Fluoroquinolones for Respiratory Infections: Too Valuable To Overuse

Abstract

In the current issue of CHEST (see page 2021), Guthrie has provided a broad and useful review of newer treatment options for the pathogens most commonly associated with both community-acquired pneumonia (CAP) and bronchitis, with a strong emphasis on the potential value of newer fluoroquinolones for empiric treatment. Guthrie discusses older fluoroquinolones such as ciprofloxacin (Bayer Pharmaceuticals; West Haven, CT) and levofloxacin (Ortho-McNeil Pharmaceutical; Raritan, NJ), and as newer fluoroquinolones moxifloxacin (Bayer Pharmaceuticals), gatifloxacin (Bristol-Myers Squibb; New York, NY), and trovafloxacin (Pfizer; New York, NY). He acknowledges his support by two of these pharmaceutical companies (Bayer Pharmaceuticals and Bristol-Myers Squibb). Many share his view (as I do) that currently available fluoroquinolones provide excellent coverage for most treatable respiratory pathogens, including atypical and more readily cultured pathogens. Excellent absorption and minimal toxicity permit comparable oral and IV therapy for the treatment of serious infections, which sets these drugs apart from most β-lactam drugs and the older macrolide erythromycin. Either newer macrolide azithromycin and older broad-spectrum doxycycline can be comparably dosed orally and IV, and both cover atypical pathogens. However, fluoroquinolones variably offer greater Gram-negative coverage, greater efficacy with highly resistant pneumococci, and/or greater anaerobic coverage, providing advantages for treating selected patients when used as monotherapy. Rapid conversion from IV to oral therapy reduces the cost of hospitalization by reducing drug costs and, potentially, the length of stays in the hospital. As such, fluoroquinolones combine exceptional efficacy with cost-effectiveness. Therefore, it is not surprising that some medical systems have adopted fluoroquinolones as empiric therapy in clinical pathways for the treatment of CAP.1Siegel RE Strategies for early discharge of the hospitalized patient with community-acquired pneumonia.Clin Chest Med. 1999; 20: 599-605Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar2Palmer CS Zhan C Elixhauser A et al.Economic assessment of the community-acquired pneumonia intervention trial employing levofloxacin.Clin Ther. 2000; 22: 250-264Abstract Full Text PDF PubMed Scopus (44) Google Scholar Efficacy and tolerance data support their use among outpatients with exacerbations of chronic bronchitis as well.3Davies BI Maesen FP Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.J Antimicrob Chemother. 1999; 43: 83-90Crossref Google Scholar Some of the older, more established fluoroquinolones, including ciprofloxacin and levofloxacin, have proven remarkably safe over time at higher doses than usually are prescribed.4Modai J High-dose intravenous fluoroquinolones in the treatment of severe infections.J Chemother. 1999; 11: 478-485Crossref PubMed Scopus (11) Google Scholar Ciprofloxacin at 750 mg bid appears to be safe and at least comparable in effectiveness for the outpatient treatment of acute bronchitis and pneumonia when compared to other commonly utilized drugs.5Cazzola M Vinciguerra A Beghi GF et al.Comparative evaluation of the clinical and microbiological efficacy of co-amoxiclav vs cefixime or ciprofloxacin in bacterial exacerbation of chronic bronchitis.J Chemother. 1995; 7: 432-441Crossref PubMed Scopus (25) Google Scholar6Anzueto A Niederman MS Tillotson GS Etiology, susceptibility, and treatment of acute bacterial exacerbations of complicated chronic bronchitis in the primary care setting: ciprofloxacin 750 mg b.i.d. versus clarithromycin 500 mg b.i.d. Bronchitis Study Group.Clin Ther. 1998; 20: 885-900Abstract Full Text PDF PubMed Scopus (73) Google Scholar High doses of ciprofloxacin were recommended by the Infectious Diseases Society of America (IDSA) in their CAP guidelines when Pseudomonas aeruginosa infection is considered.7Bartlett JG Breiman RF Mandell LA et al.Community-acquired pneumonia in adults: guidelines for management; the Infectious Diseases Society of America.Clin Infect Dis. 1998; 26: 811-838Crossref PubMed Scopus (857) Google Scholar Very high doses of ciprofloxacin and levofloxacin have successfully treated persistent osteomyelitis8Greenberg RN Newman MT Shariaty S et al.Ciprofloxacin, lomefloxacin, or levofloxacin as treatment for chronic osteomyelitis.Antimicrob Agents Chemother. 2000; 44: 164-166Crossref PubMed Scopus (71) Google Scholar and may be useful for treatment of empyema where local concentrations exceed serum concentrations.9Joseph J Vaughan LM Basran GS Penetration of intravenous and oral ciprofloxacin into sterile and empyemic human pleural fluid.Ann Pharmacother. 1994; 28: 313-315Crossref PubMed Scopus (10) Google Scholar10McLaughlin RL Managing the nonsurgical candidate with an empyema related to community-acquired lobar pneumonia.Heart Lung. 2000; 29: 378-382Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Higher tissue concentrations of levofloxacin and newer fluoroquinolones in sites of inflammation provide theoretical advantages for the treatment of empyema or infections of other poorly vascularized spaces, but clinical trials of these conditions are lacking. Two sets of guidelines for the treatment of CAP, one a combined effort of the Canadian Infectious Disease Society/Canadian Thoracic Society (CIDS/CTS)11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar and the other by the IDSA,12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar were recently published simultaneously. Readers are encouraged to seek copies of these guidelines and the accompanying editorial,13Mandell LA Guidelines for community-acquired pneumonia: a tale of 2 countries.Clin Infect Dis. 2000; 31: 422-425Crossref PubMed Scopus (16) Google Scholar which favor fluoroquinolones but somewhat less strongly than presented in the article by Guthrie. The guidelines generally favor the primary or secondary consideration of fluoroquinolones in the initial empiric treatment of patients who have the most complicated cases of CAP and are admitted to the hospital, while generally favoring macrolides or doxycycline for the treatment of less sick outpatients, at least among those without special needs for fluoroquinolones. These recommendations are summarized in tables in each of the two studies cited11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar and are compared here in Table 1. Importantly, these guidelines presume that sputum and blood cultures are collected routinely and will lead to a change to an antibiotic with narrower coverage rather than the persistent use of fluoroquinolones in hospitalized patients. However, clinicians are often reluctant to withdraw what appears to be effective therapy in very sick patients. Furthermore, cultures frequently are not sufficiently diagnostic,14Theerthakarai R El-Halees W Ismail M et al.Nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia.Chest. 2001; 119: 181-184Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar fueling controversy regarding the value of routine sputum cultures. Therefore, because most patients with CAP improve in the hospital on empiric therapy, the initial therapy is continued in most patients when feasible.Table 1Comparison of Recent Guidelines for Empiric InitialTherapy of CAP*± = with or without;PCN = penicillin.VariablesDrugs RecommendedModifying FactorsIDSA (Bartlett et al12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar)OutpatientDoxycycline, macrolide, or fluoroquinolone (no distinction)Older patients: many prefer fluoroquinolone Underlying disease: many prefer fluoroquinolone Prevalence high PCN resistance: consider fluoroquinoloneHospitalized wardCefalosporin + (macrolide or fluoroquinolone) or; β-lactam/β-lactamase inhibitor + macrolide; or; fluoroquinolone aloneICU(Cefalosporin or β-lactam/β-lactamase inhibitor)+ (macrolide or fluoroquinolone)Prior lung disease: (pseudomonal β-lactam [±β-lactamase inhibitor] or carbapenem) + fluoroquinolone (high-dose ciprofloxacin) β-lactam allergy: fluoroquinolone ± clindamycin Suspect aspiration: fluoroquinolone ± (clindamycin, metronidazole, or β-lactam/β-lactamase inhibitor)CIDS/CTS (Mandell et al11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar)Outpatient1st choice macrolide, or 2nd choice doxycyclineCOPD: 1st choice newer macrolide, or 2nd choice doxycycline COPD + recent antibiotic or steroid: 1st choice respiratory fluoroquinolone (eg, levofloxacin or newer generation), or 2nd choices (amoxicillin/clavulonate+ macrolide), or 2nd-generation cephalosporin+ macrolide Suspect aspiration: 1st choice amoxicillin/clavulonate ± macrolide or 2nd choice respiratory fluoroquinolone + (clindamycin or metronidazole) Nursing home: respiratory fluoroquinoloneHospitalized ward1st choice IV respiratory fluoroquinolone or 2nd choice (2nd-, 3rd-, or 4th-generation cephalosporin+ macrolide)ICU1st choice respiratory fluoroquinolone + (cefotaxime, ceftriaxone, or β-lactam/β-lactamase inhibitor) or 2nd choice IV macrolide + (cefotaxime, ceftriaxone, or β-lactam/β-lactamase inhibitor)Pseudomonas suspected: 1st choice antipseudomonal fluoroquinolone (eg, ciprofloxacin)+ (antipseudomonal β-lactam or aminoglycoside) or 2nd choice triple therapy with antipseudomonal β-lactam (eg, ceftazidime, piperacillin-tazobactam, imipenem, or meropenem) + aminoglycoside+ macrolide* ± = with or without;PCN = penicillin. Open table in a new tab The conditions of patients with acute exacerbations of chronic bronchitis associated with dyspnea and/or a change in sputum character generally also improve during antibiotic therapy,15Niederman MS Antibiotic therapy of exacerbations of chronic bronchitis.Semin Respir Infect. 2000; 15: 59-70Crossref PubMed Scopus (44) Google Scholar leading to the continuation of empiric therapy when these patients are admitted to hospital as well. A wide variety of drugs have been employed, and the article by Guthrie points to the potential efficacy of fluoroquinolones in this setting as well. As data continue to demonstrate efficacy, safety, and short-term overall cost reduction in treating respiratory infections with fluoroquinolones, their use is increasing. Unfortunately, bacteria that are resistant to these agents are also increasing.16Zhang L Li XZ Poole K Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system.Antimicrob Agents Chemother. 2000; 44: 287-293Crossref PubMed Scopus (147) Google Scholar17Hooper DC New uses for new and old quinolones and the challenge of resistance.Clin Infect Dis. 2000; 30: 243-254Crossref PubMed Scopus (148) Google Scholar Widespread use of fluoroquinolones among hospitalized patients has induced more frequent resistance among nosocomial pathogens.18Manhold C von Rolbicki U Brase R et al.Outbreaks of Staphylococcus aureus infections during treatment of late onset pneumonia with ciprofloxacin in a prospective, randomized study.Intensive Care Med. 1998; 24: 1327-1330Crossref PubMed Scopus (37) Google Scholar19Hanberger H Garcia-Rodriguez JA Gobernado M et al.Antibiotic susceptibility among aerobic Gram-negative bacilli in intensive care units in 5 European countries: French and Portuguese ICU Study Groups.JAMA. 1999; 281: 67-71Crossref PubMed Scopus (284) Google Scholar Surveillance data from two teaching hospitals in this community have demonstrated an increase in the isolation of resistant organisms, particularly among nosocomial pathogens. Ciprofloxacin-resistant Pseudomonas isolates in the ICU rose from 30% in 1998 to 43% in 1999; among outpatients, isolates rose from 17% in 1998 to 25% in 1999 (Lauri Thrup, MD; personal communication; May 9, 2001). While resistance among the most common community-acquired pathogens remains infrequent in the United States,20Biedenbach DJ Jones RN Fluoroquinolone-resistant Haemophilus influenzae: frequency of occurrence and analysis of confirmed strains in the SENTRY antimicrobial surveillance program (North and Latin America).Diagn Microbiol Infect Dis. 2000; 36: 255-259Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar21Klugman KP Gootz TD In-vitro and in-vivo activity of trovafloxacin against Streptococcus pneumoniae.J Antimicrob Chemother. 1997; 39: 51-55Crossref Scopus (31) Google Scholar resistance is beginning to appear among pneumococci in Canada.22Chen DK McGeer A de Azavedo JC et al.Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada: Canadian Bacterial Surveillance Network.N Engl J Med. 1999; 341: 233-239Crossref PubMed Scopus (1034) Google Scholar Recurrent use among patients in the community is likely to promote resistance among outpatients as well, particularly among patients with chronic bronchitis.3Davies BI Maesen FP Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.J Antimicrob Chemother. 1999; 43: 83-90Crossref Google Scholar23Vila J Ruiz J Sanchez F et al.Increase in quinolone resistance in a Haemophilus influenzae strain isolated from a patient with recurrent respiratory infections treated with ofloxacin.Antimicrob Agents Chemother. 1999; 43: 161-162Crossref PubMed Scopus (9) Google Scholar24Jalal S Ciofu O Hoiby N et al.Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients.Antimicrob Agents Chemother. 2000; 44: 710-712Crossref PubMed Scopus (186) Google Scholar25Speciale A Musumeci R Blandino G et al.Molecular mechanisms of resistance in Pseudomonas aeruginosa to fluoroquinolones.Int J Antimicrob Agents. 2000; 14: 151-156Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Therefore, it would seem prudent to reconsider where and how to potentially limit the overuse of this valuable new class of drugs while still capitalizing on the opportunities to utilize their unique strengths. A number of approaches could be offered. The classic approach recommended by the IDSA and CIDS/CTS11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar focuses on aggressive sampling, with cultures and sensitivities permitting the derecruitment of some patients from the long list of patients who are receiving fluoroquinolones in hospitals. Two alternative considerations are suggested here that may help to diminish the emergence of resistant strains, focused first on diminishing their use among inpatients who are expected to have a prolonged stay in the hospital, and second on outpatients who experience chronic, recurrent infections. Admittedly, these alternative strategies appear to conflict with recent North American recommendations,11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar which generally favor the empiric use of fluoroquinolones among patients with CAP who are very sick or have prior lung disease. First, among hospitalized patients it would seem wise to try to avoid placing those anticipated to have a long hospital course on fluoroquinolones unless alternative regimens could not provide comparable coverage. This effort would seem most important for patients admitted to the ICU, where resistant strains emerge most notoriously, particularly among intubated patients. Factors that argue for choosing a fluoroquinolone include intolerance to other drugs, poor clinical responses to other drugs, or isolated organisms demonstrating resistance to other drugs in vitro. However, alternative regimens should be considered for most other patients. While many alternatives to fluoroquinolones could be offered, the review by Guthrie points out the importance of initial empiric coverage of both atypical and typical pathogens with CAP. Both the IDSA and CIDS/CTS guidelines outlined in Table 1 provide alternative regimens, even if not the favored regimen. For very sick patients who are expected to have a prolonged hospital stay, consider a two-drug regimen combining a β-lactam with or without a β-lactamase inhibitor (eg, a second-generation or third-generation cephalosporin, ampicillin/sulbactam, or high doses of piperacillin/tazobactam to enhance coverage of Pseudomonas) for broad coverage of typical organisms, plus a second drug for atypical pathogens (eg, a macrolide or doxycycline). These two-drug regimens will provide broad and effective empiric coverage for most patients. The obvious exceptions would be those patients already not responding to therapy with these drugs or patients who are intolerant to these drugs. Of note, the use of doxycycline for atypical coverage in hospitalized patients is not suggested in either of the recent guidelines cited.11Mandell LA Marrie TJ Grossman RF et al.Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society; The Canadian Community-Acquired Pneumonia Working Group.Clin Infect Dis. 2000; 31: 383-421Crossref PubMed Scopus (622) Google Scholar12Bartlett JG Dowell SF Mandell LA et al.Practice guidelines for the management of community-acquired pneumonia in adults: Infectious Diseases Society of America.Clin Infect Dis. 2000; 31: 347-382Crossref PubMed Scopus (1430) Google Scholar However, a study26Ailani RK Agastya G Mukunda BN et al.Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia.Arch Intern Med. 1999; 159: 266-270Crossref PubMed Scopus (66) Google Scholar of patients hospitalized with CAP, which excluded ICU patients, found monotherapy with IV doxycycline at 100 mg q12h (converted to oral administration for outpatient continuation) provided short-term outcomes that were at least as good as off-pathway, individual, physician-directed antibiotic selection, with a markedly reduced overall cost. Monotherapy with a high dose (ie, 500 mg qd) of azithromycin also was found to be as effective and better tolerated than a combination therapy of erythromycin and a cephalosporin in hospitalized patients, again excluding ICU patients.27Vergis EN Indorf A File Jr, TM et al.Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.Arch Intern Med. 2000; 160: 1294-1300Crossref PubMed Scopus (125) Google Scholar These data do not provide an adequate basis for the use of monotherapy with either agent among patients sick enough to be admitted to the ICU. However, their efficacy as monotherapy for less sick patients supports the consideration of either for atypical coverage when combined with a β-lactam therapy with or without a β-lactamase inhibitor in ICU patients. Most hospitalized patients will respond to these alternative empiric regimens, reducing the selection pressure for the emergence of fluoroquinolone resistance in the hospital. These alternative regimens could be applied to all patients who are sick enough to need hospitalization for CAP. However, patients who are likely to tolerate discharge from the hospital within a couple of days of receiving an effective oral regimen provide good candidates for monotherapy with a fluoroquinolone.1Siegel RE Strategies for early discharge of the hospitalized patient with community-acquired pneumonia.Clin Chest Med. 1999; 20: 599-605Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar2Palmer CS Zhan C Elixhauser A et al.Economic assessment of the community-acquired pneumonia intervention trial employing levofloxacin.Clin Ther. 2000; 22: 250-264Abstract Full Text PDF PubMed Scopus (44) Google Scholar This may facilitate conversion to outpatient therapy, reducing the risk of hospital readmission that is associated with a change in therapy, while reducing the time for the emergence of resistant strains in hospitals. As noted above, the available data suggest that monotherapy with either azithromycin27Vergis EN Indorf A File Jr, TM et al.Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.Arch Intern Med. 2000; 160: 1294-1300Crossref PubMed Scopus (125) Google Scholar or doxycycline26Ailani RK Agastya G Mukunda BN et al.Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia.Arch Intern Med. 1999; 159: 266-270Crossref PubMed Scopus (66) Google Scholar also may prove to be effective for these patients, but the data are fewer. More clinical trials comparing outcomes of patients with CAP are needed, comparing monotherapy with each of these three drug classes (ie, fluoroquinolones, azithromycin, or doxycycline) in patients who are less sick, and as two-drug regimens combined with a very broad-spectrum bactericidal agent in ICU patients. Unfortunately, there is no economic incentive for a pharmaceutical company to study doxycycline in either setting. For patients admitted to the hospital with acute bronchitis or purulent acute exacerbations of chronic bronchitis, a number of regimens may be effective. However, the published data primarily reflect studies of outpatients. In a meta-analysis of otherwise healthy individuals, erythromycin, doxycycline, or trimethoprim-sulfamethoxazole alone was recommended as a cost-effective treatment of acute bronchitis.28Bent S Saint S Vittinghoff E et al.Antibiotics in acute bronchitis: a meta-analysis.Am J Med. 1999; 107: 62-67Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Few of these patients are sick enough to be admitted to the hospital. In an analysis of cost-effective management of acute exacerbations of chronic bronchitis, drugs were grouped as“ first line” (ie, amoxicillin, trimethoprim-sulfamethoxazole, tetracyclines, and erythromycin),“ second line” (cephradine, cefuroxime, cefaclor, and cefprozil) or “third line” (amoxicillin-clavulanate, azithromycin, and ciprofloxacin) for analyses.29Destache CJ Dewan N O'Donohue WJ et al.Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis.J Antimicrob Chemother. 1999; 43: 107-113Crossref PubMed Google Scholar Trends toward better outcomes with low overall cost favored the third-line drugs in this analysis. While additional direct comparisons of classes of drugs would be more valuable, the available data do not demonstrate the clear superiority of the fluoroquinolones in this setting. As with CAP patients, these drugs may be better reserved for patients who have not responded to other antibiotics, who are known to have organisms resistant to other antibiotics, or who cannot tolerate other antibiotics, with a focus again on reducing the selection pressure for the emergence of resistant strains. The second area of potential focus is outpatient therapy. A number of reasonable alternative oral agents to treat both CAP and bronchitis are outlined above. The use of fluoroquinolones in this setting could be reasonably reserved for those patients who have not responded to treatment with other agents, who have organisms isolated that are resistant to other antibiotics, or who are intolerant of other antibiotics. This approach should decrease the pressure selecting fluoroquinolone-resistant strains among patients with recurrent exacerbations of chronic bronchitis or bronchiectasis. Fluoroquinolones may be useful for the treatment of patients who are potentially sick enough to be admitted to a hospital but who prefer a trial of outpatient therapy. This approach again would reduce the selection pressure in hospitals where resistant organisms are more readily shared. When a fluoroquinolone is selected for the treatment of CAP or bronchitis, differences in these agents merit some consideration, as is suggested by Guthrie. The newer fluoroquinolones provide more enhanced coverage for Gram-positive and atypical pathogens than ciprofloxacin, while the older ciprofloxacin provides greater efficacy for Pseudomonas species.30Blondeau JM Laskowski R Bjarnason J et al.Comparative in vitro activity of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against 4151 Gram-negative and Gram-positive organisms.Int J Antimicrob Agents. 2000; 14: 45-50Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar However, it is important to note that levofloxacin also provides very good coverage for Gram-positive and atypical infections, while maintaining very good coverage for Pseudomonas species.31North DS Fish DN Redington JJ Levofloxacin, a second-generation fluoroquinolone.Pharmacotherapy. 1998; 18: 915-935PubMed Google Scholar32Segatore B Setacci D Perilli M et al.Bactericidal activity of levofloxacin and ciprofloxacin on clinical isolates of different phenotypes of Pseudomonas aeruginosa.Int J Antimicrob Agents. 2000; 13: 223-226Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Therefore, ciprofloxacin remains the fluoroquinolone of choice for patients with known Pseudomonas infections, particularly at higher doses (eg, 750 mg bid). Levofloxacin provides a useful empiric alternative to ciprofloxacin for patients in whom the role of P aeruginosa is unclear and for whom broader coverage for atypical and Gram-positive pathogens also is desired.33Casellas JM Gilardoni M Tome G et al.Comparative in-vitro activity of levofloxacin against isolates of bacteria from adult patients with community-acquired lower respiratory tract infections.J Antimicrob Chemother. 1999; 43: 37-42Crossref Google Scholar Newer fluoroquinolones lose activity against Pseudomonas but increase activity against atypical, Gram-positive, and anaerobic pathogens. Unfortunately, the treatment of acute purulent exacerbations of chronic bronchitis with a fluoroquinolone can induce resistant isolates.3Davies BI Maesen FP Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.J Antimicrob Chemother. 1999; 43: 83-90Crossref Google Scholar Therefore, one must remain cautious regarding the use of fluoroquinolones among patients who are likely to have recurrent infections. In summary, the excellent safety and efficacy of fluoroquinolones in respiratory infections, as detailed by Guthrie, has led to the markedly accelerated use of these drugs. As with any heavily utilized antibiotic class, resistance is expected also to accelerate. Because this class appears to be so valuable for serious, persistent infections, particularly among outpatients, it would seem prudent to look for opportunities to limit the overuse of these drugs. Hopefully, these and other strategies will emerge before the utility of fluoroquinolones is too severely compromised.