Background
Legionella pneumophila is an important cause of both nosocomial and community-acquired pneumonia (CAP) and must be considered a possible causative pathogen in any patient who presents with pneumonia.
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. A bacterium that would later be named L pneumophila was isolated from different organ tissues of guinea pigs inoculated with lung tissue samples from 4 individuals who died. Although this pathogen was not identified until 1976, retrospective analysis suggests that L pneumophila may have been responsible for previous pneumonia epidemics in Philadelphia; Washington, DC; and Minnesota. L pneumophila was identified in a clinical specimen dating to 1943.
Legionellosis is the term that collectively describes infections caused by members of the Legionellaceae family. Legionnaires disease (LD) is the pneumonia caused by L 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.
Pathophysiology
The Legionella bacterium is a small, aerobic, waterborne, gram-negative, unencapsulated bacillus that is nonmotile, catalase-positive, and weakly oxidase-positive. Legionella 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.
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 Legionella micdadei (otherwise known as the Pittsburgh pneumonia agent), Legionella bozemanii, Legionella dumoffii, and Legionella 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.
Legionella species are obligate or facultative intracellular parasites. Water is the major environmental reservoir for Legionella. The bacterium can infect and replicate within protozoa such as Acanthamoeba and Hartmannella species, which are free-living amoebae found in both natural and manufactured water systems. The Legionella species within the amebic cells can avoid the endosomal-lysosomal pathway and can replicate within the phagosome. Legionella can survive and grow in the amebic cells, thereby enabling the organism to persist in nature.
Legionella species infect human macrophages and monocytes, and intracellular replication of the bacterium is observed within these cells in the alveoli. The intracellular infections of protozoa and macrophages have many similarities.
Transmission is thought to occur via inhalation of aerosolized mist from water sources (eg, whirlpools, showers, cooling towers1 ) contaminated with either the bacterium or amebic cells infected with the bacterium. Direct inhalation is the most likely method of transmission, with aerosol-generating systems playing a crucial role.2 Person-to-person transmission has not been documented. The highest incidence occurs during the warmer months, when air-conditioning systems are used more frequently. Nosocomial acquisition likely occurs via aspiration3 , respiratory therapy equipment2 , 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 man-made water environments: (1) temperature of 25-42°C, (2) stagnation, (3) scale and sediment, and (4) presence of certain free-living aquatic amoebae capable of supporting intracellular growth of legionellae. Legionellae can resist low levels of chlorine used in water distribution systems.
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.
Frequency
United States
LD has a reported incidence of 8000-18,000 cases per year. In certain geographic areas, community-acquired LD is more common.
LD is reportable in all 50 states. Only 5-10% of cases are estimated to be reported. While most cases of LD are sporadic, 10-20% are linked to outbreaks. 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). LD ranks second, after pneumococcal pneumonia, as the etiology of pneumonia severe enough to require ICU admission.
Some LD cases are acquired in the hospital; they usually occur as outbreaks. Legionellae in the hospital setting is usually due to its presence 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.
International
LD is thought to occur worldwide and to be the cause of 2-15% of all CAP cases that require hospitalization.
Mortality/Morbidity
The mortality rate may approach 100% in patients with underlying disease. In untreated patients, the mortality rate may be as high as 80%.
Sex
Men have a greater risk of acquiring L pneumophila infection.
Age
Elderly persons have a greater risk of acquiring infection with Legionella species.
Clinical
History
L pneumophila causes 2 distinct disease entities. Legionnaires disease (LD) is characterized by pneumonia. Pontiac fever is a milder illness than LD and is not characterized by pneumonia; Pontiac fever manifests as fever and myalgias that resolve without treatment.
- Legionnaires disease
- The incubation period 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.
- Individuals with LD can present with a broad spectrum of symptoms.
- Symptoms of legionnaires disease
- Fever greater than 40 º C (>102 º F)
- Chills
- Cough - Dry or productive; hemoptysis rare
- Pleuritic or nonpleuritic chest pain
- Neurologic symptoms
- Headache
- Lethargy
- Encephalopathy
- Mental status changes - The most common neurologic symptom
- GI symptoms
- Diarrhea - Watery, not bloody
- Nausea, vomiting, and abdominal pain
- Myalgias
Physical
- Manifestations of LD may include the following:
- Mental status changes
- Fever greater than 40°C (range, 38.8-40.5°C)
- Hypotension
- Relative bradycardia in all (excluding patients with pacemakers or arrhythmias or those receiving beta-blockers, diltiazem, or verapamil)
- Tachypnea
- Localized rales
- Depressed mental status or agitation
- Extrapulmonary manifestations
- In addition to relative bradycardia, cardiac manifestations are common findings and include myocarditis, pericarditis, and prosthetic valve endocarditis.
- Pancreatitis
- Peritonitis
- Acute renal failure
Modified Winthrop-University Hospital Infection Disease Division's Point System for Diagnosing Legionnaires Disease in Adults
Table
| Clinical Features | Qualifying Conditions | Point Score |
| Temperature >103°F* | With relative bradycardia | +5 |
| Headache | Acute onset | +2 |
| Mental confusion/lethargy* | Not drug induced | +4 |
| Ear pain | Acute onset | -3 |
| Nonexudative pharyngitis | Acute onset | -3 |
| Hoarseness | Acute, not chronic | -3 |
| Sputum (purulent) | Excluding chronic bronchitis | -3 |
| Hemoptysis* | Mild/moderate | -3 |
| Chest pain (pleuritic) | Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome) | -3 |
| Loose stools/watery diarrhea* | Not drug induced | +3 |
| Abdominal pain* | With or without diarrhea | +5 |
| Renal failure* | Acute, not chronic | +3 |
| Shock/hypotension* | Not 2° to acute cardiac | -5 |
| /pulmonary causes | +5 | |
| Splenomegaly | Excluding non-CAP causes | -5 |
| Lack of response to beta lactams | After 72 h (excluding viral pneumonias) | +5 |
| Laboratory Features | ||
| Chest radiograph | Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS) | +3 |
| ↓ PO2 with ↑ A-a gradient (>35)* | (Excluding severe influenza/SARS) | -5 |
| ↓ Na+ | Acute onset | +1 |
| ↓ PO4 =* | Acute onset | +5 |
| ↑ SGOT/SGPT (early mild/transient)* | Acute onset | +4 |
| ↑ Total bilirubin | Otherwise unexplained | +1 |
| ↑ LDH (>400 U/L)* | Excluding HIV/PCP | -5 |
| ↑ CPK/aldolase | Otherwise unexplained | +4 |
| ↑ CRP (>30 mg/L) | Acute onset | +5 |
| ↑ Cold agglutinins (≥1:64) | Acute onset | -5 |
| ↑ Creatinine | Acute onset | +2 |
| Microscopic hematuria* | Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms | +2 |
| Likelihood of Legionella infection | ||
| Total points | >15 Legionella infection very likely | |
| 5-15 Legionella infection likely | ||
| <5>Legionella infection unlikely | ||
| Clinical Features | Qualifying Conditions | Point Score |
| Temperature >103°F* | With relative bradycardia | +5 |
| Headache | Acute onset | +2 |
| Mental confusion/lethargy* | Not drug induced | +4 |
| Ear pain | Acute onset | -3 |
| Nonexudative pharyngitis | Acute onset | -3 |
| Hoarseness | Acute, not chronic | -3 |
| Sputum (purulent) | Excluding chronic bronchitis | -3 |
| Hemoptysis* | Mild/moderate | -3 |
| Chest pain (pleuritic) | Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome) | -3 |
| Loose stools/watery diarrhea* | Not drug induced | +3 |
| Abdominal pain* | With or without diarrhea | +5 |
| Renal failure* | Acute, not chronic | +3 |
| Shock/hypotension* | Not 2° to acute cardiac | -5 |
| /pulmonary causes | +5 | |
| Splenomegaly | Excluding non-CAP causes | -5 |
| Lack of response to beta lactams | After 72 h (excluding viral pneumonias) | +5 |
| Laboratory Features | ||
| Chest radiograph | Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS) | +3 |
| ↓ PO2 with ↑ A-a gradient (>35)* | (Excluding severe influenza/SARS) | -5 |
| ↓ Na+ | Acute onset | +1 |
| ↓ PO4 =* | Acute onset | +5 |
| ↑ SGOT/SGPT (early mild/transient)* | Acute onset | +4 |
| ↑ Total bilirubin | Otherwise unexplained | +1 |
| ↑ LDH (>400 U/L)* | Excluding HIV/PCP | -5 |
| ↑ CPK/aldolase | Otherwise unexplained | +4 |
| ↑ CRP (>30 mg/L) | Acute onset | +5 |
| ↑ Cold agglutinins (≥1:64) | Acute onset | -5 |
| ↑ Creatinine | Acute onset | +2 |
| Microscopic hematuria* | Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms | +2 |
| Likelihood of Legionella infection | ||
| Total points | >15 Legionella infection very likely | |
| 5-15 Legionella infection likely | ||
| <5>Legionella infection unlikely | ||
*Otherwise unexplained (acute and associated with pneumonia)
Adapted from Cunha BA. Antibiotic Essentials. 5th ed. Royal Oak, Mich: Physicians Press; 2006.
- A clinical point score may be helpful in increasing probability of LD and prompting specific/definitive LD testing.
Causes
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.
- Risk factors for infection
- Advanced age
- Smoking
- Chronic heart or lung disease
- Immunocompromised state or immunosuppressive medication use (especially corticosteroids)
- Recent exposure to water or soil
- Pediatric cases of Legionella pneumonia are less common. Most of these cases occur in children who are immunosuppressed or in immunocompetent children who have undergone surgery or who are on a ventilator.
Differential Diagnoses
Other Problems to Be Considered
Typical CAPs
Atypical CAPs
Severe CAP
Patients diagnosed with Legionella pneumonia are not co-infected with other organisms (eg, pneumococcal species). The differential diagnoses include other atypical pathogens (eg, Mycoplasma, psittacosis), Chlamydophila pneumoniae, tularemia, and Coxiella burnetii. L pneumophila bacterium represents a definite pathogen; therefore, its isolation always indicates infection.
Workup
Laboratory Studies
- While pneumonias caused by numerous pathogens share similar laboratory findings, hyponatremia (sodium <130>
- Additional laboratory findings in LD and in pneumonias due to other causes include the following:
- Elevated liver enzyme levels
- Increased creatine phosphokinase levels
- Increased creatine phosphokinase (CPK) levels
- Increased C-reactive protein levels (>30 mg/L)
- Hypophosphatemia (specific to LD excluding other causes of hypophosphatemia)4
- Microscopic hematuria
- Proteinuria (40%)
- Gram stain
- Typically, many leukocytes and a paucity of organisms are observed.
- If visible, the organisms are small, faintly staining, gram-negative bacilli.
- 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.
- Legionella requires buffered 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 has a lower sensitivity. 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). 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 test
- 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).5
- The advantages of this test 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.5
- The urinary antigen result can remain positive for months after the acute episode has resolved.5
- Amplification with polymerase chain reaction
- Polymerase chain reaction (PCR) 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 1.6
Imaging Studies
- No typical LD radiographic presentation exists.7
- Rapidly progressive asymmetrical infiltrates are characteristic of LD.
- Approximately one quarter of patients had infiltrates that were described as interstitial. Almost half of the patients had patchy alveolar infiltrates.
- In general, the abnormalities are typically unilateral and are found in the lower lobes.
- Pleural effusions are found in one third of patients.
- Cavity and abscess formation are rare and can occur in immunocompromised hosts.
- Improvement revealed on the chest radiograph can lag behind the clinical improvement by 5-7 days. The abnormalities on chest radiograph can take up to 3-4 months to resolve completely.
Procedures
- Bronchoscopy: While the sensitivity of specimens retrieved via bronchoscopy is comparable to that of sputum, BAL fluid gives a higher yield than bronchial wash specimens.
- Thoracentesis: If a pleural effusion is present, fluid can be evaluated using DFA or LD culture.
Histologic Findings
Typically, legionellae histopathological lesions are found in interstitial lining and alveoli with polymorphonuclear cells and macrophages.
Treatment
Medical Care
- A delay in treatment significantly increases the risk of mortality. Therefore, include empiric anti-Legionella therapy in the regimen for severe CAP and in specific cases of nosocomial pneumonia.
- Although Legionella pneumonia can present as a mild illness, most patients require hospitalization with parenteral antibiotics.
- Historically, erythromycin was used for L pneumophila infection, but doxycycline, azithromycin, macrolides, and quinolones are more active against legionnaires disease (LD) than erythromycin.8
- Fluoroquinolones, telithromycin, and azithromycin have greater in vitro activity and better intracellular penetration than erythromycin.8 In addition, animal studies of L pneumophila infection have shown these agents to have superior activity.
- The fluoroquinolones doxycycline, telithromycin, and azithromycin are superior because of their activity and pharmacokinetic properties (eg, better bioavailability, better penetration into macrophages, longer half-life).
- For severe disease, a fluoroquinolone is recommended. 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 greater than or equal to 30 mg/dL
- Diastolic blood pressure lower than 60 mm Hg
- Respiratory rate greater than 30/min
- With doxycycline or fluoroquinolones, rifampin does not need to be added in severely ill patients.
- Most healthy hosts exhibit clinical response to treatment within 3-5 days.
Medication
Treat intravenously until clinically improved; then, consider changing to an oral 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.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Levofloxacin (Levaquin)
Fluoroquinolone for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.
Adult
500 mg PO/IV qd, adjust dose in renal disease
Pediatric
<18>18 years: Administer as in adults
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment
Azithromycin (Zithromax)
Macrolide antibiotic used to treat mild-to-moderate microbial infections.
Adult
Day 1: 500 mg PO
Days 2-7: 250-500 mg PO qd; may treat for 10 d
500 mg IV qd for 7-10 d
Pediatric
<6>6 months: 10 mg/kg PO on day 1, not to exceed 500 mg; 5-10 mg/kg/d PO qd on days 2-7, not to exceed 500 mg/d; may treat for 10 d
May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated
Clarithromycin (Biaxin)
Macrolide antibiotic. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult
250 mg PO bid; may increase to 500 mg PO tid or 500 mg PO q12h
Pediatric
15 mg/kg/d PO divided bid; not to exceed 1 g qd
Toxicity increases with coadministration of fluconazole and pimozide; clarithromycin effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, HMG CoA-reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmia and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Documented hypersensitivity; coadministration of pimozide
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25>
Ciprofloxacin (Cipro)
Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis, and, consequently, growth.
Adult
250-750 mg PO q12h; 200-400 mg IV q12h
Pediatric
15-30 mg/kg/d PO divided q12h; not to exceed 1.5 g/d
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment
Sparfloxacin (Zagam)
No longer available in the United States. Inhibits bacterial DNA synthesis and, consequently, growth.
Adult
200 mg PO qd
Pediatric
<18>18 years: Administer as in adults
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment
Telithromycin (Ketek)
First antibiotic in a new class called ketolides. Combats resistant bacteria by inhibiting the protein synthesis necessary for bacterial reproduction, binding 10 times tighter than macrolides at 2 different sites on bacterial ribosomes. Blocks protein synthesis by binding to 50S ribosomal subunit (23S rRNA at domain II and V). Binding at domain II retains activity against gram-positive cocci (eg, S pneumoniae) in the presence of resistance mediated by methylases (e rm genes) that alter the domain V binding site. May also inhibit the assembly of nascent ribosomal units.Resistance and cross-resistance have not been observed. Active against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis, as well as atypical bacteria (eg, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumoniae). Indicated to treat mild-to-moderate CAP, including infections caused by multidrug-resistant S pneumoniae.
Adult
800 mg PO qd for 7-10 d
Pediatric
Not established
CYP 3A4 inhibitor and substrate; coadministration with other CYP 3A4 inhibitors (eg, itraconazole, ketoconazole) decreases elimination and increases Cmax and AUC; CYP 3A4 inducers (eg, rifampin) decreases telithromycin Cmax and AUC by 79% and 86%, respectively; increases Cmax and AUC of other CYP 3A4 substrates (eg, cisapride, pimozide, simvastatin, lovastatin, atorvastatin, midazolam, triazolam); HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin, lovastatin) should be temporarily discontinued owing to increased myopathy risk when coadministered; increases digoxin and theophylline serum levels; decreases sotalol Cmax and AUC secondary to decreased absorption; caution with other drugs that increase QTc interval (eg, quinidine, procainamide, dofetilide)
Documented hypersensitivity; coadministration with cisapride or pimozide; myasthenia gravis; history of hepatitis and/or jaundice with use of macrolides
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe renal impairment (limited data exist); consider the diagnosis of pseudomembranous colitis if diarrhea occurs following antibiotic treatment; may prolong QTc interval (caution in heart conduction abnormalities); common adverse effects include diarrhea and nausea; may rarely cause visual disturbances; acute hepatic failure and severe liver injury (in some cases fatal) have been reported (if clinical hepatitis or liver enzyme elevations combined with other systemic symptoms occur, permanently discontinue)
Doxycycline (Vibramycin)
Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult
100 mg PO/IV q12h
Pediatric
<8>8 years: Not established
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Documented hypersensitivity; severe hepatic dysfunction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider measuring drug serum level in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines
Moxifloxacin (Avelox)
Inhibits bacterial DNA synthesis and growth. Activity is similar to that of ciprofloxacin and levofloxacin.
Adult
400 mg PO qd for 10 d
Pediatric
<18>18 years: Administer as in adults
Follow-up
Further 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 ICU admission for closer monitoring. Quickly initiate empiric antibiotic treatment and obtain a diagnostic workup.
Further Outpatient Care
- In milder cases, patients can be treated in the outpatient setting with oral antibiotics.
- For patients who are hospitalized and treated with intravenous antibiotics, start oral antibiotics while in the hospital and observe 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.
Inpatient & Outpatient Medications
- Patients should complete the full course of their antibiotics, whether the treatment is initiated in the outpatient setting or in the hospital.
Deterrence/Prevention
- Prevention and control of nosocomial legionellosis
- Legionellae should be sought in hospitalized patients with an increased risk for infection and subsequent death.
- If one definite case or 2 possible cases of nosocomial legionnaires disease (LD) occur among inpatients, initiate an investigation for a hospital source.
- Routinely maintain cooling towers and use only sterile water for filling and rinsing of nebulization devices.
- Improve the design and maintenance of cooling towers and plumbing systems.
- Disinfection
- Superheating water to 70-80°C, with flushing of distal sites
- Installation of copper-silver ionization units, which produce metallic ions that disrupt the bacterial cell wall, thus resulting in lysis and cell death: This method provides sustained protection and is very effective at eradicating legionellae.
- Use of ultraviolet light, which kills legionellae by damaging cellular DNA: This system is effective when disinfecting localized areas; however, 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 higher water temperatures found in hot water systems being treated.
Complications
- Decreased pulmonary function
- Abscess formation (in the lungs or at extrapulmonary sites)
- Pulmonary fibrosis or scarring
- Fulminant respiratory failure
- Death
Prognosis
- Progressive respiratory failure is the most common cause of death in patients with Legionella pneumonia. The mortality rate depends on the comorbid conditions of the patient, as well as the choice and timeliness of antibiotics administration. The site of acquisition (eg, nosocomial, community-acquired) may also affect the outcome.
Patient Education
- For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.
Miscellaneous
Medicolegal Pitfalls
- Failure to recognize L pneumophila as an important cause of CAP could lead to suboptimal treatment with inappropriate antibacterial agents and could result in unnecessary patient morbidity and mortality.
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