Antibiotic Prophylaxis with Piperacillin–Tazobactam Reduces Post-Operative Infectious Complication after Pancreatic Surgery: An Interventional,Non-Randomized Study

Abstract

Background:

This study aimed to evaluate the effectiveness of piperacillin–tazobactam as antibiotic prophylaxis in patients affected by a peri-ampullary tumor submitted to pancreatic surgery.

Methods:

A prospective, non-randomized, non-blinded, interventional study was conducted from January 2015 to March 2018. Patients were screened pre-operatively for Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL-PE). During the baseline period (January 2015–October 2016), surgical prophylaxis was performed with ampicillin–sulbactam. In the intervention phase (November 2016–March 2018), patients received piperacillin–tazobactam. Statistical analysis was performed by univariable and multivariable analysis with logistic regression models.

Results:

Overall, 383 patients were included in the baseline period and 296 in the intervention period. The surveillance strategy identified 47 ESBL-PE carriers (14%) in the baseline phase and 29 (10%) in the intervention phase. In the baseline period, the patients had a higher rate of hospital-acquired infection (43% versus 33%; p = 0.004), superficial surgical site infection (SSI) (11% versus 2%; p < 0.001), and pneumonia (16% versus 9%; p = 0.006). After the logistic regression, the baseline group had an odds ratio to develop superficial SSI and pneumonia of 7.7 (95% confidence interval [CI] 3–20) and 1.8 (95% CI 1–3.3), respectively. The ESBL colonization increased the mortality rate significantly (8% versus 3%; p = 0.017).

Conclusions:

Adopting antibiotic prophylaxis based on piperacillin–tazobactam is associated with a reduction in post-operative SSI, particularly superficial-SSIs. Further randomized studies would be warranted to evaluate this antibiotic combination more extensively in preventive strategies.

The growing number of antibiotic-resistant pathogens, strongly associated with hospital-acquired infections (HAIs), poses a substantial threat to national healthcare systems in terms of public health, morbidity, mortality rates, and costs. Gram-negative bacteria adopt several antibiotic resistance mechanisms, the most common being extended-spectrum beta-lactamase (ESBL) manufacture, which confers the ability to resist aminopenicillins, cephalosporins, and aztreonam. The production of carbapenemases extends the resistance to carbapenems, classifying these bacteria as extensively-drug resistant [1 –3].

The Infectious Diseases Society of America has identified Klebsiella spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii as “bad bugs” because the therapeutic strategies for these microorganisms are limited [4]. Recently, the World Health Organization presented a list of priority pathogens (PPL) targeted for research and development of new antibiotics. This effort points out the scientific attention to the development from the Centers for Disease Control and Prevention (CDC) of appropriate healthcare delivery services and proper stewardship to safeguard the value of current and future drugs [5]. The Priority Pathogen List identified the pathogens with a critical level of priority, such as carbapenem-resistant gram-negative and third-generation cephalosporin-resistant Enterobacteriaceae [5].

In 2018, the European Antimicrobial Resistance Surveillance Network reported high percentages of resistance in gram-negative bacteria. More than half of the Escherichia coli and more than a third of the Klebsiella pneumoniae isolated were resistant to at least one antimicrobial class. Even for Pseudomonas aeruginosa and Acinetobacter spp,, higher resistance rates were registered [6].

Surgical site infections (SSIs) account for a significant portion of HAIs [7], and despite multiple advances in prevention, they remain a frequent complication after major abdominal surgery [8]. Surgical infections after pancreatic resection are among the most frequent post-operative complications, occurring in at least one-third of patients, and gram-negative bacteria frequently are involved as causative agents [9]. The Surgical Care Improvement Project measures for SSI prevention include surgical antibiotic prophylaxis. To be effective, the drug should cover the typical bacterial flora of the biliary tract: Enteric gram-negative organisms, anaerobes, and enterococci. The CDC, the American Society of Health-System Pharmacists, and the Infectious Diseases Society of America recommend cefazolin or a second-generation cephamycin-type cephalosporin (cefoxitin or cefotetan) or a third-generation cephalosporin (ceftriaxone) or ampicillin–sulbactam for biliary tract procedures [10]. These guidelines derive from the correlation between bacterobilia and major complications after pancreatic resections [11], confirming a clear association between the presence of a biliary stent (PBD) and bacterial colonization of the biliary tract [12]. The rise in antibiotic resistance, particularly the spread of ESBLs, also affects gram-negative microorganisms colonizing the biliary tract and may reduce the effectiveness of antibiotic agents traditionally recommended for surgical prophylaxis [13]. The literature reports an extensive number of clinical trials exploring different prophylactic schemes and peri-operative strategies to prevent SSIs in pancreatic surgery, with opposite results [14,15]. Some investigators have suggested the inadequacy of traditional surgical prophylaxis schemes for hepato-biliary procedures, particularly for pancreaticoduodenectomy, and have advocated the use of broader-spectrum agents, such as piperacillin–tazobactam [16]. This antibiotic combination has demonstrated a good pharmacokinetic profile in both serum and pancreatic juice, making it a suitable alternative for surgical prophylaxis [13,14]. Few data are available about this type of use, especially in the setting of ESBL-PE colonization and the variance of the susceptibility of piperacillin–tazobactam in this subgroup of patients.

The study aimed to evaluate the effectiveness of piperacillin–tazobactam as antibiotic prophylaxis in patients affected by a peri-ampullary lesion who were submitted to pancreatic surgery.

Patients and Methods

Study design

The was a prospective, non-randomized, non-blinded, interventional cohort study, including all adult patients who underwent pancreatic resection for peri-ampullary lesions from January 2015 to March 2018 at the General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital, Verona, Italy. The study was divided into two phases: The baseline period (January 2015–October 2016), and the intervention period (November 2016–March 2018). Institutional Review Board approval was obtained for data collection and analysis.

Of note, at our institution, all patients scheduled for pancreatic surgery have undergone an active epidemiologic surveillance program. This program was based on the execution of a rectal swab to identify subjects colonized by multi–drug-resistant (MDR) gram-negative organisms. It was carried out within the three weeks preceding the surgical procedure. To be enrolled in this study, a patient was scheduled for an elective pancreatic resection for a peri-ampullary lesion was older than 18 years and provided informed consent. Patients with an impaired mental state, language problems, or pregnancy were excluded.

Peri-operative procedures

During the study period, several peri-operative bundles to prevent the occurrence of SSI were analyzed. The Institutional policy about skin cleansing was the same during both study periods, with iodinated substances being the preferred agent. The abdominal hair removal was performed by patients, who avoided shaving. Pre-operative chlorhexidine skin cleansing was performed the night before and the morning of surgery (e.g., shower, wipes). In the operating theatre, the traffic was limited to the essential personnel. Some patients were randomized to receive a wound protector [18]. During the surgery, the temperature was controlled. The fascia was closed by a knotted absorbable suture and the skin by a stapler. The use of surgical drains depended on the post-operative risk of formation of a pancreatic fistula [19,20]. The antibiotic prophylaxis followed the institution's guidance document. During the baseline period, the surgical prophylaxis recommended was ampicillin–sulbactam (2 g + 1 g intravenously before skin incision, then 1 g + 0.5 g intravenously every three hours until the end of surgery). Patients carrying a PBD received an additional short-term antibiotic course, consisting of 2 g + 1 g intravenously of ampicillin–sulbactam three times daily until the third post-operative day.

During the interventional period, all patients received piperacillin–tazobactam (4.5 g intravenously before skin incision, then 2.25 g every 3 hours until the end of surgery). During surgery, a bile sample was sent for microbiologic culture. The wound was covered by a dressing, usually removed on post-operative day two. Early mobilization was recommended from post-operative day one. All patients performed pulmonary physio-kinetic rehabilitation.

Data collection

Demographic data collected included age, gender, body mass index (BMI; kg/m²), Charlson Age-Adjusted Comorbidity Index [21], diabetes mellitus, American Society of Anesthesiologists Score, antibiotic prophylaxis (timing, type of antibiotic, and dosage), jaundice, PBD, type of PBD (endoscopic plastic or metal stent or percutaneous biliary drainage), multiple pre-operative biliary manipulation, pre-operative cholangitis, time from PBD and surgery (days), and neoadjuvant therapy.

Surgical outcomes

The surgical outcomes collected were the type of pancreatic resection (pancreaticoduodenectomy, total pancreatectomy), estimated blood loss (mL), and operation time (minutes). Post-operative complications were registered and classified according to the Clavien–Dindo system [22]. Clinically relevant pancreatic fistula (POPF) was defined and classified according to the International Study Group on Pancreatic Fistula (23), whereas delayed gastric emptying and post-operative pancreatic hemorrhage were determined according to the International Study Group of Pancreatic Surgery [24,25]. Post-operative death and morbidity were defined as death or complications occurring either within 90 days after surgery or during the hospital stay, respectively.

Infectious complications

The assessment of HAIs and SSIs was performed prospectively by trained personnel, according to the Centers for Disease Control and Prevention [26]. An HAI was considered as an infection that occurred after 48 hours of hospital stay that was not present at the time of admission or during the incubation period after access to the hospital. These HAIs included SSIs, pneumonia, urinary tract infection (UTI), primary blood stream infection (BSI), and BSIs secondary to contamination of a central venous catheter (CVC). According to the CDC definition, SSIs were defined as superficial, deep, or organ/space [27]. A UTI was diagnosed if the patient suffered from typical signs and symptoms in the presence of a positive urine culture (i.e., ≥10⁵ colonies/mL) [28]. Primary BSI was diagnosed by the positivity of at least one blood culture (two sets in case of coagulase-negative staphylococci) in the absence of another infectious focus. A CVC-BSI was defined as a laboratory-proved BSI with either a positive catheter tip culture or a positive blood culture taken from a CVC [29].

Statistical analysis

Data were analyzed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA). Continuous data are presented as the median with the interquartile range (IQR). A comparative analysis was performed to identify risk factors for the development of infections, using a χ² test or Fisher exact test for categorical variables. For non-normally distributed continuous variables, the Mann-Whitney U test was applied. P values ≤0.05 on univariable analysis were subjected to multivariable analysis with logistic regression models. A multiple linear regression was performed using the forward stepwise regression method to identify the factors most significantly associated with the risk of the infectious complication. The p values were presented as odds ratios or hazard ratios and 95% confidence intervals (CIs), as appropriate. A p value of <0.05 determined statistical significance.

Results

During the study period, 740 pancreatic resections were performed, of which 61 (8%) were excluded from the analysis because they received a different surgical prophylaxis scheme secondary to allergy or ongoing cholangitis treatment. The baseline and the intervention groups were composed of 383 (56%) and 296 (44%) patients, respectively.

Baseline and demographic data are shown in Table 1. No differences were found between the groups. During the study period, the pre-operative manipulation of the biliary tract was performed in 187 patients (49%) of the baseline group and 155 patients (52%) of the intervention group (p = 0.201). Even considering multiple biliary procedures and cholangitis, the groups were homogeneous (p = 0.066 and p = 0.358). Intra-operative and pathological data are reported in Table 2. Pancreaticoduodenectomy was performed in 329 patients (86%) of the baseline group and 236 (80%) of the intervention group. Operating time, intra-operative blood loss, and final pathology findings did not differ between the groups (p > 0.05).

Table 1.

Demographic Data of 679 Patients

	Baseline	Intervention	p
	(n = 383; 56%)	(n = 296; 44%)	p
Age (y, IQR)	66 [56–72]	65 [57–72]	0.961
Sex (male) (%)	223 (58)	163 (55)	0.228
Body Mass Index (kg/m²) [IQR]	24 [22 –27]	24 [22 –27]	0.418
ASA score III, IV	81 (21%)	63 (21%)	0.520
CACI >4	150 (39%)	127 (43%)	0.183
Jaundice	215 (56%)	169 (57%)	0.432
Pre-operative biliary drain (%)^a	187 (49)	155 (52)	0.201
Plastic stent	134 (72)	93 (60)	0.348
Metal stent	45 (24)	57 (37)
PTBD	8 (4)	5 (3)
Multiple biliary procedures	66 (35)	42 (27)	0.066
Cholangitis (%)	46 (12)	33 (11)	0.358
Neo-adjuvant treatment (%)	87 (23)	85 (28)	0.072

Percentage refers to the number of the 342 of patients submitted to pre-operative biliary drainage.

ASA = American Society of Anesthesiology; CACI = Charlson Age-Related Comorbidity Score Index; IQR = interquartile range; PTBD = percutaneous transhepatic biliary drainage.

Table 2.

Intra-Operative and Pathological Data of 679 Patients

	Baseline	Intervention	p
	(n = 383; 56%)	(n = 296; 44%)	p
Type of resection (%)
Pancreaticoduodenectomy	329 (86)	236 (80)
Total pancreatectomy	54 (14)	60 (20)
Operation time (min, IQR)	425 [370–486]	419 [365–475]	0.095
Estimated blood loss (mL, IQR)	400 [300–500]	400 [250–500]	0.759
Pathology findings (%)			0.504
PDAC	236 (62)	175 (59)
pNET	32 (8)	22 (8)
IPMN	31 (8)	31 (10)
Bile duct/ampullary cancer	52 (14)	24 (8)
Other	32 (8)	44 (15)

Time-period analysis of risk of post-operative surgical infectious complications according to antibiotic prophylaxis

The incidence of post-operative infectious complications is reported in Table 3. The ESBL-PE carrier rate during the baseline and intervention period was 14% (48 patients) and 10% (28 patients), respectively (p = 0.082). A positive bile culture was detected in 179 (84%) and 153 (77%) patients of the baseline and intervention period (p = 0.035). During the baseline period, the HAI rate was higher (43% versus 33%; p = 0.004). No differences were found in the occurrence of total SSIs (32% versus 28%; p = 0.137), but the superficial SSI rate significantly differed in the two periods (11% versus 2%; p < 0.001); no differences were found in the organ/space SSI rate (29% versus 25%; p = 0.137). Considering the other infectious complications, only pneumonia decreased during the intervention period (16% versus 9%; p = 0.006). After the logistic regression, the baseline group had an OR to develop superficial SSI and pneumonia of 7.7 (95% CI 3–20) and 1.8 (95% CI 1–3.3), respectively.

Table 3.

Time-Period Analysis of Risk of Post-Operative Surgical Infectious Complications According to Antibiotic Prophylaxis (%)

	Baseline (n = 383; 56)	Intervention (n = 296; 44)	p	MVA
				p
				(OR; 95% CI)
ESBL positive	47 (14)	29 (10)	0.099
Positive bile culture	179 (84)	153 (77)	0.035
HAI	163 (43)	99 (33)	0.004	0.970
SSI	120 (32)	83 (28)	0.137
Superficial	43 (11)	5 (2)	<0.001	<0.001 7.7 (3–20)
Deep	0	2 (1)	0.196
Organ/space	102 (27)	81 (27)	0.527
Pneumonia	56 (16)	26 (9)	0.006	0.037 1.8 (1–3.3)
UTI	10 (3)	5 (2)	0.240
Blood stream infection	13 (4)	10 (3)	0.503

Statistically significant values are printed in boldface type.

CI = confidence interval; ESBL = extended-spectrum β-lactamases; HAI = hospital-acquired infection; MVA OR = multivariable analysis odds ratio; SSI = surgical site infection; UTI = urinary tract infection.

Among the SSI, 59 patients (29%) had a poly-microbial infection. Overall, the organisms most frequently isolated from S-SSI were Enterococcus spp. (36%), followed by E. coli (14%), Enterobacteriaceae other than K. pneumoniae and E. coli (14%), K. pneumoniae (12%), staphylococci (12%), P. aeruginosa (5%), and Candida spp. (2%). Bacteria most frequently isolated from OS-SSI were Enterococcus spp. (25%), followed by E. coli (18%), staphylococci (11%), Enterobacteriaceae other than K. pneumoniae and E. coli (10%), K. pneumoniae (9%), Candida spp. (9%), and P. aeruginosa (6%).

A subanalysis of the incidence of the post-operative infectious complication in the ESBL-PE carriers is reported in Table 4. Even in this subgroup of patients, during the baseline period, the HAI's rate was higher (64% versus 38%; p = 0.025). Furthermore, no differences were found in the occurrence of total SSIs (49% versus 31%; p = 0.097). The superficial SSI rate still was significantly different in the two periods (34% versus 0; p < 0.001). Considering the other infectious complications, during the interventional period, no differences were recorded (p > 0.05).

Table 4.

Time-Period Analysis (%) of Risk of Post-Operative Surgical Infectious Complications in ESBL-PE Carriers (n = 76) According to Antibiotic Prophylaxis

	Baseline (n = 47; 56)	Interventional (n = 11; 44)	p
HAI	30 (64)	11 (38)	0.025
SSI	23 (49)	9 (31)	0.097
Superficial	16 (34)	0 (0)	<0.001
Deep	0	2 (7)	0.142
Organ/space	18 (38)	8 (28)	0.241
Pneumonia	9 (19)	2 (7)	0.126
UTI	1 (2)	0	0.618
Blood stream infection	3 (6)	1 (3)	0.506

Statistically significant values are printed in boldface type.

ESBL-PE = Enterobacteriaceae producing extended-spectrum β-lactamases; HAI = hospital-acquired infection; SSI = surgical site infection; UTI = urinary tract infection

Surgical outcomes according to antibiotic prophylaxis

As shown in Table 5, a reduction in the post-operative complications was recorded after the intervention. Particularly, POPF, biliary fistula, and abdominal fluid collection were significantly different (p = 0.011, p = 0.046, and p = 0.010, respectively). Even the major complications and post-pancreatectomy hemorrhage were reduced (18% versus 13%; p = 0.042 and 19% versus 14%; p = 0.048). No difference was found in the length of stay or the mortality rate, with a median hospitalization of 10 versus 9 days (p = 0.494) and a mortality rate of 3% versus 2%; p = 0.307), respectively.

Table 5.

Surgical Outcomes (%)

	Baseline	Intervention	p
	(n = 383; 56)	(n = 296; 44)	p
CR-POPF	75 (20)	39 (13)	0.011
Biliary fistula	26 (7)	11 (4)	0.046
Abdominal collection	129 (34)	77 (26)	0.010
DGE	40 (11)	41 (14)	0.133
PPH	72 (19)	42 (14)	0.048
Clavien-Dindo Score ≥ III	67 (18)	38 (13)	0.042
Length of stay (d; IQR)	10 [7 –20]	9 [7 –16]	0.494
Re-operation	32 (9)	24 (8)	0.465
Re-admission	24 (6)	21 (7)	0.430
Death	11 (3)	6 (2)	0.307

Statistically significant values are printed in boldface type.

CR-POPF = clinically relevant pancreatic fistula; DGE = delayed gastric emptying; IQR = interquartile range; PPH = post-pancreatectomy hemorrhage.

Discussion

The introduction of piperacillin–tazobactam as antibiotic prophylaxis in pancreatic resection was associated with fewer SSI and less HAI overall.

The microbiology of peri-ampullary tumors is still challenging, and recommendations for antimicrobial prophylaxis are variable [12]. Furthermore, adherence to international guidelines is low. A Japanese survey reported an extensive heterogeneity in the prophylactic scheme for pancreaticoduodenectomy, such as ampicillin, different classes of cephalosporins, cefoperazone–sulbactam, and carbapenems. The same survey reported many differences in terms of surgical prophylaxis duration, ranging from 1 to 14 post-operative days [30]. Several studies have suggested the risk of the inefficacy of antimicrobial surgical prophylaxis in the presence of antimicrobial-resistant pathogens colonizing the bile duct, increasing the risk of SSI occurrence [31,32].

In this scenario, a revision of the Institutional data and policy was made based on previous studies [9,17,33,34]. The introduction of piperacillin–tazobactam, as antibiotic prophylaxis, was a component of a bundle of an SSI reduction program. These results can be explained by assuming the direct correlation between SSI and bile contamination. The peri-operative antibiotic prophylaxis was introduced to reduce the occurrence of incisional SSI after surgery [35,36]. Several studies reported using penicillin or cephalosporin antibiotics classes for pre-operative prophylaxis, mostly based on the bile culture [37,38]. However, a clear indication is still lacking in patients undergoing pancreatic resection [12]. The study results were conforming to the postulation that the use of appropriate antibiotic prophylaxis can decrease the rate of incisional SSI.

The organ/space SSIs were usually correlated with post-operative pancreatic fistula after pancreatic resection. Preventive strategies for pancreatic fistula, such as a well-defined protocol for drain placement [19] and drain removal [39], and mitigation procedures to reduce its burden (40), should be integrated into an infection control program to increase antibiotic prophylaxis efficacy even in the treatment of organ/space SSIs.

Few data were available on the use of piperacillin–tazobactam. However, the results of the present study were in line with the literature. Donald et al. reported a significant decrease in the SSI rate, introducing this antibiotic in the peri-operative prophylactic strategy (32% versus 7%). Furthermore, the authors did not report an increase in antimicrobial-resistant pathogens during the study period [16]. These data increase the belief that correct antibiotic prophylaxis, in terms of molecule, dose, and duration, is crucial in reducing post-operative surgical infections. However, the broader use of piperacillin–tazobactam cannot be recommended. Further studies should demonstrate the safety and benefit of using this antibiotic in preventive strategies, avoiding additional resistance, acute renal failure, or Clostridioides difficile infection.

The revision of the Institutional antibiotic prophylaxis recommendation was part of the preventive program that also consisted of pre-operative screening with a rectal swab to identify patients colonized by MDR gram-negative bacteria. A strict infection control program was conducted for all colonized patients, mainly based on contact isolation procedures, proper training and re-training of nurses and the surgical staff on hand-hygiene, education of patients and their visitors to avoid ward dissemination of antibiotic-resistant gram-negative bacteria, and dedicated multi-disciplinary teams of surgeons, infection control specialists, infectious diseases specialists, and clinical microbiologists [18,33,41,42].

The study has some limitations. First, even if the data were extracted from a prospectively maintained database, the analysis was performed retrospectively, generating a possible information/selection bias. Second, surgical prophylaxis was the same for patients colonized and not colonized with MDR bacteria. The patients colonized with antimicrobial-resistant pathogens should receive tailored prophylaxis to optimize the results.

Conclusion

The adoption of antibiotic prophylaxis based on piperacillin–tazobactam seems to be associated with a reduction in post-operative surgical infection occurrence, particularly of superficial SSIs. Furthermore, the new prophylactic strategy correlates with a better post-operative clinical course. Further randomized studies should prove the safety and benefit of this antibiotic combination in preventive strategies.

Footnotes

Funding Information

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author Disclosure Statement

All authors have nothing to disclose. None of the authors has received research funding from any organizations. None of the authors is an employee of any organizations. None of the authors owns stocks or shares in any organizations. None of the authors owns patents.

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