Source: File TM Jr, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965-1972.
File and colleagues randomized adults with community-acquired pneumonia (CAP) to receive either levofloxacin or ceftriaxone and/or cefuroxime axetil for 7-14 days. Exclusions included the presence of significant underlying immunocompromise, cystic fibrosis, a history of seizures or major psychiatric disorder, study drug allergy, pregnancy, and renal insufficiency (creatinine clearance < 20 mL/min). Patients assigned to levofloxacin therapy initially received the drug either intravenously or orally at a dose of 500 mg qd with subsequent conversion of IV to oral administration at the investigator’s discretion. Ceftriaxone was given IV in a dose of 1 or 2 g once or twice daily with, again at the investigator’s discretion, conversion to cefuroxime axetil 500 mg po bid. Patients assigned cephalosporin therapy could also be given erythromycin if "atypical" pathogens were suspected; 22% received such therapy.
Eighty-four percent had infections of mild to moderate severity, reflected in the fact that 53% were enrolled as outpatients, as well as by the low mortality rate (3.6%) of those hospitalized. The 226 levofloxacin recipients and 230 cephalosporin recipients who were clinically assessable were each treated for a mean of 11.7 days. Only 2.2% of patients in each group received solely IV administered therapy; 61% of levofloxacin recipients and 50.4% of cephalosporin recipients received only po therapy. Patients in each group received IV therapy for a mean of 3.4 days; oral levofloxacin was received for a mean of 10.6 days, while oral cefuroxime axetil was received for a mean of 10.3 days.
Clinical success at 5-7 days post-therapy was achieved in 96% of the levofloxacin and 90% of the cephalosporin group (95% CI, -10.7 to -1.3 for the difference). Streptococcus pneumoniae and Hemophilus influenzae were the most commonly detected bacterial pathogens. None of the pneumococcal isolates were highly resistant to penicillin. Bacterial eradication was achieved in all nine patients given levofloxacin and eight given cephalosporin who had pneumococcal bacteremia. The overall microbiologic eradication rates in patients with "typical pathogens" such as these for the two treatment groups were, respectively, 98% and 85% (95% CI, -21.6 to -4.8). Of levofloxacin recipients with H. influenzae infection, 100% experienced eradication of this pathogen, while only 79% of the cephalosporin recipients did so (95% CI, -39.2 to -2.5).
Approximately 150 of the cases of CAP were believed to be due (almost exclusively on the basis of serological tests) to either Chlamydia pneumoniae (101 cases), Mycoplasma pneumoniae (41 cases), or Legionella pneumophila (8 cases). The overall clinical success rate for all three pathogens combined was 99% in those given levofloxacin and 94% in those given cephalosporin therapy. The addition of erythromycin did not improve the response rate in the latter group.
COMMENT BY STAN DERESINSKI, MD, FACP
The most commonly recommended approach to the treatment of CAP, at least in patients requiring hospitalization, has been the use of a cephalosporin together with erythromycin. Such an approach is designed to provide empiric coverage by the beta lactam against the most common pathogens of CAP, including the pneumococcus and H. influenzae, with coverage of C. pneumoniae, M. pneumoniae, and Legionella spp. provided by erythromycin. Therapy of CAP with oral agents in the outpatient setting may consist of the administration of a beta lactam together with erythromycin or a macrolide with activity against H. influenzae, such as azithromycin. These approaches, however, have been compromised by the widespread prevalence of penicillin- and macrolide-resistant pneumococci. This increasing resistance is the driving force behind the need for a new approach to the management of CAP.
This study provides us with data which allow for that new approach. File and colleagues have demonstrated the superiority of therapy with a "new" fluoroquinolone, levofloxacin, over a standard approach of ceftriaxone therapy with step-down to the oral agent, cefuroxime axetil. I put the adjective "new" in quotes because levofloxacin is not, strictly speaking, a new agent since it is the levorotatory isomer of ofloxacin, a racemic mixture that has been available for a number of years in the United States. Essentially all the antibacterial activity of ofloxacin resides in this isomer. This antibacterial activity extends to all the commonly encountered respiratory pathogens, including beta-lactamase-producing H. influenzae, multiply resistant pneumococci, and the atypical pathogens, C. pneumoniae, M. pneumoniae, and Legionella. Although 37% of the levofloxacin recipients in this trial received the drug intravenously, at least initially, this route of administration is seldom necessary since its bioavailability after oral administration approaches 100%.
Thus, the use of a fluoroquinolone, such as levofloxacin, with improved activity against the pneumococcus relative to older agents appears to be the wave of the future in the management of CAP. The availability of a drug with this spectrum of activity, which can almost always be administered orally just once daily and does not interact pharmacokinetically with drugs such as theophylline, is of great value to clinicians and patients.
Other fluoroquinolones with excellent activity against respiratory pathogens have recently become available or are soon to do so. A comparison with roxithromycin in 304 patients with CAP found that sparfloxacin admistration was associated with superior results.1 However, the outcome of treatment of CAP in 167 patients randomly assigned sparfloxacin and in 175 assigned clarithromycin was 89% in each group.2 Separately, 808 patients with CAP were randomized to receive either sparfloxacin, amoxicillin-clavulanic acid, or erythromycin. The success rates for these regimens, 87%, 80% and 85%, respectively, were not significantly different.3 The major concerns about the use of sparfloxacin are its association with QT interval prolongation and its phototoxicity. In the study comparing sparfloxacin to roxithromycin, QT interval prolongation was observed in 3% of recipients of the fluoroquinolone and in 1% of macrolide recipients.1 The incidence of photosensitivity in sparfloxacin recipients in that study was only 5%, but the study was performed in Scandinavia and, if it was performed in the winter, as most pneumonia studies are, the affected subjects must have been using tanning booths.
Grepafloxacin, likely to reach market in the United States in the near future, also has good activity against respiratory pathogens in vitro and has been shown to be associated with outcomes similar to those observed with comparator regimens in randomized trials. These comparators include cefaclor, clarithromycin, and ofloxacin.4-6 Trovafloxacin is a novel quinolone with excellent activity against respiratory pathogens and with the added potential benefit of significant in vitro activity against anaerobic bacteria. In a recently presented study, 443 adults with CAP were randomized to receive either IV alatrovafloxacin (a trovafloxacin prodrug) followed by oral trovafloxacin 200 mg qd or IV ceftriaxone followed by oral cefpodoxime with optional IV/oral erythromycin. The clinical success rates at the end of treatment were, respectively, 90% and 87%.7 In another study, ambulatory patients with CAP experienced comparable results whether randomized to trovafloxacin or clarithromycin.8
Ciprofloxacin has been demonstrated to be as effective as imipenem in the treatment of severe pneumonia in hospitalized infections.9 However, 78% of those infections were nosocomially acquired, and the pneumococcus was an infrequently recovered pathogen. It is, of course, its marginal in vitro activity against the pneumococcus that has given pause to most infectious disease specialists (if not to the most other physicians) with regard to the use of ciprofloxacin in the treatment of community-acquired respiratory tract infections. It is possible that this concern will be overcome by planned comparative trials using "high dose" ciprofloxacin.
One of the puzzles presented by the results of the comparative study of the efficacy of levofloxacin reviewed here was the apparent lack of improved outcome in the patients assigned to cephalosporin therapy and thought to be infected with "atypical" pathogens. One reason for this may be misdiagnosis as the result of inaccurate serological techniques and criteriaa not inconsiderable problem, particularly with regard to C. pneumoniae infections. Another is the possibility that C. pneumoniae infections may, in fact, be responsive to beta-lactam therapy, as has been suggested previously.10 This would not be surprising, given evidence that some genital Chlamydia trachomatis infections may respond to treatment with amoxicillin.11
If there is a defect in the study reviewed here, it is the fact that it dealt with relatively mild disease in patients without life-threatening underlying disease, judging from the low mortality rates reported. Nonetheless, this study should provide the clinician with confidence in the use of levofloxacin in the empiric treatment of most patients with CAP. This information is invaluable at a time when we are increasingly encountering pneumococci that are resistant to macrolide antibiotics and to many beta-lactams.
References
1. Ortqvist A, et al. Chest 1996;110:1499-1506.
2. Ramirez J, et al. A comparative study of sparfloxacin and clarithromycin in the treatment of outpatients with community acquired pneumonia. IDSA 35th Annual Meeting, San Francisco, September 13-16, 1997, Abstract 394.
3. Lode H, et al. Eur Respir J 1995;8:1999-2007.
4. Adams M, et al. Comparison of grepafloxacin with cefaclor in the treatment of community-acquired pneumonia. 37th ICAAC, Toronto, Ontario, Canada, September 28-October 1, 1997. Abstract LM-68.
5. Patel T, et al. Comparison of grepafloxacin with clarithromycin in the treatment of community-acquired pneumonia. 37th ICAAC, Toronto, Ontario, Canada, September 28-October 1, 1997. Abstract LM-69.
6. Kobayashi H. A Multicenter, double-blind comparative study of grepafloxacin versus ofloxacin in the treatment of pneumonia. 37th ICAAC, Toronto, Ontario, Canada, September 28-October 1, 1997. Abstract L018.
7. Niederman M, et al. A double blind, randomized, multicenter, global study in hospitalized community acquired pneumonia comparing trovafloxacin with ceftriaxone + erythromycin. 37th ICAAC, Toronto, Ontario, Canada, September 28-October 1, 1997. Abstract LM-72.
8. Sullivan J, et al. A double blind, randomized, multicenter study in ambulatory community acquired pneumonia (CAP) comparing trovafloxacin with clarithromycin. 37th ICAAC, Toronto, Ontario, Canada, September 28-October 1, 1997. LM-73.
9. Fink MP, et al. Antimicrob Agents Chemother 1994;38:547-557. (See Infect Dis Alert 1994;13: 137-139.)
10. Kauppinen MT, et al. Thorax 1996;51:185-189.
11. Toomey KE, Barnes RC. Rev Infect Dis 1990;12Suppl6: S645-655.
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