PHARMACOLOGY CONSULT
What are the latest recommendations for managing severe sepsis and septic shock? Christopher M. Bland, PharmD, BCPS; S. Scott Sutton, PharmD, BCPS; Brianne L. Dunn, PharmD, BCPS
ABSTRACT Severe sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoperfusion leading to tissue injury and organ failure. The primary goal of sepsis treatment is to prevent morbidity and mortality. Crystalloids are now recommended over colloids for volume resuscitation, one of the key interventions for patients with sepsis. Keywords: sepsis, septic shock, crystalloids, colloids, vasopressors, hemodynamic support
E
ach year, more than 750,000 patients in the United States develop severe sepsis, representing 10% of all ICU admissions.1 Although worldwide estimates are difficult to ascertain, nearly 19 million cases may occur annually.2 Pneumonia remains the leading cause of severe sepsis, followed by intra-abdominal and urinary tract infections.3 While epidemiology has vacillated between Grampositive and Gram-negative bacteria, more recent data from a single study indicate that most cases of severe sepsis are caused by Gram-negative organisms.4 However, in nearly two-thirds of patients, positive cultures are not isolated. Severe sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoperfusion leading to tissue injury and organ failure. In patients with severe sepsis, hypotension not relieved by volume resuscitation is called septic shock. Risk factors for sepsis include extremes of age, cancer, immunodeficiency, chronic organ failure, genetic factors (in North America, men and persons of nonwhite ethnic origin are more likely to be affected), bacteremia, and polymorphisms in genes that regulate immunity. Christopher M. Bland is a pharmacist in critical care and infectious diseases at Dwight D. Eisenhower Army Medical Center in Fort Gordon, Ga. S. Scott Sutton is an associate professor in the University of South Carolina’s South Carolina College of Pharmacy in Columbia, S.C., and a clinical pharmacist in infectious diseases research at the Dorn VA Medical Center in Columbia. Brianne L. Dunn is a clinical assistant professor at South Carolina College of Pharmacy. The authors have disclosed no potential conflicts of interest, financial or otherwise. Mary Lou Brubaker, PharmD, PA-C, department editor DOI: 10.1097/01.JAA.0000453869.69947.10 Copyright © 2014 American Academy of Physician Assistants
JAAPA Journal of the American Academy of Physician Assistants
The development of severe sepsis and septic shock is complex and multifactorial. The key factor in the development of sepsis is infection leading to a complex host immune response. Infection or injury is controlled through pro- and anti-inflammatory mediators. Proinflammatory mediators are believed to cause collateral tissue injury; anti-inflammatory mediators may increase risk for secondary infections.3 Systemic responses ensue when equilibrium between the pro- and anti-inflammatory process is lost. The clinical presentation of severe sepsis varies and the development of clinical manifestations may differ from patient to patient. The cumulative burden of sepsis complications is the leading factor in mortality. The most common complications are disseminated intravascular coagulation, acute respiratory distress syndrome, acute kidney injury, and hemodynamic compromise.5,6 TREATMENT Although the Surviving Sepsis Campaign guidelines have improved care and reduced mortality for patients with severe sepsis, many of the recommendations have little support and are based primarily on expert opinion.7 Also, because treatment of patients with severe sepsis often has case-by-case variance, global guidelines are difficult to develop and execute. Treatment is compounded by the fact that most treatment options studied in the last 30 years have had no favorable effect on mortality or actually increased it. Recombinant activated protein C, an initially promising drug, was removed from the market by the manufacturer in 2011 after it failed to duplicate the results that had led to its approval by the FDA. The primary goal of sepsis treatment is to prevent patient morbidity and mortality. The speed and appropriateness of therapy strongly influence the outcome. In the first 6 hours after severe sepsis or septic shock is recognized, the goals of treatment are volume resuscitation and restoration of perfusion, early administration of broadspectrum anti-infective therapy, hemodynamic support, and supportive care. Volume resuscitation and antimicrobial therapy The goals of initial resuscitation during the first 6 hours are: • Central venous pressure of 8-12 mm Hg • Mean arterial pressure (MAP) of 65 mm Hg or greater www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
15
PHARMACOLOGY CONSULT
• Urine output of 0.5 mL/kg/hour or greater • Superior vena cava oxygenation saturation (Scvo2) of 70% or mixed venous oxygen saturation (Svo2) of 65%.5 These goals collectively are termed early goal-directed therapy (EGDT) and are based on a single-center study that showed a 16% decrease in 28-day mortality compared with standard therapy.8 Over the past decade, these recommendations have been implemented as a protocol at most institutions. However, which aspects of EGDT are most beneficial is not clear, especially use of an Scvo2 catheter with higher transfusion thresholds. A recently published study compared three groups for the management of early septic shock. The first group had protocol-based EGDT, the second had protocol-based standard therapy with no Scvo2 catheter placement, and the third group had usual care.9 The study enrolled 1,341 patients at 31 EDs; the primary endpoint was 60-day hospital mortality of both protocol groups versus usual care as well as EGDT versus protocol therapy. No significant differences were found between EGDT and standard protocol groups for 60-day mortality (P=0.31). No significant differences were found between protocol groups and usual care groups (P=0.83). Secondary endpoints such as organ dysfunction, 90-day mortality, and 1-year mortality were not statistically different among the same comparisons. This study confirms the lack of need of invasive monitoring as well as the requirement for a more liberal transfusion strategy. Conservative transfusion strategies have shown to be as effective as liberal strategies with fewer complications such as pulmonary edema. Timely administration of anti-infectives is critical in the management of severe sepsis and septic shock. A stepwise approach to anti-infective therapy is: • Culture acquisition. Before administering anti-infectives, obtain appropriate cultures to maximize yield of isolating the infecting pathogen. Avoid significantly delaying antiinfective therapy (defined as a delay of more than 45 minutes) if cultures cannot be obtained promptly.5 In some hospitals, rapid identification of blood cultures within 2 hours of a positive culture is available, and can reduce morbidity and mortality, but susceptibility testing still takes 48 to 96 hours for bacterial isolates, and longer for fungal isolates.10 • Antimicrobial therapy. Administer broad-spectrum anti-infectives therapy as early as possible and within the first hour after sepsis has been recognized.5 In patients with septic shock, each hour delay in administration of effective anti-infectives is associated with a measurable increase in mortality.11-13 Appropriate empiric anti-infective therapy decreases 28-day mortality compared with inappropriate empiric therapy (24% versus 39%).14 Empiric anti-infective therapy should include two or three drugs, depending on the patient’s history, site of infection, and causative pathogens (Table 1). 16
www.JAAPA.com
TABLE 1. Potential
empiric IV antimicrobial regimens for patients with sepsis6,26-31
Specific antimicrobials are not recommended in the Surviving Sepsis Campaign guidelines due to varying susceptibility at different geographical institutions. Individual healthcare institutions should choose appropriate agents based primarily on each institution’s local susceptibility patterns demonstrated by an annual antibiogram. If available, an antibiogram should separate ICU from non-ICU isolates to show ICU-specific susceptibilities. Urinary tract infection • Community-acquired: Third-generation cephalosporin (ceftriaxone) or fluoroquinolone (levofloxacin or ciprofloxacin) • Healthcare-associated: Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside. Pneumonia • Community-acquired: Third-generation cephalosporin/ ampicillin-sulbactam, plus a macrolide or doxycycline or levofloxacin/moxifloxacin • Healthcare-associated, ventilator-associated, or nosocomial (early onset; no risk factors for multidrug-resistant pathogens): Third-generation cephalosporin or ciprofloxacin/levofloxacin or ampicillin-sulbactam or ertapenem • Healthcare-associated, ventilator-associated, or nosocomial (late onset and/or risk factors for multidrug-resistant pathogens): Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside or antipseudomonal fluoroquinolone plus vancomycin or linezolid. Intra-abdominal infection • Community-acquired: Cefoxitin or ciprofloxacin/levofloxacin plus metronidazole or moxifloxacin • Healthcare-associated: Piperacillin-tazobactam or imipenem or meropenem or cefepime plus metronidazole or ciprofloxacin or levofloxacin plus metronidazole. Skin and soft tissue infection • Community-acquired: Nafcillin or cefazolin or vancomycin (for areas with high MRSA rates) • Healthcare-associated: Vancomycin, daptomycin, or linezolid. Unknown source • Community-acquired: empiric MRSA coverage may be required in certain patients (known MRSA colonizer, cavitary/necrotizing pattern of pneumonia, recent influenza infection, multilobar infiltrates)32 • Healthcare-associated: Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside/antipseudomonal fluoroquinolone plus vancomycin.
Patients living in areas with high incidences of methicillin-resistant Staphylococcus aureus (MRSA) as well as multidrug resistant Pseudomonas or Acinetobacter species should receive three medications (one agent for MRSA and two agents of different classes for PseudoVolume 27 • Number 10 • October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What are the latest recommendations for managing severe sepsis and septic shock?
monas or Acinetobacter species). Anti-infective clinical trials in sepsis and septic shock patients are scarce and have not demonstrated differences among agents. Therefore, factors that determine selection are site of infection, causative pathogens, community-acquired or healthcare-associated infection, patient immune status, patient history, cost, and local antibiogram for the institution. Clinicians should be cognizant of growing prevalence of bacterial resistance in community and healthcare settings through close monitoring of local antibiograms. • De-escalation of antimicrobial therapy. Each patient’s clinical response should be monitored closely, including indices of infection and available culture data. Low procalcitonin levels and other clinical information may be considered to discontinue antibiotic therapy. However, data about procalcitonin use in patients with sepsis are limited and concerns over potential increased morbidity and mortality persist.5 Cultures on average require 48 to 96 hours for final identification and often reveal no growth of bacterial organisms. Remember that negative cultures do not rule out infection and often are negative in patients with severe sepsis or septic shock. Clinicians should make every effort to de-escalate antimicrobial therapy to the minimal number of agents required to achieve clinical cure, prevent resistance, minimize adverse reactions to antimicrobial therapy such as Clostridium difficile colitis, and decrease the cost of antimicrobial therapy. • Duration of therapy. The average duration of antiinfective therapy is 7 to 10 days. However, durations vary depending on the pathogen identified (for example, the minimum duration of therapy for S. aureus bacteremia is 2 weeks), site of infection, and patient response to therapy. Patients with documented Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) should be treated for 2 weeks to limit relapse.15 Initial large-volume resuscitation may alter the pharmacokinetics of anti-infectives given to patients with sepsis because of altered volume of distribution.16 Reevaluate the initial regimen daily to optimize activity, prevent development of resistance, reduce toxicity, and decrease costs. Also identify the anatomical site of infection. If feasible and indicated, this source should be contained (for example, by removing infected devices, debriding tissue, or draining abscesses) to maximize clinical cure. The first day of “effective” antimicrobial therapy in patients whose infections have drainable or surgical sources should start once the source of infection has been controlled. Rapid diagnostics for blood cultures have shown benefit but save costs only when this information is communicated in a timely fashion to the provider caring for the patient. JAAPA Journal of the American Academy of Physician Assistants
HEMODYNAMIC SUPPORT Fluid therapy Although the choice of crystalloid or colloid therapy for resuscitation has been a source of debate among critical care practitioners, recent guidelines now recommend crystalloids over more-expensive colloids. Crystalloid solutions require more volume, which may lead to edema, so use caution in patients at risk for fluid overload, such as those with heart failure or ARDS. Resuscitation studies have found that crystalloids such as 0.9% sodium chloride solution or lactated Ringer solution and colloids such as 5% albumin have equivalent effects.17 A recent comparative study of crystalloid therapy versus 20% albumin to target an albumin level of 30 g/L also did not show a decrease in 28-day or 90-day mortality.18
The ideal administration of corticosteroids in patients with septic shock remains unclear. Administer a fluid challenge to hypovolemic patients (those with hypotension or lactic acidosis) using either 500 to 1,000 mL of crystalloids or 300 to 500 mL of colloids. Aggressive fluid infusion rates (over 5 to 10 minutes) are often needed in patients with severe hypoperfusion, such as patients with septic shock.5 Vasopressors When fluid resuscitation fails to provide adequate arterial pressure and organ perfusion, administer vasopressors and/or inotropic agents to target a MAP of 65 mm Hg or greater. Place arterial catheters as soon as possible for hemodynamic monitoring. Use central venous catheters to administer vasopressors and avoid local complications such as extravasation. Continually reassess the patient’s volume status because hypovolemia may increase peripheral hypoperfusion and worsen tissue ischemia. Norepinephrine is the recommended vasopressor in patients with shock refractory to fluid resuscitation.5 A study comparing norepinephrine at 0.19 mcg/kg/min versus dopamine at 20 mcg/kg/min demonstrated no difference in 28-day mortality between the groups.19 However, the patients on dopamine had a much higher rate of dysrhythmias, so dopamine is an alternative vasopressor in selected patients (that is, those at low risk of tachyarrhythmias) who cannot tolerate norepinephrine. Epinephrine may be added to or substituted for norepinephrine in patients requiring further hemodynamic support. Vasopressin may be added to norepinephrine therapy for further hemodynamic support or www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
17
PHARMACOLOGY CONSULT
to decrease norepinephrine dosage requirements. Adding vasopressin to norepinephrine therapy has not been shown to decrease overall mortality.20 Phenylephrine is only rarely used due to lack of outcome data. Inotropes In patients with myocardial dysfunction, inotropic therapy with an agent such as dobutamine is recommended for further hemodynamic support. Inotropes are effective for improving cardiac index, but complications such as tachycardia, dysrhythmias, and myocardial ischemia require slow titration to restore MAP without impairing stroke volume. Corticosteroids Patients with septic shock refractory to resuscitation and vasopressors may be given 200 mg of IV hydrocortisone per day, although evidence about using a continuous infusion is limited.5 Adrenocorticotropic hormone concentrations should not be used to gauge initiation or response to corticosteroid therapy. The corticus study demonstrated no difference in 28-day mortality between patients receiving corticosteroids versus placebo.21 However, the study did not reach power to demonstrate this difference and patients were allowed to be enrolled within 72 hours of admission, which may have missed the ideal window for therapy initiation. Therefore, ideal administration of corticosteroids in patients with septic shock remains unclear. When vasopressors are no longer required, patients should be weaned from corticosteroid therapy over about a week.21 ADJUNCTIVE THERAPY Primary adjunctive therapies for patients with severe sepsis or septic shock consist of enteral nutrition, glycemic control, deep vein thrombosis (DVT) prophylaxis, stress ulcer prophylaxis, and analgesia and sedation in agitated patients.5 Oral or enteral (if necessary) nutrition is recommended, as tolerated, within the first 48 hours after a diagnosis of severe sepsis or septic shock. Administer up to 500 calories per day, advancing as tolerated. If possible, IV glucose and enteral nutrition is preferred over total parenteral nutrition. Tight glycemic control (110 mg/dL or less) is no longer recommended due to the increased risk of hypoglycemia as well as an increased risk of mortality.22 Following initial stabilization of patients with severe sepsis or septic shock, maintain blood glucose levels of 180 mg/dL or less.5 Patients with high glucose levels should receive IV insulin with frequent blood glucose monitoring (every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours). Although point-of-care testing is standard for glucose monitoring, arterial sampling is preferred over capillary testing when available. Capillary blood glucose measures are less reliable near or within hypoglycemic ranges and may be falsely high in these patients. DVT prophylaxis is recommended for patients with sepsis.5 Low-molecular-weight heparin therapy is recom18
www.JAAPA.com
mended over low-dose unfractionated heparin (UFH), based primarily on one study that showed a decreased risk of pulmonary embolism (but not proximal DVTs) with dalteparin compared with UFH.23 Graduated compression stockings or intermittent compression devices should be used in all patients, including those with contraindications to chemical prophylaxis. Coagulopathy, mechanical ventilation for 48 hours or more, hypotension, and systemic corticosteroid therapy put patients with severe sepsis and septic shock at high risk for stress ulcers. The two primary prophylaxis options include histamine2-receptor antagonists and proton pump inhibitors (PPIs). The guidelines recommend PPIs over histamine2-receptor antagonists; however, the potential benefits of PPIs must be weighed against the potential effect of an increased gastric pH and increased risk of
Tight glycemic control is no longer recommended due to the increased risk of hypoglycemia. infection.5 A recent study found that patients on PPI prophylaxis had an increased risk of pneumonia and C. difficile infection, as well as a higher rate of GI bleeding compared with patients on histamine2-receptor antagonist prophylaxis.24 Critically ill patients often require analgesia and sedation when complex ventilator settings are used or when patients are difficult to ventilate. Patients with progressive hypoxia leading to ARDS frequently require uncomfortable modes of mechanical ventilation. Newly updated guidelines recommend nonbenzodiazepine sedatives such as propofol or dexmedetomidine, which have shown improved outcomes compared with benzodiazepines.25 Mechanically ventilated patients should receive sedation by a protocol that includes a daily interruption of the sedative infusion until the patient is awake.5 Sedation is then restarted at half the previous rate, to limit accumulation of the sedative. Patients receiving paralytic therapy should not receive daily interruption of sedation therapy. The use of sedation protocols decreases the duration of mechanical ventilation, length of ICU stays, and tracheostomy rates. CONCLUSION Clinicians can help improve outcomes for patients with sepsis by understanding the current guidelines and promptly administering appropriate therapy as soon as severe sepsis develops. JAAPA Volume 27 • Number 10 • October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What are the latest recommendations for managing severe sepsis and septic shock?
REFERENCES 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 2. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010;376(9749):1339-1346. 3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-851. 4. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329. 5. 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. 6. Sutton SS, Bland CM, Rao GA. Sepsis and septic shock. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy Principles and Practice. 3rd ed. New York, NY: McGraw-Hill; 2013. 7. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13): 1308-1316. 8. 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. N Engl J Med. 2001;345(19):1368-1377 9. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. 10. Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacotherapy. 2012;32(8):677-687. 11. 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. Crit Care Med. 2006;34(6):1589-1596. 12. Ferrer R, Artigas A, Suarez D, et al. Edusepsis Study Group. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009;180(9):861-866. 13. Castellanos-Ortega A, Suberviola B, García-Astudillo LA, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Crit Care Med. 2010;38(4):1036-1043. 14. Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7):529-535. 15. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-2598. 16. Goncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of Beta-lactams. Crit Care. 2011;15:R206. www.biomedicalcentral.com/content/ pdf/cc10441.pdf. Accessed January 6, 2014. 17. Finfer S, Bellomo R, Boyce N, et al. SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256. 18. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014; 370:1412-1421.
JAAPA Journal of the American Academy of Physician Assistants
19. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789. 20. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. 21. Sprung CL, Annane D, Keh D, et al. corticus Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. 22. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. 23. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, Guyatt G, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364(14):1305-1314. 24. MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med. 2014;174(4):564-574. 25. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1): 263-306. 26. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. 27. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663. 28. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72. 29. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416. 30. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50 (2):133-164. 31. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52. 32. Hidron AI, Low CE, Honig EG, Blumberg HM. Emergence of community-acquired methicillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia. Lancet Infect Dis. 2009;9(6):384-392.
ASK OUR CONSULTANT To ask our consultant a drug-related question, please e-mail [email protected].
www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
19
What are the latest recommendations for managing severe sepsis and septic shock? Christopher M. Bland, PharmD, BCPS; S. Scott Sutton, PharmD, BCPS; Brianne L. Dunn, PharmD, BCPS
ABSTRACT Severe sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoperfusion leading to tissue injury and organ failure. The primary goal of sepsis treatment is to prevent morbidity and mortality. Crystalloids are now recommended over colloids for volume resuscitation, one of the key interventions for patients with sepsis. Keywords: sepsis, septic shock, crystalloids, colloids, vasopressors, hemodynamic support
E
ach year, more than 750,000 patients in the United States develop severe sepsis, representing 10% of all ICU admissions.1 Although worldwide estimates are difficult to ascertain, nearly 19 million cases may occur annually.2 Pneumonia remains the leading cause of severe sepsis, followed by intra-abdominal and urinary tract infections.3 While epidemiology has vacillated between Grampositive and Gram-negative bacteria, more recent data from a single study indicate that most cases of severe sepsis are caused by Gram-negative organisms.4 However, in nearly two-thirds of patients, positive cultures are not isolated. Severe sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoperfusion leading to tissue injury and organ failure. In patients with severe sepsis, hypotension not relieved by volume resuscitation is called septic shock. Risk factors for sepsis include extremes of age, cancer, immunodeficiency, chronic organ failure, genetic factors (in North America, men and persons of nonwhite ethnic origin are more likely to be affected), bacteremia, and polymorphisms in genes that regulate immunity. Christopher M. Bland is a pharmacist in critical care and infectious diseases at Dwight D. Eisenhower Army Medical Center in Fort Gordon, Ga. S. Scott Sutton is an associate professor in the University of South Carolina’s South Carolina College of Pharmacy in Columbia, S.C., and a clinical pharmacist in infectious diseases research at the Dorn VA Medical Center in Columbia. Brianne L. Dunn is a clinical assistant professor at South Carolina College of Pharmacy. The authors have disclosed no potential conflicts of interest, financial or otherwise. Mary Lou Brubaker, PharmD, PA-C, department editor DOI: 10.1097/01.JAA.0000453869.69947.10 Copyright © 2014 American Academy of Physician Assistants
JAAPA Journal of the American Academy of Physician Assistants
The development of severe sepsis and septic shock is complex and multifactorial. The key factor in the development of sepsis is infection leading to a complex host immune response. Infection or injury is controlled through pro- and anti-inflammatory mediators. Proinflammatory mediators are believed to cause collateral tissue injury; anti-inflammatory mediators may increase risk for secondary infections.3 Systemic responses ensue when equilibrium between the pro- and anti-inflammatory process is lost. The clinical presentation of severe sepsis varies and the development of clinical manifestations may differ from patient to patient. The cumulative burden of sepsis complications is the leading factor in mortality. The most common complications are disseminated intravascular coagulation, acute respiratory distress syndrome, acute kidney injury, and hemodynamic compromise.5,6 TREATMENT Although the Surviving Sepsis Campaign guidelines have improved care and reduced mortality for patients with severe sepsis, many of the recommendations have little support and are based primarily on expert opinion.7 Also, because treatment of patients with severe sepsis often has case-by-case variance, global guidelines are difficult to develop and execute. Treatment is compounded by the fact that most treatment options studied in the last 30 years have had no favorable effect on mortality or actually increased it. Recombinant activated protein C, an initially promising drug, was removed from the market by the manufacturer in 2011 after it failed to duplicate the results that had led to its approval by the FDA. The primary goal of sepsis treatment is to prevent patient morbidity and mortality. The speed and appropriateness of therapy strongly influence the outcome. In the first 6 hours after severe sepsis or septic shock is recognized, the goals of treatment are volume resuscitation and restoration of perfusion, early administration of broadspectrum anti-infective therapy, hemodynamic support, and supportive care. Volume resuscitation and antimicrobial therapy The goals of initial resuscitation during the first 6 hours are: • Central venous pressure of 8-12 mm Hg • Mean arterial pressure (MAP) of 65 mm Hg or greater www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
15
PHARMACOLOGY CONSULT
• Urine output of 0.5 mL/kg/hour or greater • Superior vena cava oxygenation saturation (Scvo2) of 70% or mixed venous oxygen saturation (Svo2) of 65%.5 These goals collectively are termed early goal-directed therapy (EGDT) and are based on a single-center study that showed a 16% decrease in 28-day mortality compared with standard therapy.8 Over the past decade, these recommendations have been implemented as a protocol at most institutions. However, which aspects of EGDT are most beneficial is not clear, especially use of an Scvo2 catheter with higher transfusion thresholds. A recently published study compared three groups for the management of early septic shock. The first group had protocol-based EGDT, the second had protocol-based standard therapy with no Scvo2 catheter placement, and the third group had usual care.9 The study enrolled 1,341 patients at 31 EDs; the primary endpoint was 60-day hospital mortality of both protocol groups versus usual care as well as EGDT versus protocol therapy. No significant differences were found between EGDT and standard protocol groups for 60-day mortality (P=0.31). No significant differences were found between protocol groups and usual care groups (P=0.83). Secondary endpoints such as organ dysfunction, 90-day mortality, and 1-year mortality were not statistically different among the same comparisons. This study confirms the lack of need of invasive monitoring as well as the requirement for a more liberal transfusion strategy. Conservative transfusion strategies have shown to be as effective as liberal strategies with fewer complications such as pulmonary edema. Timely administration of anti-infectives is critical in the management of severe sepsis and septic shock. A stepwise approach to anti-infective therapy is: • Culture acquisition. Before administering anti-infectives, obtain appropriate cultures to maximize yield of isolating the infecting pathogen. Avoid significantly delaying antiinfective therapy (defined as a delay of more than 45 minutes) if cultures cannot be obtained promptly.5 In some hospitals, rapid identification of blood cultures within 2 hours of a positive culture is available, and can reduce morbidity and mortality, but susceptibility testing still takes 48 to 96 hours for bacterial isolates, and longer for fungal isolates.10 • Antimicrobial therapy. Administer broad-spectrum anti-infectives therapy as early as possible and within the first hour after sepsis has been recognized.5 In patients with septic shock, each hour delay in administration of effective anti-infectives is associated with a measurable increase in mortality.11-13 Appropriate empiric anti-infective therapy decreases 28-day mortality compared with inappropriate empiric therapy (24% versus 39%).14 Empiric anti-infective therapy should include two or three drugs, depending on the patient’s history, site of infection, and causative pathogens (Table 1). 16
www.JAAPA.com
TABLE 1. Potential
empiric IV antimicrobial regimens for patients with sepsis6,26-31
Specific antimicrobials are not recommended in the Surviving Sepsis Campaign guidelines due to varying susceptibility at different geographical institutions. Individual healthcare institutions should choose appropriate agents based primarily on each institution’s local susceptibility patterns demonstrated by an annual antibiogram. If available, an antibiogram should separate ICU from non-ICU isolates to show ICU-specific susceptibilities. Urinary tract infection • Community-acquired: Third-generation cephalosporin (ceftriaxone) or fluoroquinolone (levofloxacin or ciprofloxacin) • Healthcare-associated: Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside. Pneumonia • Community-acquired: Third-generation cephalosporin/ ampicillin-sulbactam, plus a macrolide or doxycycline or levofloxacin/moxifloxacin • Healthcare-associated, ventilator-associated, or nosocomial (early onset; no risk factors for multidrug-resistant pathogens): Third-generation cephalosporin or ciprofloxacin/levofloxacin or ampicillin-sulbactam or ertapenem • Healthcare-associated, ventilator-associated, or nosocomial (late onset and/or risk factors for multidrug-resistant pathogens): Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside or antipseudomonal fluoroquinolone plus vancomycin or linezolid. Intra-abdominal infection • Community-acquired: Cefoxitin or ciprofloxacin/levofloxacin plus metronidazole or moxifloxacin • Healthcare-associated: Piperacillin-tazobactam or imipenem or meropenem or cefepime plus metronidazole or ciprofloxacin or levofloxacin plus metronidazole. Skin and soft tissue infection • Community-acquired: Nafcillin or cefazolin or vancomycin (for areas with high MRSA rates) • Healthcare-associated: Vancomycin, daptomycin, or linezolid. Unknown source • Community-acquired: empiric MRSA coverage may be required in certain patients (known MRSA colonizer, cavitary/necrotizing pattern of pneumonia, recent influenza infection, multilobar infiltrates)32 • Healthcare-associated: Antipseudomonal penicillin or antipseudomonal cephalosporin or antipseudomonal carbapenem plus aminoglycoside/antipseudomonal fluoroquinolone plus vancomycin.
Patients living in areas with high incidences of methicillin-resistant Staphylococcus aureus (MRSA) as well as multidrug resistant Pseudomonas or Acinetobacter species should receive three medications (one agent for MRSA and two agents of different classes for PseudoVolume 27 • Number 10 • October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What are the latest recommendations for managing severe sepsis and septic shock?
monas or Acinetobacter species). Anti-infective clinical trials in sepsis and septic shock patients are scarce and have not demonstrated differences among agents. Therefore, factors that determine selection are site of infection, causative pathogens, community-acquired or healthcare-associated infection, patient immune status, patient history, cost, and local antibiogram for the institution. Clinicians should be cognizant of growing prevalence of bacterial resistance in community and healthcare settings through close monitoring of local antibiograms. • De-escalation of antimicrobial therapy. Each patient’s clinical response should be monitored closely, including indices of infection and available culture data. Low procalcitonin levels and other clinical information may be considered to discontinue antibiotic therapy. However, data about procalcitonin use in patients with sepsis are limited and concerns over potential increased morbidity and mortality persist.5 Cultures on average require 48 to 96 hours for final identification and often reveal no growth of bacterial organisms. Remember that negative cultures do not rule out infection and often are negative in patients with severe sepsis or septic shock. Clinicians should make every effort to de-escalate antimicrobial therapy to the minimal number of agents required to achieve clinical cure, prevent resistance, minimize adverse reactions to antimicrobial therapy such as Clostridium difficile colitis, and decrease the cost of antimicrobial therapy. • Duration of therapy. The average duration of antiinfective therapy is 7 to 10 days. However, durations vary depending on the pathogen identified (for example, the minimum duration of therapy for S. aureus bacteremia is 2 weeks), site of infection, and patient response to therapy. Patients with documented Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) should be treated for 2 weeks to limit relapse.15 Initial large-volume resuscitation may alter the pharmacokinetics of anti-infectives given to patients with sepsis because of altered volume of distribution.16 Reevaluate the initial regimen daily to optimize activity, prevent development of resistance, reduce toxicity, and decrease costs. Also identify the anatomical site of infection. If feasible and indicated, this source should be contained (for example, by removing infected devices, debriding tissue, or draining abscesses) to maximize clinical cure. The first day of “effective” antimicrobial therapy in patients whose infections have drainable or surgical sources should start once the source of infection has been controlled. Rapid diagnostics for blood cultures have shown benefit but save costs only when this information is communicated in a timely fashion to the provider caring for the patient. JAAPA Journal of the American Academy of Physician Assistants
HEMODYNAMIC SUPPORT Fluid therapy Although the choice of crystalloid or colloid therapy for resuscitation has been a source of debate among critical care practitioners, recent guidelines now recommend crystalloids over more-expensive colloids. Crystalloid solutions require more volume, which may lead to edema, so use caution in patients at risk for fluid overload, such as those with heart failure or ARDS. Resuscitation studies have found that crystalloids such as 0.9% sodium chloride solution or lactated Ringer solution and colloids such as 5% albumin have equivalent effects.17 A recent comparative study of crystalloid therapy versus 20% albumin to target an albumin level of 30 g/L also did not show a decrease in 28-day or 90-day mortality.18
The ideal administration of corticosteroids in patients with septic shock remains unclear. Administer a fluid challenge to hypovolemic patients (those with hypotension or lactic acidosis) using either 500 to 1,000 mL of crystalloids or 300 to 500 mL of colloids. Aggressive fluid infusion rates (over 5 to 10 minutes) are often needed in patients with severe hypoperfusion, such as patients with septic shock.5 Vasopressors When fluid resuscitation fails to provide adequate arterial pressure and organ perfusion, administer vasopressors and/or inotropic agents to target a MAP of 65 mm Hg or greater. Place arterial catheters as soon as possible for hemodynamic monitoring. Use central venous catheters to administer vasopressors and avoid local complications such as extravasation. Continually reassess the patient’s volume status because hypovolemia may increase peripheral hypoperfusion and worsen tissue ischemia. Norepinephrine is the recommended vasopressor in patients with shock refractory to fluid resuscitation.5 A study comparing norepinephrine at 0.19 mcg/kg/min versus dopamine at 20 mcg/kg/min demonstrated no difference in 28-day mortality between the groups.19 However, the patients on dopamine had a much higher rate of dysrhythmias, so dopamine is an alternative vasopressor in selected patients (that is, those at low risk of tachyarrhythmias) who cannot tolerate norepinephrine. Epinephrine may be added to or substituted for norepinephrine in patients requiring further hemodynamic support. Vasopressin may be added to norepinephrine therapy for further hemodynamic support or www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
17
PHARMACOLOGY CONSULT
to decrease norepinephrine dosage requirements. Adding vasopressin to norepinephrine therapy has not been shown to decrease overall mortality.20 Phenylephrine is only rarely used due to lack of outcome data. Inotropes In patients with myocardial dysfunction, inotropic therapy with an agent such as dobutamine is recommended for further hemodynamic support. Inotropes are effective for improving cardiac index, but complications such as tachycardia, dysrhythmias, and myocardial ischemia require slow titration to restore MAP without impairing stroke volume. Corticosteroids Patients with septic shock refractory to resuscitation and vasopressors may be given 200 mg of IV hydrocortisone per day, although evidence about using a continuous infusion is limited.5 Adrenocorticotropic hormone concentrations should not be used to gauge initiation or response to corticosteroid therapy. The corticus study demonstrated no difference in 28-day mortality between patients receiving corticosteroids versus placebo.21 However, the study did not reach power to demonstrate this difference and patients were allowed to be enrolled within 72 hours of admission, which may have missed the ideal window for therapy initiation. Therefore, ideal administration of corticosteroids in patients with septic shock remains unclear. When vasopressors are no longer required, patients should be weaned from corticosteroid therapy over about a week.21 ADJUNCTIVE THERAPY Primary adjunctive therapies for patients with severe sepsis or septic shock consist of enteral nutrition, glycemic control, deep vein thrombosis (DVT) prophylaxis, stress ulcer prophylaxis, and analgesia and sedation in agitated patients.5 Oral or enteral (if necessary) nutrition is recommended, as tolerated, within the first 48 hours after a diagnosis of severe sepsis or septic shock. Administer up to 500 calories per day, advancing as tolerated. If possible, IV glucose and enteral nutrition is preferred over total parenteral nutrition. Tight glycemic control (110 mg/dL or less) is no longer recommended due to the increased risk of hypoglycemia as well as an increased risk of mortality.22 Following initial stabilization of patients with severe sepsis or septic shock, maintain blood glucose levels of 180 mg/dL or less.5 Patients with high glucose levels should receive IV insulin with frequent blood glucose monitoring (every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours). Although point-of-care testing is standard for glucose monitoring, arterial sampling is preferred over capillary testing when available. Capillary blood glucose measures are less reliable near or within hypoglycemic ranges and may be falsely high in these patients. DVT prophylaxis is recommended for patients with sepsis.5 Low-molecular-weight heparin therapy is recom18
www.JAAPA.com
mended over low-dose unfractionated heparin (UFH), based primarily on one study that showed a decreased risk of pulmonary embolism (but not proximal DVTs) with dalteparin compared with UFH.23 Graduated compression stockings or intermittent compression devices should be used in all patients, including those with contraindications to chemical prophylaxis. Coagulopathy, mechanical ventilation for 48 hours or more, hypotension, and systemic corticosteroid therapy put patients with severe sepsis and septic shock at high risk for stress ulcers. The two primary prophylaxis options include histamine2-receptor antagonists and proton pump inhibitors (PPIs). The guidelines recommend PPIs over histamine2-receptor antagonists; however, the potential benefits of PPIs must be weighed against the potential effect of an increased gastric pH and increased risk of
Tight glycemic control is no longer recommended due to the increased risk of hypoglycemia. infection.5 A recent study found that patients on PPI prophylaxis had an increased risk of pneumonia and C. difficile infection, as well as a higher rate of GI bleeding compared with patients on histamine2-receptor antagonist prophylaxis.24 Critically ill patients often require analgesia and sedation when complex ventilator settings are used or when patients are difficult to ventilate. Patients with progressive hypoxia leading to ARDS frequently require uncomfortable modes of mechanical ventilation. Newly updated guidelines recommend nonbenzodiazepine sedatives such as propofol or dexmedetomidine, which have shown improved outcomes compared with benzodiazepines.25 Mechanically ventilated patients should receive sedation by a protocol that includes a daily interruption of the sedative infusion until the patient is awake.5 Sedation is then restarted at half the previous rate, to limit accumulation of the sedative. Patients receiving paralytic therapy should not receive daily interruption of sedation therapy. The use of sedation protocols decreases the duration of mechanical ventilation, length of ICU stays, and tracheostomy rates. CONCLUSION Clinicians can help improve outcomes for patients with sepsis by understanding the current guidelines and promptly administering appropriate therapy as soon as severe sepsis develops. JAAPA Volume 27 • Number 10 • October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What are the latest recommendations for managing severe sepsis and septic shock?
REFERENCES 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 2. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010;376(9749):1339-1346. 3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-851. 4. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329. 5. 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. 6. Sutton SS, Bland CM, Rao GA. Sepsis and septic shock. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy Principles and Practice. 3rd ed. New York, NY: McGraw-Hill; 2013. 7. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13): 1308-1316. 8. 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. N Engl J Med. 2001;345(19):1368-1377 9. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. 10. Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacotherapy. 2012;32(8):677-687. 11. 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. Crit Care Med. 2006;34(6):1589-1596. 12. Ferrer R, Artigas A, Suarez D, et al. Edusepsis Study Group. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009;180(9):861-866. 13. Castellanos-Ortega A, Suberviola B, García-Astudillo LA, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Crit Care Med. 2010;38(4):1036-1043. 14. Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7):529-535. 15. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-2598. 16. Goncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of Beta-lactams. Crit Care. 2011;15:R206. www.biomedicalcentral.com/content/ pdf/cc10441.pdf. Accessed January 6, 2014. 17. Finfer S, Bellomo R, Boyce N, et al. SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256. 18. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014; 370:1412-1421.
JAAPA Journal of the American Academy of Physician Assistants
19. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789. 20. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. 21. Sprung CL, Annane D, Keh D, et al. corticus Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. 22. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. 23. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, Guyatt G, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364(14):1305-1314. 24. MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med. 2014;174(4):564-574. 25. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1): 263-306. 26. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. 27. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663. 28. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72. 29. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416. 30. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50 (2):133-164. 31. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52. 32. Hidron AI, Low CE, Honig EG, Blumberg HM. Emergence of community-acquired methicillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia. Lancet Infect Dis. 2009;9(6):384-392.
ASK OUR CONSULTANT To ask our consultant a drug-related question, please e-mail [email protected].
www.JAAPA.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
19
