US Pharm. 2012;37(8):HS-8-HS-12.

Sepsis is an all-too-common occurrence in hospitalized patients, especially in ICUs. These infections originate from a number of different sources and can be difficult to manage. Many factors must be taken into account in the treatment of sepsis, including choice of antibiotic, patient allergies, local sensitivities, origin, site, and source of infection, and so on. In addition to being difficult to manage, sepsis contributes significantly to health care burden and has considerable associated morbidity and mortality concerns.

More than 750,000 cases of sepsis occur each year in the United States, costing the health care system approximately $17 billion annually.^1,2 It is estimated that between 15% and 35% of hospitalized patients have sepsis.^1,2 Sepsis-related infection is one of the most common reasons for ICU admission and accounts for about 40% of total ICU expenditures.^1,3 Furthermore, sepsis is considered one of the leading causes of noncardiac-related ICU death, with mortality rates approaching 30%.^1,3 Proper management is vital to reducing the morbidity, mortality, and costs associated with these infections.

DEFINITIONS

To comprehend sepsis, a basic understanding of several terms is necessary. Bacteremia is simply the presence of bacteria in the blood.⁴ Systemic inflammatory response syndrome (SIRS) is denoted by two or more of the following clinical symptoms: (1) body temperature >38°C or <36°C; (2) heart rate >90 beats per minute; (3) respiratory rate >20 breaths per minute or PaCO₂ (partial pressure of carbon dioxide in arterial blood) <32 mmHg; (4) WBC count >12,000 or <4,000 or bands >10%.⁴ Sepsis may be defined as an infection with a positive systemic response (SIRS).⁵ Multiple organ dysfunction syndrome (MODS) refers to a condition in which homeostasis cannot be maintained independently in an acutely ill patient with altered organ function.⁴ Sepsis may be further categorized as severe sepsis or septic shock. Sepsis occurring in combination with MODS or hypoperfusion is termed severe sepsis.⁴ Septic shock refers to sepsis-induced hypoperfusion despite adequate fluid resuscitation.⁶

ETIOLOGY AND RISK FACTORS

Male gender and increased age are associated with a greater risk of acquiring sepsis.^1,2,7 The rate of infection rises with increasing length of ICU stay and worsening degree of organ failure.³ TABLE 1 lists predictors of mortality in sepsis patients.^1-3

Site and Source of Infection

Currently, the most common site of sepsis is the respiratory tract, accounting for 30% to 60% of infections.^1-3 The second most common site varies by geographic location.^1-3 In the U.S., the bloodstream is the second most common site of infection, followed by the genitourinary tract and then the abdomen.¹ Internationally, the abdomen takes second place, with the bloodstream at 20% and the urinary tract at 14%.^2,3 ICU-acquired infections frequently occur in the lungs, are related to catheter access, or involve urinary sites.²

Sepsis acquired in the ICU is more likely to have a mixed microbial etiology.² Gram-positive and gram-negative bacteria are currently in competition for the role of most causative pathogen of infection; anaerobic bacteria and fungi are less commonly implicated.^1-3

Gram-Positive Bacteria: Gram-positive bacteria have emerged as the pathogen most commonly associated with sepsis.^2,7 This has not always been the case, however. Gram-negative bacteria were the leading causative organisms until 1987, after which gram-positive bacteria emerged as the leader. Gram-positive bacteria now account for nearly 50% of all sepsis cases.^2,7 Among these, Staphylococcus species (namely Staphylococcus aureus) are seen most often, with 14% of cultures isolating methicillin-resistant S aureus (MRSA).^2,3

Gram-Negative Bacteria: The second most common causative organism in sepsis is typically shown to be gram-negative pathogens.^1,2 Interestingly, a 2009 study of ICU infections implicated gram-negative bacteria as the cause of 62% of all ICU-related infections.³ Pseudomonas species and Escherichia coli are the major organisms behind gram-negative–associated sepsis.^2,3

Anaerobic Bacteria: Anaerobic bacteria have also been implicated as causative organisms in sepsis infections, but at a rate of only around 4%.² The most commonly associated anaerobic bacteria are gram-negative bacilli, mainly Bacteroides fragilis.⁸ Other commonly implicated anaerobes include Peptostreptococcus and Clostridium species.⁸ These pathogens have been regularly seen in conjunction with other known causative organisms and intra-abdominal infections (50%-70%).⁸ A 20% increase in mortality and a 16-day increase in length of hospital stay have been noted with B fragilis infections.⁸

Fungi: Fungi are causative organisms in about 17% of sepsis cases.² Candida albicans is the most commonly implicated fungus, accounting for 13% of fungal-related sepsis infections.²

SUPPORTIVE THERAPY

The Surviving Sepsis Campaign provides strong recommendations regarding hemodynamic support and adjunctive therapy in sepsis. See TABLE 2 for current recommendations.

INFECTION MANAGEMENT

Infection management is necessary in order to reduce the morbidity and mortality associated with sepsis. It is important to remember that cultures should be obtained prior to initiation of antimicrobial therapy; however, antibiotics should not be delayed if cultures cannot be obtained in a timely manner. Antibiotic therapy should be reassessed daily to ensure that the therapy is appropriate and the patient is responding adequately with minimal adverse events. Current guidelines recommend continuation of antibiotics for 7 to 10 days; however, if the source is found to be noninfectious, antimicrobial therapy should be promptly discontinued.⁶

Time to Treatment

Current guidelines recommend that antimicrobial therapy be initiated within 1 hour of identification of septic shock.⁶ In one retrospective review, when antimicrobial therapy was initiated within 30 minutes to 1 hour of the onset of hypotension, survival rates were high (about 80%).⁹ Survival rates dropped rapidly when antimicrobial treatment was delayed to within the sixth hour (42%).^6,9 A recent Cochrane Review, however, found no prospective data to support the conclusion that early initiation of broad-spectrum antimicrobials reduces mortality rates in patients with severe sepsis.¹⁰ However, prompt initiation of antimicrobial therapy remains important for suspected infections.^8,11

Empiric Antimicrobial Therapy

The choice of antimicrobial agent can sometimes be daunting. Consideration should be given to the origin (i.e., community- or health care–acquired), site, and source of infection. Recently used antibiotics should be avoided if possible, and local susceptibilities should be considered. Broad-spectrum antibiotics are ideal for empiric therapy, as they provide coverage of multiple organisms. Some suggestions for empiric management follow. Of course, it is important to use clinical judgment, factor in local susceptibilities, and consider the patient’s allergies when initiating empirical antibiotics in any patient. Furthermore, treatment of the underlying cause may warrant the use of additional antibiotics.

Monotherapy Versus Combination Therapy: The efficacy of carbapenem monotherapy has been demonstrated to be equal to the combination of a beta-lactam plus an aminoglycoside.¹² Third- or fourth-generation cephalosporin monotherapy has been shown to be as effective as either a beta-lactam or clindamycin plus an aminoglycoside.¹² Additionally, in patients with pneumonia, intra-abdominal infections, or neonatal sepsis, equal efficacy was demonstrated for extended-spectrum penicillins with or without a beta-lactamase inhibitor compared with amoxicillin-clavulanate, piperacillin-tazobactam, or clindamycin in combination with an aminoglycoside.¹² Several of these studies do have limitations, however. Most of the studies utilized different beta-lactams, involved small sample sizes (<200 patients), and included very few patients with severe sepsis or septic shock.¹² In general, beta-lactam antibiotics have been shown to be as efficacious as combination therapy with beta-lactams and aminoglycosides, with fewer renal complications.¹³ Many experts, however, recommend combination therapy in neutropenic patients and when certain bacteria are suspected, such as Pseudomonas aeruginosa.^6,11,14

The take-home point is that monotherapy with broad-spectrum beta-lactams, while as efficacious as beta-lactams plus an aminoglycoside, may not be appropriate for all patients.^6,11,12,14

MRSA: Empiric coverage of MRSA is important, as higher mortality rates have been associated with inappropriate antibiotic therapy.^15,16 Vancomycin is often utilized as empiric therapy for suspected MRSA infections. It is important to ensure that the minimum inhibitory concentration is ≤1 mcg/mL upon receipt of cultures.¹⁵ If not, alternative MRSA-susceptible antibiotic therapies (e.g., linezolid, tigecycline, ceftaroline, or daptomycin) should be considered.

Sites of Infection

Lung: If the site of suspected infection is the lung, the origin of the infection must be considered. If the infection is community-acquired, likely pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Legionella species, and Mycoplasma pneumoniae.¹⁴ Respiratory fluoroquinolones as monotherapy or a macrolide antimicrobial, in addition to a beta-lactam (such as a third- or fourth-generation cephalosporin), are good empiric options for community-acquired respiratory infections.¹⁴ Health care–acquired or –associated infections are often caused by Pseudomonas species, MRSA, Klebsiella species, and anaerobic bacteria.¹⁴ These infections can be empirically treated with the combination of a carbapenem or piperacillin-tazobactam, in addition to levofloxacin or ciprofloxacin, plus vancomycin.^11,14

IV Catheter–Related Bloodstream Infections: Common bacteria associated with IV catheter–related infections include Staphylococcus epidermidis, S aureus, aerobic gram-negative bacilli, and Candida species.¹⁴ Vancomycin plus piperacillin-tazobactam is one option for empiric therapy.^11,14 If Candida is suspected, antifungal therapy should be considered.¹⁴

Urinary Tract: Urinary pathogens include aerobic gram-negative bacilli, such as E coli, Proteus species, Pseudomonas species, and Enterococcus species.^14,17 For community-acquired urinary infections, empiric treatment with ciprofloxacin or levofloxacin is a good choice, as is treatment with amoxicillin-clavulanate.¹⁴ Resistance to fluoroquinolones is increasing in some regions, so attention should be paid to local susceptibilities in these instances. For urinary infections that are health care–acquired or –associated, empiric treatment with ciprofloxacin or levofloxacin may be considered, as might treatment with piperacillin-tazobactam or cefepime.¹⁴ Pathogens to empirically cover for health care–acquired or –associated infections include Pseudomonas species, MRSA, Klebsiella species, and anaerobes.¹⁴ If MRSA is suspected, vancomycin should be added to the empiric regimen. Treatment with carbapenems is also appropriate; however, caution should be used in areas with high rates of extended-spectrum beta-lactamase–producing Enterobacteriaceae.¹⁷

Abdomen: Aerobic gram-negative bacilli, anaerobes, and Candida species are commonly associated with intra-abdominal infections.¹⁴ These infections may be empirically treated with a carbapenem or piperacillin-tazobactam with or without an aminoglycoside.^11,14 Antifungal therapy should be considered.^11,14 For suspected B fragilis or other bacteria that may be resistant to penicillins, the use of a carbapenem, metronidazole, or a combination penicillin and beta-lactamase inhibitor should be considered.^8,11

Unclear Source: If the source of infection is unknown or difficult to determine, empiric treatment options include carbapenems plus vancomycin.¹⁴ These drugs cover a wide array of bacteria, including aerobic gram-negative bacilli, S aureus, and streptococci.¹⁴

THE PHARMACIST’S ROLE

Pharmacists are optimally placed to interact with many different health care professionals, affording them many opportunities to improve patient care via the optimization of sepsis management. Among these opportunities are appropriate antibiotic selection, de-escalation of antibiotic therapy, and sepsis bundle (protocol) implementation.

Selection of Appropriate Antibiotic: As stated previously, selection of broad-spectrum antibiotics should be targeted toward likely pathogens. A simple way to accomplish this is to review the admission diagnosis when entering orders for antibiotics to verify the indication for antibiotic choice. The pharmacist can also examine reasons for a change in antimicrobial therapy.

De-escalation of Antibiotic Therapy: Antibiotic stewardship requires de-escalation of the antibiotic regimen when necessary. This serves to prevent the unwanted effects of broad-spectrum antibiotic overuse, such as increased resistance, cost, and adverse events.¹⁸ Once cultures have been obtained and results are available, antibiotic therapy should be reviewed to ascertain that the pathogen is susceptible to the prescribed drug regimen. In addition, consideration should be given to utilizing a more limited spectrum antibiotic that also shows efficacy.

Sepsis Bundle (Protocol) Implementation: Clinical evidence shows that the treatment of sepsis with evidence-based protocols, or bundles, improves treatment outcomes.¹⁹ Sepsis bundles based on the Surviving Sepsis Campaign combine individual interventions or orders with the goal of improving outcomes. These bundles place labs and medications on one order form to ensure that nothing is accidentally omitted. Unfortunately, the implementation of clinical evidence into practice can present many difficulties, including provider acceptance, a perception of “cookbook medicine,” and the approval process.²⁰ As patient advocates, pharmacists are uniquely positioned to champion acceptance and implementation of such bundles, as many of the interventions are medication-related. Education of all involved professionals is key to the buy-in, proper implementation, and success of sepsis bundles. Of course, outcomes must be continually assessed to determine the effectiveness of the sepsis bundle.

CONCLUSION

Sepsis infections, which can be difficult to manage, are common in hospitalized patients, particularly ICU patients. Proper management is vital to reducing the morbidity, mortality, and costs associated with these infections. Since pharmacists are in a position to interact with a variety of health care professionals, they have the opportunity to improve patient care through the optimization of sepsis management, including appropriate antibiotic selection, de-escalation of antibiotic therapy, and sepsis bundle implementation.

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;29:1303-1310.
2. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-353.
3. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323-2329.
4. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. Chest. 2009;136(suppl 5):e28.
5. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250-1256.
6. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.
7. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546-1554.
8. Brook I. The role of anaerobic bacteria in bacteremia. Anaerobe. 2010;16:183-189.
9. 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;34:1589-1596.
10. Siddiqui S, Razzak J. Early versus late pre-intensive care unit admission broad spectrum antibiotics for severe sepsis in adults. Cochrane Database Syst Rev. 2010;(10):CD007081.
11. Textoris J, Wiramus S, Martin C, Leone M. Overview of antimicrobial therapy in intensive care units. Expert Rev Anti Infect Ther. 2011;9:97-109.
12. Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32(suppl 11):S495-S512.
13. Paul M, Silbiger I, Grozinsky S, et al. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2006;(1):CD003344.
14. Grossi P, Gasperina DD. Antimicrobial treatment of sepsis. Surg Infect (Larchmt). 2006;7(suppl 2):S87-S91.
15. Bassetti M, Ginocchio F, Giacobbe DR. New approaches for empiric therapy in Gram-positive sepsis. Minerva Anestesiol. 2011;77:821-827.
16. Paul M, Kariv G, Goldberg E, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2010;65:2658-2665.
17. Wagenlehner FM, Pilatz A, Weidner W. Urosepsis—from the view of the urologist. Int J Antimicrob Agents. 2011;38(suppl):51-57.
18. Gomes Silva BN, Andriolo RB, Atallah AN, Salomão R. De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2010;(12):CD007934.
19. Shiramizo SC, Marra AR, Durão MS, et al. Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle in a hospital setting. PLoS One. 2011;6:e26790.
20. Stoneking L, Denninghoff K, Deluca L, et al. Sepsis bundles and compliance with clinical guidelines. J Intensive Care Med. 2011;26:172-182.
21. Vincent JL. Management of sepsis in the critically ill patient: key aspects. Expert Opin Pharmacother. 2006;7:2037-2045.

To comment on this article, contact rdavidson@uspharmacist.com.