Legionella species (Legionnaires’ disease)

MICROBIOLOGY

Legionella are gram-negative, aerobic, unencapsulated bacilli that are nutritionally fastidious requiring special media for growth. The family Legionellaceae comprises more than 49 species with more than 64 serogroups. The species L. pneumophila causes 80 to 90% of human infections and includes at least 16 serogroups; serogroups 1, 4, and 6 are most commonly implicated in human infections. To date, 8 species other than L. pneumophila have been associated with human infections, among which L. micdadei(Pittsburgh pneumonia agent), L. bozemanii, L. dumoffii, and L. longbeachae are the most common (189).

EPIDEMIOLOGY

Numerous prospective studies have ranked Legionella among the top four microbial causes of community-acquired pneumonia. Moreover, Legionella is responsible for 10 to 50% of nosocomial pneumonias when a hospital's water system is colonized with the organisms. Cases associated with traveling and long term care facilities are increasingly reported worldwide (23, 158, 173). Home-related Legionnaires’ disease have been also described but the risk of contracting Legionnaires’ disease in this setting seems to be very low (144). Aspiration is now known to be the major mode of transmission, although aerosolization also occurs (164). Risk factors include cigarette smoking, receipt of immunosuppressive medications, receipt of prior antibiotics and receipt of a transplant organ. Predisposing underlying diseases include chronic lung disease especially chronic obstructive pulmonary disease.

CLINICAL MANIFESTATIONS

Pneumonia is the predominant clinical manifestation due to Legionella infection. The symptomatic presentation is that of pneumonia and is generally nonspecific. After 2 to 10 days of incubation, high fever, headache, confusion, and myalgia appear. Respiratory symptoms such as productive cough or thoracic pain are not prevalent. Dyspnea is infrequent except in severe cases of Legionnaires´ disease. Radiologic findings are also unspecific. However, progression of pulmonary infiltrates, despite appropriate antibiotic therapy, is suggestive of Legionnaires´ disease. Extrapulmonary manifestations such as confusion, diarrhea, hyponatremia and increased CK levels are reported more often in Legionnaires disease than in pneumonia of another etiology. Suspicion of Legionnaires´ disease should be raised by an adequate epidemiologic and clinical context. A history of smoking or the absence of response to beta-lactamic drugs, and sputum full of neutrophils with scarce microorganisms are also very useful data (126). With early initiation of appropriate antibiotic therapy, the mortality of Legionnaires´ disease is now <5 percent in immunocompetent patients. However, mortality in immunosuppressed patients remains high.

Pontiac fever is a nonpneumonic infection caused mainly by L. pneumophila serogroup 1, but L. pneumophila serogroups 6 and 7, L. feeleii, L. micdadei have also been implicated (209). Malaise, fatigue, and myalgias are the most common symptoms and fever is the most common physical finding. The illness is self-limited and does not require antimicrobial treatment.

LABORATORY DIAGNOSIS

When reviewing antibiotic efficacy studies in humans, the method of diagnosis is critical in evaluating the credibility of the study. Isolation of the organism from culture on selective media is the gold standard. The selective media recommended are BCYE-alpha supplemented with polymyxin B, anisomycin and cefamandole. The sensitivity and specificity of the Legionella urinary antigen are very high and its use in every clinical laboratory is recommended. However, the test is available only for L. pneumophilaserogroup 1. Diagnosis by direct fluorescent antibody stain (DFA test) is rapid and highly specific but is less sensitive than culture because large numbers of organisms are required for microscopic visualization. Antibody testing of both acute-and convalescent-phase sera are necessary for diagnosing Legionnaires´ disease (145).

PATHOGENESIS

Cell mediated immunity is the primary host defense mechanism against Legionella as it is against other intracellular pathogens. The intracellular location is pertinent to therapy since antibiotics which fail to penetrate cells are ineffective in clinical disease despite efficacy in in vitro systems. Of the greater than 40 species of Legionella, L. pneumophila serogroup 1 is the most virulent and the most common species implicated in disease.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Susceptibility results in vitro for Legionella are not readily interpretable since no standardized method exists and correlation between in vitro results and clinical outcome is tenuous and often contradictory. An interesting facet of Legionella susceptibility testing is that circumstantial evidence in early outbreaks of Legionnaires' disease suggested that erythromycin or tetracyclines were more effective than other antimicrobial agents, testing methodologies of in vitro susceptibility favored those methods which showed that erythromycin/tetracycline were more effective than beta-lactam or aminoglycoside agents.

Three Methods of Susceptibility Testing

It is now accepted that the intracellular location of this pathogen is relevant to the efficacy of the antimicrobial agent. Antibiotics capable of achieving intracellular concentrations higher than the MIC were more likely to be clinically efficacious than antibiotics with inferior intracellular penetration (84). Susceptibility of Legionella species to antimicrobial drugs has been based on three laboratory methods: standard dilution testing in agar or broth, intracellular models in vitro, and animal models of Legionellainfection.

Dilution Testing In Vitro

Dilutional methods for extracellular susceptibility testing are considered less relevant than other methods (intracellular in vitro, animal models) since many antibiotics that are active extracellularly perform poorly in intracellular models. However, extracellular susceptibility testing does provide a screening test to determine which antimicrobial agents are likely to have clinical potential.Legionella are grown either in supplemented buffered yeast extract (BYE) broth or in supplemented buffered charcoal-yeast extract agar (BCYE). Antimicrobial agents are added in increasing concentrations. MICs and MBCs are assessed at 1-5 days of incubation.

The MIC determinations of antibiotics using BCYE agar may be up to ten-fold higher than when BYE broth is used. This difference in MICs is due to the inhibitory effect of BCYE on antibiotic activity. Reasons postulated for this inhibitory effect include: (1) acid pH of the media, (2) iron content of the media, (3) absorption of the antibiotics by charcoal, or (4) the autoclaving process (41). Although buffered starch-yeast extract (BSYE) agar is less inhibitory than BCYE, growth is better, endpoints are easier to interpret, and results are more consistent for BCYE (148).

Intracellular Models In Vitro

Several in vitro intracellular models have been developed: guinea pig peritoneal or alveolar macrophages (44,56, 65, 98, 205), human peripheral blood monocytes and monocyte-derived macrophages (10, 70, 153, 201), human neutrophils (3), and in tissue culture models using HeLa cells (76), MRC-5 human fetal lung fibroblast cells (183), the macrophage-like cell lines U937 (154), the human monocytic cell line THP-1 (192), HL-60 (184, 186) and Hep-2 cells Glass Chamber (193). Dictyostelium discoideum has been suggested as a model system for studying intracellular pathogens such as Legionella (79). Antimicrobial agents are added to the Legionella-infected cells and the degree of inhibition of intracellular bacterial growth is determined by quantifying bacterial concentration (41). Subsequent removal of the antimicrobial agent and recording the time required for regrowth of the bacteria in the tissue or cell culture gives a measure of the intracellular activity of the antimicrobial agent. Edelstein classified antimicrobial agents as not inhibitory (growth of intracellular L. pneumophila occurs despite presence of antimicrobial agent) reversibly inhibitory (slow regrowth of L. pneumophila occurs after antimicrobial agent removal from the culture), or cidal or causing prolonged inhibition of growth after antimicrobial agent removed (47).

Animal Models of Legionella

Models of respiratory tract infections (31, 67, 203) and peritonitis (37,53) have been developed. Pneumonia produced in animals is pathophysiologically more appealing than experimental Legionella infection induced by intraperitoneal inoculation. Legionella peritonitis results in localized infection without histopathologic evidence of disseminated (pulmonary, splenic, hepatic) disease (70). Antimicrobial agents presumed clinically effective (erythromycin, tetracycline) have been effective in the animal models, while those considered clinically ineffective (gentamicin, cefoxitin) are also inactive in animal models. Disadvantages of animal models include the differing pharmacokinetics in the animals as compared to humans and the expense and logistics required.

Macrolides

Erythromycin

Erythromycin's original clinical success was confirmed by studies in experimental animals showing its superiority over other antibiotics including penicillin, tetracycline, chloramphenicol, and gentamicin. The fact that Legionella is an intracellular pathogen provided the biologic basis for the success of erythromycin given its relatively high intracellular penetration (83).

Legionella pneumophila was susceptible to erythromycin when tested by in vitro dilution methods (Tables 1, 2). Growth of L. pneumophila was inhibited by erythromycin within guinea pig alveolar macrophages (44-47, 51, 52), guinea pig peritoneal macrophages (98), peripheral blood monocytes (8,10, 34, 180), human promyelocytic leukemic cells (HL-60) (184, 185, 186), and macrophage-like cells (154). Erythromycin was also active in animal models of pneumonia (53, 72,167, 182) and guinea pig model of peritonitis (37, 70) (Table 3). The non-pneumophila species were also susceptible to erythromycin when tested by in vitro dilution methods (Tables 1, 2). Growth of L. micdadei and L. bozemanii within peripheral blood monocytes (10, 34) and HL-60 cells (184, 185, 186) was inhibited by erythromycin.

Azithromycin

Azithromycin appeared to be the most active macrolide in vitro against Legionella (Tables 1, 2). By in vitro dilution methods, azithromycin was more active against L. pneumophila than erythromycin (88, 132, 184), clarithromycin (24), roxithromycin (24), and Dirithromycin (88,132,184).

Azithromycin was more active than erythromycin, clarithromycin, roxithromycin, and dirithromycin in inhibiting the growth of L. pneumophila within HL-60 cells (184, 186) and erythromycin in inhibiting growth within guinea pig alveolar macrophages (44, 56) Azithromycin inhibited intracellular replication at concentrations as low as 125mg/L, approximately one quarter of the extracellular MIC (90). In two studies in a guinea pig model of Legionella pneumonia, azithromycin resulted in 100% survival, whereas erythromycin resulted in 33% survival, and no therapy resulted in 0% survival (66, 67). In one study, in a guinea pig model of Legionella pneumonia azithromycin resulted in 100% survival (56). In a mouse model of pneumonia, azithromycin was superior to erythromycin in clearing Legionella (58). In an immunosuppressed A/J mice model of pneumonia, survival on administration of azithromycin was 92% (19).

For the non-pneumophila species, using in vitro dilution methods, azithromycin was more active than erythromycin (184), roxithromycin (88), dirithromycin (88,132,184) (Tables 1, 2). Azithromycin was more active than erythromycin in inhibiting the growth of L. micdadei within peripheral blood monocytes (34) and clarithromycin, roxithromycin, and dirithromycin within HL-60 cells (184).

Clarithromycin

In only a few in vitro dilution studies, clarithromycin was more active than azithromycin (88,132,184). Clarithromycin was more active in vitro dilution studies against L. pneumophila than roxithromycin and Dirithromycin (88, 132, 172, 184) (Tables 1, 2). In a guinea pig model of Legionella pneumonia, clarithromycin resulted in 100% survival, whereas no treatment resulted in 0% survival (67) (Table 3). Clarithromycin demonstrated greater efficacy than of azithromycin and erythromycin in broth dilution testing (186).

For the non-pneumophila Legionella species, using in vitro dilution methods, clarithromycin was more active than erythromycin, azithromycin, roxithromycin, and Dirithromycin (88) (132,184) (Tables 1,2). Clarithromycin was more active than azithromycin and roxithromycin in inhibiting the growth of L. micdadei and L. bozemanii within HL-60 cells (184). Clarithromycin has also been found to be more active than erythromycin in inhibiting the growth of L. pneumophila and non-pneumophila Legionella species within HL-60 cells (186).

Roxithromycin

In only a few in vitro dilution studies, roxithromycin was more active than azithromycin (88,132,184). Roxithromycin was more active in vitro against L. pneumophila than erythromycin, Dirithromycin (88, 98,132, 184) and josamycin (99) (Tables 1, 2).

Roxithromycin was more active than erythromycin, clarithromycin, and dirithromycin in inhibiting the growth of L. pneumophila within guinea pig peritoneal macrophages (98) and HL-60 cells (184). In a guinea pig model of Legionella pneumonia, roxithromycin was more active than either erythromycin or josamycin, resulting in 80% survival compared to 40% and 20% survival for erythromycin and josamycin, respectively (99) (Table 3).

For the non-pneumophila Legionella species, using in vitro dilution methods, roxithromycin was more active than erythromycin, azithromycin, dirithromycin (88, 132, 184) and josamycin (99) (Tables 1,2). Roxithromycin was active in inhibiting the growth of L. micdadei and L. bozemanii within HL-60 cell (184).

Dirithromycin

In in vitro dilution methods, dirithromycin was less active against L. pneumophilacompared to erythromycin, clarithromycin, azithromycin, and roxithromycin (88, 132, 184) (Tables 1, 2). Dirithromycin was less active than erythromycin, azithromycin, and roxithromycin in inhibiting growth of L. pneumophila within HL-60 cells (184).

For the non-pneumophila Legionella species, using in vitro dilution methods, dirithromycin was less active than erythromycin, clarithromycin, azithromycin, and roxithromycin (88,132,184) (Tables 1, 2). Dirithromycin was more active than clarithromycin, roxithromycin, and azithromycin in inhibiting growth ofL. micdadei and L. bozemanii within HL-60 cells (184).

Josamycin

In in vitro dilution studies, josamycin was less active than erythromycin and roxithromycin (99,167) against L. pneumophila (Tables 1, 2). In a guinea pig model of pneumonia, josamycin (20% survival) was more active than no treatment (0% survival), but less active than erythromycin (40% survival), and roxithromycin (80% survival) (99) (Table 3). In another guinea pig model of pneumonia, josamycin was the least active agent studied resulting in 0% survival compared to erythromycin, rifampin, or ofloxacin which resulted in 60%, 90%, and 100% survival, respectively (167) (Table 3). For the non-pneumophila Legionella species, using in vitro dilution methods, josamycin was less active than erythromycin and roxithromycin (99, 167) (Tables 1, 2).

Ketolides

ABT 773 was more active in vitro than erythromycin, azithromycin and telithromycin against L. pneumophila isolates (186).Telithromycin was more active in vitro than ABT 773 against L. micdadeiand L. longbeachae (186). Activity of trovafloxacin was greater than that of ABT 773 and telithromycin, while gemifloxacin, levofloxacin, ciprofloxacin, and moxifloxacin showed similar activity to the ketolides (186). HMR 3004 and telithromycin showed greater in vitro activity than eythromycin and similar activity to that of clarithromycin and levofloxacin (49).

ABT 773 was superior to azithromycin inhibiting the growth of Legionella in an HL-60 intracellular model (94, 186). ABT 773 was as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease (55). HMR3004 was more active than erythromycin and clarithromycin and less than levofloxacin in a guinea pig alveolar macrophage model (49). Telithromycin was greater than erythromycin and inferior to levofloxacin in a human monocyte intracellular model (7). Telithromycin was greater than erythromycin in a guinea pig model of pneumonia (49).

Quinolones

Quinolone agents were more active than all the macrolides by all in vitro and in vivo methods. Ciprofloxacin, enfloxacin, grepafloxacin, levofloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, alatrofloxacin, trovafloxacin, moxifloxacin, gemifloxacin, gatifloxacin grepafloxacin were all active by in vitro dilution methods (Tables 1, 2) (28,  157).

The quinolones were more active than erythromycin in irreversibly inhibiting the growth of L. pneumophila within guinea pig alveolar macrophages (51,52,53), peripheral blood monocytes (167, 10), guinea pig peritoneal macrophages (56, 98), and HL-60 cells (185, 186) and Hep-2 cells Glass Chamber (193). Levofloxacin showed greater activity than telithromycin, erythromycin or rifampin in the growth of L. pneumophila in the human monocyte intracellular model (8, 113). Levofloxacin was also more active than erythromycin, clarithromycin and telithromycin in the guinea pig alveolar macrophage model (49). Ciprofloxacin showed greater activity than ABT 773 and azithromycin in the HL-60 intracellular model (94).

Ciprofloxacin, levofloxacin, pefloxacin, sparfloxacin, alatrofloxacin, and trovafloxacin were more active than erythromycin or no therapy in guinea pig models of pneumonia (51-53, 72, 165-167) and in a guinea pig model of peritonitis (37) (Table 3).

Administration of ofloxacin resulted in a 92% survival in an immunocompromised A/J mice model of Legionella pneumonia (19). Concentrations as low as 0.015 mg/L of moxifloxacin and levofloxacin, 0.004 g/L of trovafloxacin and 0.002 mg/L of clinafloxacin markedly decreased viable intracellular bacterial counts in a Mono Mac infection model (91). For the non-pneumophila Legionella species, using in vitrodilution methods, ciprofloxacin, fleroxacin, grepafloxacin, lomefloxacin, sparfloxacin, temafloxacin, trovafloxacin and moxifloxacin were more active than erythromycin (40, 77, 88, 113, 132,166,167,175,185), clarithromycin (88, 113,132,159), azithromycin (77,88,132,175), roxithromycin (88), dirithromycin (88), and josamycin (167) (Tables 1, 2). Ciprofloxacin, levofloxacin, and ofloxacin were more active than erythromycin in inhibiting intracellular growth of L. micdadei and L. bozemanii within HL-60 cells (185). In broth microdilution susceptibility testing, the fluoroquinolones, ketolides and clarithromycin demonstrated greater activity against Legionella species than azithromycin or erythromycin (186).

Rifampicin (Rifampin)

Rifampicin is highly active in vitro against Legionella when tested by in vitro dilution methods (Tables 1, 2). Using in vitro dilution methods, rifampicin was more active than macrolides (24, 40, 78, 88,98, 132, 159, 166, 167, 201), quinolones (24, 40, 78, 88, 98, 132, 159, 166, 167, 201), beta-lactam agents with or without beta-lactamase inhibitors (98, 132), carbapenems (24, 78, 88, 98, 132), tetracyclines (78, 88, 98), aminoglycosides (98), clindamycin (88) and trimethoprim-sulfamethoxazole against L. pneumonphila ( 88) (Tables 1, 2).  

Rifampicin was more active than erythromycin, quinolones, beta-lactams and carbapenems, and gentamicin in inhibiting the growth of L. pneumophila within guinea pig peritoneal macrophages (98) and erythromycin, pefloxacin, cefoxitin, doxycycline, and trimethoprim-sulfamethoxazole within monocytes (201). In a guinea pig model of pneumonia, rifampicin was more active than ofloxacin, erythromycin, josamycin and no treatment, resulting in 100% survival, compared to 0-90% for the other agents (167) (Table 3). In another guinea pig model of pneumonia, rifampicin was less active, resulting in 62.5% survival compared to 75-87.5% for pefloxacin, erythromycin, and the tetracyclines (134) (Table 3).

In in vitro dilution methods, rifampicin was more active than the macrolides and quinolones (40,88), 132, 166, 167), beta-lactam agents with or without beta-lactamase inhibitors and carbapenems (88,132), clindamycin and trimethoprim-sulfamethoxazole (88) against the non-pneumophila Legionellaspecies (Tables 1, 2). The development of resistance to rifampicin has sporadically been reported as an in vitro phenomenon associated with mutations of the RPO B gene (131). Combination therapy in vitro with rifampicin and other antimicrobial agents will be discussed below.

Trimethoprim-Sulfamethoxazole

By in vitro dilution methods, trimethoprim-sulfamethoxazole was more active than azithromycin, dirithromycin, doxycycline, and clindamycin, but was less active than rifampicin, ciprofloxacin, clarithromycin, roxithromycin, and meropenem against L. pneumophila (88)) (Tables 1, 2). 

 Trimethoprim-sulfamethoxazole was more active than doxycycline and cefoxitin in inhibiting growth of L. pneumophila within human monocyte-derived macrophages (201); however, it was less active than rifampicin, pefloxacin, and erythromycin in the same study.

For the non-pneumophila Legionella species, using in vitro dilution methods, trimethoprim-sulfamethoxazole was more active than the macrolides, ciprofloxacin, meropenem, doxycycline, and clindamycin (88) (Tables 1). In a guinea pig model of L. micdadei pneumonia, trimethoprim-sulfamethoxazole was more active than erythromycin, rifampin, doxycycline, penicillin, chloramphenicol, gentamicin, cefazolin, cefoxitin, and no treatment, resulting in 60-100% survival, compared to 0-90% survival for the other agents (139) (Table 3).

Tetracycline/Doxycycline/Minocycline/Tigecycline

The tetracyclines are the least active of the agents used for Legionnaires disease when assessed by in vitro dilution methods ( Tables 1, 2). The tetracyclines were less active than the macrolides (88, 201), quinolones (78, 88, 98), Rifampicin (78,88, 98, 201), Carbapenems (78, 88, 98), and trimethoprim-sulfamethoxazole (88) ( Tables 1, 2).

Doxycycline was less active than rifampicin, erythromycin, pefloxacin, trimethoprim-sulfamethoxazole, and cefoxitin in inhibiting growth of L. pneumophila within monocytes (201). In a guinea pig model of Legionella pneumonia, doxycycline was more active than rifampicin, resulting in 75% survival, compared to 62.5% survival for rifampicin (134) (Table 3). In the same study, doxycycline was less active than pefloxacin and erythromycin, which resulted in 75-87.5% survival. In a guinea pig model ofLegionella peritonitis, tetracycline was less active than erythromycin, rifampicin, chloramphenicol, and gentamicin, resulting in 17% survival compared to 33-100% survival for the other agents (70) (Table 3). In another guinea pig model of Legionella peritonitis, minocycline was more active than rifampicin, amikacin, tobramycin, gentamicin, and no treatment, resulting in 50% survival compared to 0-33% for the other agents (129) (Table 3).

For the non-pneumophila Legionella species, except L. micdadei, using in vitro dilution methods, doxycycline was less active than rifampicin, ciprofloxacin, macrolides, meropenem, and trimethoprim-sulfamethoxazole (88) ( Tables 1, 2). In a guinea pig model of L. micdadei pneumonia, doxycycline was more active than erythromycin, rifampicin, penicillin, gentamicin, chloramphenicol, cefazolin, cefoxitin or no treatment, resulting in 40-90% survival compared to 0-70% survival for the other agents (139) (Table 3).

Tigecycline was less active than erythromycin and azithromycin against L. pneumophila (strains F88 and F2111) in vitro broth dilution method (57) (Table 2). Tigecycline was about as active as erythromycin and as or less active than azithromycin in the macrophage model (57). Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (57) (Table 3).

Beta-Lactam Agents

Using in vitro dilution methods, amoxicillin (132), amoxicillin/ clavulanic acid (25,132), piperacillin/ tazobactam (132), ceftazidime (98), and ceftizoxime (98) were more active than erythromycin, azithromycin, dirithromycin, and enoxacin against L. pneumophila (Tables 1, 2). However, ceftizoxime, ceftazidime, piperacillin were not active in inhibiting the growth of L. pneumophila within guinea pig peritoneal macrophages (98), nor was ampicillin active in inhibiting the growth of L. pneumophila within a macrophage-like cell line (154). Ampicillin/sulbactam was active in inhibiting the growth of L. pneumophila within a macrophage-like cell line (154). In a rat model of pneumonia, amoxicillin/ clavulanic acid and ticarcillin/ clavulanic acid (182) were more active than amoxicillin, ticarcillin, or no treatment in reducing the counts of L. pneumophila in the lungs of the animals (Table 3). In the same rat model, amoxicillin was ineffective in reducing bacterial counts in the lungs of infected rats, while amoxicillin-clavulanic acid, or clavulanic acid alone was as effective as erythromycin. The activity of co-amoxicillin was not greater than that of clavulanic acid alone. Interestingly, after cessation of therapy regrowth of L. pneumophila in rat lung was significantly higher (4.8 log10 cfu/lungs) than in co-amoxicillin-treated rats (181).

For the non-pneumophila Legionella species, using in vitro dilution methods, piperacillin/tazobactam (132) was more active than erythromycin, azithromycin, roxithromycin, and dirithromycin (Tables 1, 2). However, amoxicillin/clavulanic acid, and amoxicillin (132) were less active than the macrolides against the non-pneumophila Legionella species (Tables 1, 2).

Carbapenems

The carbapenems were active in vitro against Legionella when tested by the in vitro dilution method (Table 1), but less active than the quinolones and rifampin. Imipenem (78, 88, 98) and meropenem (88) were more active than the macrolides, beta-lactam/ beta-lactamase inhibitors, doxycycline, gentamicin, and clindamycin against Legionella (Tables 1, 2). Although imipenem was active by in vitro dilution methods, it was ineffective in a guinea pig model of pneumonia (42).

Clindamycin

Clindamycin is less active than the macrolides, quinolones, meropenem, and trimethoprim-sulfamethoxazole against the Legionella species (88) (Table 1).

Combination of Antimicrobial Agents In Vitro or In Vivo

Macrolide-Rifampicin

The combination of erythromycin and rifampicin was synergistic for two isolates of L. pneumophila in time-kill curve studies (9, 11). In a checkerboard method, the combination of erythromycin and rifampicin proved to be synergistic against 20% (4/20) L. pneumophila strains, and was indifferent against the remainder (123). The combination of erythromycin and rifampicin was effective in reducing the number of rifampicin-resistant Legionella strains using both the checkerboard method (123) and time-kill curve method (140).

Quinolone-Rifampicin

The combination of ciprofloxacin and rifampicin was synergistic (time-kill curve) against one isolate of L. pneumophila (11). The combination of ciprofloxacin and rifampicin was indifferent against 80% (16/20) L. pneumophila strains in a checkerboard method (123). The combination of ciprofloxacin and rifampicin did not eradicate the rifampicin-resistant subpopulation of L. pneumophila(123). The combinations of levofloxacin and rifampicin and ofloxacin and rifampicin were synergistic (time-kill curve) (9). In a human monocyte model of Legionella infection the addition of erythromycin or rifampin did not affect the antibacterial activity of levofloxacin (8).

Macrolide-Quinolone

Rapid, bactericidal activity of the combination of erythromycin and ciprofloxacin was seen by time-kill curve analysis. The subpopulation of ciprofloxacin-resistant L. pneumophila was reduced (11). These results were similar to those obtained with the combination of erythromycin and rifampicin, raising the possibility of using ciprofloxacin with erythromycin if rifampicin was poorly tolerated (11). The combination of erythromycin and ciprofloxacin was indifferent (checkerboard), but was effective in reducing the subpopulations of ciprofloxacin- and erythromycin-resistant L. pneumophila (123).

The combinations of erythromycin and ciprofloxacin, erythromycin and levofloxacin, and clarithromycin and ciprofloxacin were additive or indifferent (checkerboard) against 12-79% of L. pneumophila isolates (115). The combinations of azithromycin and ciprofloxacin, azithromycin and levofloxacin, and clarithromycin (and its metabolite) and levofloxacin were synergistic or partially synergistic (checkerboard) against 6-47% of L. pneumophila isolates (115, 116). 

The combinations of erythromycin and levofloxacin, erythromycin and ciprofloxacin, clarithromycin and levofloxacin, azithromycin and ciprofloxacin, azithromycin and levofloxacin, and clarithromycin and ciprofloxacin were synergistic or partially synergistic (checkerboard) against 14-28% of non-pneumophila Legionella isolates (115). These same combinations were additive or indifferent (checkerboard) against 4-42% of non-pneumophila Legionella isolates (115). No antagonism (checkerboard) was observed. Combination of telithromycin plus rifampicin showed no synergy or interference in a human monocyte intracellular model of Legionella infection (7).

Macrolide-Beta-Lactam

In a time-kill curve method (11), the combination of erythromycin and amoxicillin reduced the colony count of L. pneumophila after 75 hours of incubation to below the level of detection.

Quinolone-Cephalosporin

The combination of fleroxacin with desacetyl cefotaxime was inhibitory to the growth of L. pneumophila within guinea pig alveolar macrophages (45). A prolonged postantibiotic effect was observed with the combination.

ANTIMICROBIAL THERAPY

The drugs of choice are the newer macrolides (especially azithromycin, clarithromycin,roxithromycin) and the quinolones (levofloxacin, ciprofloxacin, moxifloxacin, gemifloxacin) and thetetracyclines. The new macrolides, especially azithromycin, have displaced erythromycin as the macrolide of choice. The new macrolides have more potent intracellular activity and superior penetration into lung tissue, alveolar macrophages, and white blood cells. Furthermore, they have improved pharmacokinetic properties such that once or twice daily dosing is possible. Gastrointestinal toxicity is significantly less for the new macrolides when compared to erythromycin.

Although oral therapy has proven effective in cases of Legionnaires' disease (103), given the gastrointestinal manifestations so prominent in some patients, parenteral therapy is preferred to remove the possibility of incomplete gastrointestinal absorption. Parenteral therapy should be given until there is an objective clinical response - often as short as three days. Then therapy can be concluded with oral agents for a total 10-14 day course. Azithromycin need be given only for seven to 10 days (200). A 21 day course has been recommended for immunosuppressed patients. The doses of commonly-used antibiotics are given in Table 4.

Macrolides

Erythromycin

Erythromycin was once the drug of choice based on retrospective review of Legionellaoutbreaks (5, 69, 97, 105) but is less often used today because of adverse effects of gastrointestinal distress and ototoxicity.  In the 1976 Philadelphia outbreak, the mortality rate was 11% (2/18) in patients treated with erythromycin compared to 28% (51/85) in patients treated with cephalothin, penicillins, aminoglycosides, or chloramphenicol (69). Mortality rates in erythromycin or tetracycline treated cases were on average two-fold lower than those seen in the untreated cases (42). A striking clinical improvement was apparent in 83% (5/6) of patients failing therapy with beta-lactam antibiotics with or without aminoglycosides when therapy with erythromycin was initiated during an outbreak of Legionnaires' disease in Columbus, OH (5). A lower mortality rate has been observed in nosocomial Legionnaires' disease in patients treated with erythromycin than in those given other antibiotics (20, 96, 97). However, clinical and microbiologic failures of erythromycin therapy have been reported (35, 62, 80, 138, 142, 161,197). Despite widespread use, emergence of resistance in vitro has not been seen for macrolides.

Erythromycin is generally a safe antibiotic. The principal toxicities of erythromycin are irritating, such as dose-related gastrointestinal discomfort (abdominal cramps, nausea, vomiting, diarrhea) and thrombophlebitis at the infusion site (187). The large volume of normal saline infusate required for the 4 gram dose can be problematic in patients with compromised left ventricular function or impaired renal ability. Symptomatic ototoxicity (tinnitis or hearing loss confirmed by audiograms) was documented in 21% (5/24) of patients with pneumonia receiving erythromycin at the 4 gram dose, in 0% (0/6) receiving erythromycin at the 2 gram dose and in 0% (0/15) receiving other antibiotics. Ototoxicity was significantly related to high peak concentration and high serum concentration time curve (AUC) as a function of decreased total systemic clearance. Ototoxicity resolved in all patients within six to 14 days after discontinuation of therapy.

Azithromycin

In a series of non-comparative studies, 46 nonimmunosuppressed patients with community-acquired Legionnaires' disease diagnosed by serology (37 patients) or urinary antigen (9 patients) were treated with oral azithromycin with a total dose of 1.5 grams over 1-5 days. The authors reported a surprising 100% cure rate (103, 104, 127). A series of 19 patients with mild community-acquired pneumonia cause by Legionella (9 diagnosed by urinary antigen and 10 exclusively by serology) were successfully treated with 3 days of 500 mg of azithromycin by oral route (170).

In a prospective, randomized trial, intravenous azithromycin (500mg daily for two to five days) followed by oral drug (500mg daily to complete a total of 10 days of therapy) resulted in 92% cure (11/12). The comparative regimen of cefuroxime plus erythromycin resulted in 88% cure (7/8). Diagnosis was confirmed by sputum culture, polymerase chain reaction, and four-fold seroconversion (199). Clinical cure was achieved in 20/21 patients with community acquired Legionnaires´ diseases diagnosed by urinary antigen receiving azithromycin (azithromycin i.v. 500 mg q.d. for 2-7 days followed by oral azithromycin for a total duration of 7-12 days) (150).

Intravenous azithromycin (500mg on day 1 and 250mg daily for 13 days) initiated after clinical failure with trimethoprim-sulfamethoxazole, erythromycin, cefotaxime, and rifampicin resulted in clinical cure in a case report (35). Failure of azithromycin occurred in a cancer patient with pneumonia caused by L. pneumophila serogroup 6. No response was observed despite 14 doses of daily intravenous azithromycin (199).

Clarithromycin

In a prospective, randomized trial, intravenous clarithromycin (500 mg bid for three to five days) followed by oral drug (500 mg bid to complete a total of 10 days of therapy) resulted in 100% cure (6/6) in patients with serologically confirmed Legionnaires' disease. There were no cases of Legionnaires' disease in the comparative regimen of amoxicillin/ clavulanic acid (74).

Dirithromycin

In a prospective, randomized trial, oral dirithromycin (500mg daily for up to 18 days) and oral erythromycin resulted in 100% clinical improvement in three patients with serologic evidence of Legionnaires' disease (107). In a prospective, randomized multicenter trial, oral dirithromycin (500mg daily for 10 to 14 days) resulted in 86% (12/14) cure in patients with serologic evidence of Legionnaires' disease. Oral erythromycin resulted in 70% (7/10) cure rate in patients with serologically confirmed Legionnaires' disease (87).

Josamycin

In one non-comparative trial of non-severe community-acquired pneumonia, oral josamycin (1000mg bid for five days) resulted in 100% (4/4) cure in patients with serologically confirmed Legionnaires' disease (119).

Roxithromycin

In a prospective, randomized trial, oral roxithromycin (150 mg bid for 10 to 14 days) resulted in 100% (2/2) cure in patients with Legionnaires' disease (both patients had mixed infections with either S. pneumonia or M. catarrhalis). In the comparative regimen, oral sparfloxacin resulted in treatment failure in one patient with serologically confirmed Legionnaires' disease (198).

Telithromycin

In an open-label multicenter study of non-severe community-acquired pneumonia oral telithromycin (800mg once daily for 7 day) clinical cure was achieved in 100% (4/4) of patients with Legionnaires´ disease (confirmed by serologically and/or antigenuria data) (68).

Macrolide Drug Interaction

The macrolides have the potential of interacting with other drugs by interfering with their hepatic route of metabolism through the cytochrome P-450 enzyme system (140). An important drug interaction is that with tacrolimus (formerly FK-506) and cyclosporine, immunosuppressive agents used in solid organ transplants whose metabolism is mediated by the cytochrome P-450 system. The 14-membered lactone ring of the macrolide complexes with the cytochrome P-450 3A isoenzymes thereby inactivated the metabolism of tacrolimus and cyclosporine. Azithromycin differs somewhat since it has a 15-membered ring structure and is known to not form complexes with the cytochrome P-450 3A isoenzymes.Azithromycin is therefore less likely to interfere with the metabolism of drugs that are hepatically metabolized through the cytochrome P-450 system, unfortunately clinical studies have not confirmed this hypothesis (140).

Quinolones

Levofloxacin

The single best studied antibiotic for Legionnaires’ disease islevofloxacin. In a prospective, randomized trial, intravenous and/or oral levofloxacin (500mg daily for seven to 14 days) resulted in 80% (4/5) in the patients with serologically confirmed Legionnaires' disease (64). The control regimen of ceftriaxone and/or cefuroxime axetil with or without erythromycin or doxycycline resulted in 67% (2/3) cure in the patients with serologically confirmed Legionnaires' disease. In a series of 6 patients with Legionnaires´ disease diagnosed by urinary antigen treatment with levofloxacin (levofloxacin 500 mg qd iv for two days followed by 12-19 days of levofloxacin 500 mg qd po), all but one patient showed clinical improvement and disappearance of fever within the first 48 hours (169). Cure was obtained in 92% (24/26) with no deaths (202, 207). In 5 prospective, randomized clinical trials for USA FDA approval of levofloxacin (500 mg q.d. or 750 mg q.d.) totaling almost 2000 patients, 75 patients were infected by Legionella species (207). More than 90% of mild-moderate and severe cases of Legionella infection resolved by 14 days. Surprisingly, not a single case treated with levofloxacin died.

Ciprofloxacin 

Monotherapy with ciprofloxacin has been described to be clinically effective in 80% (8/10) of critically ill or immunocompromised patients with community- and nosocomially-acquired Legionnaires' disease (197). In this same study, 40% (4/10) of the patients were initially unresponsive to treatment witherythromycin and rifampin, but treatment with ciprofloxacin resulted in clinical cure in 75% (3/4) of these nonresponders. Diagnosis of Legionnaires' disease was confirmed by direct immunofluorescence stain (DFA) and serology (197).

Anecdotal clinical reports have shown that therapy with ciprofloxacin is effective for Legionnaires' disease in solid organ transplant recipients receiving cyclosporine (82,176,179) or in granulocytopenic patients with acute myeloid leukemia (211). Clinical failures of ciprofloxacin treatment have been reported in three cases in which a low dosage of 400mg daily was given (101,197).

Ofloxacin

Intravenous and oral ofloxacin have been used successfully in the treatment of Legionnaires' disease. In one non-comparative trial, intravenous ofloxacin (200 mg every 12 hours for a minimum of five days) followed by oral drug (200mg every 12 hours for up to 29 days) resulted in 100% (1/1) cure in a patient with Legionnaires' disease (diagnostic details not provided) (125). In another non-comparative study, oral ofloxacin (400mg bid for 10 days) resulted in 100% (1/1) cure rate in a patient with serologically confirmed Legionnaires' disease (75). There has been one reported clinical failure of ofloxacin treatment in an HIV-infected patient receiving a low dosage of 200mg twice daily (168).

Recurrence of Legionnaires' disease was successfully treated with ofloxacin in one patient with lymphoma receiving corticosteroids previously treated with erythromycin (62).

Sparfloxacin

In four prospective, randomized trials, oral sparfloxacin (400 mg on day 1 followed by 200mg daily for 10-14 days) resulted in 75% (3/4) cure in patients with serologically confirmed Legionnaires' disease. The comparative regimens (amoxicillin/clavulanic acid, amoxicillin, amoxicillin plusofloxacin, erythromycin) resulted in 59% (10/17) cure in patients with serologically confirmed Legionnaires' disease (4, 110, 152, 198). In a prospective, randomized trial, oral sparfloxacin (400 mg on day 1 followed by 200mg daily for up to 10 days) resulted in 100% (3/3) bacteriologic response in two patients with Legionnaires' disease diagnosed by a positive sputum culture in one patient and by a positive urinary antigen in another patient (33).

Trovafloxacin

In two prospective, randomized trials of intravenous alatrofloxacin (prodrug of trovafloxacin, 200mg daily for two to seven days) followed by oral trovafloxacin (200mg daily to complete a total of seven to 14 days of therapy), resulted in 77% (10/13) cure of patients with serologically confirmed Legionnaires' disease. The comparative regimens (intravenous ciprofloxacin plus ampicillinfollowed by oral ciprofloxacin plus amoxicillin, ceftriaxone followed by oral cefpodoxime) resulted in 86% (12/14) cure of the patients with serologically confirmed Legionnaires' disease. The cure rates were not significantly different.

Grepafloxacin

In one open-label, non-comparative trial, oral grepafloxacin (600mg daily for 10 days), resulted in 100% (13/13) cure in patients with serologically confirmed Legionella pneumonia (195).

Gatifloxacin

Clinical data for Legionnaires’ disease is sparse. To our knowledge, this quinolone has not been shown to be effective in culture-confirmed cases of Legionnaires’ disease.

Rifampicin (Rifampin)

Rifampicin monotherapy has been discouraged because of theoretical concerns of emergence of resistance to the drug during therapy. In a retrospective review of cases of severe Legionnaires' disease, the addition of rifampicin (1200mg to 2400mg daily) to erythromycin resulted in a mortality rate of 25% (5/20) as compared to a mortality rate of 35% (7/20) in patients treated with erythromycin alone (36). In the same study, combination therapy with erythromycin, rifampicin, and/or pefloxacin resulted in a mortality rate of 15% (3/20) suggesting that the addition of rifampicin to anti-Legionella antibiotics may improve the clinical outcome. On the other hand, in a retrospective study, 15 patients with Legionnaires' disease were treated with combination of erythromycin and rifampicin (300mg to 600mg bid) resulting in a cure rate of 67% (10/15), whereas erythromycin alone resulted in a comparable cure rate of 80% (12/15) (85), it should be noted that patients who are more severely ill are likely to receive combination therapy. The addition of rifampicin to erythromycin may improve the clinical outcome in cases of L. bozemanii pneumonia in immunosuppressed patients.

Trimethoprim-Sulfamethoxazole

There are anecdotal reports of treatment success with trimethoprim-sulfamethoxazole in two patients with nosocomial Legionnaires' disease (97) and in one patient failing therapy with erythromycin andrifampin. High dose trimethoprim-sulfamethoxazole (400mg trimethoprim and 200g sulfamethoxazole by mouth every 8 hours) appeared to be effective in two nosocomial cases of Legionnaires' disease (97). One patient who failed erythromycin plus rifampin was successfully treated with two double strength tablets (a total of 320mg trimethoprim and 1600mg sulfamethoxazole) (161).

The prophylactic use of trimethroprim-sulfamethoxazole for Pneumocystis jiroveci in AIDS patients probably confers some protection against Legionella infection. An analysis of Legionella infection by a regimen of Pneumocystis jiroveci prophylaxis in an entire cohort of AIDs patients demonstrated that significantly more patients developed Legionnaires' disease while receiving intravenous pentamidine (4/120) than those receiving oral trimetroprim-sulfamethoxazole (0/140 p<0.5) (16). In a series of 15 patients with AIDS and Legionella infection, 14/15 were not on trimethoprim-sulfamethoxazole prophylaxis (141). On the other hand, in an outbreak of hospital acquired Legionnaires' disease in liver transplants, several patients contracted Legionnaires' disease despite receiving prophylactic TMP-SMZ (Yu, VL, unpublished data).

Tetracyclines

In the 1976 Philadelphia outbreak, the mortality rate was 10% (3/30) in patients who were treated with tetracycline (500mg four times a day), compared to 11% (2/18) for erythromycin, 23% (16/71) for penicillins, 30% (3/10) for chloramphenicol, 41% (20/49) for cephalothin, and 36% (9/25) for aminoglycosides (69). Oral tetracycline (500mg four times a day) resulted in rapid resolution of fever within 3 days of commencing therapy in a patient with Legionnaires' disease, a response comparable to that observed with erythromycin (121). Therapy with tetracycline (2g daily) was effective in curing one case of relapsing Legionnaires' disease after three separate episodes had failed to respond to treatment with beta-lactam antibiotics and aminoglycosides (1).

In a prospective, randomized trial, oral doxycycline (100mg bid for 10 days) resulted in 100% (1/1) cure in patients with serologically confirmed Legionnaires' disease (133). The comparative regimen of oral fleroxacin resulted in 100% (3/3) cure in patients with serologically confirmed Legionnaires' disease. There are two case reports documenting the effectiveness of doxycycline therapy (200 - 400mg daily) for Legionnaires' disease that was initially unresponsive to beta-lactam antibiotics and cephalosporins (30, 95). The addition of intravenous tetracycline (dose and duration not known) was seen to be effective therapy for pneumonia due to L. bozemanii initially unresponsive to erythromycin  (162).  Tigecycline intravenously has been successfully used in a limited number of patients.

Clindamycin

Intravenous clindamycin (900mg every 6h) was successful in treating cavitary disease in an immunosuppressed patient with Legionnaires' disease (21).

Beta-lactam Agents

Based on retrospective review of outbreaks of Legionnaires' disease in Philadelphia, PA in 1976, Columbus, OH in 1977, and Los Angeles, CA in 1977-78, antibiotics such as ampicillin, penicillin,cephalothin as well as other cephalosporins were relatively ineffective (5, 69,97). Numerous anecdotal case reports have also demonstrated the relative lack of clinical efficacy of penicillins (penicillin, piperacillin) and cephalosporins (cephaloridine, cephalothin) in treating Legionnaires' disease (1, 21, 30, 95).

Failures of ticarcillin and ampicillin therapy for infection with L. micdadei (161) and ofcefamandole for L. bozemanii pneumonia (162) have been reported. Progressive disease due to L. maceachernii has been reported despite treatment with ampicillin, flucloxacillin and imipenem (120). There have been several case reports describing failure of beta-lactam/beta-lactamase inhibitor combinations including amoxicillin-clavulanic acid (35, 81, 101), ticarcillin-clavulanic acid and ampicillin-sulbactam (47).

Carbapenems 

Imipenem has been reported to be an effective treatment for Legionnaires' disease in several anecdotal reports (13, 26, 149). Successful treatment of 4 patients with serologically confirmed Legionnaires' disease with imipenem in a pilot study has been reported (13). However, clinical failures of imipenem have also occurred (6, 120, 208).

Empiric Drug of Choice in Community-Acquired Pneumonia

The empiric treatment of community-acquired pneumonia remains a considerable challenge. The guidelines from different European an American societies have several key differences. Since the consequences of not covering for Legionella spp infection may be a serious problem, North American guidelines recommend coverage of this microorganism while the empiric coverage of Legionella in some European guidelines is provided in accordance with clinical data. However, a consensus exits for covering Legionella spp in severe cases of community-acquired pneumonia (2, 12, 63, 112, 204). Azithromycin as monotherapy has been recommended by the American Thoracic Society (2, 112). Note that azithromycin (and other new macrolides) and telithromycin provide coverage against the other common pathogens of community-acquired pneumonia including the other "atypical" pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae) and typical pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus). Quinolones, especially levofloxacin andciprofloxacin have been effective in Legionnaires' disease, both in community or hospital- acquired disease. Both American Thoracic Society and Infectious Disease Society of America include quinolones for treatingLegionella infection in community-acquired pneumonia (2, 12, 210).

For transplant recipients in which Legionella is a potential pathogen, we recommend a quinolone especially ciprofloxacin or levofloxacin as the drug of choice. The macrolides interact with the immunosuppressive agents, cyclosporin and tacrolimus, used in transplantation.

Special Situation

Legionella Endocarditis

Nosocomial Legionella prosthetic valve endocarditis has been described in seven patients (194). The infecting organisms isolated from blood, sternal wound, and valve cultures included L. pneumophila in three patients, L. dumoffii in three patients, and both L. pneumophila and L. dumoffii in one patient. The combination of erythromycin and rifampicin was given successfully for six to 14 months in five patients who also had replacement of the prosthetic valve. Forty percent (2/5) of these patients were cured (no evidence of continued infection), and 60% (3/5) of the patients had a clinical response (defervescence and improvement in signs and symptoms). Treatment with erythromycin and rifampicin alone for five to six months, resulted in cure in one patient and clinical improvement in the other patient (194). For patients with prosthetic valve endocarditis, we recommend consideration of combination antibiotic therapy. The optimal duration of therapy is unknown, but we would administer at least three months of therapy if the infected valve was resected and at least six months if the valve was not resected.

HIV Patients

Legionella infection is uncommon in patients with AIDS but the mortality is very high (143). Cavitating pneumonia and bacteremia due to L. pneumophila has been reported (124). In this particular case of cavitary Legionnaires’ disease with positive sputum cultures, recurrent bacteremia occurred four months after concluding an 8 week course of combination therapy with macrolides andrifampin. Re-treatment with erythromycin lead to prompt defervescence. In two series of 8 and 15 patients with AIDS relapse of Legionella infection occurred once in each series, with both patients initially treated with erythromycin (17,143). In patients with AIDS, we recommend continuing several weeks of oral maintenance antimicrobial agent therapy until the infiltrates on chest radiograph resolve. Close follow-up for detection of possible recurrence is necessary after discontinuation of therapy.

Comparative Clinical Studies on Macrolides Versus Quinolones

Three observational studies have addressed the issue of comparative efficacy of quinolones versus macrolides (18, 128, 163). Blazquez-Garrido et al conducted an observational, prospective study of 292 patients with Legionella pneumonia during the Murcia (Spain) outbreak. Mykietiuk et al conducted a prospective, observational study of 139 patients with Legionella pneumonia included in a series of 1934 consecutive cases of community-acquired pneumonia in non-immunocompromised adults. Sabrià et al. conducted a retrospective observational multicenter study of Legionnaires’ disease that included 76 patients who received macrolides and 54 patients who received quinolones. Clarithromycin was the predominant macrolide used in the patients with severe pneumonia in the Blazquez study, and clarithromycin and erythromycin were used in the Sabriá study. Azithromycin was not studied in any systematic comparison. No significant differences were found among the three studies in age, sex, cigarette smoking, chronic lung diseases or severity of pneumonia for the two treatment groups of macrolides versus quinolones. Immunosuppressed patients and cases of hospital-acquired Legionnaires’ disease were only included in the multicenter study by Sabrià et al. The delay until the initiation of an appropriate antibiotic treatment was only noted in the Sabrià study and was not significantly different in the two groups. Time to defervescence was notably shorter in patients on levofloxacin in two studies (128, 163). The mean time was 97.7 hours for patients receiving macrolides and 66.6 hours for patients receiving levofloxacin in the 3 studies. Length of hospital stay was significantly shorter or tended to be for patients receiving levofloxacin in all three studies. Finally, patients on levofloxacin had fewer complications (8.4%, 20/237) as defined by pleural effusion, empyema, cavitation, septic shock, and mechanical ventilation, than those receiving macrolides (18.5%, 41/221). The incidence of treatment-related adverse events was 23.4% (34/145) for patients receiving macrolides and 12.5% (23/183) for those on levofloxacin. No differences were found in the mortality rates in the 3 studies. In conclusion, the advantages of choosing a quinolone over a macrolide for Legionnaires’ disease in immunocompetent patients with community-acquired pneumonia may be a shorter time to defervescence with a more rapid achievement of clinical stability followed by shorter hospital stay. Based on data from intracellular susceptibility tests, animal studies and observational studies, we suggest that quinolones might warrant preference over macrolides in compromised hosts with severe infections and in those who are critically ill.

Combination Antibiotic Therapy

No comparative studies are available to support the use of combination therapy. However, the report of some anecdotal clinical cases (86, 135, 136, 146, 189, 196) treated with combination therapy warrants consideration in case of suboptimal clinical response on monotherapy or patients with bad prognostic factors such as, patients on immunosuppressive therapy, HIV-infected patients and those with severe Legionella pneumonia.  Levofloxacin plus azithromycin or levofloxacin plus a short course of rifampin are options.

 

ENDPOINTS OF MONITORING THERAPY

A clinical response, e.g. defervescence, is generally seen within three days of initiation of appropriate antibiotic therapy. Improvement on chest radiograph lags behind clinical improvement. In one study of nosocomial pneumonia, 29% of patients showed progression of infiltrate despite erythromycin administration. At 12 weeks, abnormalities on chest radiograph was still visible in 50% of patients (32).

The mortality rates for Legionnaires' disease vary depending on the underlying disease and its severity, presence of immunosuppression, severity of pneumonia, and timing of administration of appropriate antimicrobial therapy. Immunosuppressed patients who have not received appropriate antimicrobial therapy have the highest mortality rates of >80 % (97). Mortality among this group is 24% to 37 % even if appropriately treated. Mortality rates seen with community-acquired Legionnaires' disease in immunocompetent patients’ ranges from 0 to 11 percent with appropriate therapy, and as high as 31 percent if untreated. If a patient with Legionnaires’ disease experiences a clinical failure confirmed by positive sputum cultures, we would recommend fluoroquinolone therapy or combination therapy which would include rifampicin for a prolonged duration of three weeks or longer.

VACCINES

No commercially-available vaccines exist although they should be theoretically easy to develop since antigenic cell wall components have been identified.

PREVENTION

Since the source of the organism is know to be water, infection is theoretically preventable.

Infection Control

Optimal prevention of hospital-acquired legionellosis depends on knowledge of the presence ofLegionella in the hospital drinking water (206). If colonization is documented, immunosuppressed patients should avoid drinking tap water.  For hospitals, 30% or greater colonization is used as a decision point for disinfection.  Showering has not been shown to be a mode of transmission in controlled studies, so showering is now permissible in our hospital (164). The disease is not transmitted person-to-person, so isolation is not necessary.

Potable Water Disinfection

Prevention of hospital-acquired Legionnaires’ disease can be achieved by disinfecting hospital water systems (1-5). Copper-silver ionization is the best available technology today given its documented efficacy (6, 7, 8, 9, 11, 12). Chlorine dioxide is undergoing multi-center evaluation for Legionellaeradication and may be promising (13). Monochloramine is a new disinfection method for municipal drinking water distribution network, but the study in validation of its clinical efficacy has not performed. Superheat-and-flush can be used in outbreak situation to halt the nosocomial transmission. Hyperchlorination, ultraviolet light, ozonation, and instantaneous heating system are no longer recommended due to various limitations (16). Point-of-use disposable filter may be a cost effective method to control Legionella (17) in limited area (e.g. intensive care units) without systematic disinfection implemented in a large institution water system.

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Table 1:  Susceptibility of Legionella spp. To Antimicrobial Agents by In Vitro Agar Dilution Method

Drug/Species	MIC50(mcg/ml)	MIC90(mcg/ml)	MIC range (mcg/ml)	References
Erythromycin
L. pneumophila (serogroups 1-9, 12)	0.015-1.0	0.03-2.0	0.008-1.0	(18,29,35,57)(31,32,106)  (Edelstein DMID 1989;12, Rhomberg PR DMID 1994;20, Onody C JAC 1997;39, Nielsen K, DMID 2000;36
Legionella spp.	0.10-0.50	0.19-1.0	<0.0015-2.0	(35,44,64,76) (18,32,37) (31) (59, 124,134)(Schrock J DMID 1997;28, Nielsen K DMID 2000;36)
L. micdadei	0.06-1.0	0.25	0.06-1.0	(18,64,73) (26,31,32)
L. bozemanii	0.12-2.0	--	--	(18,64,73)
L. dumoffii	0.25	0.50	0.25-0.50	(31,32,64,73)
L. longbeachae	0.25-1.0	0.50	0.008-0.50	(18,31,32,106)
L. gormanii	0.12	--	--	(64, 73)
Azithromycin
Legionella spp.	0.012-0.50	0.06-2.0	0.016-4.0	(18,31,35,73)(Rhomberg PR DMID 1994;20)
L. pneumophila (serogroups 1,2,5,6)	0.06-01.5	0.50-1.0	0.03-2.0	(18,35,54,106) )(Rhomberg PR DMID 1994;20)
L. pneumophila (serogroups 1-9, 12)	0.03-0.12	0.12-0.5	0.008-0.5	(83)
L. longbeachae	0.12-1.0	0.50	0.016-0.50	(18,31,106)
L. micdadei	0.12-1.0	0.25	0.016-0.25	(18,26,31,73)
L. bozemanii	0.50-1.0	--	--	(18,73)
L. dumoffii	0.12-0.25	0.25	0.12-0.25	(31,73)
L. gormanii	0.25	--	--	(73)
Clarithromycin
Legionella spp.	<0.004-0.25	<0.004-2.0	<= 0.004-2.0	(18,32,73) (59,134) (Rhomberg PR DMID 1994;20)
L. pneumophila (serogroups 1,2,5,6)	0.03-0.50	0.06-2.0	0.03-2.0	(18,54,106)
L. pneumophila (serogroups 1-9, 12)	0.016-0.06	0.06	<0.004-0.06	(31)
L. longbeachae	0.06-0.25	0.12	0.008-0.25	(18,31,106)
L. micdadei	0.06-0.50	0.06	0.03-0.12	(18,31,73)
L. bozemanii	0.12-0.50	--	--	(18,73)
L. dumoffii	0.03-0.12	0.06	0.03-0.06	(31,73)
L. gormanii	0.12	--	--	(73)
14-OH Clarithromycin
Legionella spp.	0.06	0.12	0.03-0.50	(73)
L. micdadei	0.12	--	--	(73)
L. bozemanii	0.06	--	--	(73)
L. dumoffii	0.12	--	--	(73)
Dirithromycin
Legionella spp.	1.0	4.0	0.25-4.0	(73)
L. pneumophila (serogroups 1,2,5)	0.50	8.0	0.25-8.0	(106)
L. longbeachae	8.0	8.0	0.25-16	(106)
L. bozemanii	2.0	--	--	(73)
L. dumoffii	4.0	--	--	(73)
L. gormanii	1.0	--	--	(73)
Josamycin
Legionella spp.	0.25-0.50	0.25-1.0	0.0625-1.0	(130)
L. pneumophila	--	--	0.25-0.50	(130)
L. micdadei	--	--	<=0.0313-0.50	(130)
L. bozemanii	--	--	0.125-0.50	(130)
L. dumoffii	--	--	0.125-0.50	(130)
L. longbeachae (serogroups 1,2)	--	--	<=0.0313-.25	(130)
L. gormanii	--	--	<=0.0313-0.0625	(130)
L. jordanis	--	--		(130)
L. wadsworthii	--	--		(130)
Roxithromycin
Legionella spp.	0.06-0.25	0.125-1.0	0.016-2.0	(18,134)
L. pneumophila (1,2,5,6)	0.12-0.50	0.25-2.0	0.06-2.0	(18,81,106)
L. longbeachae	0.06-0.50	0.50	0.12-0.50	(18,106)
L. micdadei	0.125-1.0	--	--	(18)
L. bozemanii	0.12-0.25	--	--	(18,73)
L. dumoffii	0.12	--	--	(73)
L. gormanii	0.25	--	--	(73)
Telithromycin
Legionella spp.	0.015	0.03	<0.004-0.12	(134)
Ciprofloxacin
L. longbeachae	<=0.004-1.0	0.01-0.06	<=0.004-0.06	(18,31,32,106)
L. pneumophilia	0.03-0.38	0.03-0.38	0.015-0.75	(114) Gooding BB AAC 1992;36, Rhomberg PR DMID 1994;20, Nielsen K DMID 2000;36
L. pneumophilia (serogroups 1-9,12)	<=0.016-2.0	0.016-2.0	<=0.004-4.0	(18,35,57,106) (31,32) Onody C JAC 1997;39.
Legionella spp.	0.01-1.0	0.02-2.0	<=0.004-4.0	(35,44,76) (18,32,64,73) (31,59,114,124) Edelstein DMID 1989;12, Rhomberg PR DMID 1994;20, Nielsen K DMID 2000;36
L. micdadei	0.01-1.0	0.03	0.01-0.03	(18,64,73) (31,32)
L. dumoffii	0.01-1.0	0.03	0.01-0.03	(31,32,64,73)
L. bozemanii	0.015-1.0	--	--	(18,64,73)
L. gormanii	0.03	--	--	(64,73)
Enoxacin
L. pneumophila	0.125	--	--	(19)
Fleroxacin
Legionella spp.	0.06	0.06	0.005-0.06	(64)
L. micdadei	0.03	--	--	(64)
L. bozemanii	0.03	--	--	(64)
L. dumoffii	0.03	--	--	(64)
L. gormanii	0.03	--	--	(64)
Grepafloxacin
Legionella spp.	0.015-0.5	0.015-0.5	0.008-2	(59,123)
L.  pneumophila	<0.004-0.016	0.016-0.03	<0.004-0.03	(31)
Gatifloxacin
Legionella spp.	0.03	0.03	0.015-0.03	(114)
L.  pneumophila	0.015	0.03	0.004-0.03	(114)
L. pneumophila (serogroups 1)	0.016	0.016	<0.004-0.03	(30)
L. pneumophila (serogroups 2-9)	0.008	0.016	0.008-0.016	(30)
Levofloxacin
Legionella spp.	0.015-0.12	0.03-0.12	0.008-0.25	(31,59,134) Rhomberg PR DMID 1994;20.
L.  pneumophila	0.03	--	--	(19)
L. pneumophila (serogroups 1-9, 12)	0.008-0.016	0.008-0.016	<0.004-0.016	(31)
L. dumoffii	0.016	0.016	0.016	(31)
L. micdadei	0.016	0.016	0.008-0.016	(31)
L. longbeachae	0.016	--	0.008-0.016	(31)
Lomefloxacin
Legionella spp.	0.06	0.12-1	0.03-0.12	(64)Edelstein DMID 1989; 12
L. micdadei	0.03-0.06	--	--	(64)
L. bozemanii	0.06	--	--	(64)
L. dumoffii	0.12	--	--	(64)
L. gormanii	0.03	--	--	(64)
Ofloxacin
Legionella spp.	0.016-0.5	0.19-0.5	<0.004-1.5	(31,59)Rhomberg PR DMID 1994;20, Nielsen K DMID 2000; 36
L.  pneumophila	0.015-0.19	0.015-0.25	0.015-0.50	(19,57,81)Rhomberg PR DMID 1994; 20, Nielsen K DMID 2000;36
L. pneumophila (serogroups 1-9, 12)	0.016-0.03	0.016-0.3	<0.004-0.03	(31)
L. micdadei	0.03-0.06	0.03	0.03	(31,64)
L. bozemanii	0.03	--	--	(64)
L. dumoffii	0.03-0.06	0.03	0.03	(31,64)
L. longbeachae	0.03	--	0.016-0.03	(31)
L. gormanii	0.03	--	--	(64)
Pefloxacin
L. pneumophila (serogroup 1)	0.50	--	--	(29)
Rufloxacin
L.  pneumophila	0.12	0.25	0.06-0.25	(57)
Sparfloxacin
L. pneumophila (serogroups 1-8)	<0.004-0.094	<0.004-0.19	<0.004-1	(32,44,76) Rhomberg PR DMID 1994;20
L. micdadei	<0.004	<0.004	<0.004	(32)
Legionella spp	<0.004-0.50	0.008-1.0	<0.004-2.0	(32,76)
L. dumoffii	0.01	0.01	0.008-0.01	(32)
L. longbeachae	0.008	0.01	<0.004-0.01	(32)
TEMAFLOXACIN
L. pneumophila (serogroups 1-9,12)	0.015	0.015	<0.008-0.06	Gooding BB AAC 1992;36
L.bozemanii		0.015		Gooding BB AAC 1992;36
L. dumofii		0.03		Gooding BB AAC 1992;36
L. gormanii		0.015		Gooding BB AAC 1992;36
L. micdadei		0.015		Gooding BB AAC 1992;36
Trovafloxacin
Legionella spp.	<0.004-0.25	0.25	<0.004-1	(31,59)
L. pneumophila (serogroups 1-8)	< 0.004	<0.004	<0.004-0.016	(31,32)
L. micdadei	< 0.004	<0.004	<0.004	(31,32)
L. dumoffii	< 0.004	<0.004	<0.004-0.008	(31,32)
L. longbeachae	< 0.004	<0.004	<0.004	(31,32)
Legionella spp.	< 0.004	<0.004	<0.004	(31,32)
Moxifloxacin
Legionella spp.	0.008-0.03	0.018	0.008-0.12	(31,124,134)
L. pneumophila (serogroups 1-9, 12)	<0.004-0.016	0.008-0.016	<0.004-0.03	(31)
L. dumoffii	0.03	0.03	0.008-0.03	(31)
L. micdadei	0.016	0.03	0.008-0.03	(31)
L. longbeachae	0.016	--	0.008-0.03	(31)
Gemifloxacin
Legionella spp.	0.03-1	1	0.016-4	(31,59)
L. pneumophila (serogroups 1-9, 12)	0.008-0.03	0.016-0.03	0.008-0.03	(31)
L. dumoffii	0.06	0.06	0.06	(31)
L. micdadei	0.016	0.03	0.008-0.03	(31)
L. longbeachae	0.06	--	0.016-0.03	(31)
Amoxicillin
L. pneumophila (serogroups 1,2,5)	0.25-0.50	2.0	0.12-2.0	(106)
L. longbeachae	0.50-1.0	>2.0	0.25-2.0	(106)
Amoxicillin/Clavulanate
L. pneumophila (serogroups 1,2,5)	0.06-0.25	0.25	0.06-0.50	(106)
L. longbeachae	0.25-0.50	1.0	0.25-1.0	(106)
Piperacillin/Tazobactam
L. longbeachae	0.06	0.12	0.015-0.12	(106)
L. pneumophila (serogroups 1,2,5)	0.25	0.50	0.06-0.50	(106)
Imipenem
L. longbeachae	<0.03	0.03	0.015-0.06	(18,106)
L. pneumophila (serogroups 1,2,5)	0.03-0.125	0.06	<0.015-0.25	(18,106)
Legionella spp	0.03-0.50	0.06-1.0	<0.03-2.0	(18,64)
L. micdadei	0.125-0.25	--	--	(18,64)
L. bozemanii	0.25-1.0	--	--	(18,64)
L. dumoffii	4.0	--	--	(64)
Imipenem
L. gormanii	1.0	--	--	(64)
Meropenem
Legionella spp.	<0.06	0.12	<0.06-0.125	(73)
L. micdadei	<0.06	--	--	(73)
L. bozemanii	<0.06	--	--	(73)
L. dumoffii	0.12	--	--	(73)
L. gormanii	0.12	--	--	(73)
Rifampicin
Legionella spp.	<0.0005-0.03	<0.002-0.03	<0.0005-0.03	(63,73,76) (18,32) (31,134) (124)
L. pneumophila (serogroups 1-9,12)	<0.002-0.004	<0.004-0.008	<0.0004-0.008	(18,81.106) (31,32)
L. micdadei	0.008	0.008	0.008	(18,64,73) (31,32)
L. dumoffii	0.008-0.15	0.01	<0.004-0.03	(18,106) (31,32)
L. longbeachae	<0.002-0.004	0.01	<0.004-0.06	(64,73) (18,32)
L. bozemanii	<0.002-0.004	--	--	(64,73)
Clindamycin
Legionella spp.	4.0-8.0	8.0	1.0-16	(73,134)
L. micdadei	4.0-8.0	--	--	(73)
L. bozemanii	4.0	--	--	(73)
L. dumoffii	4.0	--	--	(73)
L. gormanii	4.0	--	--	(73)
Trimethoprin/Suflamethaxazole
Legionella spp.	0.50	0.50	<0.03-1.0	(73)
L. micdadei	0.50	--	--	(73)
L.bozemanii	<0.03	--	--	(73)
L. dumoffii	<0.03	--	--	(73)
L. gormanii	<0.03	--	--	(73)
Doxycycline
Legionella spp.	1.0-4.0	2.0-8	0.12-8.0	(73,134)
L. micdadei	0.12-025	--	--	(73)
L.bozemanii	1.0	--	--	(73)
L. dumoffii	1.0	--	--	(73)
L. gormanii	2.0	--	--	(73)
Tetracycline
Legionella spp.	8.0	8.0	1.0->8.0	(73)
L. micdadei	0.25-1.0	--	--	(73)
L.bozemanii	4.0	--	--	(73)
L. dumoffii	4.0	--	--	(73)
L. gormanii	4.0	--	--	(73)
Dalfopristin-Quinupristin
Legionella  spp.	0.25	0.5	0.12-1	(134)
Linezolid
Legionella spp.	4	8	4.0-8	(134)

 

 Table 2:  Susceptibility of Legionella spp. To Antimicrobial Agents by In Vitro Broth Dilution Method

Drug/Species	MIC50 (mcg/ml)	MIC90 (mcg/ml)	MIC range (mcg/ml)	References
Erythromycin
L.pneumophila sg 1	0.5	1.0	0.125-1.0	Stout JE IJJA 2005;25
L. pneumophila sg 2-7 and 15	0.125	0.5	0.125-1.0	Stout JE IJJA 2005;25
L. pneumophila	0.125-0.25	0.25-1	0.016-1.0	(35,44,81) (37,57) (121,142)(Critchley IA, CMI 2002;8)
Legionella other than pneumophila	0.25	0.25	0.125-0.5	Stout JE IJJA 2005;25
Legionella spp.	0.5-0.06	0.5-0.10	0.032-1.0	(35,37,39) (40,58)
L. micdadei	--	0.25	1.0	(26,135,142)
L. bozemanii	--	0.25	0.25	(26,135,142)
L. longbeachae	0.06	0.12-0.25	0.06-0.12	(63,135)
L. gormanii	0.12	0.5	0.06-0.5	(63)
L. dumoffii	0.12	0.5	0.12-0.5	(63)
Azithromycin
L.pneumophila sg 1	0.25	2.0	<0.06-2.0	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.125	0.25	<0.06-1.0	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.25	0.25	0.125-0.5	Stout JE IJJA 2005;25
L. pneumophila	0.06-1.39	0.5-2.77	0.016-7.80	(35,121) (63,142) (135) (Critchley IA, CMI 2002;8)
L. micdadei	--	0.25	0.50	(135,142)
L. bozemanii	--	0.125	0.25q	(135,142)
L. longbeachae	0.12	0.25	0.06-0.25	(63,135)
L. gormanii	0.25	0.5	0.12-1.0	(63)
L. dumoffiii	0.25	0.5	0.12-0.5	(63)
Clarithromycin
Legionella spp.	0.007-0.032	0.015-0.5	0.0004-2	(40,58) (49,92)
L. pneumophila	0.007-0.032	0.008-0.06	<0.001-0.125	(93,121,142) (40,135) (Critchley IA, CMI 2002;8)
L.pneumophila sg 1	0.03	0.06	0.03-0.06	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.015	0.03	0.015-0.03	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.03	0.06	0.015-0.125	Stout JE IJJA 2005;25
L. micdadei	--	0.03	0.125	(135,142)
L. bozemanii	--	<0.03	0.03	(135,142)
L. longbeachae	--	0.125	--	(135)
14-Hydroxyclarithromycin
Legionella spp.	--	--	0.004-0.03	(93)
Dirithromycin
L. pneumophila	--	--	0.50-8.0	(142)
L. micdadei	--	--	4.0	(142)
L. bozemanii	--	--	8.0	(142)
Roxithromycin
L. pneumophila	0.0625	--	0.06-0.25	(81,142)
L. micdadei	--	--	4.0	(142)
L. bozemanii	--	--	8.0	(142)
Telithromycin
Legionella spp.	0.062	0.125	0.004-0.250	(40)
L. pneumophila	0.032	0.125	0.016-0.344	(40,135)
L. micdadei	--	<0.03	--	(135)
L. longbeachae	--	<0.03	--	(135)
L. bozemanii	--	<0.03	--	(135)
ABT 773
L. pneumophila	--	0.03-0.06	--	(135)
L. micdadei	--	0.03	--	(135)
L. longbeachae	--	0.25	--	(135)
L. bozemanii	--	0.03	--	(135)
Ciprofloxacin
Legionella spp	0.007-0.016	0.015-0.06	0.0018-0.25	(35,42)(92) Jonas D, JAC 2003;51
L. pneumophila	0.0079-0.06	0.03-0.06	0.016-0.25	(35,44)(81,121)(63,135)
L.pneumophila sg 1	0.03	0.03	0.015-0.06	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.03	0.03	0.008-0.03	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.008	0.03	0.008-0.03	Stout JE IJJA 2005;25
L. longbeachae	0.016	0.03	0.008-0.03	(63,135)
L .gormanii	0.016	0.03	0.016-0.03	(63)
L. dumoffii	0.03	0.03	0.01-0.03	(63)
L. micdadei	--	0.008	--	(135)
L. bozemanii	--	0.015	--	(135)
Levofloxacin
Legionella spp	0.007-0.032	0.016-0.063	0.0039-0.5	(40,42) (58,92) (146)
L. pneumophila	0.015-0.062	0.015-0.063	0.008-0.063	(63,99) (40,135) (Critchley IA, CMI 2002;8)(Jonas D, JAC 2003;51)
L.pneumophila sg 1	0.015	0.03	0.015-0.03	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.015	0.03	0.008-0.03	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.03	0.06	0.008-0.06	Stout JE IJJA 2005;25
L. longbeachae	0.016	0.016	0.008-0.016	(63,135)
L. micdadei	--	0.015	--	(135)
L. bozemanii	--	0.03	--	(135)
L. gormanii	0.016	0.016	0.008-0.016	(63)
L. dumoffii	0.016	0.016	0.008-0.016	(63)
Ofloxacin
Legionella spp.	0.015-0.032	0.03-0.64	0.007-0.25	(39,42,81) (49,58)
L. pneumophila (serogroups 1)	0.02-0.06	0.06-0.12	0.01-0.25	(42,63,81)
L. longbeachae	0.016	0.03	0.008-0.03	(63)
L. gormanii	0.03	0.06	0.03-0.06	(63)
L. dumoffii	0.03	0.06	0.03-0.06	(63)
Sparfloxacin
Legionella spp.	0.19	0.38	0.03-1.0	(21) (92)
L. pneumophila (serogroup 1)	<=0.003	--	--	(44)
Trovafloxacin
Legionella spp.	0.0018-0.125	0.0018-0.5	0.004-0.38	(21) (92) (146)
L. pneumophila	<0.004	<0.004-0.008	0.004-0.008	(63, 135) (Jonas D, JAC 2003;51)
L.pneumophila sg 1	0.004	0.008	0.004-0.015	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.004	0.008	<0.002-0.008	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.004	0.008	0.004-0.015	Stout JE IJJA 2005;25
L. longbeachae	--	0.004-0.008	<0.004-0.004	(63,135)
L. bozemanii	--	0.008	--	(135)
L. micdadei	--	0.008	--	(135)
L. gormanii	0.004	0.004	<0.004-0.008	(63)
L. dumoffii	<0.004	0.008	0.004-0.008	(63)
Gatifloxacin
Legionella spp.	0.19	0.38	0.125-0.5	(21)
Grepafloxacin
Legionella spp.	0.007	0.007-0.03	0.0018-0.5	(49,58) (92)
L. pneumophila	--	0.03-0.06	--	(135)
L.pneumophila sg 1	0.06	0.06	0.015-0.125	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.015	0.03	0.015-0.06	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.015	0.125	0.015-0.125	Stout JE IJJA 2005;25
L. micdadei	--	0.015	--	(135)
L. longbeachae	--	0.125	--	(135)
L. bozemanii	--	0.03	--	(135)
T-3811 DES-F(6)-Quinolone
Legionella spp.	0.0156	0.0313	0.002-0.0313	(146)
Gemifloxacin
Legionella spp.	0.003	0.003	0.0009-0.03	(58)
L. pneumophila		0.03		(135)
L.pneumophila sg 1	0.015	0.03	0.008-0.06	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.015	0.03	0.008-0.06	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.015	0.03	0.015-0.06	Stout JE IJJA 2005;25
L. micdadei		0.015		(135)
L. longbeachae		0.06		(135)
L. bozemanii		0.03		(135)
Moxifloxacin
Legionella spp.	--	0.06	0.03-0.25	(92)
L. pneumophila	0.008-0.016	0.016-0.06	0.004-0.03	(63,135)
L.pneumophila sg 1	0.03	0.06	0.015-0.06	Stout JE IJJA 2005;25
L.pneumophila sg 2-7 and 15	0.03	0.06	0.015-0.06	Stout JE IJJA 2005;25
Legionella other than pneumophila	0.03	0.06	0.015-0.06	Stout JE IJJA 2005;25
L. longbeachae	0.016	0.016-0.03	0.008-0.03	(63,135)
L. gormanii	0.0016	0.016	0.008-0.03	(63)
L. dumoffii	0.016	0.03	0.008-0.003	(63)
L. micdadei	--	0.03	--	(135)
L. bozemanii	--	0.03	--	(135)
Amoxicillin
L. pneumophila	0.5	1	<0.063-1	(99)
Cefdinir
L. pneumophila	8	8	0.25-8	(99)
Cefditoren
L. pneumophila	8	16	0.25-16	(99)
Piperacillin
L. pneumophila (serogroup 1)	0.25	--	--	(81)
Imipenem
L. pneumophila	<0.063-0.0157	<0.0063	<0.063	(81) (99)
Faropenem
L. pneumophila	<0.063	<0.063	<0.063	(99)
L-036 (carbapenem)
L. pneumophila	<0.063	<0.063	<0.063	(99)
Rifampicin
Legionella spp.	0.008	0.008	<0.004-0.06	(49)
L. pneumophila	0.0000043-0.004	0.000012-0.004	<0.001-0.062	(81) (63,121)
L. longbeachae	0.008	0.03	<0.004-0.03	(63)
L. gormanii	0.004	0.004	<0.004-0.008	(63)
L. dumoffii	0.008	0.016	<0.004-0.016	(63)
Doxycycline
L. pneumophila	1.76-2.48	3.65-4.95	0.24-31.25	(121)
Minocycline
L. pneumophila (serogroup 1)	0.0313	--	--	(81)
Tigecycline
Legionella spp	4	8	0.5-8	Edelstein AAC2003
Quinupristin/Dalfopristin
Legionella  spp.	0.25	0.50	0.125-0.50	(41)

Table 3:  Activity of Antimicrobial Agents Using In Vivo Animal Model 

Species	Antimicrobials	Animal model*	Effect	References
L. pneumophila, serogroup 1
	erythromycin	gp pneumonia gp peritonitis rat pneumonia	10-90% survival 33-100% survival Significant decrease in bacterial load in lung	(44,58,82,108,128,130) (56) (140)
	erythromycin + rifampicin (po)	gp pneumonia	20% survival	(58)
	azithromycin	gp pneumonia A/J mice pneumonia	100% survival 92% survival	(54,122) (15)
	clarithromycin	gp pneumonia	100% survival	(54)
	josamycin	gp pneumonia	0-20% survival	(82,130)
	telithromycin	gp pneumonia	100% survival	(40)
	ABT 773	gp pneumonia	66% survival **	(45)
	ciprofloxacin	gp pneumonia	50-80% survival	(128,129)
	levofloxacin	gp pneumonia	91-100%	(42,46)
	ofloxacin	pg pneumonia A/J mice pneumonia	70-100% survival 92% survival	(42,43,128,130) (15)
	pefloxacin	gp peritonitis gp pneumonia	100% survival 87.5% survival	(29) (108)
	sparfloxacin	gp pneumonia	100% survival	(44,128)
	trovafloxacin	gp pneumonia	100% survival	(43)
	alatrofloxacin	gp pneumonia	100% survival	(58)
	amoxifloxacin	gp pneumonia	Significant decrease in bacterial load in lung	(88)
L. pneumophila, Serogroup 1
	gemifloxacin	gp pneumonia	92% survival	(46)
	rifampicin	gp pneumonia gp peritonitis	62.5-90% survival 67-100% survival	(108,130) (140)
	amoxicillin/clavulanate	rat pneumonia	significant decrease in bacterial load in lung	(140)
	amoxicillin/clavulanate	rat pneumonia	significant decrease in bacterial load in lung	(139)
	ticarcillin/clavulanate	rat pneumonia	significant decrease in bacterial load in lung	(140)
	amoxicillin	rat pneumonia	no decrease in bacterial load in lung	(140)
	ticarcillin	rat pneumonia	no decrease in bacterial load in lung	(140)
	minocycline	gp pneumonia gp peritonitis	75 - 87.5% survival 33-67% survival	(108) (104)
	doxycycline	gp pneumonia	75% survival	(108)
	tetracycline	gp peritonitis	17% survival	(56)
	tigeciclyne	gp pneumonia	81% survival	Edelstein AAC 2003
	chloramphenicol	gp peritonitis	33% survival	(56)
	penicillin	gp peritonitis	0% survival	(56)
	aminoglycosides	gp peritonitis	0-33% survival	(56,104)
L. micdadei
	erythromycin	gp pneumonia	70% survival	(110)
	rifampicin	gp pneumonia	60% survival	(110)
	trimethoprim-sulfamethoxazole	gp pneumonia	60% survival	(110)
	doxycycline	gp pneumonia	40% survival	(110)
	penicillin	gp pneumonia	30% survival	(110)
	cefazolin	gp pneumonia	30% survival	(110)
	chloramphenicol	gp pneumonia	20% survival	(110)
	gentamicin	gp pneumonia	20% survival	(110)
	cefoxitin	gp pneumonia	0% survival	(110)

**All of the ABT 773 treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia (45).

Table 4:  Antibiotic Doses for Legionella Infection

Antimicrobial Agent	Dosage*
Azithromycin**	500mg*** orally or intravenously every 24 hours
Clarithromycin	500mg orally or intravenously† every 12 hours
Roxithromycin	500mg orally every 12 hours
Erythromycin	1000mg intravenously every 6 hours 500mg orally every 6 hours
Dirithromycin	500mg orally every 24 hours
Levofloxacin	500mg*** orally or intravenously every 24 hours
Ciprofloxacin	400mg intravenously every 8 hours 750mg orally every 12 hours
Ofloxacin	400mg orally or intravenously every 12 hours
Moxifloxacin	400mg ***orally every 24 hours
Doxycycline	100mg*** orally or intravenously every 12 hours
Minocycline	100mg*** orally or intravenously every 12 hours
Tetracycline	500mg orally or intravenously every 6 hours
Tigecycline	100 gm intravenously, then 50 gm intravenously every 12 hours
Trimethoprim-sulfamethoxazole	160 and 800mg intravenously every 8 hours 160 and 800mg orally every 12 hours
Rifampin	300 to 600mg orally or intravenously   every 12 hours

*The dosages are based on clinical experience and not on controlled trials.

**Intravenous form not available in some European countries.

***We recommend doubling the first dose until defervescence is achieved.

† Intravenous form not available in the United States.