Legionnaires Disease

Background

Legionnaires disease (LD) is the pneumonia caused by Legionella pneumophila. LD also refers to a more benign, self-limited, acute febrile illness known as Pontiac fever, which has been linked serologically to L pneumophila, although it presents without pneumonia. (See Pathophysiology and Etiology.)

L pneumophila is an important cause of nosocomial and community-acquired pneumonia (CAP) and must be considered a possible causative pathogen in any patient who presents with atypical pneumonia. (See Clinical Presentation and Workup.)

The Legionella bacterium was first identified in the summer of 1976 during the 58th annual convention of the American Legion, which was held at the Bellevue-Stratford Hotel in Philadelphia. Infection was presumed to be spread by contamination of the water in the hotel's air conditioning system. The presentation ranged from mild flulike symptoms to multisystem organ failure. Of the 182 people infected, 29 died.

Although Legionella was not identified until 1976, L pneumophila was subsequently found in a clinical specimen dating to 1943 and, according to retrospective analysis, may have been responsible for pre-1976 pneumonia epidemics in Philadelphia; Washington, DC; and Minnesota.

Legionnaires disease is the term that collectively describes infections caused by members of the Legionellaceae family.

Bacterial characteristics

The Legionella bacterium is a small, aerobic, waterborne, gram-negative, unencapsulated bacillus that is nonmotile, catalase-positive, and weakly oxidase-positive. It is a fastidious organism and does not grow anaerobically or on standard media. Buffered charcoal yeast extract (CYE) agar is the primary medium used for isolation of the bacterium. (See Workup.)

The Legionellaceae family consists of more than 42 species, constituting 64 serogroups. L pneumophila is the most common species, causing up to 90% of the cases of legionellosis, followed by L micdadei (otherwise known as the Pittsburgh pneumonia agent), L bozemanii, L dumoffii, and L longbeachae. Fifteen serogroups of L pneumophila have been identified, with serogroups 1, 4, and 6 being the primary causes of human disease. Serogroup 1 is thought to be responsible for 80% of the reported cases of legionellosis caused by L pneumophila.^[1]

Patient education

For patient education information, see Bronchoscopy.

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Pathophysiology

Legionella species are obligate or facultative intracellular parasites. Water is the major environmental reservoir for Legionella; the bacteria can infect and replicate within protozoa such as Acanthamoeba and Hartmannella, which are free-living amoebae found in natural and manufactured water systems. (Legionellae can resist low levels of chlorine used in water distribution systems.)

Within the amebic cells, Legionella species can avoid the endosomal-lysosomal pathway and can replicate within the phagosome. Surviving and growing in amebic cells allows Legionella to persist in nature. (See the image below.)

View Image

This electron micrograph depicts an amoeba, Hartmannella vermiformis (orange), as it entraps a Legionella pneumophila bacterium (green) with an extend....

Legionella species infect human macrophages and monocytes; intracellular replication of the bacterium is observed within these cells in the alveoli. The intracellular infections of protozoa and macrophages have many similarities.

Activated T cells produce lymphokines that stimulate increased antimicrobial activity of macrophages. This cell-mediated activation is key to halting the intracellular growth of legionellae. The significant role of cellular immunity explains why legionellae are observed more frequently in immunocompromised patients. Humoral immunity is thought to play a secondary role in the host response to legionellae infection.

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Etiology

Legionella transmission is thought to occur via inhalation of aerosolized mist from water sources, such as the following, that have been contaminated with the bacterium^{[2, 3]} :

• Cooling systems
• Showers
• Decorative fountains
• Humidifiers
• Respiratory therapy equipment
• Whirlpool spas
• Ice machines
• Potting soil
• Compost
• Roadside puddles
• Tubs used for water births^[4]

Legionnaires disease may be travel associated from exposure in aircraft or hotel facilities. Person-to-person transmission, however, has not been documented.

The highest incidence of Legionnaires disease occurs during late spring and early fall, when air-conditioning systems are used more frequently.^{[5, 6]} Nosocomial acquisition likely occurs via aspiration, respiratory therapy equipment,^[3] or contaminated water. In addition, transmission has been linked to the use of humidifiers, nebulizers, and items that were rinsed with contaminated tap water.

The following features increase the likelihood of colonization and amplification of legionellae in human-made water environments:

• Temperature of 25-42°C
• Stagnation
• Scale and sediment
• Presence of certain free-living aquatic amoebae capable of supporting intracellular growth of legionellae

Risk factors

The risk of infection increases with the type and intensity of the exposure, as well as the health status of the exposed individual. Numerous factors increase the risk of acquiring legionellae infections, including the following:

• Advanced age
• Smoking
• Chronic heart or lung disease
• Immunocompromised hosts with impaired cell-mediated immunity (eg, acquired immunodeficiency syndrome [AIDS]) or immunosuppressive medication use (especially corticosteroids)
• Diabetes
• Hematologic malignancies
• End-stage renal disease
• Alcohol abuse

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Epidemiology

Occurrence in the United States

LD has a reported incidence of 8000-18,000 cases per year. In certain geographic areas, community-acquired LD is more common. Although LD is reportable in all 50 states, it is estimated that only 5-10% of cases are reported. While most cases of the disease are sporadic, 10-20% of them are linked to outbreaks. LD is more common in the summer, especially in August, and is slightly more prevalent in the northern US.

Prevalence reports for Legionella have increased with time, likely due to the availability of more effective testing modalities. However, it is also possible that Legionella infections are increasing in frequency for environmental, population-based, or behavioral reasons.

LD is among the top 3-4 microbial causes of CAP, constituting approximately 1-9% of patients with CAP who require hospitalization. LD is an even more common cause of severe pneumonia in patients who require admission to an intensive care unit (ICU), ranking second, after pneumococcal pneumonia, in such cases. In addition, it has become recognized as the most common cause of atypical pneumonia in hospitalized patients.

LD cases acquired in the hospital usually occur as outbreaks and most often result from the presence of legionellae in water sources and on surfaces (eg, pipes, rubber, plastics). The organism is also found in water sediment, which may explain its ability to persist despite flushing of hospital water systems.^{[7, 8]}

International occurrence

LD is thought to occur worldwide and to be the cause of 2-15% of all CAP cases that require hospitalization. Outbreaks have been recognized throughout North America, Africa, Australia, Europe, and South America.

Sex- and age-related demographics

Men have a greater risk of acquiring L pneumophila infection. Older age is another risk factor; the weighted mean age for patients with LD is 52.7 years, with increasing incidence until age 79 years. Mortality rates are also higher in older patients. The incidence of LD in persons younger than 35 years is less than 0.1 cases per 100,000 people.

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Prognosis

Recovery is variable in LD; some patients experience rapid improvement, while others have a much more protracted course despite treatment. The mortality rate approaches 50% with nosocomial infections.

Progressive respiratory failure is the most common cause of death in patients with Legionella pneumonia. However, the mortality rate depends on the comorbid conditions of the patient, as well as on the choice and timeliness of antibiotics administration. The site of acquisition (eg, nosocomial, community-acquired) may also affect the outcome.

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Complications

See the list below:

• Decreased pulmonary function
• Fulminant respiratory failure
• Dehydration, septic shock
• Hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
• Respiratory insufficiency, hypoxic respiratory failure
• Endocarditis
• Neurologic symptoms: Including lethargy, headache, altered mental status, and nonfocal neurologic examination findings
• Gastrointestinal symptoms: Diarrhea, vomiting
• Renal failure
• Rhabdomyolysis
• Multiple organ failure
• Coma
• Bacteremia or abscess formation (in the lungs or at extrapulmonary sites) in immunocompromised patients
• Death: In 10% of treated nonimmunocompromised patients and in as many as 80% of untreated immunocompromised patients

A study by van Loenhout et al that included 190 patients with LD found that a year after the disease’s onset, many patients were still suffering from 1 or more adverse health effects, particularly fatigue and reduced general quality of life.^[9]

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History

Legionella pneumophila causes 2 distinct disease entities. Legionnaires disease (LD) is characterized by pneumonia. Pontiac fever is a short-term, milder illness than LD and is not characterized by pneumonia, instead manifesting as fever and myalgias that resolve without treatment.

The incubation period in LD ranges from 2-10 days. Patients who develop legionellae infection and who have been hospitalized continuously for 10 or more days before the onset of illness are classified as having definite nosocomial LD. Patients with laboratory-confirmed infection that develops 2-9 days after hospitalization are classified as having possible nosocomial LD. Nosocomial LD occurs in clusters.

Symptoms of LD can occur as follows:

• Patients often experience a prodrome of 1-2 days of mild headache and myalgias, followed by high fever, and chills
• Cough is present in 90% of cases; cough usually is nonproductive at first but may become productive as the disease progresses
• Other pulmonary manifestations include dyspnea, pleuritic chest pain, and hemoptysis, which may be present in as many as one third of cases
• Gastrointestinal symptoms include nausea, vomiting, diarrhea (watery, not bloody), abdominal pain, and anorexia
• Neurologic symptoms include headache, lethargy, encephalopathy, altered mental status (the most common neurologic symptom), and rarely, focal symptoms
• Musculoskeletal symptoms include myalgias
• Nonpulmonary symptoms are prominent early in the disease

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Physical Examination

Manifestations of LD may include the following:

• Headache
• Mental status changes
• Fever greater than 40°C, or 102°F (range, 38.8-40.5°C)
• Relative bradycardia (excluding patients with pacemakers or arrhythmias or those receiving beta blockers, diltiazem, or verapamil)
• Myocarditis
• Prosthetic valve endocarditis
• Tachypnea
• Localized rales
• Blood-streaked sputum
• Extrapulmonary manifestations
• Abdominal pain
• Pancreatitis
• Acute renal failure

A clinical point score, as shown in the table below, may be helpful in increasing the probability of correctly diagnosing LD and prompting specific/definitive LD testing.

Table 1. Legionnaires Disease: Six Clinical Predictors and Diagnostic Eliminators in Adults Admitted with Pneumonia ^a

View Table

See Table

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Approach Considerations

While pneumonias caused by numerous pathogens share similar laboratory findings, hyponatremia (sodium < 130 mEq/L) secondary to the syndrome of inappropriate antidiuretic hormone (SIADH) is more common in Legionnaires disease (LD) than in pneumonias secondary to other pathogens; however, this is not specific for LD.

Other nonspecific laboratory findings in LD include the following:

• Early/mildly elevated liver enzymes
• Highly elevated erythrocyte sedimentation rate (ESR) (>90 mm/h)
• Highly elevated ferritin levels (>2 times normal)
• Increased C-reactive protein (CRP) levels (>30 mg/L)
• Hypophosphatemia (specific to LD excluding other causes of hypophosphatemia)^[10]
• Microscopic hematuria

Severe disease is defined by respiratory failure, bilateral pneumonia, rapidly worsening pulmonary infiltrates, or the presence of at least 2 of the following 3 characteristics:

• Blood urea nitrogen (BUN) greater than or equal to 30 mg/dL
• Diastolic blood pressure lower than 60 mm Hg
• Respiratory rate greater than 30/min

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Histologic Findings

Typically, legionellae histopathologic lesions are found in interstitial lining and alveoli with polymorphonuclear cells and macrophages.

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Laboratory Studies

Tests in LD can include the following:

• Complete blood count (CBC): Look for leukocytosis, left shift
• Look for elevated ESR
• Electrolytes: Look for hypophosphatemia and hyponatremia
• BUN and creatinine: Look for renal failure and dehydration
• Liver function tests (LFTs): Look for nonspecific LFT abnormalities, which are very common in LD and may help to distinguish it from other atypical pneumonias
• Look for highly elevated serum ferritin
• Creatine phosphokinase: Look for elevation indicating rhabdomyolysis, which occasionally is seen in LD; the rhabdomyolysis may be so severe as to cause renal failure
• Arterial blood gas (ABG): Look for hypoxemia
• Gram stain: Typically, many leukocytes and a paucity of organisms are observed; if visible, the organisms are small, faintly staining, gram-negative bacilli
• Sputum Gram stain: Look for increased polymorphonuclear leukocytes and monocytes without bacteria
• Urinalysis: Look for proteinuria, hematuria, and renal failure

Culture of respiratory secretions

The definitive method for diagnosing Legionella is isolation of the organism in the respiratory secretions (ie, sputum, lung fluid, pleural fluid). However, Legionella species do not grow on standard microbiologic media but instead require buffered charcoal yeast extract (CYE) agar and cysteine for growth. Optimal growth occurs at 35-37°C.

Legionella is a slow-growing organism and can take 3-5 days to produce visible colonies. The organisms typically have a ground-glass appearance.

Routine sputum cultures have a sensitivity and specificity of 80% and 100%, respectively. Transtracheal aspiration of secretions or bronchoscopy specimen increases the sensitivity. Bronchoalveolar lavage (BAL) fluid provides a higher yield than bronchial wash specimens.

Blood cultures

Legionella can be isolated from blood, but it shows a much lower sensitivity.

Direct fluorescent antibody staining of sputum

Direct fluorescent antibody staining (DFA) is a rapid test that yields results in 2-4 hours, but it has a lower sensitivity and has fallen out of favor. The specificity of DFA is 96-99% using monoclonal antibody instead of polyclonal antibody.

A positive result depends on finding large numbers of organisms in the specimen; therefore, the sensitivity is increased when samples from the lower respiratory tract are used. DFA results rapidly become negative (in 4-6 d).

Serology

The most widely used tests include the immunofluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA) tests. A single increased antibody titer confirms LD if the IFA titer is greater than or equal to 1:256.

While LD serologic tests are the most readily available, they require a 4-fold increase in antibody titer (to 1:128 or greater), which takes 4-8 weeks. Paired measurements from both the acute and convalescent periods should be obtained, since an antibody response may not be apparent for up to 3 months. Of note, antibody levels do not increase in approximately one third of patients with LD.

Urinary antigen testing

The Legionella lipopolysaccharide antigen is detected with ELISA, radioimmunoassay (RIA), and the latex agglutination test. The Legionella lipopolysaccharide antigen becomes detectable in 80% of patients on days 1-3 of clinical illness. The urinary antigen assay can be used to detect only L pneumophila (serogroup 1).^[11]

The advantages of urinary antigen testing include rapidity and simplicity. In addition, the relative ease of obtaining a urine sample compared with obtaining sputum specimens and the persistence of antigen secretion in patients who are on antibiotic therapy increase the usefulness of the urine antigen detection method.^[11]

The urinary antigen test may initially be negative, but when positive it can remain positive for months after the acute episode has resolved.^[11]

Amplification with PCR assay

Polymerase chain reaction (PCR) assay of urine, serum, and bronchiolar lavage fluid is very specific for the detection of legionellae, but the sensitivity is not greater than that of culture. The primary benefit of this procedure, like IFA titers, is that it can be used to detect infections caused by legionellae other than L pneumophila serogroup 1.

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Imaging Studies

Radiography

Legionella infection almost always produces an abnormal chest radiographic finding, with the abnormalities typically being unilateral and occurring in the lower lobes. However, the abnormalities are variable and may be focal or diffuse; no typical radiographic presentation exists for LD.^[12]

Rapidly progressive, asymmetrical infiltrates are nonetheless characteristic of the disease. Chest radiography often shows patchy alveolar infiltrates with consolidation in the lower lobe (although all lobes may be affected). Progression of the infiltrates may be seen despite antibiotic therapy. Up to 50% of patients have a pleural effusion. Cavity and abscess formation are rare in LD but can occur in immunocompromised hosts.

Improvement revealed on chest radiography can lag behind clinical improvement by 5-7 days; the radiographic abnormalities can take up to 3-4 months to resolve completely.

Noncontrast head CT scanning

Noncontrast head computed tomography (CT) scanning is indicated for patients with altered mental status. Findings should be normal in LD.

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Procedures

Bronchoscopy

Bronchoscopy with or without BAL may be helpful in establishing or excluding the diagnosis if respiratory culture specimens are difficult to obtain. BAL fluid gives a higher yield than bronchial wash specimens.

Lumbar puncture

This procedure is indicated for patients with altered mental status. In uncomplicated LD, the cerebrospinal fluid (CSF) findings are generally normal.

Thoracentesis

If a pleural effusion is present, fluid can be evaluated using DFA or LD culture.

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Approach Considerations

A delay in treatment significantly increases the risk of mortality in Legionnaires disease (LD). Therefore, include empiric anti-Legionella therapy in the regimen for severe community-acquired pneumonia (CAP) and in specific cases of nosocomial pneumonia.

Although Legionella pneumonia can present as a mild illness, most patients require hospitalization with parenteral antibiotics. Most healthy hosts exhibit clinical response to treatment within 3-5 days.

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Prehospital and Emergency Department Care

Prehospital care

Oxygen therapy is the mainstay of prehospital therapy in LD. Intravenous (IV) access and fluid therapy may be indicated for dehydration or septic shock. Restraints may be required for patients with altered mental status. Seizure precautions may be indicated.

Differentiating LD with multiple rigors and altered mental status from a seizure disorder may be possible only through a clinical examination.

Emergency department care

Patient management includes the following:

• Control the airway as indicated clinically; support ventilation and oxygenation
• Rehydrate the patient as indicated, especially in shock or diarrheal disease
• Antipyretics may be used as indicated
• Cardiac monitoring may be required if chest pain, hypotension, bradycardia, or other indicators are present
• Obtain laboratory specimens (respiratory culture and urine antigen testing), chest radiographs, computed tomography (CT) scans, and cerebrospinal fluid (CSF), as indicated
• Begin empiric antibiotic therapy

Also see the Legionella home page from the Centers for Disease Control and Prevention (CDC), as well as the Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults.^[13]

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Inpatient Care

Patients with mild to moderate pneumonia are admitted to the hospital for parenteral antibiotics and supportive measures. Patients deemed to have a severe pneumonia may require admission to the intensive care unit (ICU) for closer monitoring. Quickly initiate empiric antibiotic treatment and obtain a diagnostic workup.

Close follow-up with a pulmonologist or infectious disease specialist is recommended following discharge.

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Antibiotic Therapy

In milder cases, patients can be treated in an outpatient setting with oral antibiotics. For patients who are hospitalized and treated with IV antibiotics, start oral antibiotics while in the hospital and observe the patients for continued response. Continue oral antibiotics on an outpatient basis for 14-21 days, depending on the severity of the presenting illness. Patients should receive close follow-up care to ensure complete resolution of their respiratory symptoms.

Patients should complete the full course of antibiotics, whether the treatment is initiated in the outpatient setting or in the hospital.

Historically, erythromycin, one of the original macrolide antibiotics, was used for L pneumophila infection. Currently, however, other antibiotics, including doxycycline, tigecycline, azithromycin, and a respiratory quinolone, are preferred, because they are more active against LD activity and have superior pharmacokinetic properties (eg, better bioavailability, better penetration into macrophages, longer half-life).

For severe disease, a fluoroquinolone is recommended. With doxycycline or fluoroquinolones, rifampin does not need to be added in severely ill patients.

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Consultations

Consultation with a pulmonologist or infectious disease specialist is strongly recommended in cases of LD. Because of the protean presentation of this disease, however, consultations with other specialists, including the following, may be required at one time or another:

• General internist
• Critical care specialist
• Cardiologist
• Gastroenterologist
• Neurologist
• Nephrologist
• Oncologist
• General surgeon

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Deterrence and Prevention

Prevention and control of nosocomial legionellosis

Legionellae should be sought in hospitalized patients with an increased risk for infection and subsequent death. If 1 definite case or 2 possible cases of nosocomial LD occur among in patients, initiate an investigation for a hospital source.

Legionellae transmission can also be discouraged through the routine maintenance of cooling towers and the use of only sterile water for filling and rinsing nebulization devices. Improved design and maintenance of cooling towers and plumbing systems can also help.

Disinfection

Superheating water to 70-80°C, with flushing of distal sites, may help to prevent water contamination.

Copper-silver ionization units—which produce metallic ions that disrupt the bacterial cell wall, thus resulting in lysis and cell death—are very effective at eradicating legionellae; they provide sustained protection.

Ultraviolet light kills legionellae by damaging cellular deoxyribonucleic acid (DNA). This modality is effective when disinfecting localized areas, but because it provides no sustained protection, adjunctive treatments must be used.

Hyperchlorination of water is no longer recommended, because legionellae are fairly chlorine resistant, and chlorine decomposes at the higher temperatures found in the hot water systems it is used to treat.

Following reports of LD in newborns who were infected during water births,^[4] the Arizona Department of Health Services issues recommendation for minimizing the risk of Legionella contamination in tubs used during the water birthing process, such as flushing out stagnant water and sediment from hoses by running hot water through it for 3 minutes before using it to fill the tub.^[14]

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Medication Summary

Treat Legionnaires disease intravenously, and consider changing to oral antibiotic therapy with a 10- to 14-day course after patients begin to show signs of clinical improvement. A 21-day course is recommended in patients who are immunocompromised, who have severe underlying disease, or who develop severe Legionella pneumonia.

For immunosuppressed patients, fluoroquinolone therapy is recommended for several reasons. The fatality rate of Legionella pneumonia is high in this patient population.

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Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  Levofloxacin, a fluoroquinolone, is used for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

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Azithromycin (Zithromax, Zmax)

• Dosing, Interactions, etc.

Clinical Context:  Azithromycin is a macrolide antibiotic used to treat mild to moderate microbial infections.

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Ciprofloxacin (Cipro, Cipro XR)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and most gram-negative organisms, but with no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, bacterial growth.

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Doxycycline (Vibramycin, Adoxa, Avidoxy, Doryx, Monodox)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

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Moxifloxacin (Avelox)

• Dosing, Interactions, etc.

Clinical Context:  Moxifloxacin inhibits bacterial DNA synthesis and growth. Its activity is similar to that of ciprofloxacin and levofloxacin.

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Rifampin (Rifadin)

• Dosing, Interactions, etc.

Clinical Context:  Rifampin is the drug of choice (DOC) to use with erythromycin. It inhibits DNA-dependent RNA polymerase activity in susceptible cells by interacting with bacterial RNA polymerase (without inhibiting the mammalian enzyme).

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Tigecycline (Tygacil)

• Dosing, Interactions, etc.

Clinical Context:  A glycylcycline that inhibits protein synthesis by binding to the 30S ribosomal subunit of susceptible bacteria. It has demonstrated activity against both gram-positive and gram-negative anaerobes, as well as against gram-positive aerobic strains such as methicillin-resistant staphylococci, streptococci, and enterococci.

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Erythromycin base (Ery-Tab, E.E.S., PCE)

• Dosing, Interactions, etc.

Clinical Context:  Erythromycin inhibits ribonucleic acid (RNA) ̶ dependent protein synthesis, possibly by stimulating dissociation of peptidyl transfer RNA (tRNA) from ribosomes. This inhibits bacterial growth.

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Clarithromycin (Biaxin, Biaxin XL)

• Dosing, Interactions, etc.

Clinical Context:  Clarithromycin is a macrolide antibiotic that inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

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