British Medical Bulletin 61:231-245 (2002)
© 2002 Oxford University Press
Treatment of infections due to resistant organisms
Childhood respiratory infections
* Paediatric Infectious Disease Unit, St George's Hospital, London, UK
Department of Microbiology, St George's Hospital, London, UK
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Abstract |
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Antibiotic resistance remains rare in paediatric community-acquired pneumonia in the UK, but is more common in hospital-acquired pneumonia and in patients with chronic lung diseases. It should also be considered in children arriving from countries with a high prevalence of antibiotic resistance, children with previous heavy antibiotic exposure, those who are immunosuppressed, and those who are not responding to conventional therapy. The most frequent bacterial cause of paediatric pneumonia is Streptococcus pneumoniae and globally there are major concerns about the increasing resistance of this organism to penicillin. Intermediate resistance may be overcome with conventional doses of parenteral penicillin and there is as yet no convincing evidence that intermediate/high level resistance is associated with a worse clinical outcome. Continued vigilance and research is required. The recently introduced pneumococcal conjugate vaccines offer great promise as they are likely to prevent cases of disease due to penicillin-resistant serotypes.
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Introduction |
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TopFootnotesAbstractIntroductionClinical syndromes of LRTI...Specific organismsKey points for clinical...References |
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‘Resistance to antibiotics’ is a simple phrase which may have several meanings, depending on the context. The term may signify organisms which have acquired the means to avoid killing or inhibition by an antibiotic to which they are normally susceptible, or may refer to organisms which are intrinsically resistant to an antibiotic. This chapter will confine itself to lower respiratory tract infections (LRTI) due to bacterial pathogens – but it should be remembered that most childhood respiratory infections are viral, and thus intrinsically resistant to antibiotics. (See Table 1 for a fuller definition of resistance.)
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Acquired antibiotic resistance is a result of exposure to antibiotics leading to selective pressure on bacteria, and preferential survival of resistant clones. It is an inevitable consequence of the use of antibiotics in medicine (including veterinary medicine), but the development of resistance is thought to be more likely when antibiotics are used in a profligate way, for example by being available without prescription, by being used for an excessive duration, or by being used as growth supplements in agriculture. Examples of mechanisms of resistance are given in Tables 2 & 3.
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The data that are available on the incidence of antibiotic resistance in respiratory disease represent only part of the picture. There are a number of reasons for this. It is often difficult to make a microbiological diagnosis of paediatric LRTI and cases that are diagnosed and reported may be skewed in favour of those that are severely ill, or have failed to respond to initial antibiotics. Most reports of antibiotic resistance, therefore, refer to adult disease. Atypical pathogens are even less frequently sought and are seldom amenable to susceptibility testing. Those parts of the world with the highest rates of childhood pneumonia are also those with the poorest diagnostic facilities. Thus, these data must be viewed with a degree of caution. Nonetheless, while most respiratory infections in children remain susceptible to the common antibiotics, the proportion of infections due to resistant organisms continues to rise (Figs 1 & 2) and it is not possible to predict the endpoint. There is, therefore, increasing global concern about the emergence of antibiotic resistance, with worries of an imminent return to a ‘pre-antibiotic era’ when most infections were untreatable. This has led to efforts by health authorities in many countries to control excess use of antibiotics; it is too early to assess the effect of these interventions, but it is of interest that the rate of penicillin resistance reported in UK invasive isolates of pneumococci has decreased slightly since 1997 (Fig. 1).
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Clinical syndromes of LRTI and antibiotic resistance |
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TopFootnotesAbstractIntroductionClinical syndromes of LRTI...Specific organismsKey points for clinical...References |
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From the point of view of aetiology and the likelihood of resistance, it is convenient to consider three main scenarios.
Community-acquired pneumonia The most common cause of acute pneumonia is the pneumococcus, which is still, in the UK, predominantly susceptible to penicillin. Staphylococcus aureus can be seen in children < 2 years of age, and occasionally other pathogens such as Haemophilus influenzae or Moraxella catarrhalis. Mycoplasma pneumoniae causes a milder illness, mainly in the over 4-year-olds. Pulmonary tuberculosis is a global problem and, in recent years, drug-resistant tuberculosis has emerged as a significant threat to public health. The issue of resistance of these pathogens will be discussed below.
Hospital-acquired pneumonia
This is obviously much rarer and mainly occurs in ventilated children on high-dependency units1
. Most studies implicate a variety of Gram-negative organisms as the predominant aetiological agents. These include Pseudomonas spp, H. influenzae and, increasingly, Enterobacter spp. Staph. aureus, including MRSA, is the only commonly implicated Gram-positive organism; the pneumococcus is rarely isolated, but may be under-diagnosed1. These organisms display intrinsic or acquired resistance to ‘simple’ antibiotics (see below) and most hospitals have treatment guidelines that cover the pathogens endemic to those units. A microbiological diagnosis is usually feasible.
Hospital-acquired tuberculosis and Legionnaire's disease are very rare, but significant because of their severity. Drug resistant tuberculosis is discussed further below.
The major risk factor for nosocomial Legionella infection is immunosuppression2. Infection is acquired from the environment. The organism normally inhabits water and is spread to patients via airborne droplets. Sources within hospitals include water-cooled ventilation systems, shower heads and tap water.
Chronic suppurative lung disease
This group includes patients with cystic fibrosis (CF). Pulmonary infection is the most common cause of morbidity and mortality among patients with CF. After years of symptomatic lung disease, multiple courses of antibiotics and multiple hospital admissions these patients become colonised with a broad range of pathogens, often unusual and highly resistant. The predominant bacterium is Ps. aeruginosa and others include H. influenzae, Staph. aureus, Burkholderia cepacia and Stenotrophomonas maltophilia3–5. While the clinical significance of infection is clear for certain of these (e.g. Ps. aeruginosa and Burk. cepacia) it is not clear that the isolation of others has any impact on the course of CF. The antibiotic treatment of infective exacerbations of CF is heavily reliant on the result of recent and current sputum culture results as these pathogens have individual and variable antibiotic susceptibility profiles.
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Specific organisms |
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Streptococcus pneumoniae As indicated above, Strep. pneumoniae is the most frequent bacterium causing respiratory tract infections in children. Over the last 2 decades, pneumococci have increasingly become resistant to penicillin and other antibiotics (Fig. 1). This increase has been particularly alarming in a number of countries (e.g. the US)6
. In Europe, resistance is generally higher in southern countries and is lowest in Germany and The Netherlands (Fig. 2). Several studies suggest that children are more likely to be colonised by or infected with resistant strains6.
Mechanisms of antibiotic resistance in Strep. pneumoniae
The susceptibility of Strep. pneumoniae to penicillin is currently defined as follows: susceptible isolates are inhibited by 0.06 µg/ml, intermediate resistance isolates by 0.1–1.0 µg/ml and resistant isolates by 2.0 µg/ml or more. Penicillin inhibits the replication of Strep. pneumoniae by binding one or more enzymes (penicillin-binding proteins, PBPs) required for cell wall synthesis (e.g. transpeptidases). Resistant isolates have PBPs with decreased affinity for penicillin as a consequence of changes in the PBP genes. These genetic changes have arisen from acquisition of genetic material from other bacteria with which they co-exist (probably other oral streptococci) or by re-arrangement of their own DNA. Newly resistant strains may become prevalent by geographic spread within a community (clonal spread). This is thought to account for some examples of rapid rises in resistance in relatively closed and small communities (e.g. in Iceland).
Pneumococci that are susceptible to penicillin are usually susceptible to all other antibiotics. In contrast, a significant proportion of pneumococci with reduced penicillin susceptibility will be resistant to other antibiotics, particularly macrolides and tetracycline6. Penicillin-resistant/intermediate isolates in the UK generally remain susceptible to third generation cephalosporins, such as cefotaxime or ceftriaxone, and these are the usual choice when penicillin is inappropriate. However, although cefotaxime-resistance is rare, it is important that cephalosporin MICs are checked if penicillin susceptibility is found to be reduced.
Clinical relevance of antibiotic resistance
One might assume that pneumonia caused by pneumococci which are penicillin-resistant would not respond to therapy with this antibiotic, but this in fact is not necessarily so. In the case of intermediate resistance, standard intravenous doses of penicillin will still exceed the MIC, and thus a cure might be expected. Studies of patients with both intermediate-and high-level resistance have failed to demonstrate convincingly that those treated with penicillin do any worse that those treated with other ‘appropriate’ antibiotics (see below). However, the studies tend to be retrospective or observational, rather than randomised intervention-based trials, and most clinicians, when faced with a patient who has severe pneumococcal infection due to a known or suspected penicillin-resistant strain, would still prefer treatment with an alternative antibiotic.
Three studies have addressed the response to antibiotic treatment of children with pneumonia due to penicillin resistant Strep. pneumoniae. The US Pediatric Multicenter Pneumococcal Surveillance Study Group (consisting of 8 children's hospitals) prospectively identified children with Strep. pneumoniae. A total of 257 episodes were included; 8% of isolates were intermediate and 6% resistant to penicillin, 3% intermediate and 2% resistant to cefotaxime. There was no difference in outcome between susceptible and resistant cases. Of note, however, a high proportion received parenteral antibiotics: 80% of out-patients had an i.v. dose of a cephalosporin and then a course of oral antibiotics and 17% an oral ß-lactam course alone. Of in-patients, 48% had an i.v. course of a cephalosporin and then a course of oral antibiotic, 20% had i.v. cephalosporin with i.v. penicillin, 16% i.v. cephalosporin and i.v. vancomycin. Of those with penicillin resistant organisms, all but one had at least one dose of an i.v. antibiotic7.
In another study, Friedland compared factors in 78 South African children hospitalised with pneumonia (25 intermediate resistant to penicillin, 53 penicillin susceptible) and found no difference in outcome. Therapy included oral amoxycillin in 4, and i.v. ampicillin or penicillin in 128.
Finally, Deeks et al reviewed the clinical outcomes of hospitalised children 5 years of age in Uruguay and Argentina who had invasive Strep. pneumoniae disease. For those with pneumonia due to penicillin-resistant strains, there was no significant difference in response to penicillin/ampicillin therapy as compared with those who had penicillin-sensitive pneumonia9.
Ultimately, it seems unlikely that we will be able to rely on penicillin or cefotaxime/ceftriaxone to cure infections by highly resistant pneumococci (see case report described by Dowell et al10). At present, however, penicillin and cephalosporins appear adequate in treating susceptible/intermediate resistant organisms.
If any risk factors for pneumococcal resistance are present (see Table 4), then the use of a parenteral antibiotic, the use of a third generation cephalosporin and, potentially, the addition of vancomycin should be considered until antibiotic susceptibilities have been clarified.
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Haemophilus influenzae H. influenzae is an important cause of community acquired pneumonia in children; type b capsulate strains are now rare where vaccination is practised, but non-capsulate (non-typable) strains remain common. Ampicillin-resistance has emerged among both capsulate and non-capsulate strains, and is almost always mediated by ß-lactamases. In the US, up to 34% of isolates are ampicillin-resistant11
; in Europe, reported rates are generally lower (e.g. 6% in Germany), but France and Spain approach US rates (28% and 32%, respectively)12. A review of H. influenzae isolates from cases of paediatric pneumonia referred to the PHLS Haemophilus Reference Unit between 1991–2001, suggests the UK rate is between these extremes with 19% of isolates resistant to ampicillin (Slack M, personal communication). There are occasional rare reports of strains resistant to amoxycillin-clavulanate and clarithromycin; third generation cephalosporins, quinolones and other macrolides such as erythromycin and azithromycin remain effective. Thus, it is no longer possible to assume that ampicillin will be appropriate when dealing with H. influenzae infection; severe infections should normally be treated with a parenteral third generation cephalosporin.
Moraxella catarrhalis
The contribution of this organism to childhood LRTI is unclear; it is frequently carried in the pharynx, so it is difficult to assess its significance in cases of pneumonia. At present, virtually all strains produce ß-lactamase and are thus regarded as ampicillin-resistant11. Suitable antibiotics, which remain active against nearly all strains, include amoxicillin-clavulanate, and macrolides such as clarithromycin.
Staphylococcus aureus Staph. aureus is a rare cause of pneumonia in childhood. It should be considered particularly in children < 2 years of age with a severe pneumonia. Children with CF are frequently colonised with Staph. aureus, particularly when young and it contributes to infective pulmonary exacerbations.
Very soon after penicillin was introduced, strains that produced a ß-lactamase (penicillinase) were described. These spread quickly and now constitute the dominant population of Staph. aureus – less than 10% of strains are penicillin-susceptible.
Methicillin resistance emerged equally rapidly after methicillin was introduced in the early 1960s. This was mediated by a mutant gene, mecA, that encodes an alternative PBP which has a low affinity for methicillin; thus the organism is able to construct its cell wall despite the presence of the antibiotic. Methicillin resistance implies resistance to all penicillins (including flucloxacillin) and cephalosporins – a fact which is sometimes overlooked. Until recently, methicillin-resistant Staph. aureus (MRSA) has been rare, remaining confined to hospitals and other residential institutions. In the UK, successive new strains have emerged over the last 30 years, and gradually spread through the country; some strains seem to be more highly transmissible, and are designated ‘epidemic MRSA’ or E-MRSA. In recent years, two strains, E-MRSA 15 and E-MRSA 16 have spread to most UK hospitals, and in some institutions they account for over 50% of all invasive infections with Staph. aureus. These infections include opportunistic infections of ventilated adult and paediatric patients.
So far, MRSA infections remain very rare in the community, and when they do occur it is generally in someone with some association with a medical institution; the infections are generally of the skin/soft tissues, and rarely respiratory. There have recently been occasional worrying reports of serious community-acquired infections with MRSA13.
More alarmingly, low-level glycopeptide resistance has appeared in different parts of the world – Japan, US, UK and France14. The mechanism of resistance is uncertain, but resistant strains (known as GISAs: glycopeptide-insensitive Staph. aureus) are characterised by abnormally thickened cell walls. So far, cases are sporadic, often associated with prolonged use of vancomycin or teicoplanin, and secondary spread of infection within the community has not been described.
Management
The rare infections due to fully sensitive strains of Staph. aureus can be treated with penicillin alone; penicillin-resistant strains are best treated with flucloxacillin (or nafcillin/oxacillin in the US). As true staphylococcal pneumonia is generally a very severe infection, many clinicians and microbiologists would advise adding a second agent such as rifampicin or gentamicin, though categorical evidence that the outcome is improved is lacking.
MRSA is generally resistant to a variety of other antibiotics in addition to methicillin/flucloxacillin and the cephalosporins. These include erythromycin, clindamycin, and frequently ciprofloxacin. The standard treatment of genuine MRSA infection is, therefore, vancomycin or teicoplanin. Particularly with MRSA respiratory infections, it is important to try to distinguish genuine invasive disease from colonisation of the upper airways in a ventilated patient – this may be very difficult in practice, as such patients may have other causes of fever and lung shadowing on X-ray, apart from infection. As with methicillin-susceptible strains, there is a debate over the benefits of dual therapy, combining vancomycin with rifampicin or gentamicin. There is some evidence to suggest a better outcome in bacteraemic infections when rifampicin is added15 and it would seem reasonable to take this approach to severe infections. The precise role of newer agents such as quinupristin-dalfopristin or linezolid is yet to be established; the latter offers the theoretical advantage of being highly active in both oral and intravenous preparations, but it is expensive, and there are concerns over safety in long-term use; thrombocytopaenia seems to be a particular problem.
In managing MRSA, it is important also to try to prevent spread of the organism to other patients – the fact that a patient has acquired MRSA implies some failure in infection control, most likely due to inadequate hygienic measures, particularly hand washing.
Bordatella pertussis
Erythromycin, especially the estolate ester, appears to be the most reliable antibiotic in treating pertussis infection. Resistance to erythromycin occurs rarely (several case reports quoted by Lee16); if resistance is detected early enough in the illness to influence therapy, then trimethoprim-sulphamethoxazole is the drug of choice.
Mycoplasma pneumoniae and Chlamydia pneumoniae As would be predicted by the lack of a cell wall, ß-lactam agents are ineffective in treating M. pneumoniae and C. pneumoniae infections. The mainstay of treatment is erythromycin and tetracycline. The former is clearly more appropriate in children and no erythromycin-resistant strains have so far been described.
Mycobacterium tuberculosis Soon after drug therapy for TB became available, it was noticed that drug resistance frequently arose when one agent was used in isolation. This was principally due to the fact that normal multiplication of the organism gives rise to resistant mutants at a low but steady rate – said to be about 1 in 105 cell divisions in the case of isoniazid, and 1 in 109 divisions in the case of rifampicin. In cavitatary disease, the presence of large numbers of tubercle bacilli implies that low numbers of these resistant mutants are likely to be already present, and will survive if monotherapy is used. If dual therapy is used, however, an organism would have to have simultaneously mutated to become resistant to both, if it is to survive. Such a double mutation is much less likely, at about 1 in 1014 cell divisions – even a large cavity is unlikely to contain enough organisms for this to have occurred. This is the rationale behind the standard practice of giving drugs in combination for established disease, and giving isoniazid monotherapy to patients who have been infected but have a very low burden of organisms – in such cases, isoniazid resistant mutants are not likely to be present. The latter is often referred to as isoniazid prophylaxis, but it would be more correct to refer to it as pre-emptive treatment, as the patient is already infected.
If patients take their medication intermittently, they are in effect receiving monotherapy for short periods of time – an ideal way to select resistant mutants. Once a mutant resistant to one drug has been selected, and grown to large numbers, it is then more likely that a further mutation will occur, leading to dual or multi-drug resistance. Such intermittent or erratic dosing is more likely where resources to buy the medications are limited, where there are communication difficulties between the patients and health-care workers, where treatment is unsupervised, and where patients are less motivated to complete a long tedious course of medication, as may be the case with people with mental illness or addiction, or people who have other problems that are seen to be of greater priority. These are, therefore, the conditions where resistance is more likely to arise during therapy – a situation sometimes known as secondary resistance. In addition, a patient may become infected with a strain that is already resistant to one or more agents – this is known as primary resistance.
In the last decade, drug resistant tuberculosis has been perceived as a global health problem. Rates vary through the world in a rather complex pattern. In general, rates are low in prosperous industrialised countries, where good treatment is widely available and well supervised. For example, in the UK, 5–7% of strains are isoniazid resistant, and less than 1.5% are multi-drug resistant (MDR); these are mostly in urban areas with a large immigrant population. Extremely poor countries where there is little treatment available for TB will also have low rates of resistance. The major problems are in areas where antituberculous agents are available, but treatment is poorly organised and poorly supervised. The World Health Organization have identified 7 MDR-TB ‘hot zones’ with the highest rates: 3 are in Eastern Europe, and 2 in South/Central America. For example, in Latvia, 22% of strains were reported as multi-drug resistant in 1997. There are less specific paediatric data available, given the difficulty in making a microbiological diagnosis in a child, but where figures are available for children, they tend to mirror the resistance rates in the general adult population. For example, in the UK between 1995–2000, 6.5% of 369 isolates from children 0–14 years of age were isoniazid resistant and 0.5% were multi-drug resistant (UK Mycobacterial Resistance Network (Mycobnet) database, April 2001 – www.phls.co.uk).
As children are much less likely to have cavitatary disease, they are much less likely to develop drug resistance during treatment; thus most children with resistant tuberculosis are thought to have acquired it from adult contacts already infected with a resistant strain. Therefore, if a case of tuberculosis is diagnosed in a child, clinicians need to assess the risk of MDR-TB in the source patient, if known, or in the local population if the specific source is unknown. Given that the main way in which paediatric cases are diagnosed is on the basis of radiology or tuberculin testing rather than culture, such a risk-assessment at the start of treatment is especially important.
Other clues to drug resistance include a previous diagnosis of TB, or previous TB treatment/prophylaxis (which may be seen in older children), and (less definitely) co-infection with HIV. It is thought that HIV-infected patients tend to have a higher load of tubercle bacilli, and thus more chance of having a resistant mutant, ready for selection once treatment starts. This could apply both to an HIV-infected child, and (more likely) to another HIV-infected family member who is the source of the child's infection. During therapy, if there is a failure of clinical response or prolonged culture positivity (smear positive at 4 months or culture positive at 5 months) then resistance should also be considered17.
Drug resistant TB is not more virulent or infectious than drug-susceptible TB, but the therapy is more complex and the duration of therapy is longer. The principal errors made in the management of MDR-TB are the omission of a proper risk assessment at the start of treatment, thus delaying the diagnosis, and to add single drugs in a piecemeal fashion to a failing regimen. MDR-TB has a poorer outcome than drug-sensitive infections; this is improved if early aggressive treatment is given with at least 5 agents to which the organism is still sensitive18. There are several options available for second-line therapy – fluoroquinolones, capreomycin, ethionamide, cycloserine and aminoglycosides. In general, these are either less effective than the routine first-line agents, or more toxic, or both, and therapy needs to be carefully managed, under the supervision of a paediatrician with expertise in tuberculosis, and with close liaison with the laboratory.
In treating patients who have been infected with a resistant strain but are not ill (i.e. patients who would normally receive isoniazid monotherapy, who have tuberculin reactivity, but no radiological changes), there are several options. If the strain is only resistant to isoniazid, dual therapy can be given with rifampicin and pyrazinamide, or rifampicin alone, which has been shown to be effective19; if the strain is resistant to these agents, then two other agents may be chosen, for a minimum period of 6 months. Such agents are often very unpalatable, and are of unproven efficacy, so it might be preferable either to wait and observe the patient, treating if symptoms occur, or else start a full course of therapy without waiting for the infection to progress to overt disease18.
Pseudomonas aeruginosa
Ps. aeruginosa is inherently resistant to many antibiotics and resistance to other antibiotics may arise during therapy. Mechanisms of resistance include alterations in permeability of the outer membrane, multi-drug active efflux pumps and production of specific bacterial enzymes, e.g. aminoglycoside-modifying enzymes and ß-lactamases20. A recent UK survey of the antimicrobial susceptibility patterns of Ps. aeruginosa has determined the following resistance rates: amikacin 5.6%, gentamicin 11.1%, ciprofloxacin 8.1%, ceftazidime 2.3%, imipenum 8.1%, meropenum 4.2%, piperacillin 3.9% and piperacillin/tazobactam 2.8%. Comparison with previous UK surveys indicates little change although imipenum resistance has increased from 2.5% in 199321. It is noteworthy that resistance to imipenum and meropenum were significantly more prevalent in the isolates obtained in intensive care units and that resistance rates in general were higher in isolates from patients with CF. Local variation in resistance rates was noted for CF isolates21.
Ps. aeruginosa once established in patients with CF is rarely eradicated. However, aggressive antibiotic therapy aimed at Ps. aeruginosa during infective exacerbations can be clinically effective. Dual therapy, using two antibiotics with different mechanisms of action such as an antipseudomonal penicillin and an aminoglycoside, has been traditionally used in order to provide synergy and minimise resistance. Monotherapy has also proved efficacious. A recent Cochrane Review included a total of nine studies which compared a single agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used. Eight comparisons of a ß-lactam antibiotic (penicillin-related or third generation cephalosporin) with a ß-lactam/aminoglycoside combination and three comparisons of an aminoglycoside with a ß-lactam/aminoglycoside combination were made. The meta-analysis did not demonstrate any significant differences between monotherapy and combination therapy in terms of lung function, symptom scores and adverse effects. Single therapy was associated with an increase in the number of patients with resistant strains of Ps. aeruginosa at 2–8 weeks' follow-up. Overall, the methodological quality of studies was poor and unfortunately the systematic review was inconclusive22.
Most CF units will have individual antibiotic policies which reflect their local microbial resistance patterns
Hospital-acquired pneumonia in which Ps. aeruginosa is implicated should also be treated with two agents active against the infecting strain. This policy reflects the potential variability in antibiotic susceptibility as well as the life-threatening potential of this infection.
Legionella pneumophila
Legionella infection may present as a severe pneumonia. As the organism grows poorly, diagnosis usually depends on either serology or urinary antigen detection. Reports in children are rare2. The newer macrolides (e.g. azithromycin) and quinolones are probably the agents of choice.
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Key points for clinical practice |
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TopFootnotesAbstractIntroductionClinical syndromes of LRTI...Specific organismsKey points for clinical...References |
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- • Antibiotic resistance remains rare in paediatric community-acquired pneumonia in the UK
- • Resistance is more common in hospital-acquired pneumonia, and in patients with CF and other chronic lung diseases
- • Consider resistance in children arriving from countries with a high prevalence of antibiotic resistance, those with previous heavy antibiotic exposure, children who are immunosuppressed and children who are not responding to conventional therapy
- • Note local antibiotic resistance patterns when considering antibiotic treatment of hospital acquired pneumonia and infective exacerbations in children with cystic fibrosis
- • Measures to be taken to prevent childhood infection with resistant organisms include curtailing the inappropriate use of antibiotics in hospitals and communities. The routine use of the Haemophilus influenzae type b vaccine and the recently licensed pneumococcal conjugate vaccine will prevent childhood infections due to both susceptible and resistant organisms alike
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Footnotes |
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TopFootnotesAbstractIntroductionClinical syndromes of LRTI...Specific organismsKey points for clinical...References |
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Correspondence to:Dr P T Heath, Paediatric Infectious Disease Unit, St George's Hospital, Cranmer Terrace, London SW17 0RE, UK
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References |
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TopFootnotesAbstractIntroductionClinical syndromes of LRTI...Specific organismsKey points for clinical...References |
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