Blood cultures were negative as were 3 sets of sputum for acid-fast bacilli; however, his sputum culture grew methicillin-resistant Staphylococcus aureus (MRSA). The susceptibility profile was consistent with the community associated MRSA phenotype. Because of a rash due to vancomycin, therapy was changed to linezolid. He improved clinically and symptomatically on linezolid and was discharged home to complete a 21-day course of treatment with follow-up with his primary care physician.
BACKGROUND AND EPIDEMIOLOGY
In 1882, Alexander Ogston described staphylococcal disease and its role in sepsis and abscess formation.1 Methicillin-resistant Staphylococcus aureus emerged in the 1960s in the United Kingdom, shortly after the introduction of methicillin and is currently the most commonly identified antibiotic-resistant pathogen in US hospitals.2 Patients with S. aureus infection stay in the hospital longer, incur more charges, and are at increased risk of in-hospital death compared with those without this infection.3 In a recent and dramatic evolutionary development over the last decade, infection with novel community-associated strains of MRSA (CA-MRSA) in previously healthy individuals without either direct or indirect association with health care facilities or typical risk factors has emerged.4-9
The CA-MRSA infection is defined as an illness in which MRSA is cultured from a sterile site of infection in an outpatient setting or less than 48 hours after a hospital admission. These patients should not have been hospitalized, undergone surgery, received dialysis, or resided in a long-term care facility within 1 year before the onset of illness and should not have a permanent indwelling catheter or a previous positive MRSA culture.10 Clusters and outbreaks of CA-MRSA in adolescents and adults have been reported to occur in Native Americans, homeless youths, men who have sex with other men, jail inmates, military recruits, children in child care centers, and competitive athletes.5,7,11-14
The CA-MRSA infection gained widespread attention with the Centers for Disease Control and Prevention report of 4 deaths in North Dakota and Minnesota in 1997-1999 in previously healthy children.15 Two of these children had evidence of necrotizing pneumonia. Most infections caused by CA-MRSA are skin and soft tissue infections, less frequently, severe necrotizing pneumonia, and sepsis, and most recently, rare cases of necrotizing fasciitis have been reported.
An estimated 86.9 million persons in the United States (32.4% of the population) are thought to be colonized (usually in and around the nasal area) with S. aureus. In a study from 2001 to 2002, the estimated prevalence (colonization) of MRSA among S. aureus isolates was approximately 2.5%, for an estimated population carriage of MRSA of 0.84% or 2.2 million persons.16 The true prevalence of CA-MRSA infection remains unknown because it varies by geographic area, and rates of 18.0 cases per 100,000 population in Baltimore and 25.7 cases per 100,000 population in Atlanta were found in a recent study.17
PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS
Methicillin resistance is determined by the presence of a penicillin-binding protein with decreased affinity to penicillin.18 The mecA gene encodes this protein and is located on staphylococcal cassette chromosome mec (SCC mec). The CA-MRSA infection in the United States is predominantly caused by the USA 300 clone (although USA 400 clone has also been implicated). The CA-MRSA has been recognized by careful epidemiological evaluation; it is characterized by the presence of a distinct methicillin-resistant staphylococcal cassette chromosome (SCC mec type IV element), susceptibility to multiple antibiotics (other than β lactams), and the presence of Panton-Valentine leukocidin (PVL) genes.8 The PVL, which was described by Panton and Valentine in 1932, belongs to the synergohymenotropic (synergistic protein directed toward cell membranes) class of toxins and is known as a virulence factor for CA-MRSA. It is assembled from 2 components that are secreted separately but combine to create lytic pores in cell membranes of neutrophils.19 The binding of PVL components to neutrophils induces release of the neutrophil chemotactic factors interleukin 8 and leukotriene B4 and a variety of inflammatory mediators before bringing about cell death.20
Francis et al21 reported the first cases of CA-MRSA-associated necrotizing pneumonia by strains carrying PVL gene in healthy adults in the United States. Other fatal cases have been reported in other parts of the world.22-24 Most of the lethal cases of CA-MRSA pneumonia were preceded by influenzalike symptoms.21,24 Hemoptysis was reported in 6 (38%) of 16 patients with strains carrying PVL genes.25 Other reported findings include cough productive of purulent sputum, fever, tachycardia, tachypnea, leukopenia, onset of pleural effusion during hospital stay, septic shock, and general picture of rapidly progressive, hemorrhagic, necrotizing pneumonia requiring mechanical ventilation and vasopressors in the intensive care unit. Agwu et al26 reported florid, watery diarrhea and shock in a 14-year-old adolescent girl with CA-MRSA pneumonia.
The initial imaging procedure of choice should be a chest radiograph. In most cases, the plain film findings may be diagnostic of pneumonia and may eliminate the need for additional radiographic procedures. Computed tomography is used to look for complications in patients not responding to therapy.
The CA-MRSA pneumonia typically causes necrotizing bronchopneumonia. It can be homogeneous or patchy and is commonly seen in the lower lobes. Abscess formation with cavitation is often an early finding. Air bronchograms are rarely present. In children, thin-walled cystic structures called pneumatoceles are usually present. All of the 4 patients described by Francis et al21 had cavitary lesions. A prospective study of staphylococcal lower respiratory tract infection in 31 children showed that radiologically, patchy consolidation was the single most common lesion, followed by pleural effusion with or without pneumothorax.27
Gonzalez et al28 in their report found that 47 (67%) of 70 patients with invasive CA-MRSA infection who underwent pulmonary imaging had abnormal findings. In this report, 14 (29.7%) had empyema, 10 (21.2%) had pneumonia/effusion, 7 (14.8%) had septic emboli, and 4 (8.5%) each had lung abscess, pneumonia with pneumatoceles, diffuse air space disease and/or increased interstitial markings, or atelectasis. Of note, none of the 7 patients with CA-MRSA invasive infection and septic emboli on chest radiography or CT had cardiac vegetations noted on transthoracic echocardiography, although 2 of them had deep venous thrombosis of the lower extremities.
The CT scans have increased sensitivity for radiological findings and may further differentiate patterns on chest radiographs from other etiologies. On thin-section CT, MRSA pneumonia is generally segmental. Areas of consolidation are often associated with smaller centrilobular nodules. Volume loss of the affected lobe is often present. Pleural effusions are seen in most patients; empyemas often complicate the effusions. A spontaneous pneumothorax can occasionally be associated with MRSA pneumonia.
History and physical examination suggestive of severe community-acquired pneumonia in a high prevalence area for CA-MRSA should alert the clinician. Chest radiographs or a chest CT demonstrating lobar consolidation with cavitation (necrotizing pneumonia) is suggestive of MRSA pneumonia. Positive culture of sputum, tracheal aspirate, or bronchoalveolar lavage for MRSA in such setting is diagnostic. In patients with bacteremic pneumonia, positive blood culture for MRSA can also help in diagnosis. The susceptibility pattern of the isolates from pulmonary specimens or blood also helps with differentiating CA-MRSA from the more resistant MRSA that is found in the hospital. Genome sequencing of the MRSA strains to detect SCC mec type genes for several superantigens and toxins like PVL can also be done. In the United States, USA 300 and, less frequently, USA 400 are the dominant clones found. Pulsed field gel electrophoresis can be performed to determine genetic relatedness of isolates for epidemiological purposes.
The most effective therapy for necrotizing pneumonia caused by CA-MRSA has yet to be defined. Currently available agents active against MRSA include vancomycin; however, the growing number of infections caused by CA-MRSA would markedly increase the widespread use of vancomycin therapy that may further promote the development of resistance. The appearance of vancomycin-intermediate S.aureus and, more recently, vancomycin-resistant S. aureus is of concern.
Linezolid was superior to vancomycin in a retrospective subset analysis of 2 prospective, randomized clinical trials probably because of its good intrapulmonary penetration in treating hospital-acquired MRSA pneumonia.29 It also has antitoxin effects; however, it is more costly than other agents and can cause bone marrow suppression. Clindamycin is active against some MRSA isolates and also has an antitoxin effect that warrants its use in necrotizing pneumonia. It is recommended that microbiology laboratories screen for inducible clindamycin resistance in erythromycin-resistant strains, and if found, an alternative antibiotic should be used for treatment. Trimethoprim-sulfamethoxazole has good activity against MRSA in vitro and is well tolerated. Many experts recommend trimethoprim-sulfamethoxazole as therapy for MRSA pneumonia, but further investigation is needed.
Another antibiotic with activity against MRSA is quinupristin/dalfopristin; however, clinical experience in patients with nosocomial MRSA pneumonia is disappointing. In one study, the response rate was only 19.4% compared with 40% in vancomycin-treated patients,30 and use is also limited by its cost and adverse effects.
Daptomycin, an agent with in vitro activity against MRSA, failed in a clinical trial involving patients with pneumonia because it has limited penetration into pulmonary epithelial lining fluid, and its activity is inhibited by pulmonary surfactant.31 No data on MRSA pneumonia are available for tigecycline, a glycyclycline with activity against MRSA.
It has been shown that the action of PVL toxin on neutrophils in vitro may be blocked by specific PVL antibodies found in commercial preparations of intravenous immune globulin.32
In summary, MRSA has emerged as an important organism causing both community-acquired and health care-associated infections. The CA-MRSA generally causes skin and soft tissue infections, but pneumonia occurs as well. The diagnosis is confirmed by culturing respiratory tract secretions and performing standard susceptibility testing. Currently, there is no standard therapy for CA-MRSA pneumonia, but there are multiple different antibiotics that have activity against this organism.
The authors thank Dr Pavani Reddy for her careful review of this manuscript and her constructive feedback.
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