MRSA Infections in 2009
MRSA Infections in 2009
Author: Dante A. Pappano, MD, MPH, Department of Emergency Medicine, East Tennessee Children's Hospital, Knoxville, TN.
Peer Reviewer: Steven M. Winograd, MD, FACEP, Attending, Emergency Medicine, St. Joseph Medical Center, Yonkers, NY.
Editor's Note
Methicillin-resistant Staphylococcus aureus (MRSA) has reached almost mythic status. It has come to mean much more than an isolate of S. aureus that happens to be resistant to methicillin, an antibiotic that is no longer in clinical use. It is a slap in the face of humankind's efforts to rein in infectious illness. It is the chill in the spine of the mother who receives a notice of exposure from daycare. It is the fear in the eyes of the child who is watching the scalpel approach. It is the invisible stranger that follows you home from the hospital.
The improved scientific inquiry and communication that was part of the 20th century has left a historical sketch of the unique interplay between this versatile organism and the human species. We can track every thrust and every parry from the advent of penicillin to the appearance of b-lactamase-producing strains, from methicillin to methicillin resistance, from effective hospital control policies, to the almost hyperbolic growth of community-acquired MRSA.
While the name has changed and the epidemiologic and pathophysiologic specifics have varied over time, MRSA is no more and no less than the current incarnation of a perpetual foe.
- The Editor
Introduction
The increase over the past two decades of S. aureus isolates which are methicillin resistant and the epidemicity of the soft tissue infections that have followed are only the latest chapter in the long war that man has waged against an organism that has declared itself to be the most talented of microbial adversaries. While not chronicled, the first several million years of this war were waged on the evolutionary battlefield, pitting staphylococcal virulence factors against the development of lysozymes and other human forms of barrier, humoral, and cellular immunity. The Egyptians, through their use of honey and other topical antimicrobials for wound infections,1 were among the earliest to advance the conflict from a purely evolutionary battle to one in which humans employed their intellect and technological prowess against the organism.
An important milestone in the conflict was the recognition of the microbial nature of the enemy. Prior to the 1800s there was some understanding of contagion, but supernatural causes of infectious illnesses, "bad air," and other "miasmatic" theories were prevalent. In the mid- to late 1800s, Ignez Semmelweiss, Louis Pasteur, Joseph Lister, and Robert Koch were critical in developing and propagating the concept of the germ theory of infection.2 Carl Weigert's experimentation with dye-enhanced microscopy led him to be among the first to have seen bacterial cocci in tissues.3 In 1880, Alexander Ogston identified two kinds of "micrococci" within abscessed tissue; one formed chains, the other clusters. He named this latter group "Staphylococcus" ("staphyle" from Greek for "grape bunches," of which the microscopic clusters are reminiscent).4 (See Figure 1.) Later advancements in identification led to formal taxonomy and completion of the binomial nomenclature with "aureus" from the Latin word for "gold," owing to the golden tint that appears macroscopically on the white colonies over time.5
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Weigert's cousin Paul Ehrlich recognized that the specificity of some of the microscopy dyes to various microorganisms was a potential pathway to a "magic bullet" that might kill the bacteria without harming human tissue.2 His work, and that of others such as Domagk (sulphonamide), Fleming, Florey, Chain (penicillin), and others ushered in the era of chemotherapeutic antimicrobials. On the heels of these advances, however, came a renewed evolutionary response from the organism, thus the current chapter in man's war against staphylococcus-related disease.2
Penicillin was an effective antibiotic for staphylococcal-related illness in the 1940s, but already by 1950 half of isolates were resistant.6 In 1959, the semi-synthetic penicillin, methicillin, was introduced. While resistance to methicillin was documented as early as 1961, at that time it was a rarity noted initially in just three of more than 5,000 isolates tested at one location. It surfaced in only a handful of other locations by the mid-1960s.7 Experimental exposure, selection, and re-exposure on a repeated basis in the laboratory setting demonstrated that methicillin resistance was not a single random event, but something that was inducible. With this understanding, during the 1970s and 1980s MRSA was an occasional hospital-based problem that was managed locally with aggressive infection control and the then-relatively-new aminoglycoside, gentamicin.8 The development and then spread of MRSA outside of the reach of hospital infection control, "community-acquired MRSA" (CA-MRSA), in the 1980s heralded the modern era of epidemic MRSA-related disease.9
Disease Burden
MRSA has established itself as a prominent player in morbidity and mortality in the United States. Recent estimates place MRSA-related deaths in the United States at 19,000 per year, nearly equivalent to the number of deaths due to AIDS, tuberculosis, and viral hepatitis combined.10 Morbidity of MRSA is on the rise, as well; U.S. hospitalizations in 2005 totaled 278,203, a figure that has more than doubled from 1999 statistics.11 These numbers are related both to an overall increase in the number of S. aureus-related hospitalizations (478,000 in 2005), and the percentage of these admissions that are with strains that are methicillin-resistant.
The average cost of an individual MRSA-related hospitalization is over $16,000.12 From this, one can estimate a staggering annual economic burden in the United States of close to $5 billion. Several researchers have pointed out that MRSA-related hospitalizations are more costly than methicillin-sensitive S. aureus (MSSA)-related hospitalizations, which themselves can be estimated to add another $2.5 billion to the overall annual cost burden.12,13
Classification
Staphylococci are highly evolved organisms that are surprisingly responsive to their environment. The complexity of this organism allows for wide variability both between different Staphylococcal species and among different organisms of the same species. The result is a wide array of epidemiologic and pathologic features depending upon the organism.
Species. S. aureus is an aerobic (facultatively anaerobic) gram-positive coccus. The expression of coagulase, a factor which can cleave fibrinogen into fibrin, is a useful laboratory marker that distinguishes this organism from the less pathogenic S. epidermidis and S. saprophyticus species.14 Other staphylococcal species exist (some coagulase-positive), including S. schleiferi, S.intermedius, and S. lugdenensis, but are very rarely causes of human infection. 5
Subspecies. One of the earliest developed subclassification systems for strains of S. aureus was called "phage typing." This system, not limited to staphylococcal species, involves the exposure of growing colonies to various viral bacteria-killing "bacteriophages." The particular lytic pattern affecting the culture reflects susceptibility to one phage or another and serves to characterize different strains.15 This system played more importantly into epidemiologic research in the mid-20th century, when staphylococcal strain 80/81 was the scourge of the neonatal nursery than it does today.15,16
Many newer methodologies exist that have the ability to exploit variability within S. aureus organisms for classification purposes. These methodologies take advantage of minor differences in antigenicity of surface proteins, polyacrylamide gel electrophoresis (PAGE) of various cellular components including esterase enzymes ("zymotyping"), and finally, technologies that characterize the variability that exists in the bacterial genome itself.15 Of this latter group, pulsed-field gel electrophoresis (PFGE) of larger DNA segments resulting from restriction endonuclease exposure appears to be a classification method that is more widely accepted than others. However, currently there is not one single classification system that is employed universally.15 This is largely due to variability of technology available to researchers at different centers, as well as choices that reflect strength of one system over another for a particular topic of research.
A simpler, less accurate, but more clinically functional way to subclassify a particular strain of S. aureus is by its antibiotic susceptibility profile. This can be as simple as the distinction between MRSA and MSSA, or a more complex assessment called an "antibiogram" that may include measurement and comparison of the size of the bacteria-free zones created by the various antibiotics.15
MRSA subclassification. Any MRSA strain can be subclassified as described above. However, MRSA is most commonly discussed in terms of its most basic subclassification: hospital-acquired (HA-MRSA) or community-acquired (CA-MRSA). While these terms sound purely descriptive, in actuality the distinction between HA-MRSA and CA-MRSA strains is not simply related to the site where the case of interest was exposed to infection. (In fact, there has been documentation of nosocomial transmission of CA-MRSA.)17 Instead, important genotypic and phenotypic differences allow classification of MRSA into one of these two groups. It is not believed that CA-MRSA is derived from HA-MRSA, but instead is the product of one or more independent acquisitions by MSSA of the genetic element "mec-a" (the gene responsible for methicillin resistance) located on the staphylococcal cassette chromosome (SCC). While mec-a is highly conserved, SCC appears to be slightly different in CA-MRSA, a variant called type IV, as compared to the SCCs found in HA-MRSA.18 This genomic difference, along with other strain-related differences that existed prior to the acquisition of mec-a-containing SCCs by MSSA, as well as ongoing genetic divergence, all account for the variability in MRSA strains seen today. Phenotypically, the resistance pattern to antibiotics other than methicillin is just one way that the HA-MRSA and CA-MRSA differ.10,18 (See Table 1.)
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Epidemiology
S. aureus is considered a ubiquitous microorganism. It is both part of normal human flora and a pathogen of widely variable severity. The main sites of colonization in humans are the nasal cavity and the perineum.19 Other colonization sites include the axilla, pharynx, vagina, and rectum.17
MRSA, on the other hand, until recently was neither considered ubiquitous nor a part of normal human flora. This is rapidly changing. Nasal colonization in Tennessee children increased from 0.8% in 2001 to 9.4% in 2004.20 More recently other centers have found nasal colonization rates in children as high as 22%.17
Not surprisingly, illness related to MRSA has increased hand in hand with the observed increase in colonization. Serious bacterial infections with S. aureus were methicillin resistant in 2%-20% of cases in the 1990s. Within a 10-year time period, that proportion increased to 40%-65%.8,10 Currently the incidence of MRSA infection is in the range of 20/100,000.17
There remains geographic variability in the proportion of isolates from infections that are methicillin-resistant. In the United States, southern states have a higher percentage of pathogenic isolates that are methicillin-resistant (in the 50% to 65% range), while the northeast has the lowest percentage (35%-50%).21 In Europe, proportions are generally comparable with the northeastern United States, with the exception of The Netherlands and the Scandinavian countries, for which proportions of MRSA are very low.8
Risk factors for infection by MRSA differ substantially according to subtype (CA-MRSA versus HA-MRSA). As a brief generalization, persons infected with CA-MRSA tend to be younger, otherwise healthy, and sometimes involved in organized sports, while those infected with HA-MRSA have a tendency to be older, infirm, potentially institutionalized in a health care facility, and may have had frequent exposure to antibiotics.18 (See Table1.)
HA-MRSA, as a nosocomial pathogen, is commonly associated with sites that frequently are associated with nosocomial infections: respiratory tract (pneumonia), urinary tract, bacteremia, indwelling hardware, and skin and soft tissue.21 By contrast, the overwhelming majority of CA-MRSA sites involve the skin and soft tissue, with other sites being relatively uncommon. An exception is the upper respiratory tract-specifically, chronic otitis media due to CA-MRSA is becoming relatively common.22 Lower respiratory tract infection with CA-MRSA remains rare but disproportionately severe.21
Transmission
Transmission of MRSA is via a variety of routes. Direct contact with an infected person represents the mode with the greatest likelihood of transmission. However, contact with a person who is colonized, contact with fomites, and nosocomial spread via the hands of health care workers or contaminated medical instruments are other common ways that MRSA is transferred.14 Particularly concerning is that, in the case of environmental surfaces, MRSA has been shown to be able to survive for months.23 Contaminated bodies of water and aerosolization during dressing change are other routes through which the organism is thought to be able to be spread.24,25
Nosocomial spread. In the hospital setting isolation of MRSA has not been limited to infected patients and their immediate environments. Rather, MRSA has been isolated from a number of fomites that might serve as intermediaries in the transmission process: stethoscopes, otoscope handles, computer keyboards, blood pressure cuffs, phlebotomy tourniquets, hospital identification badges, and pens used by healthcare providers.26-30 Surprisingly, while two studies identified MSSA on white coats, MRSA strains have yet to be identified on this archetypical hospital garb.31,32
An interesting issue is the use of felt-tip markers that are often used to delineate the border of a skin infection on an affected individual. Many of these have ethanol-based ink, which is bacteriocidal but may take several minutes to have its effect. Older, drier markers, however, could serve as means of transmission, as they may lack sufficient ethanol to kill bacteria that have contacted the writing surface.33
MRSA can be spread through contaminated food.34,35 Results can be disastrous in the hospital setting when MRSA-contaminated food finds its way to immunocompromised individuals.35 Additionally, when associated with diarrhea, even as a bowel-colonizing organism rather than the causal agent, subsequent contamination of nearby environmental surfaces is especially heavy.36
Community spread. In the home environment, MRSA has been isolated from sinks, drains, faucets, counter tops, sponges, dishtowels, and door handles, among other frequently involved surfaces. A common denominator appears to be that most contaminated surfaces tend to be those often that are often contacted by human hands. This fits with the theory that the hands are intermittently contaminated and re-contaminated by contact with the anterior nares, and decontaminated in between by hand washing.37 In the sports setting little attempt has been made to discover which surfaces tend to be contaminated, however several activities have been especially associated with MRSA-related skin and soft tissue infections (SSTIs) and, or colonization: turf burns, body shaving, using the whirlpool, sharing soap or towels, and having a locker near another individual with a current SSTI.38,39
Zoonotic spread. Animals, especially pets, may be MRSA carriers. Cats, more than dogs, have been associated with increased MRSA contamination of home surfaces.37 Farm animals, especially pigs and horses, have been shown to be colonized and act as potential reservoirs for infecting humans with whom they are in contact.40,41
Pathophysiology
Virulence factors. S. aureus causes disease directly through invasion and destruction of tissue, through the effects of elaborated toxins, or both. Cell products not necessary for bacterial growth in vivo but evolved for the purpose of promoting survival in the inhospitable environment provided by the host are called virulence factors.42 (See Table 2.) Some virulence factors are not found universally among S. aureus, leading to variability in the pathogenicity of different strains.
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Overwhelmingly, for the presumed purpose of improved metabolic efficiency, these factors are not produced constituitively, but instead may be produced when needed.42 Some are elaborated during certain stages of colony growth, or in response to local environmental factors such as antibiotics or aerobic conditions. In other cases, local factors such as pH, temperature, glucose concentration, and presence of foreign material, among others, may serve to suppress or promote the production of virulence factors but the effects are not "all or none."42
MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) are surface proteins that allow adherence to host tissues at the onset of infection.43 After infection is recognized by the host, certain virulence factors function to protect the bacteria from the host's immune system. Protein A binds the Fc portion of ambient antibodies, effectively creating a shield from the antigen-recognizing portion of the antibody.42,43 Panton-Valentine leucocidin destroys approaching white blood cells in the region of infection.14,42 Other virulence factors are critical in causing local tissue destruction that is necessary to remove physical barriers to expanded growth of bacterial organisms. Among these are pore-forming cytolysins/hemolysins and an array of destructive enzymes.14,42 A third group, exfoliative toxins (also referred to as epidermolytic toxins by some sources), cleave the desmosomes linking keratinocytes to one another. This cleavage then allows spread beneath the stratum corneum-otherwise one of human's greatest barriers to infection. The spreading, relatively superficial infection allowed by the exfoliative toxins causes the bullae seen in bullous impetigo and staphylococcal scalded-skin syndrome.44
Some toxins function far from the site of infection and may cause more serious disease than the local infection. In the case of the enterotoxins (A through J), the infection may not even be within the body but within contaminated foodstuffs that have been ingested. These toxins are heat stable, and may persist in food that has been sufficiently reheated to kill all organisms. Food poisoning in its purest form thus occurs as a purely toxin-mediated disease, characterized by vomiting, diarrhea, abdominal cramping, (and when more serious, fever and hypotension).14,34 Some of the same enterotoxins responsible for food poisoning (especially enterotoxins A, B, and C) are frequently involved in septic shock and toxic shock syndrome (TSS).42,45
Toxic shock syndrome toxin (TSST-1) is a related toxin that, along with enterotoxins B and C, is responsible for the fever, hypotension, mucus membrane hyperemia, hypocalcemia, and major organ dysfunction seen in TSS.42,45 A strain of S. aureus capable of resulting in TSS need not elaborate all of these toxins. TSST-1 is present in isolates from almost all cases of menstrual-related TSS, but only about half of non-menstrual TSS. TSST-1, unlike the enterotoxins, does not tend to elicit vomiting.42,45
The manner in which TSST-1 and the enterotoxins cause human disease is starting to be understood. It appears in large part to be due to their function as "superantigens." Superantigens cause T-cell-mediated hyperstimulation of macrophages which then release massive amounts of pro-inflammatory factors.42,45 The excessive detrimental physiologic effects result in the symptoms that we associate with TSS. It is less clear how these might be beneficial to the invading organism.
Besides the previously listed virulence factors, other ways that S. aureus avoids the host defenses are through the formation of "biofilms" and small colony variants. Biofilms are slime-like collections especially associated with fomites, and prosthetic materials that make penetration by the immune system difficult. (See figure 2.) Small colony variants are small groups of bacteria that "hide" within host tissues, thereby evading immune detection.43 They act less as pathogens and more as reservoirs for recurrent infection.43
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Antibiotic resistance. Various S. aureus strains have evolved or acquired genes that confer resistance against not only against b-lactams, but also through distinct mechanisms against macrolides, aminoglycosides, tetracyclines, fluoroquinolones, vancomycin, and other antibiotics.9 b-lactams destroy staphylococcal bacteria by binding to the peptidoglycan transpeptidase penicillin binding protein (PBP), whose function for the bacteria is to cross link structural cell wall proteins that are necessary for maintaining cell wall integrity.6,8 S. aureus has two main mechanisms to protect itself from b-lactams: production of b-lactamase, and the expression of an altered (PBP) to which the b-lactam cannot bind.
b-lactamase, like other virulence factors, is expressed only after the organism has been exposed to a b-lactam. The secreted enzyme hydrolyzes the b-lactam ring, disallowing binding to the PBP whose function for the bacteria is to add structural cell wall proteins necessary for maintaining cell wall integrity.6,8 The advent of penicillin in the 1940s selected for strains expressing b-lactamase. By 1950 over 50% of isolates were penicillin resistant; currently that rate is over 95%.6 This rising b-lactamase-based resistance led to the search for b-lactamase resistant antibiotics. Methicillin, initially known as "celbenin," was one of the original choices that was felt to be ideal for penicillin-resistant staphylococcal infections.46
Methicillin resistance. S. aureus produces several peptidoglycan transpeptidase penicillin binding proteins (PBPs): PBP 1, PBP 2, and PBP 3. At some unknown time, some S. aureus acquired a novel PBP, known as PBP 2a, (or sometimes PBP 2'). It is believed that the PBP 2a originated from a more primitive ambient staphylococcal species.6 PBP 2a is encoded on a mobile genetic element called the staphylococcal cassette chromosome(SCC), by a genetic element called "mec-a."6,8 While several different SCC variants now exist (types I-V), the gene encoding PBP 2a, mec-a, is highly preserved within these varying chromosomal segments.8
Current MRSA strains are not simply products of this original acquisition, rather, since the first methicillin-resistant strain was isolated in 1961, it is estimated that at least 20 independent acquisition events have occurred.47 Many of these represent "horizontal" acquisition by MSSA of the SCC-containing mec-a from an existing MRSA strain. Existing genetic variability and stepwise evolution occurring after the time of acquisition accounts for the current variability that exists between MRSA strains. The SCC type IV, the type associated with CA-MRSA, is the smallest, thus most mobile of the SCC elements. Because of this, CA-MRSA has more variability between strains than HA-MRSA.47 Still, the genetic variability within MRSA represents a very narrow degree of divergence when compared to the variability that exists within MSSA.6
The mechanism of resistance imparted by the PBP 2a appears to be related to its three dimensional structure. The active binding portion of PBP 2a, as compared to other PBP's is located within a narrow groove.6,8 Currently available b-lactam antibiotics effectively bind and inactivate PBP 1, PBP 2, and PBP 3, but simply cannot fit into the PBP 2a groove, allowing the it to continue to maintain the structural integrity of the bacterial cell wall. Like most virulence factors, expression of PBP 2a occurs only after an appropriate b-lactam is encountered.
Clinical Manifestations
As discussed, the defining feature of MRSA as compared to other S. aureus strains is the potential to express PBP 2a. This virulence factor promotes antibiotic resistance but is not thought to directly produce symptoms in the host. However, association of certain virulence factors is not random, but in some cases highly specific to SCC types. Panton-Valentine leukocodin and fibronectin binding protein are especially closely associated with CA-MRSA (usually SCC type IV) which may relate to the preponderance of CA-MRSA involvement in skin and soft tissue infection.18 Other epidemiologic factors may influence which S. aureus strains have a proclivity to cause which illnesses: HA-MRSA tends to occur in individuals with risk of nosocomial acquired infections, thus there is a higher likelihood of HA-MRSA to be associated with bacteremia, pneumonia, urinary tract infection (UTI), and infection of implanted medical devices. Thus, while there tend to be differences between MSSA, HA-MRSA and CA-MRSA, in terms of epidemiology and presence or absence of virulence factors, in theory any S. aureus-associated illness can be caused by any of these organisms.
Bacteremia, sepsis, and endocarditis. The presence of S. aureus in blood cultures demands respect as it is usually not a contaminant and represents the risk of development of sepsis or spread to other sites.48 Roughly 30%-40% of cases are MRSA. 48,49 In adults, MRSA has been demonstrated to result in higher morbidity and mortality as compared to MSSA bacteremia.12 It is not clear that this is the case in children.49 Overall, morbidity and mortality tend to be lower in children than in adults, but the potential of serious morbidity related to development of sepsis, necrotizing pneumonia, osteomyelitis, or multifocal disease exists.50 Endocarditis may be present, or develop in up to about 10% of cases, and must be considered, especially when there is an underlying cardiac condition or persistence of bacteremia or fever despite antibiotics.51 While mortality related to bacteremia is low, when frank sepsis is present mortality climbs to about 10%.48,49,51 In these cases, identification and eradication of any identifiable focus appears important to outcome.50,51
Enterocolitis and food poisoning. S. aureus is a common cause of foodborne illness. It is probably underreported, but accounts for at least hundreds of thousands of cases annually in the U.S.34 MRSA has rarely been reported as the identified cause of food poisoning, but is expected to become more common as the prevalence of MRSA continues to rise.34 By definition, staphylococcal food poisoning is a noninfectious, enterotoxin-mediated illness; other virulence factors related to colony growth, tissue invasion, or antibiotic susceptibility do not affect the manifestations of this illness. Therefore, MRSA and MSSA food poisoning would be expected to present identically.34
However, in fact, viable MRSA has been isolated from the stool of individuals with MRSA-related food poisoning, allowing for the possibility of a mixed food poisoning and enterocolitis. Additionally, S. aureus may colonize the large and small bowel.34 Nevertheless, for reasons unknown, frank staphylococcal enterocolitis is rare outside of Japan where it has been reported to complicate many cases of adult gastroenterological surgical cases with watery diarrhea, abdominal distension, dehydration, and shock.52,53 Use of non-MRSA-effective peri-operative antibiotics and H2 blockers appears to be risk factors for this complication.
Upper respiratory tract infections. S. aureus is part of the normal upper respiratory flora, a fact that leads to controversy when attempting to determine etiology based upon culture results from these sites. S. aureus is isolated from middle ear fluid in almost 15% of cases of acute otitis media; however, some experts do not consider it a pathogen in this setting.54,55 On the other hand it is accepted that S. aureus is a major cases of chronic suppurative otitis media, making up close to half of all cases, about half of these are MRSA.22 S. aureus is responsible for an increasing proportion of sinusitis, and an increasing proportion of these appear to be MRSA. Currently, 10% of acute sinusitis and 20% of chronic sinusitis are staphylococcal.56 Despite the high frequency of staphylococcal involvement in skin abscesses, and their proximity to sites of colonization, only 2%-3% of abscesses of the retropharynx, lateral wall, and peritonsillar regions are staphylococcal.57,58
Most epiglottitis is caused by streptococcal species, although, in children, Haemophilus influenza still causes epiglottitis occasionally, even in the post-HIB vaccination era.59,60 While some adult epiglottitis is caused by S. aureus, MRSA is a very rare cause.61 MRSA epiglotittis has not been reported in children. On the other hand, just inferior to the epiglottis, S. aureus (but not MRSA) is a major cause of bacterial tracheitis.62
Meningitis. MRSA remains a very rare cause of meningitis.63,64 Most cases have occurred in the post-neurosurgical setting or in the setting of severe disseminated infections. Brain abscesses are a rare complication of congenital heart disease, sinusitis/otitis, neurosurgical procedures, and immunosuppression.65 When present, the likelihood of S. aureus involvement is close to 20%.65 The proportion that are MRSA is not clear.
Ophthalmologic infections. MRSA is an increasing cause of ophthalmologic infections. The most common MRSA-related ocular infection is periorbital cellulitis. However, conjunctivitis, dacrocystitis, keratitis, endopthalmitis, orbital cellulitis, and orbital abscesses also occur.66 While MRSA and MSSA in some recent series have become the most common causes of dacrocystitis and orbital and periorbital cellulitis, MRSA is a very rare cause of bacterial conjunctivitis, being responsible for less than 1% of all cases.67-70
Osteomyelitis and septic arthritis. S. aureus is responsible for 50%-70% of all bone and joint infections in children; MRSA makes up 30%-80% of these.71,72 As compared to MSSA, MRSA-related bone and joint infections result in longer hospitalizations, longer febrile periods, an increased likelihood of the need of surgical interventions, and increased rate of complications.71,72
Pneumonia. In the pediatric population, S. aureus is still involved in only about 1% of all pneumonias.73 There is concern that this may be poised to increase based upon a recent increase in staphylococcal pneumonia in adults. Currently, MRSA is responsible for 10%-25% of adult pneumonias, depending upon the setting (community verses hospital acquired).74
Recently, the emergence of severe CA-MRSA-associated pneumonia in children has been recognized. While still a very rare cause of pneumonia, mortality rates close to 50% indicate that this entity deserves consideration in the appropriate clinical setting.75 There is a strong association of severe CA-MRSA-associated pneumonia with recent or concomitant influenza-related illness,74,75 but it also complicates cases of sepsis and disseminated MRSA infections.50 The pneumonia is often described as "necrotizing," may be associated with multilobar infiltrates, with or without cavitary lesions, and in some cases the formation of bronchopleural fistulae.50,74 Associated features may include high fever, hemoptysis, hypotension, and leukopenia.74 Early multi-agent antibacterial therapy, often in the intensive care setting, is recommended.74
Skin and soft tissue infections. Most children suffering infection with MRSA will have it in the form of a SSTI. The recent explosion of such cases and the relatively invasive incision and drainage procedure necessary for cure in many cases, may be responsible for the increased name recognition of MRSA within the lay-community.
Surgical site infections, while occurring in a very small percentage of surgical cases, represent one type of SSTI for which MRSA has become the most common causative organism.76,77 These infections, however, make up only a tiny percentage of SSTIs seen in the emergency department (ED).
Of the SSTIs commonly encountered, impetigo is the most superficial. While often considered primarily a group A streptococcal illness,78 most cases of impetigo actually are staphylococcal, with the bullous impetigo variant being nearly exclusively staphylococcal.79,80 Staphylococcal scalded skin syndrome is the result of systemic hematogenous spread of the same exfoliative toxins present locally in bullous impetigo.81 It is not known what percentage of these staphylococcal infections are caused by MRSA.
Folliculitis, furuncles, and abscesses represent a continuum of focal pyogenic skin infection. Neither the rate of progression nor the exact mechanism by which progression occurs from folliculitis to furuncle to abscess is understood.82 In many cases some form of skin injury proceeds the development of skin abscesses.39 In the presence of bacteremia, skin abscesses as well as deeper pyomyositis may form as a result of hematogenous seeding.50,78 MRSA is the most common organism isolated from abscesses and together with MSSA are responsible for two thirds of all abscesses in children, the remainder being primarily streptococcal, coagulase-negative staphylococcal, or sterile.83 On occasion, deeper abscesses my be difficult to find; such "occult" abscesses need to be considered in the infant or child representing with fever without source.84
MRSA is commonly involved in the cellulitis that surrounds an abscess. Its role in cellulitis without a purulent focus is not clear, in large part due to the very low (2%) rate of organism recovery from blood cultures in the setting of cellulitis.17,85 Recently, a pediatric ED in Canada published low rates of failure when treating cellulitis with non-MRSA-effective antibiotics.86
S. aureus is the organism most commonly isolated from neonatal omphalitis.87 The frequency with which MRSA is involved is not known. Complications include bowel adhesions, superficial and intra-abdominal abscesses, peritonitis, necrotizing fasciitis, sepsis, and death.88
Necrotizing fasciitis is the most serious SSTI that can be caused by MRSA.78 For the most part it is a group A streptococcal disease; however a handful of other organisms, S. aureus among them, may sometimes be responsible.89 Systemic signs, severe pain, and skin discoloration representing necrosis can help distinguish this sometimes fatal illness from uncomplicated cellulitis.90
Toxic shock syndrome. Staphylococcal toxic shock syndrome is a severe, acute illness characterized by fever, hypotension, erythroderma, and multi-system involvement. Half of all cases are menstrual-related, but in children the offending staphylococcus is often isolated from skin lesions or the respiratory tract, often in the setting of recent surgery, burns, or viral infection.45 Rarely is there bacteremia, instead systemic illness results from massive T-cell mediated over-activation of inflammatory cytokines. The staphylococcal virulence factors (TSST-1 and/or various staphylococcal enterotoxins) responsible for this process are referred to "superantigens."42,45 Group A streptococcus, especially during varicella illness, may result in a similar streptococcal toxic shock syndrome.
MRSA isolates are more likely than MSSA to harbor genes encoding for superantigens. About two thirds of CA-MRSA isolates have genes encoding for superantigens, but the frequency can be as high as 96% for those SCC-type II HA-MRSA variants.91
Other sites. MRSA may present as a severe disseminated infection with scattered septic emboli, and venous thromboses.92 Mortality is high in this setting, and MRSA is often recoverable from multiple disparate sites. Some other areas from which MRSA has occasionally been found as a pathogen include the following: urine, lymph nodes, pericardium, and liver (abscess).50,93
Diagnosis
For certain disease entities (e.g., cellulitis) diagnosis is based upon clinical impression. Etiology may be presumptive or identified later. For other disease entities (e.g., bacteremia), diagnosis is based upon identifying the presence of the organism in the appropriate clinical setting.
Staphylococcus aureus. Culture on solid agar plates (usually mannitol-salt agar) remains the standard means of identifying the presence of S. aureus. Growth in enrichment broth before plating may be an option when colony counts are expected to be low, (e.g., nasal carrier state) or be part of the standard isolation process(e.g., blood).5 After initial growth and classification based upon gram staining and morphology, distinction between S. aureus and other staphylococcal species is usually performed by testing for the presence of coagulase through tube, slide, or colorimetric methodology.5,94 Uncommonly, other tests are used that distinguish S. aureus from its relatives by the presence of heat-stable nuclease, protein A, or clumping factor.5
MRSA. Resistance testing is most commonly performed by assessing growth in the presence of the antibiotic of interest. For identification of MRSA: methicillin, oxacillin, or, more recently, cefoxotin is the antibiotic employed for this purpose. The methodology may be by disk diffusion where zones of inhibition determine lack of resistance, conceptually similar agar tests, or "breakpoint" broth methods wherein growth either occurs or does not occur in wells containing varying concentrations of the antibiotic.5
Indirect tests also exist that do not test for growth in the presence of an antibiotic, but instead test for the presence of PBP 2a (the altered penicillin-binding protein to which current b-lactams cannot bind), or mec-a the genetic element encoding PBP 2a. Because these tests do not require additional bacterial growth as part of the identification process they are faster than standard methods. This had led to the idea of trying to rapidly identify MRSA directly from the original clinical sample rather than from the initial growth on the solid media culture. A PCR test has been developed that effectively eliminates false positive results that otherwise would occur from the coexistence of MSSA and "mec-a-positive" (methicillin-resistant) S. epidermidis. Results of testing for nasal colonization were available in under two hours.95 Serologic assays for rapid diagnosis of endocarditis and infection at other sites are currently being studied.96,97
Treatment
Treatment varies by illness, but often involves some combination of local drainage/decontamination, and local and/or systemic antibiotic therapy. Depending upon the severity of the illness, supportive care sometimes including intensive measures, may be required. Several special cases are discussed below.
Toxic shock syndrome. In the case of staphylococcal toxic shock syndrome, hemodynamic support, beginning with aggressive fluid management, and often requiring the use of vasoactive and inotropic agents, is the mainstay of initial treatment.45 Of critical importance, efforts must be made to eliminate ongoing superantigen release by identifying and treating focal infections. Vaginal tampons and nasal packing or other foreign material must be removed. Focal abscesses and empyemas, some of which may be deep or "occult," must be drained and irrigated.45 Dual antibiotic therapy is indicated with both a bacteriocidal agent (e.g., vancomycin, or b-lactam if MSSA is known to be the cause) and an agent that disrupts protein synthesis (e.g., clindamycin) to more quickly decrease superantigen elaboration and release. IVIG may be used as an adjunctive therapy, with the putative function of neutralizing circulating superantigen toxins, but is less effective than when used against streptococcal TSS.45
Skin abscesses. Traditional management of skin abscesses has involved incision and drainage. Adjunctive measures are frequently employed including lavage, packing, antibiotics, and some form of effort to disrupt loculations such as curettage. Most of these measures are empirically based, but two issues have received research attention.
The convention of leaving the incision open was first challenged in the 1950s. Since then most studies have suggested that incision and drainage, followed by primary closure is safe.98 Some have additionally shown improved cost effectiveness or cosmesis with this technique.99,100 However, a few studies have demonstrated an increased risk of abscess recurrence (5%-10%) with primary closure.101
The use of antibiotics for skin abscesses remains controversial. While it is clear that most abscesses will resolve with incision and drainage, it is not clear if adjunctive antibiotics can reduce the relatively low rate of treatment failure that exists with incision and drainage alone. Early efforts to clarify this issue in an evidence based manner have failed to show a benefit to antibiotic use.102 In children, based upon a retrospective analysis of children treated with antibiotics ineffective against MRSA, it has been suggested that incision and drainage without antibiotic treatment is adequate treatment for abscesses less than 5 cm in size.103 While many have accepted this conclusion,78,99 study limitations, a recent large retrospective study in adults suggesting benefit of antibiotics,104 and the unaddressed issue of how to manage concomitant overlying cellulitis102 leaves this a largely unresolved issue.
Systemic antibiotics. Choice of antibiotics when indicated can be a complicated affair. When culture results are not yet available, or obtaining "cultureable" material is not feasible, decisions must be made considering the probability of staphylococcus as the etiologic agent, the likelihood of it being MSSA versus CA-MRSA versus HA-MRSA, and local susceptibility profiles, if known, of these variants.
Daptomycin. Daptomycin is an intravenous cyclic lipopeptide antibiotic whose bacteriocidal effects stem from bacterial cell membrane depolarization with consequent interruption of cytoplasmic functions.105,106 While not approved for use in patients younger than 18 years of age, it has been successfully used to treat adults with certain MRSA-related infections, including SSTIs, bacteremia, and right-sided endocarditis. Because the drug is inhibited by surfactant, it should not be used for pneumonia, and has diminished effectiveness for left-sided endocarditis.105 Those taking daptomycin should be monitored for development of peripheral neuropathy and myopathy/rhabdomyolysis.106
Folate Antagonist Antibiotics. Introduced in the 1930s sulfonamides were the first safe and effective, commercially available antibiotic chemotherapeutic agents. However, already by 1940 high treatment failures were noted when used as the sole agent for staphylococcal infections.107
Trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole(TMP-SMX) is a combination antibiotic available for oral and intravenous administration. Each component antagonizes the production of folate (and ultimately thymidine), each at one of two different points in the production pathway.107 TMP-SMX is frequently used in the outpatient setting for SSTIs despite lack of FDA approval for use against staphylococcal infections.78 In vitro susceptibility to this antibiotic combination, remains high, and in fact may be increasing over time for unclear reasons. However, when compared to b-lactams (for MSSA) or vancomycin, performance by TMP-SMX is inferior. The reason for this is not fully understood, but a contributing factor may be the ability of S. aureus to scavenge and metabolize thymidine from mammalian DNA located in ambient cell debris such as is present in collections of purulent exudative material.107 Additional problems with TMP-SMX are its unclear efficacy against group A streptococcus whose infections may be clinically indistinguishable from those caused by MRSA, and its contraindication in very young infants.17,78
Glycopeptide antibiotics. Vancomycin.Vancomycin has become the most commonly used antibiotic for MRSA infections whose severity dictates inpatient or initial intravenous antibiotic therapy. It is classified as a "glycopeptide" antibiotic because it binds to peptidoglycan precursors inhibiting further action by enzymes involved in cell wall synthesis.108 This is mechanistically distinct from the action of b-lactam antibiotics, and free of involvement of the PBP. While frank resistance is very rare, there has been a drift towards reduced susceptibility by MRSA in a process that some have called "MIC (minimum inhibitory concentration) creep."108
One problem with vancomycin is that it is simply less toxic to the bacterium than are b-lactams. It has repeatedly been demonstrated to result in inferior outcomes as compared to b-lactam antibiotics for the treatment of serious MSSA infections.8,74 Treatment of MRSA pneumonia with vancomycin has been particularly disappointing owing in part to poor penetration into the alveolar fluids by this relatively large antibiotic molecule.74
Other glycopeptide antibiotics. Teichoplanin is a glycopeptide antibiotic used outside of the United States.
Dalbavancin, telavancin, and ortiavancin are three investigational semisynthetic lipoglycopeptides each with unique advantages that make future acceptance in common usage likely.105
Lincosamide antibiotics. Lincomycin and clindamycin are the only antibiotics in this class to have been produced commercially.109 Currently only clindamycin (the more potent of the two) has found a place in the armamentarium against MRSA.
Clindamycin. Clindamycin, available in oral and intravenous formulations, exhibits bacteriostatic activity (bacteriocidal at higher doses and prolonged courses) by disrupting protein synthesis at the 50S ribosome.109 HA-MRSA is frequently resistant to clindamycin.78 While CA-MRSA is usually susceptible, "inducible resistance" of unclear clinical importance probably decreases the true susceptibility. Rates of inducible resistance range widely by region but frequently fall in the 10%-40% range for MRSA isolates.110,111 Despite these concerns, clindamycin is widely used for SSTIs, especially when group A streptococcus is as likely an etiologic agent as is S. aureus.18,78 An additional role for clindamycin is as an adjunctive therapy in severe staphylococcal illness, such as sepsis and toxic shock.78 The ability of clindamycin to inhibit protein synthesis and thus decrease production of superantigen toxins by staphylococcal species is unrelated to the individual susceptibility profile of that isolate.42
Oxazolidinones. Linezolid, the only antibiotic in this class, is a bacteriostatic antibiotic that inhibits protein synthesis at the 50S bacterial ribosome (same site of action as clindamycin, macrolides, and a number of other antibiotics).105,108 It is available in both oral and intravenous formulations. Information regarding its use in children is limited, but it appears to have favorable effectiveness as compared to vancomycin in adult studies.78,105 Similar to clindamycin it substantially reduces the production of virulence factors, including TSST-1.74 Its use as a first-line agent is limited by expense and a developing understanding of its side effect profile which includes neuropathy, bone marrow suppression/thrombocytopenia, and serotonergic activity including risk of serotonin syndrome when used concomitantly with selective serotonin re-uptake inhibitors.105,107
Tetracycline derivatives. Doxycycline and minocycline. Most (roughly 85%) MRSA isolates remain susceptible to tetracycline,112 although HA-MRSA tends to be resistant.18 Doxycycline and minocycline are probably more effective than tetracycline for staphylococcal infections, and have more favorable dosing regimen.112 Both are available in both oral and intravenous formulations. Additionally, these two longer acting tetracycline derivatives are not susceptible to the most common mode of resistance that results in tetracycline resistance.78 Limited data in adults suggest that these medications show excellent cure rates when used for infections other than for osteomyelitis.112 Lack of data in children along with age-based restrictions on these antibiotics make this a second-line agent.
Tigecycline. Tigecycline is a new bacteriostatic intravenous minocycline derivative.105 Currently, it is not approved for use in patients under 18 years of age. In adult patients it appears to be as effective as vancomycin for the treatment of complicated MRSA SSTIs, but may not be appropriate for more serious MRSA-related infections.78,105
Others. There are a number of other antibiotics that can be considered for use against MRSA-related infections under the right circumstances. Most CA-MRSA is susceptible to rifampin, but its role in treating CA-MRSA is not well defined. Monotherapy is not recommended, and the degree to which it is useful when added to other antibiotics has not been evaluated.78 Occasional susceptibility to gentamicin and the fluoroquinolones may allow the use of these agents when isolate susceptibility is known and when patient circumstances dictate. However, it is important to know that when used as a solo agent resistance can develop rapidly to the fluoroquinolones.19
Fusidic acid is not available in the United States, but has a long history of use in its topical, oral, and intravenous forms against staphylococcal infections in Europe, Canada, and other parts of the world.113 While most MRSA isolates remain susceptible to fusidic acid, monotherapy is not recommended, as resistance has been shown to arise quickly in this setting.113
Quinupristin/dalfopristin is an intravenous combination streptogrammin antibiotic whose activity is a result of binding at the 50S bacterial ribosome.114 Its main indication is against vancomycin-resistant Enterococcus faecium infections in patients older than 16 years of age.115 While not approved for use for MRSA-related infections, multiple studies have shown that most MRSA is susceptible or borderline-susceptible to this agent.114
Local antibiotics. Mupirocin is a topical agent whose effectiveness derives from binding to the bacterial isoleucin transfer RNA synthetase.116 It is available in a cream, a topical ointment, and an intranasal ointment. For children, it is indicated for the treatment of impetigo, including those cases due to MRSA. In adults, the nasal formulation is indicated for eradication of MRSA colonization.116 Off-label uses have included successful treatment of MRSA otorrhea when applied to the external canal and middle ear repeatedly over several weeks by appropriate specialists.117
Retapamulin is a new bacteriostatic topical agent indicated for the treatment of impetigo (non-MRSA), and secondarily infected traumatic wounds and lacerations.118 Like many other antibiotics, it inhibits protein synthesis by binding to bacterial ribosomes. In vitro, it is very effective against MRSA. In vivo, retapamulin had very high cure rates and performed as well or better than topical fusidic acid for impetigo of any etiology, including against MRSA and mupirocin-resistant S. aureus. However, it failed to obtain FDA approval for superficial MRSA infections after suboptimal performance against this organism in super-infected traumatic wounds.118
There has been little susceptibility testing of topical antimicrobials that are meant purely as preventive agents. However, somewhat outdated information suggests that at least some MRSA strains are susceptible to silver sulfadiazine, mafenide acetate, and bacitracin.119
Biocides. Biocides are often used for environmental sanitation, but some have been used as part of decolonization regimens.120 Some resistance to biocides such as benzalkonium chloride, chlorhexidine gluconate, sodium hypochlorite, alkyldiaminoethylglycine hydrochloride, and triclosan have been observed, in most cases more so for MRSA than for MSSA.121-124 Resistance is especially evident when staphylococcal biofilms are present.122,123 It should be noted with these substances that the time and concentration used have an important effect on "resistance." Resistance has not been noted to glutaraldehyde, povidone iodine, and ethanol under typical-use conditions.121
Prevention
Avoidance usually is a cornerstone of illness prevention. In the case of S. aureus, avoidance is difficult because it appears that most infections are the result of autoinoculation from nasal carriage sites.43 Prevalence of nasal carriage is high for S. aureus (20%-30%).43 MRSA nasal colonization rates are lower, but can still approach the 10%-20% range.17,20 Most efforts at decolonization have been largely ineffective, although a recent very aggressive, multi-site (nose, groin, mouth, skin, vagina, etc.) regimen managed to achieve successful decolonization in 87% of participants.68,120 The CDC has suggested that decolonization be considered for patients with multiple recurrences of MRSA infection, and to interrupt ongoing transmission within a well-defined cohort.78 Additionally, the rate of surgical site infections can be importantly reduced by preoperative decolonization.125,126
More recently, the concept that autoinoculation from colonized sites leads to most MRSA infections has been challenged. The suggestion is that fomites may be playing a greater role in infection than previously thought.127 Prolonged survivability on fomites would suggest that currently popular alcohol-based waterless hand sanitizers could have an important impact on MRSA spread. In the hospital setting, hand sanitizers alone are not effective,128 but when used as part of a hospital-wide infection control program, substantial reduction of nosocomial MRSA infection has been seen.129,130 The possible benefit of such products in the community is not known.
Anticipatory guidance. Improving individual personal hygiene may decrease the risk of MRSA infection.131 In the community, cleansing surfaces that are contacted by bare skin, especially in the locker room setting, as well as cleaning shared sports equipment between use, are recommended.132 Superficial skin injuries should be cleansed with soap and water, and antibacterial paste applied. Health care providers should consider contagion when determining return-to-school and -sports recommendations. While no absolute consensus exists on the specifics, some groups suggest 48-72 hours of oral antibiotics, the absence of ongoing drainage, and two days without new lesions before returning to sports.133
Immunization. No effective vaccine exists at this time, but active immunization strategies are being explored.134 Passive immunization (IVIG) may be beneficial in staphylococcal toxic shock syndrome.45 Because of the seriousness of MRSA pneumonia and its association with influenza, flu vaccination has a role in prevention of this complication.
Summary
MRSA is the product of the evolutionary pressures placed on a versatile, rapidly reproducing organism by antibiotic use. It is responsible for a variety of illnesses that result in major morbidity and mortality in the United States. Prolonged survivability on fomites and frequent nasal colonization leads to easy spread from infected and colonized persons to their contacts. Hospital-wide and community preventive measures; judicious antibiotic use; careful antibiotic choice; local decontamination through topical agents; incision and drainage, and more advanced surgical procedures; in some cases intensive supportive care; as well as intravenous IVIG therapy are all currently part of our armamentarium against illnesses caused by this organism. Novel approaches to dealing with MRSA are on the horizon, but history would predict even novel therapies will at some point be challenged by this ever evolving organism.
While the rapid increase in incidence of MRSA infections and the appearance of vancomycin resistance6,9,108 signal a relative victory for S. aureus against man, the future is not as bleak as it might appear. New glycopeptide and cephalosporin antibiotics effective against MRSA are on the horizon, as well as a novel diaminopyrimidine antibiotic, "iclaprim."105 New specific anti-TSST antibody therapy currently being developed may soon ameliorate toxin mediated disease.45 There is renewed interest in using bacteriophages or bacteriophage components therapeutically against multi-drug resistant bacteria such as MRSA.135 Finally, natural substances such as tannins, tea-polyphenols, licorice flavonoids, and fruit proanthocyanidins are being investigated for their direct antibiotic and antibacterial-resistance-altering effects.136
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Methicillin-resistant Staphylococcus aureus (MRSA) has reached almost mythic status. It has come to mean much more than an isolate of S. aureus that happens to be resistant to methicillin, an antibiotic that is no longer in clinical use. It is a slap in the face of humankind's efforts to rein in infectious illness.Subscribe Now for Access
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