Chapter 6: Methicillin-Resistant Staphylococcus Aureus: Prevention and Treatment 2 Contact Hours

By: Jodi Dreiling, PharmD, BCPS Author Disclosure: Jodi Dreiling and Elite do not have any actual or Questions regarding statements of credit and other customer service potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $8.00. Universal Activity Number (UAN): 0761-9999-17-258-H01-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: August 21, 2017 a provider of continuing pharmaceutical education. This Expiration Date: August 21, 2019 program is approved for 2 hours (0.2 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70% is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a statement of credit. Please submit your answers online at participants who have successfully completed the post-test. Participants Pharmacy.EliteCME.com. must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives ŠŠ Summarize the mechanism of resistance of Staphylococcus aureus. ŠŠ Develop a treatment plan for infections caused by methicillin- ŠŠ Differentiate between community-acquired and health care-acquired resistant Staphylococcus aureus. methicillin- resistant Staphylococcus aureus. ŠŠ Demonstrate knowledge of medications used to treat methicillin- ŠŠ Identify prevention measures that can help prevent methicillin- resistant Staphylococcus aureus. resistant Staphylococcus aureus infections. ŠŠ Review the role of antimicrobial stewardship in the prevention and treatment of methicillin-resistant Staphylococcus aureus infections. Introduction Staphylococcus aureus (S. aureus) is a gram positive coccus that occurs S. aureus is still a major patient threat with approximately 40% of in grapelike clusters. It is a common pathogen involved in community strains being resistant to methicillin(Wiener et al., 2016). However, the and health care acquired infections. It is found in normal skin and Centers for Disease Control (CDC) published a study which reveals that mucosal flora in humans. S. aureus can cause infections ranging from life-threatening methicillin-resistant Staphylococcus aureus (MRSA) skin infections (i.e. folliculitis, impetigo, carbuncles, and cellulitis) to infection rates in the healthcare settings are declining. The study showed severe infections, such as pneumonia, osteomyelitis, endocarditis, and that between 2005 and 2011, invasive MRSA infections that started in the bacteremia. It is a virulent pathogen associated with significant morbidity hospital decreased by 54% with 30,800 fewer severe infections (Dantes and mortality. In 2011, there were over 80,000 invasive MRSA infections et al., 2011). Additionally, other studies have shown a decrease in overall and 11,285 related deaths per year (Dantes et al., 2011). central line bloodstream infections (Burton et al., 2009, CDC, 2011). Staphylococcus aureus resistance The introduction of penicillin in the 1940s improved the prognosis of beta-lactam affinity allows for ongoing cell wall synthesis despite the patients with S. aureus infections. However, two years later, strains of presence of a beta-lactam antibiotic. The term methicillin resistance penicillin resistant staphylococci were noted. The gene, B-lactamase, implies resistance to all beta-lactams including amoxicillin, ampicillin, hydrolyzes the beta-lactam ring rendering it inactive towards the cephalosporins, carbapenems, and monobactam antibiotics (Que & organism (Que & Morellion, 2015). Morellion, 2015; Stryjewski & Corey, 2014). Methicillin was the first semisynthetic penicillinase-resistant penicillin. The mecA gene is contained in the staphylococcal cassette cartridge Shortly after it was introduced, Methicillin-resistant Staphylococcus (SCC), which is a mobile chromosomal element that aids in the aureus (MRSA) was first described. Methicillin resistance is mediated successful chromosomal incorporation. Five SCC types (I-V) have by the mecA gene, which encodes for the novel penicillin- binding been isolated, which allows microbiologists to track resistance patterns protein (PBP), PBP-2a. This altered binding protein site with low (Stryjewski & Corey, 2014). Healthcare-acquired vs. community-acquired MRSA MRSA can be separated into two major categories: community-acquired MRSA isolates. CA-MRSA is more likely to be resistance to only beta- (CA-MRSA) and hospital-acquired (HA-MRSA). According CDC, lactams, but good susceptibility to trimethoprim-sulfamethoxazole and patients need to fulfill several criteria before they can be considered clindamycin. However, HA-MRSA is more multi-drug resistant, and not CA-MRSA (See Table 1) (Maree et al., 2007). Community-acquired susceptible to clindamycin (Maree et al., 2007; Pottinger, 2013). (CA) MRSA strains are genotypically distinct from healthcare-acquired Table 1: Diagnostic criteria of CA-MRSA. (HA) MRSA. Specifically, the molecular and antimicrobial resistance profiles differ between the two types of MRSA. CA-MRSA typically ●● Diagnosed as an outpatient. occurs in children and younger adults, compared to HA-MRSA, ●● Culture positive for MRSA within 48 hours after hospitalization. which usually occurs in the elderly, as they are more likely to live in a healthcare facility. When reviewing resistance patterns, CA-MRSA ●● No medical devices or indwelling catheters. has the SCCmec type IV, while HA-MRSA has SCCmec types I,II, III. ●● Medical history negative for MRSA. The current strains of CA-MRSA are also characterized by the presence ●● No history of recent stay (within 1 year) in long-term care of PVL (Panton-Valentine leukocidin) gene, which is thought to be a facility, hospital, nursing home. virulence factor for serious infections, and rarely identified in HA-

Page 67 Pharmacy.EliteCME.com Risk factors for MRSA Identification of risk factors for MRSA can help identify patients lead to an increased risk of community-acquired MRSA infection: who need targeted antibiotic treatment. The risk factors for acquiring community-acquired crowded living conditions, close skin-to-skin health care-associated MRSA include old age, multiple comorbidities, contact, compromised skin, contaminated items and surfaces, and lack the use of antibiotics within past 3 months, prolonged hospital stay of cleanliness. Common locations where the “5 C’s” may occur include duration, admission to long-term facility or hospital in past year, having schools, college dorms, daycare centers, correctional facilities, military undergone an invasive medical procedure, and/or having indwelling barracks, and gyms (Salgado et al., 2003). devices. The CDC identified five common factors, the “5Cs” that MRSA CONTROL INTERVENTIONS Hand hygiene MRSA is most commonly transmitted between patients via the water or alcohol-based hand gels. Providers and patients should be contaminated hands of health care workers. Hand hygiene should be the educated about the importance of hand hygiene. In addition, hand cornerstone for the prevention of MRSA, and other multi-drug resistant hygiene practices should be observed and feedback should be provided organisms. Health care workers should have easy access to soap and (Marimuthu et al., 2014). Contact precautions and isolation Contact precautions and isolation involve the use of gown and gloves be placed in single rooms or cohorted depending on room availability. for patient care. It also includes single use items such as blood pressure There is a lack of consensus on the appropriateness of isolating all cuffs, thermometers, and stethoscopes. Placing patients who are patients with MRSA infection or colonization and when to discontinue colonized or infected with MRSA may delay the colonization of other isolation (Calfee et al., 2014). patients, thus decreasing infection rates. If possible, patients should MRSA screening Surveillance screening of asymptomatic patients to identify MRSA of high risk patients. Once a positive screen has been identified, other carriage may help decrease transmission and active infection. The prevention methods must be implemented to decrease transmission precise role of screening has yet to be identified. Institutions vary (Fatkenheuer et al., 2015). widely in screening from screening all patients to targeted screening MRSA decolonization The goal of decolonization is to suppress or eradicate MRSA carriage in appropriate administration. Patients can also be given chlorhexidine order to decrease transmission between patients and decrease infection body washes (Ammerlaan et al., 2009). Although there is benefit for risk in the colonized patient. Decolonization is most commonly decolonization, resistance with mupirocin has been noted (Patel et al., performed with mupirocin intranasal ointment. Mupirocin is used 2009). Also, the utility of this prevention method is questioned because intranasally twice daily for 5 days. Mupirocin should be applied into of significant rates of patient recolonization. The evidence supports the nostril, pressed the side of the nose together and gently massaged to decolonization of patients undergoing clean surgical procedures (i.e. spread the ointment through the insides of the nostrils for approximately orthopedic or cardiothoracic surgery) (Bode et al., 2010). one minute. Pharmacists can counsel patients and educate nurses on the Environmental cleaning MRSA is often found in the environment close to the colonized patients. transmission after the colonized patient is discharged. While there is In a hospital setting, there are many surfaces that can be contaminated not strong data to support enhanced cleaning of MRSA rooms, good such as beds, keyboards, blood pressure cuffs, and medical devices. environmental cleaning can be a strong component of preventing MRSA can survive on surfaces for months and acts as a reservoir for transmission of other organisms (i.e. C. diff) (Han et al., 2015). Diagnosis MRSA can be diagnosed by various tests, such as in vitro culture on MRSA within 2 to 6 hours, compared to standard results, which take plates, cultures on special liquid broths, and polymerase chain reaction 24-48 hours to obtain. Once a diagnosis of MRSA is obtained, it allows (PCR) testing. The key to the rapid treatment of MRSA is the rapid the clinician to appropriately treat the patient by either expanding or diagnosis. Molecular diagnostic criteria can reduce the turnaround time narrowing antibiotic therapy (van Hal et al., 2007). to produce a rapid culture result. PCR testing allows the detection of Treatment Bacteremia Treatment of bacteremia with other antibiotics is uncertain, and further MRSA bacteremia and infective endocarditis warrant the most data is required. When selecting alternative agents, multiple factors immediate initiation of antibiotics. Vancomycin remains first-line must be considered (i.e. susceptibility testing, comorbidities, concurrent therapy for these invasive infections. Patients with MRSA due an medications). Additionally, treatment requires prompt source control, isolate with vancomycin MIC > 2 mcg/mL may not responds as well such as removal of vascular catheters or drainage of purulent collection to vancomycin; thus, daptomycin is a valid alternative for patients. (Habib et al., 2015). Skin infections MRSA is the most common cultured organism in the setting of skin tedizolid; however, use of these drugs is limited by cost and toxicity. infections. The majority of CA-MRSA infections are skin and soft tissue Their use should be limited to patients who do not respond to other infections. For any soft tissue infection, including those from MRSA, therapy or cannot tolerate other agents. the recommended primary management is incision and drainage of Patients should be hospitalized for intravenous antibiotics in the abscess formation. For abscess < 5 cm, antibiotics may not be needed, setting of severe or complicated skin infections. Those that would as incision and drainage may be sufficient. Oral antibiotics with empiric require hospitalization include: patients with extensive tissue coverage of MRSA are indicated in the setting of a moderate purulent involvement, signs of systemic toxicity, rapid progression of symptoms, infection with signs of systemic infection. Oral antibiotics of choice persistence or progression of symptoms after 48-72 hours of therapy, include: trimethoprim-sulfamethoxazole, tetracyclines (doxycycline or immunocompromised, or infection located near an indwelling device minocycline), and clindamycin. Alternate agents include linezolid and (i.e. prosthetic joint). Vancomycin is the drug of choice for MRSA skin Pharmacy.EliteCME.com Page 68 infections, unless contraindications exist. Daptomycin is an acceptable telavancin, linezolid, and tedizolid (Stevens et al., 2014; Daum, 2007; alternative agent. Although not first line, several alternative agents The Medical Letter, 2017). exist for treatment, including: ceftaroline, dalbavancin, oritavancin, Pneumonia MRSA is a major bacterial pathogen of hospital-acquired pneumonia Liu et al., 2011). An alternate agent is telavancin, as it was shown to be (HCAP) and ventilator associated pneumonia (VAP), with an incidence non-inferior to vancomycin in the setting of HA-MRSA (Rubinstein of 20 to 40% (Weiner et al, 2016). In the community, the risk of CA- et al., 2011). Daptomycin should be avoided due to its inactivation by MRSA is low (<5%), but has been increasing to become an emerging pulmonary surfactant. While tigecycline is approved for community- problem(Moran et al., 2012) . Clinical risk factors for CA-MRSA include acquired pneumonia (CAP), it has not been approved for CAP from end-stage renal disease, injection drug abuse, prior influenza, and prior MRSA. Also, ceftaroline should be avoided as it was approved for CAP, antibiotic therapy. When MRSA pneumonia is suspected, empiric therapy but not CAP due to MRSA, HCAP, or VAP (Liu et al., 2011). with vancomycin or linezolid should be initiated (Kalil et al., 2016; Antibiotics Vancomycin related adverse event. Red-man syndrome is described as an acute Vancomycin is the cornerstone for the treatment of MRSA infections. erythematous rash affecting the upper trunk and neck during or at It is a glycopeptide with activity against gram-positive organisms. The the end of the infusion. It can be treated with antihistamines, such as primary effect is the inhibition of the late stages of cell wall synthesis in diphenhydramine (Rybak et al., 2009). dividing bacteria (Barna & Williams, 1984). Daptomycin (Cubicin) The pharmacokinetic/pharmacodynamic parameter that best predicts Daptomycin is a cyclic lipopeptide that was approved for use in the vancomycin efficacy is the ratio of area under the curve (AUC) to United States in 2003. While its exact mechanism of action is unknown, minimum inhibitory concentration (MIC) of the infecting organism it is thought that daptomycin binds to the cell wall subsequently (AUC/MIC). A vancomycin AUC/MIC of > 400 has been recommended inhibiting intracellular synthesis of DNA, RNA, and protein. to predict successful outcomes. Trough serum concentrations of 15-20mg/ Daptomycin is bactericidal in a concentration dependent manner. It L are recommended for complicated infectious such as endocarditis, exerts its bactericidal effect on S. aureus without significant cell lysis, bacteremia, osteomyelitis, meningitis, and hospital-acquired pneumonia. which explains why there is decreased release of proinflammatory A trough concentration of that level will achieve the desired AUC/MIC > mediators when compared to vancomycin. The spectrum of 400 in patients with a MIC < 1mg/L. In patients with a MIC > 2 mg/L and antimicrobial activity of daptomycin includes Staphylococci, normal renal function (i.e. CrCl > 70ml/min) an alternate agent may need Pneumococci, E. faecalis and E. faecium, including MRSA, to be used, as desired AUC/MIC > 400 will not be attainable. A trough vancomycin intermediate S. aureus, and VRE isolates. Daptomycin is level of 10-15mg/L is acceptable with patients who have uncomplicated effective for the treatment of skin and soft tissue infections, bacteremia, infections (Rybak et al., 2009; Pea & Viale, 2006). endocarditis, and osteomyelitis. The poor penetration of daptomycin The typical dose of vancomycin for a patient with normal renal in the CNS precludes its use in meningitis. Also, daptomycin should function is 15mg/kg (actual body weight) administered every 8-12 not be used for pulmonary infections, as it is inactivated by surfactant hours. For patients with a serious illness, a loading dose of 25-30mg/ (Steenbergen et al., 2005). kg may be considered to rapidly achieve a target concentration. After Daptomycin is administered intravenous push over a two-minute period a loading dose, subsequent dosing schedules should be individualized or intravenous piggy back over 30 minutes. It must be administered for renal function and trough serum concentration (Rybak et al., 2009; with 0.9% sodium chloride, as it is incompatible with dextrose Wang et al., 2001). Vancomycin is poorly dialyzable by intermittent containing solutions. Standard dosing is 4mg/kg for skin and soft tissue hemodialysis; however, continuous renal replacement therapy increases infections and 6mg/kg for bacteremia. Higher dosing (8-10mg/kg) vancomycin clearance and requires more frequent dosing (Rybak et al., may be required for patients with severe infections (i.e. endocarditis, 2009; Launay-Vacher, 2002). vancomycin failure) (Falcone et al., 2013). Dosing is recommended Vancomycin trough concentrations are the most accurate and practical based on patient’s actual body weight. Daptomycin dosing is adjusted method for monitoring efficacy. Troughs should be obtained just prior in renal impairment. For dialysis patients, experts have recommended to the next dose at steady-state conditions. The trough should be drawn administering the recommended dose on 48-hour intradialytic days and prior to the fourth dose in patients with normal renal function. More increase the dose by 50% on 72-hour intradialytic days. For example, frequent monitoring is not recommended for course of therapy less than if the recommended dose for the patient is 6mg/kg, administer 6mg/ 5 days in length or for lower intensity dosing (vancomycin trough goal kg on Monday, Wednesday and 9mg/kg on Friday. All doses should be of 10-15mg/L). Once-weekly trough concentrations are recommended administered after dialysis is completed (Haselden, 2013). for patients who are hemodynamically stable and on long term Daptomycin is generally well-tolerated. Drug-induced myopathy and treatment. Frequent trough concentrations may be needed in critically increased levels of creatinine phosphokinase (CPK) have ranged from ill patients with unstable renal function and high vancomycin level 2.8 to 6.7% in phase 3 clinical trials, and is reported to be reversible requirements (Rybak et al., 2009). once daptomycin is discontinued (FDA, 2016). CPK levels should be When vancomycin was first developed in the late 1950s, it was called monitored weekly and more frequently in patients with elevated CPK “Mississippi Mud” due to its brown color. It was initially only about levels or renal impairment. Patients should also have more frequent 70% pure, which was thought to have led to the incidence of adverse CPK monitoring if they were on HMG-CoA reductase inhibitors prior reactions. However, the purity was increased to 92-95% in 1985 to or concomitantly. Daptomycin should be discontinued in patients when the product was manufactured by Eli Lilly. When the impurity with myopathy symptoms and CPK levels > 1,000 U/L or in patients increased, there was a decline in serious adverse drug reactions. without symptoms and CPK levels > 2,000 U/L. HMG-CoA reductase Vancomycin nephrotoxicity occurs in about 5-7% of patients(Cantu inhibitors should be held during daptomycin therapy. Since the rates of et al, 1994). It is typically mild and reversible. Risk factors for CPK elevation appear to increase with frequency of dosing, daptomycin vancomycin nephrotoxicity include: increase in total drug, pre-existing should be limited to once daily. There have been rare reports of renal impairment, concurrent administration of nephrotoxic agents, eosinophilic pneumonia in patients receiving daptomycin, usually critically illness, and obesity (Bamgbola, 2016). occurring after 10 days of therapy; it is not yet understood why this adverse reaction takes place (Steenbergen et al., 2005; FDA, 2016). Vancomycin is diluted to a maximum concentration of 5mg/mL and infused at a maximum rate of 500mg per 30 minutes. For example, Linezolid (Zyvox) a 1250mg dose would be diluted in 250mL of 5% dextrose (or 0.9% Linezolid is an oxazolidinone that inhibits bacterial protein synthesis sodium chloride) and administered over 90 minutes. This administration by binding to bacterial 23S ribosomal RNA of the 50S subunit. This strategy helps minimize the risk of red-man syndrome, an infusion prevents the formation of a functional 70S initiation complex that is needed for the bacterial translation process. Linezolid is bacteriostatic Page 69 Pharmacy.EliteCME.com against enterococci and staphylococci and bactericidal against most prolongs its half-life to 346 hours, allowing for once- weekly strains of streptococci. It has activity against the most common administration. It may be administered via two different regimens. The clinically relevant gram positive organisms, including MRSA, VRE, single-dose regimen is given as 1500mg intravenously one time over and penicillin resistant Streptococcus pneumonia. Linezolid has been 30 minutes. The two-dose regimen is 1000mg intravenously, followed approved for use in the treatment of bacteremia, pneumonia, simple by 500mg one week later. Dalbavancin dose require renal adjustment and complicated skin and soft tissue infections (i.e. osteomyelitis, for patients with a CrCl < 30mL/min, not on hemodialysis. The diabetic foot infection) (Moellering, 2003; FDA, 2007). single-dose regimen is given as 1125mg intravenously one time over Linezolid is dosed at 600mg every 12 hours for serious infections, 30 minutes. The two-dose regimen is 750mg intravenously, followed and 400mg every 12 hours for uncomplicated skin and soft tissue by 375mg one week later. No dose adjustment is required for patients infections. The bioavailability of linezolid approaches 100%, on regularly scheduled hemodialysis. Clinical trials showed that the which allows it to be administered intravenously or orally. The single-dose regimen had similar clinical response rates to the two- option oral step down therapy gives an advantage to Linezolid over dose regimen (81.4% vs. 84.2%). While not approved, dalbavancin is other products. Urinary excretion accounts for 85% of linezolid’s being investigated for the treatment of osteomyelitis, bacteremia, and elimination; however, there is no need for adjustment in renal failure endocarditis. or dialysis (FDA, 2007). Dalbavancin was well-tolerated in clinical trials, with the most common Linezolid is generally well tolerated, with the most common adverse adverse reactions being gastrointestinal (nausea, vomiting, diarrhea), effects are gastrointestinal symptoms of diarrhea, nausea, and headache, rash, pruritus. Infusion related reactions were rare, with less vomiting. There are some serious adverse effects that may occur in than 2% of patients experiencing flushing or phlebitis. Infusion reactions patients receiving linezolid. Reversible myelosuppression including were more frequent during rapid infusion (<30 minutes) of dalbavancin. thrombocytopenia, red blood cell aplasia, and pancytopenia have Patients may have increased liver function tests during therapy, but are been clearly described. Serial monitoring of complete blood counts reversible after discontinuation of dalbavancin. There are no significant is recommended for patients on linezolid longer than 2 weeks. drug interactions (Pope & Roecker, 2006). Peripheral neuropathy has been reported and is poorly reversible. Oritavancin (Orbactiv) Optic neuropathy causes gradual blurring of vision that may lead to Oritavancin is indicated for the treatment of acute bacterial skin and permanent blindness if linezolid is not discontinued (FDA, 2007). skin structure infections caused by susceptible organism, including Linezolid is a reversible, nonselective monoamine oxidase inhibitor MRSA. Similar to dalbavancin, it has a long half-life (~ 250 hours) that has been associated with serotonin syndrome in patients receiving allowing for a one time dosing regimen. It is administered as a concomitant serotonergic medications. Serotonin syndrome presents one-time dose of 1200mg over 3 hours. Oritavancin has not been with symptoms of fever, agitation, mental status changes, and tremors. studied in patients with a CrCl < 30 mL/min or in patients requiring Serotonin effecting medications such as selective serotonin reuptake hemodialysis. inhibitors (i.e. fluoxetine, citalopram), serotonin/norepinephrine The most common adverse reactions of oritavancin were similar to reuptake inhibitors (i.e. duloxetine, venlafaxine), tricyclic dalbavancin, including: gastrointestinal (nausea, vomiting, diarrhea), antidepressants, and multiple other medications should be avoided. headache, rash, and pruritus. Rarely, infusion- related reactions occurred. Tyramine-containing foods (i.e. aged cheese, smoked meats) should The use of unfractionated heparin is contraindicated for 120 hours (5 also be avoided due to small increases in blood pressure. Patients days) after the use of oritavancin due to the false elevation of activated should also monitor their blood pressure when taking concomitant partial thromboplastin time (aPTT). Oritavancin may elevate the PT/ pseudoephedrine and phenylpropanolamine (FDA, 2007). INR for 12 hours after administration, but has no effect on warfarin. Tedizolid (Sivextro) Thus, patients receiving warfarin may receive oritavancin. Serious Tedizolid is the second oxazolidinone to become available. It has the hypersensitivity reactions have been reported with a median onset of 1.2 same mechanism of action as linezolid, but has key structural differences days. If the reaction occurs during administration, the infusion should that have additional target binding site interactions, accounting for be stopped immediately. The treatment of the hypersensitivity reaction its greater potency and retained activity despite linezolid resistance. is supportive care of the reaction. The median time to resolution of Tedizolid is approved for the treatment of skin and soft tissue infections the adverse reaction was 2.4 days. Osteomyelitis was more commonly caused by susceptible organisms, including MRSA. reported in patients receiving oritavancin in a trial compared to vancomycin. If osteomyelitis is suspected, patients should be treated Tedizolid is prescribed as 200mg once daily for a short 6 day course of with an alternative antibiotic (Saravolatz & Stein, 2015). therapy. The bioavailability is 90%, allowing for equivalent dosing for intravenous and oral products. No dose adjustment is needed for renal Telavancin (Vibativ) or hepatic dysfunction. The side effect profile is similar to linezolid, Telavancin is indicated for the treatment of complicated skin and skin with the most common adverse events being gastrointestinal in nature. structure infections and for hospital-acquired or ventilator-associated Hematologic abnormalities may occur, and tedizolid use should be pneumonia caused by susceptible organisms, including MRSA. avoided in patients with baseline neutropenia (neutrophil counts < Telavancin should be reserved for use when alternative agents are not 1000 cells/mm3). Tedizolid has a lower monoamine oxidase inhibition available. when compared to linezolid. The risk of drug interaction between Telavancin does not have the extended half-life of dalbavancin and tedizolid and serotoninergic medications is low; however, clinical trials oritavancin. It is dosed 10mg/kg (actual body weight) every 24 hours. excluded patients receiving those medications (Burdette & Trotman, It is administered intravenously over 24 hours, and caution should be 2015). given for potential red-man syndrome. If it does occur, the infusion Lipoglycopeptides should be extended. Telavancin is primarily eliminated by the kidneys; Dalbavancin, oritavancin, telavancin are lipoglycopeptides. They thus, it is adjusted in renal dysfunction (see Table 2). are analogues of vancomycin with an enhanced mechanism of Table 2: Televancin renal dose adjustment. action. Similar to vancomycin, the lipoglycopeptides inhibit cell CrCl (Cockcroft – Gault) Dose of televancin wall synthesis. In addition, they have increased activity against gram positive cocci by greater binding to peptidoglycan precursors to 30 – 50mL/min 7.5mg/kg every 24 hours. prevent cell wall synthesis. Oritavancin and telavancin also disrupt the 10 - < 30mL/min 10mg/kg every 48 hours. membrane barrier function of S. aureus. The lipoglycopeptides contain a lipophilic side chain that prolongs their half-life (Pope & Roecker, < 10mL/min Not recommended/studied. 2006; Saravolatz & Stein, 2015; Saravolatz et al., 2009). Hemodialysis Not recommended/studied. Dalbavancin (Dalvance) Telavancin has several concerning warnings limiting is use in clinical Dalbavancin is indicated for the treatment of acute bacterial skin and practice. The use of telavancin for hospital-acquired or ventilator skin structure infections. The lipophilic side chain on dalbavancin pneumonia in patients with pre-existing moderate/severe renal

Pharmacy.EliteCME.com Page 70 impairment (CrCl < 50mL/min) had an increased risk of mortality 2.5% (66/2640) vs. 1.8% (48/2628), respectively(FDA, 2013). It is when compared to vancomycin(Corey et al., 2014). New onset recommended that tigecycline only be utilized for approved indications or worsening renal impairment has occurred in patients receiving and only when alternative therapies are not suitable (FDA, 2010;). telavancin. Patients should have renal function monitored at least For all indications, tigecycline is dosed as 100mg as a single dose, every 48-72 hours prior to, during, and after therapy. Patients are at a followed by 50mg every 12 hours for 5-14 days. Tigecycline is higher risk for nephrotoxicity if they have baseline renal dysfunction administered intravenously over 30-60 minutes. Tigecycline is or are receiving concomitant nephrotoxic agents. Telavancin contains extensively metabolized via the liver. There is no dose adjustment solubilizer cyclodextrin, which may accumulate in patients with for mild to moderate hepatic impairment (Child-Pugh class A or B); renal dysfunction; however, the clinical significance of this finding however, the maintenance dose should be adjusted to 25mg every 12 is unknown (Luke, 2010). QT prolongation can occur in patients hours for patients with severe hepatic impairment (Child-Pugh Class C) receiving telavancin. It should be avoided in patients with congenital (see Table 4). QT syndrome, known prolongation of QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy. The risk of QT Table 4: Child Pugh Class Scoring Chart. prolongation is similar to fluoroquinolones (Saravolatz et al., 2009). Measure 1 point 2 points 3 points Ceftraroline (Teflaro) Total bilirubin (mg/dL) < 2 2-3 >3 Ceftaroline is a novel 5th generation cephalosporin with activity against MRSA. It also has efficacy against Streptococcus pneumonia (including Serum albumin (g/dL) >3.5 2.8-3.5 < 2.8 multidrug-restraint strains), Haemophilus influenza, and Moraxella Prothrombin time (s) <4 4-6 >6 catarrhalis. Ceftaroline does not have activity against resistant gram- Ascites None Mild Moderate-severe negative bacteria such as Psuedomonas aeruginosa, Acinetobacter, or anaerobic organisms. Similar to other beta-lactams, ceftaroline’s Hepatic encephalopathy None Grade I-II Grade III-IV mechanism of action is binding to the penicillin -binding protein (PBP), Score: 5-6: Class A, 7-9: Class B; 10-15: Class C the enzyme that mediates the cross-linking transpeptidation of the peptidoglycan which are the terminal steps in completing the formation The most common adverse reactions for tigecycline are nausea, vomiting, of the bacterial cell wall. Ceftaroline also has a strong binding affinity diarrhea, abdominal pain, headache, and increased liver enzymes. While for PBP2a, a modified PBP in MRSA, which contributes to its spectrum rare, there have been cases of pancreatitis reported, including patients of activity against these bacteria. It is approved for the treatment of without risk factors. Since tigecycline is a tetracycline derivative, skin and skin structure infections (including MRSA) and community- photosensitivity may occur. Tigecycline use during tooth development acquired pneumonia (not due to MRSA). may cause permanent tooth discoloration (yellow-gray-brown); thus, should not be used in children and pregnancy. Tigecycline has limited Ceftaroline is dosed at 600mg intravenously every 12 hours. It is drug interactions, but may increase the effect of warfarin (FDA, 2010). administered over 5 to 60 minutes. It is approved for a 5-14 day course therapy for skin and skin structure infections, and 5-7 day course of Clindamycin (Cleocin) therapy for community-acquired pneumonia. Ceftaroline is primarily Clindamycin works by reversibly binding to 50S ribosomal subunits excreted through the kidneys, thus requires renal adjustment for preventing peptide bond formation, thus inhibiting bacterial protein patients with a CrCl < 50ml/min (see Table 3). synthesis. It is approved by the FDA for the treatment of S. aureus infections. It is has been widely used off label for the treatment of Table 3: Ceftaroline renal dose adjustment. skin and structure infections, osteomyelitis, septic arthritis, and CrCl (Cockcroft - Gault) Dose pneumonia caused by MRSA. It is not recommended for endocarditis due to its bacteriostatic action, nor for meningitis due to its limited > 50 mL/min 600mg q12h. CSF penetration. Due to potential resistance, the d-zone test is > 30 to < 50 mL/min 400mg q12h. recommended to identify the susceptibility of Clindamycin to MRSA. > 15 to < 30 mL/min 300mg q12h. Clindamycin is available in intravenous and oral formulations. The typical intravenous dose is 600 to 900mg IV every 8 hours and oral < 15 mL/min 200mg q12h. dosing is 300 to 450mg every 6-8 hours. The most common adverse ESRD – Hemodialysis 200mg q12h (dose after HD). effect is diarrhea, occurring in up to 20% of patients. Clostridium difficile may occur more frequently in patients receiving clindamycin There is no adjustment for hepatic dysfunction. Ceftaroline does when compared to other oral antibiotics (Van Eperen & Segreti, 2016). not go through the cytochrome P-450 system, so there are limited drug interactions. Ceftaroline does, however, interact with warfarin, Trimethoprim and sulfamethoxazole (TMP-SMX) (Bactrim) requiring dose adjustment. Trimethoprim is a tetrahydrofolate reductase inhibitor that, when added to sulfamethoxazole, provides a second-step block in the folate Based on clinical trials, ceftaroline is well tolerated with similar biosynthetic pathway. TMP-SMX is not FDA- approved to treat any adverse effects when compared to other cephalosporins. Since it is indication caused by MRSA. However, it is recommended as first-line a cephalosporin, there is a potential for hypersensitivity reactions in therapy for uncomplicated urinary tract infections, skin and soft-tissue patients allergic to cephalosporins and some patients with penicillin infections, and community associated MRSA infections according to allergies. Pharmacists should take a careful antibiotic allergy history clinical practice guidelines. prior to administration (Steed & Rybak, 2010). TMP-SMX is available in intravenous and oral formulations. The Tigecycline dose varies significantly based on intravenous and oral formulations, Tigecycline is a glycylcycline antibiotic derived from minocycline. indication, and renal function. The trimethoprim portion of TMP- It binds to the 30S ribosomal subunit of susceptible bacteria, thus SMX could potentially cause hyperkalemia. It is structurally similar to inhibiting protein synthesis. It has activity against many gram- triamterene and acts as a potassium sparing diuretic. Caution should positive organisms, including MRSA. Tigecycline is approved to treat be used when prescribing TMP-SMX in high doses or to patients complicated skin and skin structure infections, complicated intra- with renal impairment, older age, or who are receiving concomitant abdominal infections, and community-acquired pneumonia. While it has medications that could cause hyperkalemia (Adra & Lawrence, 2004). been studied in for the treatment of diabetic foot infections, hospital and ventilator associated pneumonia, it is not indicated for those infections. Doxycycline The FDA issued a safety warning in 2010 and a black box warning Doxycycline inhibits protein synthesis by binding with the 30S and in 2013 regarding increased risk of mortality in patients treated with possibly the 50S ribosomal subunit of susceptible bacteria. It is tigecycline when compared to other antibiotics. The FDA analyzed data indicated by the FDA for the treatment of skin and structure infections from 10 clinical trials that only used tigecycline from FDA- approved due to S. aureus, but not MRSA specifically. It is recommended by indications. The analysis showed increased mortality in patients clinical practice guidelines for the treatment of skin and structure receiving tigecycline when compared to other antibiotic medications: infections due to MRSA.

Page 71 Pharmacy.EliteCME.com Doxycycline is available in intravenous and oral formulations. It to the prescriber. The pharmacist could make recommendations to is dosed 100mg every 12 hours, regardless of route. There is no continue, adjust, change, or discontinue the antibiotic based on the dose adjustment for renal or hepatic impairment. Similar to other available microbiology results and clinical status of the patient. tetracyclines, it increases the risk of photosensitivity, and is not Another activity for pharmacists to optimize antibiotics would be recommended during tooth development (last stage of pregnancy and to establish hospital specific antibiotic guidelines based on national children < 8 years of age) (Ruhe et al., 2005). guidelines and local susceptibility data. These guidelines could be Antimicrobial stewardship incorporated into standardized order forms for prescribers. These CDC has reported that 30-50% of all antibiotics utilized in hospitals guidelines require prescribers to be complaint and adhere to the hospital are either unnecessary or inappropriate. These unnecessary antibiotics guidelines. Utilization of treatment pathways in the computerized lead to bacterial resistance, increased incidence of Clostridium physician order system increases adherence. difficile, and adverse effects (CDC, 2017). In response to the antibiotic Pharmacists can assist with antibiotic stewardship by having the resistance crisis, the White House published the National Action Plan ability to convert antibiotics from IV to oral formulations for clinically for Combating Antibiotic-Resistant Bacteria(CDC, 2017b). The goals of stable patients. Switching to oral antibiotics decreases the cost and the the National Action Plan are to slow the emergence of resistant bacteria incidence of catheter related infections. There are multiple antibiotics and prevent the spread of infection, improve surveillance, develop rapid that high bioavailability including: azithromycin, ciprofloxacin, and innovative diagnostic tests, accelerate research for development clindamycin, doxycycline, fluconazole, levofloxacin, linezolid, of antibiotics and vaccines, and improve international collaboration. moxifloxacin, metronidazole, and trimethoprim/sulfamethoxazole. According to the plan, inappropriate antibiotic use should be reduced Guidelines driving IV to PO therapy should be implemented and by 50% in outpatient settings and by 20% in inpatient settings by 2020. audited by an infectious disease pharmacist. The national target is also to reduce by at least 50% overall MRSA bloodstream infections by 2020 as compared to 2011. To complete this A core component of antimicrobial stewardship is education. Education goal, the plan recommends a regulatory requirement for antimicrobial should be provided on a regular basis to all types of healthcare stewardship be in place by 2017. providers. Education can be provided in multiple formats including presentations, flyers, weekly emails, or electronic messages. Education The CDC recommends that a successful antimicrobial stewardship should highlight system goals for antibiotic stewardship; additionally, program contain 7 core elements (see Table 5). case presentations at grand rounds, resident reports, or case conferences Table 5: Requirements of a successful antimicrobial stewardship can demonstrate and reinforce the importance of antibiotic de- program (CDC, 2017b). escalation. Antibiotic stewardship education should be included in annual provider education programs, medical education and training, Core Elements for Antimicrobial Stewardship Program and orientation for all new medical staff. Information about antibiotics Leadership commitment. could be included in patient education material. Accountability through a sing physician leader. Before implementation of a stewardship program, outcome data Drug expertise through a single pharmacy leader. should be identified. Commonly collected data includes antibiotic use, expenditures, and clinical outcome variables, such as readmission for Action, including at least one intervention. specific conditions (i.e. cellulitis, community-acquired pneumonia). Tracking prescription and resistance patterns. The most common methods to evaluation drug consumption are defined daily dose (DDD) or days of therapy (DOT). The DDD is Reporting prescription and resistance information directly to health calculated as the total number of antibiotic agent used divided by the care providers. number of grams in an average daily dose. The DDD helps compare Education for health care professionals. standardized doses among hospitals, but does not account for alternative dosing regimens dose to renal dysfunction or regimens that optimized The antimicrobial stewardship team should be multidisciplinary, pharmacokinetic or pharmacodynamic dosing. The DOT is the sum of including an infectious disease physician, infectious disease pharmacist, days that any antibiotic was administered. The DOT is not affected by clinical microbiologist, infection control professional, information dosing regimen changes. The DOT is more helpful when comparing the system specialist, nursing champion, administrative leader. use of different antibiotics within a hospital. After the data are collected, There are multiple types of interventions that can be implemented the findings should be reported to prescribers, nurses, pharmacists, and by the antimicrobial stewardship team. Pharmacists can play a key other appropriate staff. Prescriber specific reports should be provided to role in many of these activities, including formulary restrictions and help improve antibiotic prescribing. management, education, and monitoring. Antimicrobial stewardship is the key to combat the ever-growing Formulary restrictions are common among health-care systems to problem of antibiotic resistance. An antimicrobial stewardship control antibiotic use. Restrictions that require prior authorization by program has been shown to improve patient outcomes, reduce an infectious disease physician or pharmacist helps deter inappropriate antibiotic resistance, and decrease healthcare costs. Pharmacists have broad spectrum antibiotic use. Alternately, an institution could require a responsibility to be a prominent member of the stewardship team documentation of indication and duration for all antibiotics prescribed. as well as implement antimicrobial stewardship into our everyday Also, an antimicrobial steward, typically a pharmacist, could review activities (Nagel et al., 2016; ASHP, 2010; National Quality Forum, all antibiotics prescribed for more than 48 hours and provides feedback 2017; Fellner, 2016). Potential antibiotic approvals for MRSA The pipeline for antibiotics that treat MRSA is strong. Currently, it (delafloxacin), and an oral fusidic acid. Finding new treatments for includes three products that have new mechanisms of action: brilacidin, MRSA is a goal of the National Action Plan for Combating Antibiotic- debio 1450, and lefamulin. Other future agents include a new macrolide Resistant Bacteria (Fellner, 2016). (solithromycin), tetracycline derivative (omadacylcine), fluoroquinolone Conclusion MRSA continues to be an important pathogen with a high prevalence in in the setting of MRSA infection is imperative due to the high rate of the community and hospital settings. Identification of patients at high morbidity and mortality. Antimicrobial stewardship is key to improve risk for infection helps improve care. Timely and appropriate antibiotics patient outcomes and reduce antibiotic resistance. References ŠŠ Adra, M., & Lawrence, K.R. (2004). Trimethoprim/sulfamethoxazole for the treatment of severe ŠŠ Ammerlaan, H.S., Kluytmans, J.A., Wertheim, H.F., Nouwen, J.L., & Bonten, M.J. (2009). Staphylococcus aureus infections. Ann Pharmacotherapy; 38:338-341. Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis;48:922-930.

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ŠŠ Stevens, D.L., Bisno, A.L., Chambers, H.F., Dellinger, E.P., Goldstein, E.J., Gorbach, S.L., & Wade, ŠŠ van Hal, S.J., Stark, D., Lockwood, B., Marriott, D., & J. Harkness. (2007). Methicillin-resistant J.C.; Infectious Diseases Society of America. (2014). Practice guidelines for the diagnosis and Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA management of skin and soft tissue infections: 2014 update by the infectious diseases society of PCR assay and Geno Type MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, America. Clin Infect Dis; 59:147. MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. J Clin Microbiol; 45: ŠŠ Stryjewski, M.E., & Corey, G.R. (2014). Methicillin-resistant Staphylococcus aureus: an evolving 2486–2490. pathogen. Clin Infect Dis. 58(suppl1):s10-19. ŠŠ Halselden, M., Leach, M., & Bohm, N. (2013). Daptomycin dosing strategies in patients receiving ŠŠ The Medical Letter. (2017). Drugs for MRSA skin and soft-tissue infections. Retrieved from http:// thrice-weekly intermittent hemodialysis. Annals of Pharm; 1342-1347. secure.medicalletter.org/JAMA_MRSA ŠŠ Han, J.H., Sullivan, N., Leas, B.F., Pegues, D.A., Kaczmarek, J.L., & Umscheid, C.A. (2015). ŠŠ Van Eperen, A.S., & Segreti, J. (2016). Empirical therapy in methicillin-resistant Staphylococcus Cleaning hospital room surfaces to prevent health care-associated infections: a technical brief. Ann aureus infections: an up to date approach. J Infect Chemother; 22:351-359. Intern Med;163:598-607. ŠŠ Wang, J.T., Fang, C.T., Chen, Y.C., & Chang, S.C. (2001). Necessity of a loading dose when using ŠŠ Kalil, A.C., Metersky, M.L., Klompas, M., Muscedere, J., Sweeney, D.A., Palmer, L.B. & vancomycin in critically ill patients. J Antimicrob Chemother; 47:246. ŠŠ Brozek, J.L. (2016). Management of Adults With Hospital-acquired and Ventilator-associated ŠŠ Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, Edwards JR, & Siever DM. Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the (2016). Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary American Thoracic Society. Clin Infect Dis; 63:e61. of data reported to the national healthcare safety network at the Centers for Disease Control and ŠŠ Launay-Vacher, V., Izzedine, H., Mercadal, L., & Deray, G. (2002). Clinical review: use of Prevention, 2011-2104. Infect Control Hosp Epidemiol; 37:1288-1301. vancomycin in haemodialysis patients. Crit Care; 6:313-316. ŠŠ Yahav, D., Lador, A., & Leibovici, L. (2012). Efficacy and safety of tigecycline: a systematic review ŠŠ Liu, C., Bayer, A., Cosgrove, S.E., Daum, R.S., Fridkin, S.K., Gorwitz, R.J., Chambers, H.F.; and meta-analysis. J Antimicrob Chemother; 54:1699-1709. Infectious Diseases Society of America. (2011). Clinical practice guidelines by the infectious diseases METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: PREVENTION AND TREATMENT Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com

1. The fastest way to diagnosis a MRSA infection is polymerase chain 6. A dose of vancomycin 2000mg should be administered over 2 reaction testing. hours. a. True. a. True. b. False. b. False. 2. CA-MRSA strains can be identified via the SCCmec type IV. 7. Daptomycin should not be used for meningitis because it poorly a. True. penetrates the CNS. b. False. a. True. b. False. 3. Receipt of antibiotics within 3 months is a risk factor for HA- MRSA infection. 8. The appropriate dose of ceftaroline for a patient with a CrCl of a. True. 25mL/min is 600mg q12h. b. False. a. True. b. False. 4. Mupirocin intranasal ointment is the drug of choice for MRSA decolonization. 9. TMP-SX can cause hypokalemia. a. True. a. True. b. False. b. False. 5. Daptomycin may be used to treat HA-MRSA pneumonia. 10. Doxycycline should be avoided in patients that are under the age of a. True. 8 years of age. b. False. a. True. b. False.

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