Infective%20endocarditis Treatment

EMPIRIC PHARMACOLOGICAL THERAPY

General Therapeutic Principles

• Counting days of duration of therapy should start on the first day on which blood cultures (BCs) were negative in cases in which initial BCs were positive
• At least 2 sets of BCs should be obtained every 24-48 hours until bloodstream infection is cleared
• For patients with native valve endocarditis (NVE) who undergo valve resection with prosthetic valve replacement, the post-op treatment should be the one recommended for NVE, not for prosthetic valve endocarditis (PVE)
  
  • If the resected tissue is culture positive, then the entire course of therapy is recommended after valve resection
  • If the resected tissue is culture negative, then treatment should be given less the number of days of treatment administered for NVE before valve replacement

• If combination antimicrobial therapy is used, then the agents should be administered close together to improve synergistic killing effect
• Antibiotic prophylaxis has been limited to patients undergoing an invasive dental procedure in whom exists a history of infective endocarditis (IE), prosthetic valve, a heart transplant with abnormal heart valve function, or congenital heart disease with the following: Unrepaired cyanotic congenital heart disease, congenital heart defect completely repaired with prosthetic material or device for the first 6 months post procedure, or repaired congenital heart disease with residual defects
  
  • Patients with prosthetic valves are at the highest risk of developing IE
  • Recommended prophylaxis regimens include the standard Amoxicillin, Ampicillin if unable to take PO medications, and Clindamycin [PO or intravenous (IV)], Cefazolin or Cefalexin if with penicillin allergy
  • Recommended prophylaxis regimen for genitourinary and gastrointestinal procedures should include drugs against enterococci eg Ampicillin or Vancomycin

Empiric Therapy

• Initial empiric therapy for IE will depend on the following factors:
  • Acute or subacute presentation
  • Whether the infection involves native or prosthetic valves
  • Duration following prosthetic surgery: Early versus late PVE
  • Whether the patient has received previous antibiotic treatment
  • Community-acquired or healthcare-associated
  • Presence of risk factors for fastidious organisms and for multidrug resistant microorganism

• In uncomplicated cases, antibiotics may be postponed up to 48 hours until results of initial BCs are known
• Empiric antibiotic treatment should be initiated immediately after 3 BCs have been taken in cases complicated by:
  
  • Sepsis, severe valvular dysfunction, conduction disturbances or embolic events

• Empiric therapy should include use of agents that are effective against streptococci, staphylococci and enterococci
• Subsequent changes in the antibiotic regimen should be based on the results of culture and sensitivity testing
• Empiric therapy for intravenous drug abusers (IVDA) depends on the suspected microorganism, type of drug and solvent used by the addict and infection location
  • Most common causative agents are staphylococci followed by streptococci and enterococci and initial treatment should cover these organisms
  • In suspected right-sided IE empiric treatment should include penicillinase-resistant penicillins, Vancomycin or Daptomycin; empiric therapy should also cover for streptococci and enterococci in IVDAs with left-sided IE and underlying valve lesions

PATHOGEN-SPECIFIC PHARMACOLOGICAL THERAPY

General Therapeutic Principles

• Counting days of duration of therapy should start on the first day on which BCs become negative in cases in which initial BCs were positive
• At least 2 sets of BCs should be obtained every 24-48 hours until blood stream infection is cleared
• For patients with NVE who undergo valve resection with prosthetic valve replacement, the post-op treatment should be the one recommended for NVE, not for PVE
  
  • If the resected tissue is culture positive, then the entire course of therapy is recommended after valve resection
  • If the resected tissue is culture negative, then treatment should be given less the number of days of treatment administered for NVE before valve replacement

• If combination antimicrobial therapy is used, then the agents should be administered close together to improve synergistic killing effect

The therapeutic goal is to produce bactericidal levels of drugs at the infected site for a maximum period of time

Streptococcal IE

Highly Penicillin-Susceptible Viridans Group Streptococci and S gallolyticus (MIC ≤0.12 mg/L)

• Penicillin, Amoxicillin, Ampicillin or Ceftriaxone
  
  • These agents when used alone for 4 weeks obtain high bacteriologic cure rates (≥98%)
  • 4 weeks of monotherapy has the advantage of avoiding the potential ototoxic or nephrotoxic effects of Gentamicin
  • Ceftriaxone has the advantage of once-daily dosing
  • Ampicillin may be used as alternative when Penicillin is not available

• (Penicillin, Amoxicillin or Ceftriaxone) plus Gentamicin or Netilmicin for the first 2 weeks
  
  • When given in selected patients, gives similar cure rates to 4 weeks of monotherapy
  • Once-daily dosing of Gentamicin may be used

• Vancomycin
  
  • Reserved for patients who are unable to tolerate Penicillin or Ceftriaxone

• Teicoplanin
  
  • Alternative drug that may be used once daily to treat streptococcal IE in penicillin-allergic patients
  • Inadequate doses can result in treatment failure
  • Steady-state serum is achieved only after 1 week

Relatively Penicillin-Resistant Viridans Group Streptococci and S gallolyticus (MIC >0.12 to ≤0.5 mg/L)

• (Penicillin, Amoxicillin or Ampicillin) for 4 weeks plus Gentamicin for 2 weeks should be given
  
  • Once-daily dosing of Gentamicin may be used

• Ceftriaxone
  • Alternative if isolate is Ceftriaxone-susceptible

• Vancomycin
  
  • Reserved for patients who are unable to tolerate Penicillin, Amoxicillin or Ampicillin

Highly Resistant Viridans Group Streptococci (MIC >0.5 mg/L)

• Should be treated with regimens recommended for enterococcal endocarditis

• Penicillin-susceptible S pneumoniae (MIC ≤0.06 mg/L)
  • Penicillin, Amoxicillin, Cefazolin or Ceftriaxone for 4 weeks for NVE and 6 weeks for PVE
  • Vancomycin for 4 weeks for NVE and 6 weeks for PVE is reserved for beta-lactam-allergic patients

• Penicillin-resistant S pneumoniae (MIC 0.125-≥4 mg/L)
  • Without meningitis: High-dose penicillin or third generation cephalosporin or Vancomycin
  • With meningitis: High doses of Cefotaxime or Ceftriaxone alone or in combination with Vancomycin and Rifampicin depending on the susceptibility pattern

• S pyogenes IE
  • Penicillin or Ceftriaxone for 4-6 weeks is the recommended regimen
  • Vancomycin is reserved for patients with beta-lactam allergy

• IE caused by groups B, C or G streptococci
  • Recommended regimen includes Penicillin, Amoxicillin or Ceftriaxone for 4-6 weeks plus Gentamicin for at least the first 2 weeks
  • Produce abscesses and may require adjunctive surgery

• Antimicrobial susceptibility is technically difficult to determine because it is slow growing
• Recommended regimen includes Penicillin, Ampicillin, Ceftriaxone or Vancomycin for 6 weeks plus an aminoglycoside (eg Gentamicin) for at least the first 2 weeks

Enterococcal IE

• All enterococci causing IE should be tested for antimicrobial susceptibility to determine optimal therapy
  
  • In vitro susceptibility to Penicillin or Ampicillin and Vancomycin along with high-level resistance to Gentamicin and Streptomycin should be tested

• Successful treatment requires the synergistic action of Penicillin, Ampicillin or Vancomycin with either Gentamicin or Streptomycin
• Multi-daily dosing should be used for the aminoglycosides

Ampicillin or Penicillin + Aminoglycoside

• Treatment duration is 4-6 weeks
• For enterococcal strains susceptible to Penicillin:
  
  • Bactericidal activity of Ampicillin is 2 times that of Penicillin against E faecalis
  • Penicillin may be preferred because higher serum concentrations of Penicillin will compensate for the difference and because it is important to avoid Ampicillin rash during long-term treatment

• Ampicillin plus Ceftriaxone for 6 weeks
• Alternative regimen for patients with enterococcal strains susceptible to beta-lactams and with resistance to aminoglycosides or pre-existing mild or severe renal failure

Enterococci with High-level Resistance to Gentamicin

• These enterococci are usually resistant to all other aminoglycosides except Streptomycin
• Combination therapy with Ampicillin and Ceftriaxone should also be considered

Glycopeptides (Vancomycin, Teicoplanin) + Aminoglycoside

• Should be reserved for patients allergic to Penicillin or in Penicillin-resistant strains
• Glycopeptides need to be combined with aminoglycosides since they are not usually bactericidal against enterococci

Vancomycin-Resistant Strains and Strains Resistant to Both Gentamicin and Streptomycin

• Consultation with microbiologist/infectious disease specialist is recommended
• Treatment options include Linezolid or Daptomycin for >6 weeks

Staphylococcal IE

• Appropriate antibiotic therapy should be started promptly to improve overall prognosis
• S aureus in non-IVDA usually involves the left-sided cardiac valves
• Tricuspid valve is usually involved in S aureus IE in IVDA
• Factor in determining antibiotic treatment is whether the organism is sensitive to Methicillin

NVE - Penicillin-Susceptible S aureus

• <10% of IE strains of S aureus are susceptible to Penicillin
• Penicillin may be used for 4 weeks

NVE - MSSA

• Antistaphylococcal Penicillin is the treatment of choice (eg Cloxacillin, Flucloxacillin, Nafcillin, Oxacillin)
  • Combination therapy with Gentamicin is not recommended because of increased risk of Gentamicin resistance, lack of clear-cut efficacy and increased risk of nephrotoxicity

• Cephalosporin (First Generation) 
  
  • Eg Cefazolin 
  • May be used for the treatment of MSSA endocarditis when patient has non-anaphylactoid Penicillin allergy

• 6 weeks of therapy with antistaphylococcal Penicillin or cephalosporin may be used for uncomplicated infection
  
  • Complicated IE eg abscess formation or septic metastatic complications should be treated for ≥6 weeks

• Vancomycin
  
  • Reserved for patients allergic to beta-lactams; there are recent reports of suboptimal outcomes with Vancomycin therapy for serious S aureus infections
• Daptomycin
  • Alternative to Vancomycin and reserved for patients allergic to beta-lactams

NVE - MRSA

• Vancomycin
  
  • Treatment of choice in MRSA
  • Treatment duration is 6 weeks
  • Addition of Gentamicin or Rifampin to Vancomycin is not recommended for native valve IE because of increased risk of toxicity and lower survival rate

• Daptomycin
  • Alternative to Vancomycin
  • Treatment duration is 6 weeks

• Linezolid plus beta-lactams or (Co-trimoxazole plus Clindamycin) with or without Rifampicin
  
  • These agents may be an option in patients who are intolerant of Vancomycin or have failed therapy
  • Data on clinical efficacy is limited compared to other agents
  • Co-trimoxazole is inferior to Vancomycin but is used as alternative drug
  • Routine use of Rifampicin as adjunct therapy is not recommended because of increased risk of adverse effects and lower survival rate

PVE - MSSA

• (Antistaphylococcal penicillin + Rifampicin) x ≥6 weeks, + Gentamicin for the first 2 weeks of treatment
  
  • S aureus IE in PVE patients has a high mortality rate and surgery should be combined with combination antimicrobial therapy
  • Though in vitro and clinical studies are lacking, it is accepted that this 3-drug combination is used to treat MSSA in PVE
  • Cefazolin may be substituted for those with non-anaphylactoid-type Penicillin allergy
  • Rifampicin is started after 3-5 days of therapy or after blood cultures are negative to prevent resistance

• Vancomycin + Rifampicin + Gentamicin
  
  • Used for MRSA and coagulase-negative staphylococci
  • If with resistance to Gentamicin, other aminoglycosides may be used eg Amikacin

• Quinolone
  
  • May be used in combination with Vancomycin and Rifampicin when the causative microorganism is resistant to all aminoglycosides

IVDA

Right-Sided Uncomplicated MSSA in IVDA

• 2 weeks antistaphylococcal penicillin or Daptomycin
  
  • Should be reserved for uncomplicated cases

• 4 weeks oral Ciprofloxacin + Rifampicin
  
  • Can be used in uncomplicated cases when compliance can be monitored
  • Though oral Ciprofloxacin and Rifampicin combination has been shown to be effective in IV drug users, currently, oral treatment for IE is recommended only when the following criteria are strictly met:
    • Only when the tricuspid valve is involved
    • Organism involved is susceptible to oral agents
    • Long-term IV treatment is impossible or difficult

Left-Sided or Complicated MSSA in IVDA

• Patient should be treated with standard 4-6 weeks treatment if:
  
  • After >96 hours patient fails to show clinical or microbiological response to antibiotic therapy, congestive heart failure (CHF), vegetations >20 mm, acute respiratory failure, septic metastatic foci outside the lungs, extra-cardiac complications (eg renal failure) or IVDA with severe immunosuppression with or without acquired immunodeficiency syndrome (AIDS)

Organisms Other Than MSSA in IVDA

• Treat as in non-addict

IE Caused by HACEK

• HACEK group may not be identified in BCs for a week or longer and empiric antibiotics may be necessary while awaiting culture results
• Beta-lactamase-producing strains of HACEK are appearing with increased frequency
  
  • Difficult to perform antimicrobial susceptibility tests on HACEK organisms; therefore, these should now be considered Ampicillin resistant and Ampicillin should not be used for treatment

• Ceftriaxone
  
  • Single-agent use is justified by its excellent pharmacokinetic profile
  • Effective against both beta-lactamase-producing and non-beta-lactamase-producing strains of the HACEK group
  • May be administered alone for 4 weeks in NVE and for 6 weeks in PVE
  • Alternative: Another third or fourth generation cephalosporin

• Ampicillin/sulbactam
  
  • Alternative for patients not able to tolerate Ceftriaxone or other third or fourth generation cephalosporins
  • Consultation with infectious disease specialist is recommended before using in patients intolerant to beta-lactams

• Quinolone
  
  • Eg Ciprofloxacin, Levofloxacin, Moxifloxacin 
  • In vitro activity against the HACEK group but limited clinical use; therefore, consult with infectious disease specialist before using in patients intolerant to beta-lactam therapy
  • Alternative for patients not able to tolerate Ceftriaxone or other third or fourth generation cephalosporins

Other Bacterial Causes of IE

• Treatment of these less common causes of IE is still not adequately defined
• In patients with difficult-to-treat organisms (as below) and those with intracardiac device or foreign bodies, surgery combined with antibiotic therapy may be considered

Bartonella sp

• Most cases of Bartonella sp IE have required antibiotic therapy and valve-replacement surgery for cure

Brucella sp

• Few patients have been cured with antimicrobial agents alone; most require valve replacement in combination with antibiotics

Coxiella burnetii

• Clinical response only persists as long as antimicrobial therapy continues; eradication is unlikely and reinfection of prosthetic material occurs after surgical replacement of infected valves

Pseudomonas aeruginosa

• Most cases occur in IVDA and right-sided pseudomonal IE can usually be treated with antibiotic therapy with or without surgery
• Valve replacement is usually considered mandatory in left-sided pseudomonal IE since medical therapy is rarely effective alone

Enterobacteriaceae sp

• Susceptibility of these organisms can be unpredictable; therefore, treatment should be based on susceptibility testing

• Voriconazole IV for ≥6 weeks plus Amphotericin B or echinocandin IV for ≥6 weeks after surgery and suppressive long-term treatment with Voriconazole PO

• Lipid formulation of Amphotericin B IV or Amphotericin B deoxycholate IV for ≥6 weeks with or without Flucytosine PO for ≥6 weeks after surgery and suppressive long-term treatment with Fluconazole or Voriconazole PO
• High-dose echinocandin (Anidulafungin, Caspofungin or Micafungin) IV for ≥6 weeks after surgery and suppressive long-term treatment with Fluconazole or Voriconazole PO
• Valve replacement is recommended
  • Long-term suppression with Fluconazole is recommended for patients who cannot undergo valve replacement

• Safe and effective method of completing therapy in patients with IE once infection-related complications are controlled
• Patients should have a minimum of 2 weeks IV therapy
• OPAT may be considered in patients who are medically stable, without high-risk cardiac features on echocardiogram, and no heart failure, neurologic signs or renal impairment

• Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2015;132:1435-1486.
• Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2015 Nov;36(44):3075-3128.