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Risk of Clostridium difficile Infection after Perioperative Antibacterial Prophylaxis before and during an Outbreak of Infection due to a Hypervirulent Strain

  1. Alex Carignan1,
  2. Catherine Allard1,
  3. Jacques Pépin1,
  4. Benoit Cossette2,
  5. Vincent Nault1, and
  6. Louis Valiquette1
  1. 1Departments of Microbiology and Infectious Diseases, Canada
  2. 2Pharmacy, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
  1. Reprints or correspondence: Dr. Louis Valiquette, Dept. of Microbiology and Infectious Diseases, CHUS 3001, 12th Ave., N. Sherbrooke, Quebec J1H 5N4, Canada (louis.valiquette{at}usherbrooke.ca).
 
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Abstract

Background. Perioperative antibacterial prophylaxis (PAP) is an important component of surgical site infection prevention but may be associated with adverse effects, such as Clostridium difficile infection (CDI). Since the emergence of a hypervirulent strain of C. difficile, the risk of development of CDI after PAP has not been evaluated. The purpose of this study was to determine the risk of PAP-induced CDI after selected surgical procedures and to compare such risk before with such risk after the emergence of the hypervirulent strain of C. difficile.

Methods. We performed a retrospective cohort study including all patients aged ⩾18 years who underwent either abdominal hysterectomy, hip arthroplasty, craniotomy, or colon, cardiac, or vascular surgery from August 1999 through May 2005 in a tertiary care hospital in Quebec, Canada.

Results. A total of 8373 surgical procedures were performed, and PAP was used in 7600 of these interventions. Of 98 CDI episodes identified, 40 occurred after patients received PAP only. The risk of CDI was 14.9 cases per 1000 surgical procedures among patients who received PAP only during the period 2003–2005, compared with 0.7 cases per 1000 surgical procedures during the period 1999–2002 (P<.001). The independent risk factors associated with CDI in patients given PAP only were older age, administration of cefoxitin (rather than cefazolin) alone or in combination with another drug, and year of surgery.

Conclusions. In the context of a large epidemic of CDI associated with the emergence of a novel strain, 1.5% of patients who received PAP as their sole antibiotic treatment developed CDI. In situations in which the only purpose of PAP is to prevent infrequent and relatively benign infections, the risks may outweigh the benefits in some elderly patients.

Perioperative antibacterial prophylaxis (PAP) is an important component of surgical site infection prevention, especially for operations associated with a high risk of infection or when the consequences of surgical site infection would be catastrophic (e.g., prosthetic implantation and open heart surgery). However, PAP may also be associated with adverse effects, such as allergic reactions, selection of drug-resistant organisms, and Clostridium difficile infection (CDI) [1, 2]. Single-dose PAP has been associated with increased risk of C. difficile colonization [3]. Risk of CDI can be as high as 8.4% among patients undergoing colorectal, vascular, or cardiothoracic surgery; these patients often receive therapeutic antibiotics in addition to PAP [4–11]. Prior case reports, case series, and small cohort studies restricted their analyses to a single type of intervention. The emergence of a hypervirulent strain of C. difficile (variously described as BI, NAP1, or ribotype 027) in 2000—first in the United States and Canada and, more recently, in Western Europe—has led to increases in the incidence and case-fatality rate for CDI [12, 13]. The ability of this strain to cause clinically significant disease after <3 days of antibacterial exposure has been reported [14], but no data are available for patients who received antibacterials for PAP only or for those who received only 1 dose of PAP. The purpose of our study was to delineate the risk of PAP-induced CDI after selected procedures and to compare such risk before with such risk after the emergence of the hypervirulent strain of C. difficile.

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Methods

Population and design. Centre Hospitalier Universitaire de Sherbrooke (Quebec, Canada) is a 685-bed secondary and tertiary care hospital located at 2 distinct sites (Hôpital Fleurimont and Hôpital Hôtel-Dieu) that provide secondary and tertiary care to a population of ∼300,000 persons. We performed a retrospective review of all patients aged ⩾18 years who underwent either abdominal hysterectomy, hip arthroplasty, craniotomy, or colon, cardiac, or vascular surgery from 1 August 1999 through 31 May 2005 (table 1). Gynecological, neurosurgical, vascular, and cardiac procedures are performed only at the Hôpital Fleurimont, and hip and colon surgery are performed at both sites. Patients who underwent colectomy for the treatment of severe CDI were excluded. Data were extracted from a clinical data warehouse combining extensive data from the patient's computerized records with discharge diagnoses based on the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used these codes of different interventions corresponding to the National Nosocomial Infections Surveillance operative procedure categories [15]. Data were available through this database beginning in 1999 at Hôpital Fleurimont but only beginning in 2002 at Hôpital Hôtel-Dieu.

Table 1
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Table 1

Surgical procedures and antibacterials used as perioperative prophylaxis.

The primary outcome was occurrence of CDI within 2 months after surgery. Patients were considered to have developed CDI if they met at least 1 of the following criteria: presence of C. difficile toxin by cytotoxin assay, endoscopic evidence of pseudomembranous colitis, or histopathologic evidence of pseudomembranous colitis on a biopsy specimen obtained during colonoscopy, colectomy, or autopsy. Only the first episode of CDI was considered.

Data collection and analysis. Data extracted included age, sex, length of hospital stay, primary diagnosis, comorbidities, surgical procedures, and antibacterials received within a period of 3 months before and after hospitalization. To quantify the overall burden of comorbidities, the Charlson index was calculated with an enhanced International Classification of Diseases, Ninth Revision, Clinical Modification coding algorithm [16, 17]. Antibacterial therapy was categorized as PAP (given at the time of surgery or within 48 h after surgery if the patient did not have active infection), extended PAP (given ⩾48 h after surgery if the patient did not have active infection), or treatment (for patients with suspected or documented infection). For each antibacterial drug, dosage, number of doses, route of administration, and duration of therapy were recorded. Data on outcomes were extracted from our database of patients with confirmed CDI, which included 2614 patients hospitalized during the period 1991–2006 for whom extensive data on demographic characteristics, clinical and laboratory findings, and outcomes were available [12, 13, 18].

Data were analyzed with SAS, version 9.1 (SAS Institute). Proportions were compared using the Yates corrected χ2 test or Fisher's exact test (when numbers were small). Continuous variables were compared using the Wilcoxon rank sum test. Logistic regression was used for multivariate analysis of risk factors for CDI, and results are presented as adjusted ORs with 95% CIs. Models were built up sequentially, starting with the variable most strongly associated with the outcome and continuing until no other variable reached statistical significance or altered the ORs of variables already in the model. When the final model was reached, each variable was dropped in turn to assess its effect. Different models were compared using the likelihood ratio test.

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Results

We identified 7657 patients who underwent 8367 surgical procedures (716 patients underwent ⩾2 procedures). For a large majority of procedures (7978 [95.4%] of 8367 procedures), patients received antibacterials at some point during their hospitalization; for most of these procedures (5502 [65.8%] of 8367 procedures), the patients received PAP only. The most frequent interventions were cardiac (2253 [26.9%] of 8367 procedures) and vascular procedures (1833 [21.9%] of 8367 procedures) (table 1).

PAP. PAP was used in 7600 procedures (table 1). In the other 767 procedures, either no antibacterial was administered (in 389 procedures) or only therapeutic antibacterials were given either before, during, or immediately after the intervention (in 378 procedures). Six patients were excluded because data on perioperative antibacterials were missing. Overall, the most frequently used drugs for PAP monotherapy were cefazolin (in 5630 procedures), cefoxitin (1069), vancomycin (218), and clindamycin (150). The majority of patients (3910 [51.5%] of 7657 patients) received only a single dose of PAP during surgery (median number of doses, 1 dose; interquartile range, 1–3 doses; range, 1–46 doses). Prophylaxis combining different antibacterial drugs (median number of antibacterial drugs, 2) was used in 600 procedures, most of which were colon operations (319 [53.2%] of 600 procedures). Overall, cefazolin was the most frequently used PAP for all procedures except colon surgery, for which cefoxitin was preferred (table 1).

CDI. A total of 98 CDI episodes were identified within 2 months after surgery (table 2). Not a single episode of CDI occurred in the small group of patients who underwent surgery and received no antibacterial treatment. Forty patients experienced CDI after receiving exclusively PAP; none of these patients had undergone >1 procedure during the 2-month period of observation. The risk of CDI was significantly higher among patients who received a combination of PAP plus a therapeutic course of antibacterials, compared with those who received PAP only (OR, 3.3; 95% CI, 2.2–4.91; P<.001) (table 2).

Table 2
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Table 2

Risk of Clostridium difficile infection (CDI) according to intensity of antibacterial therapy used during hospitalization.

To estimate the risk of CDI after antibacterial prophylaxis, we excluded all procedures for which patients received antibacterials for other indications or were not given any antibacterial (2865 procedures). Factors associated with a higher risk of CDI in univariate and multivariate analyses are shown in table 3. Charlson score and duration of PAP were associated with CDI in univariate analysis, but the associations were no longer statistically significant after adjusting for confounders. The independent risk factors associated with CDI in patients given PAP only were age ⩾65 years, year of surgery, and administration of cefoxitin alone or in combination with another drug. No interaction was found in the multivariate model. Type of surgery and use of cefoxitin as PAP were strongly correlated with the development of CDI (table 3), resulting in colinearity when both variables were fitted into the multivariate model. Because of the well-established causal link between antibacterial exposure and CDI, we assumed that, a priori, antibacterial regimen was more important than type of surgery, and we kept only the former in the final model. To rule out the possibility that overdiagnoses of CDI occurred for patients who underwent colon surgery and were potentially colonized with C. difficile if they presented with loose stools after the surgery (prompting testing for C. difficile toxin, which does not distinguish between colonization and infection by a toxigenic strain), we compared (for a period of 72 h before or after diagnosis of CDI) the peak leukocyte count and the ratio of peak-to-preoperative creatinine concentration (both independent predictors of CDI severity) [12]. These were identical for patients who developed CDI after colon surgery and those who developed CDI after all other procedures (median peak leukocyte count, 13.3 × 109 vs. 13.3 × 109 leukocytes/L [P=.72]; median ratio of peak-to-preoperative creatinine concentration, 0.99:1.01 [P=.99]), suggesting that there was no such overdiagnosis bias and that choice of antibacterial drug was indeed the true risk factor. Among the 40 patients who developed CDI after receiving PAP, 3 died within 30 days after receiving PAP (2 patients died due to CDI, and CDI contributed to death in the other patient), 2 received vasopressors for septic shock (both survived, but 1 developed megacolon and required emergency colectomy), and 9 experienced at least 1 recurrence of infection.

Table 3
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Table 3

Risk factors for Clostridium difficile infection (CDI) in patients who received perioperative antibacterial prophylaxis (PAP) as the sole antibiotic exposure.

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Discussion

Our main finding was that, since the emergence of the BI/NAP1/027 hypervirulent strain of C. difficile, CDI has been a significant complication of PAP, and this fact needs to be considered when selecting which patients should receive PAP. We measured a risk of CDI of 14.9 cases per 1000 procedures among patients who received PAP only during the period 2003–2005, compared with 0.7 cases per 1000 procedures during the period 1999–2002. Although previous studies illustrated a possible link between surgical prophylaxis and CDI, they could not estimate the risk of CDI after receipt of PAP only, because they included patients who also received therapeutic courses of antibacterials [8, 11, 19], included patients who received extended PAP (duration of PAP, ⩾5 days), [8] lacked data to calculate a denominator [7, 9, 10, 20], or were performed for a short duration in reaction to clusters [7]. None of the studies included a variety of surgical interventions performed in the same center, precluding a comparison between PAP regimens or surgical procedures. We addressed most of these shortcomings by excluding patients who received antibacterials for indications other than prophylaxis and extending our review to 6 categories of interventions performed over 6 years.

Among patients who received PAP, we identified the 3 following independent risk factors for the development of postoperative CDI: age ⩾65 years, year of surgery, and type of antibacterial used for prophylaxis. The association between older age and CDI is consistent with the previous literature [12, 21, 22]. Because of the senescence of immunity, older individuals may develop a less effective immune response against C. difficile toxins than younger patients [23–25].

We documented a 21-fold increase in the risk of CDI during the epidemic period. The BI/NAP1/027 epidemic strain, a hyperproducer of toxins A and B [26], is associated with enhanced severity of CDI [12, 13, 21, 27]. In 2005, 67% of C. difficile strains collected in acute care centers in Quebec were the NAP1 epidemic strain [28]. Presumably, the transmission of severe diarrhea is enhanced within hospital environments. Of note, the only 2 cases that occurred during the period 1999–2002 supervened in 2002 and, in retrospect, may have been associated with the early stage of the emergence of the novel strain [12]. As supported by earlier data, this finding would imply that the risk of CDI after PAP was negligible in our center before the emergence of the BI/NAP1/027 strain [20].

PAP monotherapy with cefoxitin was associated with a higher risk of inducement of CDI than was PAP monotherapy with cefazolin, and the addition of another antibacterial to cefoxitin further increased this risk. Because there was colinearity between cefoxitin PAP and colonic surgery, we could not formally rule out the possibility that colon surgery by itself predisposed to CDI; this is less coherent with preexisting data, which generally incriminate antibiotics. C. difficile susceptibility assays performed on nonepidemic strains have consistently shown in vitro resistance to cephalosporins [29–32]. This finding, in addition to the potent anaerobic activity of cefoxitin, could have had an impact on colonic flora favoring CDI. Although the impact of cefotoxin on colonic flora varies among patients, up to 10% of cefoxitin is excreted through the bile, and the drug can be recovered in feces samples [33, 34]. In our hospital, cefoxitin was frequently used as part of a combination PAP strategy combining intravenous antibacterial treatment with preoperative oral antibacterial treatment (especially with erythromycin); this combination could have magnified bowel flora disturbances and the risk of CDI. Although such an approach will need to be validated, for most patients undergoing colorectal surgery in our center, we currently use either single-dose ticarcillin plus clavulanate or single-dose gentamicin plus 3 doses of metronidazole; both regimens are expected to be associated with a low risk of CDI [14].

There was a statistically nonsignificant trend toward an association between duration of PAP and risk of CDI. The most recent guidelines by the National Surgical Infection Prevention Project recommend limiting PAP to 1 or 2 doses (the latter during prolonged procedures) and administering longer prophylaxis (up to 48 h) to patients undergoing cardiac or vascular surgery [35]. In our center, 47% of patients received >2 doses, and optimizing PAP use should be a priority to reduce antibacterial use.

Consequences of PAP-induced CDI can be devastating, with an excess 1-year mortality of as high as 14%–17%. [21]. Among our 40 patients who developed CDI after receiving PAP as sole antibiotic exposure, 5 either died or developed septic shock, which is not trivial for a preventive intervention.

The major limitation of our study is that we could not simultaneously measure the frequency of surgical site infections associated with various regimens of PAP. The comparative efficacy of the most commonly used regimens, measured in studies typically performed 2 decades ago, would need to be reexamined because of the emergence of methicillin-resistant Staphylococcus aureus infection and the preponderance of coagulase-negative staphylococci in infections of prosthetic material. Some surgical site infections can be extremely morbid (e.g., infections of prosthetic material and mediastinitis), and their treatment can also lead to CDI. Until randomized trials of different regimens are performed, decision analysis models should be built to evaluate the benefits and risks of PAP in an era of CDI due to hypervirulent strain and cefazolin-resistant CDI.

In conclusion, we found that, in the context of a large epidemic of CDI associated with the emergence of a novel strain, 1.5% of patients who received PAP as their sole antibacterial exposure developed CDI. Future guidelines for PAP will need to take the risk of CDI into consideration in their risk-benefit analyses. When the only purpose of PAP is to prevent infrequent and relatively benign infections, the risks may outweigh the benefits in some elderly patients. For these patients, antimicrobial prophylaxis regimens associated with a lower risk of CDI and with equivalent surgical site infection prevention need to be developed.

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Acknowledgments

Potential conflicts of interests. L.V. has served on the speakers' bureau for Wyeth; has served on advisory boards for Oryx, Abbott, and Wyeth; and has received compensation to conduct clinical trials involving antibacterials from Genzyme, Wyeth, and Arpida. J.P. has served on the speakers' bureaus for Wyeth and Merck and on advisory boards for Bayer, Wyeth, Viropharma, and Acambis. All other authors: no conflicts.

  • Received November 16, 2007.
  • Accepted January 23, 2008.
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  1. Clin Infect Dis. (2008) 46 (12): 1838-1843. doi: 10.1086/588291
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