We recommend that administration of IV antimicrobials be initiated as soon as possible after recognition and within 1 h for both sepsis and septic shock (strong recommendation, moderate quality of evidence; grade applies to both conditions).
Rationale The rapidity of administration is central to the beneficial effect of appropriate antimicrobials. In the presence of sepsis or septic shock, each hour delay in administration of appropriate antimicrobials is associated with a measurable increase in mortality [57, 74]. Further, several studies show an adverse effect on secondary end points (e.g., LOS , acute kidney injury , acute lung injury , and organ injury assessed by Sepsis-Related Organ Assessment score  with increasing delays. Despite a meta-analysis of mostly poor-quality studies that failed to demonstrate a benefit of rapid antimicrobial therapy, the largest and highest-quality studies support giving appropriate antimicrobials as soon as possible in patients with sepsis with or without septic shock [57, 74, 79,80,81]. The majority of studies within the meta-analysis were of low quality due to a number of deficiencies, including small study size, using an initial index time of an arbitrary time point such as emergency department arrival, and indexing of outcome to delay in time to the first antimicrobial (regardless of activity against the putative pathogen) [82, 83]. Other negative studies not included in this meta-analysis are compromised by equating bacteremia with sepsis (as currently defined to include organ failure) and septic shock [84,85,86,87]. Many of these studies are also compromised by indexing delays to easily accessible but nonphysiologic variables such as time of initial blood culture draw (an event likely to be highly variable in timing occurrence).
While available data suggest that the earliest possible administration of appropriate IV antimicrobials following recognition of sepsis or septic shock yields optimal outcomes, 1 h is recommended as a reasonable minimal target. The feasibility of achieving this target consistently, however, has not been adequately assessed. Practical considerations, for example, challenges with clinicians’ early identification of patients or operational complexities in the drug delivery chain, represent poorly studied variables that may affect achieving this goal. A number of patient and organizational factors appear to influence antimicrobial delays .
Accelerating appropriate antimicrobial delivery institutionally starts with an assessment of causes of delays . These can include an unacceptably high frequency of failure to recognize the potential existence of sepsis or septic shock and of inappropriate empiric antimicrobial initiation (e.g., as a consequence of lack of appreciation of the potential for microbial resistance or recent previous antimicrobial use in a given patient). In addition, unrecognized or underappreciated administrative or logistic factors (often easily remedied) may be found. Possible solutions to delays in antimicrobial initiation include use of “stat” orders or including a minimal time element in antimicrobial orders, addressing delays in obtaining blood and site cultures pending antimicrobial administration, and sequencing antimicrobial delivery optimally or using simultaneous delivery of key antimicrobials, as well as improving supply chain deficiencies. Improving communication among medical, pharmacy, and nursing staff can also be highly beneficial.
Most issues can be addressed by quality improvement initiatives, including defined order sets. If antimicrobial agents cannot be mixed and delivered promptly from the pharmacy, establishing a supply of premixed drugs for urgent situations is an appropriate strategy for ensuring prompt administration. Many antimicrobials will not remain stable if premixed in a solution. This issue must be taken into consideration in institutions that rely on premixed solutions for rapid antimicrobial availability. In choosing the antimicrobial regimen, clinicians should be aware that some antimicrobial agents (notably β-lactams) have the advantage of being able to be safely administered as a bolus or rapid infusion, while others require a lengthy infusion. If vascular access is limited and many different agents must be infused, drugs that can be administered as a bolus or rapid infusion may offer an advantage for rapid achievement of therapeutic levels for the initial dose.
While establishing vascular access and initiating aggressive fluid resuscitation are very important when managing patients with sepsis or septic shock, prompt IV infusion of antimicrobial agents is also a priority. This may require additional vascular access ports. Intraosseous access, which can be quickly and reliably established (even in adults), can be used to rapidly administer the initial doses of any antimicrobial [90, 91]. In addition, intramuscular preparations are approved and available for several first-line β-lactams, including imipenem/cilastatin, cefepime, ceftriaxone, and ertapenem. Several additional first-line β-lactams can also be effectively administered intramuscularly in emergency situations if vascular and intraosseous access is unavailable, although regulatory approval for intramuscular administration for these drugs is lacking [92,93,94]. Intramuscular absorption and distribution of some of these agents in severe illness has not been studied; intramuscular administration should be considered only if timely establishment of vascular access is not possible.
We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage) (strong recommendation, moderate quality of evidence).
We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS).
Rationale The initiation of appropriate antimicrobial therapy (i.e., with activity against the causative pathogen or pathogens) is one of the most important facets of effective management of life-threatening infections causing sepsis and septic shock. Failure to initiate appropriate empiric therapy in patients with sepsis and septic shock is associated with a substantial increase in morbidity and mortality [79, 95,96,97]. In addition, the probability of progression from gram-negative bacteremic infection to septic shock is increased . Accordingly, the initial selection of antimicrobial therapy must be broad enough to cover all likely pathogens. The choice of empiric antimicrobial therapy depends on complex issues related to the patient’s history, clinical status, and local epidemiologic factors. Key patient factors include the nature of the clinical syndrome/site of infection, concomitant underlying diseases, chronic organ failures, medications, indwelling devices, the presence of immunosuppression or other form of immunocompromise, recent known infection or colonization with specific pathogens, and the receipt of antimicrobials within the previous three months. In addition, the patient’s location at the time of infection acquisition (i.e., community, chronic care institution, acute care hospital), local pathogen prevalence, and the susceptibility patterns of those common local pathogens in both the community and hospital must be factored into the choice of therapy. Potential drug intolerances and toxicity must also be considered.
The most common pathogens that cause septic shock are gram-negative bacteria, gram-positive, and mixed bacterial microorganisms. Invasive candidiasis, toxic shock syndromes, and an array of uncommon pathogens should be considered in selected patients. Certain specific conditions put patients at risk for atypical or resistant pathogens. For example, neutropenic patients are at risk for an especially wide range of potential pathogens, including resistant gram-negative bacilli and Candida species. Patients with nosocomial acquisition of infection are prone to sepsis with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci.
Historically, critically ill patients with overwhelming infection have not been considered a unique subgroup comparable to neutropenic patients for purposes of selection of antimicrobial therapy. Nonetheless, critically ill patients with severe and septic shock are, like neutropenic patients, characterized by distinct differences from the typical infected patient that impact on the optimal antimicrobial management strategy. Primary among these differences are a predisposition to infection with resistant organisms and a marked increase in frequency of death and other adverse outcomes if there is a failure of rapid initiation of effective antimicrobial therapy.
Selection of an optimal empiric antimicrobial regimen in sepsis and septic shock is one of the central determinants of outcome. Survival may decrease as much as fivefold for septic shock treated with an empiric regimen that fails to cover the offending pathogen . Because of the high mortality associated with inappropriate initial therapy, empiric regimens should err on the side of over-inclusiveness. However, the choice of empiric antimicrobial regimens in patients with sepsis and septic shock is complex and cannot be reduced to a simple table. Several factors must be assessed and used in determining the appropriate antimicrobial regimen at each medical center and for each patient. These include:
The anatomic site of infection with respect to the typical pathogen profile and to the properties of individual antimicrobials to penetrate that site.
Prevalent pathogens within the community, hospital, and even hospital ward.
The resistance patterns of those prevalent pathogens.
The presence of specific immune defects such as neutropenia, splenectomy, poorly controlled HIV infection and acquired or congenital defects of immunoglobulin, complement or leukocyte function or production.
Age and patient comorbidities including chronic illness (e.g., diabetes) and chronic organ dysfunction (e.g., liver or renal failure), the presence of invasive devices (e.g., central venous lines or urinary catheter) that compromise the defense to infection.
In addition, the clinician must assess risk factors for infection with multidrug-resistant pathogens including prolonged hospital/chronic facility stay, recent antimicrobial use, prior hospitalization, and prior colonization or infection with multidrug-resistant organisms. The occurrence of more severe illness (e.g., septic shock) may be intrinsically associated with a higher probability of resistant isolates due to selection in failure to respond to earlier antimicrobials.
Given the range of variables that must be assessed, the recommendation of any specific regimen for sepsis and septic shock is not possible. The reader is directed to guidelines that provide potential regimens based on anatomic site of infection or specific immune defects [67, 99,100,101,102,103,104,105,106,107,108,109].
However, general suggestions can be provided. Since the vast majority of patients with severe sepsis and septic shock have one or more forms of immunocompromise, the initial empiric regimen should be broad enough to cover most pathogens isolated in healthcare-associated infections. Most often, a broad-spectrum carbapenem (e.g., meropenem, imipenem/cilastatin or doripenem) or extended-range penicillin/β-lactamase inhibitor combination (e.g., piperacillin/tazobactam or ticarcillin/clavulanate) is used. However, several third- or higher-generation cephalosporins can also be used, especially as part of a multidrug regimen. Of course, the specific regimen can and should be modified by the anatomic site of infection if it is apparent and by knowledge of local microbiologic flora.
Multidrug therapy is often required to ensure a sufficiently broad spectrum of empiric coverage initially. Clinicians should be cognizant of the risk of resistance to broad-spectrum β-lactams and carbapenems among gram-negative bacilli in some communities and healthcare settings. The addition of a supplemental gram-negative agent to the empiric regimen is recommended for critically ill septic patients at high risk of infection with such multidrug-resistant pathogens (e.g., Pseudomonas, Acinetobacter, etc.) to increase the probability of at least one active agent being administered . Similarly, in situations of a more-than-trivial risk for other resistant or atypical pathogens, the addition of a pathogen-specific agent to broaden coverage is warranted. Vancomycin, teicoplanin, or another anti-MRSA agent can be used when risk factors for MRSA exist. A significant risk of infection with Legionella species mandates the addition of a macrolide or fluoroquinolone.
Clinicians should also consider whether Candida species are likely pathogens when choosing initial therapy. Risk factors for invasive Candida infections include immunocompromised status (neutropenia, chemotherapy, transplant, diabetes mellitus, chronic liver failure, chronic renal failure), prolonged invasive vascular devices (hemodialysis catheters, central venous catheters), total parenteral nutrition, necrotizing pancreatitis, recent major surgery (particularly abdominal), prolonged administration of broad-spectrum antibiotics, prolonged hospital/ICU admission, recent fungal infection, and multisite colonization [111, 112]. If the risk of Candida sepsis is sufficient to justify empiric antifungal therapy, the selection of the specific agent should be tailored to the severity of illness, the local pattern of the most prevalent Candida species, and any recent exposure to antifungal drugs. Empiric use of an echinocandin (anidulafungin, micafungin, or caspofungin) is preferred in most patients with severe illness, especially in those patients with septic shock, who have recently been treated with other antifungal agents, or if Candida glabrata or Candida krusei infection is suspected from earlier culture data [100, 105]. Triazoles are acceptable in hemodynamically stable, less ill patients who have not had previous triazole exposure and are not known to be colonized with azole-resistant species. Liposomal formulations of amphotericin B are a reasonable alternative to echinocandins in patients with echinocandin intolerance or toxicity [100, 105]. Knowledge of local resistance patterns to antifungal agents should guide drug selection until fungal susceptibility test results, if available, are received. Rapid diagnostic testing using β-d-glucan or rapid polymerase chain reaction assays to minimize inappropriate anti-Candida therapy may have an evolving supportive role. However, the negative predictive value of such tests is not high enough to justify dependence on these tests for primary decision-making.
Superior empiric coverage can be obtained using local and unit-specific antibiograms [113, 114] or an infectious diseases consultation [115–117]. Where uncertainty regarding appropriate patient-specific antimicrobial therapy exists, infectious diseases consultation is warranted. Early involvement of infectious diseases specialists can improve outcome in some circumstances (e.g., S. aureus bacteremia) [113,114,115].
Although restriction of antimicrobials is an important strategy to reduce both the development of pathogen resistance and cost, it is not an appropriate strategy in the initial therapy for this patient population. Patients with sepsis or septic shock generally warrant empiric broad-spectrum therapy until the causative organism and its antimicrobial susceptibilities are defined. At that point, the spectrum of coverage should be narrowed by eliminating unneeded antimicrobials and replacing broad-spectrum agents with more specific agents . However, if relevant cultures are negative, empiric narrowing of coverage based on a good clinical response is appropriate. Collaboration with antimicrobial stewardship programs is encouraged to ensure appropriate choices and rapid availability of effective antimicrobials for treating septic patients.
In situations in which a pathogen is identified, de-escalation to the narrowest effective agent should be implemented for most serious infections. However, approximately one-third of patients with sepsis do not have a causative pathogen identified [95, 119]. In some cases, this may be because guidelines do not recommend obtaining cultures (e.g., community-acquired abdominal sepsis with bowel perforation) . In others, cultures may have followed antimicrobial therapy. Further, almost half of patients with suspected sepsis in one study have been adjudicated in post hoc analysis to lack infection or represent only “possible” sepsis . Given the adverse societal and individual risks to continued unnecessary antimicrobial therapy, we recommend thoughtful de-escalation of antimicrobials based on adequate clinical improvement even if cultures are negative. When infection is found not to be present, antimicrobial therapy should be stopped promptly to minimize the likelihood that the patient will become infected with an antimicrobial-resistant pathogen or develop a drug-related adverse effect. Thus, the decisions to continue, narrow, or stop antimicrobial therapy must be made on the basis of clinician judgment and clinical information.
We recommend against sustained systemic antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).
Rationale A systemic inflammatory response without infection does not mandate antimicrobial therapy. Examples of conditions that may exhibit acute inflammatory signs without infection include severe pancreatitis and extensive burn injury. Sustained systemic antimicrobial therapy in the absence of suspected infection should be avoided in these situations to minimize the likelihood that the patient will become infected with an antimicrobial-resistant pathogen or will develop a drug-related adverse effect.
Although the prophylactic use of systemic antimicrobials for severe necrotizing pancreatitis has been recommended in the past, recent guidelines have favored avoidance of this approach .
The current position is supported by meta-analyses that demonstrate no clinical advantage of prophylactic antibiotics that would outweigh their long-term adverse effects . Similarly, prolonged systemic antimicrobial prophylaxis has been used in the past for patients with severe burns. However, recent meta-analyses suggest questionable clinical benefit with this approach [123, 124]. Current guidelines for burn management do not support sustained antimicrobial prophylaxis . Summarizing the evidence is challenging due to the diversity of the population. The quality of evidence was low for mortality in pancreatitis  and low for burns; therefore, we believe this recommendation is better addressed as a BPS, in which the alternative of administering antibiotics without indicators of infection is implausible [122,123,124]. Despite our recommendation against sustained systemic antimicrobial prophylaxis generally, brief antibiotic prophylaxis for specific invasive procedures may be appropriate. In addition, if there is a strong suspicion of concurrent sepsis or septic shock in patients with a severe inflammatory state of noninfectious origin (despite overlapping clinical presentations), antimicrobial therapy is indicated.
We recommend that dosing strategies of antimicrobials be optimized based on accepted pharmacokinetic/pharmacodynamic principles and specific drug properties in patients with sepsis or septic shock (BPS).
Rationale Early optimization of antimicrobial pharmacokinetics can improve the outcome of patients with severe infection. Several considerations should be made when determining optimal dosing for critically ill patients with sepsis and septic shock. These patients have distinct differences from the typical infected patient that affect the optimal antimicrobial management strategy. These differences include an increased frequency of hepatic and renal dysfunction, a high prevalence of unrecognized immune dysfunction, and a predisposition to infection with resistant organisms. Perhaps most importantly with respect to initial empiric antimicrobial dosing is an increased volume of distribution for most antimicrobials, in part due to the rapid expansion of extracellular volume as a consequence of aggressive fluid resuscitation. This results in an unexpectedly high frequency of suboptimal drug levels with a variety of antimicrobials in patients with sepsis and septic shock [125,126,127,128]. Early attention to appropriate antimicrobial dosing is central to improving outcome given the marked increase in mortality and other adverse outcomes if there is a failure of rapid initiation of effective therapy. Antimicrobial therapy in these patients should always be initiated with a full, high end-loading dose of each agent used.
Different antimicrobials have different required plasma targets for optimal outcomes. Failure to achieve peak plasma targets on initial dosing has been associated with clinical failure with aminoglycosides . Similarly, inadequate early vancomycin trough plasma concentrations (in relation to pathogen minimum inhibitory concentration [MIC]) have been associated with clinical failure for serious MRSA infections  (including nosocomial pneumonia  and septic shock .
The clinical success rate for treatment of serious infections correlates with higher peak blood levels (in relation to pathogen MIC) of fluoroquinolones (nosocomial pneumonia and other serious infections) [133,134,135] and aminoglycosides (gram-negative bacteremia, nosocomial pneumonia, and other serious infections) [129, 136]. For β-lactams, superior clinical and microbiologic cures appear to be associated with a longer duration of plasma concentration above the pathogen MIC, particularly in critically ill patients [137,138,139,140].
The optimal dosing strategy for aminoglycosides and fluoroquinolones involves optimizing peak drug plasma concentrations. For aminoglycosides, this can most easily be attained with once daily dosing (5–7 mg/kg daily gentamicin equivalent). Once-daily dosing yields at least comparable clinical efficacy with possibly decreased renal toxicity compared to multiple daily dosing regimens [141, 142]. Once-daily dosing of aminoglycosides is used for patients with preserved renal function. Patients with chronically mildly impaired renal function should still receive a once-daily-equivalent dose but would normally have an extended period (up to 3 days) before the next dose. This dosing regimen should not be used in patients with severe renal function in whom the aminoglycoside is not expected to clear within several days. Therapeutic drug monitoring of aminoglycosides in this context is primarily meant to ensure that trough concentrations are sufficiently low to minimize the potential for renal toxicity. For fluoroquinolones, an approach that optimizes the dose within a nontoxic range (e.g., ciprofloxacin, 600 mg every 12 h, or levofloxacin, 750 mg every 24 h, assuming preserved renal function) should provide the highest probability of a favorable microbiologic and clinical response [127, 143, 144].
Vancomycin is another antibiotic whose efficacy is at least partially concentration-dependent. Dosing to a trough target of 15–20 mg/L is recommended by several authorities to maximize the probability of achieving appropriate pharmacodynamic targets, improve tissue penetration, and optimize clinical outcomes [145,146,147]. Pre-dose monitoring of trough concentrations is recommended. For sepsis and septic shock, an IV loading dose of 25–30 mg/kg (based on actual body weight) is suggested to rapidly achieve the target trough drug concentration. A loading dose of 1 g of vancomycin will fail to achieve early therapeutic levels for a significant subset of patients. In fact, loading doses of antimicrobials with low volumes of distribution (teicoplanin, vancomycin, colistin) are warranted in critically ill patients to more rapidly achieve therapeutic drug levels due to their expanded extracellular volume related to volume expansion following fluid resuscitation [148,149,150,151,152].
Loading doses are also recommended for β-lactams administered as continuous or extended infusions to accelerate accumulation of drug to therapeutic levels . Notably, the required loading dose of any antimicrobial is not affected by alterations of renal function, although this may affect frequency of administration and/or total daily dose.
For β-lactams, the key pharmacodynamics correlate to microbiologic and clinical response is the time that the plasma concentration of the drug is above the pathogen MIC relative to the dosing interval (T > MIC). A minimum T > MIC of 60% is generally sufficient to allow a good clinical response in mild to moderate illness. However, optimal response in severe infections, including sepsis, may be achieved with a T > MIC of 100% . The simplest way to increase T > MIC is to use increased frequency of dosing (given an identical total daily dose). For example, piperacillin/tazobactam can be dosed at either 4.5 g every 8 h or 3.375 g every 6 h for serious infections; all things being equal, the latter would achieve a higher T > MIC. We suggested earlier that initial doses of β-lactams can be given as a bolus or rapid infusion to rapidly achieve therapeutic blood levels. However, following the initial dose, an extended infusion of drug over several hours (which increases T > MIC) rather than the standard 30 min has been recommended by some authorities [154, 155]. In addition, some meta-analyses suggest that extended/continuous infusion of β-lactams may be more effective than intermittent rapid infusion, particularly for relatively resistant organisms and in critically ill patients with sepsis [140, 156,157,158]. A recent individual patient data meta-analysis of randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis demonstrated an independent protective effect of continuous therapy after adjustment for other correlates of outcome .
While the weight of evidence supports pharmacokinetically optimized antimicrobial dosing strategies in critically ill patients with sepsis and septic shock, this is difficult to achieve on an individual level without a broader range of rapid therapeutic drug monitoring options than currently available (i.e., vancomycin, teicoplanin and aminoglycosides). The target group of critically ill, septic patients exhibit a variety of physiologic perturbations that dramatically alter antimicrobial pharmacokinetics. These include unstable hemodynamics, increased cardiac output, increased extracellular volume (markedly increasing volume of distribution), variable kidney and hepatic perfusion (affecting drug clearance) and altered drug binding due to reduced serum albumin . In addition, augmented renal clearance is a recently described phenomenon that may lead to decreased serum antimicrobial levels in the early phase of sepsis [160,161,162]. These factors make individual assessment of optimal drug dosing difficult in critically ill patients. Based on studies with therapeutic drug monitoring, under-dosing (particularly in the early phase of treatment) is common in critically ill, septic patients, but drug toxicity such as central nervous system irritation with β-lactams and renal injury with colistin is also seen [163,164,165,166]. These problems mandate efforts to expand access to therapeutic drug monitoring for multiple antimicrobials for critically ill patients with sepsis.
We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence).
Remarks Readers should review Table 6 for definitions of empiric, targeted/definitive, broad-spectrum, combination, and multidrug therapy before reading this section.
We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence).
Remarks This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence).
Remarks This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
If combination therapy is initially used for septic shock, we recommend de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This applies to both targeted (for culture-positive infections) and empiric (for culture-negative infections) combination therapy (BPS).
Rationale In light of the increasing frequency of pathogen resistance to antimicrobial agents in many parts of the world, the initial use of multidrug therapy is often required to ensure an appropriately broad-spectrum range of coverage for initial empiric treatment. The use of multidrug therapy for this purpose in severe infections is well understood.
The phrase “combination therapy” in the context of this guideline connotes the use of two different classes of antibiotics (usually a β-lactam with a fluoroquinolone, aminoglycoside, or macrolide) for a single putative pathogen expected to be sensitive to both, particularly for purposes of accelerating pathogen clearance. The term is not used where the purpose of a multidrug strategy is to strictly broaden the range of antimicrobial activity (e.g., vancomycin added to ceftazidime, metronidazole added to an aminoglycoside or an echinocandin added to a β-lactam).
A propensity-matched analysis and a meta-analysis/meta-regression analysis have demonstrated that combination therapy produces higher survival in severely ill septic patients with a high risk of death, particularly in those with septic shock [167, 168]. A meta-regression study  suggested benefit with combination therapy in patients with a mortality risk greater than 25%. Several observational studies have similarly shown a survival benefit in very ill patients [169,170,171,172]. However, the aforementioned meta-regression analysis also suggested the possibility of increased mortality risk with combination therapy in low-risk (<15% mortality risk) patients without septic shock . One controlled trial suggested that, when using a carbapenem as empiric therapy in a population at low risk for infection with resistant microorganisms, the addition of a fluoroquinolone does not improve patients’ outcomes . A close examination of the results, however, demonstrates findings consistent with the previously mentioned meta-regression (trend to benefit in septic shock with an absence of benefit in sepsis without shock). Despite the overall favorable evidence for combination therapy in septic shock, direct evidence from adequately powered RCTs is not available to validate this approach definitively. Nonetheless, in clinical scenarios of severe clinical illness (particularly septic shock), several days of combination therapy is biologically plausible and is likely to be clinically useful [152, 167, 168] even if evidence has not definitively demonstrated improved clinical outcome in bacteremia and sepsis without shock [174, 175]. Thus, we issue a weak recommendation based on low quality of evidence.
A number of other recent observational studies and some small, prospective trials also support initial combination therapy for selected patients with specific pathogens (e.g., severe pneumococcal infection, multidrug-resistant gram-negative pathogens) [172, 176,177,178,179,180,181,182]. Unfortunately, in most cases and pending the development of rapid bedside pathogen detection techniques, the offending pathogen is not known at the time of presentation. Therefore, specifying combination therapy to specific identified pathogens is useful only if more prolonged targeted combination therapy is contemplated. In addition, with respect to multidrug-resistant pathogens, both individual studies and meta-analyses yield variable results depending on the pathogen and the clinical scenario [179–184]. Infectious diseases consultation may be advisable if multidrug-resistant pathogens are suspected. One area of broad consensus on the use of a specific form of combination therapy is for streptococcal toxic shock syndrome, for which animal models and uncontrolled, clinical experience demonstrate a survival advantage with penicillin and clindamycin, the latter as a transcriptional inhibitor to pyrogenic exotoxin superantigens [109, 185, 186].
Despite evidence suggesting benefit of combination therapy in septic shock, this approach has not been shown to be effective for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock [168, 174, 175]. The term “ongoing treatment” includes extended empiric therapy for culture-negative infections and extended definitive/targeted therapy where a pathogen is identified. In the case of neutropenia in the absence of septic shock, studies using modern broad-spectrum antibiotics consistently suggest that, while multidrug therapy to broaden pathogen coverage (e.g., to include Candida species) may be useful, combination therapy using a β-lactam and an aminoglycoside for purposes of accelerating pathogen clearance is not beneficial for less severely ill “low-risk” patients . Combination therapy of this sort for even “high-risk” neutropenic patients (inclusive of hemodynamic instability and organ failure) with sepsis is inconsistently supported by several international expert groups [106, 188]. This position against combination therapy for a single pathogen in any form of neutropenic infection emphatically does not preclude the use of multidrug therapy for the purpose of broadening the spectrum of antimicrobial treatment.
High-quality data on clinically driven de-escalation of antimicrobial therapy for severe infections are limited . Early de-escalation of antimicrobial therapy in the context of combination therapy as described here has not been studied. However, observational studies have shown that early de-escalation of multidrug therapy is associated with equivalent or superior clinical outcomes in sepsis and septic shock [54, 190,191,192]; despite this, at least one study has indicated an increased frequency of superinfection and longer ICU stay .
In addition to institutional benefit with respect to limiting a driver of antimicrobial resistance, early de-escalation can also benefit the individual patient [193,194,195]. Although the data are not entirely consistent, on balance, an approach that emphasizes early de-escalation is favored when using combination therapy.
While substantial consensus on the need for early de-escalation of combination therapy exists, agreement is lacking on precise criteria for triggering de-escalation. Among approaches used by panel members are de-escalation based on: (a) clinical progress (shock resolution, decrease in vasopressor requirement, etc.), (b) infection resolution as indicated by biomarkers (especially procalcitonin), and (c) a relatively fixed duration of combination therapy. This lack of consensus on de-escalation criteria for combination therapy reflects the lack of solid data addressing this issue (notwithstanding procalcitonin data relating to general de-escalation).
We suggest that an antimicrobial treatment duration of 7–10 days is adequate for most serious infections associated with sepsis and septic shock (weak recommendation, low quality of evidence).
We suggest that longer courses are appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with
, some fungal and viral infections, or immunologic deficiencies, including neutropenia (weak recommendation, low quality of evidence).
We suggest that shorter courses are appropriate in some patients, particularly those with rapid clinical resolution following effective source control of intra-abdominal or urinary sepsis and those with anatomically uncomplicated pyelonephritis (weak recommendation, low quality of evidence).
We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock (BPS).
Rationale Unnecessarily prolonged administration of antimicrobials is detrimental to society and to the individual patient. For society, excessive antimicrobial use drives antimicrobial resistance development and dissemination . For individual patients, prolonged antibiotic therapy is associated with specific illnesses such as Clostridium difficile colitis  and, more broadly, an increased mortality risk . The basis of the increased mortality with unnecessarily prolonged and broad antimicrobial therapy has not been convincingly demonstrated, although cumulative antimicrobial toxicity; the occurrence of antimicrobial-associated secondary infections (e.g., C. difficile colitis); and selection of, and superinfection with, multidrug-resistant pathogens are all potential contributors.
Although patient factors will influence the length of antibiotic therapy, a treatment duration of 7–10 days (in the absence of source control issues) is generally adequate for most serious infections [103, 197,198,199]. Current guidelines recommend a 7-day course of therapy for nosocomial pneumonia [both hospital-acquired and ventilator-associated pneumonia (VAP)] . Recent data suggest that some serious infections may be treated with shorter courses especially if there is a need for and successful provision of source control [200, 201].
Subgroup analysis of the most critically ill subjects [Acute Physiologic and Chronic Health Evaluation (APACHE) II score greater than either 15 or 20] in the short course of antimicrobials in the intra-abdominal sepsis study of Sawyer et al. demonstrated no difference in outcome based on the duration of therapy (as with the overall group) [200, 202]. A treatment duration of 3–5 days or fewer was as effective as a duration of up to 10 days. Similarly, studies have shown that a treatment duration of <7 days is as effective as longer durations in the management of acute pyelonephritis with or without bacteremia , uncomplicated cellulitis , and spontaneous bacterial peritonitis . Some conditions are generally thought to require more prolonged antimicrobial therapy. These include situations in which there is a slow clinical response, undrainable foci of infection, bacteremia with S. aureus (particularly MRSA) [67, 104], candidemia/invasive candidiasis  and other fungal infections, some viral infections (e.g., herpes, cytomegalovirus), and immunologic deficiencies, including neutropenia .
Assessment of the required duration of therapy in critically ill patients should include host factors, particularly immune status. For example, patients with neutropenic infection and sepsis usually require therapy for at least the duration of their neutropenia. The nature of the infecting pathogen also plays a role. In particular, uncomplicated S. aureus bacteremia requires at least 14 days of therapy, while complicated bacteremia requires treatment as an endovascular infection with 6 weeks of therapy. Uncomplicated bacteremia has been defined as: (1) exclusion of endocarditis, (2) no implanted prostheses, 3) negative results of follow-up blood cultures drawn 2–4 days after the initial set, (4) defervescence within 72 h after the initiation of effective antibiotic therapy, and (5) no evidence of metastatic infection .
Patients with candidemia (whether or not catheter-associated) and deep Candida infections, whether or not associated with sepsis, require more prolonged therapy [105, 205]. Highly resistant gram-negative pathogens with marginal sensitivity to utilized antimicrobials may be slow to clear and represent another example. The nature and site of infection may also affect duration of therapy. Larger abscesses and osteomyelitis have limited drug penetration and require longer therapy. Although it is well known that endocarditis requires prolonged antimicrobial therapy, severe disease more typically presents as cardiac failure/cardiogenic shock and emboli rather than as sepsis or septic shock [206, 207]. A variety of other factors may play a role in determining the optimal duration of therapy, particularly in critically ill infected patients. If the clinician is uncertain, infectious diseases consultation should be sought.
Few of the studies noted focused on patients with septic shock, sepsis with organ failure, or even critical illness. To an extent, standard recommendations on duration of therapy in this document depend on inferences from less ill cohorts. Therefore, decisions to narrow or stop antimicrobial therapy must ultimately be made on the basis of sound clinical judgment.
There are many reasons for unnecessarily prolonged antimicrobial therapy. For complicated, critically ill patients admitted with serious infections, noninfectious concurrent illness and medical interventions may produce signs and symptoms consistent with active infection (even following control of infection). For example, pulmonary infiltrates and shortness of breath may be caused by pulmonary edema in addition to pneumonia; an elevated white cell count may occur as a consequence of corticosteroid administration or physiologic stress; fever may be associated with certain drugs, including β-lactams and phenytoin. In addition, there is a natural tendency to want to continue a therapy that is often seen as benign long enough to be confident of cure. However, as discussed, antimicrobials are not an entirely benign therapy. In low-risk patients, the adverse effects can outweigh any benefit.
Given the potential harm associated with unnecessarily prolonged antimicrobial therapy, daily assessment for de-escalation of antimicrobial therapy is recommended in patients with sepsis and septic shock. Studies have shown that daily prompting on the question of antimicrobial de-escalation is effective and may be associated with improved mortality rates [55, 208].
We suggest that measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients (weak recommendation, low quality of evidence).
We suggest that procalcitonin levels can be used to support the discontinuation of empiric antibiotics in patients who initially appeared to have sepsis, but subsequently have limited clinical evidence of infection (weak recommendation, low quality of evidence).
Rationale During the past decade, the role of biomarkers to assist in the diagnosis and management of infections has been extensively explored. The use of galactomannan and β-d-glucan to assist in the assessment of invasive aspergillus (and a broad range of fungal pathogens) has become well accepted [209, 210].
Similarly, measurement of serum procalcitonin is commonly used in many parts of the world to assist in the diagnosis of acute infection and to help define the duration of antimicrobial therapy. Various procalcitonin-based algorithms have been used to direct de-escalation of antimicrobial therapy in severe infections and sepsis [211,212,213,214,215,216]. However, it is not clear that any particular algorithm provides a clinical advantage over another. A large body of literature suggests that use of such algorithms can speed safe antimicrobial de-escalation compared to standard clinical approaches with reduced antimicrobial consumption without an adverse effect on mortality. Recently, a large randomized trial on procalcitonin use in critically ill patients with presumed bacterial infection demonstrated evidence of a reduction in duration of treatment and daily defined doses of antimicrobials . However, given the design of the study, the reduction could have been related to a prompting effect as seen in other studies [55, 218]. In addition, the procalcitonin group showed a significant reduction in mortality. This finding is congruent with studies demonstrating an association between early antimicrobial de-escalation and survival in observational studies of sepsis and septic shock [54, 55].
This benefit is uncertain, though, because another meta-analysis of randomized controlled studies of de-escalation failed to demonstrate a similar survival advantage . Meta-analyses also suggest that procalcitonin can also be used to assist in differentiating infectious and noninfectious conditions at presentation [211, 214, 216]. The strongest evidence appears to relate to bacterial pneumonia versus noninfectious pulmonary pathology [216, 220], where meta-analysis suggests that procalcitonin may assist in predicting the presence of bacteremia, particularly in ICU patients .
No evidence to date demonstrates that the use of procalcitonin reduces the risk of antibiotic-related diarrhea from C. difficile. However, the occurrence of C. difficile colitis is known to be associated with cumulative antibiotic exposure in individual patients , so such a benefit is likely. In addition, although prevalence of antimicrobial resistance has not been shown to be reduced by the use of procalcitonin, the emergence of antimicrobial resistance is known to be associated with total antimicrobial consumption in large regions .
It is important to note that procalcitonin and all other biomarkers can provide only supportive and supplemental data to clinical assessment. Decisions on initiating, altering, or discontinuing antimicrobial therapy should never be made solely on the basis of changes in any biomarker, including procalcitonin.