European Journal of Cardiovascular Medicine

Whipples’ surgery, which is otherwise a standardized procedure, often has an eventful post operative course. It is associated with significant postoperative morbidity, with reported infection rates ranging from 20% to 50% depending on the centre and patient risk factors^[1]. Common infectious complications include - Surgical site infections (SSIs), Intra-abdominal abscesses, Pancreatic fistulas, Sepsis and bacteraemia. As a result prolonged hospital stays, reoperations, and increased mortality can be attributed to these infectious complications which is commonplace in most patients after pancreaticoduodenectomy^[2].

A key source of infection is biliary contamination, particularly in patients with preoperative biliary drainage. Bile colonization with multidrug-resistant organisms can lead to SSIs and intra-abdominal abscesses postoperatively. Although prophylactic empirical antibiotic usage has been the cornerstone of Whipples’ procedure since time immemorial; it is imperative that we understand the bile microbiology and its correlation with antibiotic usage. This is crucial in providing optimum prophylactic and therapeutic strategies.

The American Society of Health-System Pharmacists (ASHP) published "Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery" in collaboration with the Infectious Diseases Society of America (IDSA), Surgical Infection Society (SIS), and Society for Healthcare Epidemiology of America (SHEA) which recommends the use of first-generation or second generation cephalosporins for clean-contaminated procedures such as pancreaticoduodenectomy^[3]. However, many centres adopt broader-spectrum antibiotics based on local microbial profiles and specific patient factors.

However, a USA based study compared Piperacillin tazobactum and cefoxitin as antimicrobial prophylaxis post Whipples’ procedure and the findings support the use of Piperacillin tazobactum for perioperative antibiotic prophylaxis^[4].

Ours is a retrospective observational study for evaluating the microbiological profile of intraoperative bile cultures and assesses its influence on antibiotic initiation, escalation, and postoperative outcomes.

Study Design: This was a retrospective, single-center, observational study conducted at a tertiary cancer centre, by reviewing records of patients who underwent Whipple’s surgery between 2022 and 2024.

Inclusion Criteria:

• Adults (>18 years) undergoing Whipple’s procedure
• Documented antibiotic regimen and postoperative outcomes

Exclusion Criteria:

• Patients with incomplete data

Data Collection: Patient records were reviewed for: Demographics (age, sex), Preoperative biliary drainage ( ERCP stents), Intraoperative bile culture and sensitivity, Antibiotic regimen (empirical and escalated) and 30-day Postoperative complications, including SSI, intra abdominal collection, leak  and sepsis.

Microbiology: Bile samples were cultured for aerobic organisms. Antibiotic sensitivity was performed using standard CLSI guidelines.

Statistical Analysis: Descriptive statistics were used for demographic and clinical variables. Chi-square and Fisher’s exact test assessed categorical variables. A p-value < 0.05 was considered statistically significant.

Data of 65 patients who had undergone whipples’ surgery between 2022 – 2024 at our institute was retrieved. Among these 35 were male and 30 were female patients. The median age of these patients was 55 ± 12.7 years. 17 out of 65 patients (26.1%) had undergone pre operative biliary stenting, while 48 patients (73.8%) did not undergo any biliary stenting prior to surgery.

Intraoperative bile culture results were available for almost all patients. Among them, 41 patients (63.0%) had positive bile cultures, 16 patients (24.6%) had negative cultures (reported as “no growth”), and for 8 patients (12.3%) bile cultures had not been sent.

Bile culture and pre op stent –

There was a strong correlation between preoperative stenting and bile culture positivity. Among the 17 patients with stents, 15 patients (88.2%) had positive bile cultures, 1 patient (5.9%) had a negative culture, and 1 patient’s (5.9%) culture was not sent. In contrast, among the 48 patients without stents, only 26 patients (54.1%) had positive cultures, while 15 patients (31.2%) had negative results and 7 patients (14.5%) did not have a culture report.This difference was statistically significant (p < 0.05), indicating that biliary stenting strongly correlates with bile colonization in patients undergoing Whipples’ surgery.

Bacterial growth pattern in culture report –

Escherichia coli (E. coli) (46.3%) and Klebsiella species (34.1%) were the most commonly isolated organisms – seen in 19 patients and 14 patients respectively; out of the 41 culture-positive patients. Other organisms grown were Enterococcus species (9.8%), Pseudomonas aeruginosa(7.3%) and Citrobacter (2.4%).

These results reinforce the significant association between preoperative biliary stenting and bile contamination with enteric organisms, particularly E. coli and Klebsiella, both of which are known to be associated with postoperative infectious complications and antibiotic resistance.

Empirical antibiotic used –

Empirical antibiotics were initiated in all patients postoperatively. Cefoperazone-sulbactam was the most commonly used empirical agent, administered in 54 patients (83.1%), while piperacillin-tazobactam was used in 11 patients (16.9%).

Need for antibiotic escalation and correlation with empirical therapy –

Antibiotic escalation was required in 28 patients (43.1%), while 37 patients (56.9%) continued on their initial empirical regimen. Among patients receiving cefoperazone-sulbactam, 20 out of 54 (37.0%) required escalation.Among those started on piperacillin-tazobactam, 8 out of 11 (72.7%) required escalation. Patients were escalated to piperacillin tazobactum, meropenem or tigecycline based on culture reports.

Sensitivity rate to piperacillin tazobactum–

Among the 41 positive culture reports only 19 patients (46.3%) demonstrated sensitivity to piperacillin tazobactum.

Rate of post operative complication and correlation with bile culture report and empirical therapy –

30-day Postoperative complications, including SSI, intra abdominal collection, leak  and sepsiswere observed in 31 out of 65 patients (47.7%) following Whipple’s surgery. The remaining 34 patients (52.3%) did not develop any complications.

In our study, post operative complication occurred in 22 of 41 patients (53.7%) with positive bile cultures, compared to 9 of 24 patients (37.5%) with negative or uncollected cultures. Although the infection rate was numerically higher in patients with bile colonization, this difference was not statistically significant (p = 0.22)

When stratified by the empirical antibiotic administered, post operative complicationoccurred in 21 of 54 patients (38.9%) who received cefoperazone-sulbactam, compared to 10 of 11 patients (90.9%) who received piperacillin-tazobactam.

This difference in complication rates was statistically significant (p = 0.0024), suggesting that empirical antibiotic selection should be guided by local antimicrobial sensitivity patterns to minimize postoperative infectious complications.

Postoperative infections remain a significant challenge following Whipple’s surgery. Reported infection rates range from 20% to 50% in global literature^[1], highlighting the burden of infectious morbidity associated with this complex procedure. In our study also, 47.7% of patients developed 30-day post operative complications in the form of surgical site infection, intra abdominal collection, post operative leaks and sepsis; which aligns with these previously reported rates. Microbiology directed antibiotic therapy should be the norm post whipples surgery. This is particularly important in those with preoperative biliary stenting.

Bile colonization is one of the most important determinants of infection risk in patients who undergo preoperative biliary stenting. There is increased risk of multimicrobial colonization with endoscopic biliary drainage. A study by Okano et al.^[5]. demonstrated bile contamination in up to 90% of stented patients and associated this with increased postoperative infectious morbidity, especially when empirical coverage fails to address the cultured organisms. Our data similarly suggest that bile colonization may be a contributing factor to postoperative infection, even if not independently predictive in this sample size. Further, larger-scale studies could help clarify this association.

Similarly, Yang et al.^[11]. reported that bile cultures in stented patients most commonly yielded gram-negative rods, including E. coli and Klebsiella, a finding consistent with our study, in which these were the predominant isolates.

Our data confirmed a strong association between preoperative ERCP stenting and positive bile culture (88.2% vs 54.1%; p = 0.009), supporting previous findings. Choice of antibiotics are crucial especially when there are resistant strains. Zhao et al.^[6], identified a predominance of gram-negative enteric organisms in bile cultures post-ERCP, underscoring the need for appropriate empirical therapy.

All patients in our study received cefoperazone-sulbactam as empirical perioperative prophylaxis. Despite the high rate of bile colonization, antibiotic escalation was required in 43.1% of patients. This escalation rate is within the 40–60% range reported by other studies^[9].

When comparing the initial empirical antibiotic used, SSI occurred in 38.9% of patients who received cefoperazone-sulbactam, compared to 90.9% among those who received piperacillin-tazobactam (p = 0.0024). This striking difference suggests that cefoperazone-sulbactam provided better prophylactic coverage in this cohort. This is consistent with studies by Lan et al.^[7] and Su J et al.^[8], which support cefoperazone-sulbactam’s broad spectrum of activity against Enterobacteriaceae and moderate effectiveness against Pseudomonas aeruginosa and Enterococcus spp.

While broader-spectrum agents such as carbapenems are often reserved for confirmed MDR infections, empirical use of cefoperazone-sulbactam in our study appears justified, balancing efficacy with judicious use of antimicrobial.

In our study, the use of cefoperazone-sulbactam was effective in preventing severe outcomes in the majority, even in patients with colonized bile. The organisms responsible for infection in most escalated cases were resistant E.Coli, Klebsiella and Pseudomonas, both known to harbor extended-spectrum beta-lactamase (ESBL) and carbapenemase genes, underscoring the need for escalation in a select subset.

We must further look a the clinical rationale behind the use of Cefoperazone-Sulbactam. Looking at clinical pharmacology of cefoperazone-sulbactam (3rd-generation cephalosporin + β-lactamase inhibitor), it offers several advantages in this context. It has high biliary penetration, making it suitable for hepatobiliary infections. It shoes activity against both gram-positive and gram-negative organisms, including ESBL-producing strains. It has favorable outcomes in Indian and Southeast Asian settings where resistance to Piperacillin-tazobactamis increasing. Added to this, cost-effectiveness and lower risk of collateral damage to gut microbiota^[12] makes it a good candidate for empirical therapy, especially in settings where local antibiograms support its use and where overuse of carbapenems could accelerate resistance trends.

Whereas, Piperacillin-tazobactam has a broader anaerobic coverage and is often first-line in Western settings. It may show higher resistance rates in bile pathogens in patients with stents or prior antibiotic exposure. It remains a valuable agent but may be less optimal as empirical monotherapy in high-risk or resistant environments unless supported by local sensitivity data^[12].

In contrast to U.S.-based studies favoring piperacillin-tazobactam^[4,10], our study supports cefoperazone-sulbactam as an equally viable, if not preferable, empirical option, particularly in the Indian subcontinent where antibiotic cost and resistance patterns differ. D'Angelica et al.^[4]  observed that , there was marginal benefit with piperacillin-tazobactum compared to cefoxitin in reduction of surgical site infection  in low-to-moderate risk patients.

Our study benefits from a focused, single-center design with consistent surgical and microbiological practices. The uniform use of cefoperazone-sulbactam across all patients enabled a direct assessment of its empirical efficacy.

However, the retrospective nature, limited sample size, and lack of anaerobic or fungal culture data limit generalizability. Resistance profiling and molecular typing of MDR organisms were not performed but could provide additional insight in future studies.

Cefoperazone-sulbactam demonstrated favorable empirical coverage in patients undergoing Whipple’s surgery, with a relatively low requirement for escalation and acceptable SSI rates. The strong association between preoperative biliary stenting, bile colonization, and infectious complications highlights the need for vigilant postoperative monitoring and prompt antibiotic adjustment when necessary. In our setting, Cefoperazone-sulbactam represents a rational and cost-effective empirical choice, this aligns well with principals of judicious use of antibiotics.

The authors have no conflicts of interest to disclose.

Authors’ Contribution:

Each author has contributed meaningfully to the study

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