Why Avoiding Anaerobic Coverage in Sepsis Faces Limitations: a Critical Review

“Do not kill the anaerobes” was one of sacrosanct rules of my former supervisor, the legendary Professor Alexander Wilmer. This meant that, when no anaerobic cause of infection was suspected, antibiotics without anaerobic coverage were preferentially selected. With the latest edition of the Surviving Sepsis Campaign Guidelines introducing a similar recommendation for sepsis and septic shock (conditional recommendation, very low certainty of evidence) (1), there is an ideal opportunity to explore this further according to the following questions:

1. What are the main arguments for this recommendation?

2. What are the practical limitations of this recommendation?

1. What are the main arguments for this recommendation?

Lets start by looking at the arguments given by the Surviving Sepsis Campaign itself:

a. Sepsis and septic shock due to anaerobic bacteria are rare (Partially True).

Most observational studies indicate that anaerobes are present in 1-5% of all infections (2-4), often as part of multitude of microorganisms (3). In critically ill patients, a large 2017 study observed a 3.5% prevalence of anaerobes across all infections (2). However, these figures may underrate the true prevalence. In a survey of 44 European reference centers, 93% of microbiologists believed that the literature underestimates the importance of anaerobic bacteria (5). Additionally, 61% acknowledged that, due to technical reasons, their laboratories underreported anaerobes in blood cultures (5). Moreover, some centers may have a higher contribution of anaerobes in sepsis. For example, historically, the Mayo clinic observed that 21% of bacteremias were caused by anaerobes in the 1970s (3).

b. Certain infections are unlikely to benefit from anaerobic coverage (Mostly True).

Specifically, the Surviving Sepsis Campaign Guidelines recommend against anaerobic coverage for respiratory and urinary tract infections (1):

Respiratory infections:

The Surviving Sepsis Campaign Guidelines state that their recommendation aligns with the 2019 Community-acquired Pneumonia (CAP) guidelines from the ATS/IDSA (6). However, the latter only discourage additional anaerobic coverage for aspiration pneumonia, except in specific circumstances (6). Some observational studies and one randomized controlled trial indicate that extended anaerobic coverage in aspiration pneumonia is not associated with improved survival and may be harmful (7). In contrast, recommended first-line antibiotics for CAP, such as ceftriaxone or levofloxacin, still provide limited anaerobic coverage (6,7). As previously noted, traditional detection methods may underestimate the contribution of anaerobes. For instance, using 16S ribosomal RNA sequencing, one study found that anaerobes were at least partially responsible for 15.6% of CAP cases (9)

Urinary tract infections:

Anaerobic urinary tract infections are rare although, surprisingly, in one center 17.1% of all anaerobic bacteremia originated from an urinary source (8).

c. Empiric anaerobic coverage in sepsis has no proven benefit and may actually be harmful (Insufficient Evidence).

The Surviving Sepsis Campaign Guidelines cite four studies, all of which have significant shortcomings:

I. Petersen et al. (10)

This systematic review of nine trials concluded that adding metronidazole offered no additional benefit in severe bacterial infections. However, all trials dated from 1980s and primarily included patients undergoing appendectomy. Metronidazole or tinidazole was often administered as a single dose, and no participants were critically ill. Moreover, the reviewed studies posed a high estimated risk of bias.

II. Chanderraj et al. (2023) (11)

This single-center cohort study included 3032 critically ill patients on mechanical ventilation to assess whether early anti-anaerobic coverage was associated with improved survival and fewer infections. Although a multivariable regression model revealed a significant association between anti-anaerobic antibiotics and the combined risk of ventilator-associated pneumonia and 30-day mortality (risk ratio:1.23; 95% confidence interval: 1.02-1.49), residual confounding factors likely persisted. For example, nearly half of the patients without anaerobic coverage, also did not receive meaningful gram-negative coverage. At best, this observational study could be hypothesis-generating.

III. Kullberg et al. (2023) (12)

This study, similar in design to the previous one, included 15908 emergency department patients. A multivariable model also demonstrated an association between anaerobic coverage and mortality. However, as the authors themselves noted, this association was highly vulnerable to indication bias and unmeasured confounding.

IV. Chanderraj et al. (2024) (13)

The starting point for this study is unique: it leveraged a nationwide shortage of piperacillin-tazobactam in the US to conduct an instrumental variable analysis comparing cefepim and piperacillin-tazobactam, in an attempt to mimic a randomized controlled trial. The study observed a 5% increase in 90-day mortality in the piperacillin-tazobactam group and concluded that ‘widespread use of empirical anti-anaerobic antibiotics in sepsis may be harmful’.

However, this study also has faced its share of criticism:

- First, although the shortage led to a 93% change in antibiotic prescribing, mortality did not differ substantially (14).

- Moreover, some authors argue that adjusting for metronidazole and other antibiotics with anaerobic coverage violates key assumptions of the instrumental variable analysis, introducing collider bias (14). They compare this to adjusting post-randomization adjustment in a randomized controlled trial. A reanalysis without adjustments demonstrated no significant mortality difference between cefepim and piperacillin-tazobactam. However, Chanderraj et al. counter that correcting for metronidazole and other anti-anaerobic antibiotics was part of the study’s secondary analysis and thus not prone to collider bias (15).

- Additionally, grouping all anti-anaerobic antibiotics into a single category overlooks potential differences in mortality effect among regimens(14).

- Finally, substantial confounding likely persists, potentially exaggerating the detrimental effect of anti-anaerobic coverage in this study (16).

My view:

Based on the evidence cited in the Surviving Sepsis Campaign Guidelines, I don’t feel you can strongly defend the aforementioned recommendation. However, there is strong indirect evidence - not quoted by the Surviving Sepsis Campaign Guidelines - suggesting that avoiding unnecessary anti-anaerobic coverage may be effective.

d. Selective digestive tract decontamination supports avoiding unnecessary anaerobic coverage

Selective digestive tract decontamination uses topical and systemic antibiotics to minimize pathogenic gram-negative colonization. It works, at least in part, by preserving the anaerobic gut flora (17). The most recent meta-analysis, which included 32 randomized controlled trials and over 27000 participants, concluded that selective digestive decontamination lowers hospital mortality with a 99.2% probability compared to standard care (18).

2. What are the practical limitations to this recommendation?

In addition to the limited evidence supporting the avoidance of anti-anaerobic coverage, several practical limitations exist to apply this recommendation in the clinical practice. The following is a non-exhaustive list:

A) Risk factors for extended-spectrum beta-lactamase (ESBL)-producing organisms

Since the MERINO trial (19), both IDSA and ESCMID recommend carbapenems for sepsis with risk factors for ESBL-producing organisms (20,21), resulting in broad anaerobic coverage.

For critical discussion of the MERINO-trial, see here

B) Low-resistance regions

As most aforementioned studies were conducted in regions with a high prevalence of MRSA, vancomycin was part of the empirical regimen (11,13). However, in regions with low prevalence for MRSA and multidrug-resistant gram-negative organisms, empirical piperacillin-tazobactam would reasonably cover the most common sepsis pathogens including E. faecalis, whereas cefepim monotherapy does not. In these cases it remains an open question whether vancomycin plus cefepim is superior to piperacillin-tazobactam.

C) Community-acquired pneumonia (CAP)

A commonly recommended regimen for CAP, in the absence of risk factors for P. aeruginosa, is amoxicillin-clavulanate or ceftriaxone combined with a macrolide (22). However, the beta-lactam in these combinations also has activity against certain anaerobes (6,7). Again, it remains unclear whether this limited anti-anaerobic coverage is harmful, particularly given that ceftriaxone is also used in many selective digestive tract decontamination protocols (18, 23).

My view:

Given the strong evidence supporting selective digestive tract decontamination, I firmly believe in the importance of preserving the intestinal anaerobes. However, this is only one of many factors in my antibiotic selection and is most often overridden by other considerations.

References:

1. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Crit Care Med. 2026 Apr 1;54(4):725-812.

 2. Vincent JL, Sakr Y, Singer M, et al. Prevalence and Outcomes of Infection Among Patients in Intensive Care Units in 2017. JAMA. 2020 Apr 21;323(15):1478-1487.

 3. De Keukeleire S, Wybo I, Naessens A, et al. Anaerobic bacteraemia: a 10-year retrospective epidemiological survey. Anaerobe. 2016 Jun;39:54-9.

 4. Di Bella S, Antonello RM, Sanson G, et al. Anaerobic bloodstream infections in Italy (ITANAEROBY): A 5-year retrospective nationwide survey. Anaerobe. 2022 Jun;75:102583.

 5. Boattini M, Bianco G, Bastos P, et al. Diagnostic and epidemiological landscape of anaerobic bacteria in Europe, 2020-2023 (ANAEuROBE). Int J Antimicrob Agents. 2025 Jun;65(6):107478.

 6. Metlay JP, Waterer GW, Long AC, et al. 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. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67.

 7. Bai AD, Srivastava S, Digby GC, et al. Anaerobic Antibiotic Coverage in Aspiration Pneumonia and the Associated Benefits and Harms: A Retrospective Cohort Study. Chest. 2024 Jul;166(1):39-48.

 8. Zouggari Y, Lelubre C, Lali SE, Cherifi S. Epidemiology and outcome of anaerobic bacteremia in a tertiary hospital. Eur J Intern Med. 2022 Nov;105:63-68.

 9. Yamasaki K, Kawanami T, Yatera K, et al. Significance of anaerobes and oral bacteria in community-acquired pneumonia. PLoS One. 2013 May 6;8(5):e63103.

 10. Petersen MW, Perner A, Jonsson AB, et al. Empirical metronidazole for patients with severe bacterial infection: A systematic review with meta-analysis and trial sequential analysis. Acta Anaesthesiol Scand. 2019 Jul;63(6):802-813.

 11. 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 Feb 9;61(2):2200910.

 12. Kullberg RFJ, Schinkel M, Wiersinga WJ. Empiric anti-anaerobic antibiotics are associated with adverse clinical outcomes in emergency department patients. Eur Respir J. 2023 May 11;61(5):2300413.

 13. Chanderraj R, Admon AJ, He Y, et al. Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime. JAMA Intern Med. 2024 Jul 1;184(7):769-777.

14. Hamilton F, Lee TC, Davey Smith G, et al. Does Piperacillin-Tazobactam Increase Mortality Risk Compared With Cefepime? Collider Bias and the Importance of Assumptions in Instrumental Variable Analyses. Clin Infect Dis. 2026 Feb 9;82(1):e17-e23.

15. Chanderraj R. Response to Hamilton et al. . 2024 [cited 29/06/2026]. Available from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2818278#article_comments

 16. Chen Z, Zhang W, Zhang C. Reconsidering causality in anti-anaerobic antibiotics, gut microbiota, and sepsis-associated acute kidney injury. Am J Respir Crit Care Med. 2026 May 12:aamag210.

 17. Davis JS, Cheng AC, 'Selective digestive tract decontamination in the intensive care unit: Life saver or recipe for disaster?', CMI Communications, 2, 105078-105078 (2025)

 18.Hammond NE, Devaux A, Vlok R, et al. Selective Decontamination of the Digestive Tract in Adult Mechanically Ventilated Patients - An Updated Systematic Review with Bayesian Meta-Analysis. NEJM Evid. 2026 May;5(5):EVIDoa2500264.

 19. 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 Sep 11;320(10):984-994.

 20. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. 2023 Jul 18:ciad428.

 21. Paul M, Carrara E, Retamar P, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. 2022 Apr;28(4):521-547.

 22. Regunath H, Oba Y. Community-Acquired Pneumonia. [Updated 2024 Jan 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430749/

 23. SuDDICU Investigators for the Australia and New Zealand Intensive Care Society Clinical Trials Group and the Canadian Critical Care Trials Group; Cuthbertson BH, Billot L, Campbell MK,  et al. Selective Decontamination of the Digestive Tract during Ventilation in the ICU. N Engl J Med. 2026 Apr 16;394(15):1491-1502.