Impact of Prophylactic Antibiotic Selection on the Prevention and Bacterial Flora of Surgical Site Infections After Colorectal Surgery

Abstract

Background:

Deep incisional and organ/space surgical site infections (SSIs) after colorectal surgery are associated with adverse outcomes. Multiple antibiotic regimens are recommended for peri-operative prophylaxis, with no particular regimen preferred over another. We compared the prophylaxis regimens used in patients with and without SSIs, and the impact of regimens on the flora involved in SSIs.

Patients and Methods:

Information was extracted from the National Healthcare Safety Network databank of patients undergoing colorectal surgery from 2015 to 2022 in a large public healthcare system in New York City. Patients with SSIs were identified, and controlling for nine variables, propensity score matching was used to create a matched control group without SSIs. Prophylactic regimens were compared between the matched groups with and without SSIs. Also, for the patients with SSIs, the impact of the prophylactic regimen on the subsequent pathogens involved the infection was examined.

Results:

A total of 275 patients with SSIs were compared to a matched cohort without SSIs. The prophylactic regimens were extremely similar between the SSI and control groups. Among the patients who developed SSIs, more patients who received cefoxitin had emergence of select cephalosporin-resistant Enterobacterales and Bacteroides spp. when compared with those who received β-lactam-β-lactamase inhibitors.

Conclusions:

The distribution of surgical prophylaxis regimens was remarkably similar between patients developing serious SSIs and a closely matched cohort that did not develop an SSI. However, given the downstream effects of more resistant and anaerobic flora should an infection develop, use of cefoxitin should be re-evaluated as a prophylactic agent.

The adverse clinical outcomes of surgical site infections (SSIs) after colorectal surgery have been well documented. Prolonged hospital length of stay, increased re-admission rates, and greater mortality are associated with these infections.^1–4 Deep incisional and organ/space infections have the greatest clinical burden, including increased mortality.^1,4,5 Modifiable risk factors for SSIs include use of oral antibiotic agents in the bowel preparation, skin preparation with chlorhexidine, and maintenance of normothermia, euglycemia, and adequate oxygenation.¹ As such, implementation of “bundles” targeting these risk objectives have been met with variable success in reducing SSIs.^6–10 These SSI bundles target patients undergoing elective colon surgery,^6–9 and successes only involved reductions of superficial SSIs.^6,7,9

Several intravenous antibiotic antibiotic regimens are recommended for prophylaxis for patients undergoing colorectal surgery. Cefazolin plus metronidazole, ceftriaxone plus metronidazole, cefoxitin, ertapenem, and β-lactam/β-lactamase inhibitor (BL-BLI) agents are included in the recommended regimens for prophylaxis.^11,12 Compared with second-generation cephalosporins, more favorable outcomes have been noted with the prophylactic use of either ertapenem or cefazolin plus metronidazole for prevention of SSIs after colorectal surgery.^13–15 Increasing resistance rates of anaerobic bacteria (particularly Bacteroides spp.) against cefoxitin have been noted.¹⁶ In addition, cefoxitin is a known potent inducer of the chromosomal cephalosporinase (AmpC) present in the “ESCAPPM” group of Enterobacterales and its use may encourage the emergence of cephalosporin-resistant pathogens.^17,18

In this report we examine the prophylactic regimens used in patients undergoing colorectal surgery across a large healthcare system. First, comparisons are made between a heterogeneous group of patients who developed SSIs with a closely matched cohort of patients who did not develop SSIs. Second, for the group of patients who developed an SSI, the impact of the particular prophylactic regimen on the resulting bacterial pathogen(s) is examined.

Patients and Methods

The New York City Health and Hospitals System consists of 11 acute care urban medical centers with academic affiliations. All are public safety net hospitals that serve patients primarily of low socioeconomic status.

The U.S. Centers for Disease Control and Prevention's National Healthcare Safety Network (NSHN) surveillance criteria were utilized to define colon procedures and SSI events. Listings of patients who underwent colon surgery from 2015 to 2022 were obtained from the NHSN database. Propensity score matching was performed using SPSS (IBM Corp, Armonk, NY) to establish a control group for the patients with deep incisional and organ/space SSIs. Superficial wound infections were not included because they represent a lower clinical burden and they are not evaluated by the Centers for Medicare and Medicaid Services. Variables included in the propensity score matching were age, body mass index (BMI), operation duration, gender, American Society of Anesthesiology (ASA) class, diabetes mellitus, emergency surgery, surgery related to trauma, and wound classification.

Additional chart review was conducted for those patients with reported SSIs and a matched control group. Information obtained from this chart review included: race/ethnicity, the indication for surgery, the antibiotic prophylaxis regimen used, and whether the antibiotic agents were continued beyond the 24-hour peri-operative period. For the patients with SSIs, the bacterial pathogens involved in the infection were recorded. Particular attention was made to the presence of resistance to third-generation cephalosporins among Enterobacterales; differentiation was made between organisms that typically develop resistance via induction of a chromosomal AmpC cephalosporinase (AmpC-possessing Enterobacterales; e.g., Enterobacter cloacae, Klebsiella aerogenes, and select Citrobacter species) and those that develop resistance via acquisition of an extended-spectrum β-lactamase (ESBL)-possessing Enterobacterales; e.g., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis).

Student t-test and χ² analysis were used to compare continuous and categorical values, respectively. The test-based method was used to compare rates of infection with particular bacteria.¹⁹ This study was approved by the SUNY Downstate Medical Center Institutional Review Board and the Health and Hospitals Systems to Track and Approve Research program.

Results

Analysis of indications for surgery and the prophylactic regimens in patients with SSIs and a closely matched control group

From 2015 to 2022 there were 5,217 colon surgeries reported from the 11-hospital system. There was a total of 387 reported SSIs, including 276 deep incisional or organ/space infections. Propensity score matching created cohorts of 275 patients with deep incisional or organ/space SSIs and 275 closely matched patients without SSIs (Table 1). Indications for surgery, as well as the antibiotic prophylaxis regimen used, were remarkably similar between the two groups; Table 2). In addition, the percentage of patients with continuation of antibiotic agents beyond the prophylaxis period (suggesting presence of an ongoing infection) was similar. The distribution of common prophylactic regimens was not different between patients undergoing non-emergent and emergent surgeries in the SSI and control groups.

Table 1.

Comparison of Matching Variables Between Patients With SSIs and the Propensity Score Matched Control Group

	SSI group (n = 275)	Control group^a (n = 275)
Matching variables
Age (mean ± SD)	53.1 ± 17.6	53.3 ± 20.0
Male (n)	184	172
Diabetes mellitus (n)	48	52
BMI (mean ± SD)	27.9 ± 7.2	27.3 ± 7.4
ASA score (n)
1	3	2
2	48	56
3	110	104
4	87	79
5	27	34
Average ASA score (mean ± SD)	3.32 ± 0.91	3.32 ± 0.96
Duration (mean ± SD)	226 ± 125	216 ± 130
Wound class (n)
Clean contaminated	108	106
Contaminated	81	79
Dirty	86	90
Trauma related (n)	50	46
Emergency surgery (n)	142	130

SSI = surgical site infection; SD = standard deviation; ASA = American Society of Anesthesiologists.

No significant difference between the SSI and control groups for any of the variables.

Table 2.

Comparison of Indications for Surgery and Antibiotic Prophylaxis Regimens Between Patients Who Developed SSIs and the Propensity Score Matched Group

	SSI group (n = 275)	Control group^a (n = 275)
Indication for surgery (n)
Cancer	70	82
Diverticulitis/intra-abdominal infection	21	27
Obstruction	38	31
Gunshot wound	39	32
Antibiotic prophylaxis (n)
BL-BLI	65	64
Carbapenem	10	10
Cefazolin + metronidazole	44	43
Cefoxitin	91	84
Fluoroquinolone + metronidazole	9	19
Antibiotics continued >24 h	136	135

SSI = surgical site infection; BL-BLI = β-lactam/β-lactamase inhibitor.

No difference between the SSI and control groups for any of the variables.

Among the 133 patients undergoing non-emergent surgery who developed an SSI, 44 (33%) received cefoxitin, 17 (13%) received a BL-BLI, and 27 (20%) received cefazolin plus metronidazole. Among the 145 patients without SSIs who underwent nonemergent surgery, 47 (32%) received cefoxitin, 23 (16%) received a BL-BLI, and 33 (23%) received cefazolin plus metronidazole. Among the 142 patients undergoing emergent surgery that developed an SSI, 47 (33%) received cefoxitin, 48 (34%) received a BL-BLI, and 17 (12%) received cefazolin plus metronidazole; for the 130 patients with emergent surgery that did not have an SSI, 37 (28%) received cefoxitin, 41 (32%) received a BL-BLI, and 10 (8%) received cefazolin plus metronidazole.

Analysis of resulting bacterial pathogens following prophylaxis with specific agents

A comparison was made between the patients with SSIs receiving cefoxitin versus BL-BLI prophylaxis. Of the 65 patients receiving BL-BLIs, 63 received piperacillin-tazobactam and two received ampicillin-sulbactam. Although there were more patients with trauma as the indication for colon surgery in the cefoxitin group (32% vs. 11%% in the BL-BLI group; p = 0.004) there were more patients in the BL-BLI group who had the indication of diverticulitis (18% vs. 3% in the cefoxitin group; p = 0.004). In addition, compared with the cefoxitin group, the BL-BLI group was more likely to have continuation of antibiotic agents after the surgery (85% vs. 44%; p < 0.001), emergent surgery (77% vs. 54%; p = 0.005), and not to have primary closure of the abdomen (35% vs. 22%; p = 0.10). For the cefoxitin and BL-BLI groups, the distribution of clean contaminated (42% vs. 29%), contaminated (32% vs. 38%), and dirty (26% vs. 32%) wounds were similar, respectively. The duration of surgery was also similar: 207 ± 100 minutes in the cefoxitin group versus 192 ± 99 minutes in the BL-BLI group (p = NS).

Of the 91 patients with SSIs who received cefoxitin prophylaxis, 10 patients (involving 12 pathogens) had infections with AmpC-possessing Enterobacterales resistant to third-generation cephalosporins, compared with one patient of the 65 who received a BL-BLI (p = 0.03). Similarly, of the 91 patients receiving cefoxitin, 25 had an infection involving Bacteroides spp., compared with seven of the 65 who received a BL-BLI (p = 0.02). There were no differences in the cefoxitin and BL-BLI groups for infections involving ESBL-possessing Enterobacterales resistant to third-generation cephalosporins or piperacillin-tazobactam, AmpC-possessing Enterobacterales resistant to piperacillin-tazobactam, Enterococcus spp., or Pseudomonas aeruginosa.

There were 167 bacterial pathogens isolated from the surgical site infections of the 91 patients who received cefoxitin prophylaxis (Table 3). In comparison, there were 92 pathogens isolated from the 65 patients who received a BL-BLI as prophylaxis. Compared with the patients who received BL-BLIs, more patients who received cefoxitin had AmpC-possessing Enterobacterales that were resistant to third-generation cephalosporins. Of the 12 such pathogens in the cefoxitin group, nine were E. cloacae and there were one each of Klebsiella aerogenes, Citrobacter braakii, and Citrobacter freundii; the one such pathogen in the BL-BLI group was E. cloacae.

Table 3.

Characteristics of Bacterial Pathogens in Patients Receiving Cefoxitin or BL-BLI Prophylaxis

	Cefoxitin group	BL-BLI group
	n = 167 bacterial pathogens	n = 92 bacterial pathogens
Bacterial pathogen	n (%)	n (%)	p
AmpC-Enterobacterales resistant to third-generation cephalosporins	12 (7%)	1 (1%)	0.03
Non-AmpC-Enterobacterales resistant to third-generation cephalosporins	7 (4%)	7 (8%)	0.24
AmpC-Enterobacterales resistant to piperacillin-tazobactam	10 (6%)	2 (2%)	0.16
Non-AmpC-Enterobacterales resistant to piperacillin-tazobactam	7 (4%)	9 (10%)	0.07
Enterococcus spp.	33 (20%)	17 (18%)	0.80
Pseudomonas aeruginosa	6 (4%)	8 (9%)	0.08
Bacteroides spp.	28 (17%)	7 (8%)	0.04

BL-BLI = β-lactam/β-lactamase inhibitor.

Patients who received cefazolin plus metronidazole comprised the third largest prophylaxis regimen group. There were 65 bacterial pathogens among the 44 patients who received cefazolin plus metronidazole. Compared with the cefoxitin group, the percentage of isolates that were AmpC-possessing Enterobacterales resistant to third-generation cephalosporins (3%) or piperacillin-tazobactam (3%), ESBL-possessing Enterobacterales resistant to piperacillin-tazobactam (3%), Enterococcus spp. (18%), Pseudomonas aeruginosa (8%), and Bacteroides spp. (9%) were similar. However, the percentage of ESBL-possessing Enterobacterales resistant to third-generation cephalosporins (12%) was higher in the cefazolin plus metronidazole group than that of the cefoxitin group (p = 0.02).

Discussion

Despite aggressive measures that include implementation of pre-operative bundles and timely administration of peri-operative antibiotic agents, SSIs (particularly after colorectal surgery) remain a frequent health-care–associated infection.²⁰ For elective surgery cases, implementation of bundles that target administration of oral antibiotic agents, preference for laparoscopic procedures, antiseptic skin preparation, and maintenance of normothermia, euglycemia, and oxygenation have led to decreases in SSIs.^6–10 However the decreases have occurred with superficial wound infections, with little impact of bundles on deep incisional or organ/space infections.^5–7,9

Considerable attention has been placed on the selection of peri-operative antibiotic agents in attempts to reduce colorectal surgery SSIs. In some reports, examining carefully selected and purely elective cases, more SSIs occurred in patients receiving cefoxitin prophylaxis compared with cefazolin plus metronidazole or ertapenem.^13,15 For trauma-related colorectal surgeries, reductions in SSIs were also noted after implementing ertapenem as the peri-operative antibiotic.¹⁴ The reductions in SSIs after the use of ertapenem involved only superficial wound infections.^14,15 However, use of ertapenem has not been adopted widely as an agent for prophylaxis, in part because of its aggressively broad coverage and comparative cost. Our study, which involved both elective and emergent colorectal surgery patients with deep incisional and organ/space SSIs, did not find any differences in prophylactic antibiotic selection when compared with a very closely matched cohort that did not develop SSIs. Although broad-spectrum peri-operative coverage is undoubtedly important, there appears to be other factors beyond the particular antibiotic regimen that are important for the development of an SSI.

Although no particular antibiotic regimen favorably impacts the prevention of a deep incisional or organ/space SSIs, the selection of a regimen may have downstream effects on the flora should infection develop. In our report, when compared with BL-BLI (largely piperacillin-tazobactam), the use of cefoxitin was associated with emergence of infections because of AmpC-possessing Enterobacterales resistant to third-generation cephalosporins. Cefoxitin is a known potent inducer of the AmpC cephalosporinase native to certain Enterobacterales, and emergence of cephalosporin resistance can occur (particularly among species of Enterobacter and Citrobacter) even after brief exposures.^17,18,21 As a result, carbapenems are often relied upon to treat serious infections with these pathogens.^23,23 Recent studies have documented the emergence of cefoxitin resistance among Bacteroides spp.¹⁶ Our results also suggest increased emergence of these anaerobic bacteria in SSIs after cefoxitin use, compared with BL-BLI agents. Recently, use of piperacillin-tazobactam was shown to be superior to cefoxitin in reducing SSIs and other complications in patients undergoing pancreatoduodenectomy.²⁴

Our study has several limitations. Although rigorous criteria were used to select the control group of patients without SSIs, the retrospective nature of this study may have introduced selection biases. Also, we presumed the mechanism of cephalosporin resistance in the AmpC-possessing Enterobacterales group was caused by upregulation of the cephalosporinase AmpC and not caused by acquisition of other β-lactamases; molecular testing would be needed to verify this correlation. Our information originated from the NHSN databank; additional information that may affect the development of resistant pathogens (e.g., prior hospitalization) was not available. Finally, susceptibility testing of anaerobic bacteria (including Bacteroides spp.) was not routinely performed by the microbiology laboratories.

Conclusions

Although no regimen has been found to be clearly superior in preventing deep incisional and organ/space SSIs after colon surgery, because of the emergence of resistant and anaerobic pathogens after cefoxitin exposure, the use of this agent for prophylaxis should be re-evaluated.

Footnotes

Authors' Contributions

Conceptualization: Abdallah, Sunny, Quale. Methodology: Quale. Formal analysis: Abdallah, Sunny, Quale. Investigation: Abdallah, Sunny, Jimenez, Ata, Lee, Episcopia, Fornek, Roudnitksy, Quale. Writing—original draft: Abdallah, Sunny, Quale. Writing—review and editing: Lee, Episcopia, Fornek, Roudnitksy, Quale. Supervision: Quale.

Funding Information

None to declare.

Author Disclosure Statement

No financial conflicts of interest have been reported by the authors.

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