Abstract
Background:
Understanding the microbiology and optimal pharmacotherapy of patients with community-onset sepsis is key to improving outcomes. Yet, empiric therapies prescribed in Canadian emergency departments as they relate to microbial etiology and focus of infection are inadequately described.
Methods:
We performed a post hoc analysis of the FABLED cohort study, which quantified the effect of antimicrobials on blood culture yield in septic patients. Patients presenting with sepsis were enrolled in six Canadian emergency departments between 2013 and 2018. We characterized the appropriateness of empiric therapies relative to the pathogens isolated and focus of infection identified.
Results:
The data of 315 patients with sepsis was analyzed. Broad-spectrum antibiotics were used in 68.6% of the cohort. Despite this, Pseudomonas was never isolated in any blood cultures, and drug-resistant organisms were only encountered in 4.8% of the cohort. Among patients with bacteremia (n = 100), 28% of patients received appropriate antibiotic therapy whereas the remainder received therapies that were either overly narrow (16%) or unnecessarily broad (56%) in spectrum. Among patients with an identified focus of infection (n = 266), 30.5% received appropriate empiric antibiotics. Prescribing patterns that were overly broad, overly narrow, or a combination of the two were observed in 39.8%, 7.5%, and 22.2% of patients, respectively. Thirty-day mortality was lowest among patients receiving appropriate therapy relative to the final pathogen isolated and presumed infectious focus.
Conclusions:
Empiric therapies for septic patients in Canada were overly broad given the rare isolation of drug-resistant pathogens. Though likely confounded by severity of illness, optimal outcomes were observed when therapy was appropriate relative to the causative pathogen and infectious focus.
Keywords: antibiotic stewardship, antibiotic therapy, antimicrobial resistance, sepsis
Abstract
Historique :
Il est essentiel de comprendre la microbiologie et la pharmacothérapie optimale des patients atteints de sepsis d'origine communautaire pour en améliorer les résultats cliniques. Pourtant, l’étiologie microbienne et le foyer de l'infection sont mal décrits dans le cas des traitements empiriques prescrits dans les services d'urgence canadiens.
Méthodologie :
Les chercheurs ont procédé à une analyse post-hoc de l’étude de cohorte FABLED, qui a quantifié l'effet des antimicrobiens à l'hémoculture des patients septiques. Les patients atteints de sepsis qui avaient consulté dans six services d'urgence canadiens entre 2013 et 2018 ont participé à l’étude. Les auteurs ont caractérisé la pertinence des traitements empiriques par rapport aux agents pathogènes isolés et au foyer d'infection déterminé.
Résultats :
Les données de 315 patients atteints de sepsis ont été analysées. Des antibiotiques à large spectre ont été utilisés chez 68,6% de la cohorte. Pourtant, le Pseudomonas n'a été isolé dans aucune hémoculture sanguine, et des organismes résistants aux antibiotiques n'ont été observés que chez 4,8 % des membres de la cohorte. Chez les patients atteints d'une bactériémie (n = 100), 28 % des patients ont reçu une antibiothérapie appropriée, tandis que les autres ont reçu un traitement qui était soit à spectre trop étroit (16 %) soit à spectre inutilement trop large (56 %). Chez les patients dont le foyer d'infection était établi (n = 266), 30,5 % ont reçu des antibiotiques empiriques appropriés. Les schémas d'ordonnance qui étaient trop larges, trop étroits ou une combinaison de deux ont été observés chez 39,8 %, 7,5 % et 22,2 % des patients, respectivement. La mortalité au bout de 30 jours était plus faible chez les patients qui avaient reçu un traitement approprié par rapport à l'agent pathogène définitif isolé et du foyer infectieux présumé.
Conclusions :
Les traitements empiriques des patients du Canada ayant un sepsis étaient trop larges en raison du rare isolement des agents pathogènes résistants aux antibiotiques. Malgré des facteurs confusionnels probables en raison de la gravité de la maladie, les résultats cliniques optimaux étaient observés lorsque le traitement était approprié par rapport à l'agent pathogène causal et au foyer infectieux.
Mots-Clés : gestion des antibiotiques, antibiothérapie, résistance aux antimicrobiens, sepsis
Introduction
Sepsis is a significant cause of morbidity and mortality, contributing up to one in five deaths worldwide (1). Of all the interventions studied in the management of sepsis, early and appropriate antibiotic administration has consistently shown itself to be a major determinant of mortality (2, 3, 4). The timely administration of appropriate antibiotic therapy to patients with sepsis and septic shock has consequently become a quality metric for numerous health care institutions (5).
Antibiotics can generally be categorized as broad spectrum or narrow spectrum. While definitions vary, narrow-spectrum agents typically do not target drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa and typically do not have the combined aerobic and anaerobic coverage as that provided by the β-lactam/β-lactamase inhibitors. Conversely, broad-spectrum antibiotics have in vitro activity against these pathogens. To ensure the timely provision of active therapy in more severe sepsis, acknowledging the possibility of resistant pathogens, a commonly employed strategy is to initiate a broad-spectrum agent empirically to maximize the probability of coverage (6). Later, when the clinical picture is clearer and microbiological results and antimicrobial susceptibility testing become available, the spectrum of activity is usually narrowed.
For patients with septic shock, it has long been recognized that the administration of antibiotics with limited or no activity against the infecting pathogen is associated with an increased risk of mortality (7). Conversely, recent observational studies have also suggested that the administration of overly broad-spectrum antibiotics may also be associated with an increased risk of mortality (8). While such retrospective studies may be confounded by the severity of illness, there is emerging evidence of the deleterious effect of broad-spectrum antibiotics on the host microbiome, with the potential for downstream harm (9).
Another important paradigm in the pharmacotherapeutic management of sepsis is to tailor the antibiotic selection based on the presumed site of infection. Identifying the infectious focus in sepsis is imperative as it helps determine the spectrum of microbes that need to be covered by the antibiotic regimen. Therefore, knowing the individual patient ecology combined with the local microbiological epidemiology of the pathogens causing sepsis and septic shock is critical to ensuring the selection of appropriate therapy.
A 2020 study reported on antibiotic prescribing patterns for patients with sepsis in community hospitals in Niagara, Ontario, Canada (10). They collected data on multiple sepsis metrics including time to antibiotic administration and fluid resuscitation parameters. They found a general reliance on narrow-spectrum antibiotics, although approximately 25% of patients in the emergency department received piperacillin-tazobactam empirically. However, the study did not report on the suitability of the antibiotic regimens relative to the presumed source of infection or relative to the final microbe isolated (in instances of culture-positive sepsis). These parameters remain crucial elements in understanding how to optimize empiric therapy in sepsis.
In this study, we set out to leverage the results of FABLED, a prospective observational cohort study that compared blood culture positivity rates before and after antimicrobial administrations in patients presenting with severe manifestations of sepsis to six large emergency departments at Canadian health centres (11). This post hoc analysis describes the antibiotic prescribing patterns for patients with sepsis and septic shock at centres in British Columbia and Quebec, Canada. We determined the rates of appropriate, inappropriately narrow, and inappropriately broad antimicrobial coverage relative to the final microbial isolate (in instances of blood-culture-positive sepsis) and relative to the presumed focus of infection.
Methods
The FABLED study was an international diagnostic cohort study that investigated the effects of antimicrobial administration on the yield of blood culture results in patients presenting to emergency departments with severe manifestations of sepsis. FABLED was conducted between November 2013 and September 2018 and included six centres in Canada (four in British Columbia and two in Québec) and one centre in the United States (Arizona). For the purposes of this study, we restricted the analysis to the six Canadian sites.
The inclusion criteria for the study have already been published (11) Briefly, adult patients were considered for enrolment if they presented to participating emergency departments with signs and symptoms suggestive of severe sepsis or septic shock. Specifically, patients needed to have either a systolic blood pressure less than 90 mmHg or a serum lactate greater than or equal to 4 mmol/L. Patients had two sets of blood cultures drawn prior to antibiotic administration and then an additional set within 240 minutes of their first antibiotic dose. Exclusion criteria included administration of antibiotics within the previous 48 hours and a perceived risk of harm attributed to additional venipunctures (thrombocytopenia with a platelet count of <20,000 [106/L], an international normalized ratio >6.0, and clinically significant bleeding). Due to their enrolment in emergency departments, all patients were assumed to have community-acquired infections. The investigators excluded patients deemed to have pseudo-bacteremia (involving common contaminating pathogens, coagulase-negative Staphylococci, and Bacillus spp, among others) from the blood-culture-positive cohort.
For each patient included within the study the following data was prospectively recorded: empiric antibiotics given, site of suspected infection, pathogens recovered in blood cultures, resistance phenotype, and mortality outcomes at 30 and 90 days.
Antibiotics were classified as broad spectrum if they possessed in vitro activity against MRSA; vancomycin-resistant Enterococcus; ceftriaxone-resistant gram-negative (CTX-RO) organisms, including P. aeruginosa; or extended-spectrum β-lactamase gram-negative organisms. Narrow-spectrum antimicrobials were all other agents. These definitions were previously published (12).
Antibiotic therapy was classified as appropriate versus inappropriate in two ways. Firstly, for patients in whom pathogens were recovered from blood cultures, the concordance of the antibiotic susceptibility testing with the empiric therapy was determined. If the pathogen was resistant to the therapy received, it was categorized as inappropriate, or overly narrow. Conversely, if the pathogen was sensitive to the empiric antibiotic regimen, it was deemed covered. Similarly, if the pathogen recovered did not require a broad-spectrum antibiotic agent as defined above but was received, regardless of in vitro susceptibility, this was categorized as inappropriately broad. The MERINO (13) randomized controlled trial suggests better outcomes when carbapenems are used in CTX-RO gram-negative bacteremia. While the trial had several methodological shortcomings and further studies such as PeterPen (14) are underway to elucidate this result, for the purposes of this study, piperacillin-tazobactam was considered inappropriately narrow for the treatment of CTX-RO even if the final microbial isolate was sensitive to it.
Secondly, if the site of sepsis was determined, the choice of empiric antibiotic used was categorized as appropriate, inappropriately broad, inappropriately narrow, or both inappropriately broad and narrow. Instances of both inappropriately broad and narrow antibiotic selection were considered when the selected regimen possessed microbiological gaps but also included agents that were unnecessary for the focus of infection. For instance, a patient receiving meropenem monotherapy for a community-acquired pneumonia was being treated with a regimen that was both overly broad (as it covers Pseudomonas and resistant gram-negative organisms) and overly narrow (as it lacks atypical coverage). When combination therapy was used, antimicrobial appropriateness was always evaluated as an aggregate, rather than by individual agent. The appropriateness of antibiotic choice by site of sepsis was evaluated as follows:
Respiratory infection: third-generation cephalosporin and either macrolide or tetracycline. Alternatively, a respiratory fluoroquinolone (levofloxacin and moxifloxacin) was also considered appropriate. Upfront use of an antipseudomonal β-lactam (piperacillin-tazobactam, meropenem, or ceftazidime) was only considered appropriate if there was concomitant febrile neutropenia. Addition of anaerobic coverage (metronidazole or piperacillin-tazobactam) was only considered appropriate if a complicated parapneumonic effusion or empyema was suspected. Addition of an anti-MRSA agent was only considered appropriate if the patient was known to have nasal or respiratory colonization with MRSA (15).
Genitourinary: third-generation cephalosporin (with or without ampicillin) or ciprofloxacin. Use of carbapenems in genitourinary infections was only considered appropriate if the patient had a history of extended-spectrum β-lactamase urinary tract infections (16). Upfront use of an antipseudomonal β-lactam (piperacillin-tazobactam, meropenem) was only considered appropriate in febrile neutropenia or a history of CTX-RO. Addition of an empiric anti-MRSA antibiotic was not considered appropriate.
Gastrointestinal: piperacillin-tazobactam, or ceftriaxone and metronidazole, or ciprofloxacin and metronidazole. Empiric addition of vancomycin was considered inappropriate unless the patient had a history of Enterococcus faecium infection. Empiric addition of antifungal agents was considered inappropriate.
Skin and soft tissue infections and endovascular infections: first-generation cephalosporin and/or anti-MRSA agent. Piperacillin-tazobactam was only considered appropriate if a polymicrobial infection was suspected (eg, diabetic foot infection) or if there was clinical suspicion of necrotizing fasciitis.
Central nervous system (CNS): ceftriaxone (CNS dosing) and vancomycin. The addition of ampicillin or penicillin G for Listeria coverage was only considered appropriate in patients above the age of 50 years old or if immunocompromised. Any antibiotic with poor CNS penetration was considered overly narrow in spectrum.
When prior microbiological data was recorded, this information was used to help arbitrate whether appropriate empiric therapy was used. For instance, if a patient had a known personal history of Pseudomonas colonization or infection of the respiratory or urinary tract, empiric antipseudomonal agent use was considered appropriate. Two reviewers independently adjudicated appropriateness of the regimens, and a third reviewer helped settle conflicting results.
Results
The original cohort included 325 patients and the six Canadian sites contributed 315 patients with complete antibiotic and culture data to analyze. Empiric antibiotic therapy for the septic episode was captured for 100% of encounters. The prevalence of antibiotics administered by class can be found in Figure 1A and 1B. The majority of patients received an antibiotic with antipseudomonal activity (68.6%), with 62.2% of all patients receiving piperacillin-tazobactam; 56.8% of patients received multiple antibiotics, with 26.6% of the total population receiving anti-MRSA coverage with vancomycin (82 patients) or linezolid (2 patients).
Figure 1: Prevalence of empiric antibiotic use by class. A, Proportion of all patients receiving the antibiotic. B, Proportion of all antibiotics prescribed (495 antibiotics were prescribed in total).
The prevalence of organisms isolated in the blood-culture-positive cohort can be found in Figure 2. Fifteen drug-resistant organisms were isolated in blood cultures, representing 15% of the bacteremic cohort and 4.8% of the entire septic cohort. The prevalence of drug-resistant phenotypes of organisms identified in blood cultures is presented in Figure 3.
Figure 2: Prevalence of bacteria isolated in blood cultures.
MRSA = Methicillin-resistant Staphylococcus aureus; Methicillin-suseptible Staphylococcus aureus
Figure 3: Prevalence of drug-resistant organisms isolated in blood cultures.
MRSA = Methicillin-resistant Staphylococcus aureus; VRE = Vancomycin-resistant Enterococcus; CTX-RO = Ceftriaxone-resistant gram-negative organism; GNR = Gram-negative rod
Appropriateness of therapy relative to pathogen identified
There were 100 patients (31.7% of the total cohort) who had positive blood cultures for one or more pathogens. The comparison of empiric therapy relative to the microbes identified in blood culture is presented in Table 1. Inappropriately narrow antibiotic selection (ie, empiric therapy did not treat the final organism isolated in blood) occurred in 16% of patients. The most common gap in the spectrum of activity identified was the lack of MRSA coverage (six of nine patients) when MRSA was eventually isolated. Other lacunes in coverage included lack of antibiotic activity against E. faecium (one patient) and anaerobes (two patients). P. aeruginosa and other non-fermenter gram-negative rods were never identified in any patients’ blood culture. Two patients were also found to be candidemic and had not received initial antifungal therapy. Inappropriately broad coverage was identified for 56% of patients with bacteremia, predominantly for the unnecessary use of agents active against CTX-RO or MRSA. Ten percent (5/50) of Enterobacterales isolates were found to be CTX-RO. None of the Enterobacterales were carbapenem-resistant organisms.
Table 1:
Appropriateness of empiric antibiotic based the organism isolated in blood cultures (100 patients has a positive blood culture)
| Categorization of spectrum | Frequency of administration, no. |
|---|---|
| Appropriate | 28 |
| Inappropriately broad | 56 |
| Inappropriately narrow | 16 |
Appropriateness of therapy as a function of site of infection
The results of the analysis based on site of infection are summarized in Table 2. Antibiotic selection was classified as appropriate, overly narrow, overly broad, or both overly narrow and broad. In 266 of the 315 patients (84.4%) patients, a presumed source of infection was documented. Of those, the sources included respiratory (110/266, 41.3%), genitourinary (55/266, 20.7%), gastrointestinal (53/266, 19.9%), skin and soft tissue (38/266, 14.3%), endovascular (7/266, 2.6%), and CNS (3/266, 1.1%). The remainder of the patients’ presumed sources were either unlisted or unknown at the time of antimicrobial prescription and were thus excluded from the analysis.
Table 2:
Appropriateness of empiric antibiotic based on site of infection (266 patients had an identified site of infection)
| Categorization of spectrum | Frequency of administration, no. (%) |
|---|---|
| Appropriate | 81 (30.5) |
| Inappropriate | |
| Narrow | 20 (7.5) |
| Broad | 106 (39.8) |
| Narrow and broad | 59 (22.2) |
The two independent reviewers’ results were 85% (226/266) concordant; the third reviewer helped settle the non-concordant entries. Appropriate empiric antimicrobial use based on site of infection occurred in 81 (30.5%) patients of the cohort. Inappropriately narrow coverage was seen in 20 (7.5%) patients with a listed presumed source of sepsis, and inappropriately broad coverage was seen in 106 (39.8%). Both inappropriately broad and narrow antibiotics were used in 59 (22.2%) patients. Piperacillin-tazobactam was the most inappropriately administered antibacterial being given for community-acquired pneumonia, urinary tract infections, and skin and soft tissue infections without evidence of necrotizing fasciitis. In addition, anti-MRSA agents were often used without a clear indication. Cases of overly narrow prescriptions included insufficient anaerobic coverage in gastrointestinal infections, lack of atypical coverage in community-acquired pneumonia, and lack of Listeria coverage in CNS infections in those older than 50 years of age. Patients who were given both overly narrow- and overly broad-spectrum therapy mostly consisted of those with community-acquired pneumonia who were treated with an antipseudomonal β-lactam but no atypical coverage.
Cohort mortality as a function of appropriateness of therapy received
Thirty-day mortality was captured for 308 of the 315 patients. The overall 30-day mortality was 19.5% (60/308 patients): 17% (17/100) in bacteremic patients and 20.7% (43/208) in non-bacteremic patients.
Within the blood-culture-positive cohort (n = 100), the patients who received initial antimicrobial agents without in vitro activity against the blood culture organism isolated had a 30-day mortality of 18.8% (3/16). In comparison, those whose initial antimicrobials covered the final organism identified had a mortality rate of 16.7% (14/84). However, a large discrepancy in mortality was observed within this group. Those treated with an inappropriately broad agent when unnecessary had a 30-day mortality of 21.4% (12/56), whereas those appropriately covered without an overly broad agent when unnecessary experienced a 30-day mortality of 7.1% (2/28) (Table 3).
Table 3:
Thirty-day mortality based on empiric antibiotic appropriateness relative to final pathogen identified in blood cultures (100 patients had blood culture isolates and 30-day mortality data)
| Categorization of spectrum | Mortality, no. (%) | ||
|---|---|---|---|
| Covered (n = 84) | |||
| Appropriate coverage (n = 28) | 14/84 (16.7) | 2/28 (7.1) | |
| Inappropriately broad coverage (n = 56) | 12/56 (21.4) | ||
| Inappropriately narrow (ie, not covered) (n = 16) | 3/16 (18.8) | ||
Within the identified source of infection cohort with mortality data available (n = 260 patients), those who received appropriate initial antimicrobials (n = 79) had a 30-day mortality of 13.9% (11/79). The cohort with overly broad coverage (n = 104) had a 30-day mortality of 21.2% (22/104), and those with overly narrow coverage (n = 19) had a 30-day mortality of 36.8% (7/19). Those who received antibiotics that were both too broad and too narrow (n = 58) had a 30-day mortality of 20.7% (12/58) (Table 4).
Table 4:
Thirty-day mortality based on empiric antibiotic appropriateness relative to the site of infection (260 patients had an identified site of sepsis and 30-day mortality data)
| Categorization of spectrum | Frequency of administration, n (%) | Mortality, n (%) | |
|---|---|---|---|
| Appropriate | 79 (30.4%) | 11 (13.9%) | |
| Inappropriate | Narrow | 19 (7.3%) | 7 (36.8%) |
| Broad | 104 (40%) | 22 (21.2%) | |
| Narrow and broad | 58 (22.3%) | 12 (20.7%) | |
Discussion
In this post hoc analysis of the FABLED study, a large percentage of Canadian patients received broad spectrum empiric antibiotic therapy without microbiologic or site-specific justification. Our findings highlight the need for better recognition of the common pathogens in sepsis to help inform stewardship efforts in Canadian emergency departments. Better identification of risk factors for MRSA and resistant gram-negative infections may improve issues related to both under- and over-treatment.
Selecting an empiric agent in sepsis is challenging as adverse outcomes are observed when therapy is both overly broad and overly narrow, relative to both the causative organism(s) and the focus of infection. Though our results indicated that most of the bacteremic cohort received overly broad agents (56%), there was still a sizable proportion of patients (16%) who received empiric antimicrobials that did not treat the final pathogen identified in the blood. If clinicians globally narrow the spectrum of their empiric therapy, the proportion of inadequately treated resistant organisms is likely to increase and presumably worsen outcomes in sepsis. This conundrum highlights the need to adequately identify and act upon the patient and demographic factors that best predict infection with resistant bacteria.
Many patients with community-acquired pneumonia received empiric therapy with piperacillin-tazobactam (either with or without atypical coverage). The most important bacterial cause of community-acquired pneumonia is Streptococcus pneumoniae. This organism may develop decreased susceptibility or resistance to penicillin via mutations in its penicillin-binding proteins, rather than via the production of β-lactamases (17). Compared to a third-generation cephalosporin, penicillin-β-lactamase inhibitors like piperacillin-tazobactam do not add additional activity against pneumococcus (18), yet they offer coverage of a wide range of organisms that are not typically causative of community-onset respiratory infections (Pseudomonas, CTX-RO gram-negatives, anaerobes).
There is growing concern that unnecessarily broad-spectrum agents may be associated with poor outcomes (12). Our data are too limited to support or refute that hypothesis with inferential statistics; however, numerically, the patients who received overly broad coverage relative to their source of infection and infecting pathogen had a 30-day mortality rate of 21.2% and 21.4%, versus 13.9% and 7.1% in those with appropriate coverage. Broad-spectrum antibiotics can lead to a multitude of adverse events (19), including selection for multi-drug-resistant pathogens (20–22), unnecessary depletion of the host microbiome (23), and Clostridioides difficile–associated colitis (21, 24). It is important to note, however, that the study's mortality outcome is likely confounded by severity of illness. Patients receiving broad-spectrum and combination antimicrobials were likely presenting with more severe sepsis, increasing the probability of death.
These results are in keeping with sepsis epidemiological trends in the United States. Rhee and colleagues (12), in conjunction with the Centers for Disease Control and Prevention's Prevention Epicenters Program, performed a similar study and analysis in the United States. Among over 17,000 patients with culture-positive community-onset sepsis, 67% received empiric broad-spectrum agents. Yet, resistant gram-positive and gram-negative pathogens warranting the use of such agents were only isolated in 13.6% and 13.2% of the cohort, respectively. Furthermore, they found that the unnecessary use of an empiric broad-spectrum agent was associated with a risk-adjusted in-hospital mortality odds ratio of 1.22 (CI 1.06 to 1.40, P = .007). In comparison, failure of empiric therapy to cover the final organism identified was associated with a mortality odds ratio of 1.19 (CI 1.03 to 1.37, P = .02). In 2021, the same group performed a cross-sectional study concluding that 91.6% of patients receiving either empiric anti-MRSA or antipseudomonal agents for community-onset sepsis did not end up having a microbiologically confirmed MRSA or Pseudomonas infection (25).
Our study has several limitations. Firstly, this is a post hoc analysis of a prospectively enrolled cohort. Residual confounding of the results can be expected. Secondly, the sample size was relatively small and only included centres in Quebec and British Columbia, as opposed to a more diverse national view. However, the uniformity in practice noted across numerous centres suggests that practice patterns elsewhere may be similar. Thirdly, our cohort had a significant number of patients with culture-negative sepsis (n = 215) based upon cultures drawn at the time of admission to the emergency department. It is difficult to comment on the appropriateness of the antibiotic therapy chosen for these patients. However, we noted that many patients were being treated for suspected community-acquired pneumonia with piperacillin-tazobactam, which is unnecessarily broad, and the low isolation of MRSA (9% of the bacteremic cohort, 2.9% of the entire cohort) and no isolation of P. aeruginosa (0 isolates) within the culture-positive group further suggests little to no value of empiric antibiotic coverage of these pathogens. We also chose not to examine the microbiology of other clinical specimens (urine or sputum cultures) given it was unclear whether these microorganisms were causative or simple bystanders (ie, patients with pulmonary sepsis who happen to have concomitant asymptomatic bacteriuria).
The methodology involved in determining antibiotic appropriateness by site of infection has intrinsic shortcomings. As a limited amount of patient-level factors was captured within the FABLED cohort, the certainty of antibiotic appropriateness is restricted. Many variables including geographical patterns of antibiotic resistance, comorbidities, previous infection, colonization with a drug-resistant organism, and exposure history add a level of nuance in antibiotic selection that may not have been captured within our standardized definitions. Nevertheless, our findings are consistent with recent studies in the United States and seem plausible. As the FABLED study only captured empiric therapy in sepsis, our group could not analyse the difference in outcomes based on choice and timing of antibiotic stepdown. Trends in mortality could certainly have been confounded by the clinicians’ choice to continue broad-spectrum antimicrobials or narrow the spectrum after the first 48 hours of clinical presentation.
Lastly, as a retrospective observational study and a post hoc analysis, inferential statistics were not calculated. This type of study can only report an association; causation would be best addressed in a prospective, randomized fashion.
In conclusion, antibiotic prescription for severe sepsis and septic shock in Canada appears to be overly broad in comparison to the pathogens recovered and focus of infection. Stewardship efforts are needed to both curtail the unnecessary use of broad-spectrum agents and better identify those who may require it. Ultimately, clinicians remain faced with a difficult decision when choosing empiric therapy for sepsis. Understanding patient risk factors for Pseudomonas infection, third-generation cephalosporin resistance in Enterobacterales, and MRSA coupled with the availability of accurate and timely local antibiograms may prove crucial to optimizing empiric therapy in sepsis.
Funding Statement
No funding was received for this work.
Contributors:
Conceptualization, DE Lasry, MP Cheng, A Lawandi; Methodology, DE Lasry, MP Cheng, A Lawandi; Formal Analysis, DE Lasry; Investigation, DE Lasry; Data Curation, D Sweet, MP Cheng; Writing – Original Draft, DE Lasry, A Lawandi; Writing – Review & Editing, DE Lasry, T Lee, K Paquette, K Demir, C Yansouni, D Sweet, MP Cheng, A Lawandi; Supervision, T Lee, K Paquette, C Yansouni, MP Cheng, A Lawandi.
Ethics Approval:
Ethics approval was not required for this article.
Informed Consent:
N/A
Registry and the Registration No. of the Study/Trial:
N/A
Data Accessibility:
All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.
Funding:
No funding was received for this work.
Disclosures:
The authors have nothing to disclose.
Peer Review:
This manuscript has been peer reviewed.
Animal Studies:
N/A
References
- 1.Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 2020;395:200–11. 10.1016/S0140-6736(19)32989-7. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Sherwin R, Winters ME, Vilke GM, et al. Does early and appropriate antibiotic administration improve mortality in emergency department patients with severe sepsis or septic shock? J Emerg Med. 2017;53:588–95. 10.1016/j.jemermed.2016.12.009. PMID: [DOI] [PubMed] [Google Scholar]
- 3.Joo YM, Chae MK, Hwang SY, et al. Impact of timely antibiotic administration on outcomes in patients with severe sepsis and septic shock in the emergency department. Clin Exp Emerg Med. 2014;1:35–40. 10.15441/ceem.14.012. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010;38(4):1045–53. 10.1097/CCM.0b013e3181cc4824. PMID: [DOI] [PubMed] [Google Scholar]
- 5.Rhee C, Chiotos K, Cosgrove SE, et al. Infectious Diseases Society of America position paper: recommended revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) sepsis quality measure. Clin Infect Dis. 2020;72:541–52. 10.1093/cid/ciaa059. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cressman AM, MacFadden DR, Verma AA, et al. Empiric antibiotic treatment thresholds for serious bacterial infections: a scenario-based survey study. Clin Infect Dis. 2018;69:930–7. 10.1093/cid/ciy1031. PMID: [DOI] [PubMed] [Google Scholar]
- 7.Zilberberg MD, Shorr AF, Micek ST, et al. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care 2014;18:596. 10.1186/s13054-014-0596-8. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Semret M, Abebe W, Kong LY, et al. Prolonged empirical antibiotic therapy is correlated with bloodstream infections and increased mortality in a tertiary care hospital in Ethiopia: bacteriology testing matters. JAC Antimicrob Resist. 2020;2:dlaa039. 10.1093/jacamr/dlaa039. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chanderraj R, Baker JM, Kay SG, et al. In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes. Eur Respir J. 2023;61(2):2200910. 10.1183/13993003.00910-2022. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lo VCK, Su H, Lam YM, et al. Management of patients with sepsis in Canadian community emergency departments: a retrospective multicenter observational study. Health Serv Res Manag Epidemiol. 2020;7:2333392820920082. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cheng MP, Stenstrom R, Paquette K, et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis: a diagnostic study. Ann Intern Med. 2019;171:547–54. 10.7326/M19-1696. PMID: [DOI] [PubMed] [Google Scholar]
- 12.Rhee C, Kadri SS, Dekker JP, et al. Prevalence of antibiotic-resistant pathogens in culture-proven sepsis and outcomes associated with inadequate and broad-spectrum empiric antibiotic use. JAMA Netw Open 2020;3:e202899. 10.1001/jamanetworkopen.2020.2899. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. Jama 2018;320:984–94. 10.1001/jama.2018.12163. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bitterman R, Koppel F, Mussini C, et al. Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open 2021;11:e040210. 10.1136/bmjopen-2020-040210. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Butler-Laporte G, De L'Étoile-Morel S, Cheng MP, et al. MRSA colonization status as a predictor of clinical infection: a systematic review and meta-analysis. J Infect. 2018;77:489–95. 10.1016/j.jinf.2018.08.004. PMID: [DOI] [PubMed] [Google Scholar]
- 16.MacFadden DR, Coburn B, Shah N, et al. Utility of prior cultures in predicting antibiotic resistance of bloodstream infections due to Gram-negative pathogens: a multicentre observational cohort study. Clin Microbiol Infect. 2018;24:493–9. 10.1016/j.cmi.2017.07.032. PMID: [DOI] [PubMed] [Google Scholar]
- 17.Cillóniz C, Garcia-Vidal C, Ceccato A, et al. Antimicrobial resistance among Streptococcus pneumoniae. Antimicrobial Resistance in the 21st Century 2018:13–38. [Google Scholar]
- 18.Pankuch GA, Jacobs MR, Appelbaum PC. Susceptibilities of 200 penicillin-susceptible and -resistant pneumococci to piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone. Antimicrob Agents Chemother. 1994;38:2905–7. 10.1128/AAC.38.12.2905. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chanderraj R, Baker JM, Kay SG, et al. In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes. Eur Respir J. 2023;61:2200910. 10.1183/13993003.00910-2022. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Yoshida H, Motohashi T, De Bus L, et al. Use of broad-spectrum antimicrobials for more than 72 h and the detection of multidrug-resistant bacteria in Japanese intensive care units: a multicenter retrospective cohort study. Antimicrob Resist Infect Control 2022;11:119. 10.1186/s13756-022-01146-3. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gontjes KJ, Gibson KE, Lansing BJ, et al. Association of exposure to high-risk antibiotics in acute care hospitals with multidrug-resistant organism burden in nursing homes. JAMA Netw Open 2022;5:e2144959-e. 10.1001/jamanetworkopen.2021.44959. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sulis G, Sayood S, Katukoori S, et al. Exposure to World Health Organization's AWaRe antibiotics and isolation of multidrug resistant bacteria: a systematic review and meta-analysis. Clin Microbiol Infect. 2022;28:1193–202. 10.1016/j.cmi.2022.03.014. PMID: [DOI] [PubMed] [Google Scholar]
- 23.Patangia DV, Anthony Ryan C, Dempsey E, et al. Impact of antibiotics on the human microbiome and consequences for host health. MicrobiologyOpen 2022;11:e1260. 10.1002/mbo3.1260. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Miller AC, Arakkal AT, Sewell DK, et al. Comparison of different antibiotics and the risk for community-associated Clostridioides difficile infection: a case-control study. Open Forum Infect Dis. 2023;10:ofad413. 10.1093/ofid/ofad413. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Rhee C, Chen T, Kadri SS, et al. Trends in empiric broad-spectrum antibiotic use for suspected community-onset sepsis in US hospitals. JAMA Netw Open 2024;7:e2418923. 10.1001/jamanetworkopen.2024.18923. PMID: [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.