommendations of the BTS that chest physiotherapy should not be recommended in children with CAP.7