Treatment and prevention of Legionella infection

INTRODUCTION — Legionella bacteria are intracellular pathogens and are important causes of community-acquired and nosocomial pneumonia. Pneumonia caused by Legionella bacteria is termed Legionnaires' disease. Legionnaires' disease can be severe, and early administration of appropriate antimicrobial therapy is associated with improved outcomes.

Legionella infection can also cause Pontiac fever, a nonspecific febrile illness typically identified during outbreaks. Pontiac fever is typically self-limited and resolves without antimicrobial therapy.

The majority of Legionella infections are acquired sporadically, but some are associated with outbreaks. Early identification of common environmental sources of infection, such as contaminated water supplies, is key to prevention.

The treatment and prevention of Legionella infections will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis are discussed separately. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection" and "Clinical manifestations and diagnosis of Legionella infection".)

TREATMENT OF LEGIONNAIRES' DISEASE (LEGIONELLA PNEUMONIA)

Empiric treatment

Community-acquired pneumonia — Legionella accounts for approximately 1 to 10 percent of cases of community-acquired pneumonia (CAP) [1-4]. For most patients with CAP, the etiology is not known at the time of diagnosis, and empiric treatment is appropriate.

We generally include an antibiotic that targets Legionella (eg, a fluoroquinolone or macrolide) when selecting an empiric antibiotic regimen for most patients with CAP. Selection among these agents and the need for treatment with additional antibiotics varies based on pneumonia severity, patient comorbidities, and local epidemiology (algorithm 1 and algorithm 2). There is a lack of standardization of in vitro resistance testing and a paucity of comparative clinical trials published, so evidence is incomplete. Consequently, we generally avoid tetracyclines for legionellosis. Destructases have been identified in both Legionella longbeachae and Legionella jordanis, and the minimum inhibitory concentrations of Legionella pneumophila on in vitro testing appear higher than with other agents [5-9]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

Although large meta-analyses have not shown consistent benefit for empiric treatment of atypical pathogens (eg, Legionella, Mycoplasma, and Chlamydia species) in all-comers with CAP [10-12], in a subgroup analysis of 43 patients with CAP caused by L. pneumophila, clinical failure was reduced when comparing empiric regimens that included coverage for atypical pathogens with regimens that lack such coverage (risk ratio [RR] 0.17, 95% CI 0.05-0.63) [11]. In addition, observational data suggest that delays in appropriate antibiotic therapy are associated with increased mortality in patients with CAP caused by Legionella spp [13,14]. Because Legionnaires' disease is indistinguishable from other forms of pneumonia without diagnostic testing, we take an inclusive approach to empiric treatment.

Our approach is largely consistent with the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guidelines, which recommend including one of these antibiotics in the empiric treatment regimen for most patients with CAP [15]. In contrast, the British Thoracic Society (BTS) and National Institute for Health and Care Excellence (NICE) guidelines reserve use of agents that target atypical pathogens, such as Legionella, for patients with moderate to severe CAP or when Legionella infection is suspected based on clinical and/or epidemiologic features [16-19].

Nosocomial pneumonia — Most cases of Legionnaires' disease are sporadic and community acquired. However, contamination of water supplies in large facilities, such as hospitals and nursing homes, can lead to outbreaks [20-22]. When a Legionella outbreak is known or suspected, we include an antibiotic that targets Legionella (eg, a fluoroquinolone or macrolide) in empiric antibiotic regimens for the treatment of pneumonia acquired in health care settings.

As with CAP, selection among these agents and the need for treatment with additional antibiotics varies based on pneumonia severity, patient comorbidities, and hospital epidemiology (algorithm 3 and algorithm 4). (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Empiric therapy'.)

Directed treatment

Antibiotic selection — Levofloxacin and azithromycin are the preferred agents for the treatment of Legionnaires' disease because these agents are bactericidal, achieve high intracellular concentrations, penetrate lung tissue, and are active against all Legionella species that cause human infection. Alternatives include other fluoroquinolones (eg, moxifloxacin, ciprofloxacin) and other macrolides (eg, clarithromycin, roxithromycin) (table 1). We generally do not use tetracyclines (eg, doxycycline) for empiric treatment because resistance is common among L. longbeachae.

For patients with microbiologically confirmed Legionnaires' disease (eg, positive polymerase chain reaction [PCR], urine antigen test, or sputum culture), we generally tailor the initial empiric regimen to a single antibiotic that targets Legionella. Coinfection with other pathogens is rare [23].

●For patients with moderate or severe pneumonia (any hospitalized patient or patient with a CRB/CURB-65 score ≥1 (calculator 1) or Pneumonia Severity Indices [PSI] >II (calculator 2)) caused by any Legionella species, we use a fluoroquinolone (eg, levofloxacin) or a macrolide (eg, azithromycin). We generally give these antibiotics intravenously for most hospitalized patients and transition to oral therapy as soon as the patient is clinically improving, hemodynamically stable, and able to tolerate oral therapy. As a general caveat, severity scores should be used as an adjunct to clinical judgement.

●For patients with mild pneumonia (CRB/CURB-65 scores of 0 or PSI of I to II) caused by L. pneumophila, we prefer to use levofloxacin or azithromycin. However, it is not necessary to change therapy to one of these agents for patients who are being treated with other fluoroquinolones, other macrolides, or tetracyclines and are responding to therapy.

●For patients with mild pneumonia caused by L. longbeachae, we use either a fluoroquinolone or macrolide because L. longbeachae is often resistant to tetracyclines [5-7].

There are no randomized trials that have directly evaluated the efficacy and side effects of anti-Legionella antibiotics. However, cohort studies have not found differences in mortality when comparing levofloxacin with azithromycin [24-27]. Higher doses of levofloxacin (ie, 750 mg daily) may lead to faster symptom resolution than lower doses (500 mg daily) [28]; we therefore choose higher doses when using this drug. Macrolides other than azithromycin are bacteriostatic against Legionella [29,30] and appear to be less effective than either levofloxacin or azithromycin [25,31,32].

Combination therapy using both a fluoroquinolone and a macrolide does not appear to improve outcomes [24,25]. Adding rifampin (an agent that achieves high intracellular concentrations and can penetrate biofilms) to either fluoroquinolone or macrolide monotherapy does not appear to improve outcomes but may increase adverse events [31,33]. Tigecycline has been reported to be effective salvage therapy for some patients with refractory L. pneumophila infections. The activity of tigecycline against L. longbeachae is not known but, like its tetracycline relatives, tigecycline may be inactive against L. longbeachae [34,35].

Duration of therapy — The optimal duration of therapy for the treatment of Legionnaires' disease has not been determined and varies with the antibiotic selected, severity of illness, and patient response to therapy (table 1). In general, we treat for a minimum of five days and do not stop therapy until the patient is clinically stable and afebrile for at least 48 hours. Patients with severe pneumonia or chronic comorbidities may be slow to respond to therapy and often require 7 to 10 days of treatment. Patients with complications (eg, lung abscess, empyema, or extrapulmonary infection) and immunosuppressed patients typically need extended courses of therapy [36]. (See 'Immunocompromised patients' below.)

Procalcitonin is increasingly used to help determine antibiotic duration in patients with CAP. However, its utility in patients with Legionnaires' disease is not well established. Procalcitonin levels do rise with Legionnaires' disease but may not rise to the same degree as with pneumonia caused by typical pathogens such as Streptococcus pneumoniae [37-39]. Thus, it is unclear whether procalcitonin thresholds used to guide antibiotic therapy in patients with CAP in general can be applied to patients with Legionnaires' disease. (See "Procalcitonin use in lower respiratory tract infections", section on 'Variability among pathogens'.)

Immunocompromised patients — Transplant recipients and other immunocompromised patients with Legionnaires' disease are at risk for both severe infection and relapse [36,40-42]. Therefore, we select either levofloxacin or azithromycin and treat for a minimum of 14 days, adjusting the total course based on clinical response. Potential drug interactions and adverse effects should be taken into account when selecting between these two antibiotics [43].

Because of the risk of relapse, we also consider reducing immunosuppression when possible. If prolonged and high levels of immunosuppression are required, a suppressive course of therapy (eg, three to six months) can be given. We make these decisions on case-by-case basis.

Adjunctive treatment — Adjunctive glucocorticoid use may be helpful in patients with severe Legionnaires' disease. Because Legionella infections induce an intense inflammatory response, glucocorticoid treatment is appealing. However, this intervention is not better studied in Legionnaires' disease than in other types of pneumonia. Indications for use are the same as those for any patient with severe pneumonia. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Adjunctive glucocorticoids'.)

Extracorporeal membrane oxygenation (ECMO) is a potential option for patients with severe, but potentially reversible, acute respiratory failure. Observational data suggest that survival rates with ECMO use may be as high as 85 percent in patients with Legionnaires' disease [44-47]. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

Surgical drainage or debridement may be needed in patients with empyema who fail medical therapy [36]. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults".)

Response to treatment — Most patients with Legionnaires' disease respond promptly to treatment, defervescing in approximately two to five days [32,48]. Resolution of radiographic changes often lag behind clinical improvement, though most clear over a period of two months [49].

Some patients progress despite therapy. Up to 44 percent of patients require intensive care unit admission, and mortality ranges from approximately 1 to 10 percent [50-52]. Factors associated with poorer outcomes include nosocomial acquisition, delay in appropriate antibiotic therapy, older age, immunosuppression, and the presence of chronic comorbidities [13,14,53-55]. The prognosis for L. longbeachae is similar to L. pneumophila [56].

For patients who are slow to respond to treatment, complications such as lung abscess, empyema, or extrapulmonary infection should be considered. Coinfection with other pathogens is rare but has been reported among patients with nosocomial Legionnaires' disease [57,58]. Other causes of nonresolving pneumonia should also be considered. (See "Nonresolving pneumonia".)

TREATMENT OF OTHER LEGIONELLA INFECTIONS

Extrapulmonary disease — Patients with extrapulmonary infections (eg, cellulitis, skin abscesses, septic arthritis, myocarditis, or endocarditis) are most often treated with a fluoroquinolone (eg, levofloxacin). However, antibiotic selection, duration, and need for other interventions (eg, incision and drainage) varies with the site and severity of infection [59]. Generally, longer courses of therapy are required for patients with extrapulmonary legionellosis than with Legionnaires' disease. Because extrapulmonary infections often occur in immunocompromised patients, reducing immunosuppression (when feasible) may help achieve cure. (See 'Immunocompromised patients' above.)

Pontiac fever — Pontiac fever is usually short lived and resolves spontaneously after three to five days. Specific therapy is not needed.

PREVENTION OF LEGIONELLA INFECTIONS

Patient precautions — Patients with confirmed or suspected Legionella infection do not require isolation or contact precautions. Although Legionella infections are associated with outbreaks, person-to-person spread is exceedingly rare, with only one possible case reported [60].

Outbreak identification — The diagnosis of a single case of Legionella infection should prompt suspicion for an outbreak. Although most cases are acquired sporadically, some are linked to a common source such as a contaminated water supply or contaminated soil. Outbreak investigations are typically prompted by the identification of Legionella in the microbiology laboratory and further coordinated by hospital epidemiologists and/or local public health authorities. However, clinicians should be prepared to assist in the investigation by obtaining clinical and epidemiologic information from the patient as appropriate.

Environmental measures

Disinfection of the water supply — Disinfection of water distribution systems and surveillance for Legionella contamination are routine practices in water management, particularly in large water distribution systems in developed countries [61-66]. The primary methods for controlling Legionella contamination in water distribution systems include copper-silver ionization, hyperchlorination, thermal shock, chlorine dioxide, monochloramine, and point-of-use filters [67,68]. However, cases of legionellosis still occur from treated water systems and may be related to the ability of the Legionella spp to survive intracellularly within water-dwelling amoeba [69]. Additionally, not all water supplies are regulated. As an example, drinking water supplies are not routinely monitored for Legionella infection, even in developed countries, and continue to serve as a source of infection [21,70,71].

Preventing soil transmission — Patients who live in areas where L. longbeachae is commonly found in soil (eg, Australia and New Zealand) should be educated on how to prevent inhalation of organism when working with soil or compost [72]. For example, gardeners should be advised to wash their hands after gardening and should avoid touching their face before washing their hands. Those handling compost should be advised to open bags away from the face and to keep compost close to the ground when moving it around. Persons at higher risk for Legionella infection (eg, smokers, persons with chronic lung disease, and immunocompromised patients) should be particularly careful.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults".)

SUMMARY AND RECOMMENDATIONS

●Rationale for antibiotic selection − Levofloxacin and azithromycin are the preferred agents for the treatment of Legionnaires' disease because these agents are bactericidal, achieve high intracellular concentrations, penetrate lung tissue, and are active against all Legionella species that cause human infection. (See 'Antibiotic selection' above.)

●Importance of early antibiotic administration − Because early administration of appropriate antibiotics has been shown to decrease mortality associated with Legionella infection, we generally include one of these agents when selecting an empiric antibiotic regimen for any patient with community-acquired pneumonia. (See 'Empiric treatment' above.)

●Antibiotic selection − For patients with confirmed Legionella pneumonia, we prefer to use levofloxacin or azithromycin. Alternatives include ciprofloxacin, moxifloxacin, clarithromycin, and roxithromycin (table 1). We generally do not use tetracyclines (eg, doxycycline) because resistance is common among Legionella longbeachae. (See 'Directed treatment' above.)

●Treatment duration (most patients) − In general, we treat patients with Legionnaires' disease for a minimum of 5 days and do not stop therapy until the patient is clinically stable and afebrile for at least 48 hours. Patients with severe pneumonia or chronic comorbidities may be slow to respond to therapy and often require 7 to 10 days of treatment. (See 'Duration of therapy' above.)

●Treatment duration (immunocompromised) − Transplant recipients and other immunocompromised patients are at risk for both severe infection and relapse. Thus, we generally treat for a minimum of 14 days and consider reducing immunosuppression (when feasible) in immunocompromised patients. (See 'Immunocompromised patients' above.)

●Response to treatment − Most patients defervesce about two to five days after starting therapy, though, in a minority, infection can be fulminant. Up to 44 percent of patients require intensive care unit admission, and the associated mortality is approximately 1 to 10 percent. (See 'Response to treatment' above.)

●Extrapulmonary diseases − Patients with extrapulmonary infections (eg cellulitis, skin abscesses, septic arthritis, or endocarditis) are most often treated with levofloxacin. However, antibiotic selection, duration of therapy, and need for additional interventions (eg, incision and drainage) vary with the site and severity of infection. (See 'Extrapulmonary disease' above.)

●Pontiac fever − In contrast with other Legionella infection, Pontiac fever is typically a self-limited illness that resolves in about two to five days without antibiotic therapy. (See 'Pontiac fever' above.)

●Precautions − Patients with confirmed or suspected Legionella infection do not require isolation or contact precautions. Although Legionella infections are associated with outbreaks, person-to-person spread is exceedingly rare. (See 'Patient precautions' above.)

●Preventive measures − Key preventive measures include early identification of outbreaks, routine water distribution disinfection, and safe handling of soil and compost. (See 'Prevention of Legionella infections' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Victor Yu, MD, Nieves Sopena Galindo, MD, and Patricia Priest, MBChB, DPhil, who contributed to earlier versions of this topic review.