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Legionella: macrolides or quinolones?L. Pedro-Botet1 and V. L. Yu2 1Infectious Diseases Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma deBarcelona, Barcelona, Spain and 2Infectious Disease, Veterans Affairs Medical Center and University ofPittsburgh, Pittsburgh, PA 15240, USA Following the first outbreaks of legionnaire’s disease, erythromycin emerged as the treatment of choicewithout the foundation of rigorous clinical trials. The number of therapeutic failures with erythromycin,as well as the side-effects and drug interactions, led to the consideration of other drugs such as the newmacrolides and quinolones for the treatment of legionnaire’s disease in the 1990s. In this article, 19studies in in-vitro intracellular models and seven animal studies that compared macrolides toquinolones were reviewed. Quinolones were found to have greater activity in intracellular models andimproved efficacy in animal models compared with macrolides. No randomised trials comparing theclinical efficacy of the new macrolides and new quinolones have ever been performed. Threeobservational studies totalling 458 patients with legionnaire’s disease have compared the clinicalefficacy of macrolides (not including azithromycin) and quinolones (mainly levofloxacin). The resultssuggested that quinolones may produce a superior clinical response compared with the macrolides(erythromycin and clarithromycin) with regard to defervescence, complications, and length of hospitalstay. Little data exist for direct comparison of quinolones and azithromycin.
azithromycin, clarithromycin, legionella, levofloxacin, macrolides, quinolones, review Clin Microbiol Infect 2006; 12 (Suppl. 3): 25–30 this practice which soon became commonplace.
Its interaction with the metabolism of numerous Controlled trials of antibiotics for the treatment of drugs, as well as the adverse effects of fluid legionnaire’s disease have never been conducted overload and ototoxicity because of high doses, for a number of reasons. In the American Legion also became problematic. In the 1990s the newer outbreak of 1976, patients treated with erythro- macrolides (azithromycin, clarithromycin, roxith- mycin and tetracycline fared better than those romycin) and quinolones were introduced, with treated with other antibiotics (especially b-lactam notably greater in-vitro activity than erythromy- antibiotics) [1]. Subsequent experience with hos- cin. Quinolones were shown to be more active pital-acquired legionnaire’s disease also sugges- than any macrolides for Legionella in in-vitro ted the superiority of erythromycin over other studies, intracellular models, and animal models, antibiotics [2,3]. Thus, erythromycin emerged as but it was unclear whether this superiority would the drug of choice based on anecdotal experience be translated into clinical practice.
The intracellular location of the pathogen On the other hand, treatment failures with proved to be relevant to the efficacy of the erythromycin [5–7] led to the empirical practice of antibiotic. Specifically, antibiotics capable of increasing the dose of erythromycin (from 500 mg achieving intracellular concentrations higher than to 1 gram four times a day) and the addition of the MIC were more clinically effective than rifampin; no data were ever generated to support antibiotics with poor intracellular penetration[8]. For example, erythromycin and rifampinwere able to prevent death in guinea pigs inocu- Corresponding author and reprint requests: V. Yu, VA Medical lated intraperitoneally with large numbers of Center, Infectious Disease Section, University Drive C, Pitts- Legionella. On the other hand, antibiotics with Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases 26 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 chlorampheniciol, tetracycline, and gentamicin) order to compare those who received macrolides were ineffective in preventing death [9,10]. Thus, (n = 65) and those who received levofloxacin the theoretical basis for the empirical observation (n = 143). Mykietiuk et al. [16] conducted a pros- that macrolides, quinolones, tetracyclines, and pective, observational series of 1934 consecutive rifampin were more likely to be efficacious was cases of community-acquired pneumonia in non- supported by a biological rationale since these immunocompromised adults [16]. One hundred antibiotics achieved relatively high intracellular and thirty-nine cases of legionnaire’s disease were diagnosed. Patients were classified into two groups The recommendation of the use of macrolides based on therapy: macrolides (n = 80) or levofl- such as azithromycin as preferred therapy was oxacin (n = 40) therapy. Sabria et al. [17] conducted introduced in the first North American consensus a retrospective observational multicentre study of guidelines for empirical therapy of patients with legionnaire’s disease that included 76 patients who community-acquired pneumonia [11–13]. Quino- received macrolides and 54 patients who received lones also became widely used for community- fluoroquinolones (50 levofloxacin and four ofloxa- acquired pneumonia because of their activity against Legionella pneumophila and the spectre of When the results of all studies were combined: penicillin-resistant pneumococci [14] (a fear 51.2% (128 ⁄ 250) were smokers [16,17]; 23.6% which is now known to be unjustified).
(59 ⁄ 250) had chronic pulmonary diseases [16,17];44.1% (202 ⁄ 458) had no underlying diseases; 6.9%(32 ⁄ 458) required ICU admission [15–17]. No S U S C E P T I B I L I T Y T E S T I N G significant differences were found among the three Dilutional tests of in-vitro susceptibility in agar or studies concerning age, sex, cigarette smoking, broth have correlated poorly with clinical out- chronic lung diseases, and severity of pneumonia come since they measure extracellular suscepti- for the two treatment groups (macrolides and bility. Thus, intracellular models and animal quinolones). Unlike the studies of Garrido and studies have supplanted the standard tests for Mykietiuk, immunosuppressed patients (13%) antimicrobial susceptibility testing. In 19 studies and cases of hospital-acquired legionnaire’s dis- in in-vitro intracellular models of Legionella sus- ease (17.6%) were included in the multicentre ceptibility, quinolones were consistently more study by Sabria` et al. [17]. Forty-five per cent active than macrolides (Table 1). Likewise, in (205 ⁄ 458) were diagnosed according to antibody seven comparative studies performed in animal seroconversion [15,16], 85.1% (390 ⁄ 458) according models, quinolones were superior to macrolides to urinary antigen test positivity for L. pneumophila serogroup 1 [15–17], and 9.3% (43 ⁄ 458) accordingto isolation from culture [16].
Time to defervescence was notably shorter in C O M P A R A T I V E C L I N I C A L S T U D I E S patients receiving levofloxacin in two studies Comparative antibiotic studies have not been [16,17]. The mean time was 97.7 h for patients performed because, in the early years following receiving macrolides and 66.6 h for those receiv- discovery of legionnaire’s disease, patients were ing levofloxacin in the three studies. Length of identified mainly in outbreaks, making it difficult hospital stay was significantly shorter for patients to perform a controlled trial. Patients with hospi- treated with levofloxacin in all three studies. The tal-acquired legionnaire’s disease were not stud- mean hospital stay for all three studies was ied because disinfection of the drinking water 9.0 days for patients receiving macrolides and reservoir was ethically required upon discovery 6.6 days for the levofloxacin group. Patients of cases; following disinfection, subsequent cases receiving levofloxacin had fewer complications were unlikely to occur. Nevertheless, three obser- (8.4%, 20 ⁄ 237), as defined by pleural effusion, vational studies have addressed the comparative empyema, cavitation, septic shock, and mechani- efficacy of quinolones and macrolides.
chal ventilation, than those receiving macrolides Blazquez et al. [15] conducted an observational, prospective study of 292 patients with L. pneumonia The incidence of treatment-related adverse during the Murcia, Spain outbreak. Patients were events was 23.4% (34 ⁄ 145) for patients receiving stratified according to the severity of pneumonia in macrolides and 12.5% (23 ⁄ 183) for those receiving Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 3), 25–30 Table 1. Activity of quinolones vs. macrolides in intracellular models Cipro > Amflo > Cino> Enox > Roso > Ery inhibited growth of Lp at concentrationsof 1 mg ⁄ L, but only WIN 57273 preventedregrowth or killed Lp after removalof extracellular antimicrobial agent.
AT-4140 > Roxi > Oflo = Cipro > Ery (2) Levo was slightly less active than Cipro (3) Levo and Oflox were more active than Ery Levo and Ery produced effective inhibition on Lp. The delay of regrowth with Erywas < 30 min The delay of regrowthwith Levo was > 72 h human monocytes,the continued suppressionof Lp was greater than that for Ery Quinupristin ⁄ dalfo > Ery > Diritho (Levo, Gati, Moxi) > Ery Lp: Moxi > Q(Gemi, Levo, Gati) > Ery the other quinolones againstL. micdadei. The PAE of Gemiagainst Lp was dose dependent Lp, serogroups 1–15 1) Q > Ketolides > M (2) Levo > Moxi > Gemi > Grepa > Cipro > Trova > Ery (3) Ketolides > Azi > Clari > Ery Azithro > Ery Levo > Moxi > Gemi > Lp, Legionella pneumophila; Azi, Azithromycin; Clari , Clarithromycin; Roxi, Roxithromycin; Ery, Erytromycin; Levo, Levofloxacin; Moxi, Moxifloxacin;Cipro, Ciprofloxacin; Clina, Clinafloxacin; Grepa, Grepafloxacin; Gemi, Gemifloxacin; Oflox, Ofloxacin; Trova, Trovafloxacin; Amflo, Amifloxacin; Enox, Enoxacin;Cino, Cinoxacin; Roso, Rosoxacin; M, Macrolides; Q, Quinolones; PAE, Post antibiotic effect.
levofloxacin. Phlebitis was the most frequent oxacin group. In summary, the results from these adverse effect, but none of the affected patients three observational studies [15–17], totalling 458 patients with legionnaire’s disease, suggested that The delay until the initiation of an appropriate levofloxacin may produce a superior clinical antibiotic treatment was only noted in the Sabria` response compared with macrolides for end- study and was not significantly different in the two groups (78.5 h for the macrolide group vs. 92.7 h (Table 3); however, the mortality rate was similar.
for the quinolone group). The time in whichintravenous administration of antibiotics was switched to oral therapy was significantly shorterin the quinolone group (3.8 days in the quinolone As mentioned, none of the above studies were group vs. 5.3 days in the macrolide group) [16,17].
randomised trials, so biases could easily have The overall mortality was 4.5% (10 ⁄ 221) for the been present. Multiple subgroup analysis was macrolide group and 2.1% (5 ⁄ 237) for the levofl- suggested as a flaw in the statistical analysis of Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 3), 25–30 28 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 Table 2. Activity of macrolides compared with quinolones in animal models but lung cultures from survivorswere significantly more frequentlypositive for Lp in the Ery-treated animals reducing the incidence of lesionsand for prolonging embryo viability Azithro, Azithromycin; Levo, Levofloxacin; Cipro, Ciprofloxacin; Oflox, Ofloxacin; Ery, Erythromycin; Peflo, Pefloxacin; Gemi, Gemifloxacin; Spar, Sparfloxacin; Josa,Josamycin; Trova, Trovafloxacin.
Table 3. Clinical response of macrolides compared with quinolones in three observational studies NA, not available; n, number of patients; M, macrolides; Q, quinolones.
the Blazquez study [19], although we agree with mycin is more active than clarithromycin and the authors of the study that the endpoints of erythromycin in intracellular models (Table 1).
outcome showed a consistent trend toward the And, in one intracellular model [40] and one superiority of levofloxacin. Forty-eight patients animal study [46], azithromycin was comparable in the macrolide group in the Mykietiuk study to the quinolones tested. So, the issue of the also received rifampicin but these patients were superiority of quinolones over azithromycin has not analysed separately, although it would seem that this inclusion should not lead to a bias A surprising 0% mortality was the case for 75 against macrolides. The doses of quinolones used patients receiving levofloxacin for legionnaire’s in the three studies were not controlled. The disease in six clinical trials performed for the US starting doses of levofloacin until defervescence Food and Drug Administration (FDA) approval of were higher (500 mg every 12 h) in the Sabria` levofloxacin [18]. This was the largest antibiotic study than the standard doses usually recom- study ever published of patients with commu- mended (500 mg once a day). Treatment failures nity-acquired pneumonia in which legionnaire’s using low doses of ofloxacin [20] or ciprofloxacin disease was identified; not a single death was A more severe limitation, in our opinion, was that the title of each of the three articles used theencompassing term ‘macrolides’. Clarithromycin The advantages of choosing a quinolone over a was the predominant macrolide used in treating macrolide for treatment of legionnaire’s disease in the patients with severe pneumonia in the Blaz- immunocompetent patients with community-ac- quez study, clarithromycin and erythromycin in quired pneumonia may be a shorter time to the Mykietiuk study, and erythromycin in the defervescence with a more rapid achievement of Sabria` study. Azithromycin was not included in clinical stability, followed by shorter hospital stay.
any systematic comparison; this is pertinent in Reduction in hospital stay of only 1 day can that numerous studies have shown that azithro- reduce healthcare costs by a notable amount.
Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 3), 25–30 Until definitive studies are performed, how 13. Niederman MS, Mandell LA, Anzuelo A et al. Guidelines should the clinician manage patients? Based on for the management of adults with community-acquiredpneumonia. Diagnosis assessment of severity, antimicro- bial therapy, and prevention. Am J Respir Crit Care Med animal studies and observational studies, we suggest that quinolones might warrant prefer- 14. Yu VL, Chiou CCC, Feldman F et al. An international ence over macrolides in compromised hosts with prospective study of pneumococcal bacteremia: Correla- severe infections who are critically ill. Respirat- tion with in vitro resistance, antibiotics administered andclinical outcome. Clin Infect Dis 2003; 37: 230–237.
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Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 3), 25–30


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