In the current issue of CHEST (see page 2021),

13 MacKinnon KL, Molnar Z, Lowe D. Use of microalbuminuria as a predictor of outcome in critically ill patients. Br J Anaesth 2000; 84:239 241 14 De Gaudio AR, Spina R. Glomerular permeability and trauma: a correlation between microalbuminuria and injury severity score. Crit Care Med 1999; 27:2105 2108 Fluoroquinolones for Respiratory Infections Too Valuable To Overuse 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 -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. 1,2 Efficacy and tolerance data support their use among outpatients with exacerbations of chronic bronchitis as well. 3 Some of the older, more established fluoroquinolones, including ciprofloxacin and levofloxacin, have proven remarkably safe over time at higher doses than usually are prescribed. 4 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. 5,6 High doses of ciprofloxacin were recommended by the Infectious Diseases Society of America (IDSA) in their CAP guidelines when Pseudomonas aeruginosa infection is considered. 7 Very high doses of ciprofloxacin and levofloxacin have successfully treated persistent osteomyelitis 8 and may be useful for treatment of empyema where local concentrations exceed serum concentrations. 9,10 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) 11 and the other by the IDSA, 12 were recently published simultaneously. Readers are encouraged to seek copies of these guidelines and the accompanying editorial, 13 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 cited 11,12 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, 14 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. 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, 15 leading to the CHEST / 120 / 6/ DECEMBER, 2001 1771

Table 1 Comparison of Recent Guidelines for Empiric Initial Therapy of CAP* Variables Drugs Recommended Modifying Factors IDSA (Bartlett et al 12 ) Outpatient Hospitalized ward ICU Doxycycline, macrolide, or fluoroquinolone (no distinction) Cefalosporin (macrolide or fluoroquinolone) or; -lactam/ -lactamase inhibitor macrolide; or; fluoroquinolone alone (Cefalosporin or -lactam/ -lactamase inhibitor) (macrolide or fluoroquinolone) Older patients: many prefer fluoroquinolone Underlying disease: many prefer fluoroquinolone Prevalence high PCN resistance: consider fluoroquinolone Prior lung disease: (pseudomonal -lactam [ -lactamase inhibitor] or carbapenem) fluoroquinolone (high-dose ciprofloxacin) -lactam allergy: fluoroquinolone clindamycin Suspect aspiration: fluoroquinolone (clindamycin, metronidazole, or -lactam/ -lactamase inhibitor) CIDS/CTS (Mandell et al 11 ) Outpatient 1st choice macrolide, or 2nd choice doxycycline COPD: 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 fluoroquinolone Hospitalized ward 1st choice IV respiratory fluoroquinolone or 2nd choice (2nd-, 3rd-, or 4th-generation cephalosporin macrolide) ICU * with or without; PCN penicillin. 1st choice respiratory fluoroquinolone (cefotaxime, ceftriaxone, or -lactam/ -lactamase inhibitor) or 2nd choice IV macrolide (cefotaxime, ceftriaxone, or -lactam/ -lactamase inhibitor) Pseudomonas suspected: 1st choice antipseudomonal fluoroquinolone (eg, ciprofloxacin) (antipseudomonal -lactam or aminoglycoside) or 2nd choice triple therapy with antipseudomonal -lactam (eg, ceftazidime, piperacillin-tazobactam, imipenem, or meropenem) aminoglycoside macrolide 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. 16,17 Widespread use of fluoroquinolones among hospitalized patients has induced more frequent resistance among nosocomial pathogens. 18,19 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, 20,21 resistance is beginning to appear among pneumococci in Canada. 22 Recurrent use among patients in the community is likely to promote resistance among outpatients as well, particularly among patients with chronic bronchitis. 3,23 25 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/ CTS 11,12 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 1772 Editorials

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, 11,12 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 -lactam with or without a -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. 11,12 However, a study 26 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. 27 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 -lactam therapy with or without a -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. 1,2 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 azithromycin 27 or doxycycline 26 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. 28 Few of these patients are sick enough to be admitted to the hospital. In an analysis of costeffective 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. 29 Trends toward better outcomes with low overall cost favored the third-line drugs in this analysis. While additional direct com- CHEST / 120 / 6/ DECEMBER, 2001 1773

parisons 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. 30 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. 31,32 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 Grampositive pathogens also is desired. 33 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. 3 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. James H. Williams, Jr, MD, FCCP Orange, CA Dr. Williams is Adjunct Professor of Medicine, Internal Medicine, Pulmonary, and Critical Care, University of California, Irvine. Correspondence to: James H. Williams, Jr, MD, FCCP, Internal Medicine, Pulmonary, and Critical Care, University of California, Irvine, 101 City Drive South, Orange, CA 92868; e-mail: j2willia@uci.edu References 1 Siegel RE. Strategies for early discharge of the hospitalized patient with community-acquired pneumonia. Clin Chest Med 1999; 20:599 605 2 Palmer CS, Zhan C, Elixhauser A, et al. Economic assessment of the community-acquired pneumonia intervention trial employing levofloxacin. Clin Ther 2000; 22:250 264 3 Davies 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(suppl):83 90 4 Modai J. High-dose intravenous fluoroquinolones in the treatment of severe infections. J Chemother 1999; 11:478 485 5 Cazzola 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; 7:432 441 6 Anzueto 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; 20:885 900 7 Bartlett JG, Breiman RF, Mandell LA, et al. Communityacquired pneumonia in adults: guidelines for management; the Infectious Diseases Society of America. Clin Infect Dis 1998; 26:811 838 8 Greenberg RN, Newman MT, Shariaty S, et al. Ciprofloxacin, lomefloxacin, or levofloxacin as treatment for chronic osteomyelitis. Antimicrob Agents Chemother 2000; 44:164 166 9 Joseph J, Vaughan LM, Basran GS. Penetration of intravenous and oral ciprofloxacin into sterile and empyemic human pleural fluid. Ann Pharmacother 1994; 28:313 315 10 McLaughlin RL. Managing the nonsurgical candidate with an empyema related to community-acquired lobar pneumonia. Heart Lung 2000; 29:378 382 11 Mandell 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; 31:383 421 1774 Editorials

12 Bartlett 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; 31:347 382 13 Mandell LA. Guidelines for community-acquired pneumonia: a tale of 2 countries. Clin Infect Dis 2000; 31:422 425 14 Theerthakarai 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: 181 184 15 Niederman MS. Antibiotic therapy of exacerbations of chronic bronchitis. Semin Respir Infect 2000; 15:59 70 16 Zhang L, Li XZ, Poole K. Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system. Antimicrob Agents Chemother 2000; 44:287 293 17 Hooper DC. New uses for new and old quinolones and the challenge of resistance. Clin Infect Dis 2000; 30:243 254 18 Manhold 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 1330 19 Hanberger 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 71 20 Biedenbach 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; 36:255 259 21 Klugman KP, Gootz TD. In-vitro and in-vivo activity of trovafloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 1997; 39(suppl):51 55 22 Chen 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; 341:233 239 23 Vila 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; 43:161 162 24 Jalal S, Ciofu O, Hoiby N, et al. Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 2000; 44:710 712 25 Speciale A, Musumeci R, Blandino G, et al. Molecular mechanisms of resistance in Pseudomonas aeruginosa to fluoroquinolones. Int J Antimicrob Agents 2000; 14:151 156 26 Ailani RK, Agastya G, Mukunda BN, et al. Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia. Arch Intern Med 1999; 159:266 270 27 Vergis EN, Indorf A, File TM Jr, 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 1300 28 Bent S, Saint S, Vittinghoff E, et al. Antibiotics in acute bronchitis: a meta-analysis. Am J Med 1999; 107:62 67 29 Destache 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(suppl):107 113 30 Blondeau 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 50 31 North DS, Fish DN, Redington JJ. Levofloxacin, a secondgeneration fluoroquinolone. Pharmacotherapy 1998; 18:915 935 32 Segatore 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; 13:223 226 33 Casellas JM, Gilardoni M, Tome G, et al. Comparative invitro activity of levofloxacin against isolates of bacteria from adult patients with community-acquired lower respiratory tract infections. J Antimicrob Chemother 1999; 43(suppl):37 42 Forthcoming Articles in CHEST Atrial Mechanical Performance After Internal and External Cardioversion of Atrial Fibrillation: An Echocardiographic Study Lehmann and colleagues Editorial comment by Dunn and coauthors Costs of Occupational COPD and Asthma Leigh and colleagues Hospice Care for Patients With Advanced Lung Disease Abrahm and Hansen-Flaschen Editorial comment by Peter B. Terry Respiratory Symptoms and Nocturnal Gastroesophageal Reflux: A Population-Based Study of Young Adults in Three European Countries Gislason and coworkers Editorial comment by William C. Orr Early Treatment of Stage II Sarcoidosis Improves 5-Year Pulmonary Function Pietinalho and colleagues Editorial comment by Albert Miller CHEST / 120 / 6/ DECEMBER, 2001 1775