The treatment of Legionnaires' disease

Martin Dedicoata and Pradhib Venkatesanb,*

a Department of Clinical Infection, City General Hospital, North Staffordshire Hospitals NHS Trust, Stoke on Trent ST4 7LN; b Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK

Introduction

The Legionellaceae family contains over 40 recognized species, but less than half of these cause disease in humans. The most frequently pathogenic species is Legionella pneumophila, of which there are 14 serogroups. L. pneumophilaaccounts for 90% (and serogroups 1- 6 for 85%) of all infections. Other important species include Legionella micdadei, Legionella bozemanii, Legionella dumoffii and Legionella longbeachae.The principal clinical illness is pneumonia (Legionnaires' disease), although L. pneumophila has also been implicated in cases of endocarditis and myocarditis, and in haemodialysis infections.

Treatment recommendations for Legionnaires' disease are largely based on clinical experience of the first recognized outbreak in Philadelphia in 1976; in a retrospective review, patients treated with erythromycin or tetracycline had a 50% lower mortality rate compared with patients treated with ß-lactams.1 Subsequently, erythromycin became the treatment ofchoice. More recently, a number of new antimicrobial agents have appeared, but formally assessing their comparative efficacy in treatment has proved difficult. No prospective controlled trials of therapy have been performed.

Assessment of antimicrobials

Assessment of the efficacy and potential utility of antimicrobials against Legionellaspp. is based on four methods. First, in-vitro susceptibility testing can be performed to screen for active agents. Legionella spp. may be grown in either buffered yeast extract (BYE) broth or buffered charcoal- yeast extract (BCYE) agar, both supplemented with {alpha}-ketoglutarate. The MICs of an antibiotic can vary between these growth media. A number of antimicrobials, including ß-lactams, are highly active in vitro. However ß-lactams do not penetrate the intracellular compartment and as legionellae are intracellular pathogens in vitro, extracellular susceptibility does not always correspond to in-vivo activity.

Second, L. pneumophila has been cultivated in vitroin a number of cell lines in order to assess the intracellular activity of antimicrobials. The cells used have included guinea pig alveolar macrophages, human monocytes or macrophages, HeLa and HL-60 cells. Results obtained with this method generally give a good correlation with animal studies. One exception is gentamicin, which is active against bacteria grown in cell lines but inactive in animal models and human disease. A disadvantage of this method is that it is time consuming and expensive, although more efficient systems are being developed. 2

Third, guinea pigs develop severe pneumonia when L. pneumophilais introduced into their lower respiratory tract by aerosol and so they can be used as an animal model to assess antimicrobials. Some studies have also used intraperitoneal infection in guinea pigs. Clinical efficacy in humans has corresponded to efficacy in the animal respiratory tract model.

Finally, clinical studies have been attempted but these have largely been case series and retrospective analyses. They suffer from being small studies, usually not controlling for severity of disease and often concentrating on severe hospitalized cases. This makes it difficult to evaluate the findings with regard to mild, community-acquired cases. It has been calculated that around 900 cases would be needed in each treatment arm of a trial on community-acquired pneumonia to demonstrate a 50% reduction in mortality by use of an antimicrobial agent. 3 However, Legionnaires' disease is not common, with c. 200 confirmed cases per year in England and Wales, 4 and there is often a delay in making the diagnosis until after empirical treatment is completed. For these reasons a large, prospective controlled trial has not been performed and is unlikely to happen.

On the basis of studies using these four methods the efficacy of major classes of antimicrobials is reviewed below. Many studies have concentrated on L. pneumophila, but there is evidence that other Legionella spp. are equally susceptible. This review will focus on L. pneumophila, and the MICs of a variety of antimicrobials are shown in the Table.


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Table. MIC values for a range of antimicrobials against L. pneumophila on in-vitro, extracellular susceptibility testing
 
Macrolides

Amongst the macrolides most experience has been gained with erythromycin. However, by in-vitro extracellular, testing it is less active than clarithromycin, azithromycin and roxithromycin, although more active than dirithromycin and josamycin (Table). In some comparative studies clarithromycin has been more active than azithromycin 5,6 but generally azithromycin has been shown to be the more active. Within HL-60 cells azithromycin achieves the greatest inhibition of growth of L. pneumophila, followed in order of activity by erythromycin, roxithromycin, dirithromycin and clarithromycin. 7 Within guinea pig alveolar macrophages azithromycin inhibits growth of L. pneumophila more effectively than erythromycin. 8 Azithromycin also exerts a post-antibiotic effect in these alveolar macrophages: after azithromycin in high concentrations (5 mg/L) is washed out, regrowth of L. pneumophila is inhibited for a further 5 days. In this model azithromycin is also bactericidal, whereas erythromycin is only bacteriostatic.

In the guinea pig model of pneumonia azithromycin concentrations in infected lung reach 13.4 mg/L. 9 After 48 h of treatment the concentration of azithromycin within alveolar macrophages is 582 times the extracellular concentration and this is fivefold greater than the concentration of erythromycin. In L. pneumophila-infected guinea pigs the use of azithromycin, 3.6 mg/kg, leads to 100% survival whereas none survive with the same dose of clarithromycin, a dosage of 28.8 mg/kg being needed for clarithromycin to achieve 100% survival.10

Traditionally erythromycin, 2–4 g/day, has been used to treat patients with Legionnaires' pneumonia. With these doses, gastrointestinal side effects are common and ototoxicity is seen at the higher dose in about a quarter of patients. 11 Macrolides other than erythromycin are not associated with the same frequency of side effects. Short courses of erythromycin have been associated with relapse and, therefore, 10–14 days of treatment is recommended. Clinical studies comparing erythromycin with other macrolides are few. A single case report of a patient with severe Legionnaires' disease described failed treatment with erythromycin plus rifampicin and recovery only after intravenous azithromycin. 12 When azithromycin is used from the outset in treating community-acquired legionellosis cure has been observed with a total dose of 1.5 g given over 3 or 5 days. 13 Other macrolides have also proved clinically effective. 3

On the basis of the available data, azithromycin would seem to be the best macrolide, with good intracellular penetration, bactericidal activity, proven clinical efficacy, short durations of treatment and a good safety profile. Furthermore, the 15-membered lactone ring of azithromycin does not interact with cytochrome P450 3A isoenzymes, unlike the other, 14-membered macrolides. This reduces the potential for drug interactions. To date, antimicrobial resistance to azithroymcin, or indeed any macrolide, has not been a problem in clinical isolates of L. pneumophila. 5,14

Quinolones

The activity of several quinolones against Legionella spp. has been tested. In one comparative study of in-vitro, extracellular susceptibility sparfloxacin and trovofloxacin were the most active, ciprofloxacin, levofloxacin, ofloxacin and lomefloxacin were slightly less active, and pefloxacin was the least active. 15 However, all the quinolones tested can be said to have good activity and low MICs (Table). Quinolones readily enter the intracellular compartment. In humans, following an 800 mg po dosage of pefloxacin serum concentrations reach 6.7 mg/L, and within alveolar macrophages concentrations reach 106 mg/L. 16 In guinea pig alveolar macrophages trovafloxacin reaches intracellular concentrations 28-fold greater than the extracellular concentration. 17 Ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin and trovafloxacin have all been shown to inhibit the intracellular growth of L. pneumophila in either guinea pig alveolar macrophages 17,18,19 or HL-60 cells. 20 In HL-60 cells the most potent inhibitors of intracellular multiplication, in order of decreasing activity, were levofloxacin, ciprofloxacin and ofloxacin, 20 but within guinea pig alveolar macrophages these three quinolones have similar potency. 19 In other studies trovafloxacin proved more active than ofloxacin 17 and sparfloxacin more active than ciprofloxacin. 18 At a concentration of 0.25 mg/L trovafloxacin exerts a post-antibiotic effect, inhibiting the regrowth of L. pneumophila for three drug-free days, 17 and a similar effect is observed with sparfloxacin 1.0 mg/L but not with ciprofloxacin 1.0 mg/L. 18 Ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin and trovafloxacin have all been shown to be effective in the treatment of L. pneumophila pneumonia in guinea pigs. 17,18,19

There are numerous case reports and small series of patients with Legionnaires' disease treated successfully with quinolones. Larger studies on the use of quinolones in all forms of community-acquired pneumonia have also included small numbers of patients who proved to have Legionnaires' disease. Collectively these studies have demonstrated the clinical efficacy of ciprofloxacin 400 mg/ day iv, grepafloxacin 600 mg/day for 10 days, 21 levofloxacin 500 mg/day for 7–14 days, 22 ofloxacin 400–800 mg/day, 23,24 pefloxacin 800 mg/day 25 and sparfloxacin at 400 mg on day 1 followed by 200 mg/day for 10–14 days. 26,27 Treatment failures have been described with ciprofloxacin and ofloxacin, but may relate to inadequate dosing or patients being immunocompromised. 3,28

On the basis of available evidence, the newer quinolones, e.g. trovafloxacin and sparfloxacin, seem better choices than older quinolones, e.g. ciprofloxacin and ofloxacin, with respect to MICs, intracellular activity and post-antibiotic effects, but clinical comparisons are limited. To date, antimicrobial resistance to quinolones has not been a problem in clinical isolates of L. pneumophila. 5,14

Other antimicrobials

Rifampicin is very active against extracellular and intracellular Legionella spp. 5 ,6,29,30,31,32 (Table) and it is also effective in the guinea pig model. 33 In vitro, rifampicin-resistant strains are described in clinical isolates of L. pneumophila and these come to predominate in broth cultures exposed to rifampicin alone. 34 In the clinical setting monotherapy is not recommended in case rifampicin resistance emerges and, therefore, it has been reserved for adjunctive therapy in severe cases of Legionnaires' disease. Another limitation with rifampicin is its potent induction of the cytochrome P450 enzyme system and its potential for drug interactions. Trimethoprim- sulphamethoxazole, tetracyclines and chloramphenical have been tested in vitro, in animal models and in the clinical setting, but they are less active than macrolides, quinolones and rifampicin. 3

Two other groups of antimicrobials evaluated against Legionellaspp. are the streptogramins and the ketolides. Quinupristin–dalfopristin, a combination of semisynthetic streptogramins, is the first injectable streptogramin. In vitro it has shown a high level of activity against a wide range of Legionellaspp. (Table). 35 Quinupristin- dalfopristin appears to be less active than azithromycin and erythromycin on intracellular testing. 35 It is actively concentrated in macrophages, with intracellular concentrations being 30- 50 times greater than extracellular concentrations. Therefore, it may prove useful in treatment, although clinical data are awaited. The ketolides, HMR3004 and HMR3647, have been shown to be active against extracellular 32 and intracellular Legionellaspp. 36 and also in a guinea pig model of pneumonia, 36 but again clinical data are awaited.

Combination therapy

In vitro, Barker and Farrell found erythromycin and rifampicin to be synergic. 34 In broth cultures the addition of rifampicin to bactericidal concentrations of erythromycin led to more rapid killing of L. pneumophila. This was also observed when ciprofloxacin was added to erythromycin, or rifampicin added to ciprofloxacin. However, within human monocytes Baltch et al. 37 did not find rifampicin and erythromycin to be synergic and neither of these antimicrobials were synergic with levofloxacin.

Anecdotal evidence suggests that dual therapy with erythromycin and rifampicin improves outcome in immunosuppressed patients. Clinical reports are restricted to severe cases of Legionnaires' disease in whom mortality is due to several factors and not just the choice of antimicrobial. In a retrospective review of matched cases on intensive care units seven (35%) of 20 patients treated with erythromycin alone died compared with five (25%) of 20 patients treated with erythromycin plus rifampicin (1.2- 2.4 g/day). 25 In another series of patients admitted to intensive care units three (27%) of 11 patients treated with erythromycin alone died compared with five (33%) of 15 patients treated with erythromycin plus rifampicin (0.6- 1.2 g/day). 38 There are even fewer data on combinations of other antimicrobials.

Choice of therapy

On the basis of the above data, when treating Legionnaires' disease, the choice is first between macrolides and quinolones, and then between available, licensed examples in each group. In the future other antimicrobials, such as streptogramins and ketolides, may be worthy of consideration.

Macrolides and quinolones have been compared in vitro and in vivo. Ciprofloxacin was more active than erythromycin, clarithromycin and azithromycin in some studies comparing extracellular susceptibility 5,6,8 but in another was less active than clarithromycin, while being more active than erythromycin and azithromycin. 29 In other studies levofloxacin and moxifloxacin were more active than erythromycin and roxithromycin, 32 and grepafloxacin and ofloxacin were similar to clarithromycin. 31 Trovafloxacin 17 and levofloxacin 19 reduce bacterial counts of L. pneumophila within guinea pig alveolar macrophages more effectively than erythromycin. In HL-60 cells erythromycin was less effective at inhibiting L. pneumophila growth than levofloxacin, ciprofloxacin and ofloxacin. 20

In a retrospective review of matched, severe cases of Legionnaires' disease, requiring admission to intensive care, none of seven patients treated with pefloxacin alone died, whereas seven of 20 patients treated with erythromycin alone did. 25 Other clinical comparisons of macrolides and quinolones are based on series of community-acquired pneumonia, within which some cases proved to be due to Legionella spp. The numbers of patients with legionella infection have been small, and drawing conclusions on relative efficacy is difficult.

The general picture to emerge from the above studies is that quinolones are more active than macrolides. However, if one specifically looks at azithromycin, the best of the available macrolides, and newer quinolones (ciprofloxacin, grepafloxacin, levofloxacin and ofloxacin are licensed in the UK) there are no direct comparative studies.

In clinical practice antimicrobials are often commenced empirically. Pneumonia may be mild, moderate or severe. Patients may have acquired infection in the community, in the hospital or be immunocompromised. A number of such factors must be taken into account in the initial, empirical choice of antimicrobial. When patients have severe pneumonia there must be adequate cover for Legionella spp. from the outset. Patients with moderate or mild pneumonia, in whom Legionnaires' disease is suspected on strong epidemiological grounds or in whom a rapid positive diagnosis has been achieved using urinary legionella antigen assays, 39 may be switched to better agents if they are failing to improve on initial therapy. Thus patients on older macrolides and ß-lactams may be switched to azithromycin or quinolones. However initial, empirical therapy increasingly includes azithromyin or quinolones for hospitalized patients with suspected legionellosis. In trials, quinolones 21,22,24,40 and azithromycin 41 have proved effective in treating community-acquired pneumonia and are better than standard therapies that include ß-lactams. Levofloxacin and grepafloxacin have good activity against Streptococcus pneumoniae, which is a concern with ciprofloxacin and ofloxacin. 42

In moderate to mild community-acquired pneumonias the differential efficacy of azithromycin and quinolones may not matter and either could be used. In severe pneumonias adjunctive therapy could be employed if there is no initial improvement. Rather than choose between azithromycin and a quinolone one could combine these, and this will have less potential for drug interactions than the addition of rifampicin. Quinolones may be preferred to azithromycin in other patients in whom drug interactions may be a problem. For instance, in immunocompromised patients the potential for interaction with cyclosporin and protease inhibitors is less with quinolones than with macrolides. Quinolones also have an advantage in nosocomial pneumonias and elderly patients with a high likelihood of Gram-negative pneumonia. In severely ill patients grepafloxacin may not be suitable as it is not available in an intravenous formulation unlike, for instance, levofloxacin. The main reservation, however, about the widespread use of quinolones for treatment of pneumonia is the selective pressure this will have on the emergence of quinolone resistance.

Table

Notes

* Corresponding author. Tel: +44-121-766-6611; Fax: +44-121-766-8752. Back

References

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Received 17 December 1997; returned 24 April 1998; revised 23 October 1998; accepted 23 March 1999