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(Chest. 2001;120:2021-2034.)
© 2001 American College of Chest Physicians

Community-Acquired Lower Respiratory Tract Infections*

Etiology and Treatment

Robert Guthrie, MD

* From the Ohio State University, Columbus, OH.

Correspondence to: Robert Guthrie, MD, Professor of Emergency Medicine, Ohio State University, 1380 Edgehill Rd, Columbus, OH 43212


   Abstract
TOP
 Abstract
Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
 References
 
The current therapy for community-acquired lower respiratory tract infections is often empiric, usually involving administration of a ß-lactam or macrolide. However, the increasing prevalence of antibiotic resistance in frequently isolated respiratory tract pathogens has complicated the antimicrobial selection process. This review will discuss the incidence of various respiratory pathogens, as well as update the clinician on the various antimicrobial alternatives available, with particular emphasis on the role of the newer fluoroquinolones in the treatment of acute exacerbations of chronic bronchitis and community-acquired pneumonia.

Key Words: bronchitis • fluoroquinolone • pneumonia


   Introduction
TOP
 Abstract
 Introduction
Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
 References
 
Globally , community-acquired respiratory tract infections account for a large proportion of antibiotic prescriptions and visits to family practitioners. Increases in the number of newly identified or previously unrecognized pathogens, the availability of new antimicrobial agents, and the evolution of bacterial resistance mechanisms have contributed to changes in the epidemiology and treatment of respiratory tract infections. Pneumonia occurs in about 12 persons per 1,000 annually in the United States, and its incidence is highest among persons at the extremes of the age range. It is the sixth leading cause of death in the United States.1 Recent increases in the incidence of community-acquired pneumonia (CAP) have been associated with dramatic rises in the rate of infection in the elderly population and in patients with comorbidities.1 From 1979 to 1992, data from the Centers for Disease Control and Prevention2 demonstrated a 22% increase in death rates, age-adjusted to a 1980 standard population, for the combined cause-of-death category of pneumonia and influenza.

Although Streptococcus pneumoniae remains the most prevalent or frequently isolated etiologic agent in cases of CAP, other organisms such as Haemophilus influenzae and Moraxella catarrhalis, as well as the so-called atypical pathogens, including Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae, are now being reported more frequently than in the past.3 4 Atypical organisms are generally intracellular pathogens thatoriginally were difficult to identify, that are often difficult to culture from specimens, and that were previously associated with infections in immunocompromised hosts.3 In one prospective multicenter study of patients with CAP,4 the most frequent etiologic agents were S pneumoniae (15.3%) and H influenzae (10.9%). However, Legionella spp and C pneumoniae were the third and fourth most frequent pathogens at 6.7% and 6.1%, respectively. Similarly, a 1995 review3 of the changing etiology of CAP noted that S pneumoniae remained the most common cause followed by H influenzae, L pneumophila, C pneumoniae, and M catarrhalis. Together, these typical and atypical organisms represent the most commonly identified pathogens in patients with CAP3 4 5 6 (Table 1 ).


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  		Table 1.. Prevalence of Major Respiratory Pathogens in Lower Respiratory Tract Infections3 6

 
Acute exacerbation of chronic bronchitis (AECB), a COPD condition, also represents a significant and increasing community-acquired respiratory tract infection. An estimated 30 million individuals in the United States have COPD.7 The preeminent pathogens associated with AECB are H influenzae, S pneumoniae, and M catarrhalis, which together account for 85 to 95% of bacterial exacerbations (Table 1) . Other less common pathogens associated with AECB include Staphylococcus aureus and Pseudomonas aeruginosa, along with opportunistic Gram-negative pathogens.8 Together, these pathogens account for 70% of all acute infectious AECBs, with the remaining 30% being caused by viruses.

Since office-based physicians can rarely, if ever, obtain sputum samples with which to identify pathogens causing lower respiratory tract infections, initial antimicrobial therapy by the primary-care physician is usually empiric. For the last few decades, therapy with a macrolide or ß-lactam was often the prescribed empiric antibiotic treatment. While erythromycin and tetracycline have been used regularly in the past to treat CAP of uncertain etiology because of their in vitro activity against the atypical pathogens as well as against S pneumoniae, their use has declined recently.9 Erythromycin has poor in vitro activity against H influenzae,10 a high incidence of GI side effects, and is only bacteriostatic. As a class, some tetracyclines are limited by a narrow spectrum that does not reliably cover the Haemophilus species, frequent GI side effects, possible drug interactions, and a bacteriostatic mechanism of action. Doxycycline, a newer tetracycline compound, has a broader antimicrobial spectrum but is less active and has increased toxicity and more adverse events compared to the newer antibiotics now available.11 The use of the newer macrolides, azithromycin and clarithromycin, has grown dramatically in the last decade. This was facilitated by their easier dosing schedule, enhanced activity against H influenzae and other pathogens, and reduced GI side effects.10 12

The increasing incidence of antibiotic resistance for respiratory pathogens complicates the use of empiric treatment with traditional agents. The results of a 1992 to 199313 survey of 2,718 respiratory tract isolates of H influenzae from Western Europe and the United States found that 57.5% of the isolates exhibited erythromycin resistance (defined as a minimum inhibitory concentration [MIC] of >= 4.0 mg/L). Data from a 1994 to 1995 survey14 of 1,537 isolates of H influenzae collected from 30 US medical centers indicated that the newer macrolides varied in their in vitro activity against this pathogen, with azithromycin typically being fourfold more active than erythromycin and clarithromycin. Surveillance of respiratory isolates obtained from patients in the United States demonstrated that 95% of M catarrhalis isolates and 38.9% of H influenzae isolates produced ß-lactamase and were resistant to penicillin, ampicillin, and amoxicillin.15 Furthermore, 4.5% of these isolates were also resistant to amoxicillin clavulanate. H influenzae also demonstrates varying degrees of resistance to tetracycline, trimethoprim-sulfamethoxazole (TMP/SMX), erythromycin, and cephalosporins. For example, in the 1994 to 1995 survey of isolates of H influenzae found at US medical centers reported by Doern et al,14 9% of the strains were resistant to TMP/SMX,1.3% were resistant to tetracycline, and from0.1 to 14.6% of isolates were resistant to the six cephalosporins evaluated. In a 1997 surveillance study, 16 approximately 20%, 23%, and 40% of H influenzae respiratory isolates were resistant to cefaclor, TMP/SMX, and clarithromycin, respectively. To date, H influenzae resistance to the fluoroquinolones is extremely rare (0.13%), and endemic or epidemic clusters of fluoroquinolone resistance have not been detected.17

The atypical pathogens are not routinely inhibited by penicillins, cephalosporins, and TMP/SMX. By comparison, L pneumophila, M pneumoniae, and C pneumoniae are highly sensitive to fluoroquinolones, especially the newer agents such as moxifloxacin and gatifloxacin.18 19 In addition, a growing body of evidence suggests that some fluoroquinolones are both bacteriologically and clinically effective against both traditional and atypical respiratory pathogens. Thus fluoroquinolones could offer an alternative for the empiric treatment of community-acquired respiratory tract infection, including pneumonia and bacterial AECBs.

This review aims to provide an update on the incidence of community-acquired lower respiratory tract infections caused by H influenzae, Haemophilus parainfluenzae, and atypical pathogens and to discuss alternative antimicrobial treatments for these infections.


   Incidence of Bacterial Pathogens in Community-Acquired Lower Respiratory Tract Infection
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
 References
 
CAP and AECB are two acute infections frequently encountered by practitioners in community practice. As discussed earlier, a variety of pathogens have been associated with CAP, including H influenzae, S pneumoniae, C pneumoniae, and L pneumophila. Among patients presenting with AECB, H influenzae, M catarrhalis, and S pneumoniae account for the majority of cases of bacterial exacerbations. While bacteriologic patterns may vary by geographic area, these pathogens continue to account for the preponderance of cases of community-acquired lower respiratory tract infections.

Surveys of the incidence of H influenzae in community-acquired respiratory infections indicate that this pathogen accounts for between 2% and 11% of cases of CAP3 and for more than half of all bacterial cases of AECB.7 Mandell3 has shown that although the incidence of pneumonia caused by S pneumoniae appears to be decreasing slowly, it remains the most common cause of infection, accounting for as much as 46% of community-acquired cases, depending on geographic location. The rates of bacteremia range from 13 to 40%, and patients with bacteremic pneumococcal pneumonia are more likely to have comorbid illnesses, such as COPD or diabetes mellitus.

Pneumococcus is also responsible for a measurable proportion of cases of bacterial AECB, although its incidence also appears to be decreasing in this patient population. Leeper et al20 found that the prevalence of the pneumococcus declined as a cause of AECB from 20.4% in the period from 1983 to 1989 to 15.5% in the period from 1990 to 1996. Although empiric therapies should include coverage for S pneumoniae, this organism does not appear to be responsible for most of the pathogenicity associated with AECB. In addition, Eller et al21 have reported that patients with less advanced disease (ie, FEV1, < 50%) were more likely to be infected with a Gram-positive organism such as pneumococcus, whereas patients with compromised pulmonary function more frequently had Gram-negative organisms isolated during an acute exacerbation.

In addition to the increasing rate of ß-lactamase-producing H influenzae discussed earlier, an important issue is the growing rate of multiple antibiotic resistance of pneumococcus. Of 1,856 S pneumoniae isolates obtained from medical centers in Western Europe and the United States during 1992 and 1993, 23% (range, 6 to 54%) were resistant to penicillin.22 Resistance to other antibiotic classes (ie, chloramphenicol, doxycycline, TMP/SMX, and macrolides), with the notable exception of the fluoroquinolones, was higher among penicillin-resistant strains than among penicillin-sensitive strains.22 A survey23 conducted from 1996 to 1997 reported that approximately 34% of pneumococcal isolates were penicillin-resistant. Of note, this study was conducted during the respiratory season and included over 9,100 clinical isolates of S pneumoniae from adults. Many of these pneumococcal isolates also showed intermediate-level or high-level resistance to relatively new ß-lactams and macrolides, including amoxicillin-clavulanate, cefuroxime, ceftriaxone, and clarithromycin. Since pneumococcal resistance to penicillin is mediated through altered penicillin-binding proteins, and not through ß-lactamase production, resistant pneumococci, thus, will be resistant to amoxicillin-clavulanate.15 Accordingly, in geographic areas where a high degree of pneumococcal resistance is observed, the newer ß-lactams and macrolides are not recommended for use. Notably, levofloxacin (the only quinolone tested in this study) exhibited low rates (< 3%) of in vitro resistance to pneumococcus. A second study by Thornsberry et al24 (from 1995 to 1996) evaluated 369 S pneumoniae isolates that were stratified by their penicillin MICs. The in vitro activity of several fluoroquinolones was determined against the penicillin-sensitive, penicillin-intermediate, and penicillin-resistant isolates. All tested quinolones were very active against all isolates of pneumococcus, regardless of penicillin susceptibility. Specifically, values for the lowest drug concentration that inhibits the growth of 90% of organisms (MIC90) were 1.0 µg/mL for ciprofloxacin, 2.0 µg/mL for ofloxacin, 1.0 µg/mL for levofloxacin, and 0.12 µg/mL for trovafloxacin. In a 1997 surveillance study, Doern et al25 reported that approximately 44% of pneumococcal strains isolated from patients with respiratory tract infections demonstrated resistance to penicillin (intermediate-level resistance, 27.8%; high-level resistance, 16%). The escalating rate of multiple antibiotic resistance to pneumococcus isolates implied by all of these studies suggests the need for alternative treatment strategies.

C pneumoniae
The diagnosis of chlamydial lower respiratory tract infection is difficult to obtain, thus, C pneumoniae (formerly known as the TWAR agent or the TWAR strain of Chlamydia psittaci) was identified only in 1998 as a clinically significant respiratory pathogen.26 Importantly, the prevalence of C pneumoniae varies among clinical studies because of controversies surrounding culture and serology techniques. However, it is now recognized as an important cause of human respiratory tract infection. It has been identified in approximately 10% of pneumonia cases and in approximately 5% of acute bronchitis cases, but it appears to play a minor role in the causation of AECBs.6 This pathogen also has been implicated in pharyngitis and sinusitis.27 Although pneumonia caused by atypical pathogens was believed to be uncommon in children, C pneumoniae and M pneumoniae together may be responsible for > 40% of such cases in children.28

Infections caused by C pneumoniae are found in all age groups, in ambulatory and hospitalized patients, and in endemic and epidemic forms. The organism has been estimated to cause 300,000 cases of pneumonia annually in the United States; however, these figures are open to question since C pneumoniae infection is not reportable in the United States and because species identification is often incomplete.29 In the study of 359 patients reported by Fang et al, 4 C pneumoniae was the fourth most commonly isolated pathogen, accounting for 6.1% of CAP cases.

C pneumoniae may persist following successful treatment of the acute infection and may be difficult to eradicate even if there is a clinical response to therapy.27 Consequently, it is often difficult to distinguish between colonization and true infection with this organism.

L pneumophila
Legionella now comprises > 30 species and > 50 serotypes30 ; however, only a few species cause disease in humans, with L pneumophila being the most prevalent. Indeed, serogroup 1 and other Legionella species are thought to be responsible for up to 15% of CAP cases. These organisms have been implicated in sporadic and epidemic outbreaks both in hospital and community settings. Risk factors for Legionella include old age, tobacco and alcohol use, lung disease, and corticosteroid use; however, Legionnaire’s disease is also common in hosts without these factors.30 In the study reported by Fang et al, 4 Legionella species was the third most commonly isolated pathogen, accounting for 6.7% of CAP cases. At the current time, this atypical pathogen is not considered to be of clinical importance in patients with AECBs.

M pneumoniae
Mycoplasmas are intracellular organisms that were first identified in the 1940s as a cause of atypical pneumonia. M pneumoniae is responsible for about one fifth of all cases of CAP.30 It is most often reported in children and young adults, especially in clusters of cases. Young children experience primary infection, but reinfection can occur in older patients with detectable M pneumoniae antibodies. Reinfection accounts for most cases in patients > 45 years of age and may be associated with severe symptoms.30 M pneumoniae is the most common cause of tracheobronchitis, after S pneumoniae, in school-aged children and accounts for up to 20% of all cases of pneumonia in the general population and for up to 50% in closed populations.30 31 The role of M pneumoniae as a causative pathogen in patients with AECBs appears to be minimal.


   Approaches to Empiric Therapy
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
 References
 
The initial therapy for community-acquired lower respiratory tract infection is of necessity empiric for the aforementioned reasons. Since few primary-care practitioners have the facilities and expertise to obtain sputum samples in the office for culture and Gram’s stains, therapy for ambulatory pneumonia and AECB is, consequently, empiric. Therefore, laboratory tests are of little assistance in the choice and selection of antibiotics for the patient initially presenting with a lower respiratory tract infection in the community setting.

Recommended Guidelines for Treatment of CAP
Several articles9 32 33 34 have been published that outline the guidelines for the management of patients with CAP. Two sets of guidelines, one from the American Thoracic Society (ATS) and one from the Infectious Diseases Society of America (IDSA), offer recommendations for the treatment of adults with CAP and will be summarized. Although new guidelines from the ATS are under development, the current recommendations are summarized below along with the new guidelines from the IDSA.

The 1993 ATS guidelines for the management of CAP9 describe the spectrum of etiologic agents and the initial empiric approach to therapy. The ATS provided antibiotic recommendations for several patient groups including the following: outpatients < 60 years of age without comorbidities; outpatients > 60 years of age or with comorbidities; hospitalized patients with severe pneumonia; and hospitalized patients with nonsevere pneumonia. In outpatients < 60 years of age and without comorbidities, the most common bacterial pathogens include S pneumoniae, M pneumoniae, C pneumoniae, and H influenzae. The recommended initial therapy for this group was treatment with a macrolide (or with tetracycline in patients who cannot tolerate a macrolide).

In older outpatients or those with comorbidities, other bacteria, including M catarrhalis, may be present. In addition, the pathogens described above in younger patients are common pathogens in these patients, with H influenzae increasing in importance. For empiric initial therapy, the ATS-recommended choices included a second-generation cephalosporin, TMP/SMX, or a ß-lactam/ß-lactamase inhibitor combination.9 In addition, the administration of a macrolide was recommended if infection with Legionella species is a concern.

Among patients requiring hospitalization who are not critically ill, common pathogens include S pneumoniae and H influenzae. The recommended therapy for this group was a second-generation or third-generation cephalosporin, or a ß-lactam/ß-lactamase inhibitor combination.

The pathogens most frequently identified among hospitalized patients with severe pneumonia include S pneumoniae, H influenzae, Legionella species, aerobic Gram-negative bacilli, M pneumoniae, and respiratory viruses. The ATS-recommended initial therapy for this patient population was a macrolide combined with either an antipseudomonal agent, such as a second-generation or third-generation cephalosporin, or ciprofloxacin.9

Using mostly evidence-based data and a standard ranking system for the strength of treatment recommendations, the IDSA32 provided treatment options for immunocompetent adult patients with CAP. For the nonhospitalized patient, in whom the determination of an etiology is unlikely, the experts recommended the administration of a macrolide, a fluoroquinolone, or possibly doxycycline (ie, the latter only for young adults between 17 and 40 years of age). For the macrolide group, clarithromycin or azithromycin was recommended only if H influenzae was highly suspected. If S pneumoniae was suspected, a fluoroquinolone with broader Gram-positive activity was recommended. Examples of agents with more potent in vitro Gram-positive activity are moxifloxacin and gatifloxacin (see the "In Vitro Spectrum of Activity of the Fluoroquinolones" section below). Alternative options included amoxicillin-clavulanate or a second-generation cephalosporin (ie, cefuroxime, cefpodoxime, or cefprozil). Fluoroquinolone therapy was especially recommended in areas with a high prevalence of penicillin-resistant or macrolide-resistant pneumococci.

For hospitalized patients, a ß-lactam plus a macrolide or fluoroquinolone monotherapy was recommended by the IDSA, 32 providing coverage for S pneumoniae, H influenzae, and atypical pathogens. For patients requiring intensive care, the preferred antibiotics were a ß-lactam/ß-lactamase inhibitor plus a fluoroquinolone or a macrolide. For the patient with underlying lung disease, coverage for P aeruginosa with a ß lactam/ß-lactamase inhibitor with or without a fluoroquinolone was recommended. Alternatively, for patients with a ß-lactam allergy, a regimen of fluoroquinolones with or without clindamycin was favored. Individuals with suspected aspiration should receive either a fluoroquinolone with or without clindamycin, metronidazole, or a ß-lactam/ß-lactamase inhibitor.

Pathogen-directed therapy, in which the organism has been isolated or is highly suspected, is the ideal approach to choosing the appropriate antimicrobial therapy, especially for the treatment of hospitalized patients with pneumonia (Table 2 ).


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  		Table 2.. Treatment of Pathogen-Specific Pneumonia*

 
Antimicrobial Treatment of AECB
The most frequently isolated pathogens in cases of AECB are H influenzae, H parainfluenzae, M catarrhalis, and S pneumoniae.6 Appropriate antimicrobial therapy for a case of AECB of suspected bacterial etiology should cover the majority of these organisms even when therapy is instituted empirically.

The use of antibiotics for the treatment of AECB remains controversial, and no comparative US guidelines have yet been agreed on for the management of acute bacterial episodes. Although several sets of guidelines35 36 37 38 have been formulated, because of the significant differences in respiratory pathogen susceptibility in different regions of the world, the broad applicability of non-US guidelines to the United States may not be appropriate.

Older antimicrobial therapies for AECB, such as amoxicillin, doxycycline, and TMP/SMX, all have been used extensively in the past to treat episodes of AECB. In younger, immunocompetent patients, these agents may still prove to be the most cost-effective option. However, in patients with comorbidities or more severe disease, the possibility of resistance may outweigh the initial cost advantage. As previously mentioned, many of these agents are not as effective today because of the increasing prevalence of resistant organisms.15 Early-generation cephalosporins (eg, cefaclor or cephalexin), which also once were used in the treatment of AECB, are no longer considered to be reliably effective because of their lack of activity against ß-lactamase-producing H influenzae. Therapy with ineffective antimicrobials may lead to prolonged morbidity and may increase the chance of hospitalization for pneumonia and/or respiratory failure. Accordingly, new antibiotic alternatives are needed to reduce the morbidity, mortality, and particularly the growing economic burden associated with AECBs.

Role of Traditional Antibiotics
Empiric treatment of CAP has employed the ß-lactam antibiotics (ie, penicillins and cephalosporins) and the macrolides. In current use, each group of antibiotics has advantages and disadvantages. Without guidance through large-scale treatment trials, empiric therapy is left to the physician’s judgment. This decision involves the factors concerning the individual patient, combined with microbial and resis-tance patterns that are present in that physician’s area.

Traditional practice patterns increasingly utilize macrolide antibiotics in CAP, particularly in younger patients in whom the presence of atypical organisms is suspected. In older patients in whom H influenzae would be more prominent, increasing rates of penicillinase production have resulted in increased use of amoxicillin-clavulanate and third-generation cephalosporins over amoxicillin and penicillin. The newer macrolide/azalides, clarithromycin and azithromycin, are also popular for these patients due to their coverage for S pneumoniae, H influenzae, and atypical organisms.10 12 However, emerging patterns of antibiotic resistance threaten these treatment patterns. Mechanisms of resistance include the traditionally understood role of ß-lactamase production along with other cellular mechanisms.39 Several studies15 16 23 40 41 42 conducted over the past 15 years illustrate these changing resistance patterns. Rates of ß-lactamase-mediated ampicillin resistance to H influenzae have risen from approximately 15% in 1983 to > 30% in 1994.16

Thornsberry et al23 tested 1,572 isolates of H influenzae for susceptibility to a variety of old and new antimicrobials. In this survey conducted from 1996 to 1997, ampicillin resistance was 35.6% (high-level resistance, 33%; intermediate-level resistance, 2.6%). Clarithromycin was the least active agent, with approximately 10% of strains exhibiting high-level resistance and 32% exhibiting intermediate-level resistance. Levofloxacin and grepafloxacin were the most active agents, although moxifloxacin and gatifloxacin were not tested in this trial.

Another assessment41 of 6,385 respiratory tract pathogens obtained from clinical centers in Western Europe and the United States found that penicillin resistance was more commonly associated with cross-resistance to antibiotics such as TMP/SMX, macrolides, and chloramphenicol; however, concurrent resistance to the fluoroquinolones was not observed.

These findings confirmed that multiple-drug-resistant community-acquired pathogens represent a growing proportion of the isolates associated with respiratory tract infections. Because there are regional differences in susceptibility patterns, specific local studies must be performed in order to truly know the levels of resistance for each of the common respiratory pathogens.

Role of the Fluoroquinolones
Due to their potency, the broad spectra of antimicrobial activity, favorable pharmacokinetics, and safety profile, newer fluoroquinolones (eg, moxifloxacin or gatifloxacin) are being increasingly recommended for use in the treatment of community-acquired respiratory tract infections. Their excellent respiratory tissue penetration and activity against respiratory pathogens have contributed to their utility in these infections. The emergence of quinolone resistance among respiratory pathogens has been uncommon, although there have been sporadic examples of resistance developing in patients with chronic respiratory disease such as COPD or bronchiectasis.43 44

In Vitro Spectrum of Activity of the Fluoroquinolones
In vitro activity of many fluoroquinolones, both old and new, has been demonstrated against the atypical respiratory organisms, as well as the common Gram-negative and Gram-positive respiratory pathogens. Ciprofloxacin inhibits H influenzae and M catarrhalis isolates at MICs <= 0.06 µg/mL.45 46 47 Even multiple-drug-resistant H influenzae isolates are still highly susceptible to ciprofloxacin (MIC, <= 0.03 µg/mL).23 The MIC for ofloxacin against H influenzae is generally <= 0.06 µg/mL,45 46 whereas that against M catarrhalis has ranged from 0.05 µg/mL48 to 0.25 µg/mL.47 The sensitivity breakpoint for M catarrhalis in a 1996 survey was <= 2 mg/L for ofloxacin and <= 1 mg/L for ciprofloxacin.41 However, these older fluoroquinolones do not have predictable in vitro activity against S pneumoniae.

The newer fluoroquinolones (ie, levofloxacin, moxifloxacin, and gatifloxacin) are highly active against Haemophilus species and M catarrhalis.49 50 51 52 53 54 Gatifloxacin, moxifloxacin, and levofloxacin MIC90 values for H influenzae and M catarrhalis are <= 0.03 µg/mL, 0.06 µg/mL, and <= 0.5 µg/mL, respectively, for each bacteria. The MICs of these fluoroquinolones were not influenced by ß-lactamase production.50 54 In addition, moxifloxacin is highly potent against S pneumoniae with the MIC90 ranging from 0.06 to 0.25 µg/mL, including penicillin-resistant isolates.54 Gatifloxacin also has improved activity against pneumococcus (0.5 µg/mL) when compared to older fluoroquinolones.50 55

Many quinolones have a high degree of in vitro activity against L pneumophila, with MICs <= 0.06 µg/mL.46 48 Ciprofloxacin and ofloxacin have higher in vitro activities against M pneumoniae compared to tetracyclines or macrolides. The ratio of the minimum bacterial concentration that inhibits growth of 50% of organisms to the lowest drug concentration that inhibits growth of 50% of organisms for each quinolone was 4, compared with a range of 32 to 2,000 for the tetracyclines and macrolides.56 Moxifloxacin and gatifloxacin also have low MIC90 values for M pneumoniae.57 58 59 For C pneumoniae, MICs vary among the quinolones tested, but all showed effective potency.60 61 62 63

Importantly, there may be discrepancies between in vitro activity and the actual clinical response to a given drug. Accordingly, pharmacokinetics, pharmacodynamics (eg, the relationship of serum and tissue pharmacokinetics with predictors of clinical response, such as MIC), and safety need to be considered.48 64 Moxifloxacin has a very favorable pharmacokinetic profile including excellent respiratory tissue penetration, a dual route of elimination (no reductions necessary for patients with renal insufficiency), and a long half-life (12 h), which permits once-a-day dosing.65 Likewise, gatifloxacin and levofloxacin have good respiratory tissue penetration and a long half-life (approximately 8 h each). However, these drugs are eliminated primarily through the renal route and may require dose modification in patients with renal insufficiency.66 67 Unlike some of the newer-generation fluoroquinolones, moxifloxacin so far has been shown to be safe and well-tolerated without any evidence of significant phototoxicity, hepatotoxicity, or clinically significant QTc prolongation.

Clinical Experience With the Fluoroquinolones
Clinical investigations have demonstrated that the fluoroquinolones provide excellent bacteriologic and clinical outcomes for community-acquired lower respiratory tract infections. In a worldwide review68 of 37 published ciprofloxacin clinical trials done from 1985 to 1994 combined with unpublished data involving a total of 3,769 patients with lower respiratory tract infections, ciprofloxacin treatment resulted in an overall bacteriologic eradication rate of 91%. Specific eradication rates for H influenzae and M catarrhalis following ciprofloxacin therapy were 96% and 95%, respectively. These eradication rates are similar to rates with traditional agents.

A surveillance69 of respiratory tract pathogens also supports the excellent in vitro activity of ciprofloxacin against pneumococcus. The MIC90 of ciprofloxacin for pneumococcal isolates collected from 1996 to 1997 from 51 US medical centers was 1.0 µg/mL, and penicillin resistance (intermediate plus high level) for these same isolates was 36%. Resistance to azithromycin, clarithromycin, and erythromycin was reported at 23%, 23%, and 24%, respectively.

The remainder of this section will summarize recent controlled clinical trials with ciprofloxacin, levofloxacin, trovafloxacin, moxifloxacin, and gatifloxacin for the treatment of patients with AECBs and CAP. In CAP studies in which atypical organisms were suspected or known to be present, ß-lactam comparator drugs were augmented with concomitant erythromycin or doxycycline. Otherwise, coverage for these pathogens was not complete. It is worth noting that most published studies are designed to demonstrate equivalence between antibiotics as per US Food and Drug Administration recommendations for licensure of a new drug.


   AECB Clinical Trials
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
Clinical Trials in CAP
 Discussion
 References
 
Older-Generation Fluoroquinolones
Ciprofloxacin: Several studies have investigated the efficacy and safety of ciprofloxacin in doses ranging from 500 to 750 mg twice daily for the treatment of patients with AECBs. In a large, prospective, double-blind, multicenter study,70 376 patients with AECBs were enrolled and randomized to receive either ciprofloxacin or clarithromycin (both 500 mg twice daily for 14 days). Although clinical success was higher for ciprofloxacin-treated patients (90%) vs clarithromycin-treated patients (82%), this difference was not found to be significant. Bacteriologic eradication was observed for 91% of ciprofloxacin-treated patients and for 77% of clarithromycin-treated patients (p = 0.01). The difference in the estimated median infection-free interval (ie, the time from the end of one exacerbation to the beginning of the next one) between the ciprofloxacin-treated group (142 days) and the clarithromycin-treated group (51 days) was not significant (p = 0.15), although it was suggestive of a potentially important health economic trend.

The efficacy of ciprofloxacin vs cefuroxime axetil, 500 mg twice daily for 14 days each, in patients with AECBs was determined in another large prospective, multicenter, double-blind study.71 Among 307 adult patients with AECBs who enrolled in the study, 231 had an exacerbation due to a bacterial pathogen. Clinical success at the end of therapy was 93% and 90%, respectively, following ciprofloxacin and cefuroxime axetil therapy. Bacteriologic eradication rates were statistically higher for ciprofloxacin recipients (96%) vs cefuroxime axetil recipients (82%) (p = 0.003).

In a community-based randomized trial,72 the efficacy of ciprofloxacin (750 mg) and clarithromycin (500 mg), each given for 10 days twice daily, was compared in patients with AECBs. Two thousand one hundred eighty patients who were > 40 years old with complicated/severe AECB episodes were enrolled. The enrollment criteria included the following: did not respond to previous administration of antimicrobials given 2 to 4 weeks before; regional susceptibility data indicated a high number of previously resistant pathogens; more than three AECB episodes per year; and/or more than three comorbid conditions. The incidence of the bacterial pathogens isolated included the following: Haemophilus spp, 28%; M catarrhalis, 18%; Enterobacteriaceae, 18%; S aureus, 17%; S pneumoniae, 7%; and P aeruginosa, 4%. Among 673 efficacy-valid patients with a pretherapy pathogen, clinical success at the end of therapy was 93% for ciprofloxacin and 90% for clarithromycin. The overall bacteriologic eradication rates at the end of therapy were 98% for ciprofloxacin vs 95% for clarithromycin. Ciprofloxacin eradicated more Haemophilus spp compared to clarithromycin, 99% and 93%, respectively (p = 0.05). The eradication rate of pneumococcus was similar in both treatment groups (> 90%).

Levofloxacin: In a prospective multicenter study73 that was conducted in the United States, adult patients with AECBs were randomized to receive either once-daily levofloxacin (500 mg) for 5 to 7 days or twice-daily cefuroxime axetil (250 mg) for 10 days. Clinical success was observed in 95% of efficacy-valid levofloxacin-treated patients and in 93% of cefuroxime axetil-treated patients. Bacteriologic success was reported for 96% of the levofloxacin recipients and for 93% of the cefuroxime axetil recipients.

In a 20-center study conducted in the United States,74 adult patients with documented bacterial exacerbations randomly received either once-daily levofloxacin (500 mg) for 5 to 7 days or twice-daily cefaclor (250 mg) for 7 to 10 days. Clinical success at the end of therapy was identical for both levofloxacin-treated patients and cefaclor-treated (92%) patients. Bacteriologic eradication rates were somewhat higher for levofloxacin recipients (94%) compared with cefaclor recipients (87%).

Newer-Generation Fluoroquinolones
Moxifloxacin: Chodosh et al75 compared the efficacy and safety of moxifloxacin to clarithromycin for the treatment of patients with acute bacterial exacerbations of chronic bronchitis in a double-blind, placebo-controlled trial. Patients randomly received either moxifloxacin, 400 mg once daily for 5 or 10 days, or clarithromycin, 500 mg twice daily for 10 days. Of 936 patients enrolled, 491 (52%) had a pretherapy pathogen isolated from an acceptable sputum specimen. The overall clinical resolution was reported in 89% of the patients treated for 5 days with moxifloxacin, in 91% the patients treated for 10 days with moxifloxacin, and in 91% of patients treated with clarithromycin. Bacteriologic eradication rates at the follow-up visit (7 to 17 days post-therapy) were 89% for the 5-day moxifloxacin treatment group, 91% for the 10-day moxifloxacin treatment group, and 85% for the clarithromycin treatment group. For S pneumoniae in particular, the 5-day and 10-day moxifloxacin regimens eradicated 100% and 95%, respectively, of organisms compared to 91% for the clarithromycin regimen. The authors concluded that once-daily moxifloxacin, 400 mg, given either as a 5-day or a 10-day regimen, was clinically and bacteriologically equivalent to a clarithromycin, 500 mg, 10-day twice-daily regimen for patients with acute bacterial exacerbations of chronic bronchitis.

A study76 conducted in Europe compared the efficacy of 5-day moxifloxacin therapy to 10-day clarithromycin therapy among patients with AECBs. Six hundred forty-nine patients (moxifloxacin, 322 patients; clarithromycin, 327 patients) were considered to be efficacy-valid; 35% of patients had a bacterial isolate identified pretherapy. H influenzae (37%), S pneumoniae (31%), and M catarrhalis (18%) were identified most often. All isolates were susceptible in vitro to moxifloxacin; however, 49 isolates were found to be clarithromycin-resistant (MIC, > 8 mg/L). The following similar end-of-therapy clinical cure rates were reported: moxifloxacin, 89%; clarithromycin, 88%. Bacteriologic success was found to be higher following moxifloxacin therapy (77%) than following clarithromycin therapy (62%). At the 1-month follow-up visit, clinical and bacteriologic success rates were similar between the two treatment groups.

Gatifloxacin: The efficacy and safety of gatifloxacin, 400 mg once daily, for AECB was compared to clarithromycin, 500 mg twice daily, in a randomized, double-blind three-arm clinical trial.77 Among 527 patients (82% with Anthonisen type I exacerbation), the clinical cure rate was comparable between a 5-day (89%) and a 7-day (88%) gatifloxacin treatment. This was equivalent to a 10-day clarithromycin treatment, which demonstrated an efficacy rate of 89%. All pretherapy isolates of S pneumoniae and H influenzae were susceptible to gatifloxacin, while 85% of S pneumoniae, 82% of H influenzae (ß-lactamase-positive), and 98% of H influenzae (ß-lactamase-negative) were clarithromycin-susceptible. Overall, a > 90% rate of microbiological eradication was achieved in each treatment group.


   Clinical Trials in CAP
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
Discussion
 References
 
Older-Generation Fluoroquinolones
Levofloxacin: In a randomized, open, comparative, multicenter study,78 590 adult patients with mild-to-moderate ambulatory CAP received either once-daily levofloxacin, 500 mg IV or po, for 7 to 14 days or ceftriaxone, 1 to 2 g IV once or twice daily for 7 to 14 days, with or without cefuroxime axetil, 500 mg twice daily for 7 to 14 days. Patients randomized to treatment with cefuroxime axetil also were given concomitant erythromycin or doxycycline if atypical organisms were suspected or known to be present. At 5 to 7 days posttherapy (ie, the end-of-therapy visit), the overall clinical success rate (ie, cure plus improvement) was 96% in levofloxacin-treated patients, compared with 90% in ceftriaxone/cefuroxime axetil-treated patients. The overall eradication rate by pathogen was 98% for levofloxacin and 90% for ceftriaxone/cefuroxime. Levofloxacin eradicated 100% of S pneumoniae isolates (respiratory isolates, 30; blood isolates, 9), including 6 isolates that were intermediately sensitive to penicillin (MIC, 0.1 to 1.0 µg/mL), while ceftriaxone/cefuroxime axetil eradicated 95% of S pneumoniae isolates.

In a second prospective, double-blind, double-placebo, randomized trial,79 adult patients with CAP received either levofloxacin, 500 mg once- or twice-daily, or amoxicillin clavulanic acid, 500 or 125 mg three times daily. The clinical cure rate was similar in the three treatment groups at 95%, 94%, and 95%, respectively. The overall eradication rates were 98% for once-daily levofloxacin, 100% for twice-daily levofloxacin, and 98% for amoxicillin clavulanic acid. Specifically, the eradication rates for S pneumoniae were 100% each for levofloxacin once daily (n = 15), levofloxacin twice daily (n = 22), and amoxicillin clavulanic acid (n = 16). H influenzae was completely eradicated in all three antibiotic groups.

Newer-Generation Fluoroquinolones
Trovafloxacin: In a double-blind, randomized study80 of 443 patients with CAP requiring hospitalization and initial IV therapy, monotherapy with alatrofloxacin (the IV prodrug of trovafloxacin) followed by once-daily oral trovafloxacin 200 mg was compared to IV ceftriaxone followed by oral cefpodoxime for 7 to 14 days. Clinical success at the end of therapy was reported for 90% of trovafloxacin-treated patients and 87% of ceftriaxone/cefpodoxime-treated patients. Slightly < 50% of patients in both treatment groups had a pretherapy pathogen. Of the patients who did not respond clinically in the trovafloxacin group, none had a persistent pathogen present compared to three patients in the ceftriaxone/cefpodoxime group. Of evaluable patients with S pneumoniae bacteremia, 93% (13 of 14 patients) of trovafloxacin-treated patients and 89% (8 of 9 patients) of ceftriaxone/cefpodoxime-treated patients achieved clinical success.

In a second double-blind, multicenter, randomized study,81 359 patients with CAP received either oral trovafloxacin, 200 mg once daily, or oral clarithromycin, 500 mg twice daily, for 7 to 10 days. Approximately 41% and 43%, respectively, of the clinically valid patients had a pretherapy pathogen. Clinical success at the end of therapy was observed for 96% trovafloxacin-treated subjects and 94% clarithromycin-treated subjects. For patients with S pneumoniae infections, clinical success was reported in 12 of 12 patients following trovafloxacin therapy and in 15 of 16 patients following clarithromycin therapy. In both trovafloxacin pneumonia trials, the most frequently reported adverse events for trovafloxacin were dizziness and nausea (approximately 5% each).

Since the completion of these studies, serious hepatotoxicity has been reported following trovafloxacin use. Liver transplantation was required in some patients, and several deaths were considered to be related to trovafloxacin-induced liver toxicity. Accordingly, trovafloxacin should be administered only to patients with serious and life-threatening infections, including pneumonia.

Moxifloxacin: In a prospective, uncontrolled, nonblind study,82 254 adult patients with CAP were administered moxifloxacin, 400 mg once daily for 10 days. Forty-six percent of patients had an organism that was identified by culture or serology, primarily including C pneumoniae (54%), M pneumoniae (25%), S pneumoniae (12%), and H influenzae (10%). At the end of therapy, moxifloxacin was associated with a 97% clinical resolution rate and an overall bacteriologic eradication rate of 91%. Eradication rates for the four most commonly isolated pathogens were 89% for C pneumoniae, 93% for M pneumoniae, 93% for S pneumoniae, and 85% for H influenzae. The investigators concluded that moxifloxacin was effective in the treatment of adult patients with CAP due to both typical and atypical bacterial organisms.

In a prospective, double-blind, multicenter study,83 474 adult patients with CAP randomly received either moxifloxacin, 400 mg once daily for 10 days, or clarithromycin, 500 mg twice daily for 10 days. Among 382 efficacy-valid patients, 56% had a pretherapy organism isolated. The most common organisms identified by culture or serology included C pneumoniae (36%), M pneumoniae (16%), H influenzae (14%), and S pneumoniae (13%). Clinical resolution at the end of therapy was achieved in 95% of patients following therapy with moxifloxacin and clarithromycin. Eradication rates for the most commonly isolated pathogens following moxifloxacin vs clarithromycin therapy were as follows: 92% vs 98%, respectively, for C pneumoniae; 96% vs 100%,respectively, for M pneumoniae; 96% vs 88%, respec-tively, for H influenzae; and 100% vs 95%, respectively, for S pneumoniae. This study established that moxifloxacin was as least as effective as clarithromycin in the treatment of patients with CAP.

Gatifloxacin: Four hundred thirty-one patients with mild, moderate, and severe CAP randomly received gatifloxacin or clarithromycin in a double-blind, multicenter study design.84 As expected, most bacteria that were isolated were S pneumoniae, H influenzae, M pneumoniae, and C pneumoniae. All bacteria were susceptible to gatifloxacin, whereas resistance to clarithromycin was found among 19% of pretherapy pathogens. Clinical cure rates were similar for both treatment groups (gatifloxacin, 92%; clarithromycin, 89%). The corresponding bacteriologic eradication rates were 95% and 89%, respectively.

In a double-blind, randomized, multicenter study,85 the efficacies of gatifloxacin and levofloxacin, both given either IV only, po only, or IV/po conversion, were compared in the treatment of patients with mild, moderate, and severe CAP. Clinical cure rates were 96% for gatifloxacin and 94% for levofloxacin. Bacteriologic eradication rates were also similar (gatifloxacin, 98%; levofloxacin, 93%). The eradication of S pneumoniae was achieved in 100% of patients (12 of 12 patients) treated with gatifloxacin compared to 78% of patients (14 of 18 patients) given levofloxacin therapy.

The efficacy of IV gatifloxacin therapy (with or without oral gatifloxacin therapy) also has been assessed in hospitalized patients with CAP.86 A clinical cure was reported for 97% of patients receiving gatifloxacin and for 91% of patients randomized to receive IV ceftriaxone with or without erythromycin (with or without step-down oral clarithromycin therapy). Eradication rates for the two most common pathogens were similar (S pneumoniae and M catarrhalis, 95%; gatifloxacin, 100% vs comparator, 88%).


   Discussion
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
References
 
The selection of appropriate antibiotic therapy for the treatment of lower respiratory tract infections must evolve based on the changing patterns of isolated organisms and emerging resistance to conventional therapies. The increasing importance of pathogens such as H influenzae and M catarrhalis in CAP and AECB, and of atypical pathogens such as C pneumoniae, L pneumophila, and M pneumoniae in CAP, has become apparent. By contrast, the importance of S pneumoniae appears to be declining in patients with AECBs. None of the ß-lactam antibiotics provide coverage for atypical respiratory organisms, and traditional empiric therapy with erythromycin or tetracycline is less than ideal because of the limited efficacy of tetracycline in infections caused by C pneumoniae and M pneumoniae and by the relative lack of in vitro activity of both drugs against H influenzae. A high incidence of GI side effects is also associated with erythromycin. Doxycycline is a low-cost alternative, but it is less active than newer compounds and can have side effects.11 The increasing development of drug resistance, especially in ß-lactamase-producing H influenzae and multi-drug-resistant S pneumoniae, poses a challenge to family practitioners who have traditionally prescribed empiric treatment with agents such as the ß-lactams, macrolides, cephalosporins, tetracycline, and TMP/SMX. The clinical value of these various agents may be compromised by their ability to adequately penetrate respiratory tissues, by their mode of action (bactericidal vs bacteriostatic), and by the growing resistance to these agents among respiratory tract pathogens.

One therapeutic option for the treatment of community-acquired respiratory infections is the appropriate use of fluoroquinolones, which have demonstrated targeted in vitro activity against typical and atypical respiratory tract pathogens.45 46 47 48 54 59 Although the relatively older-generation fluoroquinolones (eg, ciprofloxacin or levofloxacin) have broad-spectrum activity, the recent availability of newer-generation fluoroquinolones (eg, moxifloxacin or gatifloxacin) with expanded Gram-positive activity has made these agents potential first-line therapies for the management of patients with lower respiratory tract infections. The newer fluoroquinolones also have improved pharmacokinetic/pharmacodynamic properties that fully support once-daily dosing. Moxifloxacin and gatifloxacin achieve significant levels in sputum and bronchial secretions that exceed the MICs of most respiratory pathogens, in addition to having a 12-h and 8-h, respectively, elimination half-life.65 87 In addition, fluoroquinolones penetrate alveolar phagocytes and kill at an acid pH, giving this class of antimicrobials an advantage over previously standard antibiotics in inhibiting the replication of intracellular pathogens. For all of these reasons, the newer-generation fluoroquinolones are rational alternative empiric therapies for selected patients with CAP or acute bacterial exacerbations of chronic bronchitis. The practitioner must keep in mind that not all fluoroquinolones provide identical in vitro coverage against respiratory pathogens and that they do not have identical clinical effectiveness rates or safety profiles. Importantly, trovafloxacin should be administered only to hospitalized patients with serious and life-threatening infections due to concern over hepatotoxicity.

Although in vitro activity and pharmacodynamic properties are guides to probable clinical activity, clinical response is clearly the best indicator of the efficacy of an antibiotic. In particular, the newer fluoroquinolones (eg, moxifloxacin and gatifloxacin) have been proven to be effective for community-acquired respiratory tract infections.75 76 80 81 Although pathogens are seldom identified in patients with community-acquired lower respiratory tract infection, in vitro activity and clinical experience suggest that the newer fluoroquinolones are appropriate therapies for respiratory tract infections due to typical and atypical pathogens.


   Footnotes
 
Abbreviations: AECB = acute exacerbation of chronic bronchitis; ATS = American Thoracic Society; CAP = community-acquired pneumonia; IDSA = Infectious Diseases Society of America; MIC = minimum inhibitory concentration; MIC90 = the lowest drug concentration that inhibits the growth of 90% of organisms; TMP/SMX = trimethoprim-sulfamethoxazole

This article was prepared with support from Bayer Pharmaceutical. Additionally, Robert Guthrie, MD, has served as a speaker and consultant for Bayer Pharmaceutical, SmithKline Beecham, Bristol Myers Squibb, Solvay, and AstraZeneca.

Received for publication July 10, 2000. Accepted for publication March 13, 2001.


   References
TOP
 Abstract
 Introduction
 Incidence of Bacterial Pathogens...
 Approaches to Empiric Therapy
 AECB Clinical Trials
 Clinical Trials in CAP
 Discussion
 References
 

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