MRSA: Challenges and Updates

Selection of optimal antibiotic therapy is crucial in the treatment of MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be among the most common causes of health care— associated and community-acquired infections worldwide.¹ While its overall incidence has been reduced by 31%, MRSA remains prevalent and a major public health problem.^2,3 Determining the optimal antibiotic therapy for a MRSA infection is an ongoing challenge. While vancomycin has been the main therapeutic agent for MRSA infections over the last 50 years, there has been increasing concern with its efficacy in the face of increasing minimum inhibitory concentrations (MIC), which may be associated with treatment failure and mortality.^4,5 In this discussion, the focus will be on the nosocomial MRSA treatment challenges and the roles of the newer alternative MRSA agents.

Choosing the Right Drug

Global trends of increasing MIC (“the MIC creep”) for vancomycin coupled with the emergence of hVISA (heteroresistant vancomycin intermediate S aureus), VISA (vancomycin intermediate S aureus), and VRSA (vancomycinresistant S aureus) isolates challenge the effectiveness of vancomycin.⁶ Whereas VRSA remains rare, infections caused by VISA and hVISA may respond slowly or incompletely to vancomycin. Although vancomycin is the agent with the greatest cumulative experience for MRSA, it has been suggested that alternative agents should be considered for isolates with vancomycin MICs >1 mg/L, even though there may be considerable variability in MIC determination based on different testing methods.⁷

Linezolid is the first bacteriostatic oxazolidinone antibiotic to inhibit the initiation of protein synthesis at the 50S ribosome.⁸ It is currently approved by the FDA for the treatment of nosocomial pneumonia and complicated skin and soft tissue infections (cSSTIs) due to MRSA. It is considered to be noninferior to vancomycin in the treatment of nosocomial pneumonia and superiority has also been suggested, given its excellent bioavailability and extensive tissue distribution, including in the lungs.⁹ Linezolid may also be considered the drug of choice in community-acquired MRSA pneumonia, suppressing the formation of the Panton- Valentine leukocidin toxin that tends to cause necrotizing pneumonia.¹⁰

Adverse effects (AEs) of linezolid include myelosuppression (usually with prolonged therapy of more than 2 weeks), peripheral neuropathy, and serotonin toxicity.⁸

Tedizolid is the second drug in the class of oxazolidinones that was recently approved by the FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in 2014. Compared with linezolid, it is bactericidal and has a lower incidence of myelosuppression.¹¹

Daptomycin is a cyclic lipopelide bactericidal antibiotic that causes cell membrane depolarization.⁸ It is currently approved by the FDA for the treatment of cSSTIs, bacteremia, and right-sided native valve endocarditis.¹² Daptomycin should not be used in the treatment of pneumonia due to its inactivation by pulmonary surfactant.¹³ Emergence of daptomycin- nonsusceptible MRSA isolates is a growing concern, with observations that the daptomycin MIC may increase during therapy. Susceptibility testing to daptomycin is also advised during ongoing therapy.¹⁴ Serum creatinine kinase should be monitored during therapy with daptomycin to rule out myopathy, and extra caution should be taken when it is used concurrent with statins and in patients with renal impairment.⁸

Tigecycline is a bacteriostatic glycylcycline antibiotic derived from minocycline, inhibiting the 30S ribosomal subunit.⁸ While initially showing promise, given its broad spectrum of activity, it has been relegated to a position as a second- or third-line choice in terms of MRSA treatment due to its inadequate plasma drug levels.¹⁵ This is also compounded by the FDA safety statement issued on September 2010, followed by a boxed warning in 2013, pertaining to increased risk of mortality associated with use of tigecycline compared with other agents for similar infections. Pooled data from 10 clinical trials conducted for FDA-approved uses showed a higher risk of death among patients receiving tigecycline compared with other antibacterial drugs: 2.5% (66/2640) versus 1.8% (48/2628), respectively.¹⁶ Main AEs include nausea and vomiting.⁸

Ceftaroline is a fifth-generation cephalosporin that inhibits bacterial cell wall synthesis by binding to penicillinbinding- proteins. While it has MRSA activity, it is currently FDA-approved only for the treatment of cSSTIs and community-acquired pneumonia. Being the first beta-lactam with MRSA activity, it has been used successfully in salvage therapy for MRSA bacteremia as monotherapy and also in combination with daptomycin (synergy mechanism) in various case series.^17,18

Telavancin is a once-daily dosing bactericidal lipoglycopeptide that inhibits cell wall synthesis and cell membrane permeability.⁸ While considered to be at least as effective as vancomycin for the treatment for cSSTIs including MRSA, it is not considered to be a first-line agent due its teratogenicity issues and its higher rates of renal events, altered taste, nausea, and vomiting compared with vancomycin.¹⁹

Another drug in the same class is dalbavancin, a lipoglycopeptide with an extended half-life permitting onceweekly dosing schedules, which received FDA approval for treatment of ABSSSIs by gram-positive bacteria, including MRSA.⁸ Oritavancin, which is administered as a single dose for skin and skin structure infections, was also recently approved by the FDA in 2014 for the same indication of ABSSSIs.⁸ There is currently a paucity of data for all lipoglycopeptides pertaining to their roles in the treatment of invasive MRSA infections.

Choosing the Right Dose

While we are largely familiar with the usual dosing regimens of the MRSA antibiotic agents, determining the optimal dosing in obese patients is an ongoing challenge. There has been great interest in the pharmacokinetic differences of certain MRSA agents in the setting of obesity. Online Table 1 outlines the MRSA agents with their respective approved dosing regimens and off-label dosing regimens as reported in literature.

Table 1: Agents for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA)

Class

Mechanism of Action

Dosing Information

(normal renal function)

Adverse Effects

Comments

vancomycin

glycopeptide

Inhibits bacterial cell wall synthesis

IV 15-20 mg/kg every 8-12 hours to attain target trough of 15-20 mg/L for most infections

Red Man syndrome, nephrotoxicity

Dosing based on ABW. For obese patients, empiric dosing should be based on ABW and followed with therapeutic drug monitoring

linezolid

oxazolidinone

Inhibits protein synthesis at 50S subunit

IV/oral:

600 mg every 12 hours

Myelosuppression usually related to prolonged therapy >2 weeks, peripheral neuropathy, serotonin syndrome

Current data suggest standard dosing across body weight extremes up to 150 kg

May have anti-toxin effect useful for treatment of Panton-Valentine leukocidin toxin in community-acquired MRSA necrotizing pneumonia

Good tissue distribution and lung pharmacokinetics

daptomycin

cyclic lipopeptide

Causes cell membrane depolarization

Complicated skin and skin structure infections: IV 4 mg/kg every 24 hours;

S aureus bacteremia: IV 6 mg/kg every 24 hours;

off-label: 8-10 mg/kg every 24 hours for bacteremia/endocarditis

Creatine kinase elevation, myopathy

Weekly creatinine kinase monitoring

Inactivated by lung surfactant, hence, not used to treat pneumonia

Dosing mostly based on ABW in obesity; newer studies are investigating using ideal body weight due to small volume of distribution

tedizolid

oxazolidinone

Inhibits protein synthesis at 50S subunit

IV/oral: 200 mg every 24 hours

Approved by the FDA in 2014 for acute bacterial skin and skin structure infections (ABSSSI)

Nausea

Bactericidal; less myelosuppression compared with linezolid

tigecycline

glycylcycline

Inhibits protein synthesis at 30S subunit

IV: Loading dose 100 mg, 50 mg every 12 hours thereafter

Nausea, vomiting

Higher doses of 100 mg every 12 hours used in multidrug-resistant Gram-negative infections²⁸

FDA warnings of increased mortality risks have limited its utility

Low plasma levels; do not use for bacteremia

ceftaroline

fifth-generation cephalosporin

Inhibits bacterial cell wall synthesis

IV: 600 mg every 12 hours.

FDA-approved for ABSSSI and community-acquired pneumonia

Diarrhea, rash, nausea, direct Coombs’ seroconversion

Higher doses of 600 mg every 8 hours have been used in salvage therapy for MRSA bacteremia

Has been used successfully in combination with daptomycin (synergism) for salvage therapy

telavancin

lipoglycopeptide

Inihibits bacterial cell wall synthesis

IV: 10 mg/kg every 24 hours

Nephrotoxicity, teratogenicity, QT prolongation, nausea, vomiting

Higher nephrotoxicity rates than vancomycin

^{ABSSSI = acute bacterial skin and skin structure infections; ABW = actual body weight; IV = intravenous.}

Vancomycin

The pharmacokinetics of vancomycin in obesity have been studied extensively, with positive correlations between actual body weight (ABW) and volume of distribution (Vd) and clearance of the drug.²⁰ Empiric dosing based on ABW is recommended, followed by therapeutic drug monitoring.²¹

Daptomycin

Dosing at ABW has been proposed across several trials although 1 case report has advocated for dosing at adjusted body weight.^22,23 The concern with dosing at ABW was the increased risk of daptomycin myotoxicity in obese patients because their clearance of the drug is reduced. Recently, a retrospective study suggested no significant differences between dosing at ideal body weight or ABW, which is a plausible result given that daptomycin’s Vd is relatively small at 0.1 L/kg.²⁴ Of note is that these studies were generally dosing patients at the usual 4- to 6-mg/ kg dose. However, higher doses of 8 to 10 mg/kg have been used off-label for critically ill patients, and safety data are limited for evaluating high doses based on total body weight in these patients.²⁵

Linezolid

In a study of 20 adult volunteers with body mass index (BMI) of 30 to 54.9 kg/ m2, researchers assessed the pharmacokinetics of 5 intravenous doses of 600 mg of linezolid every 12 hours. They concluded that linezolid exposure in obese patients was similar to that of nonobese patients, advocating that dosage adjustments based on BMI alone are not required and standard doses may be used in patients weighing up to approximately 150 kg.²⁶ It is currently appropriate to use traditional dosing in obese patients. In the critical care setting, linezolid levels were found to be potentially subtherapeutic over 24 hours and at single time points observed for 63% and 50% of the patients, respectively, suggesting that therapeutic drug monitoring may be needed for these patients.²⁷

Ceftaroline

Ceftaroline has been used in salvage therapy for MRSA bacteremia in several case-series, with a higher than usual dose of 600 mg every 8 hours, capitalizing on its time-dependent antimicrobial killing characteristic.^17,18 There are no direct comparison studies between the 2 dosing strategies, but potential considerations may be made for the off-label dosing in salvage therapy and severe infections.

Treatment Duration

The duration of treatment for MRSA infections remains controversial. MRSA pneumonia, for example, has a relatively wide recommended duration of 7 to 21 days, which is largely based on expert opinion.¹⁴ Uncomplicated bacteremias are recommended to be treated for a minimum of 2 weeks; shorter durations of treatment were found to lead to higher rates of relapsed infections.²⁹ Table 2 shows a summary of the recommended durations of treatment for various MRSA infections.¹⁴

Pharmacists play a vital role in the selection of alternative agents for the treatment of MRSA infections given their expertise in the differential pharmacodynamic and pharmacokinetic characteristics, ultimately choosing the right drug, and its optimal dose, duration, and monitoring parameters for each patient.

Caroline Tee, PharmD, BCPS, is a clinical pharmacist working in the areas of infectious diseases and critical care at National University Hospital in Singapore.

References

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