The elusive concept of appropriate antibiotic for septic patients when a pathogen is not detected by standard culture methods

Dear Editor,

In a recent study [1], Chang et al. highlighted a critical challenge in the management of sepsis: the lack of etiological data in culture-negative cases, complicating the concept of therapeutic appropriateness. Their large multicentre cohort study demonstrated that, while empirical antibiotic therapy was deemed more “appropriate” in culture-negative cases (based on adherence to guidelines) than in culture-positive ones (based on susceptibility profile of causative organisms), patients in the former group faced worse mortality outcomes.

We propose reframing the understanding of “appropriateness” in antibiotic therapy to address the unique challenges of culture-negative sepsis.

Several points should be considered when interpreting these apparently contradictory findings, which question the adequacy of the defining “appropriate treatment” relying on empirical benchmarks derived from culture-positive cases to guide decisions for culture-negative patients. Moreover, the inclusion/exclusion criteria of the study imply a not negligible risk of misclassification bias, particularly differential misclassification, where the probability of being misclassified differs between groups [2].

Addressing this requires careful evaluation of diagnostic protocols to minimize bias and to ensure accurate stratification of sepsis cases.

First, the study focused on bacterial sepsis identified via standard culture methods, and not by other techniques, also excluding newer options such as molecular testing. This approach appears outdated given the current availability of “fast microbiology” tools designed to reduce the time to effective therapy in septic patients [3], as well as to lower the rates of so-called “culture negative sepsis”. Furthermore, the authors do not report whether blood culture volumes were sufficient, a critical factor as under-inoculated bottles correlate with lower diagnostic yields and higher rates of negative blood cultures [4]. Without this information, comparison between study groups is less reliable. At any rate, molecular diagnostics, including metagenomic sequencing, represent promising advancements for identifying pathogens in culture-negative cases, also overcoming limitations of standard techniques, such as the issue of blood inoculum.

Certain bacterial pathogens inherently elude identification via traditional culture-based methods: a textbook example is Legionella pneumophila, which causes community-acquired pneumonia (CAP) or systemic disease often fulfilling criteria for sepsis [5]. Diagnosis typically relies on urinary antigen detection or polymerase chain reaction (PCR) in respiratory specimens [5]. Following the inclusion/exclusion criteria of Chang et al., a case of severe Legionnaires’ disease wherein extrapulmonary manifestations predominate could be considered in the category of “appropriate treatment” if an empirical guideline-directed medical therapy for suspected central nervous system infection is initiated in cases of fever, confusion, and disorientation, thereby implying a regimen with vancomycin plus ceftriaxone or cefotaxime and possibly ampicillin [6].

This underscores the need to incorporate molecular and rapid diagnostics into sepsis management. Additionally, in the antibiotic stewardship era, narrower-spectrum therapies targeting isolated pathogens should be prioritized. The study would have benefited from describing the spectrum of antibiotic therapies used in the two groups.

Second, the authors acknowledge the limited generalizability of their findings beyond bacterial sepsis. However, this does not rule out the possibility that a fraction of culture-negative cases had non-bacterial infectious etiology: viruses, fungi, parasites [7,8,9]. Current definitions of sepsis or septic shock according to the Sepsis-3 consensus are not pathogen-sensitive [10]. This limitation underscores the necessity of pathogen-agnostic diagnostic strategies to ensure that non-bacterial etiologies are accurately identified and treated. Considering viral sepsis, likely the most common non-bacterial scenario, the risks of empirical antibiotic overuse have been debated for years [11]. The prime example is represented by CAP: guidelines recommend a beta-lactam plus a macrolide for severe cases, with added coverage for Pseudomonas or methicillin-resistant Staphylococcus aureus if needed [12]. Therefore, while the association between a third-generation cephalosporin plus azithromycin is guideline-concordant, it would retrospectively appear inappropriate if a viral pathogen were identified via multiplex PCR. Such scenarios likely occurred in the study, raising concerns about definition of appropriateness and antibiotic overuse.

Third, another potentially underestimated risk is the genuine absence of an infectious process in a subset of “culture-negative” cases, that might have explained by immune-mediated inflammatory conditions mimicking sepsis. The authors acknowledge that insufficient testing or technical issues may have affected culture results in their study. There are plausible explanations for many cases without microbiological yield: perhaps the most common is prior antibiotic exposure, representing the primary cause of blood culture-negative endocarditis (BCNE), arguably the most recognized “culture-negative” entity in the infectious disease field [13]. Nevertheless, BCNE is rooted in objective findings like vegetations on cardiac valves, and newer microbiological methods (e.g., targeted or shotgun metagenomic sequencing) as well as histopathology can distinguish between an infectious process and a non-infectious entity, such as non-bacterial thrombotic endocarditis [13]. In sharp contrast, the definition of sepsis, even after the 2016 consensus, remains controversial and somewhat subjective, as it implies that infection must be suspected in any patient with unexplained dysfunction of any organ [10]. Unfortunately, there is neither a universal biomarker allowing diagnosis of ongoing infection (whichever the cause) nor a pathobiological hallmark to distinguish sepsis from infection; therefore, even when an infection of any type is ascertained, to date there is no means to correlate beyond reasonable doubt the infectious process to ongoing organ dysfunction in a causal pathway, in contrast to myocardial infarction wherein specific findings such as ST-elevations can be relied upon [14]. Indeed, the current definition of sepsis is based on a prognostic tool, the SOFA score, which has been converted into a quasi-diagnostic one [15]. Until the discovery of the “holy grail,” namely biomarkers allowing rapid diagnosis of infection and sepsis, every study on the topic will be affected by the risk of including cases not actually linked with an infection. In a study heavily relying on traditional culture methods, the burden of cases mistakenly identified as sepsis risks being substantial, especially in the group of “culture-negative” patients, thus further compromising the association between “appropriate treatment” and clinical outcomes.

In conclusion, “culture-negative” sepsis should be interpreted literally, to describe cases in which standard culture techniques yield no results, not as a synonym for sepsis without a causative agent. Expedited identification of pathogens using all available methods, including molecular diagnostics, is essential. These tools are integral to modern microbiology, although their results should always be interpreted judiciously to avoid overdiagnosis. Indeed, with regard to appropriateness of therapy, discrepancies between genotype and phenotype are not uncommon and should be considered when deciding an empirical treatment based on detection of some resistance genes, for instance [16]. In Fig. 1 we summarize challenges and solutions of “culture-negative” sepsis management.

Fig. 1

Challenges and solutions in culture-negative sepsis management

Full size image

We advocate integrating advanced diagnostics into clinical practice to enhance the precision of sepsis management and reduce the reliance on empirical guidelines that may not adequately address culture-negative cases.

Finally, defining antibiotic therapy as “appropriate” solely based on adherence to guidelines risks overlooking mismatches between empirical antibiotic therapies and actual etiologies, contributing to antibiotic misuse and its consequences.

No datasets were generated or analysed to deliver the present commentary.

1. Chang Y, Oh JH, Oh DK, Lee SY, Hyun DG, Park MH, Lim CM, Korean Sepsis Alliance (KSA) investigators. Culture-negative sepsis may be a different entity from culture-positive sepsis: a prospective nationwide multicenter cohort study. Crit Care. 2024;28(1):385.

   Article PubMed PubMed Central Google Scholar

2. Pham A, Cummings M, Lindeman C, Drummond N, Williamson T. Recognizing misclassification bias in research and medical practice. Fam Pract. 2019;36(6):804–7.

   Article PubMed Google Scholar

3. Liborio MP, Harris PNA, Ravi C, Irwin AD. Getting up to speed: rapid pathogen and antimicrobial resistance diagnostics in sepsis. Microorganisms. 2024;12(9):1824.

   Article PubMed PubMed Central Google Scholar

4. Michael Miller J, Binnicker MJ, Campbell S, Carroll KC, Chapin KC, Gonzalez MD, Harrington A, Jerris RC, Kehl SC, Leal SM, Patel R, Pritt BS, Richter SS, Robinson-Dunn B, Snyder JW, Telford S, Theel ES, Thomson RB, Weinstein MP, Yao JD. Guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2024 update by the infectious diseases society of America (IDSA) and the American Society for microbiology (ASM). Clinic Infect Diseases. 2024. https://doi.org/10.1093/cid/ciae104.

   Article Google Scholar

5. Rello J, Allam C, Ruiz-Spinelli A, Jarraud S. Severe Legionnaires’ disease. Ann Intensive Care. 2024. https://doi.org/10.1186/s13613-024-01252-y.

   Article PubMed PubMed Central Google Scholar

6. The Korean Society of Infectious Diseases. Clinical practice guidelines for the management of bacterial Meningitis in Adults in Korea. Infect Chemother. 2012;44(3):140–63.

   Article Google Scholar

7. Hartlage W, Imlay H, Spivak ES. The role of empiric atypical antibiotic coverage in non-severe community-acquired pneumonia. Antimicrob Steward Healthc Epidemiol. 2024;4(1): e214.

   Article PubMed Central Google Scholar

8. Lochkart SR. Current Epidemiology of Candida Infection. Clinical Microb News. 2014;36(17):131–6.

   Article Google Scholar

9. White NJ. Severe Malaria. Malar J. 2022;21(1):284.

   Article PubMed PubMed Central Google Scholar

10. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.

    Article PubMed PubMed Central Google Scholar

11. Lin GL, McGinley JP, Drysdale SB, Pollard AJ. Epidemiology and immune pathogenesis of viral sepsis. Front Immunol. 2018;9:2147.

    Article PubMed PubMed Central Google Scholar

12. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR, Metersky ML, Musher DM, Restrepo MI, Whitney CG. Diagnosis and treatment of adults with community-acquired Pneumonia. an official clinical practice guideline of the american thoracic society and infectious diseases society of America. American J Respiratory Critical Care Med. 2019;200(7):e45-67. https://doi.org/10.1164/rccm.201908-1581ST.

    Article Google Scholar

13. McHugh J, Saleh OA. Updates in Culture-Negative Endocarditis Pathogens. 2023;12(8):1027.

    PubMed Google Scholar

14. IDSA Sepsis Task Force. Infectious diseases Society of America (IDSA) position statement: Why IDSA did not endorse the surviving sepsis campaign guideline. Clin Infect Dis. 2018;66(10):1631–5.

    Article Google Scholar

15. Sprung CL, Trahtemberg U. What definition should we use for sepsis and septic shock? Crit Care Med. 2017;45(9):1564–7.

    Article PubMed Google Scholar

16. Yee R, Dien Bard J, Simner PJ. The genotype-to-phenotype dilemma: How should laboratories approach discordant susceptibility results? J Clin Microbiol. 2021;59(6):e00138-e220.

    Article PubMed PubMed Central Google Scholar

Download references

Not applicable.

None.

Authors and Affiliations

1. Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131, Naples, Italy

   Alberto Enrico Maraolo

2. Sezione Malattie Infettive, Dipartimento Salute e Bioetica, Università Cattolica del Sacro Cuore, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

   Rita Murri & Massimo Fantoni

3. Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

   Danilo Buonsenso

4. Area Pediatrica, Dipartimento di Scienze della Vita e di Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy

   Danilo Buonsenso

5. Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

   Maurizio Sanguinetti

Authors

1. Alberto Enrico MaraoloView author publications

   You can also search for this author in PubMed Google Scholar

2. Rita MurriView author publications

   You can also search for this author in PubMed Google Scholar

3. Danilo BuonsensoView author publications

   You can also search for this author in PubMed Google Scholar

4. Massimo FantoniView author publications

   You can also search for this author in PubMed Google Scholar

5. Maurizio SanguinettiView author publications

   You can also search for this author in PubMed Google Scholar

Contributions

A.E.M. worked on the concept of the article and drafted the initial version of the manuscript. R..M., D.B., M.F. and M.S. proofread and critically revised the manuscript.

Corresponding author

Correspondence to Alberto Enrico Maraolo.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors do not report any competing interest.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

Cite this article

Maraolo, A.E., Murri, R., Buonsenso, D. et al. The elusive concept of appropriate antibiotic for septic patients when a pathogen is not detected by standard culture methods. Crit Care 29, 7 (2025). https://doi.org/10.1186/s13054-024-05240-3

Download citation

• Received: 21 December 2024

• Accepted: 28 December 2024

• Published: 06 January 2025

• DOI: https://doi.org/10.1186/s13054-024-05240-3

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Sorry, a shareable link is not currently available for this article.

Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative