HYMR1

Tuesday, December 19, 2017

Empiric Antibiotic Considerations for Infective Endocarditis

There have been two recent FOAMed posts on the topic of endocarditis by REBEL EM and EMDocs. Both posts do a great job discussing risk factors, pathophysiology, signs and symptoms, and the diagnosis of endocarditis. However, we believe a more in-depth review of appropriate empiric antibiotic selection is prudent. As the ED pharmacist, we are ultimately responsible for making sure our patients get the most appropriate antibiotics. Additionally, whatever regimen is started downstairs is commonly continued upstairs. Therefore, if a patient is started on inappropriate therapy in the ED, it’s likely to continue until ID is able to see the patient, which may not be until the next day. Aside from decreased efficacy, inappropriate empiric antibiotics can also result in harm (e.g., AKI with aminoglycosides in native valve patients). We’re only giving one dose of antibiotics in the ED, so you’ve got one chance to get it right.

The 2016 IDSA Infective Endocarditis Guidelines(1) separate antimicrobial treatment recommendations into categories based on the causative pathogen(s) and the patient’s valve status (native versus prosthetic). Often empiric therapy for endocarditis is initiated in the ED because a patient is considered unstable. Unfortunately for us, this means we don't regularly have culture results to guide therapy and therefore must choose empiric regimens to cover all of the most likely pathogens.When considering which empiric antibiotics to use, we have always found it useful to split patients into two categories much the same way the IDSA guidelines do: native valve versus prosthetic valve as the pathogens differ slightly between these groups.

Native Valve
The IDSA recommendation for empiric antimicrobial therapy for native valve endocarditis in patients with acute presentation is cefepime + vancomycin. Cefepime provides coverage of aerobic gram-negative bacilli, Streptococcus spp., and superior methicillin-susceptible Staphylococcus aureus (MSSA) coverage when compared to vancomycin. Vancomycin primarily provides coverage of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus spp. when used in this regimen. Aminoglycosides are omitted from these empiric regimens as no benefit has been found with their addition in regards to clinical response, overall cure, or mortality for Staphylococcal endocarditis; although increased rates of nephrotoxicity were seen(2).

Prosthetic Valve
The IDSA recommendation for prosthetic valve endocarditis is cefepime + vancomycin + gentamicin + rifampin. Gentamicin is added for synergistic activity against Staphylococcus spp., Streptococcus spp. and Enterococcus spp., and rifampin is used to diminish Staphylococcal biofilms. Gentamicin is the preferred empiric aminoglycoside as some Enterococcus spp. possess an aminoglycoside acetyltransferase that confers high-level resistance to tobramycin and amikacin.

Dosing considerations
Cefepime-- 2 g IV; aggressive dosing is warranted in this high bacterial burden infection.

Rifampin-- 300 mg IV/PO; primarily studied at a dose of 900 mg/day divided in 3 separate does (i.e., 300mg q8 hours) in endocarditis, a dosing scheme unique to this disease state.

Gentamicin-- 1 mg/kg IV (based on ideal body weight, unless total body weight > 120% ideal body weight, then adjusted body weight). This is not extended-interval dosing, but instead synergistic dosing targeting a peak of 3-4 mcg/ml.

Vancomycin-- There is some variation in the IDSA’s endocarditis recommendations for trough targets depending on the pathogen:

  • For native valve Streptococcus spp., the trough goal is 10-15 mg/L
  • For native valve MRSA, the trough goal is 10-20 mg/L 
  • For prosthetic valve MRSA, the trough goal is 10-20 mg/L 
  • For PCN-resistant Enterococcus spp., the trough goal is 10-20 mg/L 

Again, as we are in the ED, we haven’t isolated a pathogen yet, so empirically we should be erring on the side of caution and tailor our dosing towards the higher trough targets of around 20 mg/L. Interestingly, the 2009 IDSA Vancomycin Guidelines(3) offer slightly different recommendations for goal vancomycin trough levels: 

Summary and recommendations: Based on the potential to improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital- acquired pneumonia caused by S. aureus, total trough serum vancomycin concentrations of 15–20 mg/L are recommended.
As you can see, higher trough ranges of 15-20 mg/L
have been previously recommended by the IDSA so it’s unclear why those recommendations are different than what’s stated in the endocarditis guidelines (10-15 mg/L and 10-20 mg/L). Either way, as you are empirically covering these patients for endocarditis and a bacteremia, it is best to go with the higher/more aggressive dosing targets (i.e., a trough goal of 15-20 mg/L). To achieve steady-state as quickly as possible, a loading dose can be utilized to help saturate the volume of distribution. In our practice we generally use a 25 mg/kg loading dose, capping doses at 2500 mg. Other institutions may have their own limits on the weight-based or maximum single dose, or employ a divided-load protocol. Either way, we recommend being aggressive and encourage giving as large a dose as permitted with the aim of reaching steady-state as soon as possible. 

Take Home Points

  • Definitive endocarditis treatment is based on the patient’s valve status (native vs prosthetic) as well as the causative pathogen(s) identified via blood cultures 
  • For our patients in the Emergency Department, most treatment is empirical and should be directed against the most likely pathogens for each patient 
  • Empiric endocarditis therapy using vancomycin should target a trough of 15-20 mg/L 
  • Ensure blood cultures are obtained prior to initiation of antibiotics 
  • Empiric treatment recommendations: 

Valve Status
Empiric Regimen
Empiric Regimen if Severe PCN Allergy,
Challenge Not Feasible
Native valve
Cefepime 2 g IV
Vancomycin 25 mg/kg IV*
Aztreonam 2 g IV
Vancomcyin 25 mg/kg IV*
Prosthetic valve
Cefepime 2 g IV
Vancomycin 25 mg/kg IV*
Gentamicin 1 mg/kg IV
Rifampin 300 mg IV/PO
Aztreonam 2 g IV
Vancomcyin 25 mg/kg IV*
Gentamicin 1 mg/kg IV
Rifampin 300 mg IV/PO
*Or maximum allowable loading dose per institutional guidelines

Scott Dietrich, PharmD
@PCC_PharmD
Emergency Medicine Clinical Pharmacist
University of Colorado Health, North Region

Tony Mixon, PharmD, BCPS
@MixonMarkA
Emergency Medicine/Infectious Disease Clinical Pharmacist
University of Colorado Health, North Region

Edited by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD BCPS (@Nadia_EMPharmD)


References

  1. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation. 2016;134:1435-1486 
  2. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97: 496–503. 
  3. Rybak, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(11):1275-1279 

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