Staphylococcus aureus

Updated December, 2008

John Turnidge, M.D., Nalini Rao, M.D., Feng-Yee Chang, M.D., Vance G. Fowler Jr, M.D. Susan M. Kellie, MD, MPH, Sandra Arnold, MD, MS,

Bruce Y. Lee, M.D., MBA, Anne Tristan, PharmD, Ph.D.

MICROBIOLOGY Guided Medline Search

               Staphylococcus aureus is facultative anaerobic gram-positive cocci which occur singly, in pairs, and irregulular clusters.  S. aureus is nonmotile, non-spore forming, catalase and coagulase positive. Typical colonies are yellow to golden yellow in color, smooth, entire, slightly raised, and hemolytic on 5% sheep blood agar.  However, many strains may appear dirty white and nonhemolytic.  It also gives a positive mannitol fermentation and deoxyribonuclease test. 

               The major criterion for identification is the organism’s ability to clot plasma.  There are three coagulase-positive Staphylococcal species; S. aureus in humans and animals, and S. intermedius, and S. hyicus in animals.  The presence of the enzyme coagulase separates the virulent pathogen, S. aureus, from the less virulent coagulase-negative Staphylococci species.  There are two different tests that can be performed to detect the presence of coagulase: a tube test to detect free coagulase and a slide test to detect bound coagulase. The slide test is a rapid test; however, a small percentage of S. aureus strains may yield a negative result.  If the organism is suspected as S. aureus, negative slide tests should be followed up with a tube test.

MRSA/VISA/GISA/VRSA:  Since the 1970s, S. aureus strains have emerged resistant to the penicillinase-stable penicillins (cloxacillin, dicloxacillin, methicillin, nafcillin, and oxacillin).  The resistance is the result of a supplemental penicillin binding protein (PBP 2a) encoded by the chromosomal mecA gene.  These strains historically are termed methicillin resistant S. aureus (MRSA) and are resistant to all beta-lactam agents. Laboratory confirmation of these strains can be problematic.  The resistant strains are often heteroresistant.  That is, two populations coexist, on susceptible and the other resistant.  Each cell has the genetic information for resistance, but only a very small number express this resistance in vitro (1 in 10⁴ to 1 in 10⁸).  Successful detection of MRSA largely depends on promoting the growth of the resistant population.  This is done by lowering the incubation temperature to 35^oC, using a 0.5 McFarland suspension directly from the colonies, supplementing with 2% sodium chloride, and incubating for a full 24 hours in ambient air.  Even with these refinements, the heterogeneous expression of some isolates may be interpreted as susceptible.  The oxacillin-salt screening plate which supplemented with 4% sodium chloride and 6 µg/ml of oxacillin can be used to improve detection of these strains.  The growth of more than one colony indicates resistance.   

               Most isolates of S. aureus are susceptible to vancomycin. The MIC is typically between 0.5 and 2 micrograms/mL (μg/mL). In contrast, S. aureus isolates for which vancomycin MICs are 8-16 μg/mL are classified as vancomycin intermediate (VISA), and isolates for which vancomycin MICs are ≥32 μg/mL are classified as vancomycin-resistant (VRSA). The glyopeptide class of antibiotics includes both vancomycin and teicoplanin.  And, some of the original VISA strains were also intermediate for teicoplanin, hence the name, GISA.  However, not all strains of VISA show intermediate susceptibility to teicoplanin. 

               CLSI (formerly NCCLS) lists only susceptible disk diffusion interpretive criteria (in mm) for vancomycin and Staphylococcus spp.  Insufficient numbers of non-susceptible isolates from patients have been isolated to develop resistant and intermediate breakpoints. Organisms for which the vancomycin zone diameters are ≥15mm are considered susceptible, although this breakpoint is unreliable for detecting VISA strains.

               As of November 2005, only four patients infected by vancomycin-resistant S. aureus (VRSA) have been confirmed by the U.S. Centers for Disease Control.  Automated susceptibility systems have not been reliable in detecting these strains. When using MIC methods that have not been validated to detect VRSA, BHI vancomycin agar screening plates containing 6 μg/mL of vancomycin can be used to enhance the sensitivity of detecting vancomycin-resistant strains. 

[Abigail Orenstein: The Discovery and Naming of Staphylococcus aureus]

[Kathryn Hillier: Babies and Bacteria: Phage Typing, Bacteriologists, and the Birth of Infection Control]

EPIDEMIOLOGY Guided Medline Search

               S. aureus is widely distributed in nature and carried by 25-33% of normal individuals in the anterior nares and skin. It can colonize and infect both healthy, immunologically competent people in the community and hospitalized patients with decreased host defenses. S. aureus is one of the commonest and most important Gram-positive hospital-acquired organisms. It has a high propensity to colonize abnormal skin surfaces and open wounds, where it may merely reside rather than cause active infection.

CDC. MRSA in Horses and Horse Personnel, 2000-2002. Emerg Infect Dis. March 2005.

Review Article: Rybak MJ, LaPlante KL. Community-Associated Methicillin-Resistant Staphylococcus aureus: A Review. Pharmacotherapy 2005;25(1):74-85.

History:  Methicillin-resistant Staphylococcus aureus (MRSA) has become a major problem in many countries, resulting in significant morbidity, mortality, and health care costs. The origins of antibiotic-resistant S. aureus trace back to 1941 when penicillin was first introduced. Two years after this landmark event, strains of Penicillin-resistant S. aureus had already emerged. These strains produced penicillinases, enzymes that can break down and deactivate penicillin. In the ensuing decade, these penicillin-resistant S. aureus strains became highly prevalent in hospitals. By the 1960’s, the strains had spread outside healthcare settings into the community. To combat this growing problem, researchers developed methicillin, a semi-synthetic penicillin resistant to bacterial penicillinases. However, within a year of methicillin reaching the market in 1961, the first documented MRSA case occurred in the United Kingdom (15a, 119a). As the use of methicillin and other similar penicillins increased, so did the incidence and prevalence of MRSA. This suggested that selection pressure from antibiotic use (i.e., antibiotics eliminate the methicillin-sensitive strains and leave the resistant strains to flourish) was largely responsible. The first documented United States outbreak of MRSA occurred in 1968 (296a). In the ensuing decade, after a brief decline, MRSA continued to spread throughout health care facilities but remained largely confined to health care facilities until 1981 (11).  Until the 1980’s, most patients with MRSA colonization or infection had had a recent hospitalization, defined as being hospitalized within four months of the MRSA diagnosis, and nearly all had had substantial contact with health care facilities.

Community-Associated MRSA (CA-MRSA)

               However, a 1980-1981 Detroit, Michigan, MRSA outbreak became the first significant exception to this rule, marking the emergence of “Community-Associated MRSA” (CA-MRSA) (355b, 355c).  A large proportion of this outbreak’s affected population, many of whom were intravenous drug users, had no clear link to health care facilities. Although no definitive source was ever identified, the high prevalence of intravenous drug users suggested that frequent needle sharing may have been the culprit. The Detroit outbreak and subsequent similar outbreaks led to the term CA-MRSA (i.e., MRSA that has no clear link to health care facilities) in contrast to the “Healthcare Associated MRSA" that had been seen since 1961.

               As the spread of CA-MRSA and healthcare-associated MRSA continues, the line between the two is becoming increasingly indistinct. Healthcare-associated MRSA no longer exclusively resides in health care facilities. Cases now are permeating settings outside the health care system, which has led to the term "healthcare-associated MRSA with community onset.” At the same time, CA-MRSA is becoming more common in health care settings. In fact, patients colonized with one form of MRSA can develop infections in another form. Nevertheless, healthcare-associated MRSA and CA-MRSA still have distinguishing characteristics. Table 1 lists some of the major differences between healthcare-associated MRSA and CA-MRSA.

Incidence and Prevalence:  According to a population surveillance study, the prevalence of nasal CA-MRSA colonization is less than 1% (156b).  However, the frequency of CA-MRSA infections and outbreaks has been steadily increasing since the 1980’s. CA-MRSA outbreaks have occurred in sports teams (football players, fencers, rugby players, and wrestlers) (156b, 260a, 25b, 83c, 235b, 342a), prisons (260b, 296b), day care centers (175a, 180a, 403a, 367a, 308a), and military quarters (2b, 20a, 25c, 92a, 114a, 216a, 246a, 459a) and among homeless people (66a, 138a, 148a, 454a), intravenous drug users (3a, 113a, 155c, 405a), and men who have sex with men. CA-MRSA is now the most common cause of soft tissue infections among patients who present to the emergency room.

Risk Factors:  The role of CA-MRSA colonization in and transmission patterns of CA-MRSA infections are not clear. Studies have shown that only 31-44% of patients with CA-MRSA were nasally colonized, suggesting that infection may occur without prior colonization (138a, 457a). Fomites such as contaminated towels, athletic equipment, clothes, and wound dressings may be transferring CA-MRSA directly to infect patients without intervening colonization (201a).  Other body areas such as the groin or axillae may likely serve as colonization sites.

               CA-MRSA infection rates are higher in African Americans, Pacific Islanders, and Native Americans. However, there is no established reason why CA-MRSA would have a predilection for certain racial or ethnic groups. The following are risk factors for CA-MRSA infection inoutbreaks (25a, 45b, 154a, 235a, 237b, 350a, 355d, 457b):

               • Skin trauma

               • Poor personal hygiene

               • Incarceration (260b, 296b)

               • Antibiotic use

               • Living in crowded quarters

               • Physical contact with other colonized or infected individuals.

Outcomes:  Although severe CA-MRSA can result, CA-MRSA infections tend to be less severe and less invasive than health-care associatedMRSA infections. But CA-MRSA is generally more aggressive and results in more adverse outcomes than MSSA (46% of CA-MRSA infected patients were hospitalized versus 18% of CA-MSSA infected patients in one study (94a). Recurrences of CA-MRSA infections may be more common than CA-MSSA infection recurrences. The most common manifestations are skin and soft tissue infections, including wound infections and necrotizing fasciitis. Other possible manifestations include otitis media, otitis externa, sinusitis, brain abscesses, myositis, osteomyelitis, prosthetic joint infection urinary tract infection, endocarditis, sepsis, and necrotizing pneumonia. CA-MRSA colonization appears to put individuals at greater risk for soft tissue infections. One study of soldiers showed that 38% of colonized subjects subsequently developed soft tissue infections (114a).

Healthcare-Associated MRSA (HA-MRSA)

Incidence and Prevalence: The prevalence of healthcare-associated MRSA continues to increase. A 2006 study found the overall U.S. healthcare-associated MRSA prevalence to be 46.3 per 1000 hospital inpatients (34 infections and 12 colonizations per 1000 inpatients) (179b). Over the past decade, the percentage of S. aureus clinical specimens that are methicillin-resistant has been steadily increasing in the United States and much of the world. In March 2005 data from the Surveillance Network-USA, MRSA accounted for 59.2%, 55%, and 47.9% of all non-ICU inpatient, ICU inpatient, and outpatient S. aureus specimens, respectively. Data from the same network showed that by 2005 inpatient MRSA rates had surpassed 50% in all regions of the country except for New England (49.9%). Outpatient MRSA rates ranged from lows of 36.3% in the Mid-Atlantic region and 37.6% in New England to a high of 63% in the East South Central region. Rates were highest (55.9%) in inpatient lower respiratory specimens and lowest (37.6%) in outpatient skin and soft tissue specimens (386a). MRSA is significantly less common in Scandanavia (<1 percent of S. aureus specimens). Rates in Japan, Israel, the United Kingdom, and the rest of Europe are more comparable to that of the United States (9, 10).

Risk Factors:  Patients colonized with healthcare-associated MRSA are at greater risk for healthcare-associated MRSA infection (349b). In fact, nasal colonization may be necessary for infection to occur. The most common site for colonization is the anterior nares but MRSA may colonize a number of other body locations, such as the hands, axillae, perineum, wounds, catheter sites, throat, genitourinary tract, and gastrointestinal tract (83a, 355a).  Colonization can persist from a few days up to several years. MRSA colonization may result from physical contact with either a colonized patient or MRSA contaminated objects (such as dressings or medical devices). A nasally colonized patient can transmit MRSA through aerosolized droplets and is more likely to do so if the patient has a sinus or upper respiratory infection (2b, 457a, 141a, 435a, 213a).

Other risk factors for healthcare-associated-MRSA include:

               • Exposure to antibiotics (especially fluoroquinolones or cephalosporins) (156a).

               • Admission to health care facilities where antibiotics are frequently used (2b, 430a, 234a, 49a, 420a).

               • Prolonged hospitalization (9a, 9b, 41a)

               • Admission to the intensive care unit (83b)

               • Stay in a long-term care facilities (234a,  264a, 202a, 164b, 15b, 25a)

               • Hemodialysis/peritoneal dialysis (237a, 164a, 178a, 109a, 238a)

               • Indwelling vascular catheters  (264b, 263a, 46a, 74a)

               • Diabetes mellitus (234a, 263a, 155b)

               • Immune system dysfunction: (e.g., AIDS, Chediak-Higashi syndrome, chronic granulomatous disease, Job’s syndrome, or                   significant co-morbidities) (173a, 253a)

               • Proximity to others colonized or infected with MRSA (2b, 430a, 234a, 49a, 420a)

Outcomes:  Healthcare-associated MRSA can result in severe invasive infections and substantial complications. Most commonly, healthcare-associated MRSA can cause skin and soft tissue infections, bacteremia, sepsis, endocarditis, and pneumonia. MRSA infected patients tend to have longer intensive care unit and hospital stays, higher rates of ventilator use, greater risks of death, and more adverse clinical outcomes (such as renal failure and hemodynamic instability) than MSSA infected patients (90a, 90b, 327a, 33a). This greater associated morbidity and mortality translates to greater health care costs. A 1999 study found that treating a MRSA infection cost approximately $17,000 more than treating a MSSA infection (1a).

CLINICAL MANIFESTATIONS Guided Medline Search

               Infections caused by S. aureus range from minor skin disorders such as wound infections, furuncles and carbuncles, and bullous impetigo, through locally invasive diseases such as cellulitis, osteomyelitis, sinusitis, and pneumonia, to major life-threatening septicemia and meningitis. It is also a frequent cause of medical device-related infections such as intravascular line sepsis and prosthetic joint infections. Although minor skin infections may resolve naturally without antibiotic intervention, once S. aureus invades deeper structures, it often spreads hematogenously to other organ systems, leading to metastatic infection. Endocarditis and septicemia have significant morbidity and mortality despite aggressive antimicrobial therapy.

               Toxin mediated disease include the toxic shock syndrome that presents with profound hypotension and a generalized erythematous rash. While TSS was commonly associated with menstruation and the use of hyperabsorbable tampons, the nonmenstrual form is commonly associated with wounds from different surgical procedures. Staphylococcal food poisoning occurs with a short incubation period of 2-6 hours and is characterized by nausea and vomiting, that is followed by abdominal cramps and diarrhea, which can be hemorrhagic. It is mediated by enterotoxin B and occurs due to ingestion of food contaminated with preformed toxins.

LABORATORY DIAGNOSIS Guided Medline Search

               The definitive diagnosis of disease is made by isolation and identification of the species of Staphylococcus. Depending in the conditions being investigated, samples of sputum, purulent material, blood and urine should be obtained. Several sets of blood cultures are required to make a diagnosis of S. aureus septicemia or endocarditis. Echocardiography, especially transesophageal, is crucial for confirming the diagnosis of endocarditis.

PATHOGENESIS Guided Medline Search

              Staphylococcus aureus is both a commensal, which colonizes the nares, axillae, vagina, pharynx, or damaged skin surfaces, and an extremely versatile pathogen. It causes superficial lesions (boils, furonculosis), deep-seated and systemic infections (endocarditis, osteomyelitis), and toxemic sydromes (food poisoning by releasing enterotoxin into food, toxic shock syndrome by release of superantigens into the blood stream, localized and generalized exfoliation by the production of exfoliative toxins) (236a). In pyogenic infections the pathogenesis results from the combined action of a variety of factors (155a). Infection is initiated when a breach of the skin or mucosal barrier allows Staphylococci access to adjacent tissues or to the bloodstream. Whether an infection is contained or spreads depends on a complex interplay between S. aureus virulence determinants and host defense mechanisms.

Adherence to Host Tissue

              The nose is the main ecological niche of S. aureus and about 20% (range 12–30%) of individuals are persistent S. aureus nasal carriers, increasing risk of acquiring an infection with this pathogen. Staphylococcus aureus adheres to cells and extra cellular matrix components by the joint action of MSCRAMM (microbial surface component recognizing adhesive matrix molecules) and secreted expanded repertoire adhesive molecules. MSCRAMMs bind molecules such as collagen, fibronectin and fibrinogen, and different MSCRAMMs may adhere to the same host-tissue component. Thus, these molecules act in initiation of endovascular infections, endocarditis and bone and joint infections. By the heterogeneity of MSCRAMMs types, different S. aureus strains may be predisposed to causing certain kinds of infections (78a). Coagulase is an extracellular protein, belonging to the secreted expanded repertoire adhesive molecules class, which binds to prothrombin to form a complex called staphylothrombin. The protease activity of the thrombin complex is activated, resulting in the conversion of fibrinogen to fibrin. Coagulase is produced by almost all clinical isolates of S. aureus; thus it is a traditional marker for identifying S. aureus in the clinical microbiology laboratory.

Invasion of Host Tissues

              The invasion of host tissues by staphylococci involves the production of a large number of extracellular proteins.

The α, β, d-Toxins

              The α-toxin is expressed as a monomer that binds to the eukaryotic cell membranes, the subunits oligomerize to form heptameric rings with a central pore through which cellular contents leak. This toxin also induces the death of innate and acquired immunity cells, interferes with the metabolism of arachidonic acid, exocytosis and induces dysfunctions in contractility, leading to bacterial spread and alterations of the hemostasis (28a).

              The β-toxin or sphingomyelinase C is a haemolysin, which targets lipid-rich membranes. It causes lysis of erythrocytes and mononuclear cells, and also induces a strong inflammatory response. The majority of human isolates of S. aureus do not express ß-toxin, but it is frequently found among strains responsible for bovine mastitis (250a).

              The d-toxin consisting of a peptide 26aa, but its role in disease is unknown.

Phospholipase C

              S. aureus secretes a phospholipase C, which specifically hydrolysis membrane lipid and protein-containing glycosyl phosphatidylinositol (92b).

Metalloproteases

              The aureolysine, member of the thermolysines family, is an extracellular and zinc dependent metalloprotease. This enzyme destroys host defences molecules (14a).

Hyaluronidase and hyaluronate lyase

               These enzymes digest hyaluronic acid, polymer present in the vitreous humour, skin, bones and synovial fluid, promoting the infection process by dispersal and tissue degradation (123a).

Exfolative Toxins

               There are two major biologically and serologically distinct S. aureus exfolative toxin isoforms, exfolative toxin A and exfolative toxin B, that are primarily responsible for the skin manifestations of staphylococcal scalded skin syndrome and bullous impetigo. Five percent of clinical S. aureus isolates produce either exfoliative toxin A, exfoliative toxin B or both toxins. They cleave the stratum granulosum from the stratum spinosum by targeting desmosomes (4a).

Epidermal Cell Differentiation Inhibitor

               The epidermal cell differentiation inhibitors which are mono-ADP ribosyltransferases belonging to the Rho family, are found in 8% of disease strains and in 3.7% of nasal carrier strains under 3 isoforms: epidermal cell differentiation inhibitors-A, B and C. Although epidermal cell differentiation inhibitor-A inhibits the differentiation of keratinocytes in vitro, the role of epidermal cell differentiation inhibitors in human diseases is not established (453a).

Avoidance of Host Defenses

               The S. aureus wall consists of two major components, i.e. peptidoglycan and lipoteichoic acid, both analogous to the lipopolysaccharide in gram-negative bacteria. They are able to induce the release of cytokines by macrophages, the activation of the complement system and the platelets aggregation, thus triggering a disseminated intravascular coagulation (236a).

Capsular Polysaccharides

               Bacterial biofilms provide a niche for bacterial adherence and persistance on implantable medical devices. S. aureus synthesizes exopolysaccharides, or glycocalix, components of this biofilm. These capsular polysaccharides are found in 90% of clinical strains. Eleven serotypes have been described, type 5 and 8 are most common among human isolates (80%). Their role in virulence, however, is controversial, because these capsular polysaccharides are also a target for protective antibodies.

Enterotoxins

               S. aureus can produces a large diversity of exoproteins belonging to the family of superantigens, stimulating polyclonal T-cell proliferation through co-ligation between major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and the variable portion of the T-cell antigen receptor β chain or α chain with no need for prior antigen-presenting cells processing. T-cell/ antigen-presenting cells activation by these toxins leads to the release of large amounts of various cytokines/lymphokines which are deleterious for the host (99). Twenty different enterotoxins have been described, among them, staphylococcal toxic shock syndrome toxin (TSST-1), staphylococcal enterotoxin A, B, C or enterotoxins coded by egc cluster (179a). Beside their superantigenic properties, they are also pyrogenic and enteropathogenic for the majority, thus explaining their implication in both staphylococcal toxic shock symdrome (TSS) and food poisoning. The enterotoxins have also been implicated in a number of autoimmune disorders (rheumatic arthritis, etc.) and other abnormal immunologic states such as psoriasis, atopic dermatitis and Kawasaki syndrome (255a).

Protein A

               Protein A is a multifunctional virulence factor produced by almost all clinical isolates: it inhibits opsonophagocytosis via binding of immunoglobulin Fc fragment, it is also a B cell “superantigen” promoting B cell activation. It is a MSCRAMM, allowing the attachment of vonWillebrand factor which is present on the injured endothelium. Finally, protein A plays a pro-inflammatory role, via the activation of the tumor necrosis factor receptor (TNFR1) present on the respiratory epithelium.

The Fatty Acid Modifying Enzyme and Lipases

               More than 80% of strains of S. aureus express fatty acid modifying enzyme which modify antibacterials lipids and thus may contribute to bacterial survival, including in abscesses.

V8 Protease

               The V8 protease is an extracellular serine protease witch possesses many structural similarities with exfoliative toxin. It cleaves the peptide bonds, inactivating in vitro and in vivo the action of antibodies and may protect against antimicrobial peptides such as neutrophil defensin proteins and bactericidal platelet proteins thus contributing to tissue proteins destruction during the invasion (310a).

Leukocidins

               These toxins consist of two separately secreted and non-associated proteins (class S and class F components) acting synergistically and promoting eukaryotic cell lysis. They are: γ-haemolysin, Panton Valentine leukocidin (PVL) and leukocidins LukD/E and LukM/F. The γ haemolysin is produced by almost all (≥ 99%) S. aureus strains.

               The Panton-Valentine leukocidin is a pore forming toxin which damages human neutrophils, recovered from less than 2% of S. aureus strains It has been epidemiologically linked to primary skin and soft tissue infections and to deep seated infections such as necrotizing pneumonia and severe recurrent osteomyelitis occurring in young immunocompetent patients. The genes coding for leukotoxins LukE-LukD were detected in a high prevalence (82%) among blood isolates and 61% among nasal isolates (422a).

Lina G, Vandenesch F, Etienne J. A brief history of Staphylococcus aureus Panton Valentine leucocidin

John JF, Lindsay JA. Clones and Drones: Do Variants of Panton-Valentine Leukocidin Extend the Reach of Community-Associated Methicillin-Resistant Staphylococcus aureus? J Infect Dis 2008;197:175-178.

Staphylokinase

               The staphylokinase, 136AA protein encoded by a bacteriophage, has two important properties. Acting on the immunity, staphylokinase inhibits neutrophils bactericides peptides by linking to the α-defensin. On the haemostasis, staphylokinase acts as a plasminogen activator which causes dissolution of fibrin clots, and lyse fibrin (34a).

               Throughout in vitro growth and during an infection, Staphylococcus aureus responds to environmental signals by selectively generating specific virulence proteins. A complex regulatory network, based on the accessory gene regulator (agr), a quorum-sensing system, settles precise and flexible coordination of protein expression in response to the microenvironment. Thus during infection, the early expression of the MSCRAMM proteins facilitates initial colonization of tissue sites, whereas the later elaboration of toxins facilitates spread and promotes acquisition of additional nutrients of S. aureus.

SUSCEPTIBILITY In VITRO AND IN VIVO  Guided Medline Search In Vitro and In Vivo

Evolution of Resistance for Staphylococcus aureus

               Following its introduction into clinical practice in the 1940s, penicillin G became the treatment of choice for infections caused by S. aureus. However, S. aureus resistant to penicillin through the production of a beta-lactamase (penicillinase) rapidly emerged (274). High levels of resistance to penicillin (80-95%) are standard for community strains in almost all countries now. Since the 1970s, S. aureus strains resistant to the penicillinase-resistant penicillins (represented by the original member of the class, methicillin) have gradually emerged worldwide (11). Until recently, these strains have generally been multiresistant, exhibiting resistance to macrolides and lincosamides, and usually to tetracyclines and gentamicin. Resistance to trimethoprim and sulfonamides is also prevalent in some countries. This type of methicillin-resistant S. aureus (MRSA) is now a common cause of nosocomial infection in many countries in both the developed and the developing world. The rapidity with which MRSA developed in Europe after the introduction of methicillin in 1959 and its subsequent spread throughout the world have created therapeutic problems for physicians, in part because of the high propensity of MRSA to acquire new resistances.

               Methicillin resistance in MRSA isolates is chromosomally mediated and results, at least in part, from the presence of an additional and modified penicillin-binding protein (PBP-2a), which has reduced affinity for methicillin and other beta-lactams, and hence retains critical functions necessary for cell survival (40,54). PBP-2a is encoded by the mec A gene located on the staphylococcal chromosome within a discrete region called the staphylococcal cassette chromosome (SCCmec), for which a range of types have been described (295). Resistance to all beta-lactams including cephalosporins, penicillinase-resistant penicillins, beta-lactamase inhibitor combinations and carbapenems should be assumed once methicillin resistance has been demonstrated (monobactams have no anti-staphylococcal activity).

               Recently different types of MRSA has been described with origins in the community in several countries, including Australia, United States, Canada, New Zealand, Saudi Arabia, Finland and Taiwan (88,237). Resistance to penicillin and methicillin but susceptibility to most or all other drug classes characterizes these types of MRSA. It appears to be principally a community-acquired organism (320,337), but hospital outbreaks have been described (294). Methicillin resistance is also encoded by mecA in these strains, and they have different SCCmec types to those of classical hospital-acquired strains (295,117).

               In England and Wales, a further pattern of MRSA has emerged since 1990. Two types of MRSA called EMRSA-15 and EMRSA-16 have became widespread across hospitals (87, 276). Unlike classical hospital-acquired MRSA from other countries, EMRSA-15 and-16 harbors a few additional resistances beyond penicillin and methicillin, mainly erythromycin and ciprofloxacin (336, 449,276).

               The emergence of different types of MRSA with a reservoir in the community rather than the hospital has created two kinds of problems. The first relates to recognition and nomenclature. Given their different epidemiologies and rates of resistance to antibiotics other than beta-lactams, it is useful to have terminology to differentiate two types, as it has potential impact in choosing treatment alternatives to beta-lactams. In this chapter, the term haMRSA (hospital-acquired multiresistant oxacillin-resistant Staphylococcus aureus) is used to describe classical hospital-acquired MRSA, the term caMRSA (community-acquired oxacillin-resistant Staphylococcus aureus) to describe the new, predominantly community-acquired, strains, and the term EMRSA-15/16 the new epidemic-hospital acquired strains in England and Wales. These three types can be distinguished, at least for the present, by the number and types of resistances harbored in addition to beta-lactams: haMRSA strains are resistant to 3 or more of the following: erythromycin, clindamycin, rifampicin, ciprofloxacin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole or chloramphenicol (414). EMRSA-15/16 are usually resistant to erythromycin and ciprofloxacin in addition to beta-lactams, and susceptible to others classes. For clarity the acronym MSSA is used for penicillin-resistant, methicillin-susceptible strains.

               Strains with increased MICs to vancomycin were first described in Japan in 1996 (175). More recently, similar strains have been detected in the United States, France, the United Kingdom, Spain, Hong Kong, Italy Germany, India, South Korea, the Philippines, Singapore, Thailand, Vietnam, Australia, the Netherlands and Poland (29, 77, 194, 246, 397, 377, 47, 176, 204, 212). These strains have been termed VISA (vancomycin-intermediate S. aureus) or GISA (glycopeptide-intermediate S. aureus). MICs are typically in the range of 6-16mg/L. Resistance may be heterogeneous or homogeneous. Heterogeneous strains are more difficult to detect and a reliable screening test is still being sought. The clinical significance of heterogeneous resistance is uncertain, but failures of vancomycin treatment in homogeneously resistant strains are now well documented (397,140; 176, 238) and failures with heterogeneously resistant strains are be reported (67). All VISA strains described to date have been MRSA. Antimicrobial activity of the different antibiotics for both methicillin-susceptible S. aureus (MSSA) and MRSA is listed in Table 2.

               There have now been three reports, all from the United States, of methicillin-resistant S. aureus clinical isolates harbouring the vanA gene complex previously found in enterococci (50, 51, 52, 67, 427, 428). These strains have MICs to vancomycin well into the resistant range.

Review Article: Hiramatsu K. Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis. 2001 Oct;1(3):147-55.

Single Drugs

Penicillins: Most staphylococci are resistant to penicillin (G, benzylpenicillin) and other beta-lactamase labile penicillins such as the aminopenicillins, carboxypenicillins and the ureidopenicillins through the production of specific beta-lactamase which was originally called penicillinase. All formulations of penicillin itself are affected: benzylpenicillin, procaine penicillin, benzathine penicillin, phenoxymethyl-and phenoxyethylpenicillin. A small proportion ( 5 to 10% ) of community-acquired strains of S. aureus do not produce a beta-lactamase and remain susceptible to penicillin G. beta-lactamase-mediated resistance results from production of an enzyme that is excreted extracellularly by S. aureus that inactivates the antibiotic by opening the beta-lactam ring.

Penicillinase-Resistant Penicillins: Currently, the majority of community-acquired S. aureus strains remain susceptible to the antistaphylococcal, semisynthetic penicillins and first-generation cephalosporins (Table 2), although this is changing rapidly in some countries. Agents classified as penicillinase-resistant penicillins include methicillin and nafcillin, and the isoxazoyl penicillins oxacillin, cloxacillin, dicloxacillin, and flucloxacillin. Although there is minor variation in their relative beta-lactamase stability, this does not appear to be of clinical importance. Differences in the in vitro potency of the penicillin-resistant penicillins are small, with modal minimum inhibitory concentrations (MICs) in the range of 0.125 to 0.5 ug/mL (213).

Cephalosporins: Cephalosporins show variable stability to staphylococcal beta-lactamase, depending on their chemical structure. Cephalothin is relatively resistant, while cefazolin is more sensitive to staphylococcal beta-lactamase degradation (130,328). Although this in vitro phenomenon has not been clearly demonstrated to be clinically significant, some prefer cephalothin for the treatment of life-threatening S. aureus infections (314). Data from animal studies suggest that cephalosporins are probably less effective than the penicillinase-resistant penicillins for treatment of serious staphylococcal infections. Cefazolin and cephalothin were less effective than nafcillin in the rabbit model of endocarditis (49,381).

               Compared with first-generation cephalosporins, the second-and third-generation cephalosporins in general have inferior in vitro activity against S. aureus. With the exception of cefamandole, cefuroxime, and possibly cefaclor, cephalosporins of later generations generally have lower activity against staphylococci and offer no advantages over first-generation cephalosporins when they need to be used in the management of staphylococcal infection. However, almost all cephalosporins have sufficient activity to provide initial coverage pending the results of laboratory investigations.

               Cephalosporins are not active against MRSA strains in vivo, despite the fact that some strains may appear susceptible in routine laboratory tests. Exceptions to this rule have been found in new cephalosporin molecules under development, such as ceftobiprole, LB11058 and RWJ-33341 (150, 425, 62).

Penicillin/ beta-Lactamase Inhibitor Combinations: Staphylococcal beta-lactamase is readily inhibited by the currently available beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam. Thus, combination of these inhibitors with beta-lactamase-labile penicillins restores activity against penicillin-resistant, methicillin-susceptible staphylococci (Table 2). Like cephalosporins, they are not active against MRSA strains.

Carbapenems: Imipenem and meropenem have a very broad spectrum of activity that includes S. aureus. However, MRSA is also resistant to imipenem and meropenem (Table 2). Although some strains of MRSA appear susceptible to carbapenems in vitro, they are not susceptible in vivo (28,60).

Macrolides: In general, the macrolides show a fairly uniform activity against staphylococci (16, 20, 443). haMRSA is always resistant to the macrolides (167) while many caMRSA are susceptible, although resistance can range up to 25%. Resistance to erythromycin is also prevalent worldwide in community-acquired MSSA strains. The newer macrolides -- dirithromycin, roxithromycin, clarithromycin, and azithromycin -- have activity similar to that of erythromycin against staphylococci (Table 2). Strains resistant to erythromycin are also resistant to these newer macrolides. A new class of agents that are derivatives of macrolides, the ketolides, are active against erythromycin-susceptible staphylococci, but not against resistant strains of S. aureus (165).

Lincosamides (Clindamycin and Lincomycin): S. aureus resistant to erythromycin demonstrate two types of resistance: inducible and constitutive. Inducibly-resistant strains test as susceptible to lincosamides in vitro when tested alone, but as resistant when tested in the presence of erythromycin. Strains that are constitutively resistant test as resistant to lincosamides (222). The clinical significance of inducible resistance in unknown, as formal prospective studies have not been conducted to determine whether inducibly-resistant strains respond to treatment with lincosamides. Recent in vitro evidence shows that they have a higher rate of mutation to lincosamide resistance than erythromycin-susceptible strains (297), There is anecdotal evidence that they respond clinically, but that selection of resistance during treatment and relapse are common (107,138,230,256, 323,370). A consensus is emerging that infections caused by strains with inducible resistance should not be treated with clindamycin unless the infection is minor (234). MSSA is usually susceptible to clindamycin with an MIC range, < 0.06 ug/mL-0.125 ug/mL (Table 2). haMRSA is resistant to clindamycin with a consistent MIC above 256 ug/mL (Table 2). caMRSA strains generally test as susceptible to lincosamides. In a rabbit model of endocarditis, clindamycin is associated with a relatively slow rate of eradication of organisms from the infected vegetation, and relapse was more likely in rabbits given clindamycin than in those treated with penicillin or vancomycin (352).

Fluoroquinolones: Fluoroquinolones are DNA gyrase inhibitors that are active in vitro and in vivo against S. aureus, including some MRSA strains (48, 148, 387). In terms of gram-positive activity, and activity against staphylococci, the older quinolones such as ciprofloxacin, ofloxacin and levofloxacin are less potent than the new generation agents such as trovafloxacin, moxifloxacin, gatifloxacin and garenoxacin. The MICs of ciprofloxacin are typically between 0.5 and 1 µg/mL for MSSA strains (Table 2), and two to four-fold lower for the new generation agents. Most strains of MORSA are now resistant to fluoroquinolones (92, 366, 412), including the new generation. Resistance to fluoroquinolones has been found in MSSA and MRSA strains (192,275). Both altered gyrase and energy-dependent efflux mechanisms account for the development of resistance to fluoroquinolones (192). Newer quinolones such as levofloxacin and trovafloxacin have been shown in animal models to be as effective as vancomycin in the treatment of S. aureus endocarditis, including that caused by methicillin-resistant strains (24, 59, 119,188). A new quinolone (TG-873870) with excellent anti-MRSA activity and anti-anaerobic activity is undergoing phase 2 trials (Biotechnology Co., Ltd., Taipei, Taiwan). In animal model studies at least, 24-hour AUC/MIC ratios of 100 for quinolones appear to be optimum for favourable outcome (6).

Glycopeptides: Until recently, MRSA strains were invariably susceptible to vancomycin and teicoplanin (Table 2). MICs range between 0.25 and 4µg/mL (Table 2). However, vancomycin is slowly and incompletely bactericidal against MSSA in vitro compared with nafcillin (23,163,197).

               Newer glycopeptides under development (oritavancin, dalbavancin, telavancin) show potential advantages over other glycopeptides (317, 417, 386). They are rapidly bactericidal, and is active against VISA (172, other refs). Oritavancin shows efficacy equivalent to vancomycin in the rabbit endocarditis model (189).

               Teicoplanin (not available in the United States) is another glycopeptide with a spectrum of activity similar to that of vancomycin but which may be less active against some coagulase-negative staphylococci. In animal models, teicoplanin has activity equivalent to that of vancomycin for treatment of experimental endocarditis caused by both MSSA and MRSA (9,58). Teicoplanin MICs for VISA are usually increased more than vancomycin (397).

Mariani-Kurkdjian P. et.al.  Monitoring serum vancomycin concentrations in the treatment of Staphylococcus infections in children. Arch Pediatr. 2008 Oct 8. [Epub ahead of print]

Stryjewski ME et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis. 2008 Jun 1;46(11):1683-93.

Tetracyclines: Resistance to tetracyclines is common in community-acquired strains of S. aureus. Some tetracycline-resistant strains appear susceptible to minocycline and doxycycline. The incidence of tetracycline resistance is over 90% in haMRSA (114). In vitro susceptibility of S. aureus to minocycline has been documented for a number of years (262). There is recently evidence of efficacy against tetracycline-susceptible MRSA. Minocycline and vancomycin are equally effective in reducing bacterial density in infected vegetations in a rabbit model of MRSA endocarditis (285).

Glycylcyclines: Glycylcyclines are chemical modifications of tetracyclines (458). The only agent in this class so far to have reached and advanced stage of development is tigecycline. Like tetracycline, tigecycline has quite a broad spectrum, and has the advantage of having activity against almost all tetracycline-resistant strains. Its potential as an important antistaphylococcal agent has not been explored, but phase III studies in an array of infections, including complicated skin and skin structure infection (310), have shown efficacy when S. aureus was the cause.

Trimethoprim-sulfamethoxazole (TMP-SMX): Most strains of MSSA are susceptible to TMP-SMX. In vitro susceptibility of haMRSA to TMP-SMZ varies around the world. In one study, up to 95% of haMRSA strains were susceptible to TMP-SMX (116), while in other areas almost all strains are resistant (412). TMP-SMX was strikingly inferior to vancomycin for infection caused by either an MSSA or an MRSA strain in the rabbit model of aortic valve endocarditis (96). The numbers of bacteria in the vegetations of rabbits treated for 3 days with TMP-SMX were minimally reduced, compared with untreated controls, and no infection was sterilized, versus a rate of 70 to 80% for vancomycin.

Mupirocin: Mupirocin is used as a topical agent for the treatment of superficial skin infections and S. aureus carriage. Some 414 nasal and 586 non-nasal S. aureus isolates, both methicillin resistant and methicillin susceptible, showed similar MIC ₉₀ s and a susceptibility of 99.1% to the topical antimicrobial agent mupirocin (Table 2) (416) However, there is evidence of resistance to mupirocin emerging to significant rates when used widely (89).

Fusidic Acid: Fusidic acid (available in Europe and some Western Pacific countries) is the only marketed antibiotic in a class of agents that has a unique mechanism of action and a distinct Gram-positive spectrum (excluding streptococci). It is active against both MSSA and MRSA strains (420,86). S. aureus is inhibited by fusidic acid at very low concentrations, usually between 0.03 and 0.25 µg/mL, regardless of their susceptibility to methicillin or oxacillin (244,420). Fusidic acid-resistant mutants are harbored at relatively high frequencies. However, the rates of resistance have remained low in almost all regions where fusidic acid is regularly used (415).

Fosfomycin: Fosfomycin is an epoxide antibiotic that has a different structure and mode of action from other antimicrobials. The MIC ₉₀ for MRSA is 4µg/ mL. Fosfomycin, alone or in combination with ß-lactam antibiotics, has been said to be active against MRSA in vitro (4).

Rifampin: Rifampin (rifampicin) is highly active against staphylococci, with an MIC ₅₀ for about 0.03 µg/mL. Resistant mutants can be easily selected in vitro and are thought to be naturally present in susceptible populations at frequencies of 10 ^-6 to 10 ^-7 (202,214). Because of this resistance, rifampin is almost always used in combination with other anti-staphylococcal drugs when treating established infection. Resistance to rifampin is more prevalent in classical haMRSA than in caMRSA, EMRSA-15/16 or MSSA in most regions of the world (412).

Streptogramins: Streptogramins are antibiotics that are a combination of two types: streptogramins A and B. Streptogramins B share the same site of action as macrolides and lincosamides, while streptogramins A act at a separate site on the ribosome that enhances the effect of the streptogramins A (83). The original agent in the class, pristinamycin, has been available as an oral medication in France for many years. More recently, a semisynthetic injectable streptogramin combination, quinupristin-dalfopristin, has been developed particularly aimed at the treatment of multi-resistant Gram-positive infections. The advantage of these agents is that activity is usually retained against staphylococci and other gram-positives that are resistant to macrolides and lincosamides (36,184), and thus all forms of MRSA. Resistance to quinupristin-dalfopristin is currently very rare (184,185).

Oxazolidinones: Oxazolidinones are synthetic agents, the original members of which were MAO inhibitors (98). One, linezolid, is now available in some countries for the treatment of resistant staphylococcal infection (79). These drugs have a novel mechanism of action on ribosomal protein synthesis, and are active against strains resistant to other classes of antibiotics (293). Linezolid can be given orally as well as parenterally.

Daptomycin: Daptomycin is the first of a novel class of cyclic lipopeptides. Originally developed by Eli Lilly, its development was dropped, and was later taken up and completed by Cubist. Its unique mechanism of action involves calcium-dependent binding to the cell membrane, membrane depolarization, cessation of protein and DNA synthesis, potassium leakage and cell death. It is active against all types of S. aureus and licensed as a parenteral formulation for the treatment of serious skin and skin structure infections (236,382).

Combination Drugs

In Vitro

               Addition of gentamicin to nafcillin produces an enhanced bactericidal effect in vitro (351,354). The combinations of vancomycin-gentamicin and vancomycin-tobramycin are synergistic against most MSSA and MRSA strains (433). If synergism is defined as a decrease in colony counts of at least 100-fold at 24 h with the combination compared with that of the most active single drug, vancomycin-gentamicin synergism is not predictable for strains of MRSA with gentamicin MICs of 0.5 to more than 128 µg/mL (271). However, a gentamicin MIC above 500 µg/mL predicts a lack of vancomycin-gentamicin synergism for strains of MRSA (152). The in vitro effect of rifampin in combination with semisynthetic penicillins, vancomycin, and aminoglycosides is highly variable (163, 407, 433, 460). For both MSSA and MRSA, minocycline-rifampin synergism had been demonstrated by checkerboard evaluation (75, 363). Rifampin reduces the extracellular bactericidal activity of dicloxacillin but not fusidic acid, but neither of the latter agents reduce the intracellular killing effect of rifampin against S. aureus (289). The combination of linezolid and ampicillin/sulbactam was found to be either additive or synergistic against 48 clinical isolates of MRSA, including 10 strains with reduced susceptibility to vancomycin (200).

               Resistance in vitro does not appear to emerge if MRSA are exposed to a combination of fusidic acid and rifampin (257), and sub-MIC concentrations of trimethoprim also appear to be able to prevent selection of rifampin resistant-mutants (183). Similarly, rifampin can suppress the emergence of ciprofloxacin resistance in an in vitro pharmacodynamic model (193).

               Combinations of older agents to overcome resistance is a possibility only now being explored. An in vitro pharmacodynamic model has shown that combinations of cefepime with a wide range of other agents such as aminoglycosides, and the more recent agents linezolid, daptomycin and tigecycline (177).

Narita M.  In Vitro and animal studies of antibiotic synergy for newer antistaphylococcal agents for Staphylococcus aureus. 2008.

In Vivo (Animal Studies)

               Adding gentamicin to nafcillin accelerates killing of MSSA within experimentally induced cardiac vegetations in animal models (351). The addition of MiKasome, a new liposome-encapsulated formulation of conventional amikacin, enhances the in vivo bactericidal effects of oxacillin in S. aureus experimental endocarditis and may preserve selected physiological functions in target end organs (453). Some animal models favor the use of rifampin (171,190). In animal studies, rifampin has been shown to play a unique role in the complete sterilization of foreign bodies infected by S. aureus (77). Addition of rifampin to combination antibiotic regimens has proven highly effective in an animal model of MRSA osteomyelitis (171). In experimental MRSA endocarditis in rabbits, an ampicillin/sulbactam/rifampin regimen (with a high ampicillin dosage at 625-800mg/kg/day) was as effective as vancomycin (55). In animal models, use of quinolone combinations with rifampin may prevent resistance to both drugs (190,356).

               Several studies have evaluated the effectiveness of quinupristin-dalfopristin combined with other antimicrobial agents. In animal models of S. aureus endocarditis, the activity of quinupristin-dalfopristin combined with beta-lactam antibiotics (423,424) or vancomycin (299) was additive or synergistic against both macrolide-lincosamide-streptogramin B (MLS B) susceptible and resistant bacteria. The combination of quinupristin-dalfopristin and rifampin is highly synergistic in experimental S. aureus prosthetic joint infection (350).

ANTIMICROBIAL THERAPY  

Drug of Choice Guided Medline Search

               Treatment of staphylococcal infections depends on the site and severity of infection, the antibiotic susceptibility pattern of the organism and the presence of any patient allergy or drug intolerance.

Penicillin-Susceptible S. aureus: Benzylpenicillin ( penicillin G) is still the drug of choice for ß-lactamase-negative strains because on a weight-for-weight basis, it is more active than penicillinase-resistant penicillins. Penicillin-susceptible S. aureus strains have not been reported to become resistant to penicillin during treatment. Phenoxymethylpenicillin (penicillin V) and amoxycillin can both be used as oral agents for penicillin-sensitive S. aureus, with amoxycillin preferred when higher levels are required to achieve adequate penetration.

Methicillin-Susceptible S. aureus (MSSA): Penicillinase-resistant penicillins are the preferred drugs for all S. aureus infections caused by penicillin-resistant MSSA strains. These agents have gained wide acceptance because they are bactericidal and, like other penicillins, have a low incidence of adverse reactions. A variety of penicillinase-resistant penicillins are available, including the isoxazoyl penicillins cloxacillin, dicloxacillin, flucloxacillin, and oxacillin for both oral and parenteral use and methicillin and nafcillin for parenteral use. There are no apparent differences in efficacy between these agents, and they have similar pharmacokinetic profiles. Continuous infusions of these agents are being used increasing in serious staphylococcal infection, especially as outpatient therapy, with satisfactory outcomes (223).

               In most countries, methicillin has been superseded by the other agents in this group because of its association with a higher incidence of adverse reactions, especially hypersensitivity and interstitial nephritis. A serious reaction to flucloxacillin, characterized by prolonged hepatic cholestasis, has been described with some frequency and has been associated with both parenteral and oral therapy (122,408).

               Cephalosporins, particularly those of the first generation, have proven useful alternatives to penicillinase-resistant penicillins, since they are relatively stable to staphylococcal beta-lactamase. They are most commonly used in patients with a history of allergy or intolerance to penicillins. However, it is considered imprudent to administer them to patients with a history of accelerated reactions (e.g., angioedema or anaphylaxis). Patients with this type of history should not be given beta-lactams of any class, and other antistaphylococcal agents such as clindamycin or vancomycin should be used. Cephaloridine, the cephalosporin with the greatest potency in vitro against staphylococci, has been abandoned due to the risk of nephrotoxicity and relative instability to staphylococcal beta-lactamases. Suitable first-generation cephalosporins for staphylococcal infections include cephalothin, cefazolin , cefapirin and cephradine for parenteral use and cephalexin , cefapirin and cephradine for oral use.

               Currently available combinations of penicillin/beta-lactamase inhibitor include amoxycillin/clavulanic acid, ticarcillin/clavulanic acid, ampicillin/sulbactam and piperacillin/tazobactam. These combinations have no in vitro or in vivo superiority over penicillinase-resistant penicillins, but they do have the advantage of possessing a broad spectrum of activity against Gram-negative bacteria, including anaerobes. Therefore, they should not be used as substitutes for penicillinase-resistant penicillins when staphylococci are the sole pathogens. However, their broader spectrum gives them a significant advantage when staphylococci are involved in mixed infections with enteric Gram-negative organisms and anaerobes.

               Imipenem and meropenem provide adequate staphylococcal coverage in mixed infections but, again, have no role in the specific treatment of pure staphylococcal infection.

               Erythromycin has been used extensively for treatment of both minor and serious staphylococcal infections. It is bacteriostatic against staphylococci and, for this reason, has generally lost favor for the management of serious and life-threatening infection, being largely supplanted by penicillinase-resistant penicillins. Moreover, the role of erythromycin in empirical treatment is further limited because of drug resistance. Nevertheless, oral erythromycin is still suitable for minor skin infections caused by S. aureus, especially in penicillin-allergic patients, provided the strain has demonstrated susceptibility on laboratory testing. For erythromycin-susceptible strains, other macrolides are likely to be equally effective.

               The newer macrolides, roxithromycin, clarithromycin , dirithromycin, and azithromycin , have activity similar to that of erythromycin against staphylococci. In general, strains resistant to erythromycin are also resistant to these newer macrolides. The latter two agents have very high tissue penetration, which may be of advantage in some sequestrated staphylococcal infections. Although there is good experience with the newer macrolides for staphylococcal skin infections, there is little experience with these drugs in the treatment of osteomyelitis. These drugs are not currently recommended for the treatment of bacteremia or endocarditis.

               Like erythromycin, lincosamides (clindamycin and lincomycin) have been available for many years and have been used frequently for treatment of staphylococcal infections. They are also bacteriostatic and have been mostly relegated to reserve agents. However, the lincosamides are perhaps more useful second-line agents than macrolides, and are gaining acceptance as first-line agents for the treatment of caMRSA (252).

               Clindamycin is better absorbed than lincomycin when administered orally and is the preferred agent for oral use. It demonstrates good penetration into tissues, notably bone, and oral clindamycin in particular is less likely than erythromycin to cause gastrointestinal upset at high doses. This makes clindamycin potentially useful in patients with a history of accelerated reactions to penicillins, when cephalosporins are contraindicated.

               Fluoroquinolones have been used but never strongly advocated for the treatment of S. aureus infections. They do provide some coverage when S. aureus is present in a mixed infection with aerobic Gram-negative bacteria, and oral therapy is adequate. It is likely that the new generation fluoroquinolones will supersede ciprofloxacin, and (lev) ofloxacin in this setting due to their greater intrinsic activity.

               Vancomycin and teicoplanin may occasionally be considered for treatment of life-threatening staphylococcal infection in patients with a history of accelerated allergic reactions to beta-lactams. It is not clear whether they are superior to macrolides or lincosamides in this setting, but they are usually preferred because of greater experience gained in the management of life-threatening MRSA infections. However, there is growing concern about their efficacy compared to beta-lactams. Caveats for their use are given below.

               The new classes of drugs, the streptogramins, oxazolidinones and lipopeptides, should be reserved for MRSA infections. There may, however, be the occasional need to use these agents for MSSA infections, especially if there is intolerance/allergy to other drug classes.

Kim SH, Kim KY, et al. Outcome of Vancomycin Treatment in Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia.  Antimicrob Agents Chemother 2008;52:192-197.

Methicillin-Resistant S. aureus (MRSA): Guided Medline Search

                Vancomycin is the drug of choice for serious infections caused by S. aureus strains that are resistant to beta-lactam antibiotics and for patients who have potentially life-threatening allergy to the latter drugs. Recently, several anecdotal reports have questioned the efficacy of vancomycin for both MSSA and MRSA (66, 198, 232, 374). Vancomycin treatment of deep-seated staphylococcal infections such as endocarditis has been reported to clear bacteremia more slowly than beta-lactam treatment (268). Bacteremia is often prolonged more than 6 days in patients receiving vancomycin therapy (231, 232, 332, 374). In contrast, almost all the blood cultures of the patients receiving nafcillin or other beta-lactams become sterile within 6 days (56, 118, 211). Higher rates of relapse, complications, treatment failure and mortality in S. aureus bacteremia and endocarditis are associated with vancomycin therapy (57, 65, 66,132, 145, 146, 153, 152, 169, 250, 347, 374) Indeed, a recent study from Spain of bacteremic S. aureus pneumonia showed a significant mortality rate for vancomycin treatment of MSSA, compared to no mortality when patients were treated with cloxacillin (152). The slower bactericidal rate than beta-lactams has been suggested as a possible reason for the higher failure rate seen with vancomycin therapy in patients with MSSA endocarditis (374). However, it is possible that tolerance to vancomycin in some strains may also play a part (254,378). Slower eradication by vancomycin was considered an important factor in the delayed clinical response in a recent study of intensive care patients with S. aureus lower respiratory tract infections (266). It is possible that high doses may result in better efficacy. A prospective study in patients with staphylococcal lower respiratory tract infections showed that vancomycin AUC/MIC ratios of >400 gave much better clinical outcomes (78%) than ratios below that ratio (23%) (265, 266).

               In an effort to reduce costs and selective pressure for resistance, once daily dosing of vancomycin has been tried. However, early experience suggests that the risk of failure is high in patients with normal renal function (216, 247, 248,302).

Forouzesh A, Moise PA, Sakoulas G. Vancomycin Ototoxicity: A Re-Evaluation in an Era of Increasing Doses. Antimicrob Agents Chemother. 2008 Nov 10. [Epub ahead of print]

Lodise TP, Lomaestro B, et al.  Larger Vancomycin Doses (>=4 grams/day) are Associated with an Increased Incidence of Nephrotoxicity. Antimicrob Agents Chemother 2008 Jan 28 [Epub ahead of print].

Soriano A, Marco F, et al.  Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia.  Clin Infect Dis 2008;46(2):193-200.

Hall RG 2nd, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008 Jun;121(6):515-8.

Lee DH et al.  Successful Treatment of Methicillin-resistant Staphylococcus Aureus Meningitis with Daptomycin. Clin Infect Dis. 2008 Aug 15;47(4):588-90

               For patients with bacteremia, it is not mandatory to have chosen effective antibiotic therapy prior to blood cultures results (341). This is particularly important in settings where MRSA is prevalent. Thus, when S. aureus bacteremia is suspected, therapy can be initiated with beta-lactams without increase in mortality of those patients who subsequently prove to have MRSA (341). However, when MRSA is documented, failure to switch to an effective antimicrobial is associated with increased morbidity and mortality (178).

               For teicoplanin to be efficacious in the treatment of S. aureus endocarditis, the trough serum concentration should be maintained at 20 ug/mL during the first week of therapy (233, 239,444). Long-term teicoplanin therapy can rarely result in emergence of strains resistant to teicoplanin; however, these strains remain susceptible to vancomycin (191).

               The use of alternatives to vancomycin and teicoplanin might be considered for serious infections caused by caMRSA. Clindamycin is possibly the best choice if the organism is erythromycin susceptible. For strains with inducible clindamycin resistance, the weight of evidence suggests that there is a significant risk of failure or relapse, and clindamycin should not be used unless the infection is minor (234).

               There are a number of alternatives for oral therapy for less serious infection or step-down therapy. In general, combination oral therapy with two active agents is recommended for haMRSA. Most experience has been gained with rifampin, fluoroquinolones, and (in countries where it is available) fusidic acid. Chloramphenicol was used in the past but has fallen into disfavour. Linezolid is a suitable alternative as a single agent and has proven effective in the short and long term management of bone and joint (including prosthetic) infections (18, 325, 326). Pristinamycin has found a role in MRSA infections when patients are intolerant of other drugs (284).

               There has been a resurgence of interest in the role of trimethoprim-sulfamethoxazole for MRSA infections, given that the great majority of caMRSA are susceptible. A recent review of clinical studies suggested that while evidence of efficacy is still largely anecdotal, that in general this combination agent is effective (160).

Staphylococcus aureus, glycopeptide-intermediate (GISA): Guided Medline Search

The optimum treatment for vancomycin intermediate S. aureus has yet to be established. In Japan, most experience has been gained with the combinations of agents such as ampicillin-sulbactam and arbekacin, an aminoglycoside approved specifically for MRSA treatment in Japan (175). Current options include quinupristin-dalfopristin and linezolid. There is some animal model experience to support the use of ampicillin-sulbactam (14) and combinations of vancomycin and nafcillin (81). Other agents used over the years for the treatment of serious MRSA infections might also be considered, depending on their availability, such as fosfomycin (321). Some promise is being shown with lysostaphin, a peptidase produced by Staphylococcus similans, in experimental endocarditis models (82,298).

Review Article: Hiramatsu K. Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis. 2001 Oct;1(3):147-55.

Considerations in the Choice of Regimen: The traditional approach to serious and deep staphylococcal infections has been to use high dose therapy intravenously for a number of weeks. With the exception of line sepsis with a removable focus and no evidence of metastatic seeding, where 10 to 14 days therapy is considered adequate, the general approach to deep infections has been to administer treatment for 4 to 6 weeks. In the past, this treatment has been administered intravenously and in hospital, but now many infections are managed by (i) completing the intravenous course as an outpatient (OPAT) (224, 442, 400) or (ii) by a switch to high dose oral therapy after an adequate intravenous course, such has been practiced for osteomyelitis in children for many years (158,199). Use of or combinations such as fluoroquinolones with rifampin have also been shown to be effective when introduced early in management (300, 361).

               Outpatient intravenous therapy is now a reasonable alternative in most situations where prolonged intravenous administration is felt to be optimum (224). For OPAT generally, drugs with prolonged half-lives such as ceftriaxone or teicoplanin are preferred as the number of administration visits is minimized. However, although ceftriaxone is thought to have only marginal activity against S. aureus, recent experience in acute and staphylococcal chronic osteomyelitis has shown acceptable cure rates (161). The short half-lives of the antistaphylococcal penicillins have made standard scheduling of these drugs impractical for outpatient use. Instead, continuous infusion is recommended for these agents and early experience with cloxacillin (422) flucloxacillin (223) and oxacillin (224) is very favourable.

               In many clinical circumstances it is probable that switch to high-dose oral therapy for completion of the course is adequate. Important exceptions are meningitis and endocarditis, where the high levels achieved by maximum IV doses are necessary to ensure adequate delivery of antibiotic. Apart from the published experience in pediatric osteomyelitis (158,199) and orthopedic implant infections (105, 106, 384), there are limited published data. Nevertheless, there is considerable experience with this approach, and hence Table 3 provides some suggestions for oral regimens following initial intravenous treatment.

Special Situations

               Suggested antibiotics, doses, and duration for treatment of S. aureus infections are shown in Table 3. Some special situations are discussed below.

Skin and Soft Tissue Infections Guided Medline Search

               Most causes of cellulitis are caused by streptococci and S. aureus, so that beta-lactam antibiotics with activity against penicillinase-producing S. aureus are the typical antibiotics of choice for uncomplicated cellulitis in an immunocompetent host. Parenteral cefazolin (1.0g intravenously every 6 to 8 hours) or nafcillin (1.0 to 1.5g intravenously every 4-6 hours) are most commonly-used. Oral antibiotics for established MSSA infections include clindamycin, dicloxacillin, doxycycline, trimethoprim-sulfamethoxazole.

               If MRSA is the suspected cause (nosocomial infection or infection with community acquired MRSA in areas of prevalence of such strains) and in penicillin-allergic individuals, vancomycin (1.0 g intravenously every 12 hours) is the most commonly used antibiotic. Daptomycin (4mg/kg every 24 hours intravenously) is an alternative agent for treatment of established MRSA soft tissue infections. For invasive cellulitis unresponsive to standard therapy, combination agents including rifampin and gentamicin (low dose) are often added, although clinical data supporting these additions are based on anecdotes.

Rajendran PM, Young D, et al.  Randomized, Double-Blind, Placebo-Controlled Trial of Cephalexin for Treatment of Uncomplicated Skin Abscesses in a Population at Risk for Community-Acquired Methicillin-Resistant Staphylococcus aureus Infection.  Antimicrob Agents Chemother 2007;51:4044-4048.

               A switch to oral therapy (e.g. dicloxacillin, 0.5g every 6 hours) may be made after clinical responsive has occurred with objective improvement in erythema, tenderness, heat or swelling. First generation oral cephalosporins (cephradine, cephalexin, or cefadroxil) are common alternatives. Linezolid 600 gm. every 12 hours, orally can be used for MRSA skin and soft tissue infections.

               Cellulitis in the setting of a diabetic foot infection may involve a much wider spectrum of potential pathogens and warrants broader antimicrobial coverage such as ampicillin/sulbactam (3.0g intravenously every 6 hours in adults) or other antimicrobial combinations targeting anaerobes as well as gram negative aerobes. If MRSA is suspected, tigecycline might be an ideal choice.

               Broadening the spectrum of initial antimicrobial therapy for additional bacterial species may be indicated in specific clinical settings. These include, human or animal bites, for which initial therapy might include ampicillin/sulbactam intravenously (1.5-3g intravenously every 6 hours) (MN) or amoxicillin/clavulanate (500 mg orally every 8 hours in an adult). In the setting of cellulitis after an abrasion or laceration occurring with salt water exposure, where Vibrio vulnificus might be the pathogen, treatment with doxycycline (200 mg intravenously per day in two divided doses) might be preferred. Doxycycline also covers MSSA. In the setting of cellulitis after an abrasion or laceration occurring with fresh water exposure, where Aeromonas hydrophila might be involved, treatment with ciprofloxacin (400 mg intravenously every 12 hours) might be preferred. Quinolones also cover MSSA, but are not the antibiotics of choice. A combination of  ceftazidime plus gentamicin may be added to antistaphylococcal antibiotics for invasive infection in immunosuppressed patients.

Awad SS, et al.  Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy. Am J Surg 2007;194(5):606-610.

Proctor RA. Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis. 2008;46:584-593.

Pallin DJ, et al. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Ann Emerg Med. 2008 Mar;51(3):291-8. Epub 2008 Jan 28.

Recurrent or Persistent Staphylococcus aureus Skin and Soft Tissue Infection: A number of approaches have been devised although none of these have yet been validated in controlled trials.

                  1. Sustained and regular application bathing with a disinfectant.

                              a. Chlorhexidine

                              b. Hexachlorophene

                              c. Bleach. Add 1 cup of household bleach per bathtub (or 20 gallons)

                                  Soak for no longer than 20 minutes twice a week for 3 months.

                       No data exists for the comparative superiority or the ease of use for any of

                       these three disinfectants.

                  2. Nasal mupirocin b.i.d. for 5 days every month or b.i.d. for 5 days every 3

                      months. Reculture anterior nares at 6 months (325a).

                  3. Keep nails clipped and short. Avoid scratching of pruritic areas.

                  4. Wear light clothing to minimize perspiration.

                  5. Use antibacterial soap for hand washing.

                  6. Aerate intertriginous areas.

                  7. Eradicate nasal carriage with Mupirocin in spouses.

               Administration of oral antimicrobial agents is discouraged for long-term use because of risk for emergence of S. aureus resistance to the antibiotics and the adverse effects of the antibiotics. For severe cases, an initial 10-14 day course of minocycline or trimethoprim-sulfamethoxazole (TMP-SMZ) might be given if the cutaneous infection has been persistent; addition of rifampin for combination therapy is also an option.

Catheter-Related Bacteremia Guided Medline Search

               Several prospective studies have identified S. aureus as one of the leading causes of catheter-related bacteremia (31, 79, 85, 242, 368). More than 30% of S. aureus bacteremia is attributable to an infected intravascular device (58, 83, 118, 126, 157). It is a particular problem in certain clinical settings where central lines are frequently used such as haemodialysis (68, 250, 288, 301, 395), adult and neonatal intensive care areas (91, 335, 343) oncology (154) and coronary care units (334) Cure rates without removal of the intravascular device are generally below 20% (68,109). Risk factors for hematogenous complications include symptom duration, hemodialysis dependence, presence of a long-term catheter or non-catheter device, failure to remove the catheter and infection with MRSA (136).

               Most authors advocate shorter courses of antibiotic therapy for uncomplicated catheter-related S. aureus bacteremia, claiming that this infection has a low rate of complications after a 2-week course of intravenous antistaphylococcal antibiotics. On the other hand, a few studies have suggested that short-course therapy is inadequate, citing experiences with patients who had complications and relapse (181, 263, 253, 319, 434,445). In a well-reasoned meta-analysis, an average late complication rate of 6.1% was found for 11 studies totalling 132 patients treated with short-course therapy for uncomplicated catheter-related S. aureus bacteremia (181). These investigators also estimated the rate that might be observed after 4 to 6 weeks of therapy to be in the range of 0.07-0.99%. In another study (not included in the meta-analysis) of 12 patients with S. aureus bacteremia associated with intravenous catheter infection, three of eight patients who received 2-week treatment were considered failures: one each developed endocarditis 3 days and 7 weeks later, respectively, and one developed epidural abscess and meningitis after the first week of therapy and underwent 6 weeks of antibiotic therapy (318). A further recent study of 276 patients failed to show any relationship between relapse of deep-seated infection and duration of treatment (399).

               One study of S. aureus bacteremia in patients on chronic hemodialysis showed that less than 4 weeks of treatment was associated with a higher occurrence of primary treatment failure (definition not given) than treatment for more than 4 weeks (313), but this was not confirmed in another study (225). Ideally, catheters should be removed regardless of type (i. e. peripheral vs. central venous catheters, non-tunnelled vs. tunnelled catheters). Delayed removal of the infected catheter was associated with persistence of bacteremia (243). Only 18% of those with Hickman catheter-related S. aureus bacteremia and only 10% of patients with exit site infections are cured without catheter removal (109). In a study that controlled for other variables using logistic regression, it has been shown that patients in whom the intravascular device is not removed are 6.5 times more likely to experience complications or die than those in whom the device was removed (135). Some investigators have shown higher cure rates without catheter removal recently (345), and acidification of central lines may be able to increase the useful life of infected lines prior to removal (402).

               If the focus of infection has been promptly removed with rapid documented resolution of the bacteremia (< 3 days), 2 weeks of antibiotic therapy with a penicillinase-resistant penicillin, first-generation cephalosporin or glycopeptide is likely to be enough. Serious infectious complications such as septic thrombosis, deep-seated infections and sepsis-related death have often resulted from vascular catheter-related S. aureus bacteremia (315). If signs of endocarditis, metastatic infection, or prolonged bacteremia are present, longer therapy is needed (209). Large doses of oral dicloxacillin sodium (for MSSA) that can be taken at home for two weeks to supplement an initial 2-week intravenous regimen have been recommended (320). Under no circumstances should patients simply have the catheter removed without antibiotic treatment. It is likely that transesophageal echocardiography will become a standard investigation in catheter-related bacteremia to exclude complicating endocarditis, and further define the duration of therapy (2 or 4-6 weeks for negative and positive TOE respectively). A recent analysis has confirmed the cost-effectiveness of this strategy (344).

[Victor L. Yu: Repeat blood cultures after 3 days in patients with Stapylococcus aureus bacteremia]

Review Article: Raad, I., Hanna, H. and Maki, D. Intravascular Catheter-related Infections: Advances in Diagnosis, Prevention and Management. The LANCET Infectious Diseases 2007; Vol.7, Issue 10, 645-657.

Endocarditis Guided Medline Search

               S. aureus endocarditis is the predominant cause of endocarditis throughout the world. Among 1490 cases of Duke definite endocarditis collected from 5 sites in 4 countries, S. aureus was the single most common pathogen, accounting for 32.5% of cases (2). Endocarditis caused by S. aureus is a very serious disease associated with a high rate of morbidity and mortality. In non-injecting drug users it primarily involves valves in the left side of the heart and is associated with mortality rates of 25 to 40%. By contrast, staphylococcal endocarditis occurring in injecting drug users usually involves the tricuspid valve (right-sided endocarditis) and has a low mortality. Using traditional diagnostic means (clinical criteria and transthoracic echocardiography (TTE)), the incidence of infective endocarditis in patients with community-acquired S. aureus bacteremia ranges from 6 to 64% (23, 128, 187, 207, 219, 263, 269, 277, 338, 347, 365,445) although rates are generally below 15%. The introduction of transesophageal echocardiography (TEE) has substantially increased the rate of diagnosis of endocarditis in the setting of bacteremia. In unselected community plus hospital-acquired cases, TEE detects endocarditis in upwards of 25% of cases (132, 388). As might be expected, patients with a positive TTE have higher rates of embolism and death than those whose TTE is negative but TEE is positive (134).

MSSA Endocarditis: Guided Medline Search

              The drugs of choice for endocarditis (Table 3) caused by MSSA are the semisynthetic penicillinase-resistant penicillins. Benzylpenicillin is preferred in the uncommon circumstance that the strain is shown to be penicillin susceptible. First-generation cephalosporins are effective alternatives, usually reserved for patients with a history of minor penicillin allergy. There is lingering concern about cefazolin , however, as highlighted by a recent case of relapse in a strain of MSSA producing type A beta-lactamase (281). The third-generation cephalosporin, ceftriaxone, has been used but the relapse rate is unacceptably high at 28%, even when combined with gentamicin for 2 weeks (97). Vancomycin is currently the drug of choice for patients with life-threatening penicillin allergy and those with endocarditis due to MRSA.

               Daptomycin is an alternative treatment option at a dose of 6 mg/kg once daily. The efficacy of Daptomycin in the treatment of patients with S. aureus bacteremia was evaluated in a randomized, multicenter open-label study (136b).  Patients received either IV daptomycin or a comparator regimen of vancomycin, plus initial low-dose gentamicin if the patient had MRSA, or a semisynthetic penicillin plus initial low-dose gentamicin, if the patient had methicillin susceptible S. aureus.  Success rate of daptomycin was 45% compared to comparator of 49% for MSSA endocarditis and 44% and 32% for MRSA endocarditis, respectively. 

               Clindamycin has been successfully used for S. aureus endocarditis, but clinical data are limited. Relapse and treatment failure are documented (44,72,406,435). Moreover, the efficacy against strains which are erythromycin resistant and have inducible lincosamide resistance is unresolved, but accumulating evidence suggests that it is unlikely to be efficacious (234, 297, 323), and clindamycin is therefore not recommended for endocarditis caused by them.

               Although vancomycin is still recommended therapy for S. aureus endocarditis in patients with life-threatening penicillin allergy, recent experience suggests caution, as suboptimal outcomes have been associated with the use of this agent. One early study showed failure rates of approximately 40% have been documented in patients with S. aureus endocarditis treated with vancomycin despite right-sided involvement (374). Evidence supports the contention that patients with MSSA bacteremia and endocarditis treated with vancomycin fare worse than those treated with beta-lactams (66, 250, 145, 392 and see above) and alternative drugs or strategies are keenly sought. beta-lactam desensitization should be carefully considered for MSSA endocarditis in patients with beta-lactam allergy and suboptimal response to vancomycin (21). In patients with a questionable history of immediate-type hypersensitivity to penicillins, decision analysis confirms that skin testing prior to starting therapy has the best cost-utility (101).                Alternative methods of antibiotic dosing are currently being examined. Continuous infusion beta-lactams are being used increasing in endocarditis. Early experience has been favorable (223).

Lodise TP, McKinnon PS, Levine DP, Rybak MJ.  Impact of Empirical-Therapy Selection on Outcomes of Intravenous Drug Users with Infective Endocarditis Caused by Methicillin-Susceptible Staphylococcus aureus.  Antimicrob Agents Chemother 2007;51:3731-3733.

Left-Sided Endocarditis: A minimum of 4 weeks of intravenous treatment is recommended for left-sided endocarditis (426). This duration is also recommended for S. aureus septicemia complicated by metastatic infection, on the presumption that endocarditis may well be present. Of 20 patients with S. aureus endocarditis receiving at least 4 weeks of treatment, all were cured at 1 month follow-up (318). For endocarditis occurring on prosthetic devices, a 6-week course of a penicillin with an aminoglycoside has been recommended (426).

               The combination of nafcillin and gentamicin was associated with a more rapid clearance of bacteremia in MSSA endocarditis. Addition of gentamicin for the first 2 weeks of a 6-week course of intravenous nafcillin therapy led to more rapid defervescence but did not improve the cure rate (211). However, an increased risk of renal dysfunction was observed (211). Addition of gentamicin for the first 3 to 5 days of therapy may avoid nephrotoxicity and should be considered (30). A case can be made for not adding gentamicin for these reasons, and based on a recent retrospective study of mon- versus combined therapy (108). Although aminoglycosides have been added to the vancomycin regimen for MRSA endocarditis, this addition should be restricted to endocarditis caused by aminoglycoside-susceptible strains, and aminoglycoside use should be limited to 3 to 5 days (30) to minimize synergistic toxicity.

               Treatment of MRSA endocarditis is problematic. Vancomycin remains the treatment of choice, but the efficacy possibly suboptimal. The emergence of vancomycin-intermediate S. aureus has further compromised vancomycin, and failures are observed even with strains that are heterogeneously resistant (267, 391). For patients with MRSA endocarditis unresponsive to vancomycin, addition of rifampin and/or gentamicin (if susceptible) should strongly be considered (65,66). The use of minocycline, trimethoprim-sulfamethoxazole, linezolid, ciprofloxacin plus rifampin, daptomycin can also be considered if the strain is susceptible, although experience with these regimens is limited (19, 110, 111, 125, 136b, 249, 228). Caution should be used with the quinolone-rifampicin combinations as data from animal models suggest antagonism for some strains (59). Quinupristin/dalfopristin is also an alternative agent, although no comparative studies have been performed.

               The in vivo effect of rifampin in combination with nafcillin, oxacillin, vancomycin, or aminoglycosides is highly variable. Routine use of rifampin is not recommended for treatment of native valve S. aureus endocarditis. Although the addition of rifampin to vancomycin for patients with MRSA endocarditis failed to show either enhanced survival or reduced duration of bacteremia in comparison with vancomycin alone (232), it could be used as a supplemental therapy in patients who do not respond adequately to conventional antimicrobial therapy. In support of this, one recent retrospective analysis of septicemia due to EMRSA-15 suggested that rifampin may have played a role in the prevention of deaths caused by this epidemic MRSA (45).

               Breakthrough bacteremia was shown in patients with S. aureus endocarditis receiving teicoplanin in a graduated dosing regimen of 20mg/kg/day for 3 days, 12 mg/kg/day for 4 days, and 7 mg/kg/day thereafter (131,226). Teicoplanin is not currently recommended as initial therapy for severe S. aureus infection (i. e., septicemia and endocarditis).

Levine DP. Clinical experience with daptomycin: bacteraemia and endocarditis. J Antimicrob Chemother. 2008 Nov;62 Suppl 3:35-39.

Right-Sided Endocarditis: Right-sided endocarditis has a high cure rate, and carefully selected regimens as short as 2 weeks have been efficacious, provided there are no other foci of infection (57, 98, 333, 405). Effective regimens have included intravenous nafcillin and tobramycin (57), intravenous cloxacillin and amikacin (405), and intravenous cloxacillin with and without gentamicin (333) and daptomycin (136b). Four weeks of oral ciprofloxacin plus rifampin was also shown to be effective (170).

Prosthetic Valve Endocarditis: Because prosthetic valve staphylococcal endocarditis has a high mortality, combination therapy seems prudent. It is clearly associated with better bacteriological outcomes (108). The addition of rifampin and gentamicin to the beta-lactam or vancomycin is most commonly recommended, although controlled studies have not been done. Gentamicin should be given for 2 weeks rather than for 3 to 5 days as with native valve endocarditis. A favorable response of MRSA prosthetic valve endocarditis to minocycline therapy after unsuccessful treatment with vancomycin has been reported (220). Because of the very limited clinical data, minocycline should probably be regarded as an alternative agent for MRSA endocarditis. Daptomycin or combinations using daptomycin might be considered, although no data exist to support this option. Survival is probably more dependent on whether valve replacement surgery can be performed than on the choice of antibiotic regimen (182,455). Recent evidence favours ceasing rather than continuing with anticoagulant treatment to reduce morbidity from cerebral events (404).

[Victor L. Yu: Repeat blood cultures after 3 days in patients with Stapylococcus aureus bacteremia]

Meningitis Guided Medline Search

               Meningitis caused by S. aureus is often found early after neurosurgery or trauma in those with cerebrospinal fluid shunts (203) and can occur spontaneously as part of a staphylococcal sepsis syndrome (308). Other underlying conditions include diabetes mellitus, alcoholism, chronic renal failure requiring hemodialysis, intravenous drug abuse, and malignancy (155, 203,357). Mortality rates have ranged from 14 to 77%. Like all penicillins, penicillinase-resistant penicillins show minimal penetration into the cerebrospinal fluid in the absence of inflammation, but acceptable concentrations are seen in the presence of inflammation, despite the high level of protein binding (213). Hence, recommended treatment of meningitis caused by MSSA is a penicillinase-resistant penicillin in high dose (120, 203, 357). For MRSA and for patients allergic to penicillin, vancomycin 2 g/day for adults and 60 mg/kg daily for children in 2 divided doses is recommended. In MRSA infection, the cerebrospinal fluid should be monitored during therapy, and if the spinal fluid continues to yield viable organisms after 48 h of intravenous antibiotic therapy, then either intrathecal or intraventricular vancomycin (20 mg once daily in adults) can be added (120,162). Teicoplanin has also proven to be effective in post-neurosurgical methicillin-resistant S. aureus meningitis (8).

               Therapy of cerebrospinal fluid shunt infections caused by MRSA should include a combination of intravenous vancomycin and either oral rifampin (1200 mg/day in adults; 20 mg/kg daily in children) or intrashunt or intraventricular vancomycin at a dose of 20 mg once daily (120,143). Many shunt infections will require shunt removal to achieve a cure.

Kallweit U, et al.  Successful treatment of methicillin-resistant Staphylococcus aureus meningitis using linezolid without removal of intrathecal infusion pump. Case report.  J Neurosurg 2007;107:651-653.

Jorgenson L, et al.  Vancomycin disposition and penetration into ventricular fluid of the central nervous system following intravenous therapy in patients with cerebrospinal devices.  Pediatr Neurosurg 2007;43:449-455.

Bone and Joint Infections Guided Medline Search

               S. aureus is the most common cause of osteomyelitis in all settings, including acute hematogenous infection, chronic osteomyelitis and prosthesis infection. Septic arthritis, an acute infection of joints, is also most commonly caused by S. aureus. As in other staphylococcal infections, penicillinase-resistant penicillins are considered the drugs of choice for MSSA infections, and vancomycin is recommended for acute MRSA infections. Chronic MRSA infections are probably best managed with a combination of two oral agents (e.g., rifampin plus ciprofloxacin or fusidic acid ). Given the success of quinolones in the management of Gram-negative osteomyelitis, the role of the new fluoroquinolones with enhanced Gram-positive activity merits further study (229).

Acute Hematogenous Osteomyelitis: Acute hematogenous osteomyelitis usually involves long bones in children and vertebrae in adults (383). Antibiotic treatment alone is usually sufficient treatment, if initiated early enough to prevent bone necrosis. The cure rates of adequately treated S. aureus hematogenous osteomyelitis are usually above 90%. Surgery is indicated only with medullary or periosteal abscess formation, persistence of fever, presence of a sequestrum, or doubt about the offending organism. Short-term parenteral antibiotic therapy (i.e., 5-9 days of intravenous therapy) followed by 14 to 26 days of oral therapy has given a cure rate of more than 90% in both adults and children (32,398).

               In general, antibiotic treatment should be continued for 4 weeks (427). A recent systematic review of studies in children demonstrated that shortened initial parenteral therapy (≤ 7 days) is as effective as longer courses of parenteral therapy (227). Shorter total courses, 3 to 3.5 weeks, may be possible in children and would benefit from prospective study (421).

               Community-acquired MRSA infection is being seen increasing as a cause of acute hematogenous osteomyelitis, especially in children (151, 69, 195, 140, 141, 251). Clindamycin parentally and then orally is favoured for treatment, except if the strain has inducible resistance (252). In this case vancomycin is preferred for parenteral treatment and combinations of rifampin and a fluoroquinolone or fusidic acid for oral treatment. Failures still occur with vancomycin, and some advocate combination therapy if vancomycin is being used (144). Parenteral fosfomycin has recently been shown to be effective (90), as has three times weekly teicoplanin (221).

Review Article: Arnold, S.  Antibiotic Management of Pediatric Osteomyelitis.

Lamp KC, et al.  Clinical experience with daptomycin for the treatment of patients with osteomyelitis.  Am J Med 2007;120:S13-20.

Chronic Osteomyelitis: Chronic osteomyelitis with S. aureus usually occurs when acute osteomyelitis is not recognized early or is inadequately treated. Infection can be low-grade or remain dormant for years and then flare up to clinically resemble acute osteomyelitis. Surgery is usually required to remove necrotic bone and occasionally for diagnosis. Prolonged antibiotic therapy is recommended. Although the optimum duration of antibiotic therapy has never been established, most authors recommend therapy for 6 weeks to 6 months (10). Management of this condition is particularly suited to outpatient intravenous therapy (400), although direct comparisons between this mode of delivery and oral therapy is lacking. Combination therapy with nafcillin and rifampin was studied in chronic osteomyelitis but appears to offer no additional benefit to nafcillin alone (292). Vancomycin is associated with a higher risk of recurrence compared to antistaphylococcal penicillins and first generation cephalosporins (400, 401), and therefore should not be used if the strain is methicillin-susceptible.

Joint Prosthetic and Fixation Device Infections: Surgical intervention is essential in prosthetic and fixation device infections. In the acute postsurgical setting, the prosthesis or fixation device may be left in place if the joint or bone union is stable, and treated expectantly with antibiotics. In chronic or late infections, the prosthesis or fixation device must be removed to affect a cure (179,359). When removal of the prosthesis or device is impractical, long-term suppressive therapy has been effective with agents such as cloxacillin (26) or rifampin plus a fluoroquinolone (106).

Barberan J, Aguilar L, Carroquino G, Gimenez M-J, Sanchez B, Martinez D, Prieto J.  Conservative Treatment of Staphylococcal Prosthetic Joint Infections in Elderly Patients.  Am J Med 2006;119:993.e7-e10.

Septic Arthritis: Medical management of septic arthritis involves the same antibiotic regimens as acute hematogenous osteomyelitis. Repeat joint aspiration will alleviate pain, allow bacteriological monitoring, and probably reduce joint damage. Open joint drainage is generally unnecessary except for hip infections in children, where it seems to prevent necrosis of the femoral head (427). Poor outcomes are sequelae are more common with MRSA septic arthritis (430).

Prosthetic Joint Infections: Most prosthetic joint infections are hospital-acquired. Infection rates following hip arthroplasty range from 0.5 to 1% and from 1 to 2% following knee arthroplasty. Staphylococcus aureus and coagulase-negative Staphylococci account for more than 50% of these infections, and the staphylococci are often methicillin-resistant.

               Prosthetic joint infections are unusually difficult to manage. Meticulous debridement, usually with removal of the prosthetic component is the primary modality for successful management (264). Removal of the prostheses is performed with 2-stage revision arthroplasty. Antimicrobial therapy is always administered but its role is secondary to surgical management. Host factors such as nutrition and comorbid conditions may have a notable impact on the outcome of the infected joint (5). Antibiotic therapy is hindered by the encasement of the infected prosthetic device by a layer of biofilm composed of glycocalyx products secreted by the bacterium and host proteinaceous material such as fibrin.

Review Article:  Schaudin C, Stoodley P, Kainovic' A, O'Keeffe T, Costerton B, Robinson D, Baum M, Ehrlich G, Webster P.  Bacterial Biofilms, Other Structures Seen as Mainstream Concepts.  Microbe 2007;2:231-237.

               Conventional treatment of prosthetic joint infections includes initial intravenous antibiotic therapy (6-8 weeks) followed by long-term oral therapy (6-12 weeks). Once the infected implant is removed, antibiotics are also delivered locally into the joint space via antibiotic-impregnated beads or spacers. The most common antibiotics used are vancomycin (3-4gm/40gm batch of bone cement) or tobramycin (3.6gm/40gm batch of bone cement) or both. There are few randomized, controlled prospective studies with sufficient follow-up comparing therapeutic alternatives for the treatment of Staphylococcus aureus prosthetic joint infection. The studies that exist are difficult to analyse in that definitions of infection are nonstandardized (isolation of microorganisms from wound or fistula may not be true pathogens), endpoints are variable with inadequate microbiologic confirmation, inclusion of Staphylococcus epidermidis infection which respond to antibiotics more readily than S. aureus or are contaminants rather than pathogens, severity of illness and duration of symptoms may not be considered, and stratification by co-existing surgical removal or prosthetic implants is not done.

               MSSA should be treated with either a beta-lactamase-resistant penicillin, such as oxacillin, nafcillin or first generation cephalosporins such as cefazolin . Vancomycin is not as effective as nafcillin and should be reserved for MRSA infections. Clindamycin is a suitable alternative for susceptible S. aureus as it has been shown to inhibit glycocalyx production by the bacterium while achieving relatively high bone concentrations (362). Long-term outpatient treatment with oral antibiotics is being increasingly used following initial intravenous antibiotic therapy.

               The use of rifampin in combination with other antibiotics for S. aureus prosthetic joint infections is supported by in vitro assays and animal model (33). Because S. aureus is considered an intracellular pathogen, use of rifampin and quinolones have enjoyed increasing popularity for bone and joint infections caused by S. aureus because of their excellent intracellular penetration and oral forms of administration.

               An oral regimen consisting of the combination of ofloxacin (200 mg t.i.d.) and rifampin (900 mg. q.d.) has been studied in a non- comparative trial for S. aureus prosthetic joint infections of the hip (n=10) and knee (n=7) (105). Patients with hip infections received oral therapy for five months preoperatively and one month postoperatively with removal of the infected joint. The cure rate was 70% (7/10). Patients with knee infections received oral therapy for six months preoperatively and three months postoperatively with removal of the infected joint. The cure rate was 71% (5/7). Failures with emergence of resistant S. aureus occurred in 1 patient from each group. In another study of prosthetic joint infections caused by staphylococcal species, patients were randomized to oral ciprofloxacin (750 mg every 12 hours) plus placebo or ciprofloxacin plus rifampin (450 mg every 12 hours), after receiving an initial two weeks of intravenous therapy following debridement surgery (459). This group was a select group limited to patients with stable orthopedic implants and short duration of symptoms (< 21 days). 100% (12/12) in the ciprofloxacin/rifampin group who completed the study were cured of infection with a retention of their prosthesis compared to 58% (7/12) in the ciprofloxacin/placebo group (22). In an open trial comparing oral rifampin with either fusidic acid or ofloxacin for S. aureus implant infections, a cure rate of 56% (14/25) was found in both groups, four of whom had the device removed. Two out of eight failures in the rifampin/fusidic acid group were due to S. aureus, one of which was resistant to rifampin but susceptible to fusidic acid and ofloxacin. Similarly, two out of eight failures in the rifampin/ofloxacin group were due to S. aureus, both of which were resistant to rifampin (105). This experience contrasts with the previous study in which rifampin resistance was not encountered when the combination of rifampin plus ciprofloxacin was given (459).

               Stein and co-workers used high dose trimethoprim-sulfamethoxazole (trimethoprim 20mg/kg/day and sulfamethoxazole 100 mg/kg/day) in patients with infected prosthetic implants caused by multi-resistant staphylococcus species. 55% (6/11) patients infected with S. aureus were cured after a post treatment follow-up of 24 to 75 months (average 38 months) (384). These authors found that trimethoprim/sulfamethoxazole had higher incidence of adverse effects than that observed with quinolones, fusidic acid and rifampin and were severe enough to require discontinuation in 21%.

               Quinupristin/dalfopristin and linezolid may be alternatives in patients who are allergic to beta-lactam agents and vancomycin. However, the experience with these agents in the treatment of prosthetic joint infections has not yet been reported.

Surgical options: For those patients who have failed or are unable to undergo two-stage revision arthroplasty, surgical options include: resection arthroplasty, arthrodesis or amputation (322, 372).

Chronic antibiotic suppression: In certain situations, removal of the prosthetic joint may not be feasible including elderly patients who are too frail for surgery, the remaining bone stock is insufficient for further prosthetic implantation or the patient may refuse further surgery. Oral suppressive therapy is a reasonable alternative in such patients. These have been several retrospective and uncontrolled series addressing this issue. French investigators have evaluated a variety of oral antibiotic regimens including ofloxacin (600 mg/day) or fusidic acid (1.5 gm/day) combined with rifampin (900 mg/day). The results with these two regimens were similar with a cure rate of 39% after a post-treatment follow-up of 38 months (105,106). The same group of investigators evaluated high-dose trimethoprim-sulfamethoxazole (20 mg/100mg/kg/day) for nine patients with prosthetic hips (n=5) and knees (n=4) with a cure rate of 55% after a post-treatment follow-up of 38 months (384).

               In a Chicago study, 8 patients (5 knees, 3 hips) with S. aureus prosthetic joint infection were treated with cephalexin, clindamycin, dicloxacillin or minocycline/rifampin for 4-103 months. The cure rate was 63% (5/8). Three failures were due to MSSA: two patients had their joints removed and the third relapsed within a month after completing a 22-month course of dicloxacillin. Only two patients had infection due to MRSA and both were cured with minocycline and rifampin (364).

               In another small study of five patients with infected prosthetic hips (n = 2) and knees (n=3), a regimen consisting of minocycline (100 mg/day) combined with rifampin (600 mg/day) or cephalexin (500 mg/qid) led to a cure rate of 60% after post-treatment follow-up of 24 months. Two patients, both with prosthetic knees (one each with MSSA and MRSA), were considered failure with development of chronic draining sinus; nevertheless, both patients were ambulatory with a functioning prosthesis (325).

Pulmonary Infections Guided Medline Search

               Pulmonary manifestations of Staphylococcus aureus infection include pneumonia, lung abscess, and empyema. Inhalational pneumonia, which is associated with influenza infection in the community, and aspiration due to intubation in the hospital setting are precipitating factors. Pneumonia due to hemogenous spread can arise from contamination of the venous system, as in hemodialysis patients or IV drug abusers who develop endocarditis of the tricuspid valve with subsequent septic emboli.

               A second categorization of pneumonia due to S. aureus is community-acquired vs. hospital-acquired. If gram stains show that gram-positive cocci in clusters are predominant in respiratory secretions, empiric treatment for MSSA with nafcillin or oxacillin for community-acquired infections is appropriate. Antistaphylococcal beta-lactam antibiotics are superior to vancomycin for MSSA pneumonia (152). If the local susceptibility patterns within a specific community shows a high incidence of MRSA, initial treatment with vancomycin is indicated, pending susceptibility results.

               There is evidence of increasing rates of caMRSA causing pneumonia, especially a necrotizing form with poorer outcomes associated with strains of caMRSA that have the Panton-Valentine leukocidin (149, 296, 205, 39, 303, 291, 137). caMRSA also appears to be contributing to an increase in the prevalence of parapneumonic effusions (3). This suggests that vancomycin may be required initial therapy in patients with severe presumptive staphylococcal pneumonia, although caveats about the suboptimal efficacy of vancomycin apply equally to pneumonia (see above and below).

               Staphylococcus aureus is the second most common pathogen causing hospital acquired pneumonia according to the National Nosocomial Infections Surveillance. MRSA pneumonia has high mortality rates; in two prospective observational studies, MRSA pneumonia treated with vancomycin resulted in death in 50-60% of patients (152, 373). Two randomized controlled trials of vancomycin in nosocomial pneumonia showed bacteriologic failure in 35% (346) and clinical failure in 59% of patients (121). The strikingly high failure rates have led some investigators to look at more aggressive dosing of vancomycin via continuous infusion (450) as well as newer agents such as linezolid as primary therapy for pneumonia due to MRSA. Two similar randomized controlled trials of linezolid plus aztreonam vs. vancomycin plus aztreonam in nosocomial pneumonia due to MRSA showed no difference in clinical or microbiologic cure rates (346, 451). A combined analysis of these two studies (452) showed superiority of linezolid over vancomycin in both survival and clinical cure rates (survival rates 80% vs. 64%, p = 0.03; clinical cure rates 59% vs. 36%, p<0.01). Prospective, randomized controlled trials are needed to confirm these findings.

               Quinupristin/dalfopristin is another alternative for S. aureus pneumonia including MRSA pneumonia (121).

               A 2-week course may be satisfactory for uncomplicated infection (where endocarditis can be ruled out); however, if bacteremia is present, prolonged treatment of 4 weeks is appropriate.

               Consultation with an infectious disease specialist is recommended to guide therapy based on prevailing antibiotic susceptibility patterns and to recommend duration of antibiotic therapy.

Rubinstein E, et al. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008 Jun 1;46 Suppl 5:S378-85.

Eradication of S. aureus Carriage Guided Medline Search

               Topical mupirocin, sometimes combined with other antibacterial strategies, has overall shown the greatest efficacy in reducing nasal carriage of S. aureus (41). Use of mupirocin to eliminate nasal carriage has a range of potential applications (218, 264, 70) has been associated with concomitant eradication of carriage on hands (327, 102) and on other body sites (174). In addition, the MRSA colonization rate decreases significantly when both nares and wounds were treated with mupirocin (201). Control of MRSA in patients entering intensive care units may be worthwhile when MRSA prevalence is low (< 10%) (53). Topical mupirocin can contribute to this control, but low level resistance to mupirocin can result in failure to eradicate (167). Several studies have demonstrated that preoperative mupirocin can reduce the incidence of postoperative wound infection (147, 206,454), but a systematic review has failed to show any overall benefit as a routine in all patients, not just those colonized with S. aureus (218). Staphylococcal infection in dialysis and continuous ambulatory peritoneal dialysis patients can also be reduced with regular application of mupirocin to suppress nasal carriage (93, 173, 279, 35).

               The combination of oral trimethoprim-sulfamethoxazole, oral rifampin, and topical bacitracin has been evaluated in uncontrolled studies (339, 297,446). Success rates of 100% were seen for MRSA nasal carriage, but lower rates of 66 to 81% were seen for extranasal sites (431,446). Failures in patients receiving bacitracin/ rifampin resulted from development of rifampin resistance (431).

               Trimethoprim-sulfamethoxazole, novobiocin, ciprofloxacin, minocycline and fusidic acid used singly or in combination with rifampin have been tried. Rifampin-resistant staphylococci have emerged during therapy when rifampin was used as a single agent (353,446). Combinations of trimethoprim-sulfamethoxazole plus rifampin and novobiocin plus rifampin have been used with modest success (50-75%) in eradicating MRSA nasal carriage (115,429). Clearance of extranasal sites, especially wounds, was less successful. Resistance has emerged even for the combination regimens. Ciprofloxacin, even when combined with rifampin, has proven disappointing for eradicating MRSA nasal carriage; emergence of resistance to ciprofloxacin has been commonplace following therapy (210, 273, 307, 375, 376). Minocycline plus rifampin was no more effective than rifampin alone in either eradicating nasal carriage or preventing emergence of rifampin resistance (270). Fusidic acid cannot be used alone as eradication rates are low and resistance will emerge (63). Enteral vancomycin with or without topical mupirocin may have a role in outbreaks but more experience is needed, and increases the risk of colonization with vancomycin-resistant enterococci (245, 371). Topical polysporin ointment (142) and tea tree oil (45a, 129) have also been shown to be effective in reducing carriage but experience is limited and are not currently recommended.

Wertheim HFL, Melles DC, et al. The role of nasal carriage of Staphylococcus aureus infections. Lancet Infectious Diseases 2005;5:751-762.

Bhalla A, et al.  Staphylococcus aureus intestinal colonization is associated with increased frequency of S. aureus on skin of hospitalized patients.  BMC Infect Dis. 2007;7:105.

Muñoz P, Hortal J, et al.  Nasal carriage of S. aureus increases the risk of surgical site infection after major heart surgery.  J Hosp Infection 2008;68:25-31.

van Rijen MM, et al. Intranasal mupirocin for reduction of Staphylococcus aureus infections in surgical patients with nasal carriage: a systematic review. J Antimicrob Chemother. 2008;61:254-61.

Toxic Shock Syndrome

               Toxic shock syndrome (TSS) is an acute and potentially fatal illness that is characterized by a high fever, diffuse erythematous rash, desquamation of the skin 1 to 2 weeks after onset, hypotension, and involvement of three or more organ systems (73, 94,330, 367,403). Toxic shock syndrome toxin 1 (TSST-1) is currently accepted as the cause of 100% of menstruation-associated TSS cases. Of the S. aureus strains isolated in TSS cases not associated with tampon usage, approximately 50% produce TSST-1, 47% produce staphylococcal enterotoxin B (SEB), and 3% produce staphylococcal enterotoxin C (SEC) (34,358). The incidence of staphylococcal TSS in the United States was estimated to be 6000 cases per year (99). The overall case fatality rate for staphylococcal TSS has remained at 5%.

               Treatment of TSS includes aggressive fluid replacement with saline, colloid, or both, and vasopressors, penicillinase-resistant antibiotics, and drainage of infected sites. Vaginal examination with removal of any tampon and with vaginal and cervical culturing for S. aureus should be done immediately. Oxacillin or nafcillin should be administered intravenously at a dosage of 8 to 10 g/day. If MRSA is cultured from the infection sites, a glycopeptide should be used. Overall, antibiotics have only a small impact on mortality and other techniques to manage sepsis secondary to superantigen stimulation are required (7).

               Beta-lactam antibiotics have been suspected to increase TSST-1 production, therefore, it is commonly suggested that clindamycin be used in the first few days. If there is no deep-seated infection, the duration of treatment need not exceed 10 to 15 days (428). In vitro studies showed that silver sulfadiazine cream leads to increased toxin production by S. aureus, suggesting mupirocin ointment or povidone iodine solution may be better choices for topical care of infected sites (112). Intravenous immune globulins have been used sporadically in very severe cases (428). Effective prevention of recurrences included parenteral antibiotic treatment of the first episodes of TSS, education of the patient, and avoidance of tampons.

Alternative Antistaphylococcal Therapy

               Alternative antibiotics with good activity against MRSA include the parenteral antibiotics, teicoplanin and fosfomycin, and the orally absorbed antibiotics, rifampin, the fluoroquinolones, fusidic acid , quinupristin/dalfopristin, daptomycin and linezolid.

Review Article:  Lentino JR, Narita M, Yu VL.  New Antimicrobial Agents as Therapy for Resistant Gram-Positive Cocci.

               Teicoplanin has a longer elimination half-life, permitting once-daily dosing, and studies suggest a lower propensity for toxicity, including that seen on co-administration with aminoglycosides. For these reasons, teicoplanin is often considered useful for home intravenous therapy (113). Suboptimal outcomes have been shown with S. aureus endocarditis in patients receiving teicoplanin (131), almost certainly as a result of inadequate doses. For optimum efficacy in serious and deep-seated infections, initial doses of 6mg/kg are recommended, and levels should be measured to ensure troughs exceed 20mg/L (233, 239,444). Second daily doses of 6mg/kg, after a three day loading course of 6mg/kg daily, appear to be effective in non-deep-seated infections (15).

               The oral formulation of fusidic acid is similar to rifampin in having good oral bioavailability and good tissue penetration, and a propensity for resistance emergence during treatment (409,410). Originally promoted as a primary antistaphylococcal agent, including a topical formulation for superficial skin infections, it is now most often used for MRSA infections (439). It is occasionally used in combination with rifampin for the continuing oral and outpatient treatment of MRSA infections (13,439). Emergence of fusidic acid resistance has been observed when the antibiotic is administered alone (311,415), and significant gastrointestinal intolerance limits use in some patients. The intravenous formulation is usually reserved for serious infections. Its use is associated with hyperbilirubinemia in up to 50% of patients (76). Rifampin, which is remarkably active against S. aureus, cannot be used as a single agent because of the high one-step mutation rate of 10^-7 -10^-8 to resistance (268).

               Trimethoprim-sulfamethoxazole (TMP-SMX) has been successfully used for skin and soft tissue infections, osteomyelitis, meningitis, endocarditis and bacteremia caused by S. aureus (27,249). It has been largely supplanted by other drugs but has been shown to be effective even for infections such as endocarditis. TMP-SMX can be a valuable alternative treatment for staphylococcal disease, particularly that caused by MRSA (249), if strains are susceptible, although data from animal models are discouraging (96). Nevertheless, high dose oral TMP-SMX has proven to be useful in the management of prosthetic joint infections (384).

Spellberg B. Oral Trimethoprim-Sulfamethoxazole for S. aureus and MRSA Osteomyelitis. 2008.

               Fosfomycin is used in a number of countries for treatment of staphylococcal infections, particularly parenterally for serious infection caused by MRSA strains. It is frequently used in combination therapy for this purpose (166, 208), although it can be used alone (90).

               The streptogramin combination of quinupristin and dalfopristin has been shown to be effective in serious infections such as nosocomial pneumonia and complicated skin and skin structure infections, some of which have involved susceptible and multi-resistant S. aureus (217). A pilot study in staphylococcal catheter-related bacteremia showed results comparable to vancomycin (316), and prospective emergency use against MRSA infections in patients who failed on or were unable to tolerate other drugs has shown clinical and bacteriological success rates in excess of 60%, including strains with constitutive and inducible MLS B resistance (217, 355). Quinupristin-dalfopristin also showed good efficacy similar to vancomycin in Gram-positive nosocomial pneumonia (121). Adverse reaction rates, mainly local venous intolerance, are higher than with comparator agents (217), suggesting that this drug has greater value as a reserve agent than as a primary MRSA drug.

               Linezolid is a promising agent in the treatment of staphylococcal infection, especially MRSA. The agent can be given both parenterally and orally. Early published clinical evidence in hospitalized patients with skins and soft tissue infections, community-acquired pneumonia and MRSA infections is quite favorable (79). A variety of staphylococcal infections, including bacteremia and osteomyelitis, have been successfully treated under compassionate use programs (74, 79,259). In nosocomial pneumonia, superior outcomes for linezolid were seen compared to vancomycin (80% versus 63.5%) (451). Preliminary experience suggests that adverse reactions are relatively infrequent (79). However, long-term use is associated with marrow toxicity, and hence should be used only in highly selected circumstances (139).

Combination Therapy

               Korzeniowski et al. (211) showed that eradication of bacteremia in non-addicts with endocarditis was significantly faster with nafcillin plus gentamicin group compared to nafcillin alone [2.8 days vs. 4.1 days, p< 0.05]; 8 of 16 (50%) patients treated with nafcillin plus gentamicin had sterile blood cultures on day 2 compared with only 1 of 9 (11%) patients treated with nafcillin alone. However, the more rapid clearance of bacteremia in the nafcillin plus gentamicin group did not correlate with a more rapid clinical response (211). An increased incidence of renal dysfunction was associated with addition of gentamicin for the first 2 weeks (211).

               Chambers (57) showed a cure rate of right-sided endocarditis in intravenous drug abusers of 33% (1 of 3) with vancomycin plus tobramycin versus 100% (47 of 47) with nafcillin plus tobramycin for 2 weeks.

               Because of slow clearance of bacteremia and clinical failure, adding an additional antimicrobial agent to vancomycin to achieve synergistic bacterial killing for treating deep-seated staphylococcal infections has been attempted. Although combination therapy is recommended by some experts for treatment of deep-seated infections such as prosthetic valve endocarditis (272), there are no controlled trials demonstrating the superiority of the combination over vancomycin alone. Combination of vancomycin and gentamicin was reported to be more nephrotoxic than gentamicin alone (123,125). Three studies failed to show better cure rates with combination therapy than with single-drug therapy for S. aureus endocarditis when the total length of therapy was 4 to 6 weeks (1, 211,432). Definitive guidelines for the use of vancomycin-gentamicin combination therapy for MRSA infections await results of clinical trials correlating outcome with in vitro synergy studies (271).

               Aminoglycosides are considered by some authorities to have a major supportive role in endocarditis and other forms of high-grade or persistent bacteremia. Used in combination with first-line agents during the initial stabilization phase of therapy, aminoglycosides shorten the duration of bacteremia (95,211).

               Rifampin has been used in combination with a semisynthetic penicillin or vancomycin/teicoplanin for severe staphylococcal infections (196,457). Although rifampin has been used as supplemental therapy in patients who do not respond adequately to conventional antimicrobial therapy (126,253), reported clinical experience is still limited. Prospective studies of these combinations, however, have demonstrated modest or no benefit (418) for most patients or no benefit at all (411). In contrast, anecdotal clinical experience (126, 253,394) favors the addition of rifampin. Rifampin appeared to be a safe and effective addition to therapy when staphylococcal bacteremia persisted despite vancomycin treatment in neonates (394).

               A combination of rifampin and ciprofloxacin cured 100% (10 of 10) intravenous drug users with right-sided S. aureus endocarditis (110). Quinolone-rifampin combinations have potential. A recent study showed that a combination of oral fleroxacin and rifampicin has been shown be equally effective to standard parenteral therapy in serious S. aureus infections, and permits earlier discharge (361). Clinical experience with fusidic acid and a rifampin indicates that fusidic acid resistance does not emerge readily, although strains resistant to rifampin are possible (180). As stated above, rifampin cannot be used as a single agent because of its high one-step mutation rate to resistance (268).

               At present the fluoroquinolones should probably be reserved for oral treatment of infections caused by MRSA, and only used in combination with other drugs such as rifampin or fusidic acid. When ciprofloxacin has been used as a single agent to treat staphylococcal carriage or infection, it has failed to eradicate the organism or resistance has developed in a proportion of patients (159,273).

               Fusidic acid has been used mostly in combination for a variety of serious staphylococcal infections such as bone and joint infections, skin and soft tissue infections, septicaemia and endocarditis and MRSA infections (13, 105, 380, 438,439). A recent retrospective study showed that the combination of fusidic acid and flucloxacillin was superior to flucloxacillin alone, suggesting a possible role for routine addition (156). Prospective studies are required to confirm this observation.

Narita M.  In Vitro and animal studies of antibiotic synergy for newer antistaphylococcal agents for Staphylococcus aureus. 2008.

Alternative Non-Antimicrobial Agent Therapy

               The increasing prevalence of resistant S. aureus has kindled intense interest in new classes of Antimicrobial agents for the treatment of this dangerous pathogen. An Phase I investigation evaluating Staphylococcus aureus tefibazumab, a humanized immunoglobulin (Aurexis®, Inbitex Inc) in the treatment of patients with MRSA endocarditis has been completed (329). Tefibazumab is a purified immunoglobulin G (IgG) product currently derived from polled human plasma selected for high titers of antibody to S. aureus adhesions, termed Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMM) proteins. The MSCRAMM-specific IgG in tefibazumab interferes with S. aureus adherence to extracellular matrix proteins in vitro, and may enhance opsonophagocytosis of S. aureus by polymorphonuclear leukocytes (290). The product is currently in Phase II clinical trials. Other innovative potential therapies, including lytic bacteriophages targeting specific pathogens, are also being explored (260).

(Printable Version of Antimicrobial Therapy for Staphylococcus aureus)

ADJUNCTIVE THERAPY Guided Medline Search

               Early and aggressive surgical exploration is essential in patients with suspected necrotizing fasciitis, myositis, or gangrene for (1) visualizing the deep soft tissue structures, (2 )removal of purulent drainage and necrotic tissue, (3) reducing compartment pressure and (4) obtaining material for Gram’s stain and for aerobic and anaerobic cultures.

               Experimental animal model data supports the use of antiplatelet agents in S. aureus endocarditis. Compared with controls, animals treated with aspirin and/or ticlopidine have smaller vegetations and better rates of sterilisation (286, 287) as well as bacterial dissemination and frequency of embolic events (215). This is in contrast to a recent retrospective study showing increased mortality and cerebral events in patients with left-sided S. aureus endocarditis (404). The difference may lie in the fact that in the clinical study, most patients were fully anticoagulated with vitamin K antagonists because of prosthetic valves, rather than receiving antiplatelet agents only.

Catheter-Related Bacteremia

               As discussed above, removal of infected catheter is ideal (135,243). The indications for surgical removal or debridement of infected hemodialysis sites is less clear (225). If the hemodialysis access site is nonfluctuant without erythema, a trial of antistaphylococcal antibiotics is often attempted before resorting to surgery.

Endocarditis

               Valve replacement surgery has become an important adjunctive therapy in the management of both native valve and prosthetic S. aureus endocarditis. The decision to perform valve replacement surgery is an individualized one that requires careful consideration of the numerous patient-specific characteristics. Nonetheless, a number of generally accepted indications for surgical intervention have emerged (25). Such indications include congestive heart failure, uncontrolled infection, hemodynamically significant valvular dysfunction, and/or local suppurative complications such as paravalvular abscess. Because of the high mortality associated with S. aureus prosthetic endocarditis treated medically (340,448,455), early surgical intervention for this condition is also usually recommended (340,448,455,331). The role of echocardiography in the decision to perform valve replacement surgery is incompletely defined. The American Heart Association Committee on Infective Endocarditis identified the following echocardiographic features of endocarditis as associated with the potential need for intervention: 1) persistent vegetation after systemic embolization, 2) large (> 1cm) anterior mitral valve vegetations, 3) increase in vegetation size after 4 weeks of antimicrobial therapy, 4) acute aortic or mitral insufficiency with signs of ventricular failure, 5) valve perforation or rupture, and 6) perivalvular extension (e. g. valve dehiscence, rupture or fistula, or large abscess (21).

Bone and Joint Infection

               For acute osteomyelitis, surgery is indicated only with abscess formation or persistent fever. For chronic osteomyelitis, surgery with frequent debridements is virtually always necessary for successful outcome. For prosthetic joint infection, surgical intervention is a major part of therapy as discussed above.

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

               Fever and breakthrough bacteremia are useful for monitoring antistaphylococcal therapy. For patients with bacteremia without an obvious portal of entry, we recommend repeating blood cultures three days after initiation of antistaphylococcal antibiotic therapy (66). If cultures are persistently positive, an aggressive search for the source of infection is indicated. If the persistent bacteremia occurs while receiving vancomycin therapy, combination therapy or therapy with other antistaphylococcal antibiotics (linezolid, quinupristin/dalfopristin, rifampin) should be considered. Erythrocyte sedimentation rate (ESR) is only useful for osteomyelitis follow-up.

[Victor L. Yu: Repeat blood cultures after 3 days in patients with Stapylococcus aureus bacteremia]

               Serum inhibitory and bactericidal titers to assess the adequacy of antibiotic therapy are often recommended for osteomyelitis and endocarditis (12,437). Peak and trough bactericidal titers of at least 1:64 and 1:32, respectively, were suggested as good predictors of a successful therapeutic outcome in patients with infective endocarditis (436). However, the serum bactericidal titer (SBT) is subject to variation and lack of reproducibility with staphylococci (305,263). The serum test does not predict efficacy in animal models of endocarditis (104,164). Clinically, the test lacks precision in predicting outcome or bacteriological failure (84, 197, 258,436). Clinical response and results of follow-up blood cultures remain the best indicators of clinical outcome. Re-analysis of data from two large multicenter studies showed that outcome was strongly correlated with trough titers of SBTs (436, 437). This supports the concept that the efficacy of beta-lactams depends on the time above the MIC, as most patients in these studies received beta-lactams as their principal therapy (413). Currently, it is not possible to define the optimal trough titer for a successful outcome.

               New information regarding the pharmacodynamic predictors of efficacy of vancomycin, at least in the context of lowered respiratory tract infection, suggests that monitoring levels and determining AUC/ MIC ratios will be of value (265, 266).

VACCINES Guided Medline Search

               A bivalent conjugate vaccine containing capsular S. aureus type 5 and 8 capsular polysaccharides is undergoing clinical trials (StaphVAX, Nabi, Boca Raton, FL). It elicited an antibody response in 75% of hemodialysis patients and conferred partial immunity against S. aureus bacteremia for about 40 weeks, with an estimated efficacy of 57% (369). Booster doses are safe and immunogenic (124).

PREVENTION Guided Medline Search

General

               The Hospital Infections Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control (CDC) recommends that hospitals use “Standard Precautions” for dealing with all hospitalized patients, regardless of their diagnosis or presumed infection status (Table 5). This includes most patients with MSSA colonization or infection. However, for patients with major S. aureus infections (e.g. large skin, wound or burn infections) for which a dressing cannot be used or the dressing does not contain wound drainage, “Contact Precautions” are recommended. Contact Precautions require more frequent use of gloves and gowns by health care workers entering the rooms of affected patients (Table 5).

               HICPAC of the Centers for Disease Control (CDC) has recommended that patients with multidrug resistant organisms, including MRSA, be placed in Contact Precautions (Table 5). Whenever possible, patients should be placed in a private room or cohorted. Careful hand washing by personnel between patients is considered the single most important infection control measure. Unfortunately, compliance with hand washing is frequently poor. As a result, use of gloves by all personnel entering the room of patients with MRSA, and removal of gloves before leaving the room, has been recommended to reduce the likelihood that personnel will contaminate their hands following contact with the patient or contaminated objects in the patient’s room. Hands should be washed with an antimicrobial soap or waterless antiseptic agent even if gloves are worn, as S. aureus may sometimes penetrate the gloves, and personnel may contaminate their hands when removing gloves or gowns. The wearing of gowns when contact with the patient or objects in the patient’s room should reduce the risk of contaminating personnel clothing. The use of masks by health care personnel during aerosol-generating procedures seems reasonable, although unproven. Equipment such as sphygmomanometer cuffs and stethoscopes has been shown to become contaminated thus dedicating such equipment to the infected/colonized patient may be beneficial. In addition, disinfection of such equipment with 70% isopropyl alcohol decreases bacterial counts significantly.

Surgery

               General measures have been recommended for prevention of surgical infections. Bathing patients preoperatively with an antimicrobial soap has been suggested as a preventive strategy. Preoperative removal of hair from the operative site by clipping rather than by shaving, reduces the overall incidence of surgical site infections and should minimize the risk of S. aureus infection. Perioperative antimicrobial prophylaxis has been widely adopted as a means of preventing surgical site infections. Culturing patients preoperatively to detect nasal carriage of S. aureus and eradicating carriage before cardiothoracic surgery has been shown to reduce the incidence of postoperative wound infections (306).

               Eradication of nasal carriage of S. aureus by using intermittent or continuous therapy with topical intranasal mupirocin has also been shown to reduce the incidence of invasive S. aureus infections in patients undergoing chronic hemodialysis or chronic ambulatory peritoneal dialysis (309,390).

Nosocomial Pneumonia

               General recommendations, including contact precautions, for prevention of nosocomial pneumonia should be applied. In 1996, CDC redefined contact precautions and eliminated the need for a mask. However, some studies have indicated that a mask may be somewhat beneficial in preventing MRSA nasal colonization of health care workers (HCWs) and, in turn, prevents spread to patients. The CDC recommends mask use when caring with a patient with VISA or VRSA (Table 5). Thus a mask would be prudent for care of any patient with Staphylococcal pneumonia (278).

Newborn Nurseries

               Application of triple dye, hexachlorophene powder, or iodophor ointment to the umbilical stump of newborns has been used to prevent colonization and subsequent infection of infants with S. aureus. Full-term infants may be bathed after birth and daily with 3 percent hexachlorophene; the hexachlorophene should be thoroughly rinsed off after bathing the infant. Hexachlorophene bathing is recommended only for full-term infants. Other recommended measures during nursery outbreaks include cohorting of infants and staff, and re-emphasis on the need for careful handwashing by personnel. Culturing the umbilicus and anterior nares of infants, and the nares and any skin lesions of personnel for S. aureus can help establish the extent of the outbreak. Personnel may be treated with mupirocin ointment if they are possible sources of infection.

               In hospitals with endemic MRSA infections, the infection control practitioner should maintain a list of MRSA patients. Expressing the incidence of nosocomially acquired MRSA as an incidence density ratio, such as the number of new nosocomial cases per 100 admissions, or the number of new nocosomial cases/1,000 patient-days, can be used to monitor the efficacy of infection control measures. Alternatively, the prevalence of MRSA can be expressed as the percent of all S. aureus isolates that are resistant to oxacillin or methicillin.

Review Article: Kellie SM. Methicillin-resistant Staphylococcus aureus (MRSA) in pregnancy: epidemiology, clinical syndromes, management, prevention, and infection control in the peripartum and post-partum periods. 2007.

Community-Acquired MRSA in Athletes

               MRSA has now been found with increasing regularity in the community wherever large groups of individuals are in close proximity with each other such as sports teams, prisons, and the military. This problem has developed in athletes at all levels of play- high school, collegiate, and professional. The MRSA infections are primarily related to skin trauma. The community-acquired MRSA clone found in athletes is present in many regions of the country and differs from hospital-acquired MRSA. Factors that led to the development of MRSA infection in athletes include: 1) increase use of antibiotics, 2) skin injury, 3) close player contact, 4) close person-to-person proximity, 5) contaminated environment and 6) poor personal hygiene (Kazakova NEJM 05). Guidelines have been developed by CDC and the NCAA (Table 7).

Menace in the Locker Room, Sports Illustrated, February 28, 2005.

CDC. MRSA infecting the St. Louis Rams football team. N Eng J Med. February 3, 2005.

[Kathryn Hillier: Babies and Bacteria: Phage Typing, Bacteriologists, and the Birth of Infection Control]

Clinical Microbiology Tasks

               The clinical microbiology laboratory must employ antimicrobial susceptibility testing methods that accurately detect MRSA in clinical specimens. Infection control personnel should be notified as soon as MRSA isolates recovered from patients not known previously to have MRSA. The laboratory should also have the capabilities to save MRSA isolates for phenotypic and genotypic typing studies. Analysing the antimicrobial susceptibility pattern of isolates from cases can sometimes be helpful in determining whether MRSA cases are caused an outbreak strain or by multiple unrelated strains.

               Laboratories face greater challenges in detecting vancomycin-intermediate S. aureus. There is no reliable routine method available. Rather laboratories should ensure short term storage of MRSA, such that a case of failing vancomycin therapy can be examined by the more complex methods designed to detect and characterize VISA. VRSA with the vanA genotype are sufficiently rare that no recommendation for their detection have emerged.

               Routine use of the D-test to detect inducible clindamycin resistance in erythromycin-resistant stains of S. aureus, especially caMRSA, is now recommended (234).

Nasal Decolonization with Mupirocin

               Point prevalence culture surveys of patients or personnel on affected wards have proven useful in identifying patients with MRSA colonization who have not been detected by routine clinical cultures. Roommates of patients found to harbor MRSA should be screened. If unusual clustering of cases occurs on a ward, other patients on the affected ward should be screened for MRSA carriage. Culturing the anterior nares, and any wound if present, will detect most patients who are colonized with MRSA. Culturing high-risk patients upon admission may identify individuals who are colonized and require isolation, but the clinical circumstances under which such screening is cost effective have not been established.

               During outbreaks, or in facilities where the endemic level of MRSA is high, administration of decolonization therapy to patients with nasal carriage of MRSA, when used in conjunction with other control measures, has been shown to contribute to the control of the organism. Intranasal administration of mupirocin ointment three times a day for 5 days is currently the most effective regimen for eradication of S. aureus nasal carriage.

               In centers where MRSA is endemic, selected personnel on affected wards or services can be monitored with anterior nares cultures. Nasal carriers can be treated with topical intranasal mupirocin. Eradicating nasal carriage will usually cause the organism to disappear from the hands of personnel who are nasal carriers.

Robicsek A, et al. Universal Surveillance for Methicillin-Resistant Staphylococcus aureus in 3 Affiliated Hospitals. Ann Intern Med 2008;48:409-418

Deresinski S. Active surveillance for detection of MRSA colonization. Clin Infect Dis 2008;47:v-vi.

               The hospital records of MRSA patients can be flagged as “MRSA” to facilitate recognition of colonized patients at the time of readmission, so that they can be placed in isolation until repeat cultures establish whether the individual is still colonized. Some hospitals require two or three consecutive negative cultures (often performed at weekly intervals) from the anterior nares and any other body site known to have been colonized before discontinuing isolation procedures. Careful cleaning of patient rooms (especially horizontal surfaces) frequently touched by health care workers or housekeeping personnel is warranted to minimize contamination of environmental surfaces.

Patient Handout:  Methicillin-resistant Staphylococcus aureus (MRSA)

TABLES

Table 1: Comparison of Healthcare Associated and Community Associated MRSA

Table 2. In vitro Activity of Antimicrobial Agents Against Staphylococcus aureus

Table 3. Suggested Antibiotics, Doses and Duration for Treatment of Staphylococcus aureus Infections   [Download PDF]

Table 4. Most Commonly Recommended Treatment Regimens for Staphylococcus aureus Endocarditis [Download PDF]

Table 5. Isolation Precautions Recommended for Hospitalized Patients [Download PDF]

Table 6.  Recommendations to Prevent The Spread of Vancomycin-Resistant Staphylococcus aureus [Download PDF]

Table 7.  Recommendations to prevent MRSA in Athletes [Download PDF]

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