August 2013 FAQs

Does the development of direct acting antivirals for hepatitis C virus mark the end of an era for treatment with interferon?

Background

It is estimated that 3.2 million people in the United States are chronically infected with hepatitis C virus (HCV).1 While the incidence of new infection is decreasing, there is increasing focus on the management of chronic infection. This difficult-to-treat disease has seen recent advances in the past couple years with the development of direct acting antivirals (DAAs), including telaprevir and boceprevir.2 The oral protease inhibitors are now used in combination with the historical standard of care combination – interferon (IFN), an injectable, and oral ribavirin – for HCV genotype 1. The new regimen, or “triple therapy” (boceprevir or telaprevir plus IFN plus ribavirin) has allowed for improvement in sustained virologic responses (SVRs), and shorter durations of therapy for some.3 The standard of care for other genotypes is still IFN and ribavirin alone. Due to the serious adverse effects of this combination (fatigue and flu-like syndromes, depression or neuropsychiatric conditions, and blood disorders) and the better understanding of the HCV lifecycle, targeted agents with better safety profiles are a high priority for pharmaceutical companies.2,4 Other characteristics of treatment options that are desired include a high barrier to development of resistance, low pill burden, fewer drug interactions, ability to use in patients with mental illness, cirrhosis, and human immunodeficiency virus (HIV) and affordability.3

HCV drug classes in development

The approval of boceprevir and telaprevir was just the beginning of the explosion of new oral agents for HCV treatment.2,3 These are considered to be the first generation of NS3/NS4A protease inhibitors. Second generation or “second-wave” protease inhibitors are in development, and will likely have the same high antiviral potency, but improved tolerance and safety profiles. Polymerase inhibitors (nucleoside/nucleotide and non-nucleosides) will also play an important role in HCV treatment. They prevent viral replication through binding to the NS5B RNA-dependent RNA polymerase. The nucleoside/nucleotide polymerase inhibitors have greater potential to be used for multiple HCV genotypes. Another class of HCV drugs in development is the NS5A inhibitors. The NS5A phosphoprotein is essential for viral replication, although its exact role is poorly understood.

Pharmaceutical companies are moving at breakneck speed to develop DAA-containing regimens that are similarly effective and better tolerated than the current standards of care.2 The emphasis in HCV drug development is especially on IFN-free regimens, as well as ribavirin-free regimens, which are termed “triple DAA” regimens. As of July 11, 2013, there were over 1640 registered clinical trials on the treatment of HCV.5 A list of DAAs in advanced development can be seen in Table 1.2 Updates from liver meetings have kept the medical world abreast of HCV drugs in phases 2 and 3 that are expected to be approved by the Food and Drug Administration (FDA) in the near future.6 With all of these developments, the possibility of IFN-free regimens is becoming more tangible.

Table 1. Direct acting antivirals in advanced development for hepatitis C virus. 2

Preliminary evidence for HCV drugs in development

Drugs on the brink of FDA approval include Sofosbuvir (GS-7977), a nucleotide NS5B polymerase inhibitor, and ledipasvir (GS-5885), a NS5A inhibitor. 5,7 These have been studied in combination with ribavirin for HCV genotype 1 in a phase 2 study (ELECTRON). After 12 weeks, 84% of genotype 1 treatment-naïve individuals achieved SVR, while 68% of genotype 2 or 3 treatment-experienced individuals achieved SVR. Both investigational drugs were developed by Gilead Sciences Inc. and are now in phase 3 (ION-I). Sofosbuvir is also being studied in combination with IFN in patients with HCV genotypes 1, 4, 5, or 6, as well as in combination with antiretroviral therapy for patients coinfected with HIV.

Abbott currently has investigational drugs in the protease inhibitor class (ABT-450), non-nucleoside NS5B polymerase inhibitor class (ABT-333 and ABT-072), and the NS5A inhibitor class (ABT-267).2,8 A phase 2b trial (Aviator) on triple DAA therapy in genotype 1 patients found that a 12 week regimen of ABT-333, ABT-267, and ABT-450 boosted with ritonavir resulted in SVR in 93% to 95% of treatment-naïve patients.9 Sustained virologic response was achieved in 47% of patients who received previous HCV treatment. This regimen is now in phase 3 with ABT-450, ritonavir, and ABT-267 as a co-formulated tablet.

Another triple DAA regimen including the protease inhibitor asunaprevir, NS5A inhibitor daclatasvir, and non-nucleoside NS5B polymerase inhibitor BMS-791325 showed promising results in phase II trials.10 Ninety-four percent of treatment-naïve patients with HCV genotype 1 achieved SVR after 12 weeks with this regimen. These drugs are being developed by Bristol-Myers Squibb, and asunaprevir and daclatasvir are now in phase 3.

Merck also has an investigational protease inhibitor, MK-5172.2,11 Interim data showed undetectable viral loads in 86% to 92% of patients with HCV genotype 1 after 24 weeks of therapy when used in combination with IFN and ribavirin. Another protease inhibitor in development by Achillion Pharmaceuticals Inc. is sovaprevir.12 This is currently in a phase 2, IFN-free study with the NS5A inhibitor ACH-3102 and ribavirin. 5

Boehringer Ingelheim is developing the protease inhibitor faldaprevir and the non-nucleoside polymerase inhibitor BI-207127, which are currently in a phase 3, IFN-free trial.13 Results from a phase 2b study (SOUND-C2) on these agents in combination with ribavirin showed that after 28 weeks, 69% of patients achieved SVR. However, patients with genotype 1b were 6 times more likely to achieve SVR than those with genotype 1a. In the arm without ribavirin, overall SVR was only 39% after 28 weeks.

A summary of IFN-free regimens, with and without ribavirin, can be viewed below in Table 2.

Table 2. Interferon-free hepatitis C virus regimens under investigation. 5,7,8,10-14

Conclusion

Many of the DAAs are also being studied in combination with IFN for HCV genotypes other than 1.2 Second-wave protease inhibitors will likely receive FDA approval for use with and without IFN. This class of drugs may be the first to reach the market among the drug classes in development. The new protease inhibitors may be more potent, less likely to confer resistance, and less frequently administered (once daily) than boceprevir and telaprevir. The nucleoside and nucleotide NS5B polymerase inhibitors have had some setbacks during development, but their advantages are that they have a high threshold for development of resistance and they may be effective for HCV genotypes other than 1. Non-nucleoside NS5B polymerase inhibitors have lower potency than the aforementioned classes, and there are considerable safety issues. The NS5A inhibitors have shown to be effective in both standard of care (IFN and ribavirin) and all-oral regimens. They may be less effective in patients with subgenotype 1a, however.

Other agents that are a focus of research include host-targeting agents (cyclosporine A and derivatives) and a new IFN, PEG-IFNλ, which may have less adverse effects than the currently approved interferons.2 Overall, the excitement over the new drugs stems from the hope that all-oral regimens with high efficacy, less frequent administration, and better safety profiles will soon become the new standard of care. Interferon-free regimens are certainly on the horizon, although most would agree that is too early to determine if IFN will soon become obsolete.

References

1. Hepatitis C FAQs for health professionals. Centers for Disease Control and Prevention website. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section1. Updated May 28, 2013. Accessed July 1, 2013.

2. Manns MP, von Hahn T. Novel therapies for hepatitis C- one pill fits all? Nat Rev Drug Discov. 2013 Jun 28. doi: 10.1038/nrd4050. [Epub ahead of print].

3. Casey LC, Lee WM. Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol. 2013;29(3):243-249.

4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. http://clinicalpharmacology-ip.com/default.aspx. Accessed July 1, 2013.

5. National Institutes of Health website. http://www.clinicaltrials.gov/. Accessed July 1, 2013.

6. In the news. Hepatitis Foundation International website. http://www.hepatitisfoundation.org/NEWS/News.html. Accessed July 1, 2013.

7. Gilead announces 100 percent sustained virologic response rate (SVR4) for an interferon-free regimen of sofosbuvir (GS-7977), GS-5885 and ribavirin in treatment-naïve genotype 1 hepatitis C infected patients. Gilead website. http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&ID=1757156&highlight= . Accessed July 1, 2013.

8. Press release. Abbott website. http://www.abbott.com/news-media/press-releases/abbott-announces-phase-3-hepatitis-c-program-details.htm . Accessed July 1, 2013.

9. Poordad F,Lawitz E, Kowdley KV, et al. Exploratory Study of Oral Combination Antiviral Therapy for Hepatitis C. N Engl J Med. 2013;368(1):45-53.

10. Investigational triple DAA regimen of daclatasvir, asunaprevir and BMS-791325 achieved SVR12 of 94% in treatment-naïve patients with genotype 1 chronic hepatitis C infection in phase II trial. Bristol-Myers Squibb website. http://news.bms.com/press-release/rd-news/investigational-triple-daa-regimen-daclatasvir-asunaprevir-and-bms-791325-achi&t=634884909713877512 . Accessed July 1, 2013.

11. Interim phase II data of Merck's investigational MK-5172 in combination therapy in chronic hepatitis C virus genotype 1 infection to be presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting. Merck website. http://www.mercknewsroom.com/press-release/research-and-development-news/interim-phase-ii-data-mercks-investigational-mk-5172-com . Accessed July 1, 2013.

12. Achillion Provides Update on Clinical HCV Development Programs. Achillion website.

http://ir.achillion.com/releasedetail.cfm?ReleaseID=720415 . Accessed July 1, 2013.

13. Phase 2b Data of Boehringer Ingelheim’s Interferon-Free Hepatitis C Treatment Show Viral Cure Achieved in Up to 85% of Treatment-Naïve Patients. Boehringer Ingelheim website. http://us.boehringeringelheim.com/news_events/press_releases/press_release_archive/2012/11-10-12-phase-2b-data-boehringer-ingelheims-interferon-free-hepatitis-c-treatment-viral-cure-treatment-naive-patients.html . Accessed July 11, 2013.

14. Idenix Pharmaceuticals Reports Clinical Data for HCV Drug Candidates – IDX719 and IDX184 – at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting. Idenix Pharmaceuticals website. http://ir.idenix.com/releasedetail.cfm?ReleaseID=720334. Accessed July 11, 2013.

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What evidence led to the boxed warning on hydroxyethyl starch solutions?

Introduction

Hydroxyethyl starch (HES) solutions have been used in the U.S. for plasma volume replacement since the 1970s.1 These products are indicated for treatment of hypovolemia when plasma volume expansion is desired.2-6 Theoretical benefits of these synthetic carbohydrate polymer colloid solutions compared to other fluids used for volume replacement include lower volume requirements than crystalloids, less cost compared to human albumin, and better risk/benefit profiles than other colloids such as dextran and gelatin.7 Hydroxyethyl starches are identified by 3 numbers: concentration, mean molecular weight in kilodaltons (kDa), and molar substitution.1 Pharmacokinetic parameters such as elimination are affected by the molecular weight. Molar substitution refers to the average number of hydroxyethyl groups per glucose subunit in the starch molecule. Solutions with greater molar substitution are eliminated from plasma more slowly due to their need for more extensive enzymatic breakdown. All HES solutions currently available in the U.S. are 6% concentrations, with molecular weights of 670 kDa (Hextend, 6% HES 670/0.75), 600 kDa (Hespan, 6% HES 600/0.75) and 130 kDa (Voluven, 6% HES 130/0.4).2-6 Due to differences in these physical properties, HES solutions cannot be substituted for one another.1

Known safety concerns with HES solutions have included anaphylaxis, coagulopathy and bleeding, renal injury, and accumulation of molecules with higher molar substitution.7 However, recent data have brought the safety of HES solutions under further scrutiny. In June 2013 the Food and Drug Administration (FDA) notified the public and healthcare providers that a boxed warning will be added to the prescribing information for HES solutions. 8 The boxed warning will describe recently identified risks of increased mortality and renal injury requiring RRT in critically ill adult patients including those with sepsis and those admitted to the intensive care unit (ICU). This article summarizes the literature on the effects of HES solutions on mortality and renal injury in critically ill adult patients.

Outcomes with hydroxyethyl starch solutions in sepsis

Patients with severe sepsis and septic shock benefit from early volume resuscitation and fluids are often given in this setting.9 A few publications in recent years have hinted at safety concerns with HES solution administration in septic patients.10-12 The multicenter, randomized, 2-by-2 factorial, open-label Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial conducted in 537 patients was stopped early for safety reasons.10 One of the safety findings was a greater need for RRT with HES solutions compared to Lactated Ringer’s in patients receiving both intensive insulin therapy (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.01 to 2.83) and conventional insulin therapy (OR 2.65, 95% CI 1.51 to 4.68). Similarly, a prospective, observational, single center study compared outcomes in 1046 ICU patients with severe sepsis or septic shock over 3 consecutive time periods during which the major fluids administered for resuscitation were HES solutions (mostly 6% HES 130/0.4), 4% gelatin, and crystalloids, respectively.11 Multiple logistic regression analysis revealed that HES solutions significantly increased the odds of acute kidney injury (OR 2.55, 95% CI 1.76 to 3.69, p<0.001) and RRT (OR 2.01, 95% CI 1.34 to 3.02, p<0.001). Another multicenter, prospective, randomized trial in 129 patients with severe sepsis or septic shock identified an increased risk for acute renal failure (OR 2.57, 95% CI 1.13 to 5.83, p=0.026) with 6% HES 200/0.6-0.66 (products not available in the U.S.) compared to 3% gelatin.12

These early safety concerns, in addition to a lack of compelling efficacy data in this population, led investigators to conduct 2 large, multicenter, randomized, controlled trials to firmly determine the efficacy and safety of modern HES solutions (those with low molar substitution) in patients with sepsis.13,14 These trials are summarized in Table 1. The CRYSTMAS trial did not identify an increase in renal injury or 90-day mortality with 6% HES 130/0.4 compared to 0.9% sodium chloride, but the trial was not powered for either of those outcomes.13 In contrast, the 6S trial reported an increase in 90-day mortality and RRT with 6% HES 130/0.42 compared to Ringer’s acetate.14 Limitations of the 6S trial include that many patients had acute kidney injury at baseline (35%) and patients in the HES group received more red blood cell transfusions than the Ringer’s acetate group (p<0.001), which has been associated in other trials with increased mortality. In addition, neither study solution used in the 6S trial is available in the U.S. so it may not be appropriate to extrapolate these results to U.S. products.

Table 1. Randomized, controlled trials with hydroxyethyl starch (HES) solutions in patients with sepsis.13,14

ARF=acute renal failure; AKIN=Acute Kidney Injury Network; CI=confidence interval; HES=hydroxyethyl starch; NaCl=sodium chloride, RIFLE=Risk, Injury, Failure, Loss, End-Stage Kidney Disease; RR=relative risk; RRT=renal replacement therapy.

Two recent meta-analyses have attempted to resolve the conflicting safety findings in randomized, controlled trials in patients with sepsis. 15,16 A meta-analysis by Patel and colleagues included 3 randomized, controlled trials in 3033 patients with severe sepsis that compared 6% HES 130/0.4 or 0.42 with non-HES solutions.15 The analysis revealed an increased risk of 90-day mortality (relative risk [RR] 1.13, 95% CI 1.02 to 1.25, p=0.02) and an increased risk of RRT (RR 1.42, 95% CI 1.09 to 1.85, p=0.01) with HES solutions compared to crystalloids. Another meta-analysis of 9 trials that included 3456 patients with sepsis who received 6% HES 130/0.38 to 0.45 or crystalloids/albumin did not find an increased risk of death (RR 1.04, 95% CI 0.89 to 1.22, p=0.64) but HES solutions did increase the risk of RRT compared to crystalloids/albumin (RR 1.36, 95% CI 1.08 to 1.72, p=0.009). 16

In summary, several recent well-designed, randomized, controlled trials and meta-analyses provide evidence that HES solutions are associated with adverse renal outcomes in patients with sepsis.14-16 Mortality outcomes have been less conclusive but the potential risk of increased mortality with HES solutions in this population is concerning. The current international Surviving Sepsis guideline states that crystalloids are the fluid of choice for resuscitation of patients with severe sepsis and septic shock, and that HES solutions should not be used but albumin can be considered for patients who require large volumes of crystalloids.9 Currently available published literature support this guideline recommendation to avoid use of HES solutions in patients with sepsis.

Outcomes with hydroxyethyl starch solutions in critical illness

Numerous trials and meta-analyses have examined the effects of HES solutions in critically ill patients in the ICU, including those who are post-surgery. Efficacy and safety in this population have been difficult to determine because these evaluations often include patients with severe sepsis or use older HES solutions; therefore, there remains an interest in the safety of newer HES solutions in the general ICU population. Two recent meta-analyses produced largely inconclusive results.17,18 Gattas and colleagues identified a RR of death of 0.95 (95% CI 0.64 to 1.42, p=0.73) in a meta-analysis of 25 trials in 1608 acutely ill patients who received 6% HES 130/0.4 versus other colloids/crystalloids, but data regarding acute kidney injury were too limited and low quality to allow for analysis.17 Similarly, a meta-analysis of 13 studies with 1131 patients did not find an increased risk of mortality with 6% HES 130/0.4 but there was a significant publication bias (p=0.038).18

In order to clarify the safety of HES solutions in ICU patients, a large, prospective, multicenter, blinded, parallel group, randomized, controlled trial was conducted.19 The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) is summarized in Table 2. This trial included a large number of patients but was not adequately powered for mortality (17.5% observed vs. 26% expected). Other limitations include that there was no protocol for fluid administration and almost one-third of included patients had sepsis. Despite these limitations, CHEST provides compelling evidence that HES solutions in critically ill patients increase adverse renal outcomes and other adverse effects.

Table 2. Randomized, controlled trial with hydroxyethyl starch (HES) solution in critically ill patients.19

CI=confidence interval; HES= hydroxyethyl starch; ICU=intensive care unit; NaCl=sodium chloride; RIFLE=scoring system to evaluate risk, injury, failure, loss, and end-stage kidney injury; RR=relative risk; RRT=renal replacement therapy.

Conclusion

In order to address the lingering mortality question in ICU patients, several analyses that include the CRYSTMAS, 6S, and CHEST results have been performed.20-22 The meta-analysis by Zarychanski and colleagues included 31 trials that compared HES solutions to crystalloids, albumin, or gelatin in 10,290 patients.20 Hydroxyethyl starch solutions were associated with an increased risk of death (RR 1.09, 95% CI 1.02 to 1.17), renal failure (RR 1.27, 95% CI 1.09 to 1.47), and RRT (RR 1.32, 95% CI 1.15 to 1.50). Another meta-analysis of 35 trials with 10,391 patients found a RR of death of 1.08 (95% CI 1.00 to 1.17) with 6% HES 130/0.4 compared to other resuscitation fluids.21 The risk of RRT was also increased (RR 1.25, 95% CI 1.08 to 1.44). Although few studies in these analyses had a low risk of bias, the results suggest both adverse renal outcomes and an increased risk of mortality with HES solutions. Finally, a 2013 Cochrane Collaboration review of 25 trials that compared HES solutions with crystalloids for fluid resuscitation in 9147 critically ill patients found a RR of death of 1.10 (95% CI 1.02 to 1.19).22

Most clinical trials with HES solutions include varying patient populations, HES and comparator solutions used, outcome measures, and dosing. Most trials also had a short duration of follow-up compared to the 90-day mortality reported in recent trials. Trials with older HES solutions or those that are not available in the U.S. cannot be extrapolated to current clinical practice. In addition, a large number of early trials with HES solutions have been retracted due to investigator misconduct and earlier meta-analyses that include these trials have been called into question.23 Despite the numerous limitations of earlier data with HES solutions, recent randomized, controlled trials and meta-analyses support the addition of a boxed warning describing increased risks of adverse renal effects and mortality in critically ill patients to the HES product labeling. These risks combined with the lack of compelling efficacy data should prompt clinicians to minimize or abandon use of HES solutions in critically ill patients.

References

1. Westphal M, James MFM, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H. Hydroxyethyl Starches: different products – different effects. Anesthesiology. 2009;111(1):187-202.

2. Hextend [package insert]. Lake Forest, IL: Hospira, Inc; 2008.

3. Hetastarch [package insert]. Lake Forest, IL: Hospira, Inc; 2009.

4. Hespan [package insert]. Irvine, CA: B. Braun Medical, Inc; 2010.

5. Hetastarch [package insert]. Irvine, CA: Teva Parenteral Medicines, Inc; 2008.

6. Voluven [package insert]. Lake Forest, IL: Hospira, Inc; 2012.

7. Hartog CS, Bauer M, Reinhart K. The efficacy and safety of colloid resuscitation in the critically ill. Anesth Analg. 2011;112(1):156-164.

8. FDA Safety Communication: Boxed Warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. U.S. Food and Drug Administration website. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm . Updated June 24, 2013. Accessed July 8, 2013.

9. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

10. Brunkhorst FM, Engle C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139.

11. Bayer O, Reinhart K, Kohl M, et al. Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med. 2012;40(9):2543-2551.

12. Schortgen F, Lacherade JC, Brunell F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicenter randomized study. Lancet. 2001;357(9260):911-916.

13. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care. 2012;16(3):R94.

14. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012:367(2):124-134.

15. Patel A, Waheed U, Brett SJ. Randomised trials of 6% tetrastarch (hydroxyethyl starch 130/0.4 or 0.42) for severe sepsis reporting mortality: systematic review and meta-analysis. Intensive Care Med. 2013;39(5):811-822.

16. Haase N, Perner A, Hennings LI, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: a systematic review with meta-analysis and trial sequential analysis. BMJ. 2013;346:f839.

17. Gattas DJ, Dan A, Myburgh J, et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis. Anesth Analg. 2012;114(1):159-169.

18. Wiedermann CJ, Joannidis M. Mortality after hydroxyethyl starch 130/0.4 infusion: an updated meta-analysis of randomized trials. Swiss Med Wkly. 2012;142:w13656.

19. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911.

20. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309(7):678-688.

21. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S; CHEST Management Committee. Fluid resuscitation with 6 % hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013;39(4):558-568.

22. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013;2:CD000567.

23. Reinhart K, Takala J. Hydroxyethyl starches: what do we still know? Anesth Analg. 2011;112(3):507-511.

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What literature is available supporting short-term use of systemic antibiotics for prevention of ventilator-associated pneumonia?

Background/Introduction

Ventilator-associated pneumonia (VAP) is defined as pneumonia in intubated patients that is acquired more than 48 to 72 hours after intubation. 1-4 Though the incidence of VAP is difficult to estimate due to the fact that infection with VAP often overlaps with hospital-acquired pneumonia (HAP), it is well-established that the highest risk of VAP infection occurs within the first 4 days of intubation, known as early-onset VAP. Early-onset VAP typically occurs from aspiration before or during intubation in comatose patients. Underlying pathogens tend to be antibiotic-sensitive with this form of VAP. Common pathogens include methicillin-sensitive S. aureus, H. influenzae, and S. pneumonia. In contrast, late-onset VAP develops after longer periods of mechanical ventilation (> 4 days) and has a poor prognosis due to infection caused by resistant microorganisms.

Risk factors for VAP can include aspiration, chronic obstructive pulmonary disease (COPD), coma, trauma, age > 60 years, recent antibiotic use, multiple intubations within a short period of time, nasogastric tube use, enteral nutrition, and use of antacids or histamine type-2 receptor antagonists. Ventilator-associated pneumonia is associated with increased length of hospital stay, mortality rates as high as 30% to 70%, and increased healthcare costs.

The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines provide recommendations for non-pharmacologic and pharmacologic interventions for VAP prophylaxis.1 Non-pharmacologic measures include use of orogastric tubes over nasogastric tubes, continuous aspiration of subglottic secretions, reduced duration of intubation and mechanical ventilation, removal of condensation from ventilator circuits, positioning patient in the semirecumbent position, and use of enteral nutrition over parenteral nutrition. With respect to pharmacologic interventions, routine use of antibiotics for selective decontamination of the digestive tract (SDD), use of systemic antibiotics for 24 hours at the time of intubation, and use of chlorhexidine are recognized as potentially effective interventions but cannot be considered standard of care until more data become available. Specifically, the guideline states that prophylactic use of antibiotics in patients with closed head injury may be beneficial. This review summarizes the current literature available on short-term use of systemic antibiotics for prevention of early-onset VAP.

Literature review

A randomized, multicenter trial published in 1989 evaluated 570 intensive-care unit (ICU) patients for prevention of early-onset pneumonia.5 Patients admitted with infection or conditions requiring antibiotics were excluded. Patients received either cefoxitin 2 g every 8 hours for 3 doses, penicillin G 2 million units every 6 hours for 4 doses, or no prophylaxis. Antibiotic prophylaxis was administered within 24 hours of ICU admission. The incidence of pneumonia and early-onset pneumonia was 11.6% and 6.1%, respectively with cefoxitin, 8.7% and 6.1% with penicillin G, and 13.5% and 7.2% in the control group. Although, no difference in the incidence of pneumonia or mortality was observed between the 3 groups, subgroup analysis suggested that patients in the cefoxitin group that were comatose and intubated for prolonged periods may have a lower incidence of early-onset pneumonia.

An open-label, randomized, controlled trial, published in 1997 by Sirvent and colleagues, studied the effects of pneumonia prophylaxis with cefuroxime compared to no antibiotic in 100 comatose subjects.6 Patients with head injury or coma due to stroke with a Glasgow score of ≤ 12 qualified for study enrollment. The antibiotic group (n=50) received 2 cefuroxime 1500 mg doses 12 hours apart after intubation. Although the control group (n=50) did not receive VAP antibiotic prophylaxis, antibiotic use was allowed for other indications such as surgical prophylaxis. Approximately, 34% of patients in the control group received an antibiotic. Eight-six percent of patients in both groups were head trauma cases and 14% of the included patients in each group underwent surgery for head lesions. The study protocol began within 6 hours of intubation in all patients. Thirty-seven patients developed microbiologically-confirmed pneumonia; 12 patients (24%) in the cefuroxime group and 25 patients (50%) in the control group (relative risk [RR] 0.54, 95% confidence interval [CI] 0.32 to 0.89, p=0.007). Early-onset VAP accounted for 70% of the cases and occurred in 8 patients (30%) in the cefuroxime group compared to 18 patients (70%) in the control group (p=0.022). The most common causative microorganisms in both groups included S. aureus, H. influenza, S. pneumoniae, Enterobacteriae, P. aeruginosa, and Acinetobacter species. No significant differences in hospital stay or mortality were observed between the 2 groups. Based on the results, the authors concluded that high dose cefuroxime is an effective VAP prevention strategy in patients who are comatose from head trauma or stroke. Although, a significant difference in the incidence of VAP was demonstrated, the open-label design, early-onset VAP as a secondary outcome, and high use of concomitant antibiotics in the control group decrease internal and external validity.

Another small, open-label, randomized study, published in 2005, evaluated the use of ampicillin-sulbactam versus standard treatment to reduce the risk of early-onset VAP in comatose patients.7 Patients on mechanical ventilation with a Glasgow coma score of ≤ 8 were eligible for inclusion. Patients requiring antibiotic treatment for other indications or use of antibiotics 48 hours prior to intubation were among those excluded. Patients randomized to antibiotic prophylaxis (n=19) received ampicillin-sulbactam 3 grams every 6 hours for 3 days while the control group received standard treatment (n=19). Standard treatment of VAP prophylaxis was not described, however. Over 70% of patients were admitted for either head trauma or subarachnoid hemorrhage. The incidence of early-onset VAP was significantly lower in patients receiving ampicillin-sulbactam compared to standard treatment (21.0% versus 57.9%, p=0.022, RR 0.36, 95% CI 0.14 to 0.94). Causative microorganisms of early-onset VAP in the treatment group included methicillin-resistant S. aureus (MRSA), S. pneumoniae, and P. aeruginosa; the control group had similar causative organisms except S. aureus was methicillin-sensitive. Gram-negative microorganisms and MRSA were common for late-onset VAP cases in both groups. The incidence of late-onset VAP, duration of intubation, length of stay and mortality was not significantly different between groups. The authors concluded that a large, multicenter trial should be conducted to assess the effect of ampicilin-sulbactam prophylaxis on mortality and antibiotic resistance in patients on mechanical ventilation. The lack of description of preventive measures used in the control group and the small sample size of this study warrant a larger, controlled clinical trial to evaluate the impact of ampicillin-sulbactam on not only the incidence of early-onset VAP but also length of ICU stay, duration of mechanical ventilation, development of resistant microorganisms, and mortality.

Results of a cohort study published in May 2013 compared the incidence of early-onset VAP of a single dose of ceftriaxone in comatose patients to a historical control group who did not receive antibiotics.4 Patients included in the prophylaxis group were those on mechanical ventilation with a Glasgow score of ≤ 8 admitted to a single institution between 2009 and 2010. These patients received ceftriaxone 2 g within 4 hours of intubation (n=71). The historical cohort (n=58) consisted of mechanically ventilated patients admitted between 2007 and 2008 and patients admitted to the ICU more than 4 hours after intubation between 2009 and 2010 without antibiotic prophylaxis. Preventive measures used in the historical cohort included subglottic suctioning, semirecumbent positioning, and use of chlorhexidine rinses. Approximately 70% of patients in the prophylaxis group and 85% of control group patients were intubated for head trauma, stroke, or cardiac arrest. At baseline, the control group had a significantly greater number of patients with COPD, neurosurgical interventions, and antibiotic use compared to the prophylaxis group.

This study showed a significant decrease in the incidence of microbiologically-confirmed early-onset VAP in the ceftriaxone group compared to the control group (2.8% versus 22.4%, p=0.001).4 Patients in the prophylaxis group also had a significantly shorter length of stay in the ICU (9.7± 9.8 days vs. 14.9 ± 13.9 days, p=0.01) and a shorter duration of intubation (6.4 ± 6.5 days vs. 14.9 ± 13.9 days, p=0.01). No significant differences were found between the 2 groups in the incidence of late-onset VAP or mortality. Microorganisms that were isolated in the prophylaxis group in patients who developed early-onset VAP included S. aureus, Peptostreptococcus species; whereas P. aeruginosa and S. aureus were causative organisms of late-onset VAP in the prophylaxis group. The authors concluded that single dose ceftriaxone may decrease the incidence of early-onset VAP in comatose patients without increasing antimicrobial resistance and further prospective, randomized trials are needed to confirm these findings.

Conclusion

The current data on short-term use of antibiotics for prophylaxis of early-onset VAP are limited.4-7 Treatment courses range from a single dose of a long-acting third generation cephalosporin to a 3 day course of an aminopenicillin. The population for whom use of short-term antibiotics has been studied includes comatose patients suffering from head trauma, stroke, or cardiac arrest. Although a reduction in the incidence of early-onset VAP has been demonstrated in the published literature, small sample size, study design, and confounding factors, limit the ability to make firm recommendations for routine antibiotic use for early-onset VAP prevention. Larger, randomized, prospective, multicenter trials evaluating VAP prevention, morbidity, antibiotic resistance, and mortality are warranted based on the positive preliminary data that are currently available.

References

1. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

2. Sirvent JM, Torres A. Antibiotic prophylaxis in the prevention of ventilator-associated pneumonia. Expert Opin Pharmacother. 2003;4(8):1345-1354.

3. Kollef MH. Prevention of hospital-associated pneumonia and ventilator-associated pneumonia. Crit Care Med. 2004;32(6):1396-1405.

4. Valles J, Peredo R, Burgueno M, Rodriques de Freitas P, Millan S, et al. Efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated. Chest. 2013;143(5):1219-1225.

5. Mandelli M, Mosconi P, Langer M, Cigada M. Prevention of pneumonia in an intensive care unit: a randomized multicenter clinical trial. Intensive Care Unit Group of Infection Control. Crit Care Med. 1989;17(6):501-505.

6. Sirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med. 1997;155(5):1729-1734.

7. Acquarolo A, Urli T, Perone G, Giannotti C, Candiani A, Latronico N . Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients: a randomized study. Intensive Care Med. 2005;31(4):510-516.

Prepared by:

Seema Patel, PharmD

PGY-1

University of Illinois at Chicago

July 2013

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