Third generation cephalosporins and piperacillin/tazobactam have distinct impacts on the microbiota of critically ill patients

www.nature.com/scientificreports OPEN Third generation cephalosporins and piperacillin/tazobactam have distinct impacts on the microbiota of critically ill patients Hasinika K. A. H. Gamage1,9, Carola Venturini2,9, Sasha G. Tetu1, Masrura Kabir2,8, Vineet Nayyar3, Andrew N. Ginn2,4, Belinda Roychoudhry2, Lee Thomas2, Mitchell Brown4, Andrew Holmes5, Sally R. Partridge2, Ian Seppelt6,7, Ian T. Paulsen1* & Jonathan R. Iredell2* Effective implementation of antibiotic stewardship, especially in critical care, is limited by a lack of direct comparative investigations on how different antibiotics impact the microbiota and antibiotic resistance rates. We investigated the impact of two commonly used antibiotics, third-generation cephalosporins (3GC) and piperacillin/tazobactam (TZP) on the endotracheal, perineal and faecal microbiota of intensive care patients in Australia. Patients exposed to either 3GC, TZP, or no β-lactams (control group) were sampled over time and 16S rRNA amplicon sequencing was performed to examine microbiota diversity and composition. While neither treatment significantly affected diversity, numerous changes to microbiota composition were associated with each treatment. The shifts in microbiota composition associated with 3GC exposure differed from those observed with TZP, consistent with previous reports in animal models. This included a significant increase in Enterobacteriaceae and Enterococcaceae abundance in endotracheal and perineal microbiota for those administered 3GC compared to the control group. Culture-based analyses did not identify any significant changes in the prevalence of specific pathogenic or antibiotic-resistant bacteria. Exposure to clinical antibiotics has previously been linked to reduced microbiota diversity and increased antimicrobial resistance, but our results indicate that these effects may not be immediately apparent after short-term real-world exposures. The human gut microbiota plays an integral role in host metabolic functions and immunity. Intensive care has been associated with substantial changes in the intestinal microbiota of patients, including reduced microbial diversity, altered composition with a propensity for expansion of pathobionts such as Proteobacteria, and increased levels of antibiotic resistance1–3. However, the magnitude of these changes is not uniform among individuals due to large interpersonal variation in baseline microbiota c omposition4,5. Antibiotics are heavily used in intensive care units (ICUs) and timely antibiotic intervention, immediately upon presentation, saves lives6. Antimicrobial exposure, however, can have long-lasting detrimental impacts on gut microbiota health, including reduced resistance against subsequent infections7–9, with recovery from dysbiosis dependent on the type of antibiotic treatment r eceived5,10–12. There is therefore urgent need to define ways to preserve microbiota integrity in ICU patients, including the use of probiotics and selective digestive tract decontamination to reduce microbiota dysbiosis13–15. 1 Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia. 2Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia. 3Intensive Care Unit, Westmead Hospital and The University of Sydney, Sydney, NSW, Australia. 4Centre for Infectious Diseases and Microbiology Laboratory Services, NSW Health Pathology, Sydney, NSW, Australia. 5Charles Perkins Centre, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia. 6Department of Intensive Care Medicine Unit, Nepean Hospital, Sydney University Medical School (Nepean), The University of Sydney, Sydney, NSW, Australia. 7Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia. 8Present address: Westmead Breast Cancer Institute, Westmead Hospital, Sydney, NSW, Australia. 9These authors contributed equally: Hasinika K. A. H. Gamage and Carola Venturini. *email: ; Scientific Reports | (2021) 11:7252 | https://doi.org/10.1038/s41598-021-85946-4 1 Vol.:(0123456789) www.nature.com/scientificreports/ Antibiotic stewardship programs aim to reduce unnecessary and inappropriate antimicrobial use through optimal therapeutic c hoices16,17. Antibiotic regimens in critical care typically include broad-spectrum drugs targeting the main nosocomial pathogens18,19, and associated colonisation by antibiotic-resistant bacteria and perturbations of gut microbiota composition and functions are largely predictable20,21. However, different antibiotics vary in the spectrum of activity, route of administration, pharmacokinetics (distribution and elimination in the host) and pharmacodynamics (interactions between drug and pathogen)21–23. Some antibiotics may be more harmful to the microbiota than o thers20,22. Third-generation cephalosporins (e.g. ceftriaxone, cefotaxime; 3GC) and penicillin/β-lactamase inhibitor combinations (piperacillin/tazobactam; TZP) are broad-spectrum antimicrobials commonly used in critical care24. They have very similar pharmacokinetic and pharmacodynamic characteristics and spectra of activity against medically important pathogens but data from animal models12,23,25 and accumulated clinical experience suggest different ecological o utcomes3,26,27. Both antibiotic classes are associated with an increased presence of antibiotic-resistant Enterobacteriaceae, staphylococci, Clostridioides difficile and Pseudomonas aeruginosa in the microbiota28–30 but 3GC has been shown to result in poorer microbiota recovery and longer-lasting c hanges12,31 and antibiotic guidelines often recommend restricted use due to concerns linked to ‘collateral damage’ to the commensal microbiota32. Despite this, there is a lack of direct comparative data. We, therefore, examined the differential impact of 3GC and TZP on the endotracheal, perineal and faecal microbiota of ICU patients in two hospitals in Sydney, Australia. Results and discussion The impact of administrating 3GC or TZP on the endotracheal, perineal and faecal microbiota composition was examined using 16S rRNA amplicon sequencing. A total of 222 samples were collected over time (from 24 h to 11 days after ICU admission) from patients receiving either 3GC, TZP or no β-lactams (control group), details on the number of samples collected per treatment group and patient are provided in Supplementary Table S1. All patients in the 3GC and TZP groups received the respective antibiotics within the first 48 h of ICU admission. None of the patients enrolled in the study had exposure to antibiotics in the two weeks before ICU admission. Each body site had a unique initial microbial composition. Samples collected within 48 h of antibiotic administration (for 3GC and TZP groups) or ICU admission (for control group) were considered representative of the initial microbiota of each patient. This classification was based on prev (...truncated)