Antibiotic therapy
An antibiotic that has intracellular activity is required because Legionella survive and replicate within cells.[60]Benin AL, Benson RF, Besser RE. Trends in Legionnaires disease, 1980-1998: declining mortality and new patterns of diagnosis. Clin Infect Dis. 2002 Nov 1;35(9):1039-46.
http://www.ncbi.nlm.nih.gov/pubmed/12384836?tool=bestpractice.com
[61]Heath CH, Grove DI, Looke DFM. Delay in appropriate therapy of Legionella pneumonia associated with increased mortality. Eur J Clin Microbiol Infect Dis. 1996 Apr;15(4):286-90.
http://www.ncbi.nlm.nih.gov/pubmed/8781878?tool=bestpractice.com
Using an antibiotic with activity against atypical bacteria (including Legionella) is recommended by the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) in all patients at the time of diagnosis of community-acquired pneumonia (CAP), before a causative pathogen is known.[54]Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812437
http://www.ncbi.nlm.nih.gov/pubmed/31573350?tool=bestpractice.com
[62]Arnold F, Summersgill JT, Lajoie AS, et al. A worldwide perspective of atypical pathogens in community-acquired pneumonia. Am J Respir Crit Care Med. 2007 May 15;175(10):1086-93.
http://www.ncbi.nlm.nih.gov/pubmed/17332485?tool=bestpractice.com
However, there is no international consensus for this approach. The British Thoracic Society (BTS) and UK National Institute for Health and Care Excellence (NICE) guidelines reserve use of agents that target atypical pathogens for patients with moderate to severe CAP or when Legionella infection is suspected based on clinical and/or epidemiological features.[63]Mills GD, Oehley MR, Arrol B. Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis. BMJ. 2005 Feb 26;330(7489):456.
http://www.bmj.com/cgi/content/full/330/7489/456
http://www.ncbi.nlm.nih.gov/pubmed/15684024?tool=bestpractice.com
[64]Shefet D, Robenshtok E, Paul M, et al. Empirical atypical coverage for inpatients with community-acquired pneumonia: systematic review of randomized controlled trials. Arch Intern Med. 2005 Sep 26;165(17):1992-2000.
http://archinte.ama-assn.org/cgi/content/full/165/17/1992
http://www.ncbi.nlm.nih.gov/pubmed/16186469?tool=bestpractice.com
[65]British Thoracic Society. 2015 - annotated BTS guideline for the mangement of CAP in adults (2009) summary of recommendations. Jan 2015 [internet publication].
https://www.brit-thoracic.org.uk/quality-improvement/guidelines/pneumonia-adults
[66]National Institute for Health and Care Excellence. Pneumonia (community-acquired): antimicrobial prescribing. Sep 2019 [internet publication].
https://www.nice.org.uk/guidance/ng138
The patient should be treated with a fluoroquinolone, such as levofloxacin, or a newer macrolide, such as azithromycin or clarithromycin.[67]Mykietiuk A, Carratala J, Fernandez-Sabe N, et al. Clinical outcomes for hospitalized patients with Legionella pneumonia in the antigenuria era: the influence of levofloxacin therapy. Clin Infect Dis. 2005 Mar 15;40(6):794-9.
http://www.ncbi.nlm.nih.gov/pubmed/15736010?tool=bestpractice.com
Erythromycin was used in early outbreaks and noted to be better than beta-lactam antibiotics (e.g., penicillins) but has been superseded by the newer macrolides and levofloxacin.[68]Edelstein PH, Shinzato T, Doyle E, et al. In vitro activity of gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and its pharmacokinetics in guinea pigs with L. pneumophila pneumonia. Antimicrob Agents Chemother. 2001 Aug;45(8):2204-9.
http://aac.asm.org/cgi/content/full/45/8/2204
http://www.ncbi.nlm.nih.gov/pubmed/11451675?tool=bestpractice.com
Observational studies have shown improved outcomes in patients receiving levofloxacin as opposed to erythromycin or clarithromycin, but others found them to be equivocal.[69]Blazquez-Garrido RM, Espinosa-Parra FJ, Alemany-Frances L, et al. Antimicrobial chemotherapy for Legionnaires disease: levofloxacin versus macrolides. Clin Infect Dis. 2005 Mar 15;40(6):800-6.
http://www.ncbi.nlm.nih.gov/pubmed/15736011?tool=bestpractice.com
[70]Sabria M, Pedro-Botet ML, Gomez J, et al. Fluoroquinolones vs macrolides in the treatment of Legionnaires disease. Chest. 2005 Sep;128(3):1401-5.
http://www.ncbi.nlm.nih.gov/pubmed/16162735?tool=bestpractice.com
[71]Griffin AT, Peyrani P, Wiemken T, et al. Macrolides versus quinolones in Legionella pneumonia: results from the Community-Acquired Pneumonia Organization international study. Int J Tuberc Lung Dis. 2010 Apr;14(4):495-9.
http://www.ncbi.nlm.nih.gov/pubmed/20202309?tool=bestpractice.com
The annotated British Thoracic Society guidelines for CAP in 2015 favour use of a fluoroquinolone.[65]British Thoracic Society. 2015 - annotated BTS guideline for the mangement of CAP in adults (2009) summary of recommendations. Jan 2015 [internet publication].
https://www.brit-thoracic.org.uk/quality-improvement/guidelines/pneumonia-adults
If there is a known patient allergy to these drugs, or they are not available, then a tetracycline may be tried.
Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. These include, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[72]Rusu A, Munteanu AC, Arbănași EM, et al. Overview of side-effects of antibacterial fluoroquinolones: new drugs versus old drugs, a step forward in the safety profile? Pharmaceutics. 2023 Mar 1;15(3):804.
https://www.mdpi.com/1999-4923/15/3/804
http://www.ncbi.nlm.nih.gov/pubmed/36986665?tool=bestpractice.com
Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.
The dose and route of administration of treatment (oral versus intravenous) is guided by severity, underlying risk factors, consciousness level, and gastrointestinal disorders.[4]Phin N, Parry-Ford F, Harrison T, et al. Epidemiology and clinical management of Legionnaires' disease. Lancet Infect Dis. 2014 Oct;14(10):1011-21.
https://www.doi.org/10.1016/S1473-3099(14)70713-3
http://www.ncbi.nlm.nih.gov/pubmed/24970283?tool=bestpractice.com
The recommendations from the IDSA/ATS guidelines for CAP treatment may be applied to patients with Legionnaires' disease in that, when a patient is clinically stable, intravenous therapy may be changed to oral therapy, followed by patient discharge.[54]Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812437
http://www.ncbi.nlm.nih.gov/pubmed/31573350?tool=bestpractice.com
No response to initial therapy or severely ill
Patients with persistent fever, productive cough, hypoxia, hypercapnia, worsening pulmonary function, and systemic signs of sepsis with hypotension may benefit from a combination of fluoroquinolone and macrolide therapy.[73]Dournon E, Mayaud CH, Wolff M, et al. Comparison of the activity of three antibiotic regimens in severe LD. J. Antimicrob Chemother. 1990 Oct;26(suppl B):129-39.
http://www.ncbi.nlm.nih.gov/pubmed/2258340?tool=bestpractice.com
However, caution is recommended as this combination has significant potential toxicity, such as prolongation of the QT interval and torsades de pointes arrhythmia.[74]Roig J, Rello J. Legionnaires' disease: a rational approach to therapy. J Antimicrob Chemother. 2003 May;51(5):1119-29.
http://jac.oxfordjournals.org/cgi/content/full/51/5/1119
http://www.ncbi.nlm.nih.gov/pubmed/12668578?tool=bestpractice.com
Combination therapy with a macrolide or quinolone plus rifamycins (rifampin, rifampicin) has been studied, but is not advocated, even in severe cases, due to poorer outcomes. This is likely related to induction of liver metabolism of the macrolide or quinolone by the rifamycin.[75]Grau S, Antonio JM, Ribes E, et al. Impact of rifampicin addition to clarithromycin in Legionella pneumophila pneumonia. Int J Antimicrob Agents. 2006 Sep;28(3):249-52.
http://www.ncbi.nlm.nih.gov/pubmed/16870401?tool=bestpractice.com