Legionnaires’ Disease Treatment

Legionnaires’ disease is an important cause of community-acquired pneumonia as well as hospital-acquired pneumonia. Legionella pneumophila is an important but uncommon respiratory pathogen with significant morbidity and mortality. Initially recognized as a fatal cause of pneumonia in the 1970s. Untreated Legionnaires’ disease conveys high mortality, therefore a prompt treatment with appropriate antibiotics is of extreme importance. Currently, therapeutic options include macrolides and fluoroquinolones mainly, that have an effective therapeutic profile. Potential issues of bacterial resistance have risen, but overall, this is not a significant limitation of therapy. In addition, attempts to identify other cases related to the case will help find potential sources.


Introduction
Legionella pneumophila is responsible for 90% of Legionnaires' disease (LD) [1][2][3]. Legionella pneumonia, or LD has an increasing incidence, its mortality has progressively improved from 34% in 1980, to 12% in 1998, to 3.1% in 2010, however 20-25% of patients require mechanical ventilation with a mortality rate as high as 25% [4]. It is believed that the evolution of antibiotic therapy has improved outcomes [4]. Legionella pneumonia may have an atypical presentation that will contribute to its underdiagnosing and under-reporting [5], majority of reported cases are due to Legionella pneumophila serotype-1 (80%), that may reflect the relatively wide availability of commercial kits to test for this specific serotype [5]. Legionella is an ubiquitous environmental intracellular Gram-negative bacteria, therefore antibiotics capable of penetrating phagocytic cells should be selected, then macrolides and quinolones have become the recommended therapies [6][7][8]. Risk factors associated with higher mortality rates are older age, smoking, chronic cardiopulmonary disease, diabetes, alcohol abuse, cancer and immunosuppression [9]. Appropriate antibiotic selection will drop mortality significantly, from 60-70% to 10-20% [2,7,10,11].

Treatment
For years, macrolides, specifically erythromycin, has been the mainstay of therapy until the 1990s [4,12], however with the emergence of newer macrolides and quinolones, the therapeutic selection has shifted, and now Azithromycin or Levofloxacin are considered the mainstay of LD treatment [12]. Beta-lactam and aminoglycoside antibiotics are ineffective in the treatment of LD, then empiric therapy based on either macrolides or quinolones for initial moderate to severe pneumonia will be a reasonable approach [12][13][14].
Effective antibiotic therapy depends on the ability to concentrate in alveolar macrophages, and for these concentrations to be effective, it will need to range from 10 to 30 times greater than serum concentrations [15] Fluoroquinolones are antimicrobials with concentration-dependent bactericidal activity [16].
In cases of severe LD, combination therapy has been advocated without evidence of superiority [12]. The incidence of LD as cause of severe pneumonia requiring ICU admission has been reported as high as second most common behind Streptococcus pneumonia (17.8 versus 21.6%, respectively) [2,13].
In a retrospective review of 3157 adult cases, from more than 400 U.S. hospitals between 2008 and 2013, it was noted that quinolones alone were used in 28.8%, whereas azithromycin alone was used in 34% of patients, only 1.8% of patients received combination therapy (see Figure 1). Hence, the majority of patients with LD in the US are treated with azithromycin and/or quinolone [4]. No prospective randomized trial has compared outcomes of levofloxacin versus azithromycin [14].

Empiric therapy
The choice of empiric antibiotic therapy is based on the premise of providing optimal therapy, the epidemiological features of the probable agents, and an inference of the most likely pathogen [17].
The empirical coverage for Legionnaires' disease is still a matter of debate, in view of low testing frequency that underscores poor emphasis on Legionella role in pneumonia [18]. The incidence of LD is higher in cases of severe pneumonia, hence patients admitted to an ICU setting should be tested and treated as potential Legionella pneumonia [17]. Historically empirical optimal monotherapy treatment has been based on doxycycline, a quinolone or azithromycin [19]. Respiratory fluoroquinolones are an effective empiric treatment for bacterial community-acquired pneumonia, used as monotherapy in the outpatient setting, and hospitalized patients, as a first-line or alternative agents; in addition to be used as combination therapy in the ICU setting [20]. Azithromycin has a comparable antibiotic profile to fluoroquinolones, in addition has a favorable safety profile, higher intracellular concentrations and longer post antibiotic effect [21].
In a prospective observational study of 3934 hospitalized patients by Viasus et al., performed in Spain at a tertiary teaching hospital between 1995 and 2010, 214 (5.4%) patients were diagnosed with LD, and 24 patients (11.2% of the LD patients) received inappropriate empirical antibiotic therapy; among the other 190 patients, 111 received levofloxacin, 74 patients received macrolides, and three combination of quinolones and macrolides, 1 doxycycline and 1 clindamycin [22] ( Table 1).

Targeted therapy
Early, targeted therapy that covers LD has shown to improve overall outcomes [19]. The most frequently identified of LD is Legionella pneumophila serogroup 1 in 80% of cases [23]. New diagnostic test had been added to the testing armamentarium (urinary antigen and polymerase chain reaction). Empirical therapy should be replaced by targeted therapy as soon as Legionella has been identified [17].
Garcia-Vidal et al. reported an observational cohort in Spain of all patients admitted with community acquired pneumonia from 2000 to 2014, 446 patients were diagnosed with LD; 335 patients (75.1%) received appropriate initial therapy with either quinolones, macrolides, combination with rifampin, or combination macrolide and quinolones. Primary outcome was overall 30-day in-hospital mortality. Thirty-six patients were excluded, 175 patients received levofloxacin, 177 patients received azithromycin and 58 patients received clarithromycin, without statistical significant difference for in-hospital 30-day mortality between the cohorts [24].
Once LD has been diagnosed, some experts suggest combined therapy instead of monotherapy for severe pneumonia, although there is no solid evidence support it [13]. In a retrospective observational multicenter Spanish series of 779 ICU patients admitted to the ICU with severe pneumonia, 25 patients (3.2%) were found to have LD, and prescription of monotherapy versus combination therapy was not protocolized, with ICU mortality as primary endpoint; it was found that there was no statistical significant difference of overall ICU mortality among both treatment groups; however if the severe pneumonia was associated to shock the difference became statistically significant [13].

Antibiotic selection and duration
There may be a role for a specific antibiotic choice based on severity of illness: need for intensive care unit (ICU) admission, need for invasive mechanical ventilation [4]. Dose and route of antibiotic delivery will be dictated by the severity, level of consciousness, and gastrointestinal function integrity [12]. Most of the antibiotics are available in oral presentations with excellent bioavailability (>90%), therefore transition among IV to oral regimens is seamless [19].
Despite absence of evidence, initial levofloxacin dose is recommended at 750 mg daily, and azithromycin 500 mg daily [14].
Levofloxacin use was associated with a shorter length of stay in the hospital, and shorter time to reach clinical stability [22]; moreover a small retrospective series showed no inferiority of ciprofloxacin to erythromycin in Japan [25]. In a retrospective single-center study at University of Michigan from 1999 to 2011, 41 patients with LD were analyzed after been treated with azithromycin versus fluoroquinolones, comparing clinical outcomes: all-cause mortality, length of stay in the hospital, time to clinical stability and development of complications, showing no significant differences among the two therapies [19,21] ( Table 2).
Duration of therapy is important to provide cure and prevent relapse [19]. The Infectious Diseases Society of America/American Thoracic Society (IDSA/ ATS) recommend that patients with LD to be treated for 5-14 days, shorter courses maybe appropriate if Azithromycin is the antibiotic of choice. Treatment should not be stopped until patients are afebrile for 48-72 hours [22].

Macrolides
Azithromycin 500 mg IV q24h or clarithromycin 500 mg IV q12h Preferred regimen in most settings, or a fluoroquinolone  Immunocompromised patients have a higher incidence of LD; cavitation, empyema, extrapulmonary disease may occur; and urinary antigen is less sensitive. In this population an antibiotic combination, and longer course maybe indicated (21 days) [3], and despite this this population has a higher mortality rate than matched groups [26]. An extended course up to 21 days is recommended for immunocompromised patients, severe disease, extrapulmonary manifestations, and inappropriate initial therapy [14].
Older macrolides will interact with drugs like tacrolimus and ciclosporin through the cytochrome P-450 enzyme system, then quinolones, doxycycline or azithromycin maybe used in transplanted hosts [14].

Therapy outcome
Early initiation of appropriate antibiotics, improves outcomes, therapy with quinolones within 8 hours of ICU admission reduces mortality [5,19].
In the Viasus' Spanish series, 41 (19.1%) patients with LD developed severe disease (ICU admission or death), independent factors were identified in this group: current/former smoker, macrolide use, initial inappropriate antibiotic therapy and high risk pneumonia severity index (PSI) class. The overall cure rate is 95% at 10-14 days after therapy [22] (Table 3).
In a Portuguese observational series, it was noted that patient with severe LD complicated by refractory respiratory failure were able to be supported by extra corporeal membrane oxygenation (ECMO) with high survival rates (86%); those patients had a faster clinical deterioration with very early ECMO initiation [27]. In a retrospective case review from University of Michigan between 1994 and 2006, survival rates were also noted to be high (67%) [28].
Antibiotic resistance is always a concern, it was noted that acquired resistance to macrolides, fluoroquinolones or rifampin could be easily selected in vitro; however in clinical practice, antibiotic susceptibility testing is not commonly performed [29], due to the fact that Legionella pneumophila serogroup 1 strains did not show any in vitro resistance towards eight antibiotics tested by Vandewalle-Capo et al.