Infective%20endocarditis%20(pediatric) Treatment

Treatment

Principles of Therapy

In uncomplicated cases, antibiotics should be postponed up to 48 hours until results of initial blood culture are known
Empiric antibiotic treatment should be initiated immediately after 3 blood cultures 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 & enterococci
- Community-acquired native valve endocarditis/late prosthetic valve endocarditis: Ampicillin IV plus antistaphylococcal Penicillins IV plus Gentamicin IV/IM or Vancomycin IV plus Gentamicin IV/IM
- Early prosthetic valve endocarditis: Vancomycin IV plus Gentamicin IV/IM plus Rifampin IV/PO

Subsequent changes in the antibiotic regimen should be based on the results of culture & sensitivity testing

Initial Antibiotic Regimen

Combining an antistaphylococcal penicillin with an aminoglycoside covers against S viridans, S aureus & Gram negative organisms
Vancomycin can be substituted for a semisynthetic penicillin if methicillin-resistant Staphylococcus aureus infection or Penicillin allergy is suspected

General Therapeutic Principles

Counting days of duration of therapy should start on the 1st day on which blood cultures become negative in cases in which initial blood cultures were positive
At least 2 sets of blood cultures should be obtained every 24-48 hours until blood stream infection is cleared
Prolonged therapy of at least 4 weeks or 6-8 weeks is recommended
For patients with native valve endocarditis who undergo valve resection with prosthetic valve replacement, the post-op treatment should be the one recommended for prosthetic valve endocarditis
- 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 native valve endocarditis before valve replacement

Determination of the minimum inhibitory concentration (MIC) of an antibiotic may be used in choosing the best treatment against the causative agent especially against atypical organisms, agents resistant to 1st-line treatments, & uncontrolled bacteremia
Bactericidal agents should be used rather than bacteriostatic antimicrobials based on reported high incidence of treatment failures & relapses with bacteriostatic agents
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

Pharmacotherapy

Streptococcal Infective Endocarditis

Penicillin-Susceptible Viridans Group Streptococci (MIC ≤0.1 mcg/L)

Ceftriaxone or Penicillin G
- Both agents when used alone for 4 weeks obtain high bacteriologic cure rates
- 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, Ceftriaxone or Penicillin) plus Gentamicin
- When given in selected patients, gives similar cure rates to 4 weeks of monotherapy
- (Ampicillin, Ceftriaxone or Penicillin) x 6 weeks plus Gentamicin x 2 weeks is recommended for those with prosthetic valve endocarditis
- Should be used with caution in children especially those at increased risk for aminoglycoside-related adverse events
- Once daily dosing of Gentamicin may be used

Relatively Resistant Viridans Group Streptococci (MIC >0.1 to 0.5 mcg/L)

(Ampicillin, Ceftriaxone or Penicillin) x 4 weeks plus Gentamicin x 2 weeks should be given
(Ampicillin, Ceftriaxone or Penicillin) plus Gentamicin x 6 weeks is recommended for those with prosthetic valve endocarditis

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

Should be treated with regimens recommended for enterococcal endocarditis

Nutritionally variant Viridans Streptococci

Should be treated with regimens recommended for enterococcal endocarditis

Special cases

Vancomycin plus Gentamicin x 4 weeks is recommended for those unable to tolerate β-lactam antibiotic agents
- Given for 6 weeks for those with prosthetic valve endocarditis

Patients with native valve endocarditis caused by S pneumoniae may be given Penicillin with or without aminoglycosides

Enterococcal Infective Endocarditis

All enterococci causing infective endocarditis should be tested for antimicrobial susceptibility to determine optimal therapy
- In vitro susceptibility to Penicillin & Vancomycin along with high-level resistance to Gentamicin & 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
Cephalosporins should not be used to treat enterococcal infective endocarditis regardless of in vitro susceptibility

Ampicillin or Penicillin G + Aminoglycoside

For enterococcal strains susceptible to Penicillin:
- Bactericidal activity of Ampicillin is 2x that of Penicillin against E faecalis
- Penicillin may be preferred because higher serum concentrations of Penicillin will compensate for the difference & because it is important to avoid Ampicillin rash during long-term treatment
- Recommended treatment duration is 4-6 weeks for native valve endocarditis & prolonged to 6 weeks for those with prosthetic valve endocarditis

Enterococci with High-level Resistance to Gentamicin

These enterococci are usually resistant to all other aminoglycosides except Streptomycin (test independently for Streptomycin sensitivity)

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 & Strains Resistant to Both Gentamicin & Streptomycin

Consultation with microbiologist/infectious disease specialist is recommended

Staphylococcal Infective Endocarditis

Appropriate antibiotic therapy should be started promptly to improve overall prognosis
S aureus in non-IVDA usually involves the left-sided cardiac valves
Factor in determining antibiotic treatment is whether the organism is sensitive to Methicillin
Gentamicin in the following regimens should be administered in multiple daily-dosing at 3 mg/kg/day

Native Valve Endocarditis - Methicillin-Susceptible Staphylococcus aureus (NVE-MSSA)

Antistaphylococcal Penicillin (Nafcillin or Oxacillin) with or without Gentamicin
- Antistaphylococcal Penicillin is the treatment of choice
- Adding Gentamicin for the 1st 3-5 days may protect the infected valve from further damage & may decrease the duration of bacteremia which may result in faster defervescence

Antistaphylococcal penicillin + Fusidic Acid
- This combination may be an option for Fusidic acid sensitive strains

Cephalosporin (1st Generation) with or without Gentamicin
- May be used for the treatment of methicillin-susceptible Staphylococcus aureus endocarditis when patient has non-anaphylactoid Penicillin allergy

4-week therapy with antistaphylococcal penicillin or cephalosporin may be used for uncomplicated infection
- Complicated infective endocarditis eg abscess formation or septic metastatic complications should be treated x 6 weeks

Vancomycin + Gentamicin
- Reserved for patients allergic to beta-lactams; there are recent reports of suboptimal outcomes with Vancomycin therapy for serious S aureus infections
- Vancomycin + Gentamicin x 3-5 days in methicillin-susceptible Staphylococcus aureus is associated with faster clearing of bacteremia

Native Valve Endocarditis - Methicillin-Resistant Staphylococcus aureus (NVE-MRSA)

Vancomycin
- Treatment of choice in methicillin-resistant Staphylococcus aureus
- Most methicillin-resistant Staphylococcus aureus are also resistant to aminoglycosides therefore addition of Gentamicin is not likely to change the course of infection; if the strain is susceptible may use x 3-5 days
- Rifampicin is not necessary in uncomplicated cases

Linezolid or (Co-trimoxazole, Doxycycline or Minocycline with or without Rifampicin)
- These agents may be an option in patients who are intolerant of Vancomycin or fail therapy
- Data on clinical efficacy is limited compared to other agents

Prosthetic Valve Endocarditis- Methicillin-Susceptible Staphylococcus aureus (PVE-MSSA)

Antistaphylococcal Penicillin + Rifampicin + Gentamicin
- S aureus infective endocarditis in prosthetic valve endocarditis patients has a high mortality rate & surgery should be combined with antimicrobial therapy
- Though in vitro & clinical studies are lacking, it is accepted that this 3 drug combination is used to treat methicillin-susceptible Staphylococcus aureus in prosthetic valve endocarditis
- Cefazolin may be substituted for those w/ non-anaphylactoid-type Penicillin allergy

Vancomycin + Rifampicin + Gentamicin
- Used for methicillin-resistant Staphylococcus aureus & coagulase negative staphylococci

Infective Endocarditis Caused by HACEK

HACEK group may not be identified in blood culture for a week or longer & empiric antibiotics may be necessary while awaiting culture results
β-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 & Ampicillin should not be used for treatment

Ceftriaxone
- Single agent use is justified by its excellent pharmacokinetic profile
- Effective against both β-lactamase producing & non-β-lactamase producing strains of the HACEK group
- May be administered alone x 4 weeks in native valve endocarditis & x 6 weeks in prosthetic valve endocarditis
- Alternative: Another 3rd or 4th generation cephalosporin or Ampicillin plus Gentamicin

Other Causes of Infective Endocarditis

Treatment of these less common causes of infective endocarditis are still not adequately defined
May consider giving an extended-spectrum penicillin (Piperacillin/Tazobactam) or cephalosporin (Ceftazidime, Ceftriaxone, Cefotaxime) plus an aminoglycoside x >6 weeks
- There are limited data on the pediatric use of quinolones for infective endocarditis

Bartonella sp

Most cases of Bartonella sp infective endocarditis have required antibiotic therapy & 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 & reinfection of prosthetic material occurs after surgical replacement of infected valves

Pseudomonas aeruginosa

Most cases occur in IV drug abusers & right-sided pseudomonal infective endocarditis can usually be treated with antibiotic therapy with or without surgery
Valve replacement is usually considered mandatory in left-sided pseudomonal infective endocarditis since medical therapy is rarely effective alone

Enterobacteriaceae sp

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

Fungi

Amphotericin B with or without Flucytosine remains the 1st-line therapy for fungal infective endocarditis
Surgery combined with antifungal agents is necessary for most patients

RECOMMENDED ANTIMICROBIAL THERAPY
Choice of therapy will depend on results of culture & sensitivity, patient’s allergy profile, patient status & cardiovascular risk factors. If possible, reserve Vancomycin for patients with severe Penicillin allergy.
Pathogen	Native Valve Endocarditis	Prosthetic Valve Endocarditis
Viridans group streptococci, Streptococcus bovis Penicillin-susceptible	Ceftriaxone IM/IV x 4 weeks	Ceftriaxone IM/IV x 6 weeks with or without Gentamicin IM/IV x 2 weeks
	Penicillin G IV x 4 weeks
	Penicillin G IV or Ceftriaxone IM/IV x 2 weeks plus Gentamicin IM/IV x 2 weeks	Penicillin IV x 6 weeks with or without Gentamicin IM/IV x 2 weeks
	Vancomycin IV x 4 weeks	Vancomycin IV x 6 weeks
Viridans group streptococci, Streptococcus bovis Penicillin-relatively resistant (Pen MIC >0.1 but ≤0.5 mcg/L)	Ceftriaxone IM/IV x 4 weeks plus Gentamicin IM/IV x 2 weeks	Ceftriaxone IM/IV x 6 weeks plus Gentamicin IM/IV x 6 weeks
	Penicillin G IV x 4 weeks plus Gentamicin IM/IV x 2 weeks	Penicillin IV x 6 weeks plus Gentamicin IM/IV x 6 weeks
	Vancomycin IV x 4 weeks	Vancomycin IV x 6 weeks
Viridans group streptococci, Streptococcus bovis Penicillin-resistant (Pen MIC >0.5 mcg/L) or Enterococci strains susceptible to Vancomycin, Penicillin, Gentamicin	Ampicillin IV x 4-6 weeks plus Gentamicin IM/IV x 4-6 weeks
	Amoxicillin IV x 4-6 plus Ceftriaxone IM/IV x 6 weeks
	Penicillin G IV x 4-6 weeks plus Gentamicin IM/IV x 4-6 weeks
	Vancomycin IV x 6 weeks plus Gentamicin IM/IV x 6 weeks
Enterococci strains susceptible to Penicillin, Streptomycin & Vancomycin but resistant to Gentamicin	Ampicillin IV x 4-6 weeks plus Streptomycin IM/IV x 4-6 weeks
	Penicillin IV x 4-6 weeks plus Streptomycin IM/IV x 4-6 weeks
	Vancomycin IV x 6 weeks plus Streptomycin IM/IV x 6 weeks
Enterococci strains resistant to Penicillin & susceptible to aminoglycoside & Vancomycin	Beta-lactamase - producing strain: Ampicillin-Sulbactam IV x 6 weeks plus Gentamicin IM/IV x 6 weeks Vancomycin IV x 6 weeks plus Gentamicin IM/IV x 6 weeks
	Intrinsic Penicillin resistance: Vancomycin IV x 6 weeks plus Gentamicin IM/IV x 6 weeks
Enterococci strains resistant to Penicillin, aminoglycoside & Vancomycin	*E. faecium:* Linezolid IV/PO x ≥8 weeks Quinupristin-Dalfopristin IV x ≥8 weeks
	*E. faecalis:* Imipenem/Cilastatin IV x ≥8 weeks plus Ampicillin IV x ≥8 weeks Ceftriaxone IM/IV x ≥8 weeks plus Ampicillin IV x ≥8 weeks
Methicillin-susceptible S aureus (MSSA)	Antistaphylococcal penicillin IV x 4-6 weeks with optional addition of Gentamicin IM/IV x 3-5 days	Antistaphylococcal penicillin IV x ≥6 weeks plus Rifampicin PO/IV x ≥6 weeks plus Gentamicin IM/IV x 2 weeks
	Antistaphylococcal penicillin IV x 4-6 weeks plus Fusidic acid PO x 4-6 weeks
	For Penicillin-allergic patients: Cephalosporin (1st gen) IV x 6 weeks with optional addition of Gentamicin IM/IV x 3-5 days
	Co-trimoxazole IV X 1 wk plus PO x 5 weeks plus Clindamycin IV x 1 week
	Vancomycin IV x 4-6 weeks
Methicillin-resistant S aureus (MRSA)	1st-line agent: Vancomycin IV x 4-6 weeks	Vancomycin IV x ≥6 weeks plus Rifampicin PO/IV x ≥6 weeks plus Gentamicin IM/IV x 2 weeks
	Vancomycin treatment failure/intolerance may try the following: Daptomycin IV x 4-6 weeks or Co-trimoxazole IV x 1 week plus Clindamycin IV x 1 week or Linezolid or Doxycycline or Minocycline with or without Rifampicin
Fungi	Amphotericin B IV x 4-6 weeks or Flucytosine PO x 4-6 weeks	-
HACEK organisms	Ceftriaxone IM/IV x 4 weeks or Cefotaxime IV x 4-6 weeks or Ampicillin/Sulbactam IV x 4 weeks or Gentamicin or Tobramycin IV x 4-6 weeks or Amikacin IV x 4-6 weeks	-
Culture negative endocarditis including Bartonella sp	Ampicillin/Sulbactam IV x 4-6 weeks plus Gentamicin IM/IV x 4-6 weeks	Early, Prosthetic Valve Endocarditis (≤1 year) Vancomycin IV x 6 weeks plus Gentamicin IM/IV x 2 weeks plus Cefepime IV x 6 weeks plus Rifampicin PO/IV x 6 weeks
	Vancomycin IV x 4-6 weeks plus Gentamicin IV/IM x 4-6 weeks plus Ciprofloxacin¹ PO/IV x 4-6 weeks	Late, Prosthetic Valve Endocarditis (>1 year) Ampicillin/sulbactam IV x 4-6 weeks plus Gentamicin IM/IV x 4-6 weeks Or Vancomycin IV x 4-6 weeks plus Gentamicin IV/IM x 4-6 weeks plus Ciprofloxacin¹ PO/IV x 4-6 weeks
		*Suspected Bartonella* negative culture** Ceftriaxone IM/IV x 6 weeks plus Gentamicin IM/IV x 2 weeks with or without Doxycycline PO/IV x 6 weeks
		Bartonella confirmed Doxycycline PO/IV x 6 weeks plus Gentamicin² IM/IV x 2 weeks
Pseudomonas aeruginosa	Treatment should be based on in vitro sensitivity studies Antipseudomonal beta-lactam x 6 weeks plus Tobramycin x 6 weeks	Treatment should be based on in vitro sensitivity studies Antipseudomonal beta-lactam plus Tobramycin
Enterobacteriaceae sp (E coli, Klebsiella sp, Enterobacter sp & Serratia sp)	Treatment should be based on in vitro sensitivity studies Beta-lactam at high doses x 4-6 weeks plus Gentamicin x 4-6 weeks	Treatment should be based on in vitro sensitivity studies Beta-lactam at high doses plus Gentamicin
¹Ciprofloxacin is generally not recommended for patients <18 years of age. ²May be replaced with Rifampin PO/IV if Gentamicin cannot be given

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