E m e r g e n c y De p a r t m e n t Antimicrobial C o n s i d e r a t i o n s i n S e v e re Se p s i s Robert S. Green, MD, FRCPC, FRCP(Edin)a,b,*, Sean K. Gorman, BSc(Pharm), PharmDc KEYWORDS  Severe sepsis  Emergency medicine  Timing of antimicrobials  Antimicrobial pharmacodynamics and pharmacokinetics  Procalcitonin  Antimicrobial shortages KEY POINTS  The administration of antimicrobials in the emergency department (ED) is of paramount importance for optimal patient outcomes.  Various factors need to be considered when choosing antimicrobials in the ED, including patient factors, infective microbe factors, and drug-related factors.  Prompt administration of antimicrobials is a key management strategy.  Clinicians should use a basic understanding of pharmacokinetic and pharmacodynamic properties when empirically selecting antimicrobials in septic ED patients.  Antimicrobial shortages are a recurrent threat to the optimal treatment of septic patients, and clinicians should understand how a systems approach can ensure adequate antimicrobial options during these periods.

INTRODUCTION

There were more than 3.5 million emergency department (ED) visits in the United States in 2010 associated with a primary diagnosis of infectious and parasitic diseases.1

Disclosures: The authors have no actual or perceived conflicts of interest to disclose. a Division of Critical Care Medicine, Department of Anesthesia, Faculty of Medicine, Trauma Nova Scotia, Dalhousie University, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada; b Department of Emergency Medicine, Faculty of Medicine, Trauma Nova Scotia, Dalhousie University, Room 377 Bethune Building, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada; c Clinical Quality & Research, Critical Care, Pharmacy Services, Interior Health Authority, Faculty of Pharmaceutical Sciences, The University of British Columbia, #200-1835 Gordon Drive, Kelowna, British Columbia V1Y3H5, Canada * Corresponding author. Department of Emergency Medicine, Faculty of Medicine, Trauma Nova Scotia, Dalhousie University, Room 377 Bethune Building, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada. E-mail address: [email protected] Emerg Med Clin N Am 32 (2014) 835–849 http://dx.doi.org/10.1016/j.emc.2014.07.014 0733-8627/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Sepsis, which is defined as the systemic inflammatory response syndrome (SIRS) accompanied by the probable or documented presence of infection, is an advanced manifestation of infectious diseases and can lead to severe sepsis, septic shock, and multiple organ dysfunction syndrome.2 Between 1992 and 2001, approximately 2.8 million visits to EDs in the United States were related to sepsis, and more than 10% of these patients required admission to an intensive care unit (ICU).3 The most prevalent sources of infection leading to sepsis were the lower respiratory tract and the genitourinary tract.3 Despite recent advances in the understanding and treatment of severe sepsis and septic shock, this syndrome remains a leading cause of death.4 Clinical practice guidelines have been developed to aid clinicians in the identification and treatment of patients with severe sepsis and septic shock. Recommended treatment strategies include early goal-directed therapy, obtaining appropriate microbiological specimens before antimicrobial administration (if feasible), identifying and controlling the source of infection in a timely fashion, and administering timely, appropriate empiric intravenous antimicrobial therapy.2 Appropriate initial antimicrobial therapy has been defined in numerous ways, and a recent systematic review identified that most studies incorporated in vitro antimicrobial susceptibility test results in the definition of appropriateness; however, timeliness and dosage were rarely included in the definition.5 Therefore, it is suggested that antimicrobial appropriateness be defined based on the spectrum of activity, route of administration, dosage, and timing.6–9 The published literature concerning appropriate antimicrobial utilization in severe infections is rapidly expanding. Accordingly, the aim of this article was to provide a comprehensive, up-to-date review of the key antimicrobial-related considerations in the critically ill patient presenting to the ED. General Approach to Antimicrobial Selection in ED Patients with Sepsis

Emergency medicine (EM) physicians have a critical role in the management of patients with severe sepsis and septic shock. In many cases, the EM physician is the initial point of contact for a patient’s medical care. The identification and timely intervention of septic patients in the ED may be the most important phase of care, because delays in therapy are associated with increased morbidity and mortality.10 Although guidelines have been published to assist clinicians in the identification and management of patients with severe sepsis/septic shock, optimal antimicrobial administration principles have received relatively little attention.2,11 Elements that should be considered when administrating antimicrobials include the following: (1) patient-related factors, (2) microorganism-related factors, (3) the importance of the timing of antimicrobial administration, and (4) source control.12 EM physicians should primarily consider their patient’s age, weight, allergy status, and comorbidities when choosing antimicrobial medication.13 Renal and hepatic dysfunction may impact the pharmacokinetic properties of antimicrobials, with some medications eliminated primarily by one system or the other.14 Patients who are pregnant or lactating require special consideration to minimize any potential negative impact on the fetus or newborn. In addition, any recent exposure to antimicrobials is very important to consider, as previous exposure to an antimicrobial may increase the incidence of resistance, therefore leading to treatment failure and increased morbidity and mortality.15 Important microorganism factors include the site of infection, intrinsic microbial susceptibility to anti-infectives, and local resistance patterns.13 Often the site of infection is suspected in EM patients with severe sepsis/septic shock, which provides the clinician valuable information for antimicrobial selection. For instance, infections of the

Antimicrobial Considerations in Severe Sepsis

lower respiratory tract are often caused by predictable organisms and therefore clinicians should administer antimicrobials that cover these bacteria. Similarly, microbes that are unlikely to cause an infection in the presumed site of infection need not be covered, therefore limiting broad-spectrum antimicrobial use. Although the susceptibility of a microbe in ED patients is usually unknown, knowledge of local antimicrobial resistance patterns is extremely important to protect against inadequate antimicrobial coverage. Resistance patterns vary from hospital to hospital and, in some cases, ward to ward, and every effort should be made to ensure that accurate patterns of resistance are available and reviewed regularly because antimicrobial administration with insufficient activity against a microbe can result in treatment failure and progression of the sepsis syndrome.13 Bacteria of particular concern in the ED include drugresistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multi-drug-resistant gram-negative infections caused by extended spectrum b-lactamases (ESBL). Valid screening tools to help identify patients at risk for antibiotic-resistant organisms (ARO) do not exist. However, there are several ARO risk factors that should be considered, in addition to local susceptibility patterns, when choosing empiric antibiotic therapy. Risk factors for infection with b-lactam-resistant S pneumoniae in adults include age greater than 65 years, previous b-lactam therapy within 90 days, alcoholism, medical comorbidities, immunosuppression, and exposure to a child in a daycare center.16 The risk of S pneumoniae resistance to b-lactams, macrolides, or fluoroquinolones appears highest if the patient has been exposed to the respective antibiotic within 90 days.16 Therefore, administration of a different class of antibiotics with activity against the most likely organisms is a recommended strategy in this situation.16 Risk factors for MRSA in patients presenting to the ED include past colonization or infection with MRSA, history of previous antibiotic use in the past 90 days, hospitalization in the past 3 months, a history of hospitalization for an acute illness, residence in a long-term care facility, chronic dialysis, home wound care or infusion therapy, immunosuppression, and contact with family members with MRSA.17,18 Patients with these risk factors who present to the ED with severe sepsis should be provided a regimen that includes vancomycin or linezolid. The rate of ESBL production among the most common Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) approaches 8% in North America.19 Urinary tract infections (UTI) due to E coli represent the most frequent community-acquired infection because of ESBL and important risk factors include advanced age, diabetes mellitus, recurrent UTI, and previous receipt of aminopenicillins (eg, amoxicillin, ampicillin), cephalosporins, or fluoroquinolones.19 Patients suspected to be infected with ESBL-producing bacteria should be treated with a carbapenem or a fluoroquinolone; however, co-resistance to fluoroquinolones is frequent in these organisms.19 The timing of appropriate antimicrobial medication administration is of paramount importance for patient outcomes in severe sepsis/septic shock.8,20,21 Kumar and colleagues8 demonstrated an increase in mortality of 7.6% for every hour delay in administration of appropriate antimicrobials after onset of hypotension in septic shock patients. Therefore, after the recognition and diagnosis of a septic patient in the ED, every effort should be made to administer appropriate empiric antimicrobials as soon as possible. Guidelines have called for antimicrobial administration within 30 to 60 minutes.2,11 An often-overlooked aspect in the management of septic patients is the importance of source control of infected tissue.22,23 Tissue infected with a significant burden of microbes, such as a soft tissue abscess, obstructive pyelonephritis, or pleural empyema, is best managed with both antimicrobial administration and surgical drainage.

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Similar to antimicrobial administration, source control should be performed as soon as possible. In some instances, this will require consultation and transfer to a surgical theater and therefore emergency physicians should ensure that the appropriate specialties are rapidly notified. Perhaps the best example of the importance of these principles comes from the management of patients with necrotizing fasciitis. In these patients, immediate surgical debridement of infected tissue in addition to appropriate antimicrobial is necessary for patient survival. Any delay in source control is associated with poor patient outcomes. Although necrotizing fasciitis is an extreme example, surgical drainage of any potential source should be a time-sensitive management objective in the ED. In addition to inappropriate antimicrobial selection and delayed administration, low initial dosing may also lead to suboptimal outcomes. Consequences of suboptimal dosing in sepsis include treatment failure, higher mortality rates, increased costs and adverse effects, and emergence of antimicrobial-resistant organisms.24–26 Suboptimal low initial dosing is primarily driven by pharmacokinetic changes associated with severe sepsis and septic shock and the fear of toxicity in the setting of organ dysfunction.27,28 Both of these factors can be mitigated by considering the key pharmacologic characteristics of antimicrobial agents when determining dosing.27 Patients with severe sepsis and septic shock are often transferred to the ICU within 6 hours; therefore, ED clinicians should aim to provide delivery of an appropriate initial antimicrobial dose to maximize the chances for a positive outcome.29,30 Important Pharmacokinetic and Pharmacodynamic Principles for the EM Physician

Antimicrobial selection should also be guided by its pharmacokinetic and pharmacodynamic profile.31 Pharmacokinetics is the study of the time course of the primary pharmacokinetic processes of absorption, distribution, metabolism, and elimination and the overall disposition of the drug. In basic terms, it describes the relationship between the dose administered and the changes in drug concentration with time.28,32 When selecting an antimicrobial and its respective initial dose in severe sepsis and septic shock, the primary pharmacokinetic consideration is the degree of distribution of the antimicrobial to the site of infection. Absorption, metabolism, and elimination are important factors to consider when considering subsequent maintenance dosing regimens. The pharmacokinetic parameter that reflects the relationship between initial dose and initial intravascular concentration is the apparent volume of distribution (Vd). In general, the initial antimicrobial concentration (mg/L) achieved in the vascular compartment is equal to the dose (mg) administered divided by the Vd (L). Fluid shifts lead to an increase in Vd for many hydrophilic antimicrobials, such as aminoglycosides, b-lactams, vancomycin, and linezolid in severe sepsis and shock, whereas lipophilic agents, such as ciprofloxacin, are largely unaffected.28 For antimicrobials that are highly bound to serum albumin, hypoalbuminemia results in higher than usual unbound fractions and therefore a higher tissue distribution and Vd. Increased tissue distribution of antimicrobials should be advantageous because the unbound antimicrobial is free to distribute to the interstitial space that is most often the site of infection; however, this is usually offset by the antimicrobial dilutional effect caused by third spacing during early goal-directed therapy.28 Because of the higher Vd for many antimicrobials administered in severe sepsis and septic shock, a higher initial dose is often required to achieve the same desired intravascular concentrations as in nonseptic patients with a normal Vd.28 Pharmacodynamics is the study of the relationship between serum drug concentration and the clinical (and microbiological) response observed.32 Table 1 provides

Antimicrobial Considerations in Severe Sepsis

Table 1 Antimicrobial pharmacodynamic properties Pharmacodynamic Parameter

Definition

Relevance to EM

Bacteriostatic

Antibacterial inhibits bacterial growth (but does not “kill” at usual concentrations)

Avoid if possible for treatment of endocarditis, meningitis, and infections in the neutropenic host

Bactericidal

Antibacterial kills bacteria at similar concentrations needed to inhibit growth

Proven or hypothesized to produce improved cure rates in patients with endocarditis, meningitis, and neutropenia

Concentrationdependent killing

Demonstrates a greater rate and extent of activity when the microorganism is exposed to higher concentrations of drug

Dosing regimens that result in higher concentration at some point during the dosing interval are desired. In general, give higher doses less often

Time-dependent killing

Demonstrates a greater rate and extent of activity by maintaining drug concentrations above a threshold for a greater proportion of time

Dosing regimens that result in maintaining drug concentrations at a threshold higher than the MIC (usually 4–5 times higher than MIC) are desired. In general, give lower doses more often

antimicrobial pharmacodynamic properties of relevance when considering initial antimicrobial dosing in patients with sepsis. Antimicrobials that require significantly higher concentrations to kill a microorganism than are required to inhibit microorganism growth are considered bacteriostatic agents. Antimicrobials that kill at concentrations similar to those required to inhibit in vitro growth are considered bactericidal. This method of classifying antimicrobials is based on lethality and is useful to guide antimicrobial selection and dosing in patient subpopulations with sepsis, such as those with neutropenia. These patients should receive bactericidal agents because of a relatively poor host immune response.33 Antimicrobials can also be classified based on the rate and extent of bacterial killing. Antimicrobials can be considered concentration-dependent bacterial killers or time-dependent bacterial killers. Aminoglycosides are considered concentrationdependent bactericidal agents because they demonstrate a greater rate and extent of bacterial killing when the microorganism is exposed to higher concentrations of drug. A clinically relevant example of exploitation of this effect is the administration of single daily dosing of aminoglycosides. Rather than administering smaller doses more frequently, one large dose is given once daily to achieve high postdose concentrations. The aminoglycosides also possess another pharmacodynamic characteristic that allows for single daily dosing and that is the postantibiotic effect (PAE). The PAE is defined as the time required for an organism to demonstrate viable regrowth after the removal of an antimicrobial.34,35 Penicillins, cephalosporins, and carbapenems are examples of time-dependent bactericidal antimicrobials because the rate and extent of bacterial killing activity becomes saturated at a particular drug concentration. For example, desired activity for time-dependent bactericidal antimicrobials is usually achieved by maintaining drug

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concentrations at various thresholds above the minimum inhibitory concentration (MIC), most commonly 4 to 5 times higher than the MIC.32 Using traditional intermittent infusion dosing strategies, patients with severe sepsis and septic shock may experience insufficient b-lactam concentrations.36 A potential strategy to optimize the efficacy of time-dependent bactericidal antimicrobials is to extend the duration of intermittent infusion or administer via continuous infusion. These strategies have been investigated for the carbapenems and piperacillin/ tazobactam and have been shown to improve pharmacokinetic/pharmacodynamic endpoints such as the frequency of plasma antimicrobial concentrations above the MIC in patients with severe sepsis.37 However, it is not clear whether these strategies improve clinical outcomes compared with standard intermittent infusion administration and it has not been adequately evaluated in the ED setting.38 Larger randomized controlled studies are required to determine whether this strategy improves clinical cure and survival in severe sepsis. It is also important to note that certain antimicrobials, such as fluoroquinolones and vancomycin, demonstrate both concentration-dependent and time-dependent activity.28 Table 2 outlines the integrated antimicrobial pharmacokinetic/pharmacodynamic targets with dose recommendations from the manufacturer as compared with the best available evidence.39–48 A good example of the importance of these principles applies to the initial dosing of antibiotics in severe sepsis and septic shock. These patients will often have multiple organ dysfunction, including acute kidney injury. Tertiary references provide drug-dosing recommendations for varying degrees of renal function; if these recommendations are implemented for certain antibiotics in these situations, the patient

Table 2 Pharmacokinetics/pharmacodynamic parameters and initial dosing recommendations for bactericidal antibiotics in severe sepsis and septic shocka Antibiotic

PK:PD Parameter

Recommended Initial Doseb

Literature-Based Initial Dose

Cmax: MIC

15 mg/kg

25 mg/kg39,40

Aminoglycosides Amikacin

Cmax: MIC

4.5–7 mg/kg

7 mg/kg41

T > MIC

1–2 g

1–2 g42

1–2 g

1–2 g43

T > MIC

3–4 g

4 g44

Ciprofloxacin

AUC0-24/MIC

400 mg

400 mg45

Levofloxacin

AUC0-24/MIC

500–750 mg

500–750 mg46

AUC0-24/MIC

15 mg/kg

25–30 mg/kg47

AUC0-24/MIC

500 mg

500 mg48

Gentamicin/Tobramycin

c

b-Lactams Ceftriaxone Meropenem Piperacillin Fluoroquinolones

Glycopeptides Vancomycin Macrolides Azithromycin

Abbreviations: AUC 0-24, area under the concentration-time curve from 0 to 24 hours; Cmax, peak serum concentration; PD, pharmacodynamic; PK, pharmacokinetic; T, time. a Intermittent infusion administration. b Derived from tertiary drug information references/manufacturer. c Once daily dosing.

Antimicrobial Considerations in Severe Sepsis

may receive subtherapeutic doses. For example, a patient with septic shock caused by Pseudomonas aeruginosa pneumonia has an estimated creatinine clearance (CrCL) of 25 mL/min. After incorporating the aforementioned considerations for selection of antimicrobial therapy, it is decided to initiate piperacillin/tazobactam plus ciprofloxacin as initial therapy because of the relatively high incidence of multidrug-resistant P aeruginosa in the location. This antibiotic choice provides double-bactericidal coverage in a time-dependent (piperacillin/tazobactam) and concentration-dependent (ciprofloxacin) fashion. Many tertiary drug information references will recommend reducing the dose of piperacillin/tazobactam when CrCL decreases to less than 40 mL/min to 2.25 to 3.375 G per dose. Piperacillin/tazobactam is a hydrophilic antibiotic whose Vd significantly increases in severe sepsis and septic shock; therefore, concentrations achieved with the aforementioned dose may be significantly lower than required to ensure cure. To mitigate this, an initial loading dose of 4.5 G of piperacillin/tazobactam is recommended in this situation. The initial 400 mg intravenous loading dose of ciprofloxacin does not change because fluid shifts observed early in severe sepsis and shock do not significantly alter the Vd of this lipophilic antibiotic. The maintenance dosing regimen should be selected after considering the potential safety implications of antibiotic accumulation in end-organ dysfunction, such as renal failure. SEPSIS BIOMARKERS IN THE ED

A biological laboratory marker, otherwise known as biomarker, “refers to a broad subcategory of medical signs which can be measured accurately and reproducibly”.49 More than 150 biomarkers have been evaluated in the context of sepsis, and they reflect several pathophysiological mechanisms.50 Biomarkers can potentially indicate the presence, absence, or severity of sepsis, differentiate bacterial from viral and fungal infection, assist with prognostication, guide initial antimicrobial therapy decisions, and help evaluate the response to therapy to guide antimicrobial de-escalation decision-making.50 The various types of biomarkers include cytokines, receptors, coagulation system markers, acute phase proteins, cell surface markers, apoptosis markers, and markers of endothelial function.51 Although there are numerous biomarkers of sepsis, procalcitonin (PCT) has recently been the focus of much investigation in patients with sepsis. PCT is a prohormone of calcitonin and is synthesized in the C cells of the thyroid.52 Bacterial toxins and bacterial-specific proinflammatory cytokines trigger an increased PCT release from parenchymal organs.52,53 One of the most attractive properties of PCT supporting its investigation as a clinically useful biomarker in sepsis is its attenuated release in response to viral infection-triggered cytokine release, therefore potentially allowing a degree of discrimination between bacterial and viral infections.53 Within 2 to 12 hours of bacterial infection onset, serum PCT demonstrates a measurable increase.53 Serum PCT concentrations rapidly drop by approximately 50% each day when the infection is well under control by a combination of host response and antimicrobial therapy.52,53 It is also noteworthy that the serum dynamic profile of PCT is not affected by neutropenia or the administration of systemic corticosteroids.53 There are several PCT assays available; however, the most commonly investigated assays in sepsis are quantitative. The most relevant application of PCT in the context of sepsis in the ED is as a diagnostic marker. The specific aim of using PCT is to help guide timely diagnosis and treatment of sepsis. Three meta-analyses have been published since 2006 that have evaluated the diagnostic accuracy of PCT in sepsis.54–56 The results of the first

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2 meta-analyses were conflicting in terms of the diagnostic accuracy of PCT in critically ill patients.54,55 However, because of methodological limitations of these analyses, an additional meta-analysis was performed with the aim to determine the ability of PCT to differentiate between sepsis and SIRS of noninfectious origin in a heterogeneous mix of critically ill patients.56 This meta-analysis included 30 studies accounting for 3244 patients. Four studies included only critically ill pediatric patients representing 177 patients, and 4 studies were conducted in the ED. Most studies used quantitative manual PCT assays; however, the sepsis diagnostic cutoff for PCT concentration differed substantially between studies with a median cutoff of 1.1 ng/mL and interquartile range of 0.5 ng/mL to 2 ng/mL. The mean sensitivity and specificity of PCT as a diagnostic marker were 0.77 (95% CI 0.72–0.81) and 0.79 (95% CI 0.74–0.84), respectively, and the area under the receiver operating characteristic curve was 0.85 (95% CI 0.81–0.88). The results of this meta-analysis were limited by the presence of significant statistical heterogeneity between the included studies and the presence of publication bias. Therefore, PCT should not be used as the single definitive test for sepsis diagnosis, but can be a helpful marker when used in the context of information provided from medical history, physical examination, and microbiological assessment.56 When used as a tool in assisting with diagnosis, a PCT diagnostic cutoff of 1 to 2 ng/mL could be useful to discriminate sepsis from other inflammatory conditions.56 Further investigation in this population of patients presenting to the ED is warranted. Clinical Practice Guidelines Review The surviving sepsis guidelines

Clinical practice guidelines are “systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances.”57 Adherence to high-quality clinical practice guidelines in clinical practice can reduce variations in care and ultimately improve the quality of care.58 Since the launch of the Surviving Sepsis Campaign in 2002, there have been 3 published versions of international guidelines focusing on the management of severe sepsis and septic shock.2,59,60 The initial version of these guidelines was of variable quality; however, the most recent versions are of high quality and their recommendations should be incorporated into clinical decision-making.61 The most recently published severe sepsis and septic shock guidelines make 18 recommendations related to infection diagnosis, antimicrobial therapy, source control, and infection prevention. However, not all of these recommendations are applicable to the initial management of a patient with severe sepsis or shock in the ED. Diagnostic recommendations in the latest iteration of these guidelines are very similar to the 2008 version. The recommendation is to obtain clinically appropriate cultures that include at least 2 sets of blood cultures before antimicrobial initiation provided that there will be no significant delay in the start of antimicrobials.2 Two sets of blood cultures remains a strong recommendation based on low-quality evidence. However, the latest guidelines now define a significant antimicrobial delay as greater than 45 minutes, whereas the older version of the guidelines did not define delay.2,60 The recommendation to promptly perform imaging studies to confirm a potential source of infection remains; however, it has changed from a strong recommendation to an ungraded recommendation because the guideline development committee did not think that topic was conducive to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) process. Antimicrobial-related recommendations that are most applicable to the ED patient with severe sepsis and shock remain largely unchanged. Strong recommendations

Antimicrobial Considerations in Severe Sepsis

remain for administration of effective intravenous antimicrobials within 1 hour of onset of severe sepsis and shock and for administration of an initial intravenous antimicrobial regimen that consists of at least one drug with activity against likely pathogens and that adequately penetrate into infected tissues. There also remains the strong recommendation that antimicrobial regimens should be reassessed daily for potential de-escalation to prevent resistance development, reduce toxicity, and reduce costs, although this is likely outside the ED phase of care. A new weak recommendation has been made for using PCT or other biomarkers to assist clinicians in discontinuation of antimicrobials in patients who initially appeared septic but no subsequent evidence of infection was found. However, there is no recommendation addressing whether biomarkers should assist with the decision whether to initiate empiric therapy or guide initial antimicrobial choice. Consistent with the previous version of the guidelines, combination empiric antimicrobial therapy is weakly recommended in neutropenic patients with severe sepsis and patients with difficult-to-treat multidrug-resistant pathogens such as Acinetobacter and Pseudomonas species. A new weak recommendation is made to combine a b-lactam and macrolide for patients with septic shock due to bacteremic S pneumoniae infections. If empiric combination therapy is initiated, the latest guidelines continue to weakly recommend that combination empiric therapy should not exceed 3 to 5 days and should be de-escalated to monotherapy once the microbial susceptibility profile is known. Another new weak recommendation is to initiate antiviral therapy if severe sepsis or shock is of viral origin. This recommendation is focused on early antiviral therapy with a neuraminidase inhibitor (oseltamivir or zanamivir) for patients with suspected or confirmed influenza. The recommendations related to source control are not dramatically different in the new guidelines; however, it is now strongly recommended that a target time window of no more than 12 hours elapse before achieving source control, if applicable, after diagnosis. For those patients who are intubated and ventilated for a prolonged period in the ED, there are 2 new weak recommendations suggesting the use of selective oral and digestive tract decontamination to reduce the risk for ventilator-associated pneumonia in settings where this strategy has been found to be effective. Specifically, it is suggested that oral chlorhexidine gluconate topical antiseptic be used with oral care in the intubated patient as a form of oropharyngeal decontamination. Clinical equipoise exists around the effectiveness of selective decontamination of the digestive tract in these critically ill patients; future research that involves longer follow-up to assess antimicrobial resistance is required.62 A broader review of the latest sepsis guidelines for ED clinicians has been published elsewhere.63 Other sepsis-related guidelines

Lower respiratory and genitourinary infections are the most common reasons patients present to the ED with severe sepsis in the United States.29 However, a recent search for North American adult community-acquired pneumonia clinical practice guidelines revealed that the latest version was published in 2007, although an update is currently in progress.16 The latest clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women were last updated in 2010 and are considered current by the Infectious Disease Society of America (IDSA). However, because uncomplicated cystitis rarely progresses to sepsis in otherwise healthy, nonpregnant women, the authors have reviewed only the section addressing the management of

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pyelonephritis.64 It is recommended that a urine culture and susceptibility test be performed followed by timely administration of empiric antimicrobial therapy. Initial antimicrobials for women with pyelonephritis requiring hospitalization should provide coverage for the most common uropathogens, which primarily consist of E coli. Other species may occasionally cause uncomplicated pyelonephritis, and these include other species of Enterobacteriaceae and Staphylococcus saprophyticus. Recommended initial therapy should be dictated by local resistance data. For example, expert opinion drives the recommendation that a local fluoroquinolone resistance prevalence threshold of 10% should prompt using alternative empiric antimicrobial agents.64 Depending on local resistance patterns, initial options include intravenous ciprofloxacin, an aminoglycoside with or without intravenous ampicillin, an extended-spectrum penicillin such as piperacillin/tazobactam with or without an aminoglycoside, or a carbapenem, which subsequently should be tailored based on the culture and susceptibility results. ANTIMICROBIAL SELECTION IN THE ERA OF ANTIMICROBIAL SHORTAGES

A drug shortage is defined as “a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent.”65 Several factors affecting the supply chain contribute to drug shortages and can be attributed to reduced supply or increased demand. Common reasons for drug shortages include disruptions in the supply of raw or bulk materials, manufacturing disruptions due to regulatory issues such as noncompliance with current good manufacturing practices and voluntary recalls related to manufacturing problems, changes in a product’s formulation or manufacturer, and manufacturer business decisions to reduce production. In addition, manufacturer mergers that result in decisions to narrow the product-line focus or move production to another facility, restricted distribution methods that are the result of market approval requirements or postmarketing surveillance, “just-in-time” inventory management practices, unexpected increases in demand and shifts in clinical practice, and natural disasters have also been cited as potential reasons for drug shortages.65 Patient-specific consequences of antimicrobial shortages include delays in treatment, use of antimicrobials that are not considered first-line therapy, and increased potential for worsened patient outcomes.66,67 These shortages also impact health systems by increasing time-expenditures and labor costs associated with managing the shortages.68 As of November 2013, antimicrobials represented approximately 12% of the 235 currently unavailable drugs in the United States.69 These shortages are further exacerbated by the reality that there are significantly fewer new antimicrobials coming down the pipeline and increasing antimicrobial resistance.66 American guidelines for the management of drug shortages have been published, but these guidelines are broad in scope and do not discuss managing the specific challenges associated with antimicrobial shortages.65 To lessen the impact of antimicrobial shortages on patient care, a prospective management strategy has been proposed.70 This approach recommends institutional prospective tracking of shortages and maximizing inventory through antimicrobial usage management, preferably by an interprofessional team that specializes in antimicrobial stewardship. The institutional antimicrobial stewardship team can play a large role in spearheading these efforts to achieve the best possible outcomes in the era of antimicrobial drug shortages.71 Identification of potential foreign suppliers of first-line antimicrobials is a recommended early step. Other tactics necessary for successful management include the

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selection of appropriate alternative agents before the inventory of a first-line antimicrobial has been completely depleted. This inventory can be accomplished using a multidisciplinary approach to assessing clinical practice guidelines, such as those from the IDSA, and by incorporating local antimicrobial resistance patterns into the decision to use alternative agents. Ongoing shortages should be regularly communicated to clinical leadership and creation of temporary guidelines for alternatives should be created that are supported by ongoing educational support for clinicians. Other strategies for managing ongoing shortages include rationing the inventory of first-line agents, which should be supported by ethical considerations.70 The ultimate role of the EM physician caring for critically ill patients with infections is to understand the current state in terms of which antimicrobials are currently on shortage and which antimicrobials have zero inventories. EM physicians should work with the stakeholders, such as the pharmacy department inventory managers, the antimicrobial stewardship team if available, infectious disease specialist physicians and pharmacists, EM clinical pharmacists, and other colleagues in emergency and critical care medicine to proactively manage this challenge. SUMMARY

The recognition and rapid institution of appropriate management strategies in septic ED patients are paramount in optimizing good outcomes. Although available guidelines address most strategies, evidence-based antimicrobial administration methods for EM physicians are required. These factors include patient illness, microorganism, timing of antimicrobial administration, and source control. EM physicians should also use a basic understanding of pharmacokinetic and pharmacodynamic principles when choosing appropriate antimicrobials and their method of delivery. Finally, because of the recent problem of antimicrobial deficiencies that limit the availability of medications, EM physicians should also proactively address issues relating to the administration of antimicrobials during shortages. REFERENCES

1. Centers for Disease Control and Prevention. National Hospital Ambulatory Medical Care Survey: 2010 Emergency Department summary tables. Available at: http://www.cdc.gov/nchs/data/ahcd/nhamcs_emergency/2010_ed_web_tables. pdf. Accessed October 15, 2013. 2. 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;41:580–637. 3. Strehlow MC, Emond SD, Shapiro NI, et al. National study of emergency department visits for sepsis, 1992 to 2001. Ann Emerg Med 2006;48:326–31. 4. Levy MM, Dellinger RP, Townsend SR, et al. The surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010;38:367–74. 5. McGregor JC, Rich SE, Harris AD, et al. A systematic review of the methods used to assess the association between appropriate antibiotic therapy and mortality in bacteremic patients. Clin Infect Dis 2007;45:329–37. 6. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115:462–74.

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