New role of quinolones in respiratory tract infections

role in Because of limited activity of the standard quinolones such as ciprofloxacin and ofloxacin against some clinically imponanr or ganisms includingStreptococrns pneumoniae and methicillin-resistantStap/rylococcus aureus, new quinolones have been de veloped. In addition to their improved activity againstS pnewnoniae, some also demonstrate excellent anaerobic activity. None of the quinolones have a role to play in the treatment of paediatric infections. Quinolones (both older and newer agents) have demonstrated equivalent efficacy to standard antimicrobials in the treatment of acute sinusitis. Several groups have suggested that quinolones are excellent agents in the treatment of high risk patients with acute exacerbations of chronic bronchitis. These patients include the elderly, and those with frequent exacerbations, significant co morbid conditions. long duration of chronic bronchitis and major impairment of lung function. There is no evidence to suggest that the newer quinolones will differ from the currently available agents for this disease. The major advantage of the newer quinolones appears to be in the treatment of pa tients with community-acquired pneumonia where pneumococcal infection is a real concern. A new parenteral quinolone with pneumococcal activity may replace the standard macrolide/cephalosporin combination that is commonly prescribed. For pa tients with nosocomial pneumonia, the newer agents are alternative choices, especially among patients with early onset pneu monia (less than five days of hospitalization), but are unlikely to replace ciprofloxacin in the intensive care unit setting because of poor Pseudomonas aeniginosa coverage.


UPPER AIRWAY INFECTIONS
Quinolones do not play a role in the treatment of pharyngitis or simple otitis media. Because the new fluoroquinolones have safety profiles similar to the older quinolones , it is unlikely that they will be used in the treatment of these mainly paediatric disorders. Fluoroquinolones have been used in the treatment of acute and chronic sinusitis, chronic otitis media and malignant external otitis. Haemophilus ir!fluenz ae, S pneumoniae and Moraxella catarrhalis are the principle pathogens in acute sinusitis (4,5) ( Table 1). The role of antibiotics in the treatment of acute maxillary sinusitis has been questioned. In a recent placebo-controlled trial, antibiotic treatment did not improve the clinical course of patients with acute maxillary sinusitis presenting to physicians in a primary care setting (6) . Others have demonstrated that patients suffering from the common cold, who also have respiratory pathogens (H ir!fluenzae, M catarrhalis, S pneumoniae) isolated from nasopharyngeal secretions, benefit clinically from the administration of antibiotics (7). Until recently, the available fluoroquinolones were not indicated for the treatment of acute purulent sinusitis because of their perceived inactivity against S pneumoniae (8). While not generally considered to be the drugs of first choice, older quinolones have comparable efficacy to cephalosporins and beta-lactams in randomized clinical trials (9). In the treatment of chronic bacterial sinusitis, ciprofloxacin has been reported to be as effective as amoxicillin/clavulanic acid, with clinical resolution and/or improvement reported in more than 80% of patients in both groups (10). The newer fluoroquinolones have been studied in 36E patients with acute bacterial sinusitis because of the drugs' improved activity against all respiratory pathogens. In a double-blind , multicentre trial , 382 patients with acute purulent sinusitis were treated with either sparfloxacin or cefuroxime axetil (11) . The success rates were 82.6% and 83 .2%, respectively; the success rates in the subset of patients with S pneumoniae as the offending pathogen were equivalent (89.5% for sparfloxacin versus 92 .3% for cefuroxime axetil). Clinical trials with grepafloxacin and trovafloxacin are in progress, but similar success rates can be expected.
Pseudomonas aeruginosa, S aureus and Proteus mirabilis are the main pathogens identified in patients with chronic otitis media , a disease characterized by mucopurulent otorrhoea (12) . Patients receiving ciprofloxacin for this indication had a significantly higher clinical response and bacteriological cure rate than patients receiving amoxycillin/clavulanic acid ( 13). It is difficult to imagine that the new quinolones will improve on this performance because their activity against P aeruginosa is less than that observed with ciprofloxacin. Malignant external otitis, a disease caused by P aeruginosa, occurs in elderly diabetic patients and can lead to osteomyelitis of the base of the skull (14). Treatment of this syndrome with ciprofloxacin has been associated with excellent clinical and bacteriological responses and shorter hospital stays, although controlled clinical trials have not been performed (15 , 16). Given these observations, it seems prudent to continue to recommend ciprofloxacin as the best agent for these disorders.

LOWER RESPIRATORY TRACT INFECTIONS
Acute exacerbations of chronic bronchitis: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and continues to afflict 20% of the population despite public education about the risks of smoking ( 17,18) . The mortality rate from this disease has increased, while mortality rates from coronary artery disease, stroke and all other causes of death have declined ( 19) . Acute bronchitis and acute exacerbations of chronic bronchitis (AECB) are common illnesses encountered by general and family physicians, and account for approximately 14 million physician visits per year in the United States (20,21 ). In Europe, more than 80% of all lower respiratory trace infections are treated with anLibiotics (22) . Most physicians do not differentiate acute bronchitis, AECB , community-acquired pneumonia (CAP) and viral respiratory tract infections. The pattern of antibiotic prescribing for these infections varies from country to country, but there is no clear rationale for antimicrobial choices (23) . For example, penicillins are used most frequently in the United Kingdom, tetracyclines in Germany, but third-generation oral cephalosporins predominate in Italy. All countries use quinolones in roughl y the same proportion.
An acute exacerbation of COPD is usually defined as an episodic respiratory decompensation without an objectively documented cause, such as pneumonia. It is characterized clinically by increased cough and sputum production, purulence, and dyspnea. Many of these patients are treated with antibiotics , but the efficacy of this treatment has been questioned (24). Patients with at least two of these symptoms have a better outcome and improve more quickly if treated with an antibiotic than with placebo (25). A large study conducted in Italy confirmed the beneficial role of antibiotics, and a recent meta-analysis indicated a small but statistically significant overall benefit in antibiotic-treated patients (26,27). Bacterial pathogens are cultured from lower respiratory secretions in approximately 50% of patients (28). Other pathogens, such as viruses and bacterial pathogens (for example, chlamydia or mycoplasma), are responsible for a further 20% to 30% (29,30). In bacteriologically defined exacerbations, H ir;Jluenzae is the most commonly isolated organism (31-36) ( Table 2). More recent data indicate that M catarrhalis is the second most common pathogen while S pneumoniae is next in frequency (37). New evidence suggests that Haemophilus parairyluenzae, an organism usually assumed not to be a pathogen, may also be significant (38 In a more recent survey conducted between 1994 and 1995, the percentage of H ir!/luenzae strains producing betalactamase increased to 36.4% (43). Another 2.5% of H iryluenzae isolates were beta-lactamase negative, but ampicillinresistant. Beta-lactamase producing M catarrhalis increased to 95.3% of all isolated strains, while the overall frequency of penicillin-resistants pneumoniae increased to 23.6% (44.45) . Overall. 14.1 % of S pneumoniae isolates demonstrated intermediate resistance, while 9.5% demonstrated high level resistance. Of particular concern was the observation that 9.1 % of strains demonstrated multiple drug resistance.
In managing COPD, it may be advantageous to define a target population at risk based upon severity of disease, as has been done for patients with pneumonia (46). An aggressive approach to the treatment of exacerbations ofCOPD in this target population may lead to improved outcomes. Risk  To demonstrate the potential advantages of using quinolones in this group of patients, high risk patients with at least two new respiratory symptoms (increased cough , increased sputum volume, and purulence and dyspnea) should be included (60). In a recently completed study, patients with at least three treated exacerbations in the previous year were randomly assigned to receive either ciprofloxacin or any nonquinolone-based antimicrobial therapy for their next acute exacerbation of chronic bronchitis (61) . In this prospective, health economic study, clinical end-points (days of illness , hospitalizations, time to next exacerbation) were blended with quality of life measurements (Nottingham Health Profile, St George's Hospital Respirato1y Questionnaire, Health Utility Index) and total respiratory costs from a societal perspective. While the overall results indicated no preference for either treatment arm , the use of ciprofloxacin led to improved clinical outcome, higher quality of life and less costs in patients with risk factors (severe underlying lung disease, more than four exacerbations per year, duration of bronchitis greater than LO years, elderly, significant comorbid illness). The results of this study suggest that aggressive antimicrobial therapy directed toward resistant organisms in high risk patients is a more effective strategy than no therapy or therapy with older antimicrobials, which would not be effective against beta-lactamase producing H i,Jjluenzae or M catarrhalis.
There is considerable interest in examining the role of the newer quinolones because these have an excellent spectrum against the pathogens usually found in acute exacerbations of chronic bronchitis. In a randomized, multicentre, open label trial , levotloxacin 500 mg once daily for five days was compared with cefuroxime axetil 250 mg twice daily for 10 days (62). Clinical improvement (greater than 90%) and microbiological eradication rates (greater than 90%) were similar in both groups. In a randomized, prospective, double-blind trial, grepatloxacin in two doses, 400 mg once daily or 600 mg once daily for 10 days, was compared with ciprotloxacin 500 mg bid for 10 days. The findings indicated that a 10-day course of either dose of grepatloxacin was as effective, clinically and bacteriologically, as ciprofloxacin (63). Preliminary data suggest that the new fluoroquinolones will be as effective as the older quinolones in patients with AECB. Whether there will be any additional advantage over the older agents quinolones is yet co be determined.
CAP: Pneumonia is the sixth most common cause of death in the United States and accounts for approximately 10 million physician visits , 500 ,000 hospitalizations and 45,000 deaths in the United States (64)(65). The most recent Canadian, American and British published guidelines do not recommend quinolones for the treatment of CAP mainly because of the concern about adequate coverage of S pneumoniae (46,66,67). Only the Infectious Diseases Society of America guidelines for the management of CAP recommend the new ' respiratory' quinolones as an alternative single agent in the treatment of these patients (68).
Older quinolones used as monotherapy for CAP have good clinical results. In a study of hospitalized patients with CAP, ofloxacin was as effective as a standard regimen consisting of a beta-lactam with or without a macrolide (69). In a recent randomized , double-blind, parallel group study of patients with mild to moderate CAP, patients receiving sparfloxacin had similar outcomes as those receiving either amoxycillin/clavulanic acid or erythromycin (70). In another study of patients with mild to moderate CAP, levofloxacin had a higher clinical success rate and microbiological eradication rate compared with ceftriaxone and/or cefuroxime axetil (71 ). In patients with life-threatening CAP, one suggested regimen includes a quinolone in combination with an aminoglycoside and macrolide as initial empirical therapy until the results of microbiological investigations are available (46). Oral fluoroquinolones have also been recommended as acceptable alternatives to macrolides for Legionnaires ' disease and probably for Mycoplasma pneumoniae and Chlamydia pneumoniae infections (72) .
In an open label study, grepafloxacin 600 mg once daily was highly effective in the management of patients with CAP, including patients with S pneumoniae, H i1ifluenz ae , M pneumoniae and Legione//a pneumophi/a as the causative pathogens (73). Registration studies have indicated that the eradication of pneumococci from sputum in patients with CAP is greater than 90% and comparable with amoxycillin, cefaclor and clarithromycin (73). In these same studies , the eradication rate for H ir!fluenz ae was greater than 90% and better than amoxycillin, cefaclor and clarithromycin .
The current American Thoracic Society and Canadian Consensus Conference Group guidelines for the management of out-patients with CAP suggest a macrolide or tetracycline as 38E first-line therapy, particularly in young patients without significant comorbidity (46 ,66). Given the spectrum of the new fluoroquinolones , their ability lO penetrate extremely well into lung tissue and the limited supportive clinical data , these compounds should be considered as possible alternatives in the management of these patients. Both documents also recommend either a cephalosporin as a single agent or the combination of a macrolide and cephalosporin for hospitalized patients . Quinolones that can be administered parenterally (levofloxacin, trovafloxacin) may be alternative choices to combination therapy. More data are required to define the role in this setting adequately, but cost considerations will likely be very important in the final decision to use these agents. Nosocomial pneumonia: Gram -negative organisms and S aureus are the most commonly isolated pathogens in patients with nosocomial pneumonia (75 -77). In the recently published American Thoracic Society statement on the treatment of hospital-acquired pneumonia (78), patienLs were stratified according to the time of onset, presence of specific risk factors and severity of pneumonia. Among patients with early onset pneumonia (less than five days hospitalization), the likely pathogens are enteric Gramnegative rods, H i1ifluenz ae, methicill in -sensitive S aureus and S pneumoniae. A fluoroquinolone is recommended only for patients allergic to penicillin. Among patients with severe hospital -acquired pneumonia, P aeruginosa or Acinetobacter species become a serious consideration. Because of the emergence of multi ply resistant aerobic Gramnegative bacilli, a fluoroquinolone is recommended in combination with a beta -lactam agent , especially a thirdgeneration antipseudomonal cephalosporin , a betalactam/ beta-lactamase inhibitor or an antipseudomonal penicillin. In the absence of P aeruginosa , monotherapy with a quinolone has been demonstrated to be as effective as treatment with third-generation cephalosporins or imipenem (79,80). Monotherapy with high dose ciprofloxacin was compared with monotherapy with high dose imipenem/cilastatin in patients with severe pneumonia. Ciprofloxacin was associated with a better clinical response and an enhanced eradication rate of Enterobacter species. If P aeruginosa was present, neither regimen performed particularly well and resistance developed frequently during therapy. It is possible to step down to oral tluoroquinolone therapy once an adequate clinical response has been demonstrated to initial intravenous therapy (81).
The new fluoroquinolones are active against the usual pathogens causing nosocomial pneumonia. With the exception of trovafloxacin, they demonstrate relatively poor activity against P aeruginosa. Because of the importance of this pathogen, particularly in an intensive care unit setting, ciprofloxacin will likely remain an important agent. These newer agents will be alternative choices for the management of early onset nosocomial pneumonia among patients without specific risk factors . Agents with anaerobic coverage (trovafloxacin , moxifloxacin) may be considered in patients suspected of having anaerobic lung infection (post-thoracoabdominal surgery , witnessed aspiration).

SUMMARY
Fluoroquinolones are important broad spectrum antimicrobials used in a wide variety of upper and lower respiratory tract infections. With the introduction of the new 'respiratory' quinolones with improved antipneumococcal activity, their role will undoubtedly expand into the treatment of CAP and nosocomial pneumonia. Whether they will provide additional benefits to our present armamentarium remains to be proven.