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Overcoming Current Obstacles in the Management of Bacterial Community-Acquired Pneumonia in Ambulatory Children

Posted on: Wednesday, 9 February 2005, 03:00 CST

Introduction

Worldwide, community-acquired pneumonia (GAP) is a leading cause of infectious morbidity and mortality in children.1 Despite this, childhood CAP has been the subject of few evidence-based, consensus recommendations for diagnosis and treatment,2-4 although individual experts have published recommendations.1,5,6

The physician faces various challenges in diagnosing and managing CAP in children. Indeed, variations exist even in the definition of the condition. In some cases, childhood CAP has been defined solely on clinical grounds,4,7 whereas in others the diagnosis of CAP has required evidence of parenchymal infiltrates on chest radiography.1 The microbial etiology of CAP is notoriously difficult to establish.1,4,6 A variety of viruses, bacteria, and atypical/ intracellular organisms may be implicated within single- or mixed- pathogen infections. As it is often difficult to identify the causative pathogen (s), the selection of initial antibacterial therapy is primarily empiric. Compounding this problem is an increasing concern regarding the rising numbers of bacterial pathogens with minimum inhibitory concentrations (MICs) that exceed achievable site-specific antibacterial concentrations.

This paper aims to evaluate current knowledge regarding these obstacles to the optimal diagnosis and treatment of CAP in children, focusing on outpatient management. It also considers what impact bacterial resistance to existing antibacterials may have on outcomes and treatment recommendations.

Epidemiology of Childhood CAP

Studies performed from the perspective of outpatient clinics, health management organizations, and public health authorities8-15 have given remarkably similar estimates of the incidence of CAP in developed countries (Table 1). CAP is most common in young children (i.e., in those aged <5 years). In the United States, a prospective 11-year study in an outpatient pediatric practice9 found a peak CAP incidence of 40/1,000 patients/year in children aged from 6 months to 5 years and a subsequent decrease with age during childhood (Table 1). A further US study13 found the overall incidence of pneumonia in children <5 years of age to be 45.8/1,000 children/ year, with an incidence of 41.9/1,000 children/year in children aged <12 months, 47.1/1,000 children/year in children aged 12-24 months, and 52.3/1,000 children/year in children aged >2-5 years. In a prospective, population-based study in Finland (n=546 patients),11 the overall incidence of CAP was 86.0/1,000 children/year in children aged <5 years and 16.2/1,000 children/year in those aged 5- 14 years. These data compared with incidences of 4.4-8.4/1,000 patients/year in adolescents and adults aged 15-59 years and 15.4- 34.2/1,000 patients/year in those aged ≥60 years. The mortality rate due to CAP was 0.1/1,000 patients/year in children aged <15 years, compared with 0.03/1,000 patients/year in those aged 15-59 years and 2.1/1,000 patients/year in those aged ≥60 years.

Table 1

DATA FROM EPIDEMIOLOGIC STUDIES INVOLVING CHILDREN WITH COMMUNITY- ACQUIRED PNEUMONIA

Gender is also a risk factor for CAP. Among Finnish children aged <5 years, the incidence of CAP was higher in males than in females (47.4 vs 23.6/1,000 patients/year).11 In those aged 5-14 years, the incidence was identical in males and females (16.2/1,000 patients/ year). Differences may also exist among different socioeconomic and ethnic populations. For example, rates of pneumococcal pneumonia are higher in native Alaskans than in nonnatives (Table 1).12 In another study, Black et al13 reported a greater risk of pneumonia in US children aged <5 years of Asian, African-American, or Hispanic ethnicity compared with those of Caucasian ethnicity (47.6-57.6 vs 42.2/1,000 patients/year). The epidemiology of CAP is also subject to environmental influences. Studies in the United States8,9 and Israel16 have found that childhood CAP occurs most commonly in the winter and spring months. Seasonal outbreaks of respiratory syncytial virus (RSV), influenza A, and-in older children- Mycoplasma pneumoniae also result in peak pneumonia incidences.9

Approximately half of children aged <5 years with CAP are hospitalized, while most older children are treated as outpatients.11 In Finland, a peak incidence of hospitalization due to CAP of 20/1,000 patients/year was reported in children aged <2 years.14 In Spain, the rate of hospitalization for CAP was found to be substantially higher in children aged <4 years than in older children (Table 1).15

Lower respiratory tract infections (RTIs) are particularly common in developing countries. Estimated incidences among children aged 0- 5 years from 10 developing countries ranged from 0.2 to 8.1 new episodes/100 child-weeks at risk.17 While mortality from pneumonia has declined to low levels in developed countries,11,18,19 these infections remain a major cause of death in developing countries.20 In 1990, respiratory infections were the third most common cause of death worldwide, accounting for 4.3 million deaths (4.0 million of which were in developing countries).20 Of the deaths that occurred in developing countries, nearly 70% were in children aged 0-4 years.

Microbiologic Etiology

A variety of pathogens can cause CAP in children (Table 2). In 20- 60% of cases, no pathogen is isolated.3,4 Viruses such as RSV, influenza virus, parainfluenza viruses, and adenovirus are often implicated, especially in younger children. In ambulatory children in the United States (n=168)21 and Finland (n=201),22 the viral infection rate peaked at 28-37% in patients aged 0-4 years. This rate fell to 10-21% in children aged 5-9 years, and to 0-4% in those aged 9-16 years. Viruses were identified by serology and culture from nasopharyngeal swabs in the US study and by serology alone from serum and urine samples in the Finnish study.

Streptococcus pneumoniae is the primary bacterial pathogen causing CAP in children. A clear understanding of its role in CAP is, however, hampered by the lack of standardization among different identification methods employed. In the aforementioned etiologic studies, S. pneumoniae was implicated by use of serology in 27-28% of cases.21,22 s. pneumoniae infection rates were influenced relatively little by age, accounting for 14-36% of cases across the age groups studied. Note, however, that there were too few patients in these studies for subtle changes in the etiology of CAP to be observed.

The atypical/intracellular pathogens M. pneumoniae and Chlamydophila (Chlamydia) pneumoniae are now recognized as important pathogens causing CAP. As these pathogens cannot be isolated by use of routine microbiologie methods, many studies of their role in CAP have relied on evidence from serologic or polymerase chain reaction (PCR) tests.22-26 As discussed below, such data should be interpreted with caution because these tests remain to be standardized and validated according to culture results. Two large studies of cultures from outpatient children in the United States (n=260;27 n=420(28)) found bacteriologic or serologic evidence of M. pneumoniae infection in 26.5-29.5% of cases and of C. pneumoniae in 15.0-28.5% of cases. However, the correlation between culture and microimmunofluorescence serology for C. pneumoniae was very poor, as <5% of culture-positive children met the serologic criteria for acute infection in use at that time and >70% of culture-positive children remained seronegative even after 4-6 weeks' follow-up. Although these atypical/intracellular pathogens are most common in children aged >5 years, they are also implicated in a significant proportion of younger children.21,27,28 To illustrate this, data from the study by Harris et al28 are shown in Table 3. In this study, the rate of culture-defined C. pneumoniae infection in children <5 years of age was the same as in those aged >5 years.

Table 2

KEY BACTERIAL AND ATYPICAL/INTRACELLULAR PATHOGENS RESPONSIBLE FOR COMMUNITY-ACQUIRED PNEUMONIA (CAP)* IN AMBULATORY PEDIATRIC PATIENTS, AND RECOMMENDED INITIAL EMPIRIC ANTIBACTERIAL THERAPY, BY AGE1,3,4,6

The etiology of CAP differs somewhat in ambulatory and hospitalized children, owing largely to differences in the age distribution and-as already noted-the fact that hospitalization is most common among young children, especially those ≤2 years.3 Thus, in children hospitalized with CAP, viruses-in particular RSV- are the primary causative pathogens; S. pneumoniae remains the main bacterial cause.14,29,30 An increase in the relative frequency of complicated disease in hospitalized children with pneumococcal CAP was recently reported in the United States.31

Other, far less common, pathogens that may cause childhood CAP, especially in patients requiring hospitalization, include group A β-hemolytic streptococci, Haemaphilus influenzae, Slaphylococcus aureus, and Moraxella catarrhalis.1,4,14,22,30,32,33 Perinatally acquired Chlamydia trachomatis pneumonia, formerly a relatively common infection in neonates, has been largely eliminated in developed countries through the systematic screening and treatment of pregnant women. The incidence of infection by type b H. influenzae has been greatly reduce\d by vaccination in the United States. However, both C. trachomalis (in infants) and H. influenzae type b may still be important pathogens in developing countries.23,34.

Table 3

MICROBIOLOGIC AND SEROLOGIC EVIDENCE OF INFECTION IN CHILDREN WITH COMMUNITY-ACQUIRED PNEUMONIA (CAP) (REPRODUCED WITH PERMISSION FROM HARRIS ET AL28)*

Mixed infections are common. In particular, viral infections may lead to bacterial infection. In a Finnish hospital, serologic evidence of concomitant bacterial and viral infection was found in 30% of 254 children with CAP over a 3-year period.30 At a second Finnish center, viral and bacterial antigen and antibody assays showed viral infection alone in 19%, bacterial infection alone in 15%, and mixed bacterial/viral infection in 16% of 195 children hospitalized with CAP in 1 year.14

Clinical and Microbiologic Considerations

Various approaches to the overall assessment of children with CAP and for identification of the infection etiology have been evaluated.1,3-6 These include the following:

* Clinical presentation

* Epidemiologic factors

* Radiographic examination

* Microbiologic and other laboratory tests

Clinical Presentation

There are mixed data concerning the value of clinical syndrome for identification of the specific etiology of CAP in children and adults. Certain clusters of clinical features have been suggested to aid physicians in differentiating among bacterial, viral, and atypical CAP, although the evidence base for this is insubstantial.4 For example, it has been suggested that fever, arthralgia, headache, cough, and crackles in school-age children indicate mycoplasma infection.35 However, this clinical presentation also resembles pneumococcal or staphylococcal pneumonia or pneumonia due to adenovirus, particularly if wheezing is present. Clinical syndromes based on infectious etiology are not well defined and, owing to the nonspecific nature of the signs and symptoms, it is generally not possible to identify the infectious etiology by using clinical findings.1,6

Epidemiologic Factors

Certain epidemiologic factors give some clues as to the etiology of CAP. As discussed above, for some organisms the etiology is influenced by factors such as the age of the child (Table 2) and seasonal fluctuations. The vaccination status of the child (i.e., with type b H. influenzae and pneumococcal vaccines) should also be taken into account.1,6 However, it should be noted that pneumococcal conjugate vaccines do not cover all virulent serotypes and therefore pneumococcal disease continues to occur in fully immunized children (e.g., S. pneumoniae serotype 1).

Radiologic Examination

Where available, a chest radiograph is often used to confirm the presence of pulmonary infiltrates/consolidation in patients with suspected CAP. Indeed, the presence of radiographic infiltrates is stipulated in definitions of CAP used by some authors.1 However, the routine use of radiography is not supported in children with mild uncomplicated CAP.4 Moreover, intraobserver and interobserver variations exist in the use and interpretation of radiographic features.1,4,5

There are conflicting data concerning the usefulness of the chest radiography in identifying the microbial etiology of CAP. Several studies have found that radiographic findings cannot be used to distinguish the etiology of CAP in children21,25,36 and that observer agreement is low.36 Other research suggests that the presence of alveolar infiltrates is an insensitive, but reasonably specific, indicator of bacterial infection.37,38 In Finland, a study of children hospitalized with CAP (n=254) found that 71% of those with alveolar infiltrates had bacterial infections, while conversely 72% of those with bacterial CAP had alveolar infiltrates.38 Some experts maintain that lobar consolidation is characteristic of pneumococcal pneumonia.5 A study, involving 368 children hospitalized with pneumococcal pneumonia, found that 133 (36.1%) had complicated disease.31 Of these, the number who had loculated pleural fluid was 114 (85.7%) on chest radiograph, 35 (26.3%) on chest ultrasound, and 65 (48.9%) on chest computed tomography. Sixty (45.1%) had pleural fluid parameters consistent with empyema. However, these features are not considered to be sufficiently reliable to guide decision-making with regard to treatment.4

Microbiologic and Other Laboratory Test

Microbiologic tests have no role in children with CAP managed in the community.4,6 Cultures of nasopharyngeal specimens are of no value because these are not representative of lower respiratory tract secretions. Moreover, many patients are unable to produce a sputum sample. Cultures of blood, although frequently performed on children with radiography-proven pneumonia, are positive in only a small percentage of cases. Invasive procedures (e.g., lung puncture and bronchoalveolar lavage) are generally reserved for hospitalized patients because of the technical skills and equipment required, and the distress such investigations may cause to the child.

Various acute-phase reactants (including the total and differential white cell count, erythrocyte sedimentation rate, and C- reactive protein) have been evaluated for their usefulness in identifying specific etiology in CAP.21,25,37,38 These have generally shown poor sensitivity and specificity and they have a limited role, if any, in routine clinical management.1,3,4,6

Various serologic tests have been developed to diagnose infection by S. pneumoniae, M. pneumoniae, and C. pneumoniae.39,40 These tests measure changes in immunoglobulin, complement fixation, or (for M. pneumoniae) cold agglutinin levels. While some tests have shown moderate specificity, they have highly variable sensitivity.40-43 In addition, these tests lack reproducibility and standardization, and correlate poorly with culture positivity.27,28 Even the microimmunofluorescence antibody assay-the serologic method of choice for detecting C. pneumoniae infection39-is not standardized or properly validated. In a study using the microimmunofluorescence antibody assay and assessing the prevalence of nasopharyngeal carriage of C. pneumoniae in healthy adults, nearly one-fifth (19/ 101) of asymptomatic individuals with negative culture and PCR results met the serologic criteria for acute infection.44 Furthermore, several studies have shown that most children with culture-documented C. pneumoniae infection are seronegative by microimmunofluorescence (Table 3),21,27,28 although most have antibodies detectable by immunoblotting.45 Crucially, serologic tests can be used only for retrospective diagnosis because they require comparison of acute-phase and convalescent measurements. As such, they have a limited role in routine clinical management.4 The United States Food and Drug Administration (FDA) has not yet approved any serology assays.

PCR tests have received considerable attention in recent years. These detect S. pneumoniae, M. pneumoniae, and C. pneumoniae DNA in clinical samples.40 Recent studies have supported the use of PCR in detecting nonbacteremic pneumococcal CAP in children.43 However, current PCR techniques have several drawbacks preventing routine use, not least of which is their complexity. Further evaluation is required to establish their sensitivity and specificity and to assess the influence of confounding factors.39,40 The interlaboratory and intralaboratory reproducibility of PCR assays is particularly poor for C. pneumoniae,39,46-48 and these tests remain to be validated against cultures. For example, Hammerschlag et al49 detected C. pneumoniae by culture in nasopharyngeal samples taken from 12 patients with pneumonia; however, PCR tests were positive in only 2 of these. In a multicenter study, Gaydos et al50 compared culture, PCR, direct fluorescent-antibody stain, and serology in 56 patients with respiratory symptoms and 80 control individuals. Cultures were positive for C. pneumoniae in 30 symptomatic patients and 1 control patient. PCR was positive in 23 culture-positive individuals. In total, 35/56 (62.5%) patients were positive by either culture or PCR; only 8 (14.2%) of these had antibody titers indicative of acute infection. Moreover, 15/80 (18.8%) controls had antibody levels suggestive of acute infection. At present, there are no commercially available PCR assays for C. pneumoniae, M. pneumoniae, or S. pneumoniae that have been approved by the FDA, and the results of PCR assays cannot be used as the sole basis for clinical diagnosis or patient management decisions.

Special Patient Populations

Children with Asthma

Asthma is one of the most common causes of childhood hospitalization and absenteeism from school.51 There is clinical and laboratory evidence to suggest a link between respiratory tract infections, including CAP, and asthma. The prevalence of asthma in children hospitalized with pneumonia has been reported in a prospective study.52 This study of a cohort of children who were admitted to a UK hospital with a diagnosis of pneumonia revealed a 45% cumulative incidence of asthma after a median time of 68 months after admission. This rate is much higher than would be expected in the general population; however, the study was not designed to investigate whether the pneumonia was a predisposing factor for asthma or whether it occurred as a result of undiagnosed asthma.

Many studies have been conducted to investigate the association between RTIs and asthma in children. It has been, suggested that while up to four-fifths of all asthma exacerbations in children may be associated with viral upper RTIs, atypical/intracellular pathogens such as C. pneumoniae and M. pneumoniae may also precipitate asthma symptoms.53 The first study of C. pneumoniae in children with asthma, conducted by Emre and colleagues,54 concluded that infection with C. pneumoniae may precipitate acute episodes of wheezing in children with asthma. In this study, cultures for C. \pneumoniae and serum samples for antibody testing were obtained from asthmatic subjects and age- and sex-matched healthy controls. C. pneumoniae was isolated from IS/118 (11.0%) children with wheezing, compared with 2/41 (4.9%) controls. The limitations of serologic tests were highlighted, as only 5/12 (41.7%) culture- positive children had detectable antibodies to C. pneumoniae and only 3/12 (25.0%) had serologic evidence of acute infection. The authors also noted that 9/12 (75.0%) of these children with wheezing showed clinical and laboratory improvement of the reactive airways disease after eradication of chlamydial infection with erythromycin or clarithromycin.

A number of subsequent studies and case reports have investigated the role of C. pneumoniae and M. pneumoniae in children with asthma. A study involving 71 children with an acute episode of wheezing and 80 age-matched healthy controls detected acute C. pneumoniae and M. pneumoniae infections significantly more frequently in children with wheezing than in control subjects. Furthermore, a history of recurrent wheezing was more common in children with C. pneumoniae or M. pneumoniae infections than in those without either infection.55 During a 3-month follow-up period among children who were not treated with an antibiotic, those with acute C. pneumoniae and/or M. pneumoniae infection had a significantly higher recurrence rate of wheezing compared with those who were not infected with either pathogen (p=0.03). Two of the investigators of this study subsequently published a review of clinical and laboratory evidence of the involvement of C. pneumoniae or M. pneumoniae in children with asthma exacerbations.56 They concluded that infections caused by these organisms may trigger 5-30% of wheezing episodes and asthma exacerbations. The authors presented data from a number of case reports and studies indicating that atypical bacterial infections could exacerbate established asthma, initiate asthma in previously asymptomatic patients, and precipitate wheezing during acute lower respiratory tract diseases in nonasthmatic patients. Furthermore, they also reported evidence that the use of antibacterial therapy with activity against these atypical pathogens can lead to an improvement in asthma symptoms.

Whereas the first study by Emre et al54 obtained cultures for C. pneumoniae in addition to serum samples for antibody testing, most of the other studies used only PCR, with or without serum antibody testing. As discussed in the previous section, C. pneumoniae PCR is not standardized and poor interlaboratory reproducibility is a major issue. Therefore, the findings of studies that rely on PCR as the sole basis for diagnosis may be unreliable.

Although some current guidelines for childhood CAP acknowledge that wheezing may indicate infection by atypical organisms,1,4 they offer no specific guidance on the selection of antibacterial therapy for CAP in children with asthma.

Children with Sickle Cell Disease

Acute chest syndrome (ACS) is a common cause of hospitalization in patients with sickle cell disease (SCD) and is responsible for up to 25% of SCD-relatcd mortality.57-60 Both infectious and noninfectious etiologies for ACS have been described, and some reports indicate that CAP may be a more common cause of ACS in children with SCD than was previously believed.61,62 The findings of a 30-center study reported by Vichinsky and co-authors62 demonstrated that infection, especially CAP, is a common cause of ACS in patients with SCD. In this study, 671 episodes of ACS in 538 patients with SCD were analyzed to determine the cause, response to therapy, and outcome. Data on 1 patient were excluded because the patient's date of birth was not known. Among the remaining 537 patients, approximately one-half (n=264) were aged ≤9 years, approximately one-quarter (n=145) were aged 10-19 years, and the remaining patients (n=128) were aged ≥20 years. Sixty-seven percent of patients had a medical history of ACS or pneumonia. Among the specific causes identified were 27 different infectious pathogens and pulmonary fat embolism. Of the infectious pathogens, C. pneumoniae and M. pneumoniae were the most prevalent, accounting for 71/671 (10.6%) and 51/671 (7.6%) episodes, respectively. Eighteen patients died, with infectious bronchopneumonia being one of the most common causes of death (6 deaths). Moreover, infection was considered to be a contributing factor in 56% of deaths. These results confirm the findings of earlier, smaller studies (30-50 patients each) that also demonstrated evidence of C. pneumoniae and M. pneumoniae infection in SCD patients with ACS.63,64

De Ceulaer and colleagues65 demonstrated that, from the age of 8 months onward, the prevalence of pneumonia in children with SCD becomes significantly higher than that in age- and sex-matched controls with normal hemoglobin genotype. By the age of 4 years, the relative risk of pneumonia is more than 4 times greater in children with SCD, who are also more prone to multiple episodes. Furthermore, there is evidence that pneumonia in children with SCD has a more serious clinical course than normally seen in otherwise healthy children.65,66 In the study reported by De Ceulaer et al,65 children with SCD and pneumonia were hospitalized more frequently and their stay in hospital was longer. Furthermore, deaths occurred only in the group of patients with pneumonia and SCD. The results of this study, which involved more than 400 children, supported the findings of an earlier report of unusually severe mycoplasma pneumonia in 5 children with SCD.66

As discussed above, M. pneumoniae and C. pneumoniae appear to be the most common organisms involved in pneumonia and ACS associated with SCD, although other potential bacterial pathogens include S. pneumoniae, S. aureus, and H. influenzae.61-63,67 These findings highlight the need for activity against atypical/intraccllular pathogens in selecting suitable antibacterial coverage for patients with severe ACS.

Principles of Treatment

Current Recommendations for Therapy

Some experts have recommended that all children with CAP should receive antibacterial therapy, as it is impossible to exclude the presence of bacterial infection.3 Other experts have suggested that antibacterial therapy may be withheld in young, ambulatory children with mild symptoms.4,6

Owing to the lack of rapid, reliable, cost-effective tests to identify the etiology of CAP, the selection of initial antibacterial therapy is usually empiric. Most children with CAP can be treated with oral antibacterials. The treatment choice depends primarily on age, clinical features, and epidemiologic factors. Other relevant factors include the cost, tolerability, acceptability, and convenience of treatment.1

Antibacterial therapy for CAP should always be active against S. pneumoniae, as this is the most common bacterial pathogen. Amoxicillin has been recommended for first-line use in outpatient children younger than 4-5 years (Table 2).1,4 However, this agent and other β-lactams are not active against atypical/ intracellular organisms. Thus, macrolides are commonly recommended in children aged >5 years or whenever infection with atypical/ intracellular pathogens is suspected.1,4,6 Indeed, some experts have recommended macrolides for all ambulatory children with CAP,1 as well as for infants aged from 3 weeks to 3 months.1 In children hospitalized with severe CAP, options for parenteral treatment include macrolides, penicillin, ampicillin, and second-/third- generation cephalosporins, depending on the age of the child and the severity of disease.

Impact of Antibacterial Resistance

The global spread of antibacterial resistance has an increasingly important influence on the selection of antibacterial therapy for childhood CAP. Resistance in S. pneumoniae is of particular concern owing to the importance of this organism in CAP etiology and the frequency of resistance to multiple classes of antibiotics.68 Although the spread of antibacterial resistance in S. pneumoniae is well documented, its clinical impact is poorly understood.69 In vitro MIC breakpoints must be interpreted in relation to the pharmacokinetic (PK) and pharmacodynamic (PD) effects of antibacterials at infection sites.

β-lactams. Penicillin resistance in S. pneumoniae occurs as a result of structural alterations in the bacterial penicillin- binding proteins (PBPs) that are the targets for all β- lactams. The dissemination of these mutations has resulted in incremental increases in the MICs of penicillin in S. pneumoniae isolates. By 1999-2000, 55.7% of 1,531 clinical isolates of S. pneumoniae collected in vitro from across the United States were nonsusceptible to penicillin: 34.2% were intermediate (MIC 0.12-1 g/ mL), while 21.5% were resistant (MIC ≥2 g/mL).70 International surveillance data from the PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study and other studies suggest that, across Europe, approximately 9-10% of S. pneumoniae isolates, are intermediate and 16-20% are resistant to penicillin.68 Rates of penicillin nonsusceptibility vary greatly among European countries, with the highest rates (>50%) observed in France and Spain and the lowest in northern Europe. Other areas where pneumococcal penicillin resistance is especially prevalent include Japan, Korea, Hong Kong, Mexico, South Africa, and parts of Eastern Europe (Figure 1).68 Risk factors for CAP caused by penicillin-nonsusceptible S. pneumoniae include young age, recent antibiotic use, and the presence of underlying conditions.71-74

In vitro resistance to β-lactarns does not necessarily imply clinical failure in the treatment of CAP. MIC breakpoints for β- lactams were originally developed for meningitis. They are less applicable to the treatment of pneumonia because of the higher drug con\centrations achieved in lung tissue and alveolar fluid. Animal models suggest that sufficient doses of amoxicillin are likely to eradicate S. pneumoniae with penicillin MICs of 2-4 g/mL causing pneumonia.75 Current National Committee for Clinical Laboratory Standards (NCCLS) pneumococcal MIC breakpoints for amoxicillin are ≤2 (susceptible), 4 (intermediate), and ≥8 g/mL (resistant).76 For the oral cephalosporins, ceftriaxone, cefotaxime, cefaclor, and cefuroxime, current MIC breakpoints for noncerebrospinal fluid isolates are ≤1 (susceptible), 2 (intermediate), and ≥4 g/mL (resistant).

Overall, the available data in children with CAP71-74,77 concur with those in adults78-83 in suggesting that pneumococcal β- lactam nonsusceptibility does not have a significant clinical impact in hospitalized patients treated with adequate doses of parenteral β-lactams. Certainly, there is good evidence that intermediate nonsusceptibility (MIC ≤1 g/mL) does not increase the risk of treatment failure. There is some evidence to suggest that resistant strains with MICs of 2-4 g/mL may be treated successfully with β-lactams, although the number of cases is small and conflicting data exist. Very few patients with higher levels of resistance (MICs >4 g/mL) have been treated and PK modeling provides reasons to suspect that this level of resistance may exceed achievable antibacterial concentrations.84 Moreover, there is an upper limit to the doses of β-lactams that can be safely used. Thus, recommendations will need to be re-evaluated if the prevalence of pneumococcal strains with high-level resistance continues to increase. Studies looking at the impact of penicillin resistance on clinical outcomes in pediatric outpatients with CAP are lacking.

Macrolides. Macrolides (e.g., erythromycin and clarithromycin) andazalides (i.e., azithromycin) are widely used for the treatment of RTIs in children and adults.85 All of these drugs inhibit bacterial protein synthesis by binding to the 23S RNA subunit of ribosomal RNA. They all show similar activity in vitro against gram- positive bacteria such as S. pneumoniae, but variable activity against H. influenzae.86 In vivo, they have more complex PK/PD properties than the β-lactams.87 Erythromycin and clarithromycin show time-dependent killing, while the efficacy of azithromycin is thought to be concentrationdependent. All macrolides/ azalides are accumulated within white blood cells and are thereby transported to infection sites via chemotactic attraction. However, differences exist between class members in their penetration and retention in inflamed tissues.88 Murine models indicate that lung concentrations correlate better with therapeutic efficacy than serum levels do.89,90 However, the relatively low serum and extracellular concentrations achieved by macrolides and azalides may be disadvantageous in the treatment of infections caused by S. pneumoniae and other extracellular pathogens (e.g., H. influenzae).91,92 This is of concern with regard to the rapid spread of macrolide resistance.

Figure 1. Estimated prevalence of penicillin nonsusceptibility in Streptococcus pneumoniae across the world (various sources, data correct up to February 2001) (reproduced with permission from Felmingham et al).68

International surveillance data suggest that approximately 25% of S. pneumoniae isolates from Western Europe and the United States are macrolide resistant (erythromycm MIC ≥1 g/mL).68,70 The prevalence may exceed 75% in some countries in Asia.68 Importantly, resistance to macrolides and other antibacterials (e.g., trimethoprim-sulfamethoxazole and tetracyclines) is increasingly becoming linked with penicillin resistance.

Macrolide resistance occurs via 2 main mechanisms.93 Globally, the most common mechanism is the methylation of the macrolide target sites within bacterial ribosomal RNA. This mechanism is encoded by the erm(R) gene (also known as the erm(AM) gene) and can confer resistance to macrolide-lincosamide-streptogramin^sub B^ (MLS^sub B^ resistance). Furthermore, this resistance phenotype typically results in very high macrolide MICs (>64 g/mL) that exceed the levels that are clinically achievable.88 The second main form of resistance occurs via an efflux mechanism, whereby the drug is pumped out of the cell. Encoded by the mef(A) gene, this mechanism confers resistance to 14- and 15-membered ring macrolides only (e.g., erythromycin, clarithromycin, and a/ithromycin). This so- called 'M phenotype' is associated with macrolide MICs of 1-32 g/ mL. Results from the PROTEKT study93 indicate that erm(B) resistance is predominant in most countries in Europe and in South Africa, while mef(A) resistance is more common in North America. The two mechanisms appear more evenly distributed in the Asian countries studied. It is notable that a growing minority of isolates exhibit both the erm(B) and mef(A) genotypes,93 while a macrolide-resistant mutant with neither mef nor erm determinants was recently selected during macrolide therapy.94

The MICs observed for erm(B) and mef(A) pneumococcal isolates suggest that macrolide resistance may compromise the effectiveness of treatment. This has not been extensively studied but is supported by case reports of treatment failure in CAP-including the development of bacteremia after initiation of treatment-in adults and children,87,94-100 even in infections documented to be caused by mef strains (which have relatively low macrolide MICs compared with erm strains).101,102 Workers from the Centers for Disease Control and Prevention (CDC) concluded in 2001 that most macrolide- resistant pneumococci causing invasive infections in the United States have MICs in the range for which treatment failures have been reported.103

Resistance to macrolides has not been reported in atypical/ intracellular pathogens. Studies in children indicate that macrolides are clinically and bacteriologically efficacious in the treatment of CAP caused by these organisms.27,28 Eradication rates of C. pneumoniae from the nasopharynx in children with pneumonia have averaged 80%. It has been shown that the MICs of isolates of C. pneumoniae persisting in children with CAP after treatment with macrolides usually remain the same as those of isolates obtained at baseline.104,105 In one of these studies, 2 isolates obtained after treatment with azithromycin had MICs that had increased 4-fold but were still within the range considered to be susceptible.

Vaccination

The use of vaccines may be instrumental in reducing the role of specific pathogens in RTIs. Widespread immunization has nearly eliminated cases of CAP due to H. influenzae type b in the United States.1 The development of pneumococcal conjugate vaccines offers potential for a considerable reduction in the morbidity and mortality from invasive pneumococcal disease in children.106 In recent trials, administration of a heptavalent CRM (197) conjugate vaccine to infants at 2, 4, 6, and 12-15 months of age reduced the incidence of a first radiographically confirmed pneumonia episode by 20.5% (p=0.02 compared with controls).13 The benefit from the vaccine decreased with age, from a 32.2% reduction in pneumonia episodes in the first year of life to a 23.4% reduction in the first 2 years, and a 9.1 % reduction in children aged >2 years. Vaccination may, however, promote changes in the bacterial etiology of CAP. Nontypeable strains of H. influenzae are now increasingly being recognized as etiologic agents in CAP,107 and there is already evidence that pneumococcal serotypes not represented in the heptavalent conjugate vaccine are replacing vaccine serotypes as the cause of acute otitis media.108

The development of antiviral vaccines may be of potential use in preventing CAP in young children. A vaccine for RSV has not yet been developed; however, administration of humanized mouse monoclonal antibody against RSV (palivizumab) to high-risk premature infants has been shown to decrease hospitalization rates clue to RSV.109 The indications for this agent may expand as further studies are completed.

The Role of New Antibacterials

The development of new antibacterials is necessary to address the increasing prevalence of raised MICs among pediatric respiratory pathogens. With the anecdotal reports of breakthrough bacteremia in macrolide-treated patients with CAP and the increasing prevalence of macrolide resistance among S. pneumoniae, new agents that are active against the full spectrum of pediatric respiratory pathogens are needed.

The properties of an ideal agent for use in the treatment of childhood CAP include the following: an antibacterial spectrum specifically targeted towards the causative pathogens, including atypical/intracellular pathogens and penicillin- and macrolide- resistant pneumococci; PK/PD properties ensuring effective antibacterial concentrations in lung tissues and fluids; a low propensity for resistance selection/induction; excellent safety with good tolerability and palatability; and a convenient administration schedule.

The ketolides are a new class of antibacterials-structurally similar to the macrolides-that have been specifically designed for the treatment of community-acquired upper and lower RTIs.110 Telithromycin-the first ketolide to become available for clinical use in adults-provides bactericidal activity against the common causative agents of childhood CAP, including S. pneumoniae (both penicillin- and macrolide-resistant strains) and atypical/ intracellular pathogens.111,112 Unlike macrolides, telithromycin has a low potential to select or induce MLSB resistance or cross- resistance in vitro,110 which enables it to retain activity against resistance mechanisms that degrade the utility of macrolides. The enhanced antibacterial activity of telithromycin against respiratory pathogens (including macrolide-resistant strains) and its li\mited ability to select for or induce resistance are attributed to 2 key structural features.113 The carbamate extensions at positions 11 and 12 allow a more effective interaction with 23S rRNA, through tight binding to domain II as well as domain V, enhancing binding to bacterial ribosomes and allowing binding to MLS^sub B^-resistant ribosomes. The keto group in place of the cladinose moiety at position 3 of the macrolactone ring prevents the induction of MLS^sub B^ resistance in vitro. Furthermore, telithromycin has advantageous PK/PD properties that result in high and sustained concentrations in respiratory tissues and fluids following a convenient once-daily close.114

Clinical trials have shown telithromycin (800 mg once daily) to be effective in the treatment of CAP in adults.115,116 In a pooled analysis, the overall clinical cure rate achieved was 93.1% in open- label studies and 91.0% in comparative studies.116 Telithromycin was also effective in patients with CAP caused by atypical/ intracellular or resistant pathogens: clinical cure rates exceeded 90% in the subsets of patients with C. pneumoniae, M. pneumoniae, and Legionella pneumophila infections; in addition, 87% of patients infected with penicillin- or macrolide-resistant pneumococci were clinically cured.116 Other ketolides, specifically cethromycin (ABT- 773), have demonstrated clinical and bacteriologic efficacy against C. pneumoniae in small numbers of adults with CAP.49 Further studies of the ketolides in pediatric populations are awaited.

Respiratory fluoroquinolones have good activity against respiratory pathogens that have become resistant to some antibacterial agents, and they have a favorable PK/PD profile. However, concerns about potential toxicity (abnormal bone development and arthropathy reported in juvenile animal models) have restricted their experimental development in children.85,117 Furthermore, there is evidence to suggest that resistance to the respiratory fluoroquinolones is already developing in pneumococci and other pathogens following their widespread use in adult patient populations.117-122 Approval of fluoroquinolones in selected pediatric indications is expected in the near future, although there is apprehension that their widespread use in children will lead to more rapid selection of antibiotic-resistant pathogens, which may limit their future utility.117 Given the concerns outlined above, it has been proposed that the use of fluoroquinolones in pediatric patients be limited to specific infections complicated by special conditions for which there is no other safe and effective treatment option.117

Conclusions

Optimal management of childhood CAP is complicated by etiologic, diagnostic, and therapeutic uncertainties. Present understanding of the etiology of the infection is confounded by a lack of rapid, reliable, and cost-effective tests. The tests currently in development must be standardized and validated by using cultures. In the meantime, however, antibacterial therapy must be chosen empirically.

Antibacterial resistance continues to increase, both in prevalence and in degree, especially in S. pneumoniae. Recommendations for empiric therapy will need to be re-evaluated as the usefulness of existing agents is eroded. It is not clear what level of pneumococcal β-lactam resistance is clinically important in treating ambulatory children with CAP. However, the effectiveness of β-lactams is likely to be threatened as isolates with high-level amoxicillin (MIC >4.0 g/mL) and cephalosporin (MIC >2.0 g/mL) resistance become more prevalent. Similarly, the appropriateness of currently available macrolides may need to be reassessed, as pneumococcal macrolide resistance becomes widespread. Further research to define the clinical impact of resistance to these and other antibacterials is required. Immunization using pneumococcal conjugate vaccines-in areas where these are available-will play a role in future efforts to reduce the disease burden from pneumococcal CAP and to address the problem of antibacterial resistance. New antibacterials such as the ketolides, which offer spectra of activity targeted toward CAP pathogens (including penicillin- and macrolide-resistant S. pneumoniae and atypical/intracellular organisms), are also likely to play a role in the treatment of childhood CAP.

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Source: Clinical Pediatrics

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