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MRSA – Practical approach to therapy and post antibiotics Era. Khalid Dousa, MD PGY-3 MRSA – Practical approach to therapy and post antibiotics Era. Khalid Dousa, MD PGY-3 Resident CWRU

Presentation Welcome Post antibiotics Era Overview of antibiotics and classification MRSA Basics MRSA – Presentation Welcome Post antibiotics Era Overview of antibiotics and classification MRSA Basics MRSA – Case based approach to therapy Final Massage

A young doctor is not so young nowadays; you typically don’t start in independent A young doctor is not so young nowadays; you typically don’t start in independent practice until your mid-thirties We live in the era of the super-specialist ‘’of clinicians who have taken the time to practice, practice and practice at one narrow thing until they can do better than anyone else’’

Do some thinking first - Indication? Evidence of infection What are you treating ? Do some thinking first - Indication? Evidence of infection What are you treating ? Any history/risk factor of MDR or MRSA ? If MRSA – What is the MIC ? Need to cover PSA/MRSA? Broad coverage - Have a plan for stewardship Always try to obtain cultures before starting antibiotics

S. Aureus • Clinical Isolates of Staphylococcus A that is resistant to nafcillin and S. Aureus • Clinical Isolates of Staphylococcus A that is resistant to nafcillin and other semi -synthetic anti Staph Penicillin's. • The emergence of antibiotic-resistant strains of S. aureus such as methicillinresistant S. aureus (MRSA) is a worldwide problem in clinical medicine. • Methicillin resistance in Staphylococcus aureus is defined as an oxacillin minimum inhibitory concentration (MIC) ≥ 4 mcg/m. L.

What is the MIC (Minimal inhibitory concentration): - • Is the lowest concentration of What is the MIC (Minimal inhibitory concentration): - • Is the lowest concentration of the antibiotic that prevents visible growth of the bacteria. • - Methicillin resistance in Staphylococcus aureus is defined as an oxacillin minimum inhibitory concentration (MIC) ≥ 4 mcg/m. L.

Terminology • MRSA: Methicillin resistant Staph A. to all Beta-lactams antibiotics except Ceftaroline • Terminology • MRSA: Methicillin resistant Staph A. to all Beta-lactams antibiotics except Ceftaroline • CA-MRSA: Strains of MRSA that are prevalent in the community; tend to be antibiotic susceptible (except to macrolides and fluroquinolones). • HA-MRSA: Strains of MRSA that are prevalent in hospitals (Hospitalacquired), tend to be multiple drug resistant. • VISA: Intermediate Vancomycin resistant Staph A (MIC 4 -8) VRSA: Vancomycin resistant Staph A (MIC >8). Fewer than 20 world wide

 • Was described shortly in 1961 after the introduction methicillin – outbreaks reported • Was described shortly in 1961 after the introduction methicillin – outbreaks reported in 1960’s • Prevalence of MRSA among S. Aureus isolates in ICU in USA is 60 %. • Methicillin resistance is mediated by PBP-2 a, a penicillin-binding protein encoded by the mec. A gene. The mec. A gene is located on a mobile genetic element called staphylococcal chromosome cassette (SCCmec).

IV Drugs used for management of MRSA IV Drugs used for management of MRSA

 • Vancomycin Glycopeptide – IV – Oral Form • Initial Dose and actual • Vancomycin Glycopeptide – IV – Oral Form • Initial Dose and actual body weight • Subsequent dosing depends on Through level • Always check for the MIC • Consensus guidelines support target through level of 15 -20 • Obesity frequently results in underdosing – See dosing

 • Special consideration – Common issues Red Neck Syndrome - pruritus, an erythematous • Special consideration – Common issues Red Neck Syndrome - pruritus, an erythematous rash that involves the face, neck, and upper torso. • This i not Allergy BUT infusion related – Slow the infusion 1. 5 – 2 Hr • Drug Induced Immune thrombocytopenia • Vancomycin through level of 5 -10 is adequate for infections of mild to moderate severity BUT if bacteremia is present 15 -20

 • Clindamycin • Good activity against MRSA and is also capable of inhibiting • Clindamycin • Good activity against MRSA and is also capable of inhibiting bacterial production of toxins, including Panton-Valentine leukocidin and other virulence factors. • Bacteriostatic and therefore should not be used for endovascular infections • It has excellent tissue penetration, particularly into bone and abscesses.

 • Isolates that appear susceptible to clindamycin and resistant to erythromycin by standard • Isolates that appear susceptible to clindamycin and resistant to erythromycin by standard susceptibility testing techniques may be capable of inducing resistance to clindamycin in the presence of the drug.

Trimethoprim-sulfamethoxazole • Not advisable for empiric management of soft tissue infections that may be Trimethoprim-sulfamethoxazole • Not advisable for empiric management of soft tissue infections that may be due to group A streptococci. • Some favor combination therapy using a beta-lactam antibiotic with activity against streptococci together with trimethoprim-sulfamethoxazole for empiric MRSA coverage. • Monotherapy with trimethoprim-sulfamethoxazole for treatment of uncomplicated skin infection may be reasonable for relatively young patients in the absence of systemic manifestations or comorbid conditions.

 • Tetracyclines • Not advisable for empiric management of soft tissue infections that • Tetracyclines • Not advisable for empiric management of soft tissue infections that may be due to group A streptococci. • Some favor combination therapy using a beta-lactam antibiotic with activity against streptococci together with trimethoprim-sulfamethoxazole for empiric MRSA coverage

 • Oxazolidinones (linezolid or tedizolid) • Linezolid has activity against both MRSA and • Oxazolidinones (linezolid or tedizolid) • Linezolid has activity against both MRSA and streptococci and has been shown to be as effective as vancomycin for the treatment of skin and soft tissue infection. • Renal impairment: No dosage adjustment necessary • Hepatic impairment: No dosage adjustment necessary

Special consideration when using Linezolid • Lactic acidosis: Has been reported with use. Patients Special consideration when using Linezolid • Lactic acidosis: Has been reported with use. Patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate levels need immediate evaluation • Myelosuppression • Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyperreflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs, agents which reduce linezolid's metabolism. • Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months post antibiotic treatment.

 • Daptomycin: • Increased incidence of myopathy Discontinue signs and symptoms of myopathy • Daptomycin: • Increased incidence of myopathy Discontinue signs and symptoms of myopathy in conjunction with an increase in CPK (>5 times ULN or 1, 000 units/L) or Asymptomatic patients with a CPK ≥ 10 times ULN. • Myopathy may occur more frequently at dose and/or frequency in excess of recommended dosages. Consider temporarily interrupting therapy with other agents associated with an increased risk of myopathy (eg, HMG-Co. A reductase inhibitors) during daptomycin therapy.

MRSA Bacteremia • Cause of community-acquired and hospital-acquired bacteremia • Mortality rates of 20 MRSA Bacteremia • Cause of community-acquired and hospital-acquired bacteremia • Mortality rates of 20 to 40 percent have been described • Mortality appears to be higher with methicillin-resistant (MRSA) compared with methicillin- sensitive S. aureus (MSSA) bacteremia • GPC in cluster – CNS vs Staph A. – Number of bottles

Evaluation: • H&P – Entry – Skin – Indwelling prosthetic devices • Symptoms of Evaluation: • H&P – Entry – Skin – Indwelling prosthetic devices • Symptoms of metastatic infection 30 % - Bone – protracted fever IE – Abdominal Pain – CP angle tenderness renal infarct (Psoas/Renal Infracts), Headache and focal neurological difict. • Examination: New murmur / Heart failure – Stigmata of IE, CNS Examination. • Serial bedside examinations - Complications may develop after initial assessment. • Catastrophic complications

All patients with S. aureus bacteremia should undergo TTE first TEE: • • • All patients with S. aureus bacteremia should undergo TTE first TEE: • • • Persistent S. aureus bacteremia despite appropriate antimicrobial therapy Unknown duration of bacteremia (ie, community-acquired infection) Presence of cardiac prosthetic material Presence of predisposing valvular abnormality Absence of evident removable source of bacteremia Hemodialysis dependency Evidence of infection involving the back (osteomyelitis, discitis, and/or epidural abscess) Presence of peripheral stigmata for IE Intravenous drug use

TREATMENT: • Prompt source control (such as removal of implicated vascular catheters and/or surgical TREATMENT: • Prompt source control (such as removal of implicated vascular catheters and/or surgical drainage of abscess if present) and antimicrobial therapy. Empiric treatment should consist of antimicrobial therapy with activity against methicillin-resistant S. aureus (MRSA) • Vancomycin • Daptomycin

 • Follow up: Document clearance of bacteremia (Repeat blood culture day 2 -4 • Follow up: Document clearance of bacteremia (Repeat blood culture day 2 -4 on antibiotics). • Growth after 48 hours of therapy is failure to clear, (prompt further evaluation). • Treatment failure: Relapse or prolonged bacteremia > 4 days Consider salvage therapy

 • Deescalate when cultures available – MSSA, (Oxacillin, Nafcillin, Cefazolin. . ) • • Deescalate when cultures available – MSSA, (Oxacillin, Nafcillin, Cefazolin. . ) • Vancomycin is less effective for treatment of S. aureus bacteremia than beta-lactam agents and should not be administered as primary therapy for methicillin-sensitive strains unless the use of a beta-lactam agent is precluded by drug intolerance

MRSA SSI: • Beta-lactam antibiotics are no longer reliable empiric therapy for skin and MRSA SSI: • Beta-lactam antibiotics are no longer reliable empiric therapy for skin and soft tissue infections • MRSA coverage if MRSA is suspected based upon local epidemiology, risk factors, or if the clinical features are not sufficient to make this determination

 • Incision and drainage alone may be sufficient for abscesses smaller than 5 • Incision and drainage alone may be sufficient for abscesses smaller than 5 cm. • Patients with larger abscesses and/or systemic signs of infection should be managed with incision and drainage plus antimicrobial therapy. • IV antibiotic’s Consider for patients with extensive soft tissue involvement, multiple soft tissue infections, fever or other signs of systemic illness, or patients with diabetes or other immunodeficiency (eg, HIV infection, transplant patients, or those receiving chemotherapy). • Clindamycin for its antitoxin effects against toxin-elaborating strains of streptococci and staphylococci in Necrotizing soft tissue infections.

Septic arthritis Documented septic arthritis when synovial fluid WBC > 25, 000 (>50, 000 Septic arthritis Documented septic arthritis when synovial fluid WBC > 25, 000 (>50, 000 is more specific) Risk factors – RA , DM, IV drug users, Skin infection Treatment Always need drainage – Ortho consult MRSA – Vancomycin – Alternative Dapto/Linezolid De-escalate if MSSA

MRSA PNA: MRSA is a frequent nosocomial pathogen in the institution. HCAP/HAP/VAP/CAP/Influenza associated PNA, MRSA PNA: MRSA is a frequent nosocomial pathogen in the institution. HCAP/HAP/VAP/CAP/Influenza associated PNA, IV drug abusers and Rt IE, Necessary first choice for anti-staphylococcal coverage • Vancomycin • Linezolid Use nasal swab PCR for Staph A. to exclude the possibility of Staph. A as the etiology of PNA. NPV of 99. 2%

Discontinue if MRSA is not isolated. • Daptomycin: cannot be used to treat pneumonia Discontinue if MRSA is not isolated. • Daptomycin: cannot be used to treat pneumonia because it does not achieve sufficiently high concentrations in the respiratory tract (Deactivated by pulmonary Surfactant). • Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA, which has been approved by the FDA for CAP but not for CAP caused by MRSA or for HAP, VAP, or HCAP

MRSA and meningitis: • Staphylococcus aureus meningitis is typically associated with penetrating head trauma MRSA and meningitis: • Staphylococcus aureus meningitis is typically associated with penetrating head trauma or neurosurgery. • Use Vancomycin • De-escalate if MSSA • Cover for gram negative empirically • A significant drawback to vancomycin is its poor penetration into the CSF. • Note: Vancomycin is standard empiric therapy for management of bacterial meningitis – it’s mainly used to cover penicillin-resistant pneumococcus and NOT MRSA.

 • MRSA prevention • Basic infection prevention principles include attention to careful hand • MRSA prevention • Basic infection prevention principles include attention to careful hand hygiene and adherence to contact precautions for care of patients with known MRSA infection. • Treat carriers • The optimal regimen and duration of therapy for eradicating MRSA colonization is uncertain. If decolonization is pursued, we favor a 5 - to 10 -day course of therapy with the following topical agents: • Chlorhexidine daily washes (2 or 4 percent solution) • Mupirocin ointment (2 percent) applied to nares with a cotton-tipped applicator two to three times daily • When to D/C contact precautions? 3 negative

References MKSAP 17 Upto. Date Sanford guide for antimicrobial therapy Youtube – Post antibiotic References MKSAP 17 Upto. Date Sanford guide for antimicrobial therapy Youtube – Post antibiotic Era