REVIEW

CURRENT
OPINION Culture-negative sepsis
Jonathan Thorndike and Marin H. Kollef

Purpose of review
The traditional approach to sepsis treatment utilizes broad-spectrum antibiotics. Unfortunately, a significant
proportion of infected patients have ‘culture-negative’ sepsis despite appropriate microbiologic assessment.
Recent findings
There has been increased interest in the past decade on the treatment of culture-negative sepsis. Outcome
data comparing culture-negative sepsis with culture-positive sepsis are mixed and it is unclear if culture-
negative sepsis is a distinct entity. Recent recommendations promoting antibiotic de-escalation in culture-
negative sepsis can be difficult to implement. A variety of strategies have been suggested for limiting
antibiotic courses among patients with negative cultures, including limiting antibiotic durations, use of
antibiotic stewardship programs, early consideration of narrow antibiotics, rapid diagnostic technology,
and eliminating anti-MRSA therapy based on surveillance swabs.
Summary
Owing to the difficulty inherent in studying the lack of positive data, and to the uncertainty surrounding
diagnosis in patients with culture-negative sepsis, prospective data to guide antibiotic choices are lacking.
However, antibiotic de-escalation in culture-negative sepsis is both recommended and feasible in patients
showing clinical signs of improvement. Increased use of rapid diagnostics, careful consideration of antibiotic
necessity, and antibiotic stewardship programs may result in less antibiotic days and better outcomes.
Keywords
antibiotic de-escalation, antibiotic stewardship, culture negative, sepsis

INTRODUCTION patients with sepsis remain ‘culture-negative’

Sepsis is a dysregulated bodily response to infection
and is associated with high mortality rates ranging
from 15 to 60%. It is diagnosed clinically by the
presence of the systemic immune response syndrome
(SIRS) and the suspicion of an infection. Sepsis
accounts for over 750 000 emergency department
visits yearly, and is present in 6% of hospitalized
patients [1 ,2 ]. Guidelines and protocols for sepsis
& &
treatment have been published and modified over
the past two decades. These guidelines widely recom-
mend empiric use of broad-spectrum antibiotics, and
include the administration of empiric antibiotics
prior to obtaining cultures, misdiagnosis of a non-
infectious process, such as alcohol withdrawal or
serotonin syndrome, and infection with bacteria or
viruses that are not readily cultured and have no
rapid diagnostic tests. The FABLED trial examined
blood culture sensitivity before and after antibiotics
in an emergency department population and found
that cultures obtained between 30 and 240 min after
antibiotics were administered resulted in an approx-
imately 50% decrease in blood culture sensitivity
[7 ]. Although many of these patients are labeled
&&

several trials have demonstrated that time to effective

antibiotic therapy reduces patient mortality [3 ].
&&
with culture-negative sepsis and have a similar phe-
After the initial decision to use antibiotics for treat- notype, there may be significant variability in the
ment of sepsis, further decisions regarding antimicro-
bial therapy are made with consideration of
Division of Pulmonary and Critical Care Medicine, Washington University
microbiologic data; however, patients with sepsis
School of Medicine, St. Louis, Missouri, USA
frequently have no positive cultures to guide therapy.
Correspondence to Marin H. Kollef, MD, Division of Pulmonary and
Critical Care Medicine, Washington University School of Medicine,
4523 Clayton Avenue, Campus Box 8052, St. Louis, MO 63110, USA.
EPIDEMIOLOGY Tel: +1 314 454 8764; fax: +1 314 454 5571;
Unfortunately, anywhere from 28 to 89% of patients e-mail: kollefm@wustl.edu.
with sepsis never have a definitive pathogen identi- Curr Opin Crit Care 2020, 26:473–477
fied by culture [4,5 ,6 ]. Explanations for why
&& &
DOI:10.1097/MCC.0000000000000751

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections
KEY POINTS
! It is unclear whether culture negative sepsis is
associated with less or more organ dysfunction,
ventilator days, in-hospital, and 90-day mortality.
! The use of appropriate cultures before antibiotics and
available rapid diagnostic technologies are essential
for informing antimicrobial de-escalation.
! Early discontinuation or narrowing of antibiotics can be
considered in patients with clinical improvement and
negative microbiologic data by 24–48 h. Clinicans
should frequently re-evauate if coverage is needed for
Gram-Positive, Gram-negative, anaerobic, fungal and/
or viral pathogens.
underlying cause and outcomes. Recently, use of the
sequential organ failure assessment (SOFA) and
‘quick’ SOFA have been proposed for rapid identifi-
cation of patients with infection who are at risk for
mortality [8]. Although both qSOFA and SIRS sys-
tems identify patients who may be infected, SIRS
suffers from lack of specificity, qSOFA has been
shown to be an inadequate screening tool for sepsis,
and there is significant discrepancy between both
systems [9]. One large retrospective study of 14 000
emergency department patients found that while
SIRS is up to 86–87% sensitive for severe sepsis and
septic shock-related mortality, it is only 34% spe-
cific. qSOFA was far more specific, at 98%, but was
only 28–33% sensitive [10 ]. Given the fact that
&
research on culture-negative sepsis is often retro-
spective, and generally defined as suspected infec-
tion based on either clinical criteria or clinician
actions, such as drawing blood cultures, many
patients in a culture-negative sepsis cohort may
not be infected at all but are part of large databases
because of the presence of SIRS or SOFA criteria.
Supposing that patients who remain culture-nega-
tive are indeed infected, culture-negative sepsis may
also represent an entirely different clinical entity
than culture-positive sepsis. Recently, there has
been increasing interest in culture-negative sepsis,
and several outcome papers have been published
with variable results.
COMPARING CULTURE-NEGATIVE AND
CULTURE-POSITIVE SEPSIS
In a retrospective study of 870 patients with health-
care-associated pneumonia, severity of illness,
length of stay and in-hospital mortality were all
lower among culture-negative patients than cul-
ture-positive patients [11]. Culture-positive patients
were more likely to receive initial antibiotics in
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accordance with national guidelines for HCAP,
and to experience de-escalation than culture-nega-
tive patients. A prospective observational study of
1001 patients with severe sepsis published in 2013
noted a lower average mortality, length of stay, and
less multiorgan failure among culture-negative
patients than culture-positive patients [4]. By con-
trast, a large database study of patients with severe
sepsis found that of the examined 6.8 million
patients, culture-negative cases demonstrated more
comorbidities, end-organ dysfunction, and higher
mortality [5]. Still others have found that culture-
positive and culture-negative patients have similar
outcomes with respect to ICU and hospital mortality
and degree of illness measured by APACHE II scores
[12]. Considering this comparative data en bloc, it is
unclear if culture-negative sepsis is associated with
overall worse or better survival, and differences in
outcomes could be because of patient selection.
ANTIBIOTIC DE-ESCALATION
Although recommendations strongly promote the
initial use of broad-spectrum antibiotics [13], and
data agree on the importance of appropriate initial
coverage [3], there is growing concern about the
incidental cultivation of antibiotic-resistant patho-
gens. Bacteria may develop resistance to antibiotics
through a variety of mechanisms because of envi-
ronmental pressure from antimicrobials [14]. A ret-
rospective study of 7000 patients with severe
sepsis or septic shock who received at least one dose
of cefepime, meropenem, or piperacillin-tazobac-
tam demonstrated that each day of broad-spectrum
antibiotic exposure was associated with increased
odds of resistance development [15 ]. Antibiotic
&&
use can also cause acute kidney injury, hepatitis,
cytopenia, and predispose patients to other infec-
tions like Clostridioides difficile. Given these con-
cerns, emphasis on antibiotic de-escalation (ADE)
has increased.
ADE is generally defined as stopping an antibi-
otic, changing to an antibiotic with a narrower spec-
trum of activity, or eliminating an agent that is
providing double coverage for a potential pathogen.
Research is heterogenous because of differing defini-
tions of ADE and the difficulty inherent in grading
antimicrobial therapy, but some studies have sug-
gested that there may be patient-centered outcome
improvements attributable to ADE. Multiple obser-
vational studies and a 2016 systematic review suggest
a mortality benefit for ADE, though this is likely to
represent clinical improvement or reduced severity of
illness leading to ADE, rather than ADE as the cause of
improved mortality [16]. Others have suggested that
ADE may be associated with increased total antibiotic
Volume 26 ! Number 5 ! October 2020

days, possibly because of superinfections [17],
although in general, it is recommended.
In a joint position statement and review of the
evidence, the European Societies of Intensive Care
Medicine, Clinical Microbiology and Infectious Dis-
eases recommended ADE in culture-negative
patients [18 ]. Authors note that the available evi-
&&
dence is low quality, but ADE has been employed
successfully without worse outcomes. Cowley et al.
demonstrated that discontinuation of anti-MRSA
agents could be performed in HAP patients who
had negative MRSA swabs with no change in mor-
tality or length of stay, and lack of discontinuation
was associated with increased rates of AKI [19]. In a
secondary analysis of a prospective observational
trial on VAP, Joffe et al. evaluated patients who
received ‘targeted therapy’, which was defined as
discontinuation of antibiotics in culture-negative
patients, unless providers had a high pretest proba-
bility for VAP, in which case, antibiotics could be
continued. Patients in the targeted therapy group
had lower pretest probabilities for VAP than patients
in the group that did not receive targeted therapy.
Patients who received targeted therapy had more
antibiotic discontinuation compared with patients
who were continued on antibiotics, had less venti-
lated days, lower multiorgan dysfunction scores,
FIGURE 1. Antibiotic de-escalation algorithm.
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Culture-negative sepsis Thorndike and Kollef
and similar mortality rates. Authors noted that as
patients who received targeted therapy had lower
pretest probabilities of VAP than patients without
targeted therapy, clinicians likely determined,
which patients could safely have antibiotics discon-
tinued, despite negative cultures [20]. Rello et al.
performed a prospective trial on a guideline-based
protocol for ADE. In the portion of the cohort that
remained culture-negative despite an aggressive pro-
tocol for obtaining appropriate cultures, patients
who remained culture-negative did not experience
de-escalation, which likely reflects the difficulty
inherent in ADE without positive data [21]. In one
of the only randomized controlled trials on ADE in
patients receiving empiric antibiotics for severe sep-
sis, there was no mortality difference between those
who had ADE and those who did not [17]. Although
it appears that ADE is well tolerated in patients who
are culture-negative, the question of how remains. A
number of strategies have been described in the
literature and are summarized with additional sug-
gestions in Fig. 1.
In patients with negative MRSA swabs of the
nares, it appears safe to discontinue anti-MRSA ther-
apy in patients with clinical pneumonia, as has been
discussed [19,22]. Among patients with VAP, limit-
ing duration of therapy to 8 days, instead of 15,
www.co-criticalcare.com 475
Severe infections
could result in less total antibiotic days without
increased mortality or length of stay [23]. Patients
with VAP who have had a bronchoalveolar lavage
performed may be able to de-escalate even earlier
than the recommended 7 days if the BAL shows no
growth [24], though Gram stain alone is likely not
sensitive enough to justify early de-escalation.
Patients with complicated intraabdominal infec-
tions who have adequate source control can likely
receive 4-day courses of antibiotics rather than con-
tinuing antibiotics until 48 h of no fever (up to 10
days), according to the STOP-IT trial [25]. If cultures
remain negative at 24–48 h, the odds of cultures
becoming positive range from 1.8 –0.2%, so it may
be possible to discontinue antibiotics after 1–2 days
of empiric treatment [26 ,27].
&
NEW STRATEGIES FOR ANTIBIOTIC DE-
ESCALATION IN CULTURE-NEGATIVE
SEPSIS
Looking away from infection-specific recommenda-
tions to broader methods of de-escalation, there has
been increased interest in Antibiotic stewardship
programs (ASP) as a way to potentially promote
ADE in both culture-positive and culture-negative
patients. Antibiotic stewardship programs have been
shown to reduce antibiotic exposure and antibiotic
days, as well as cost, and use of ASPs in some form is
likely beneficial [28,29]. However, others have found
less encouraging results. Trupka et al. performed a
prospective cross-over trial in two medical ICUs com-
paring standard of care to ‘enhanced antimicrobial
de-escalation’ (EAD), which consisted of a second
team of an ICU fellow, attending and pharmacist
who reviewed antimicrobials for possible ADE in
patients with community onset, hospital-acquired,
or ventilator-associated pneumonia. Patients with
immunosuppression, bronchiectasis or a second
infection were excluded. 35.3% of the study popula-
tion was classified as culture-negative. Authors found
no difference between the two groups in rates of ADE,
total antibiotic days, or ventilator days [30].
Lastly, improving technology in the form of
rapid diagnostic technology (RDT) may limit future
antibiotic use in culture-negative sepsis. The tradi-
tional gold standard for identification of pathogens
– blood cultures – can take days to isolate a bacte-
rium, whereas nucleic acid amplification (NAAT)
and other RDTs can identify viruses, bacteria, and
fungi within hours. A systematic review and meta-
analysis regarding commercially available rapid
diagnostics found that the use of RDT had a mortal-
ity benefit in culture-positive sepsis, with a number
needed to treat of 20 [31]. However, given the
increased sensitivity of RDT, it is unclear how many
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of the patients in this review would have remained
culture-negative by conventional testing. Although
several commercially available panels use semiquan-
titative results to limit false positives, these tests are
imperfect, and specificity has been limited in prior
studies. Some have suggested that falsely positive
NAAT testing could represent even prior controlled
infection, leading to freely circulating nonpatho-
genic DNA. Some RDTs have the added advantage
of being able to distinguish between immune system
triggered responses and nonimmune reactions by the
utilization of specific RNA biomarkers known to be
involved in the innate immune response [32]. RDTs
have the added advantage of being able to detect
fungi, which can take weeks with traditional cultures,
and viruses. Lastly, it is worth noting that many RDTs
approved for use in the United States are ‘postcul-
ture’, meaning that blood must first be cultured
before the test can be used, which limits the utility
of these tests by slowing results. This is a rapidly
evolving sphere in the field of infectious disease.
CONCLUSION
Culture-negative sepsis may represent an entirely dif-
ferent phenotype of infection, recognizing that many
patients with no positive microbiologic data may not
be infected. Broad spectrum antibiotic use is recom-
mended in sepsis and septic shock but ADE should be
encouraged whenever possible. Suggestions for ADE in
patients with culture-negative sepsis are summarized
in Fig. 1. The use of appropriate cultures prior to
antibiotics, respiratory cultures where appropriate,
MRSA swabs, ASPs, and rapid diagnostic testing can
help reduce antibiotic courses and to more rapidly
choose appropriate antimicrobials.
Acknowledgements
None.
Financial support and sponsorship
M.H.K.’s efforts are supported by the Barnes-Jewish
Hospital Foundation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Rhee C, Dantes R, Epstein L, et al. Incidence and trends of sepsis in US
& hospitals using clinical vs claims data. JAMA 2017; 318:1241–1249.
An epidemiologic study shedding light on the prevalence of sepsis in the United
States.
Volume 26 ! Number 5 ! October 2020

2. Wang HE, Jones AR, Donnelly JP. Revised national estimates of emergency
& department visits for sepsis in the United States. Crit Care Med 2017;
45:1443–1449.
An analysis focusing on the impact of sepsis in the pre-Covid 19 era on emergency
department utilization and burden.
3. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality
&& during mandated emergency care for sepsis. N Engl J Med 2017;
376:2235–2244.
A key study highlighting the impact of empiric antimicrobial timing on clinical
outcomes.
4. Phua J, Ngerng W, See K, et al. Characteristics and outcomes of culture-
negative versus culture-positive severe sepsis. Crit Care 2013; 17:R202.
5. Gupta S, Sakhuja A, Kumar G, et al. Culture-negative severe sepsis: nation-
&& wide trends and outcomes. Chest 2016; 150:1251–1259.
One of the largest studies published on CN outcomes with over 6.8 million
included patients. CN patients more likely to have end-organ dysfunction, and
in-hospital mortality.
6. Sigakis MJG, Jewell E, Maile MD, et al. Culture-negative and culture-positive
& sepsis: a comparison of characteristics and outcomes. Anesth Analg 2019;
129:1300–1309.
Recent retrospective comparison of culture-positive and culture-negative sepsis.
Liberal inclusion criteria of any patient with blood cultures led to high proportion of
culture-negative (89%). Similar outcomes between both groups.
7. 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; 171:547–554.
In an emergency department population, microbiologic cultures obtained between
30 and 240 min after antibiotics administered resulted in an approximately 50%
decrease in blood culture sensitivity.
8. Singer M, Deutschman CS, Seymour CW, et al. The Third International
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA
2016; 315:801–810.
9. Luo J, Jiang W, Weng L, et al. Usefulness of qSOFA and SIRS scores for
detection of incipient sepsis in general ward patients: a prospective cohort
study. J Crit Care 2019; 51:13–18.
10. Usman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS
& for the early identification of sepsis in the emergency department. Am J Emerg
Med 2019; 37:1490–1497.
A clinical study highlighting the limitations of current definitions for the identifica-
tion of patients with sepsis.
11. Labelle AJ, Arnold H, Reichley RM, et al. A comparison of culture-positive and
culture-negative health-care-associated pneumonia. Chest 2010;
137:1130–1137.
12. Kethireddy S, Bilgili B, Sees A, et al., Cooperative Antimicrobial Therapy of
Septic Shock (CATSS) Database Research Group. Culture-negative septic
shock compared with culture-positive septic shock: a retrospective cohort
study. Crit Care Med 2018; 46:506–512.
13. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: inter-
national guidelines for management of sepsis and septic shock:. Crit Care
Med 2017; 45:486–552.
14. Bell BG, Schellevis F, Stobberingh E, et al. A systematic review and meta-
analysis of the effects of antibiotic consumption on antibiotic resistance. BMC
Infect Dis 2014; 14:13.
15. Teshome BF, Vouri SM, Hampton N, et al. Duration of exposure to antipseu-
&& domonal b-lactam antibiotics in the critically ill and development of new
resistance. Pharmacotherapy 2019; 39:261–270.
An important retrospective study demonstrating that each day of inpatient parenteral
antibiotic administration is associated with an increase in the likelihood of subse-
quent emergence of infection or colonization with antibiotic resistant pathogens.
1070-5295 Copyright ! 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Culture-negative sepsis Thorndike and Kollef
16. Tabah A, Cotta MO, et al. A systematic review of the definitions, determinants,
and clinical outcomes of antimicrobial de-escalation in the intensive care unit.
Clin Infect Dis 2016; 62:1009–1017.
17. Leone M, Bechis C, Baumstarck K, et al. De-escalation versus continuation of
empirical antimicrobial treatment in severe sepsis: a multicenter nonblinded
randomized noninferiority trial. Intensive Care Med 2014; 40:1399–1408.
18. Tabah A, Bassetti M, Kollef MH, et al. Antimicrobial de-escalation in critically ill
&& patients: a position statement from a task force of the European Society of
Intensive Care Medicine (ESICM) and European Society of Clinical Micro-
biology and Infectious Diseases (ESCMID) Critically Ill Patients Study Group
(ESGCIP). Intensive Care Med 2020; 46:245–265.
A position paper with a review of the literature on the topic of antimicrobial de-
escalation in critically ill patients that summarizes the existing literature and open
questions.
19. Cowley MC, Ritchie DJ, Hampton N, et al. Outcomes associated with de-
escalating therapy for methicillin-resistant Staphylococcus aureus in culture-
negative nosocomial pneumonia. Chest 2019; 155:53–59.
20. Joffe AR, Muscedere J, Marshall JC, et al., Canadian Critical Care Trials
Group. The safety of targeted antibiotic therapy for ventilator-associated
pneumonia: a multicenter observational study. J Crit Care 2008; 23:82–90.
21. Rello J, Vidaur L, Sandiumenge A, et al. De-escalation therapy in ventilator-
associated pneumonia. Crit Care Med 2004; 32:2183–2190.
22. Boyce JM, Pop OF, Abreu-Lanfranco O, et al. A trial of discontinuation of
empiric vancomycin therapy in patients with suspected methicillin-resistant
Staphylococcus aureus healthcare-associated pneumonia. Antimicrob
Agents Chemother 2013; 57:1163–1168.
23. Chastre J, Wolff M, Fagon JY, et al., PneumA Trial Group. Comparison of 8 vs
15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a
randomized trial. JAMA 2003; 290:2588–2598.
24. Kollef MH, Kollef KE. Antibiotic utilization and outcomes for patients with
clinically suspected ventilator-associated pneumonia and negative quantita-
tive BAL culture results. Chest 2005; 128:2706–2713.
25. Sawyer RG, Claridge JA, Nathens AB, et al., STOP-IT Trial Investigators. Trial
of short-course antimicrobial therapy for intraabdominal infection. N Engl J
Med 2015; 372:1996–2005.
26. Lambregts MMC, Bernards AT, van der Beek MT, et al. Time to positivity of
& blood cultures supports early re-evaluation of empiric broad-spectrum anti-
microbial therapy. PLoS One 2019; 14:e0208819.
Presence of negative blood cultures can be used to support early antimicrobial de-
escalation.
27. Pardo J, Klinker KP, Borgert SJ, et al. Time to positivity of blood cultures
supports antibiotic de-escalation at 48 h. Ann Pharmacother 2014;
48:33–40.
28. Davey P, Brown E, Fenelon L, et al. Interventions to improve antibiotic
prescribing practices for hospital inpatients. Cochrane Database Syst Rev
2005; 4:CD003543.
29. Karanika S, Paudel S, Grigoras C, et al. Systematic review and meta-analysis
of clinical and economic outcomes from the implementation of hospital-based
antimicrobial stewardship programs. Antimicrob Agents Chemother 2016;
60:4840–4852.
30. Trupka T, Fisher K, Micek ST, et al. Enhanced antimicrobial de-escalation for
pneumonia in mechanically ventilated patients: a cross-over study. Crit Care
2017; 21:180.
31. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid
diagnostic testing on clinical outcomes in bloodstream infections: a systema-
tic review and meta-analysis. Clin Infect Dis 2017; 64:15–23.
32. Sinha M, Jupe J, Mack H, et al. Emerging technologies for molecular diagnosis
of sepsis. Clin Microbiol Rev 2018; 31:. doi: 10.1128/cmr.00089-17.
www.co-criticalcare.com 477