Staphylococcus Aureus Pneumonia: Emergence of MRSA in the Community
Suzanne F. Bradley, M.D., Semin Respir Crit Care Med. 2005;26(6):643-649. Thieme Medical Publishers, 02/22/2006

Abstract

The clinical presentation of staphylococcal pneumonia is changing. Healthy young people without traditional risk factors for Staphylococcus aureus disease are presenting with severe necrotizing infection and high mortality. The clinical picture is reminiscent of outbreaks of post-influenzal staphylococcal pneumonia seen in the past century. Most of these staphylococcal strains are methicillin-resistant and are not health care associated. Many strains contain toxins that are likely responsible for the severity of illness seen. Panton-Valentine leukocidin has rarely been identified in S. aureus until recently. It appears that the genetic element for methicillin resistance has been introduced into multiple highly virulent methicillin-susceptible strains with great potential for further spread. Early recognition and treatment of possible community-acquired methicillin-resistant S. aureus (CA-MRSA) is essential. It is equally important to attain microbiological confirmation of the diagnosis for optimal treatment and to initiate appropriate infection control procedures.

Community-Acquired Methicillin-Resistant Staphylococcus Aureus - an Evolving Definition

Classic Centers for Disease Control and Prevention (CDC) definitions of nosocomially acquired versus community-acquired infections have been based on the presumed site of acquisition of the infection. In general, patients who developed infection within 48 to 72 hours of admission were presumed to have an infection acquired from the community.[1]

Since its initial description in the United States in 1968, methicillin-resistant Staphylococcus aureus (MRSA) infection was almost exclusively associated with acquisition from hospitals, nursing facilities, dialysis units, and other health care settings where skilled care was provided.[2,3] In the 1980s and 1990s, it was recognized that an increasing number of patients were admitted from the community with their MRSA infection. However, these individuals generally had some epidemiological link to health care settings through recent admission, contact through dialysis or infusion centers, or contact with a family member who worked in the health care industry.[4] Many patients were known MRSA carriers, a risk factor for subsequent infection that persists for months to years. Other MRSA infections were associated with the use of intravenous drugs in some communities.[5] Terminology began to change to health care-associated (HA-MRSA) and community-associated or community-onset MRSA to reflect the concept that the place of MRSA infection could no longer be ascertained.[2] Those community-associated strains were closely linked to health care-associated strains on the basis of antimicrobial susceptibilities and molecular typing methods.[3]

In the late 1990s, true community-acquired MRSA (CA-MRSA) was found among clusters of severe and fatal MRSA infections described in healthy children from Minnesota, North Dakota, and Illinois who had no identifiable link to the health care setting.[6-8] Subsequently, many reports of CA-MRSA in otherwise healthy persons rapidly emerged from various geographic areas in the United States, Canada, Australia, New Zealand, and others. Necrotizing pneumonia and outbreaks of skin and soft tissue infections (SSTIs) among athletes, native peoples, and prisoners have primarily been reported.[3,8,9]

How Does CA-MRSA Differ from HA-MRSA? Clues from the Laboratory

All MRSA are characterized genotypically by the presence of mecA, which encodes for altered penicillin binding proteins (PBPs) (PBP2A) on their cell walls. The low affinity binding of PBP2A to antistaphylococcal penicillins results phenotypically in resistance to all β-lactam antibiotics.[8] It is possible that MRSA arose when mecA was transferred from coagulase-negative staphylococci on a mobile genetic element termed SCCmec and incorporated into the chromosome of a methicillin-susceptible S. aureus (MSSA) strain by recombination.[2,8,9,10]

There are at least five types of SCCmec now identified that may carry genes in addition to mec required for recombination [cassette chromosome recombinase (ccr)], antibiotic resistance, and virulence factors.[2,8,9] HA-MRSA has been associated with SCCmec types I to III. These HA-MRSA SCCmec types may contain resistance elements for numerous antibiotic classes, including macrolides, lincosamides, aminoglycosides, fluoroquinolones, tetracyclines, and sulfonamides. These health care-associated SCCmec types are so large that they cannot be incorporated into a phage, or they lack the genes required for recombination. It has been suggested that these large genetic elements may actually impair the growth and fitness of HA-MRSA to the point where they might not survive without the selective pressure of antibiotics. Perhaps as a result, the spread of mecA throughout S. aureus has been inefficient with only five phylogenetically distinct MRSA lineages worldwide.[3,8-10]

In contrast, CA-MRSA is characterized by the presence of SCCmecIV, and more recently SCCmecV.[2,8,9] SCCmecIV has been present in coagulase-negative staphylococci since the 1970s but was not found in S. aureus until decades later.[2] Discovery of recent clusters of severe MSSA and MRSA infection with identical pulsed gel electrophoresis (PFGE) types suggests that insertion SCCmecIV might have occurred in highly virulent MSSA strains.[9,10]

SCCmecIV from CA-MRSA contains primarily mecA, ccr, and on some occasions, genes that encode for various toxins. SCCmecIV is small enough that efficient transfer by phage or transposon into MSSA is possible. In addition to the increased efficiency of transfer of a smaller cassette, CA-MRSA has been associated with more rapid growth rates than HA-MRSA, which may confer some survival advantage that might facilitate spread of these organisms. As a result, there is the potential that the horizontal transfer of SCCmecIV from CA-MRSA to multiple MSSA clones could occur efficiently with the potential for rapid dissemination worldwide.[8,9] Outbreaks of CA-MRSA have been associated primarily with PFGE strains types USA400 and USA300 and multiple locus sequence typing (MLST) types ST1 and ST8 in the United States; ST80 and ST30 have been found in Europe.[2,9,11,12]

The Prevalence of S. aureus Pneumonia: is it Changing?

In the past, staphylococcal pulmonary infection has been uncommon in healthy children and adults from developed countries.[13] It has been estimated that 1 to 10% of community-acquired pneumonia (CAP) and ≥ 10% of hospital-acquired pneumonia (HAP) are due to S. aureus.[14] In past reviews of serious S. aureus infection requiring hospitalization, invasive disease occurred in patients at the extremes of age with predisposing diseases; most of the infections were nosocomially acquired or health care related.[13-16] S. aureus accounted for 6% of pneumonias and 13% of empyemas at one medical center; ~40% of these cases were associated with bacteremia.[16] Respiratory infections (pneumonia with or without empyema or empyema alone) constituted the second or third cause of serious S. aureus infection, after skin and soft tissue infection (SSTI) and bone infection.[15,16]

Currently, there is little information about the actual incidence of CA-MRSA pneumonia nationwide. In a recent multicenter survey of population-based data and laboratory data from 2001 to 2002 in Atlanta, Baltimore, and Minnesota, 8 to 20% of MRSA infections occurred in patients without traditional risk factors, for an incidence of 18.0 to 25.7 per 100,000.[17] SSTIs account for the majority of CA-MRSA infections (75-77%); pneumonia occurred in only 2 to 6% of cases.[17,18] In a cohort of Minnesota hospitals, HA-MRSA pneumonia (22%) occurred more often than CA-MRSA cases, 22% versus 6%, respectively.[18] Thus one can anticipate that more cases of staphylococcal pneumonia, and CA-MRSA in particular, will be seen in addition to those populations that were traditionally at risk for S. aureus respiratory tract infection.

Lessons from Staphylococcal Pneumonia: What was Old is New Again

The demography and clinical presentation of staphylococcal pneumonia have continuously changed since its initial description in the late 19th and early 20th centuries. In young, healthy military personnel during World War I, vivid descriptions of postinfluenza staphylococcal pneumonia included “dirty salmon-pink anchovy sauce” purulent sputum, lack of signs of consolidation, and inflammation followed by “cherry-red indigo-blue cyanosis” and a progression to death so rapid that the patients were frequently unaware of its approach.[19] Others described remitting fever, tachypnea out of proportion with clinical findings, pleuritic chest pain, and normal chest roentgenographic findings in the first 24 to 48 hours.[20] In those patients, autopsy findings frequently revealed hemorrhage and microabscess formation. If the patient survived 4 to 5 days, clinical findings of bronchopneumonia ensued, microabscesses coalesced into cavitary lesions, and pneumatoceles, empyemas, bronchopleural fistulae, pyopneumothoraces, and pulmonary gangrene were found.[20,21] In the pre-antibiotic era, mortality rates approached 80 to 90%.[13,19,20]

In the 1950s, sporadic cases of staphylococcal pneumonia were increasingly described in very young infants < 6 months and among adults without prior influenza infection. These adults typically had predisposing cardiopulmonary disease, alcoholism, or diabetes and acquired their infection primarily in hospital. The clinical presentation was often more insidious and less explosive than previously described.[13,20,22-24] In that postantibiotic era, mortality rates ranged from 12 to 15% in children, 20% in young adults, 30 to 50% postinfluenza, and 84% in patients with bacteremic primary pneumonia.[13,14,23,25]

It was also noted that not all patients with staphylococcal pneumonia had primary infection following inhalation or aspiration. Some patients developed secondary staphylococcal infection of the respiratory tract following hematogenous dissemination from another site such as SSTI or as a consequence of right-sided endocarditis.[20,26-28] These secondary staphylococcal pneumonia cases were also less severe than primary pneumonia cases associated with influenza.

Has the emergence of HA-MRSA altered the epidemiology and clinical presentation of staphylococcal pneumonia? Studies that have compared the clinical presentation and outcome of HA-MRSA pneumonia versus MSSA cases have been infrequent.[29-32] In one series of ventilator-associated pneumonia (VAP), patients with MRSA were more likely to have bacteremia and had greater mortality than patients with MSSA pneumonia.[32] However, a more recent study of bacteremic primary pneumonia found no differences in clinical presentation, radiological findings, or complications between the two organisms, even though MSSA patients were younger and had fewer predisposing illnesses.[31] So the increasing prevalence of HA-MRSA strains alone has not had a convincing impact on the changing demography and increased virulence seen in staphylococcal pneumonia.

Reports of severe necrotizing pneumonia due to CA-MRSA have been described in the United States and France.[10,33-37] Further characterization of some isolates confirmed the presence of SSCmecIV and the USA300 PFGE type.[10,11,33,34] Some of these respiratory infections have been associated with toxic shock, hemoptysis, respiratory failure, purpura fulminans, and recent influenza infection.[10,33,34,36,38-40] Despite the availability of antibiotics, the clinical presentation of these infections in young healthy patients is reminiscent of the infections seen in the early part of the 20th century. What has changed?

The Role of Toxins in the Changing Epidemiology and Clinical Presentation of Staphylococcal Pneumonia

In recent years, increasingly severe cases of MSSA community-acquired primary pneumonia have also been recognized among persons who should not be at risk of the infection.[10,33-37] In many instances, MSSA isolates contained the toxin Panton-Valentine leukocidin (PVL).

PVL is a member of the synergohymenotropic toxin family that induces pores in the membranes of cells.[2,37,41-43] Pairs of secretory proteins S and F work synergistically on cell membranes (hymen) as superantigens with release of intracellular interleukin-8, leukotrienes, proteases, and oxygen metabolites with resulting chemotaxis, vasodilitation, infiltration and death of neutrophils, and tissue necrosis.[2,37,42] SF protein pairs composed of S and F PVL-associated proteins (LukSPV + Luks FPV) and S and F α-hemolysin-associated proteins (HlgA (class S), HlgB (class F), HlgC (class S) have been found in various combinations in necrotizing pneumonia.[2,37,42] The presence of PVL in severe staphylococcal pneumonia isolates appears to be a recent phenomenon; in the past, the toxin had been identified in < 5% of strains.[37,40,42]

The clinical presentation of pneumonia appears to be different in PVL-producing strains. In cases of staphylococcal necrotizing CAP, 85% were PVL positive, whereas none of HAP strains were positive for the toxin.[42] Patients with PVL-positive strains were significantly more likely to have had an antecedent influenza-like illness, fever > 39°C, tachycardia, hemoptysis, pleural effusion, and leukopenia.[37] PVL-positive patients were also younger and less likely to survive their infection; overall mortality was > 40%.[37,38,42] Necrosis and hemorrhage of the trachea, alveoli, and blood vessels were commonly seen on autopsy and bronchoscopy specimens.[37,38] The presence of PVL may, in part, explain the changing epidemiology and clinical presentation of staphylococcal pneumonia whether it is due to MSSA or MRSA.

CA-MRSA infecting strains are more likely to have genes for toxins such as the leukocidins, staphylococcal enterotoxins B, C, and K (SEB, SEC, and SEK), and toxic shock staphylococcal toxin-1 (TSST-1) than HA-MRSA strains, but not all CA-MRSA strains are toxin producing.[10,18,34,36,43] Genetic factors that control the regulation and expression of toxins and other virulence factors, such as agr, may be important; most CA-MRSA strains contain agr1 and agr3.[18,35,44] Therefore, the presence of toxin genes and the ability to express those genes may explain, in part, how CA-MRSA causes severe and frequently fatal respiratory tract infections in healthy people.

Detection of CA-MRSA

Most medical centers cannot perform typing for SCCmecIV or other molecular methods to detect CA-MRSA. Currently, the diagnosis is suspected based on a clinical presentation consistent with severe staphylococcal infection and lack of patient risk factors for HA-MRSA. Patients with CA-MRSA are significantly younger (median age 23 years vs 68 years) and without significant health problems (85% vs 24%) than patients with HA-MRSA.[18] The diagnosis of CA-MRSA should also be considered in severely ill young persons with a preceding history of influenza-like illness, severe respiratory symptoms, high fever, hemoptysis, leukopenia, and hypotension.[2]

As CA-MRSA becomes more widespread in health care facilities, epidemiological definitions based on place of acquisition and risk factors for MRSA will be less useful. For this reason, experts recommend that appropriate cultures from samples of blood, sputum, skin and soft tissue, and other sources be obtained as early as possible rather than relying on clinical criteria alone and empirical treatment. Cultures of sputum are 92% sensitive for the detection of S. aureus.[14] However, the presence of a positive sputum culture for S. aureus is not specific for infection and may represent oropharyngeal colonization in patients with suspected pneumonia.

Currently, CA-MRSA is likely if the isolate is resistant to all β-lactam antibiotics and susceptible to most other antibiotic classes such as aminoglycosides. lincosamides, sulfonamides, fluoroquinolones, and macrolides. CA-MRSA isolates are significantly more likely to be susceptible to gentamicin (94% vs 80%), clindamycin (83% vs 21%), ciprofloxacin (79% vs 16%), and erythromycin (44% vs 9%) than HA-MRSA isolates.[18] Unfortunately, as CA-MRSA becomes more common, it is likely that it too will acquire resistance genes that will make detection by routine antimicrobial susceptibility testing more difficult.

General Guidelines for Treatment of CA-MRSA Pneumonia

Given its high morbidity and mortality, the treatment of staphylococcal pneumonia has primarily relied on intravenous therapy with a bactericidal antibiotic. Experts have recommended 10 to 14 days of therapy in patients with rapid resolution of symptoms and chest roentgenographic findings.[16,25] Duration of therapy should be based on careful follow-up for resolution of signs and symptoms of infection in patients with primary pulmonary infection with cavitary disease or empyema. All bacteremic patients should be carefully assessed for the presence of endocarditis, empyema, metastatic abscesses, and other complications that might require longer therapy and surgical intervention. For S. aureus, clinical examination and duration of bacteremia are not useful to exclude the diagnosis of endocardtis.[45] Prolonged intravenous therapy is required unless the patient has well-documented and uncomplicated isolated right-sided endocarditis.

Treatment Options for CA-MRSA Pneumonia

Empirical antibiotic choices for treatment of CAP are increasingly difficult to make in the era of CA-MRSA. Vancomycin has remained the cornerstone of therapy for suspected CA-MRSA. However, once CA-MRSA is identified, is vancomycin the optimum treatment for respiratory infection? Failure rates of 40% have been reported and attributed to an inadequate duration of therapy < 21 days.[46] In addition, poor vancomycin penetration into epithelial cell lining fluid and rising vancomycin minimum inhibitory concentrations for MRSA have led some experts to increase trough levels to 20 µg/mL.[47]

Unfortunately, although there are more antibiotic choices, there is little information about the use of alternative agents for pneumonia due to CA-MRSA. Most information on the use of other antimicrobial agents is based on treatment of HA-MRSA infection.

Linezolid (Zyvox; Pfizer Inc., New York, NY) is an oxazolidinone antibiotic that is bacteriostatic for MRSA.[48] In an open-label trial of linezolid versus vancomycin for confirmed MRSA pneumonia, rates of clinical cure were equivalent (75% vs 75%) by intent to treat analysis, as were rates of microbiological cure (52% vs 54%) in evaluable patients.[49] Outcomes for linezolid and vancomycin groups did not differ for patients with multilobar involvement, bacteremia, or effusion. When, a retrospective subanalysis of MRSA cases was done from two prospective double-blinded clinical trials of HAP, results suggested that linezolid treatment was superior to vancomycin with clinical cure rates of 59% versus 36%, OR 3.3 (95% CI 1.3-8.3, p < .01).[50-53] No differences were seen in outcomes for pneumonia patients with bacteremia, but the efficacy of linezolid in patients with documented endocarditis has not been formally studied.

The streptogramin, quinupristin-dalfopristin (Synercid; Monarch Pharmaceuticals, Inc., Bristol, Tennessee) is a bactericidal for clindamycin-susceptible isolates of MRSA.[54] However, clinical response rates of MRSA pneumonia were only 19% for quinupristin-dalfopristin when compared with a 40% response rate for vancomycin.[55] Experience with trimethoprim-sulfamethoxazole and clindamycin for treatment of HA-MRSA pneumonia and bacteremia has also been very limited.[9,56,57]

For MRSA infections failing conventional therapy, the addition of quinupristin-dalfopristin or imipenem to vancomycin has been tried with some success, but pneumonia has rarely been studied.[58] Addition of rifampin to conventional therapies has also been tried in patients with refractory pneumonia due to MRSA, but no controlled trials demonstrating superiority have been done.[2] Daptomycin cannot be recommended for treatment of MRSA pneumonia because its activity is inhibited by pulmonary surfactant, penetration into epithelial lining fluid is poor, and its efficacy was not established in trials of CAP.[9,59]

Pitfalls in Antimicrobial Susceptibility Testing for CA-MRSA

CA-MRSA may harbor inducible resistance genes for macrolides, lincosamides, streptogramins, and tetracycylines; resistance may emerge on therapy.[9,60] Similarly, MRSA frequently contains clones with varying degrees of resistance to ciprofloxacin (heteroresistance). This drug should be used with caution because rapid selection of resistance is likely to occur.[9]

In the past, resistance to macrolides automatically implied that lincosamides such as clindamycin could not be used due to cross resistance. However, some erythromycin resistance is mediated by an efflux gene mrs(A) that has no impact on clindamycin susceptibility. To determine if inducible lincosamide resistance is present in macrolide-resistant strains, a D test can be performed. In a truly lincosamide-resistant strain, the placement of an erythromycin disk in close proximity will blunt the normally circular zone of inhibition caused by clindamycin forming a D shape, or positive, test. A positive D test means that inducible resistance to clindamycin is present and the drug should not be used.[60]

Other Treatment Strategies for CA-MRSA

Antistaphylococcal antibodies and inhibition of toxin production have also been suggested as additional strategies for the treatment of CA-MRSA.[9,61] Anti-PVL antibodies have been detected in commercial preparations of IgG, and inhibition of the leukocidin has been achieved in vitro.[61] However, the efficacy of IgG in severe staphylococcal infections overall has not been established.[43] Use of clindamycin to inhibit toxin production by CA-MRSA has also been suggested but has not been studied. Surgical drainage of empyema and debridement of necrotic tissue are also important in the treatment of toxin-mediated infection. Treatment with recombinant activated protein C (Xigris; Eli Lilly and Company, Indianapolis, Indiana) for associated septic shock should also be considered.[43]

Prevention of CA-MRSA Infection

There is no information on methods to prevent recurrent CA-MRSA in patients. Whether carriage of the organism persists long term is unknown in patients who were previously without traditional risk factors. Risk of spread to contacts of CA-MRSA is also unknown; spread to health care workers, prisoners, and family has occurred. Methods to permanently decolonize carriers of their MRSA have generally not been very effective.[2] Contact isolation procedures for HA-MRSA should be effective, but many institutions have eliminated policies for isolation of MRSA.

Summary

Infections due to CA-MRSA appear to be increasing worldwide and most are due to SSTI. Severe necrotizing pneumonia, bacteremia, and shock occur in relatively few persons with CA-MRSA infection, but fatal outcomes are common. Rapid recognition of possible staphylococcal infection in otherwise healthy persons with severe pneumonia and sepsis syndrome is essential. Early initiation of appropriate therapy for severe CA-MRSA and toxic shock is also critical for successful management of this infection. The diagnosis of CA-MRSA should be confirmed by cultures of sputum, blood, and other sites as appropriate to direct antibiotic therapy and to initiate infection control procedures.

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