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
Emergency Medicine Clinical Pharmacist
University of Colorado Health, North Region

Tony Mixon, PharmD, BCPS
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)


  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 

Wednesday, November 15, 2017

The Tramadol of Antimicrobials: Fluoroquinolones

Many institutions have implemented antimicrobial restriction programs where specific agents, based on toxicity, cost, or broad-spectrum of activity, require special permission for use. Often a page is required to initiate the request. During my infectious diseases PGY-2 I carried this antimicrobial approval pager, either approving the use of restricted agents or offering suggesting on alternative therapy. Fluoroquinolones (FQs) were by far, the most requested restricted antimicrobials, and also the most denied. In emergency departments without such programs, pharmacists play a vital role in antimicrobial stewardship, steering therapy to optimize clinical outcomes while minimizing unintended consequences. With their broad spectrum of activity, oral formulation, and seemingly minimal adverse effect profile, FQs were highly touted when originally approved. However, after decades of clinical use and research, is it time we rethink their greatness?

The most commonly reported side effects of FQs are what you will see as the most common side effects for just about every drug out there: nausea, vomiting, and diarrhea. Where FQs really separate themselves is the frequency and variety of severe safety issues they have been associated with, including but not limited to the following:

Commonly Known Adverse Effects
Lesser Known Adverse Effects
QT prolongation
GI perforation
Clostridium difficile infection
Aortic aneurysm/dissection
Retinal detachment
Peripheral neuropathy
Black box warnings
Seizures/Psychiatric AEs

  • QT prolongation- FQs prolong the QT interval in a dose dependent fashion by blocking voltage-gated potassium channels.1 A rare but potentially fatal consequence is torsades de pointes.2  A retrospective review of patients experiencing torsades de pointes associated with the administration of a FQ found that 96% of patients had at least one additional risk factor.3 These included electrolyte abnormalities, concurrent use of a QT-prolonging medication, prolonged QT interval at baseline, cardiovascular disease, bradycardia, and female sex.
  • Clostridium difficile Infection (CDI)- The most important modifiable risk factor for CDI is exposure to antimicrobial agents. While exposure to just about every antibiotic has been associated with CDI, more broad spectrum agents generally place patients at a higher risk. A retrospective study conducted over an 18 month period found FQs as the antibiotic class most strongly associated with CDI (Adjusted HR, 3.44; 95% CI, 2.65–4.47).4 The next highest class, 2nd generation cephalosporins, was almost half of FQs (Adjusted HR, 1.89; 95% CI, 1.45-2.46). Furthermore, an interrupted time-series analysis evaluating CDI pre- and post-implementation of a FQ restriction program found a reduction in FQ usage was associated with a reduction in CDI cases (rate ratio: 0.332; 95% CI: 0.240-0.460).5
  • Seizure- Certain FQs lower the seizure threshold by displacing GABA or competing with GABA binding at receptor sites within the central nervous system (CNS).6 While the overall risk of serious CNS reactions is low, it is likely more pertinent in susceptible patients, such as those with underlying CNS disorders, such as epilepsy, cerebral trauma, or anoxia.7,8 Furthermore, concomitant NSAID use increases the risk of seizures with FQs.9
  • Peripheral Neuropathy- Beginning August 2013, the Food and Drug Administration (FDA) required FQs to carry a black box warning regarding peripheral neuropathies.10,11,12 A case-control study of male subjects concluded the risk of peripheral neuropathy was doubled in patients newly taking FQs (RR = 2.07, 95% CI 1.56-2.74).13 A finding that becomes more troubling when taking into account case reports describing that these neuropathies may be irreversible.14
  • Psychiatric Adverse Reactions- The CNS effects of FQs can also include mental health adverse reactions. A potential mechanism for this is FQ induced decreases in brain serotonin and GABA levels,26 In July 2018, the FDA strengthened current warnings in the prescribing information to include that FQ antibiotics may cause significant mental health side effects; Recommending that clinicians inform patients about the risk of psychiatric adverse reactions that can occur after just one dose.25
  • Glucose abnormalities- The package inserts for ciprofloxacin, levofloxacin and moxifloxacin all warn of the possibility of both hypoglycemia and hyperglycemia.10,11,12 Hypoglycemia is explained by the ability of FQs to close K+-ATP channels in pancreatic islet cells causing the release of insulin.15 The mechanism leading to hyperglycemia is not well understood. Patients with diabetes are at the highest risk of experiencing glucose abnormalities. Chou et al conducted a population-based inception cohort study with 78,433 diabetic patients enrolled in order to evaluate the risk of dysglycemia among patients receiving levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins, and macrolides.15 The absolute risk of hyperglycemia per 1000 persons was found to be 1.6 for macrolides, 2.1 for cephalosporins, 3.9 for levofloxacin, 4.0 for ciprofloxacin, and 6.9 for moxifloxacin. The absolute risk of hypoglycemia was found to be 3.2 for cephalosporins, 3.7 for macrolides, 7.9 for ciprofloxacin, 9.3 for levofloxacin, and 10.0 for moxifloxacin. In July 2018, the FDA strengthened the the current warnings in the prescribing information that FQ antibiotics may cause significant decreases in blood sugar; Suggesting that clinicians should alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in patients receiving FQs.25
  • Gastrointestinal (GI) Perforation-  FQs can reduce the expression and size of type I collagen fibrils causing deleterious effects on collagen and connective tissues.16 This is the likely mechanism behind FQs increased risk of GI perforation, and many of the adverse events listed below (tendinopathy, retinal detachment and aortic dissection/aneurysm). A nested case control study conducted over a 13 year year period found that current use of a FQ was associated with an increased risk of GI perforation (RR, 2.16; 95% CI, 1.85±2.53).17 The increase in risk of GI perforation remained even after adjusting for disease risk score  (RR, 1.90; 95% CI, 1.62-2.22) and disease risk score matching (RR, 1.88; 95% CI, 1.44 -2.46).
  • Tendinopathy-  Since July 2008, the FDA has required FQs have a black-box warning regarding adverse events, specifically citing tendonitis and tendon rupture. In a large population-based case control analysis, patients taking FQs were 4.1 times more likely to experience achilles tendon rupture than control patients.18 Elderly patients, and patients taking concurrent corticosteroids appear to be at an even higher risk of tendinopathy. In fact, the author’s determined the concomitant use of corticosteroids and FQs increased the risk of achilles tendon rupture 43.2-fold.
  • Retinal detachment- While a rare occurrence in general, FQ use has been associated with an increased risk of retinal detachment. A nested case-control study, with 4,384 cases of retinal detachment and 43,840 controls, found current use of FQs was associated with a significantly higher risk of developing a retinal detachment (adjusted RR, 4.50, 95% CI, 3.56-5.70).19 Additionally, a case-crossover study including 27,540 patients found a 1.46-fold increased risk for retinal detachment during the 10-day period after the dispensing of oral FQs.20
  • Aortic dissection/aneurysm- In another nested case-control analysis, after propensity score adjustment, current use of FQs was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio, 2.43; 95% CI, 1.83-3.22).21
  • Black box warnings- As previously mentioned, FQs have a black box warning regarding tendinopathy and peripheral neuropathy. They also carry a black box warning for use in patients myasthenia gravis as they may exacerbate muscle weakness. Additionally, in May of 2016 the FDA added that due to safety concerns, FQs should be reserved for patients with no other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.
  • Drug-drug interactions- In addition to additive QT prolongation with other QT prolonging medications  and  increased risk of tendinopathy with corticosteroids, ciprofloxacin is a CYP1A2 inhibitor. This property is of particular importance when considering the interaction between ciprofloxacin and tizanidine which increases the area under the curve (AUC) of tizanidine 10-fold, leading to an increased risk of hypotension and extreme sedation.22

If the above list of adverse effects wasn’t convincing enough, there is an entirely different aspect to be concerned about, resistance. FQ resistance has grown rapidly since their invention.23 Part of the rapid emergence is due to a low barrier to resistance. A single mutation in the bacterial topoisomerase gene can confer high-level resistance.24 A great way to get an idea of FQ susceptibilities specific to your patient population is to look at your institution's antibiogram. Below is a real antibiogram. Notice levofloxacin isn’t the best option against any pathogen listed when it comes to in-vitro susceptibility. For example, systemic E.coli and Pseudomonas aeruginosa susceptibilities to levofloxacin are only 58% and 66%, respectively! Compare that with 82% susceptibility of E.coli to 3rd generation cephalosporins and 90% susceptibility to this institution’s antipseudomonal work-horse, piperacillin-tazobactam, and you’ll get an idea of just how inferior FQs can be empirically. Take a look at your own antibiogram, I’d be willing to bet it looks similar. Feel free to share in the comments.

With all of the negative information presented above, one might be asking exactly when, or if FQs should be used? While FQs should rarely be the first choice antibiotic, I believe there is a role for them in emergency medicine, and when making recommendations I tend to use them in a few scenarios. The first scenario is to provide gram-negative coverage in patients with true IgE-mediated beta-lactam allergies. Situations like these underscore how important it is to clarify allergies so that only patients who cannot safely receive a beta-lactam are being given less active therapy, like FQs. Another situation in which I use FQs may be when monotherapy is preferred due to patients specific factors, such as cost or compliance, for a condition that may require multiple antibiotics otherwise (ie community acquired pneumonia- levaquin vs 2nd/3rd gen cephalosporin + azithromycin). Next, acknowledging it is a clinical controversy, if faced with a situation in which we must treat a gram-negative bacteremia with oral therapy, I always reach for a FQ given their high level of oral bioavailability. Lastly, I recommend FQs in any situation where a Pseudomonas spp. has been isolated, or there is strong suspicion of it, and oral therapy is desired. This highlights another great reason to use FQs sparingly; ciprofloxacin and levofloxacin are our only reliable oral antipseudomonal agents, overuse could compromise this activity and leave us in a situation where all Pseudomonas spp. infections would require intravenous therapy.

FQs are no longer the catch-all antibiotic they were once thought to be. Resistance rates have increased rapidly while a laundry list of severe safety issues have come to light. We are now in an era where both the safety and the efficacy of FQs is questionable, at best. It’s time we start utilizing them that way.

Take Home Points
  • FQs have been associated with many severe adverse reactions, including but not limited to QT prolongation, CDI, seizures, peripheral neuropathy, psychiatric issues, hypo/hyper glycemia, GI perforation, tendinopathy, retinal detachment, aortic dissection/aneurysm, as well as causing  drug-drug interactions.
  • FQs carry multiple black box warnings surrounding their safety.
  • FQs have a low barrier to resistance.
  • Resistance rates to FQs have increased rapidly. Look at your antibiogram!
  • Ciprofloxacin and levofloxacin are our only oral agents with reliable activity against Pseudomonas spp.
  • FQs should be reserved for a few clinical scenarios where other antibiotics are not safe  or feasible.

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

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


  1. Briasoulis A. Agarwal V. Pierce W.J. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-10.
  2. Mehrzad R, Barza M. Weighing the adverse cardiac effects of fluoroquinolones: A risk perspective. J Clin Pharmacol. 2015 Nov;55(11):1198-206
  3. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine. 2003; 82:282–290
  4. Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005 Nov 1;41(9):1254-60
  5. Sarma JB,, Marshall B, Cleeve V. Effects of fluoroquinolone restriction (from 2007 to 2012) on Clostridium difficile infections: interrupted time-series analysis. J Hosp Infect. 2015 Sep;91(1):74-80
  6. Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials, J Antimicrob Chemother , 1994, vol. 33 (pg. 685-706)
  7. Christ W, Central nervous system toxicity of quinolones: human and animal findings. J Antimicrob Chemother. 1990 Oct;26 Suppl B:219-25
  8. Owens RC Jr,  Ambrose PG. Clinical use of the fluoroquinolones, Med Clin N Am , 2000, vol. 84 (pg. 1447-69)
  9. Akahane K, Kimura Y, Tsutomi Y, et al. Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites. Antimicrob Agents Chemother. 1994 Oct;38(10):2323-9.
  10. Product Information: CIPRO(R) IV injection, ciprofloxacin IV injection. Bayer HealthCare Pharmaceuticals, Inc. (per FDA), Montville, NJ, 2011.
  11. Product Information: LEVAQUIN(R) oral film coated tablets, solution, intravenous injection solution, levofloxacin oral film coated tablets, solution, intravenous injection solution. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2016.
  12. Product Information: AVELOX(R) oral tablets, intravenous injection, moxifloxacin HCl oral tablets, intravenous injection. Bayer HealthCare Pharmaceuticals Inc. (per manufacturer), Whitehouse Station, NJ, 2015.
  13. Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study. Neurology. 2014 Sep 30;83(14):1261-3.
  14. Francis JK, Higgins E. Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration. J Investig Med High Impact Case Rep. 2014 Jul 27;2(3)
  15. Chou HW, Wang JL, Chang CH et al. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis. 2013 Oct;57(7):971-80.
  16. Tsai WC, Hsu CC, Chen CP, Chang HN, Wong AM, Lin MS, et al. Ciprofloxacin up-regulates tendon
    cells to express matrix metalloproteinase-2 with degradation of type I collagen. Journal of orthopaedic
    research: official publication of the Orthopaedic Research Society. 2011; 29(1):67±73
  17. Hsu SC, Chang SS, Lee MG et al. Risk of gastrointestinal perforation in patients taking oral fluoroquinolone therapy: An analysis of nationally representative cohort. PLoS One. 2017 Sep 5;12(9):e0183813
  18. Corrao G, Zambon A, Bertù L. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29(10):889-96.
  19. Etminan M, Forooghian F, Brophy JM et al. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012 Apr 4;307(13):1414-9.
  20. Raguideau F, Lemaitre M, Dray-Spira R et al. Association Between Oral Fluoroquinolone Use and Retinal Detachment. JAMA Ophthalmol. 2016 Apr;134(4):415-21.
  21. Lee CC, Lee MT, Chen YS et al. Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone. JAMA Intern Med. 2015 Nov;175(11):1839-47
  22. Granfors MT, Backman JT, Neuvonen M et al. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004 Dec;76(6):598-606
  23. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005 Jul 15;41 Suppl 2:S120-6
  24. Redgrave LS, Sutton SB, Webber MA et al. Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success.Trends Microbiol. 2014 Aug;22(8):438-45.
  25. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm612979.htm
  26. Ilgin S, Can OD2, Atli O. Ciprofloxacin-induced neurotoxicity: evaluation of possible underlying mechanisms. Toxicol Mech Methods. 2015;25(5):374-81

Thursday, October 26, 2017

FTFY: Prothrombin Complex Concentrate, That Is

logo-kcentra.pngThe last post on EMPharmD concerning fixed-dose Kcentra was way back in June, 2015 and discussed a newly published article by Klein et al. examining 1500 units of 4-factor prothrombin complex concentrate (4PCC) for warfarin reversal.(1)  Since that post, only one additional article has been published regarding fixed-dose 4PCC, and unfortunately, Abdoellakhan et al. only used 1000 units per dose as part of their protocol. As to be expected with the lower dosing, achievement of a goal INR < 1.5 was worse in the fixed-dose group compared to variable dosing group (68% vs 96%, p= 0.013).(2)

Although little has been published lately regarding fixed-dose 4PCC, there were a handful of posters presented at the last ASHP Midyear Clinical Meeting on fixed-dose PCC. Additionally, Gorlin et al. published survey results from 48 hospitals in the US, Europe, Canada, and South America on their VKA reversal protocols. Six institutions (18% of respondents) reported using a fixed-dose 4PCC protocol, with half of them dosing at 1500 units.(3) Currently, there are two trials listed on ClinicalTrials.gov evaluating fixed-dose protocols. One study is using 1500 units of 4PCC while the other is looking at activated-4PCC compared to standard 4PCC dosing. I know of at least two more ongoing studies examining fixed-dose PCC protocols and I’m sure there are several others out there.

If you don’t have a fixed-dose protocol in your hospital, you should consider implementing one. Why? Well, for starters, the ideal dose of Kcentra is unknown. Dose-finding studies were not completed as part of the FDA approval process for Kcentra and they aren’t due for submission until 2019.(4) You can rest assured that CSL Behring is going to wait as long as possible to submit those studies as they are likely to show that 5000 units of 4PCC is overkill. To put that amount of 4PCC in perspective, each unit (~250 ml) of FFP has approximately 200-250 units of FIX.(5) Therefore each 500 unit vial of Kcentra is equivalent to about 2 units of FFP, so 10 vials (i.e., the maximum dose) is about 20 units, or 5 liters, of FFP.

Additionally, by implementing a fixed-dose protocol you will save your hospital, and your patients, lots of money. Klein et al.’s study reported cost savings to the hospital of over $40,000 with only 36 patients; that’s over $1,000 per patient! When combined with equivalent efficacy (when used at the right doses), potentially less thrombotic complications with the lower dosing (6,7), and the dramatic cost savings, it becomes hard to argue against a fixed-dose protocol.

money gif.gif

I have implemented fixed-dose protocols in two health-systems so far and I want to help anyone else interested in implementing one at their hospital. With this post is a 19 page document with a review of the five most recent fixed-dose 4PCC studies and 1 systematic review that I have used as evidence to support the adoption of a fixed-dose Kcentra(R) protocol. The document can be found on the blog’s home page under the tab “Protocols and Additional Information.” I am including the document so any other healthcare professional who is interested in implementing a fixed-dose PCC protocol at their institution can use this to support their cause.

My protocol:
Proposed Kcentra® Dosing Protocol For Emergent Warfarin Reversal:
  • Kcentra® should be initiated prior to INR results to aid in rapid administration of therapy
  • All patients will receive 10 mg IV Vitamin K with Kcentra®
  • All patients will receive an initial fixed dose of 1500 units FIX (3 vials) of Kcentra® for severe life-threatening bleeding due to warfarin therapy
    • Non-life threatening bleeding recommended to be managed with FFP + Vit K
  • For the following patients, or at the discretion of the physician, consider increasing empiric dose to 2000 units FIX (4 vials):
    • TBW > 100kg
    • INR > 7.5-10 (if known prior to initiation of therapy)
  • For patients who have already received Kcentra® prior to INR results, and the baseline INR returns > 7.5-10, consider an additional 500 units FIX (1 vial) for a total of 2000 units FIX (4 vials)
  • Consider ordering a repeat PT/INR 10-60 minutes after Kcentra® infusion
  • If repeat INR is > 2, consider additional 500-1000 units FIX (1-2 vials) if patient has not had a positive clinical response to initial therapy
Avoid in patients with DIC, history of HIT, or recent history of thrombosis, MI or ischemic stroke

This protocol is slightly different than the standard 1500 units for everyone. First, for patients > 100 kg, the dose is increased to 2000 units. This recommendation was based on the post-hoc analysis by Klein et al which showed patients in the failure group had a median weight of 95 kg compared to 78.5 kg in the success group.(1) I choose 100 kg as the cutoff as it was a little “cleaner” and easier to remember than 95 kg. Additionally, as this was a post-hoc analysis (and only included 39 patients), my general takeaway is that larger patients require higher doses.  Secondly, for patients with a baseline INR > 7.5-10 (if known), the dose is increased to 2000 units. Again, in the post-hoc analysis by Klein, patients in the failure group were almost 10 times more likely to have their baseline INR > 10 (27.3% vs 3.6%). Additionally, based on Khorsand’s 2012 study (although only a 1000 units per dose), patients with a baseline INR of > 7.5 were less likely to reach post-PCC INR goal of < 2 compared to the standard dosing group (80% vs 91%).(8) Although most recommendations for post-PCC INR goals are < 1.3-1.5 (compared to < 2 in the Khorsand study), I still think you can extrapolate these results to 1500 unit regimens as the higher the INR, the more PCC is needed for adequate INR reversal.

As these protocols have only been recently implemented, I don't have enough data yet to evaluate their efficacy compared to standard dose regimens (anecdotally, they seem equivalent so far). Hopefully within the next year or so we’ll have more answers regarding the efficacy compared to not only a standard dosing regimen but also a flat 1500 unit protocol.

You can use my protocol, you can use the more common 1500 units for everyone protocol (you can even use activated-4PCC). Either way, I believe fixed-dosing is the most cost-effective way to use 4PCC.

Scott Dietrich, PharmD
Emergency Medicine Clinical Pharmacist
University of Colorado Health – North

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

Editor Commentary:
Fixed dose PCC is certainly on its way to becoming the standard, rather than the exception. In my own practice, there are clinical circumstances where 500 IU may be the best dose for a patient, particularly after discussing with the surgeons and EM physicians and putting the amount of FIX in PCC into context of FFP (as Scott outlined above).  
I think this is one of the best demonstrations of the benefits of the integration of social media/FOAM and traditional literature. Most of the initial buzz, and at minimum tweeting of the initial protocols of fixed dose PCC, pushed us to critically appraise what we knew about PCC dosing. It led to numerous stories of people in EDs everywhere that started a fixed dose protocol, and it seemed to have anecdotal success. This spread like wildfire around FOAM and now most EDs with EM pharmacists that I spoke with at ACCP indeed had these protocols. All of this accomplished in the 3 years since Kcentra was released. Take that 10 year knowledge-translation!


1. Klein L, Peters J, Miner J, et al. Evaluation of fixed dose four-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015 [Epub ahead of print].
2. Abdoellakhan RA,  Miah IP, Khorsand N, Meijer K, Jellema K. Fixed versus variable dosing of prothrombin complex concentrate in Vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocritical Care. 2017;26(1):64-69. 
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