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Washington University School of Medicine
Barnes-Jewish Hospital, St. Louis, MO
Dr. Kollef is Director, Medical Intensive Care Unit, Washington University School of Medicine. Dr. Micek is Pharmacy Director, Medical Intensive Care Unit, Barnes-Jewish Hospital.
Correspondence to: Marin H. Kollef, MD, FCCP, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Ave, St. Louis, MO 63110; e-mail: mkollef{at}im.wustl.edu
Pneumonia, an infection of the lungs usually due to bacterial, viral, or fungal pathogens, is classified according to the location of the patient at the time the infection occurs. Hospital-associated pneumonia (HAP) is defined as occurring > 48 h after hospital admission. HAP is the second most common hospital-acquired infection but leads to the greatest number of nosocomial-related deaths.12 Treatment of HAP has become problematic in the face of escalating emergence of antibiotic-resistant bacteria.34 Successful outcomes depend on the prevention of HAP when possible and the administration of appropriate antibiotics in a timely manner when infection develops.5 The latter can be difficult to achieve when the etiology of HAP is initially unknown.
Ventilator-associated pneumonia (VAP), one form of HAP, specifically refers to pneumonia developing in a patient receiving mechanical ventilation > 48 h after tracheal intubation.56 Although not included in this definition, some patients may require intubation after severe HAP develops and should be managed in a manner similar to patients with VAP. Pneumonia occurring within 48 h of hospital admission can be difficult to differentiate from community-associated pneumonia (CAP). These early onset pneumonias may have begun prior to hospital admission or possibly as a result of aspiration resulting from tracheal intubation at the time of hospital admission.
Health-care-associated pneumonia (HCAP) has been described as pneumonia developing in patients admitted to the hospital from high-risk environments. These high-risk environments include nursing homes and extended-care facilities or patients’ homes if they are receiving long-term dialysis, home infusion therapies (antibiotics, chemotherapy, blood product transfusions), home wound therapy, or have had a recent hospitalization.7 These risk factors increase the likelihood of infection with antibiotic-resistant bacteria that are more commonly seen in HAP and VAP as compared with CAP.8910 Patients with HCAP and HAP may go on to respiratory failure, further blurring the differences between these various classifications of pneumonia.
Infectious organisms resulting in HAP, as well as HCAP and VAP, have traditionally differed from those that are most commonly associated with CAP. Gram-negative aerobes have usually comprised the majority of hospital and health-care-associated infections while more antibiotic-sensitive pathogens (Streptococcus pneumoniae, Haemophilus influenza, Escherichia coli) have been associated with community infections.21112 The individual organisms most commonly reported to be associated with HAP and VAP, Staphylococcus aureus (18.1%), Pseudomonas aeruginosa (17.0%), and Enterobacter species (11.2%), are also the most likely to be resistant to prescribed antimicrobial regimens.2512
The recent emergence of methicillin-resistant S aureus (MRSA) as an increasingly common pathogen in all forms of pneumonia (CAP, HCAP, HAP, and VAP) has weakened the overall clinical importance of this classification scheme.13 Community-associated MRSA (CAMRSA) is the newest threat to patients hospitalized with pneumonia. The Centers for Disease Control and Prevention uses the following clinical criteria to differentiate CAMRSA from hospital strains: (1) diagnosis of MRSA made in the outpatient setting or by a culture finding positive for MRSA within 48 h after admission to the hospital; (2) the patient has no medical history of MRSA infection or colonization; (3) the patient has not been hospitalized, resided in a nursing home, received hospice care, required dialysis, or undergone surgery in the past year; and (4) the patient has no permanent indwelling catheters or medical devices that pass through the skin into the body.14
The virulence of the newly identified MRSA strains, including CAMRSA, has resulted in the designation of "superbug" to describe this pathogen.15 MRSA is considered to be a superbug due to the multiple features it can possess resulting in enhanced antibiotic resistance and greater mortality compared to methicillin-sensitive S aureus (MSSA) strains.141516 These features include the presence of the mecA gene that encodes a penicillin-binding protein, PBP2a, which is intrinsically insensitive to methicillin and all ß-lactam antibiotics that have been developed, including the isoxazolyl penicillins (eg, oxacillin) and broad-spectrum ß-lactams (third-generation cephalosporins, cefamycins, and carbapenems); the occurrence of surface molecules that promote greater adherence to living surfaces (endothelium, bone, cartilage), as well as to artificial surfaces (endotracheal tubes, medical devices, locker room floors); and the ability of S aureus to produce various toxins.
Two recent metaanalyses1718 of S aureus bacteremia have demonstrated that MRSA infections have an almost twofold greater mortality risk compared to MSSA infections. The greater intrinsic antibiotic resistance and virulence of the MRSA strains likely contributes to this difference in mortality. Similarly, MRSA pneumonia has been associated with a greater risk of death compared to MSSA pneumonia.19 Delays in the administration of appropriate initial antibiotic treatment for MRSA infections has been identified as one potential explanation for the excess mortality observed with this organism.20 Such delays have been attributed to clinicians’ failure to recognize risk factors for infection due to MRSA, including prior antibiotic administration and exposure to high-risk environments such as the ICU setting.21
Toxin production is an important aspect of the virulence associated with MRSA and MSSA infections. Most clinicians are aware of the toxin associated with toxic shock syndrome, staphylococcal enterotoxins, and the dermolytic toxin resulting in the scalded skin syndrome. More recently the Panton-Valentine leukocidin (PVL) toxin has been described as an important promoter of virulence in many strains of MRSA most prominent in CAMRSA.151622 The PVL toxin is a potent mediator of inflammation and can also destroy leukocytes by creating lytic pores in their cell membranes, contributing to the tissue necrosis observed in patients with PVL-positive infections.1522 PVL has been associated with necrotizing pneumonia and severe skin infections originating in the community setting.1523 In a study24 of S aureus pneumonia, the mortality rate was 32% in patients with infection with PVL-positive strains vs 6% mortality for infection with the PVL-negative strains.
In this issue of CHEST (see page 1414), DeRyke et al25 describe their experience with bacteremic S aureus VAP. The main limitation of their study is the relatively small sample size examined predisposing to type II errors for the comparisons they report among patient subgroups. Nevertheless, their study confirms many of the earlier observations of S aureus VAP. DeRyke et al25 found that patients with MRSA VAP were more likely to have had prior antibiotic exposure as a risk factor for infection with this specific antibiotic-resistant pathogen. Additionally, the high overall mortality they observed supports the importance of bacteremic S aureus pneumonia as a cause of patient morbidity and nosocomial-related death. Interestingly, these investigators observed a trend toward greater mortality among patients treated with vancomycin compared to ß-lactams for both MRSA and MSSA infections. Although not statistically significant, this observation suggests that vancomycin may have limitations in the treatment of serious S aureus infections.
In vitro studies26 have shown that vancomycin is a slowly cidal antibiotic that requires serum concentrations above the minimum inhibitory concentration (MIC) of MRSA throughout the dosing interval to achieve optimal killing of this pathogen. Clinical data and animal models2728 suggest that bacteremia is more prolonged with MSSA endocarditis treated with glycopeptide antibiotics (vancomycin, teicoplanin) compared to ß-lactam antibiotics. Similarly, MSSA endocarditis treated with vancomycin has been shown to have greater overall failure rates (37% to 50%) compared to similar patients treated with nafcillin (1.4% to 26%).2930313233 Comparable results have also been found for endocarditis due to MRSA, with even more prolonged bacteremia when rifampin is added to vancomycin suggesting clinical antagonism between these agents compared to treatment with vancomycin alone.3435
Potential limitations of vancomycin for the treatment of S aureus pneumonia have also been observed. Gonzalez et al36 reported that patients with bacteremic MRSA pneumonia had a greater mortality compared to MSSA pneumonia. Patients with MSSA infection treated with vancomycin were also found to have a significantly greater risk of hospital mortality compared to patients with MSSA pneumonia treated with oxacillin.36 Available studies263738 examining the treatment of MRSA pneumonia with vancomycin have found treatment to be successful in only 35 to 57% of patients.
A metaanalysis38 of two studies performed by the same group of investigators using the same study protocol found that patients with MRSA HAP treated with linezolid had a statistically greater survival compared to patients treated with vancomycin. When examining the cohort of patients with MRSA VAP, these investigators39 also found a greater eradication of MRSA among the patients treated with linezolid. An important limitation of this analysis is that the mortality benefit for MRSA was determined from a subgroup analysis. A confirmatory study has been undertaken to validate these findings by comparing linezolid to high-dose vancomycin (30 mg/kg/d) for microbiologically confirmed MRSA pneumonia.
Potential explanations for the clinical failures observed with vancomycin treatment of pneumonia, endocarditis, and bloodstream infections attributed to S aureus include the slow killing of vancomyin for this pathogen, the degree of protein binding of vancomycin relative to unbound or free drug concentrations at the infection site, the inability to achieve tissue concentrations of vancomycin above the MIC for MRSA throughout the dosing interval, the observed upward drift in the MICs for MRSA strains, and the large inoculum size associated with MRSA infections, especially in the lungs (pneumonia, empyema) and soft-tissue abscesses. Additionally, vancomycin, unlike clindamycin and linezolid, acts on the cell wall of S aureus, having no effect on toxin production at the ribosomal level.
Vancomycin epithelial lining fluid (ELF) concentrations may be increased in patients with lung injury due to leakage of vancomycin bound to albumin and other proteins into the alveolar compartment. However, the achievable free drug levels of vancomycin in the ELF appear to only reach concentrations > 4 µg/mL, the susceptibility breakpoint of MRSA, when plasma levels are > 20 to 25 µg/mL. Thus, plasma levels of vancomycin and "active" ELF concentrations of vancomycin are linearly related in patients with S aureus pneumonia, in approximately a 5:1 ratio.40 Another study41 of in vivo lung tissue concentration measurements of vancomycin observed mean vancomycin levels at or below the 4 µg/mL susceptibility breakpoint of MRSA 4 to 6 h after administration of a 1-g dose of vancomycin in patients undergoing thoracotomy. The limited tissue penetration of vancomycin, resulting from protein binding of the drug in plasma, along with upward drift of the MICs of MRSA to vancomycin offers the best explanation for the clinical failures of vancomycin reported in patients with serious MRSA infections.424344
The enhanced ability of linezolid, compared to vancomycin, to penetrate into lung tissue at therapeutic concentrations may explain the microbiologic and clinical differences observed in the available clinical trials38394546 comparing these agents for MRSA pneumonia. Teicoplanin is another glycopeptide antibiotic available in Europe for the treatment of MRSA that is also highly protein bound.47 A trial48 comparing linezolid to teicoplanin for the treatment of suspected or proven Gram-positive infection found that clinical responses were greater in the linezolid-treated patients, including the patients with pneumonia, further supporting a potential role for linezolid in the treatment of this infection. CAMRSA isolates may retain susceptibility to a number of non–ß-lactam antibiotics including trimethoprim-sulfamethoxazole, clindamycin, tetracyclines, and fluoroquinolones. However, despite this phenotypic expression, the efficacy of these treatment options has not been established clinically, and the potential for resistance development is currently unknown.
In summary, pneumonia due to MRSA does appear to be a superbug infection due to the antibiotic resistance and overall virulence of this pathogen. Fortunately, a number of new currently available (linezolid) and investigational antibiotics (glycylcycline, dalbavancin, cephalosporin antibiotics with MRSA activity) hold promise for improved treatment of MRSA pneumonia, as well as other infections caused by MRSA. However, clinicians must balance the use of antibiotics for the treatment of MRSA pneumonia with the need to minimize the emergence of antimicrobial resistance. Strategies have emerged that allow clinicians to treat patients with suspected or microbiologically proven nonbacteremic HAP and VAP with courses of therapy that are often < 10 days in duration.4950 At present, we need additional studies to define the optimal antibiotic choices for the treatment of MRSA pneumonia. The emergence of this superbug along with concerns for the future appearance of avian influenza, potentially further increasing outbreaks of MRSA pneumonia,24 makes this an important health-care concern for the community as well as the hospital setting.
Footnotes
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestjournal.org/misc/reprints.shtml).
References
This article has been cited by other articles:
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  S. T. Micek, M. Dunne, and M. H. Kollef Pleuropulmonary Complications of Panton-Valentine Leukocidin-Positive Community-Acquired Methicillin-Resistant Staphylococcus aureus: Importance of Treatment With Antimicrobials Inhibiting Exotoxin Production Chest, October 1, 2005; 128(4): 2732 - 2738. [Abstract] [Full Text] [PDF]
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