David Cluck, PharmD, BCPS, AAHIVP

KEY UPDATES IN 2016 SURVIVING SEPSIS GUIDELINES

Emphasis remains on early and adequate fluid resuscitation for patients who meet clinical criteria for sepsis.

Removal of most specific EGDT end points, with greater emphasis place on patient-centric resuscitation approach.

Timely initiation of antimicrobials is paramount, with increased emphasis on appropriate de-escalation and antimicrobial stewardship as a key health care initiative.

The Surviving Sepsis Campaign was launched in 2002 by representatives from the Society of Critical Care Medicine and the European So&shy;ciety of Intensive Care Medicine. The Surviving Sepsis Guidelines were published soon thereafter, in 2004, with revisions in 2008, 2012, and 2016. Moreover, as revisions occurred the definition of sepsis has con&shy;tinued to evolve. A list of updates to the definitions is shown in the 

. Given the pervasiveness of sepsis and its associated high mortality rate, the introduction and implementation of Surviving Sepsis Campaign ini&shy;tiatives improved patient care and decreased mortal&shy;ity.

 The revisions to these guidelines, as new literature emerged, have undoubtedly also significantly improved patient care. Select updates to the 2012 guidelines, which are available in the 2016 version, are described herein.

Initial resuscitation of patients with crystalline fluids continues to be a cornerstone of therapy in patients with sepsis. Perhaps the most noticeable change is the shift away from protocolized resuscitation efforts, bet&shy;ter known as early goal-directed therapy (EGDT).

 EGDT comprises specific endpoints that should be achieved within 3 and 6 hours from the identification of sepsis, while, usual care includes fluid administration, anti&shy;biotics and supportive care in a less formalized fash&shy;ion. This paradigm shift is in response to findings from a trio of large randomized controlled trials: ARISE, ProCESS and ProMISe.

 Compared with usual care, these trials failed to demonstrate a mortality benefit when EGDT was implemented. It is worth noting that the definition and implementation of “usual care” has improved since the original EGDT trial was conducted. Moreover, in the aforementioned trials, the lack of harm when using the protocolized EGDT led to the guidelines continuing to endorse EGDT targets.

 Another highlight of the 2016 guidelines is the use of different variables to assess fluid responsiveness. Pre&shy;vious iterations of the guidelines suggested that clini&shy;cians target a central venous pressure (CVP) of 8 to 12 mmHg (12-15 mmHg if mechanically ventilated) for fluid resuscitation goals. This shift away from using CVP as a marker of responsiveness was based on findings from the FENICE study, among others, which revealed little clinical utility of this static factor when CVP is within normal range.

 The FENICE findings also highlighted the need to promptly discontinue fluids once they are deemed no longer beneficial, as poor patient outcomes are a proven consequence of excess net fluids.

 From this, the 2016 guidelines shifted to a resuscitation approach more focused on measurements in the individual patient, with assessment based on dynamic variables such as pulse or stroke volume.

Source control and timing of antimicrobial therapy is reiterated in the 2016 guidelines. Regarding timing, several observational studies have demonstrated in&shy;creased risk of mortality when antimicrobial therapy is delayed.

 The guidelines reemphasize the 1-hour time threshold to initiate appro&shy;priate therapy after sepsis or septic shock is recognized, noting that feasibility has not been directly assessed and may be challenging for some centers. Although the timing of therapy is important, selection and dose are equally important. The 2016 guidelines highlight the use of pharmacokinetic/phar&shy;macodynamic principles when selecting and dosing antimicrobials. Clinical pharmacists should be able to assist clinicians in doing both, and clinicians should strongly consider consulting them.

Other recommendations remain from the 2012 guide&shy;lines, including appropriate de-escalation, the use of procalcitonin to expedite de-escalation or discontinuation, and appropriate durations of therapy. The em&shy;phasis on appropriate de-escalation and antimicrobial stewardship, in general, in this iteration of the guide&shy;lines is particularly noteworthy, as those areas have be&shy;come key initiatives in all health care facilities in 2017.

 The concept of “double coverage” with antimicrobials in critically ill patients has been the subject of debate for many years and has become essentially clinician-specific. The 2016 update suggests the use of empiric combination therapy in patients with septic shock; however, the evidence for this recommendation is weak, with little sup&shy;port found in randomized controlled clinical trials. The importance of combination therapy is emphasized by the heightened risk of mortality with inadequate coverage.

Clinicians may experience a certain sense of comfort in initiating empiric combination antimicrobial therapy in any patient, not just in those who are critically ill. However, this sense can be fallacious and should be off&shy;set somewhat by the ques&shy;tionable benefit that double coverage imparts to patients who have pathogens that are resistant to multiple drugs. Organisms that are resistant to beta-lactams are also likely to be resistant to a second, added agent, such as a fluo&shy;roquinolone or an aminogly&shy;coside; even if the resistance is not present, the second agent may simply provide no benefit.

 Although many attempts have been made to address this question, the resulting data have provided mixed answers and the need for empiric combination therapy in all critically ill patients remains controversial.

Despite recent data from trials that suggest EGDT is no better than usual care, the evolution of care for septic patients continues to improve. However, challenges re&shy;main, particularly with drug-resistant pathogens and the relative dearth of new agents. Fortunately, ongoing clin&shy;ical trials will continue to shed light on areas of contro&shy;versy in this most recent iteration of the guidelines, and certainly there is promise in the progress being made.

Dr. Burchette graduated from Gatton College of Pharmacy in 2010 before completing 2 years of postgraduate residency. She has been a faculty member for 5 years, with a didactic emphasis in pulmonary and critical care PharmD coursework. Clinically, she works in the acute care setting with an academic family medicine team. She is an active member of SIDP.

Dr. Cluck is an assistant professor in the Department of Pharmacy Practice at East Tennessee State University (ETSU) Gatton College of Pharmacy. He maintains a clinical pharmacy practice in infectious diseases at Johnston Memorial Hospital in Abingdon, Virginia, as well as a weekly outpatient HIV clinic with the ETSU HIV Center of Excellence. He is also an active member of SIDP, ACCP, ASHP, IDSA, and AAHIVM.

Damiani E, Donati A, Serafini G, et al. Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. 

 2015;10(5):e0125827. doi: 10.1371/journal.pone.0125827.

Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. 

. 2017;45(3):486-552. doi:10.1097/CCM.0000000000002255.

Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. 

Peake SL, Delaney A, Bailey M, et al; ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. 

. 2014;371(16):1496-1506. doi: 10.1056/NEJMoa1404380.

Yealy DM, Kellum JA, Huang DT, et al; ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. 

. 2014;370(18):1683-1693. doi: 10.1056/NEJMoa1401602.

Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. 

. 2015;372(14):1301-1311. doi: 10.1056/NEJMoa1500896.

Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. 

 2014;40(12):1795-1815. doi: 10.1007/s00134-014-3525-z.

Eskesen TG, Wetterslev M, Perner A. Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. 

 2016;42(3):324-332. doi: 10.1007/s00134-015-4168-4.

Cecconi M, Hofer C, Teboul JL, et al; FENICE Investigators; ESICM Trial Group. Fluid challenges in intensive care: the FENICE study: a global inception cohort study. 

. 2015;41(9):1529-1537;1737-1738. doi: 10.1007/s00134-015-3850-x.

Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. 

Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. 

 2014;42(8):1749-1755. doi: 10.1097/CCM.0000000000000330.

Pollack LA, van Santen KL, Weiner LM, Dudeck MA, Edwards JR, Srinivasan A. Antibiotic stewardship programs in US acute care hospitals: findings from the 2014 National Healthcare Safety Network Annual Hospital Survey. 

 2016;63(4):443-449. doi: 10.1093/cid/ciw323.

Kumar A, Ellis P, Arabi Y, et al; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. 

 2009;136(5):1237-1248. doi: 10.1378/chest.09-0087.

Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. 

Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee Including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent J, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). 

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Care continues to improve; however, drug-resistant pathogens and a lack of new agents to treat these infections remain a constant challenge.

Guidelines to Caring for Patients With Sepsis: Promise or Progress?

For the past several years, patients infected with hepatitis C virus (HCV) were virtually “warehoused” as clinicians awaited the introduction of newer and less toxic direct-acting antivirals (DAAs). Although the pipeline is rich with new DAAs, available agents, such as Harvoni (sofosbuvir/ledipasvir) and Epclusa (sofosbuvirvelpatasvir), are being used routinely since “cure” rates approach 100% with these medications in many cases. Without question, these drugs have revolutionized the therapeutic approach to patients infected with HCV.

Prior to approval by the US Food and Drug Administration (FDA) in November 2013, DAAs were already being touted as a panacea in many ways, highlighting their superior tolerability compared with older available agents and their significantly shortened treatment durations. Recently, however, safety precautions have begun to emerge that might cause concern for clinicians treating patients with HCV.

It is well known that drug—drug interactions (DDIs) and adverse drug reactions have a significant influence on the risk for hospitalization, morbidity, and mortality in all patients.

 Most clinicians recognize the DDIs present with many of the DAAs, especially in patients who are coinfected with HIV and receiving antiretroviral therapy (ART). Common interacting medications include proton-pump inhibitors, thyroid hormones, and dihydropyridine derivatives.

 While most of the interactions can be managed with monitoring or slight dose adjustments, some can be more detrimental to patient outcomes. For example, amiodarone was one of the first DDIs to be reported as clinically significant, garnering an FDA warning for the combination of amiodarone- and sofosbuvir-containing regimens. Concurrent use of these two agents yielded reports of life-threatening bradycardia, with 1 death and 3 other patients requiring a pacemaker.

 As a result, patients who are on these medications concurrently should be monitored in an inpatient facility for at least 48 hours, with outpatient monitoring for an additional 2 weeks.

More recently, concerns have emerged regarding reactivation of hepatitis B virus (HBV) in patients treated for HCV with DAAs.

 (It is worth noting this risk was not identified in clinical trials because patients coinfected with HBV and HCV were excluded.) The mechanism behind the reactivation of HBV is unknown; however, it is plausible that clearance of HCV could result in a resurgence of HBV replication since the DAAs have no activity against HBV.

 Furthermore, HCV has shown suppressive effects on HBV replication in coinfected patients.

At present, 24 cases of HBV reactivation have been reported to the FDA Adverse Event Reporting System, with 3 cases of acute liver failure. It should be noted 2 of these patients died and one required a liver transplant.

 These reports led to the uncovering of an additional 524 reported cases of liver failure in conjunction with more than 1000 reports of serious liver injury.

 Mortality attributed to the liver failure in these cases exceeded 30%, which is unacceptably high if the current paradigm of treatment is to continue. Interestingly, over 700 cases of antiviral failure have also been reported, contrary to what has been seen in most clinical trials. Of the DAAs, paritaprevir-containing regimens (34.5%) and sofosbuvir-containing regimens (32.6%) were most commonly implicated in the 524 reported cases.

The signal of increased risk of liver injury in any capacity is troubling, and perhaps even more so as most recommended HCV regimens contain sofosbuvir. Further, according to data from the Institute for Safe Medication Practices, clinicians who reported cases were almost exclusively specialists in the management of hepatitis reinforcing the validity of the findings.

As the era of DAAs was ushered in, the possibility of the beginning of the end of HCV also seemed to be on the horizon. With the introduction of the DAAs came the pressure to treat most patients who were infected. This was a move made secondary to direct to consumer advertising; patient characteristics, such as HIV or HCV coinfection; or simply patient preference. Whereas the consequences of DDIs can be appropriately managed in the clinic, heightened awareness of liver failure should result in greater vigilance in who receives antiviral therapy and who does not.

Given that newer agents, such as glecaprevir/pibrentasvir, ruzasvir, voxilaprevir, and MK-3682 are currently in clinical trials, this begs the question of whether we should place patients back in the warehouse until newer and safer agents become available. At present, it is unknown if these agents will carry the same risks described above. At the very least, perhaps the door should be reopened.

Dr. Lindquist, PharmD, BCPS, is a clinical pharmacist at the University of Tennessee Medical Center in Knoxville, Tennessee, and holds a faculty appointment as an assistant professor in the Department of Clinical Pharmacy at the University of Tennessee Health Science Center. She is also an active member of SIDP.

Dr. Cluck, PharmD, BCPS, AAHIVP, is an assistant professor in the Department of Pharmacy Practice at East Tennessee State University (ETSU) Gatton College of Pharmacy. He maintains a clinical pharmacy practice in infectious diseases at Johnston Memorial Hospital in Abingdon, Virginia as well as a weekly outpatient HIV clinic with the ETSU HIV Center of Excellence. He is also an active member of SIDP, ACCP, ASHP, IDSA, and AAHIVM. 

Dechanont S, Maphanta S, Butthum B, Kongkaew C. Hospital admissions/visits associated with drug-drug interactions: a systematic review and meta-analysis. 

Höner zu Siederdissen C, Maasoumy B, Marra F, et al. Drug-drug interactions with novel all oral interferon-free antiviral agents in a large real-world cohort. 

 2015;62(5):561-567. doi: 10.1093/cid/civ973. 

US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral drug. FDA website. https://www.fda.gov/Drugs/DrugSafety/ucm439484.htm. Published March 24, 2015. Accessed February 6, 2017. 

US Food and Drug Administration. FDA drug safety podcast: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. FDA website. www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm524589.htm. Updated December 28, 2016. Accessed January 28, 2017. 

Yalcin K, Degertekin H, Yildiz F, Kilinc N. A severe hepatitis flare in an HBV-HCV coinfected patient during combination therapy with alpha-interferon and ribavirin. 

Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection.

Moore TJ, Furberg CD, Mattison DR, Cohen MR. ISMP QuarterWatch: perspectives from new adverse events reports Institute for Safe Medication Practices website. https://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf. Published January 25 2017. Accessed February 6, 2017.

Should clinicians be extra vigilant when deciding who receives antiviral therapy, or are the adverse effects few and infrequent?

David Cluck, PharmD, BCPS, AAHIVP

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