Update on the Treatment and Prevention of MRSA Infections

Release Date: August 1, 2012

Expiration Date: August 31, 2014

FACULTY:

Elias B. Chahine, PharmD, BCPS (AQ-ID)
Assistant Professor of Pharmacy Practice
Palm Beach Atlantic University
Lloyd L. Gregory School of Pharmacy
West Palm Beach, Florida

Ashley N. Johnson, PharmD
PGY1 Pharmacy Practice Resident
Palm Beach Atlantic University
Lloyd L. Gregory School of Pharmacy
West Palm Beach, Florida

M. Steven Mayberry, PharmD
PGY1 Pharmacy Practice Resident
Palm Beach Atlantic University
Lloyd L. Gregory School of Pharmacy
West Palm Beach, Florida

FACULTY DISCLOSURE STATEMENTS:

Dr. Chahine serves on the Speakers' Bureau for Forest Pharmaceuticals, Inc., and Optimer Pharmaceuticals, Inc. Drs. Johnson and Mayberry have no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy acpe
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-12-018-H02-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists with the knowledge necessary to appropriately manage adult patients with methicillin-resistant Staphylococcus aureus (MRSA) infections.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Describe changes in the epidemiology of MRSA infections in the community and
    health care settings.
  2. Characterize the differences between community-acquired and health care–
    associated MRSA infections.
  3. Compare and contrast the newer anti-MRSA agents based on efficacy and safety profiles.
  4. Given an individual patient with MRSA infection or colonization, recommend the
    most appropriate regimen to manage this patient.

What was once a four-letter acronym known only by scientists and health care providers, MRSA, or methicillin-resistant Staphylococcus aureus, has become a widely recognized term by laypeople. MRSA is a virulent drug-resistant organism and has become a major threat to public health. In 2002, the proportion of S aureus isolates from intensive care units in the United States that were resistant to antistaphylococcal penicillins was more than 55%.1 Fortunately, the rates of invasive MRSA infections are now declining. In a surveillance study conducted from 1997 to 2007, there was a 50% decline in the incidence of MRSA central line-associated bloodstream infections in most ICUs.2 In an another surveillance study conducted from 2005 to 2008, there was a 28% decline in the incidence of hospital-onset invasive MRSA infections and a 17% decline in the incidence of community-onset health care-associated MRSA (HA-MRSA) infections.3 Conversely, the rates of noninvasive community-associated (CA-MRSA) infections have rapidly increased in the past decade and are not following the same trend as invasive MRSA infections.4 While the rates of invasive MRSA infections are declining, this organism is still endemic not only in medical centers, but also in the community and in long-term care facilities.4

Therefore, pharmacists across all practice settings are challenged every day to help protect patients from this potentially fatal organism. The Infectious Diseases Society of America (IDSA) released evidence-based guidelines for the treatment of MRSA infections in January 2011 to assist health care professionals in managing patients with MRSA infections.5

This review is intended to educate pharmacists about the proper management of MRSA infections in adult patients according to these guidelines.

Microbiology

Staphylococci are gram-positive aerobic cocci that belong to the family Micrococcaceae, which form grapelike clusters upon Gram's staining.6 When cultured on blood agar plates, S aureus isolates form golden beta-hemolytic colonies, whereas coagulase-negative staphylococci form small, white, nonhemolytic colonies.6 Unlike MSSA (methicillin-sensitive S aureus), MRSA produces specific penicillin-binding proteins (PBPs) known as PBP2a.7 These unique PBPs have reduced affinity for beta-lactams, resulting in resistance to all available beta-lactams except ceftaroline, a new, fifth-generation cephalosporin.8 PBP2a is encoded by a specific gene known as staphylococcal cassette chromosome mec (SCCmec) that is integrated on the chromosomes of MRSA strains.9 While CA-MRSA and HA-MRSA classifications are no longer clearly distinct, it is important to note the following differences. CA-MRSA is commonly associated with SCCmec VI and V genes, whereas HA-MRSA is commonly associated with SCCmec I, II, and III genes.6,9,10 CA-MRSA is also commonly associated with genotypes USA300 and USA400, whereas HA-MRSA is commonly associated with USA100 and USA200.11 CA-MRSA strains tend to be more transmissible and to produce more virulent exotoxins such as the Panton-Valentine leukocidin toxins associated with severe skin abscesses and necrotizing pneumonia.11-13 Finally, it is important to note that CA-MRSA strains tend to be more sensitive to trimethoprim-sulfamethoxazole, clindamycin, and tetracyclines than HA-MRSA strains.10

Risk Factors

Risk factors for acquiring MRSA differ depending on whether a person resides in a health care setting or in a community setting. Risk factors for MRSA infections have traditionally included recent hospitalization, surgery, residing in a long-term care facility, dialysis, and indwelling percutaneous medical devices and catheters.14-16 However, cases of MRSA infections are being reported more frequently in otherwise healthy individuals with no exposure to the health care system.4

These cases demonstrate the need to extend the classic list of risk factors, taking into account the sites of infection as highlighted in TABLE 1. According to the CDC, CA-MRSA is commonly isolated from patients with skin and skin structure infections (SSSIs), and anyone is at risk.16 These infections tend be elusive and spread where close skin-to-skin contact is likely, such as in crowded living situations and when personal items such as towels, razors, and sporting equipment are shared.19 These conditions are often more prevalent in younger individuals, which may explain why SSSIs due to CA-MRSA are more commonly seen in younger patients.15 In addition, poor personal hygiene and limited access to health care are also risk factors for CA-MRSA.19,20 HA-MRSA is commonly isolated from hospitalized patients with traditional risk factors for MRSA, and unlike CA-MRSA, HA-MRSA is more commonly encountered in the elderly.15,17-19 However, the distinction between CA-MRSA and HA-MRSA is becoming more and more difficult as outbreaks of CA-MRSA infections have been identified in hospital settings and cases of HA-MRSA have been isolated in community settings.21


Clinical Presentation and Diagnostic Considerations

S aureus is a pyogenic pathogen with the capacity to form abscesses. It typically elicits a strong initial host response with infiltration of polymorphonuclear leukocytes followed by macrophages and fibroblasts.6 This immune response contributes to the nonspecific symptoms patients may present with, such as fatigue, chills, fever, malaise, headache, and muscle aches.19 Signs and symptoms of MRSA infections depend on the site of infection. SSSIs caused by MRSA often appear as a pustule or boil resembling a spider bite. They are often erythematous, swollen, and painful and may have purulent drainage from the affected site.22 A skin culture is not always necessary when assessing SSSIs but may be helpful in diagnosing recurrent or persistent cases of skin infections, in cases of antibiotic failure, and in cases of invasive infections.23 Other MRSA infections are classified as invasive and usually present with more severe symptoms and are potentially life-threatening. A specimen culture is often necessary in these cases to direct antimicrobial therapy.23 Although all cultures should be obtained using aseptic techniques, clinicians should be aware that common contaminants may be present in samples, and traditional microbiology culture and sensitivity methods may take up to 4 days to provide final results. Currently, many rapid diagnostic technologies are available to assist clinicians in quickly identifing whether MRSA organisms are present.24 Using these tests may result in more effective management and faster isolation of patients when needed; however, the tests are expensive and their use is still limited.24

Treatment

TABLE 2 summarizes the recommendations for the treatment of noninvasive MRSA infections based on guidelines released by the IDSA.5 For minor superficial skin infections, topical mupirocin may be effective.5 For cutaneous abscesses, incision and drainage alone may be sufficient except in the following cases: severe infections, extensive disease, systemic illness, presence of comorbidities, immunosuppressive conditions, extremes of age, area difficult to drain, septic phlebitis, and lack of response to nonpharmacotherapy.5 For nonpurulent cellulitis, the causative organism is likely group A streptococcus or Streptococcus pyogenes, and anti-MRSA therapy may not be necessary.5 For purulent cellulitis, the causative organism is likely S aureus, and anti-MRSA therapy is necessary pending culture and sensitivity.5 For more severe complicated SSSIs, empiric antibiotic therapy should be directed towards MRSA pending culture and sensitivity.5 For recurrent SSSIs, education on personal hygiene, environmental hygiene, and wound care is recommended.5 Decolonization with topical agents may be considered in patients who develop recurrent SSSIs despite optimizing nonpharmacotherapy and if transmission is occurring among close contacts.5 TABLE 3 summarizes the recommendations for the treatment of invasive MRSA infections based on the IDSA guidelines. Vancomycin has been the gold standard for the treatment of MRSA infections for decades and is generally considered the first-line option for the treatment of bacteremia, endocarditis, osteomyelitis, septic arthritis, and meningitis due to MRSA.5 However, reports of clinical failures associated with vancomycin particularly when used for the treatment of staphylococcal bacteremia, endocarditis, and pneumonia are emerging, and clinicians are questioning the supremacy of vancomycin in the management of MRSA infections.26,27 These failures could be explained by the slow bactericidal activity of vancomycin, its poor tissue penetration, and an increase in minimum inhibitory concentration (MIC) for MRSA, known as MIC creep.26 The Clinical and Laboratory Standards Institute susceptibility breakpoint for vancomycin is currently set at 2 mg/L.28 High MIC values are associated with treatment failure, and the vancomycin consensus review recommends alternative therapies to vancomycin when dealing with MIC values above 2 mg/L.28 However, there is currently some debate as to whether this breakpoint should be lowered, as MIC levels greater than or equal to 1.5 mg/L are also associated with treatment failure.29 In determining the most appropriate treatment options for patients presenting with MRSA infections, clinicians should consider not only the available evidence behind the anti-MRSA agents, but also the MIC value of the isolated strain of MRSA, the site and severity of infection, and patient-specific factors such as age, comorbidities, renal impairment, and allergies. Daptomycin is generally considered an alternative option for the treatment of bacteremia and endocarditis due to its bactericidal activity, but cannot be used for the treatment of pneumonia because it binds to pulmonary surfactant.5



Linezolid is generally considered an alternative option for the treatment of pneumonia and meningitis, and some recent data suggest superiority over vancomycin in nosocomial pneumonia, possibly because of an enhanced tissue penetration.5,30 Both daptomycin and linezolid are considered alternative options for the treatment of osteomyelitis and septic arthritis.5 TABLE 4 highlights selected adverse reactions and drug interactions associated with the following anti-MRSA antibiotics, listed in alphabetical order:


Ceftaroline is a fifth-generation cephalosporin antibiotic that inhibits bacterial cell wall synthesis by binding to PBPs.25 It is the only available beta-lactam with activity against MRSA.31 Ceftaroline was shown to be noninferior to vancomycin plus aztreonam in the treatment of complicated SSSIs, including those in patients with MRSA infections, and was approved by the FDA for the treatment of acute bacterial SSSIs.25,32,33 Ceftaroline was also shown to be noninferior to ceftriaxone in the treatment of community-acquired pneumonia and was approved by the FDA for the treatment of community-acquired bacterial pneumonia.29,34,35 Ceftaroline is not currently approved by the FDA for the treatment of pneumonia due to MRSA because there were an insufficient number of MRSA isolates in the pneumonia studies.25,32,33 Patients allergic to penicillin may react to ceftaroline, and the dose of ceftaroline should be reduced in patients with renal impairment.25

Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosomes.25 It is commonly used in the treatment of SSSIs and has the advantage of covering both CA-MRSA and S pyogenes.5 It can also be used as an adjunctive therapy in the treatment of necrotizing infections and severe sepsis because of its ability to block toxin production.5 It carries a boxed warning as it is associated with severe and possibly fatal colitis including Clostridium difficile infection.25 Inducible macrolide-lincosamide-streptogramin resistance by erythromycin limits its broad use for the empiric treatment of MRSA infections, and the disk diffusion (D) test should be performed when the isolate is sensitive to clindamycin and resistant to erythromycin. If the D test is positive, clindamycin should not be used for the treatment of serious infections, and patients receiving clindamycin therapy should be reassessed for response.5,31 There is no need to adjust the dose of clindamycin in patients with renal impairment and in patients with mild-to-moderate hepatic impairment.25

Daptomycin is a cyclic lipopeptide antibiotic that inhibits intracellular synthesis of DNA, RNA, and proteins by binding to the bacterial cell membrane, causing rapid depolarization.25 It exhibits a concentration-dependent bactericidal activity against MRSA.25 Daptomycin is approved by the FDA for the treatment of complicated SSSIs and for the treatment of bacteremia and right-sided native valve endocarditis, including that in patients with MRSA infections.25 Daptomycin is also commonly used in the treatment of osteomyelitis and septic arthritis.25 As previously mentioned, daptomycin should not be used for the treatment of pneumonia because it binds to pulmonary surfactant.5

Reports of daptomycin-nonsusceptible MRSA are emerging; therefore, it is important to check daptomycin susceptibility, defined as a MIC value of 1 mcg/mL or less, and use higher doses between 8 and 10 mg/kg/day or alternative agents to overcome resistance.5,36 Patients with creatinine clearance less than 30 mL/min should be dosed every other day instead of every day.25 Daptomycin is associated with myalgia, particularly at high doses.5,25 Thus, monitoring creatine phosphokinase elevations is recommended weekly with more frequent monitoring when combined with statins and in the setting of renal impairment.5,25

Doxycycline and minocycline are two tetracycline antibiotics that inhibit bacterial protein synthesis by binding to the 30S and possibly 50S subunits of the ribosomes.25 They are commonly used in the treatment of SSSIs because of their ability to cover CA-MRSA; however, they do not have a reliable coverage for S pyogenes.5 Tetracyclines may cause fetal harm when given to pregnant women.25 They have excellent oral bioavailability.29 There is no need to adjust the dose of doxycycline in patients with renal impairment.25

Linezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit.25 It exhibits bacteriostatic activity against MRSA.25 Linezolid is approved by the FDA for the treatment of SSSIs and for the treatment of pneumonia including in patients with MRSA infections.25 As mentioned previously, there is some evidence that suggests superiority of linezolid over vancomycin in the treatment of nosocomial pneumonia.30 Since linezolid is a weak monoamine oxidase inhibitor, it is associated with serious central nervous system reactions. These include serotonin syndrome when combined with other sero-tonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reup-take inhibitors (SNRIs).25 Linezolid is also associated with myelosuppression, particularly when used for longer than 2 weeks and in the setting of renal impairment.37 It has excellent oral bioavailability.25 There is no need to adjust the dose of linezolid in patients with renal impairment and in patients with mild-to-moderate hepatic impairment.25

Quinupristin-dalfopristin is a streptogramin antibiotic that inhibits bacterial protein synthesis by binding to different sites on the 50S ribosomal subunit.25

Although it is approved by the FDA for the treatment of complicated SSSIs, it is seldom used in practice because of its side-effect profile and the availability of better alternatives.5,25 Quinupristin-dalfopristin is associated with a high incidence of infusion-site reactions, arthralgia, myalgia, and hyperbilirubinemia.25

Rifampin is a rifamycin antibiotic that inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase and blocking RNA transcription.25 Since resistance develops quickly during therapy, rifampin is never used as monotherapy for the treatment of staphylococcal infections. Nonetheless, it plays a role as an adjunct in the treatment of MRSA infections, particularly in patients with prosthetic infections because of its ability to penetrate into cells and biofilms.38 Rifampin is a very potent inducer of cytochrome-mediated metabolism and thus interacts with numerous drugs.25 Rifampin has excellent oral bioavailability.25 While there is no need to adjust the dose of rifampin for patients with renal impairment, dose reductions are necessary in patients with hepatic impairment.25

Telavancin is a lipoglycopeptide antibiotic that inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine portion of the bacterial cell wall, blocking polymerization and cross-linking of peptidoglycan.25 It exhibits concentration-dependent bactericidal activity against MRSA.25

Telavancin was shown to be noninferior to vancomycin and antistaphylococcal penicillins in the treatment of SSSIs, including those in patients with MRSA infections, and was approved by the FDA for this indication.25,39,40 Telavancin was also shown to be noninferior to vancomycin in the treatment of hospital-acquired pneumonia due to gram-positive pathogens, but is not approved yet by the FDA for this indication.25,41 It should be administered with a medication guide, and it carries a boxed warning as it may increase the risk of adverse developmental outcomes when given to pregnant women.25 While there is no need to adjust the dose of telavancin in patients with mild-to-moderate hepatic impairment, the dose of telavancin should be adjusted in patients with renal impairment.25 Telavancin is temporarily not commercially available in the U.S.25

Tigecycline is a glycylcycline antibiotic that inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit.25 It is approved by the FDA for the treatment of complicated SSSIs, including those in patients with MRSA infections.25 It is also approved by the FDA for the treatment of community-acquired bacterial pneumonia and complicated intra-abdominal infections.25 Tigecycline demonstrated lower cure rates in the treatment of ventilator-associated pneumonia and should not generally be used for the treatment of hospital-acquired pneumonia.25 It is bacteriostatic against MRSA and does not achieve a sufficient concentration in the blood, which may explain the increase in all-cause mortality observed in clinical trials.25 Tigecycline is associated with a high incidence of nausea and vomiting.25 It may cause fetal harm when given to pregnant women.25 There is no need to adjust the dose of tigecycline in patients with mild-to-moderate hepatic impairment and in patients with renal impairment.25 Patients with severe hepatic impairment should receive 100 mg followed by 25 mg every 12 hours.25

Trimethoprim-sulfamethoxazole is a sulfonamide antibiotic that interferes with bacterial folic acid synthesis by inhibiting dihydrofolic acid formation from para-aminobenzoic acid and by inhibiting dihydrofolic acid reduction to tetrahydrofolate.25 Trimethoprim-sulfa-methoxazole is commonly used in the treatment of SSSIs because of its ability to cover CA-MRSA; however, it does not have a reliable coverage for S pyogenes.5 Patients allergic to sulfa drugs should not receive this antibiotic.25

Trimethoprim-sulfamethoxazole has excellent oral bio-availability.25 Patients with renal impairment as defined by a creatinine clearance between 15 and 30 mL/min should receive 50% of the recommended dose, and the use of this antibiotic in patients with creatinine clearance less than 15 mL/min is not recommended.25

Vancomycin is a glycopeptide antibiotic that inhibits bacterial cell wall synthesis by binding to the D-ala-nyl-D-alanine portion of cell wall precursor, blocking glycopeptide polymerization.25 It is slowly bactericidal against MRSA and is generally considered the gold standard for the treatment of MRSA infections.5,25 Vancomycin should be dosed based on total body weight, and the desired vancomycin trough should be 10 to 15 mg/L for mild-to-moderate infections and 15 to 20 mg/L for serious infections such as pneumonia, bacteremia, endocarditis, osteomyelitis, and meningitis.28 The dose of vancomycin should be adjusted in patients with renal impairment.25

Prevention

Infection control is key to limiting the spread of MRSA.42 The CDC offers specific guidance for preventing MRSA in the community and in health care centers.42 Initiatives to prevent the spread of CA-MRSA focus on implementing personal prevention strategies such as covering all possible infected wounds with clean bandages; washing hands with soap and water or alcohol-based hand sanitizers before and after coming in contact with nonintact skin; and avoiding the sharing of personal items including bar soap, clothing, uniforms, towels, and razors.43 Prevention strategies targeted against HA-MRSA consist of adhering to standard precautions, including monitored hand-hygiene practices, environmental cleaning and disinfection procedures, identification of patients colonized with MRSA, and management of MRSA-infected or -colonized patients.44,45

In general, personal and environmental hygiene measures are adequate in preventing cross-contamination of MRSA. However, there may be circumstances that warrant decolonization, such as recurrent SSSIs in patients despite hygienic practices or if there is ongoing transmission among close contacts.5 Recommended decolonization methods include nasal decolonization with mupirocin twice daily for 5 to 10 days with or without body decolonization with chlorhexidine for 5 to 14 days or dilute bleach baths twice weekly for 3 months.5 Oral antimicrobial therapy is not recommended for decolonization unless recurrent infections occur despite optimizing other decolonization measures.5

Another method to control the spread of MRSA is antimicrobial stewardship. Pharmacists play an important role in developing institutional antimicrobial stewardship programs to optimize patients' outcomes while halting antimicrobial resistance, decreasing adverse events, and controlling cost.46 For example, limiting the use of fluoroquinolones may decrease the risk of MRSA colonization, and a switch from third-generation to first-generation cephalosporins in surgical prophylaxis may reduce the incidence of MRSA infections.47,48

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