Review
Emerging resistance to antibiotics against respiratory bacteria: impact on therapy of community-acquired pneumonia in children

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Abstract

Perhaps because of its etiologic complexity, community-acquired pneumonia (CAP) in infants and children remains a significant problem worldwide. Over the last few years, difficulties related to CAP treatment in children have greatly increased because of the emergence of resistance to the most widely used antibiotics against some of the bacterial pathogens involved in the development of the disease. There are few data describing the impact of antibiotic resistance on clinical outcomes in CAP, but many experts believe that the clinical impact is limited. We here discuss the prevalence of different etiologic agents in CAP of children, the diagnostic criteria, problems related to antibiotic resistance, therapeutic strategies, and future implications.

Introduction

Despite the availability of effective therapy, community-acquired pneumonia (CAP) in infants and children remains a significant problem worldwide (McIntosch, 2002, Selwyn, 1990, Baqui et al., 1998, Brown and Lerner, 1998, Marrie, 1994, Mulholland, 1999). In developing countries, it is very common and severe and the largest killer of children (McIntosch, 2002, Selwyn, 1990, Baqui et al., 1998); in the industrialized world, it involves substantial morbidity-related costs to society and the health care system (Brown and Lerner, 1998, Marrie, 1994, Mulholland, 1999).

Over the last few years, difficulties related to CAP in children have greatly increased because of the emergence of resistance to the most widely used antibiotics against some of the bacterial pathogens involved in the development of the disease (Heffelfinger et al., 2000, Heffelfinger et al., 2000, Finch, 2001, McCracken, 2000a, Musher et al., 2002). This paper describes the impact of such resistances on the outcome of CAP in pediatrics and possible changes in antibiotic therapy regimes to overcome them.

Section snippets

Etiology of CAP in children

The etiology of CAP is much more difficult to identify in children than in adults because lower-airway secretions can rarely be obtained and invasive methods of diagnosis cannot be routinely applied (Thomson, 1999, Menendez et al., 1999, Jadavji et al., 1997). In addition, as in the case in adults, cultures of the upper respiratory tract secretions are not useful as the normal flora include the bacteria commonly responsible for pneumonia (McIntosch, 2002). This may explain why most of the

Diagnosis

The definitions of pneumonia vary widely. Some require only the presence of infiltrates or consolidations on a chest radiograph, and others only certain respiratory symptoms or signs (Murphy et al., 1981, World Health Organization, 1981). The World Health Organization has defined pneumonia solely on the basis of clinical findings obtained by visual inspection and by timing the respiratory rate (Bachur et al., 1999). However, there is ample evidence that a chest radiograph is useful to confirm

Emerging resistance of bacterial pathogens of pediatric CAP

Several reports of bacteria with a reduced susceptibility to antibiotics had been published by the end of the 1960s, and this problem has grown in recent years. The development of resistance is of particular concern when treating respiratory tract infections, for which antibiotics are most frequently used.

Among the bacterial pathogens that play the greatest role in causing pediatric CAP, the most significant changes in sensitivity to antibiotics have been observed in the case of S. pneumoniae

Penicillin resistance

The resistance of S. pneumoniae to penicillin and other beta-lactams is related to target-mediated changes in the size and configuration of the PBPs that enable the cross-linking of bacterial cell wall precursors (Kellner, 2001, Bauer et al., 2001, Klugman, 1996, Mlynarczyk et al., 2001). These changes lead to a decrease in PBP affinity for penicillin and thus increase penicillin resistance. Resistance develops in a stepwise and apparently irreversible manner because of mutations in one or more

Suggested therapeutic regimens in children with CAP

Because definite information about the causative pathogens is seldom available, the treatment of CAP is usually empiric.

It is first necessary to decide whether or not to withhold antibiotic treatment. Some clinicians suggest that antibiotic therapy is always indicated in CAP because of the difficulty of excluding the possibility of bacterial infection (Ruuskanen and Mertsola, 1999). Others—including ourselves—believe that antibiotic therapy can be withheld in mildly ill patients with probable

New antibiotics for the therapy of CAP in children

Several new drugs have been developed to overcome the resistance of respiratory pathogens to the antibiotics usually used to treat CAP (McIntosch, 2002, Cazzola et al., 2001, Lee et al., 1999, Moellering, 1998). However, few pediatric clinical trials have yet been performed, and we do not know the real safety and tolerability of these compounds in children. Only their clinical use will establish whether they will play an innovative role in the treatment of childhood CAP.

Screening for isolated

Conclusions and future directions

Possibly because of its etiologic complexity, CAP remains a common illness and a major cause of childhood morbidity worldwide. The use of treatment algorithms in industrialized countries has led to lower mortality rates but, given the rate of development of antimicrobial resistance, the future of this approach is uncertain. The past decade has witnessed a dramatic increase in the prevalence of antimicrobial resistance in respiratory pathogens, such as S. pneumoniae and H. influenzae, much of

References (99)

  • V.J. Lee et al.

    What’s new in the antibiotic pipeline

    Curr. Opin. Microbiol.

    (1999)
  • G. Mlynarczyk et al.

    Epidemiological aspects of antibiotic resistance in respiratory pathogens

    Intern. J. Antimicrob. Agents

    (2001)
  • K. Mulholland

    Magnitude of the problem of childhood pneumonia

    Lancet

    (1999)
  • N. Principi et al.

    Emerging role of Mycoplasma pneumoniae and Chlamydia pneumoniae in paediatric respiratory tract infections

    Lancet Infect. Dis.

    (2001)
  • American Academy of Pediatrics Committee on Infectious Diseases (1997). Therapy for children with invasive pneumococcal...
  • G.W. Amsden

    Pneumococcal macrolide resistance: myth or reality?

    J. Antimicrob. Chemother.

    (1999)
  • D. Andreotti et al.

    Overview of recent developments in carbapenem and trinem antibiotics

    Curr. Opin. Anti-infect. Invest. Drugs

    (2000)
  • A.H. Baqui et al.

    Causes of childhood deaths in Bangladesh: results of a nationwide verbal autopsy study

    Bull. World Health Organ.

    (1998)
  • J.A. Barman Balfour et al.

    Telithromycin

    Drugs

    (2001)
  • S. Black et al.

    Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children

    Pediatr. Infect. Dis. J.

    (2000)
  • S. Block et al.

    Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric communityacquired pneumonia: comparative efficacy and safety of clarithromycin versus erythromycin ethylsuccinate

    Pediatr. Infect. Dis. J.

    (1995)
  • J.M. Blondeau

    Expanded activity and utility of the new fluoroquinolones: a review

    Clin. Ther.

    (1999)
  • M. Cazzola

    Novel oral cephalosporins

    Exp. Opin. Invest. Drugs

    (2000)
  • E. Choi et al.

    Clinical outcome of invasive infections by penicillin-resistant Streptococcus pneumoniae in Korean children

    Clin. Infect. Dis.

    (1998)
  • I. Courtoy et al.

    Accuracy of radiographic differentiation of bacterial from non-bacterial pneumonia

    Clin. Pediatr.

    (1989)
  • W.A. Craig

    Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men

    Clin. Infect. Dis.

    (1998)
  • H.D. Davies et al.

    Reliability of the chest radiograph in the diagnosis of lower respiratory infections in young children

    Pediatr. Infect. Dis. J.

    (1996)
  • S.L. Deeks et al.

    Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae

    Pediatrics

    (1999)
  • G.V. Doern et al.

    Antibiotic resistance among clinical isolates of Haemophilus influenzae in the United States in 1994 and 1995 and detection of β-lactamase-positive strains resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study

    Antimicrob. Agents Chemother.

    (1997)
  • G.V. Doern et al.

    Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY Antimicrobial Surveillance Program

    Clin. Infect. Dis.

    (1998)
  • G.V. Doern et al.

    Antimicrobial resistance with Streptococcus pneumoniae in the United States 1997–1998

    Emerg. Infect. Dis.

    (1999)
  • S. Esposito et al.

    Characteristics of Mycoplasma pneumoniae and Chlamydia pneumoniae infections in children with pneumonia

    Eur. Resp. J.

    (2001)
  • D. Feikin et al.

    Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance 1995–1997

    Am. J. Public Health

    (2000)
  • D. Felmingham et al.

    The Alexander Project 1996–1997: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections

    J. Antimicrob. Chemother.

    (2000)
  • T.M. File

    Community-acquired pneumonia: new guidelines for management

    Curr. Opin. Infect. Dis.

    (2001)
  • I.M. Forgie et al.

    Etiology of acute lower respiratory tract infections in Gambian children. I. Acute lower respiratory tract infections in infants presenting at the hospital

    Pediatr. Infect. Dis. J.

    (1991)
  • A.L. Frank et al.

    Increase in community-acquired methicillin-resistant Staphylococcus aureus in children

    Clin. Infect. Dis.

    (1999)
  • I.R. Friedland

    Comparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease

    Pediatr. Infect. Dis. J.

    (1995)
  • Garau J., Lonks J.R., Gomez L., Xercavins M., Medeiros A.A. (2000). Failure of macrolide therapy in patients with...
  • J. Garau

    The clinical impact of macrolide resistance in pneumococcal respiratory infections

    Intern. J. Antimicrob. Agents

    (2001)
  • T.H. Haight et al.

    Resistance of bacteria to erythromycin

    Proc. Soc. Exp. Biol. Med.

    (1952)
  • R.E. Hancock et al.

    Peptide antibiotics

    Antimicrob. Agents Chemother.

    (1999)
  • J.S. Harris et al.

    Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children

    Pediatr. Infect. Dis. J.

    (1998)
  • W.P. Hausdorff et al.

    The contribution of specific pneumococcal serogroups to different disease manifestations: implications for conjugate vaccine formulation and use. Part II

    Clin. Infect. Dis.

    (2000)
  • J.D. Heffelfinger et al.

    Management of community-acquired pneumonia in the era of pneumococcal resistance

    Arch. Intern. Med.

    (2000)
  • J.D. Heffelfinger et al.

    Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group

    Arch. Intern. Med.

    (2000)
  • T. Heiskanen-Kosma et al.

    Etiology of childhood pneumonia: serologic results of a prospective, population-based study

    Pediatr. Infect. Dis. J.

    (1998)
  • P.R. Hsueh et al.

    Extremely high incidence of macrolide and trimethoprim-sulfamethoxazole resistance among clinical isolates of Streptococcus pneumoniae in Taiwan

    J. Clin. Microbiol.

    (1999)
  • T.B. Hyde et al.

    Macrolide resistance among invasive Streptococcus pneumoniae isolates

    JAMA

    (2001)
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