MRSA: Medication Regimens for Community and Hospital Acquired

-Gita Wasan Patel PharmD, Clinical Coordinator, Medical Center of Plano-Joel McKinsey, MD, Infectious Disease Specialist, Co-director of Hospital Epidemiology, Research Medical Center, Kansas City-Tamara Fohr, PharmD, Clinical Coordinator, Denton Regional Medical Center

February 2007

Goals

• Provide information on peri-operative eradication of MRSA• Provide information on decolonization of MRSA• Provide clinicians with knowledge about the etiology and

treatment of community and

healthcare-acquired MRSA • Discuss the pharmacist’s role in making recommendations

to physicians for safe and appropriate treatment of the disease.

Objectives

• Upon completion and mentored practice, the clinician should be able to:– Discuss the definition and diagnosis of the different

types of MRSA– Understand the established guidelines for treatment– Understand surgical prophylactic issues and therapy– Understand decolonization recommendations– Make appropriate recommendations to physicians

regarding ordered medication – Appropriately document interventions and the results

Perioperative Eradication of MRSA Carriage

Perioperative Eradication of MRSA Carriage

• Due to prevalence in community, some surgeons culturing pt nares prior to procedure and if positive for MRSA, order mupirocin nasally and/or on wound post surgery (esp. orthopedics and CABG’s)

• Some inconsistent data regarding preventing SSIs in orthopedic surgeries. Since mupirocin is inexpensive and resistance rates are low (approx 5%), still a good option

• Data does suggest that nasal mupirocin can prevent sternal wound infections after CABGs

CID 2002; 35: 353-358

Journal of Hospital Infection 2003; 54:196-201

Ann Thorac Surg 2001; 71: 1572-1579

Perioperative Eradication of MRSA Carriage

Cardiac Surgery: Open Heart Procedures including,– Coronary Artery Bypass– Valve Replacements

Orthopedics: Open procedures of the Hip, Knee, and spine including:

– Total hip and knee– Revision total hip and knee– Partial total hip and knee– Unicompartmental knee – Endo/ Unipolar hip and bipolar hip– Lumbar spine with and without implants– Cervical spine with and without implants– Thoracic spine with and without implants

Perioperative Eradication of MRSA Carriage

• Surgical Scrub (CHG 2-4%) night before and morning of surgery with instruction/informational handout

• Mupirocin nasal ointment applied pre-op and post-op twice daily for 5 days total

• Vancomycin 15 mg/kg IV pre-op (120 minutes prior) and additional dose may be required if therapeutic level (5-10 mcg/ml trough) cannot be maintained for 24 hours post-procedure– Renal dosing considerations

• Contact Precautions

Perioperative Eradication of MRSA Carriage

• Mupirocin Nasal Ointment is not recommended for patients who are not known to be colonized with MRSA– May increase risk of subsequent MRSA colonization

• Vancomycin is currently not recommended for patients who are not known to be colonized with MRSA

Antimicrobial Agents and Chemotherapy 2004; 49(4):1465Clinical Infectious Diseases 2004; 38:1706

MRSA Decolonization

• Completely inappropriate if patient has active infection• Unsuccessful if pt has open or draining sites or if

indwelling lines or tubes needed for ongoing care • No consensus regarding use/effectiveness • Not routinely recommended• May be prudent to consider if:

– Patient has recurring infections (admissions with MRSA) despite treatment

– Ongoing MRSA transmission in a well-defined cohort with ongoing contact

Infection 2006; 34: 117

MRSA Infection Versus Colonization

• Clinicians must be able to differentiate between colonization and active infection to provide appropriate therapy.

• Colonization cultures are obtained from nasal swabs versus active infections that are usually in the blood, tissue, etc.

• The number of colonies isolated also indicate a true infection versus colonization

• Clinical picture of patient is imperative to the diagnosis of an active infection.

Hospital Acquired MRSA

Hospital-Acquired MRSA

• Initially reported in the 1970’s• Infections seen all over the body: respiratory,

bloodstream, skin, bone, etc., typically bacteremia with no infection focus

• Resistant to non-Beta-Lactam antibiotics• Usually non-virulent and slowly progressing• Typically diagnosed in an inpatient setting• Typical patient is elderly, debilitated and/or critically

or chronically ill• Community spread is limited• PVL (Panton-Valentine leukocidin) gene absent

Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. Philadelphia: Elsevier, 2005:2328-2333.

HA-MRSA Therapy Options

Vancomycin

• Glycopeptide• Dose 15 mg/kg - adjust frequency for renal function• Target trough of 15-20 mcg/ml for pneumonia or

bone infections• Side Effects: “Red Man Syndrome”, nephrotoxicity,

ototoxicity• 10-14 day length of therapy unless endocarditis or

osteomyelitis (6 weeks)• Bacteriostatic agent

Mayo Clin Proc 199; 74:928-935Lexi-Comp

Amin A, Batts D. Community Acquired and Healthcare Associated MRSA. Medscape 2006

Linezolid (Zyvox)

• Oxazolidinone• Dose 600mg IV or orally q12h with no renal or

hepatic adjustment• Penetrates lung tissue better than vancomycin• Side effects: thrombocytopenia (higher incidence

seen in patients with end-stage renal disease), myelosuppression

• Should not give to patients on SSRIs (multiple reports of serotonin syndrome)

• Bacteriostatic against enterococci and staphylococci• Bactericidal against a majority of streptococci

CID 2006; 42:66-72Lexi-Comp

Amin A, Batts D. Community Acquired and Healthcare Associated MRSA. Medscape 2006

Daptomycin (Cubicin)

• Lipopeptide• Dose:

– 4 mg/kg for skin/skin structure infections– 6 mg/kg for bacteremia or endocarditis; renal

adjustment needed if CrCl <30 ml/min• Side Effects: anemia, myopathies• Monitor CPK levels• Does not penetrate the lungs and is inactivated by

pulmonary surfactants - cannot be used to treat pneumonia

• BactericidalLexi-Comp

Tigecycline (Tygacil)

• Glycylcycline• Dose: 100mg IV X1 then 50mg q12h;

– no renal adjustment needed, but does need to be adjusted for severe hepatic impairment

• Side Effects: nausea/vomiting, diarrhea; similar side effects of the tetracyclines

• Not a good choice for monotherapy in patients with intestinal perforation

• Also has broad-spectrum gram-negative activity, but does not cover Pseudomonas

• Bacteriostatic

CID 2005; 41: S303-314

Therapy Issues RegardingHA-MRSA Pneumonia

• Much concern regarding the penetration of Vancomycin into the lung tissue

• New IDSA/ATS Guidelines recommend a target trough of 15-20 mcg/ml

• Meta-analysis showed that linezolid may be more efficacious than vancomycin when treating HA-MRSA pneumonia

• Head-to-head trial currently enrolling patients• Definitive clinical data not yet available

Chest 2003; 124: 1789-1797Am J Respir Crit Care Med 2005; 171: 388-416

Therapy Issues Regarding HA-MRSA Pneumonia

• 2 recent articles have examined the pharmacokinetic parameters of vancomycin and MRSA pneumonia

• Jeffries et al. showed that greater vancomycin concentrations did not correlate with improved hospital outcome

• Hidayat et al. showed that 54% of their MRSA had a high vancomycin MIC (>2 mcg/ml) and that these patients had higher infection-related mortality despite achieving high vancomycin trough levels (>15 mcg/ml)

Chest 2006; 130: 947-955

Arch Intern Med 2006; 166: 2138-2144

Vancomycin for Surgical Prophylaxis

• No concensus among ID physicians or regulatory bodies• Look to your antibiogram to provide direction

– If there is a large percentage of MRSA (>50%) in CABG or joint replacement patients, there may be a need in these specific populations

– No definitive clinical data available that would warrant the use of pre-operative vancomycin on all CABG or joint replacement patients

• Overuse of vancomycin in penicillin-allergic patients– Watch for routine use of vancomycin without investigation of a

stated penicillin “allergy”. In many cases, there was no significant reaction or the patient has a history of taking cephalosporins, therefore cross resistance is not a problem

Vancomycin Resistance

• 3 cases of VRSA have been reported in the U.S.• Attributed to plasmid-based vanA genes of E. faecalis

origin• Vancomycin MICs > 32 mcg/ml• Can emerge in the absence of prior vancomycin

treatment• Remain susceptible to older agents and newer

compounds• Linezolid-resistant S. aureus has also been reported

CID 2006; 42: S25-34

IV Medication Combination Effects

  Vancomycin Aminogly Quinolones B-lactam Linezolid Quin/Dal Dapto

Vancomy   S I I A A if MLSb I

Aminogly S   I S I I DI

Quinolones I I   I A A N

B-lactam I S I   N S&A S

Linezolid A I A N   N N

Quin/Dal A if MLSb I A S&A N   N

Daptomycin I DI N S N N  

A = Antagonism, DI = drug interactions, I = indifferent, N = no data, S = synergy,

MLSb=macrolide, lincosamide resistant MRSA

New drugs……

Dalbavancin

• Lipoglycopeptide related to teicoplanin• Covers VISA, VRSA, and linezolid-resistant S. aureus• Dosing: 1000mg IV x 1 dose

– then 500mg IV x 1 dose 7 days later• Studied in skin/skin structure and catheter-related

bloodstream infections• Side Effects: nausea, diarrhea, constipation, oral

candidiasis• Not yet FDA approved • Also on the horizon: Telavancin and Ortivancin

Pharmacotherapy 2006; 26(7): 908-918

Community Acquired MRSA

Community-Acquired MRSA

• Initially reported in the 1990’s• Infections usually seen in skin and soft tissue, bone and

joint, and pneumonia• Predilection for skin; cellulitis, abscesses; often mistaken

for spider bites (note: abscesses must be drained in order for therapy to be effective)

• Non-Beta-Lactam antibiotics usually work• Very virulent, especially due to toxins

Ann Pharmacother 2006; 40: 1125-1133

CA-MRSA (‘cont)

• Typically diagnosed initially in outpatient setting• Patients can be young, healthy people; common in

athletes• CA-MRSA has different genotype than HA-MRSA• Contains SCCmec IV and the PVL virulence factor

Ann Pharmacother 2006; 40: 1125-1133

Therapy for CA-MRSA

• Expert consensus recommendations not available• Double antibiotic coverage should be considered

due to resistance issues:

– Doxycycline/Minocycline: bacteriostatic, minimal data– TMP/SMX: dose at 10-15mg/kg… seeing resistance issues– Clindamycin: Inducible resistance may be a problem– Levofloxacin (750mg) – Vancomycin– Linezolid and Daptomycin

Note: Rifampin an be added to any of the above - never use alone as resistance will develop

Ann Pharmacother 2006; 40: 1125-1133

Dosing for CA-MRSA (Adults)

• TMP-SMX: 1-2 DS (double strength) tabs orally q8-12h– typically dosed 2 twice daily; if pt can’t tolerate, give 1 QID – take with FULL glass of water.

• Doxycycline or Minocycline: 100mg orally BID• Clindamycin: 300-450mg orally QID• Levofloxacin: 750mg orally daily x 5 days• Rifampin (in combination with other agents): 300mg orally

BID for 5 days

2006 Georgia Guideline ; GUARD Coalition, June 2006

CA-MRSA in Children

• Clindamycin and TMP-SMX are reasonable empiric choices for mild to moderate CA-MRSA

• Vancomycin should be given with or without rifampin and/or gentamicin for severe infections

• Linezolid should be reserved for VRE, VISA or VRSA

Pharmacotherapy 2006; 26 (12):1758-1770

Dosing for CA-MRSA (Children)

• TMP/SMX (Base dose on TMP): 8-12mg TMP per kg/day in 2 doses

• Clindamycin: 10-20 mg/kg per day in 3-4 doses• Rifampin (in combination with other agents): 10-12

mg/kg per day in 2 doses• Do not exceed adult doses• Doxycycline or Minocycline not recommended in

children.• Tetracycline can be used in children greater than 8

years old

2006 Georgia Guidelines; GUARD Coalition June 2006

Inducible Clindamycin Resistance

• If a sensitivity report shows a CA-MRSA is erythromycin resistant and clindamycin sensitive, clindamycin might not work

• 20-26% of CA-MRSA has inducible clindamycin resistance

• Local susceptibility patterns should be taken into account when making treatment decisions

Inducible Clindamycin Resistance

• Macrolides can induce Clindamycin resistance• D-test can be done to confirm and visualize resistance• Place an erythromycin and clindamycin disk on an agar

plate• If exposure to erythromycin triggers inducible clindamycin

resistance, the normally circular zone of inhibition around the clindamycin disk will appear flattened, creating a “D” shape

Inducible Clindamycin Resistance

Antimicrob Agents Chemother 2005; 49(3): 1222-1224

Antimicrobial Susceptibilities: CA- and HA-MRSA

JAMA 2003, 290: 2976-2984

Estimated SusceptibilityCA-MRSA

• 100% to linezolid, vancomycin, and daptomycin• 95-100% to TMP-SMX, doxycycline, minocylcine • 91-99% to rifampin• 80-95% to clindamycin• 64-79% to levofloxacin (750mg) and moxifloxacin (do not

use Cipro)

NEJM 2006; 355: 666-674

Therapy Considerations

• Resistance will continue to grow– Use your hospital’s antibiogram to direct therapy– Make sure dose is adequate to achieve penetration– Reserve the newer agents for pts unable to tolerate/unresponsive

to traditional choices

• Direct comparative trials between new and old drugs are lacking

• Oral options are more limited than IV– If pt unable to afford oral Zyvox, consider Pfizer’s RSVP program

(1-888-327-7787)

MRSA ABX Acq. Cost ComparisonDrug Acq Cost Dose Freq/Day Cost/Day** Duration

Bactrim DS PO $0.25 1 3 $0.75 10 days

alternative regimen $0.25 2 2 $0.50 10 days

Cleocin 300mg PO $0.61 300 4 $2.44 10 days

Cubicin 500mg IV $156.70 4mg/KG 1 $0.00 7-14 days

Doxycycline 100mg PO $0.37 100 2 $0.74 10 days

Levaquin 750mg IV $17.21 750 1 $17.21 5 days

Levaquin 750mg PO $15.14 750 1 $15.14 5 days

Minocin 100mg PO $0.42 100 2 $0.84 10 days

Minocin 50mg PO $0.21 50 4 $0.84 10 days

Mupirocin 0.9gm PKT*** $0.47 1 2 $0.94 5 days

Rifampin 300mg PO $1.03 300 2 $2.06 5 days

Rifampin 600mg IV $76.38 300 2 $152.76 5 days

Synercid 500mg IV $110.13 7.5mg/KG 2 $0.00 Min 7 days

Tygacil 50mg IV $41.07 50 2 $82.14 5-14 days

Vancomycin 1GM ADV $6.33 wt/renal based   $0.00 10-14 days

Vancomycin 1GM FRZ $7.35 wt/renal based   $0.00 10-14 days

Vancomycin 1GM IV $5.85 wt/renal based   $0.00 10-14 days

Vancomycin 500mg IV $2.92 wt/renal based   $0.00 10-14 days

Vancomycin 500mg IV ADV $3.19 wt/renal based   $0.00 10-14 days

Zyvox 600mg IV $70.47 600 2 $140.94 10-14 days

Zyvox 600mg PO $55.00 600 2 $110.00 10-14 days

Short Case Studies

Case Study #1

A 24 year old woman presented in the ER with a large abscess that she thought was caused by a spider bite. She has an elevated temperature and white blood cell count and has been admitted to the facility. The attending physician ordered Levaquin and Rifampin. The dose seems appropriate, but she is not getting better.

What is the next step to best treat this patient?

Case Study #2

A surgeon has a patient with MRSA he wants to put on Zyvox as she has previously failed treatment with Vancomycin. The physician would like to discharge patient on oral therapy. The patient has a history of thrombocytopenia invoking concern of medication side effects.

How should this patient be monitored?

Case Study #3

A 66 year old nursing home patient was brought to the ER in an unresponsive state with vomit on his gown. He has dark urine and decreased urinary output. He has diabetes, HTN, chronic renal disease, COPD and dyslipidemia. His history is significant for bypass surgery, stents, hip fracture and back surgery. He is admitted to the ICU and placed on a ventilator. The ID physician consultant placed him on Zosyn and Vancomycin. Today a sputum culture came back positive for MRSA.

The attending physician asks you for a decolonization protocol for MRSA. What is your response?

If the intervention is not documented…

Document your interventions!– If the intervention is not documented, it did not happen– Receive credit for your efforts– If the patient is readmitted, the information is necessary

for optimal care– Physician trending is a useful P&T tool for identifying

credentialing issues– Successful interventions are a corporate goal for

improving patient safety, reducing LOS, and controlling supply costs