Lower respiratory tract infections
Respiratory tract infections (RTIs) are classified as either upper RTIs (URTIs) or lower RTIs (LRTIs). Although the majority of URTIs are caused by viral pathogens, are not severe, and are self-limiting, LRTIs, in contrast, are more likely to have a bacterial etiology, are more severe, and more often require antimicrobial intervention. LRTIs are among the most common infections worldwide and a significant cause of mortality, morbidity, and utilization of hospital resources. These infections are a common reason for hospital outpatient visits and antimicrobial prescription. The most important LRTIs are community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and acute exacerbations of chronic bronchitis (AECB).
Studies have shown that the most common causative agent of CAP is Streptococcus pneumoniae, which accounts for up to two thirds of all bacteremic pneumonias [1,2]. Another common bacterial pathogen is Haemophilus influenzae. Less frequently occurring pathogens include Moraxella catarrhalis, Staphylococcus aureus and enteric gram-negative bacteria. Among “atypical” pathogens, the most common is Mycoplasma pneumoniae, followed by Chlamydia and Legionella species .
The causative agents of HAP consist of a number of “core” organisms, which include enteric gram-negative bacteria (e.g., Escherichia coli, Klebsiella species and H. influenzae) and gram-positive organisms (e.g. S. pneumoniae and methicillin-sensitive S. aureus) . Infection with the highly resistant gram-negative organisms Pseudomonas aeruginosa and Acinetobacter species may result in higher HAP mortality . The organisms predominantly implicated in cases of AECB include H. influenzae, S. pneumoniae, and M. catarrhalis .
Guidelines for lower respiratory tract infections
The serious nature of LRTIs and the associated mortality mean that it is imperative that treatment is initiated early and makes the best use of the available resources. However, the optimum management strategy for LRTIs is controversial, and may differ according to local factors, e.g., antimicrobial resistance patterns, or etiology.
Treatment guidelines present the available data in a comprehensive and organized manner, providing a consensus framework for efficient and effective therapy, as well as highlighting areas where there are weaknesses or deficiencies in management and research. Guidelines should also promote responsible antimicrobial use, to minimize the impact and spread of resistance, and consider possible cost implications—issues that have become increasingly important in recent years. All guidelines need to take account of developments in certain key areas of LRTI management, as discussed in the following sections.
The increasing prevalence of atypical pathogens such as Chlamydia, Mycoplasma, and Legionella species should be considered when formulating guidelines for CAP.
Correctly identifying the causative agent allows “directed therapy,” i.e., the selection of a narrow-spectrum antibiotic to eradicate a specific pathogen. This is in contrast to empiric therapy, where treatment selection is based on epidemiologic findings, and uses broad-spectrum agents directed against the “most likely” pathogens. The need to identify pathogens results from concerns arising from issues such as the increasing incidence of atypical pathogens, antimicrobial resistance, and serious side effects. However, diagnostic tests can be time consuming and inconclusive, and so guidelines must balance the need for specific identification of pathogens, with the requirement for prompt initiation of treatment.
Resistance has become an issue in recent years. Indiscriminate antibiotic use has resulted in increased resistance to many commonly used antibiotics. Of particular concern in the therapy for community LRTIs is the increasing prevalence of resistance among S. pneumoniae isolates.
Guidelines should provide for the use of newer agents, in line with their spectrum of activity, either as first-line treatments or as alternatives to established therapies, subject to the availability of supporting clinical data.
This review will summarize the current status of guidelines for CAP, HAP, and AECB.
Guidelines for the Management of Community-Acquired Pneumonia
Pneumonia is a serious medical problem, and is the sixth most common cause of death in the United States. The incidence of CAP requiring hospitalization in the United States is approximately 258 per 100,000 of the adult population per year in the United States, rising to 962 per 100,000 of the population over the age of 65 . In Europe, rates of hospitalization vary according to country from 22% to 51% of cases . Studies have revealed mortality from CAP of between 2% and 30% in hospitalized patients in the United States, with a mean of 14% , whereas in nonhospitalized patients the mortality is 1% . A recent prospective study in five countries estimated the mortality as 20% in the United States and Spain, 13% in the United Kingdom, 8% in Sweden, and 6% in Canada .
A number of management guidelines have been published during the last decade, with the aim of providing a framework for disease management and so providing standardized levels of care and improving patient outcomes. The first guidelines were produced independently in 1993 by the British Thoracic Society (BTS) , the American Thoracic Society (ATS) , and the Canadian Consensus Group . There followed publication of a number of other treatment guidelines, which included, in 1998, those from the IDSA , and the European Respiratory Society (ERS) . Revised IDSA guidelines and Canadian guidelines (produced jointly by the Canadian Infectious Diseases Society and the Canadian Thoracic Society) were published in 2000 [3,12,13], and updated guidelines from the ATS and BTS were published in 2001 [14,15]. These revisions have been produced to take into account recent developments in the field. Although there have been questions raised about the value of these guidelines, there is now evidence to suggest that the implementation of treatment recommendations can lead to reductions in mortality, length of hospital stay, and treatment costs [16,17].
Issues and principles
The list of published guidelines is quite lengthy. The question of why so many have been published can best be answered by an extract from the most recent IDSA guidelines: “Despite extensive studies, there are few conditions in medicine that are so controversial in terms of treatment.” The problems associated with the successful management of CAP vary geographically and include variations in etiology, patterns of resistance, and the delivery of healthcare resources to patients. Treatment guidelines must reflect these differences in their treatment recommendations, but in general they all address certain key areas:
* Diagnostic procedures
* Microbiological studies
* Optimal site of care (community or hospital)
* Local healthcare practices
* Antimicrobial therapy
* Other features (switch therapy, treatment failure, and infection prevention)
Most of these considerations are beyond the scope of this article, which focuses primarily on the guidelines as they apply to antimicrobial therapy.
General principles of therapy
Empiric therapy with an appropriate antibiotic should be started as soon as possible after the initial diagnosis of pneumonia, and should be directed against the most likely pathogens. The selection of an antibiotic depends very heavily on epidemiologic factors (pathogen prevalence and resistance patterns), as well as individual patient factors (severity of illness, age, immunologic status, and antimicrobial intolerance).
The most likely pathogen is S. pneumoniae, so the choice of initial antimicrobial therapy should be appropriate for this infection. However, the presence of drug-resistant strains must also be considered, as should the possibility of infection with an atypical pathogen. The likelihood of either of these complicating factors occurring can be estimated on the basis of local epidemiologic data. In this section, we will primarily discuss the latest incarnation of the IDSA guidelines, and draw a comparison with other recent recommendations from other countries.
Guidelines for empiric therapy
The first, and possibly most important management decision to be made in cases of CAP is whether to treat the patient as an outpatient or admit them to hospital. The IDSA guidelines  recommends using the Pneumonia Patient Outcomes Research Team clinical prediction rule of Fine et al.  to assess whether admission to the hospital is required. This prediction rule is also recommended in the most recent Canadian guidelines . According to this rule, patients are scored according to the presence of certain risk factors, and the overall score is used to calculate the “risk” of mortality (and hence the need for enhanced care) .
Although both guidelines recognize that this prediction rule has a number of weaknesses, they also recognize that it has been validated as a mortality prediction rule and provides a reliable and consistent basis for the decision to hospitalize a patient. The ERS guidelines , in contrast, list criteria both for hospital admission and for admission to the intensive care unit. These criteria are similar to those of the IDSA and Canadian guidelines. However, the ERS guidelines do not recommend a quantitative risk assessment method, suggesting that its implementation would be too complex to operate in either the community or the hospital emergency rooms in Europe .
In the IDSA guidelines, treatment recommendations are made according to whether the patient is treated as an outpatient or whether they are hospitalized (see Fig. 1) . It is worth noting that all the current guidelines recommend switching to pathogen-directed therapy in hospitalized patients as soon as a microbiological diagnosis has been made [3,5,11,12].
In both the 1998 and 2000 IDSA guidelines, the preferred treatment options for most outpatients are (in no particular order): a macrolide (erythromycin, clarithromycin, or azithromycin; clarithromycin or azithromycin is preferred if H. influenzae is suspected), doxycycline, or a respiratory fluoroquinolone (levofloxacin, moxifloxacin, gatifloxacin, or other fluoroquinolone with enhanced activity against S. pneumoniae) [3,11]. For suspected cases of S. pneumoniae or H. influenzae, some second-generation cephalosporins are appropriate alternative therapies. A β-lactam/β-lactamase inhibitor combination (amoxicillin/clavulanate in the United States or ampicillin/sulbactam elsewhere) is also suitable, particularly against β-lactamase-producing organisms, such as H. influenzae, anaerobes, and M. catarrhalis. However, these agents have no activity against atypical pathogens, so the addition of a macrolide may be required if such an infection is suspected [3,11].
The latest version of the IDSA guidelines now acknowledges the presence of penicillin-resistant S. pneumoniae that may be resistant to macrolides or doxycycline, or both . Where patients are at risk of infection with resistant strains, the use of a respiratory fluoroquinolone is preferred. However, the Centers for Disease Control and Prevention have emphasized the need for caution when using these newer agents to ensure that resistance does not become a problem .
The focus of the ERS guidelines is toward the management of S. pneumoniae pneumonia . For outpatients, the recommended first-line treatment is a penicillin, in particular a β-lactam/β-lactamase inhibitor combination, whereas possible alternatives are a macrolide, tetracycline, or fluoroquinolone . The ERS guidelines highlight the potential problems of treating CAP due to penicillin-resistant S. pneumoniae. They go on to state that treatment with a penicillin at high doses can be effective against strains with low-level resistance or intermediate susceptibility. In cases where penicillin resistance is high, treatment with a third-generation cephalosporin (cefotaxime or ceftriaxone) is recommended. In cases of cephalosporin resistance, an alternative regimen of vancomycin or imipenem is advocated .
In both the ATS and Canadian guidelines, outpatients are stratified according to modifying risk factors, such as chronic obstructive lung disease [12,14]. Both guidelines recommend either a macrolide or doxycycline for patients with no modifying factors. The Canadian guidelines further divide patients with modifying factors into those who have had no antibiotic therapy during the preceding 3 months, and those who have . In the former case, the recommended treatment is a new macrolide or doxycycline, whereas for the latter a fluoroquinolone or the combination of a β-lactam (including a β-lactam/ β-lactamase inhibitor combination) plus a macrolide is recommended. The ATS guidelines recommend a similar regimen in patients with comorbid conditions or an infection due to drug-resistant S. pneumoniae .
In Japan, guidelines recommend the use of β-lactams, including β-lactam/β-lactamase inhibitor combinations (such as ampicillin/sulbactam) . In cases where an atypical pathogen is suspected, a macrolide is preferred.
For those patients admitted to hospital, the IDSA guidelines divide patients into those treated on the general medical ward and those treated in the intensive care unit . For patients on the general medical ward, the recommended therapy is either an extended-spectrum cephalosporin or a β-lactam/β-lactamase inhibitor combination combined with a macrolide, or alternatively, monotherapy with an antipneumococcal fluoroquinolone. The Canadian and ERS guidelines make similar recommendations [5,12]. The ATS guidelines also advocate treatment with either a β-lactam or β-lactam/β-lactamase inhibitor. Monotherapy with intravenous azithromycin is also proposed in the ATS statement for patients with no risk factors. In patients with risk factors, the recommended treatment options are a new fluoroquinolone or a β-lactam (cephalosporin or β-lactam/β-lactamase inhibitor) in combination with a macrolide or doxycycline .
For patients who have been admitted to the ICU with severe CAP, the IDSA guidelines recommend a β-lactam or β-lactam/β-lactamase inhibitor combination, such as ampicillin/sulbactam or piperacillin/tazobactam, combined with either a macrolide or a fluoroquinolone . This regimen is preferred because it provides cover against the two most common causes of lethal pneumonia, S. pneumoniae and Legionella . Similar treatment recommendations are found in the Canadian guidelines . If P. aeruginosa is suspected or likely (e.g., in cases of structural lung disease), then the use of an antipseudomonal agent (piperacillin, piperacillin/tazobactam, carbapenem, or cefepime) is recommended [3,12].
The Japanese guidelines recommend treating younger patients with a fluoroquinolone. In elderly patients (more than 65 years old) or in the presence of comorbid disease, the recommended treatment is a carbapenem in combination with tetracycline or a macrolide, or a third-generation cephalosporin in combination with clindamycin and a macrolide or tetracycline .
Guidelines for the management of hospital-acquired pneumonia
Hospital-acquired (or nosocomial) pneumonia is defined as a pneumonia that occurs at least 48 hours after admission. It is an important cause of mortality and morbidity, occurring at a rate of 5–10 cases per 1000 hospital admissions. This frequency of occurrence increases by 6- to 20-fold in patients undergoing mechanical ventilation. Mortality associated with HAP has been estimated to be between one third and one half of all cases and may be higher if the causative agent is P. aeruginosa or Acinetobacter species .
The only international guidelines for HAP are those published by the ATS in 1995 . These guidelines recommend stratification of patients according to several factors (severity of illness, presence of risk factors and time of onset), which have been used to produce a classification algorithm (see Fig. 2).
The time of onset in HAP is an important factor, because it predicts the presence of specific pathogens (Table 1). Many of the pathogens seen in early onset are those associated with CAP. In late onset, there is a move toward more resistant gram-negative bacilli, such as Pseudomonas species or Acinetobacter species. The algorithm classifies patients into three groups, each with its own set of likely pathogens and, therefore, treatment options .
In group 1 patients, the core organisms are typically enteric non-pseudomonal gram-negative bacilli, methicillin-susceptible S. aureus and S. pneumoniae (Table 2). Recommended treatment regimens are a second-or third-generation non-antipseudomonal cephalosporin or a β-lactam/β-lactamase inhibitor combination. If the patient is allergic to penicillin, a fluoroquinolone or clindamycin plus aztreonam is recommended (Table 2) .
Patients in group 2 have specific risk factors for certain pathogens. Likely pathogens include anaerobes, S. aureus, Legionella and P. aeruginosa (Table 2). β-Lactam/ β-lactamase inhibitor combinations are very effective against anaerobes, and vancomycin is recommended where methicillin-resistant S. aureus is suspected. Patients in this group with P. aeruginosa infections are treated identically to those in group 3 .
Patients in group 3, including those with severe HAP and ventilator-associated pneumonia, are at greater risk of infection with resistant organisms, such as P. aeruginosa, Acinetobacter species, and methicillin-resistant S. aureus. For these patients, an aminoglycoside or ciprofloxacin should be used in combination with an antipseudomonal penicillin, β-lactam/β-lactamase inhibitor combination, ceftazidime, imipenem, or aztreonam to counter possible pseudomonal resistance. Vancomycin should be added if methicillin-resistant S. aureus is suspected .
Guidelines for the management of acute exacerbations of chronic bronchitis
AECB is a common condition in the United States, where approximately 14.5 million episodes are recorded each year. Chronic bronchitis is indicated by the presence of a mucus-producing cough on most days for a period of at least 3 months in each of 2 consecutive years . An acute exacerbation is recognized by an abrupt worsening of the symptoms of chronic bronchitis (increased dyspnea, sputum volume, and/or sputum purulence) .
The role of bacterial infections in AECB has been unclear, but several studies have estimated the prevalence of bacterial infections at 50%–60% of all cases [22,23]. H. influenzae is implicated in approximately 50% of all bacterial exacerbations, while S. pneumoniae or M. catarrhalis have been implicated in approximately 20% of episodes [22,23].
Given that many exacerbations occur as a result of other infections, such as viruses and possibly Chlamydia species, the question of appropriate antimicrobial use has been the subject of some debate. Saint et al. performed a metaanalysis of a number of randomized studies where antibiotics had been used in the treatment of AECB, and concluded that antimicrobial therapy provided a small, but significant benefit .
Several studies have attempted to classify AECB, and provide guidance on the use of antimicrobials. There are several methods for classifying AECB, based on the number of exacerbations, and risk factors for poor outcomes [21,25].
The first attempt to classify AECB was made in 1987 by Anthonisen et al., who grouped patients according to a number of criteria . Patients with increased dyspnea, increased sputum volume, and increased sputum purulence were described as type-1 exacerbations, whereas those with any two were described as type-2 exacerbations and those with one, type-3. Treatment of these patients with placebo or antibiotic revealed a significant clinical benefit, which was greatest in type-1 patients (see Fig. 3).
Balter and co-workers proposed classifying patients with AECB into simple and complicated cases with or without comorbidity, according to the patient’s age, the number of exacerbations, forced expiratory volume in 1 second, and the presence of comorbid conditions . Patients with complicated AECB were those more than 65 years old, with more than four exacerbations per year and a forced expiratory volume in one second of less than 50% of that predicted.
The ERS guidelines  recommend treating only those patients who fall into the type-1 category described by Anthonisen et al. . The most widely used treatment is an aminopenicillin, such as ampicillin or amoxicillin. However, given that there is a substantial risk of β-lactamase–producing strains (H. influenzae and M. catarrhalis) in these patients, the addition of a β-lactamase inhibitor to high-dose amoxicillin is recommended . New macrolides (azithromycin or clarithromycin) are also suggested as effective treatments, particularly against H. influenzae. The ERS guidelines also highlight the potential of fluoroquinolones as a potential first-line therapy .
Recently, The American College of Chest Physicians and American College of Physicians–American Society of Internal Medicine published recommendations for the management of acute exacerbations of chronic obstructive pulmonary disease . This statement recommends the use of antibiotics for patients with more severe exacerbations (type 1). The statement furthermore indicates that “narrow-spectrum” antibiotics (i.e., amoxicillin, trimethoprim–sulfamethoxazole, and tetracycline) are reasonable first-line agents since the “superiority of newer, more broad-spectrum antibiotics has not been established” in clinical trials. This rationale can be questioned, however, since most of the studies were done before the emergence of multi-resistant organisms.
In an era of increasing antibiotic resistance and emerging pathogens, the rationale for guidelines is clear. They provide a standardized framework for diagnosis and treatment, which will increase the likelihood of satisfactory patient outcomes. However, at the same time, one must be aware that the problems associated with LRTIs in one country are unlikely to be duplicated in another. Therefore, it is important that close attention be paid to developing local guidelines to account for local resistance patterns, local etiology, and healthcare practices.
It is also important that guidelines are flexible. Changes in resistance patterns, etiology within countries, and efforts to develop new antimicrobials will affect the recommendations for appropriate antimicrobial use, and these changes must ultimately be reflected in the healthcare setting. Finally, it is important to revisit current procedures for preventing LRTIs. Prevention represents the most effective method, ultimately, for reducing antibiotic use and healthcare costs. There are a number of risk factors for developing LRTIs associated with particular lifestyle choices (for example, smoking) and other infections (for example, influenza). Efforts to reduce these risk factors in the community, either through education (cessation of smoking) or medical intervention (influenza vaccination), will prove highly effective in reducing the incidence of LRTIs.