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Use of surveillance data to identify target populations for Staphylococcus aureus vaccines and prevent surgical site infections: A pilot study ab

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Marie-Paule Gustin , Marine Giard , Thomas Bénet

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& Philippe Vanhems

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Service d’Hygiène; Epidémiologie et Prévention; Hôpital Edouard Herriot; Hospices Civils de Lyon; Lyon, France b

Département de santé publique; Pôle biostatistique, Faculté de Pharmacie; Université de Lyon; Université Lyon 1; Lyon, France c

Centre de Coordination de la Lutte contre les Infections Nosocomiales Sud-Est; SaintGenis-Laval; France;

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Equipe d’Epidémiologie et de Santé Publique; Université de Lyon; Université Lyon; Lyon, France Published online: 10 Feb 2015.

To cite this article: Marie-Paule Gustin, Marine Giard, Thomas Bénet & Philippe Vanhems (2014) Use of surveillance data to identify target populations for Staphylococcus aureus vaccines and prevent surgical site infections: A pilot study, Human Vaccines & Immunotherapeutics, 10:12, 3517-3521, DOI: 10.4161/21645515.2014.979625 To link to this article: http://dx.doi.org/10.4161/21645515.2014.979625

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SHORT REPORT Human Vaccines & Immunotherapeutics 10:12, 3517--3521; December 2014; Published with license by Taylor & Francis Group, LLC

Use of surveillance data to identify target populations for Staphylococcus aureus vaccines and prevent surgical site infections: A pilot study Marie-Paule Gustin1,2,*, Marine Giard3, Thomas B
enet1,4, and Philippe Vanhems1,3 1 Service d’Hygi ene; Epid
emiologie et Pr
evention; H^ opital Edouard Herriot; Hospices Civils de Lyon; Lyon, France; 2D
epartement de sant
e publique; P^ ole biostatistique, Facult
e de Pharmacie; Universit
e de Lyon; Universit
e Lyon 1; Lyon, France; 3Centre de Coordination de la Lutte contre les Infections Nosocomiales Sud-Est; Saint-Genis-Laval; France;; 4Equipe d’Epid
emiologie et de Sant
e Publique; Universit
e de Lyon; Universit
e Lyon; Lyon, France

Keywords: orthopedic surgery, Staplylococcus aureus, surgical site infection, surveillance, target population, vaccination

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Abbreviations: SSI, surgical site infection; SA, Staphylococcus aureus; ASA, American Society of Anesthesiologists; OR, Odds ratio; CI, confidence interval

The development of anti-staphylococcal vaccines is nowadays a priority to prevent surgical site infections (SSI). The objective of the present study was to identify a potential target population by assessing surveillance data on surgery patients for possible anti-staphylococcal vaccine administration. Individuals at high risk of SSI by Staphylococcus aureus (SA) were targeted by the French SSI Surveillance Network in south-eastern France between 2008 and 2011. Among 238,470 patients, those undergoing primary total hip replacement appeared to be an interesting and healthy enough population for anti-staphylococcal vaccine testing. These male patients, subjected to multiple procedures and with American Society of Anesthesiologists score >2, had a probability of SA SSI about 21 times higher than females with no severe systemic disease and no multiple procedures. Our study indicates that surveillance data on SSI might be an interesting epidemiological source for planning vaccine trials to prevent nosocomial infections.

Introduction Vaccines have been proposed as promising preventive interventions against hospital-acquired infections by bacteria such as Staphylococcus aureus1 (SA) or Clostridium difficile,2 and viruses, such as influenza virus.3-5 Surgical site infections (SSI) are the third most frequent healthcare-associated events, and SA is the main etiological agent. Methicillin-resistant SA SSI, which increase length of hospital stay, costs and mortality, are now recognized as a public health imperative.6,7 Anti-staphylococcal vaccines might be alternatives to antibiotics with no risk of antimicrobial resistance. Ongoing anti-staphylococcal vaccine development has not yet been successful in humans,8 but potential causes of failure have been reported recently.9,10 One stage of anti-staphylococcal vaccine development is the identification of appropriate target populations, especially surgical patients. In addition, to test vaccine efficacy, target populations must be at high risk of SA SSI, but healthy enough to mount effective immune responses. Patient populations hospitalized for planned surgery may have time to develop effective immune responses before surgery. They may be reliable populations for the demonstration of vaccine efficacy. Surveillance data are being explored regularly to identify independent risk factors of SSI11 as they provide opportunities to compute cumulative risks and distinguish patients at high risk.

The objective of the present study was to identify a target population for testing anti-staphylococcal vaccine efficacy through a large SSI surveillance network in France.

Results Among 290,121 patients under surveillance, 18,051 with missing data, 32,029 subjected to emergency procedures, 132 with American Society of Anesthesiologists (ASA) score of 5 and 1,439 SSI by agent other than SA were excluded (Fig. 1). A total of 238,470 were analyzed. These patients were allocated to 647 participating wards for 65 surgical procedures. Patient characteristics are summarized in Table 1. Median patient age at admission was 60.8 years, with 130,317 (54.6%) being female. In the analyzed dataset, 426 SA SSI (0.2%) occurred. Table 1 reports the odds ratios (ORs) of SA SSI according to different risk factors. Factors carrying the most risk were duration of surgery, wound contamination class, ASA score, preoperative hospital stay, and gender. Because of adjustment for all risk factors, the effect of age was weak and non-significant (P D 0.29). Figure 2 gives the predicted adjusted risk of SA SSI by surgical procedure independently of surgical ward (reference level for each covariate). Among 9 surgical procedures with higher risk

© Marie-Paule Gustin, Marine Giard, Thomas B
enet, and Philippe Vanhems *Correspondence to: Marie-Paule Gustin; Email: [email protected] Submitted: 05/27/2014; Revised: 08/13/2014; Accepted: 08/27/2014 http://dx.doi.org/10.4161/21645515.2014.979625

www.landesbioscience.com

Human Vaccines & Immunotherapeutics

3517

544 SA SSI

513 SA SSI

290,121

Excluding 18,051 cases with missing values. Number of missing values per variable: 199 : age 65 : gender 7,025 : ASA score 5,042 : surgery duraon 2,001 : wound class 3 : preoperave stay 7,261 : mulple operave procedure 589 : emergency surgery

272,070 Excluding : 32,029 : Emergency procedure

426 SA SSI

240,041 Excluding : 132 : ASA score = 5

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239,909 Excluding : 1,439 : SSI by agent other than SA

426 SA SSI

238,470

Figure 1. Flow chart of hospitalizations in the French SSI Surveillance Network during the period 2008–2011. Abbreviation: SA SSI: surgical site infections by Staphylococcus aureus. The right side of the figure reports successively excluded observations, and the left side, the remaining numbers of SA SSI.

(predicted adjusted incidence > 0.5 per 1,000 patients), 7 benefited from priority surveillance according to national objectives: 3 orthopedic surgical procedures for hip replacement, 2 procedures related to gynecology and 2 neurosurgeries. Orthopedic operations (23,455/50,146) were primarily retained because they were the most frequent procedures (47%) included in priority surveillance. Hip replacement revision was excluded because patients’ previous status was unknown. The remaining procedures were undertaken for primary total or partial hip prostheses. Their crude SA SSI incidence was 3.5 and 8.5 per 1,000 patients, respectively. Among the 22,113 patients retained, those most at risk of SA SSI were i) men: 44% of total hip replacements (OR D 2.3; 95% confidence interval (CI): 1.3–4.0) and 29% of partial hip replacements (OR D 2.1; 95% CI: 1.0–4.5), ii) patients with ASA score > 2: 25% of total hip replacements (OR D 2.6; 95% CI: 1.5– 4.4), and iii) patients undergoing multiple procedures: 2% of total hip replacements (OR D 3.8; 95% CI: 1.3–11) and 4% of partial hip replacements (OR D 5.6; 95% CI: 2.0–16). Four-point additive scores were computed for each patient according to gender (female D 0 / male D 1), ASA score (“1” D 0, “2” D 1, “> 2” D 2), and multiple procedures (absence D 0, presence D 1). Figure 3 depicts the association between score and the risk of SA SSI in patients undergoing primary hip replacement. The probability of SA SSI was about 2.1 times higher when scores increased by 1 point. Patients with a score of 4 had SA SSI probability about 21 times higher than patients with a score of 0.

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Discussion The objective of our study was to identify patients who could be a potential target population for anti-staphylococcal vaccination before planned surgery. Appropriate statistical modeling of surveillance data led to select primary hip prostheses implantation surgery as being of high risk for SA SSI among priority surgical procedures. Our results confirmed the impact of underlying diseases and multiple surgical procedures on the probability of infection. Among preoperative risk factors, age appeared to have no effect on infection risk, likely because of its association with other covariates and its small variability in the retained population. Estimation of a 4-point score with patient gender, ASA score and the presence or absence of multiple procedures was a convenient way of selecting patients most at risk at hospital admission and contributed to surveillance data evaluation. Patients who cumulate these characteristics may represent a population with the most to gain from anti-staphylococcal vaccination. Anti-staphylococcal vaccination Anti-staphylococcal vaccine development could represent valuable progress in preventing hospital-acquired infections with high attack rates and related antimicrobial resistance. Such advances remain challenging for many reasons, including the choice of antigens,12-14 and target populations for vaccine efficacy and effectiveness calculation. Large clinical trials implemented in high-risk populations, namely hemodialysis patients and patients undergoing cardiac surgery, failed to find vaccine efficacy which may have been partially linked to immune dysfunction and/or population selection.9 A worthwhile population for anti-staphylococcal vaccine testing would be healthy enough and immuno-competent. Fortunately, based on our results, many patients undergoing primary total hip replacement exhibited one of these characteristics: 75% had no severe systemic disease, and very few (0.3%) were exposed to cancer surgery that would likely have disclosed immune deficiency. To the best of our knowledge, anti-staphylococcal vaccines have never been tested in patients undergoing total hip replacement, and no results have yet been published. Use of surveillance data in clinical vaccine studies/projects The advantage of surveillance data is their timeliness, geographic coverage and large number of patients sampled. However, they provide limited covariates for etiological analysis. They fail to systematically report patients’ co-morbidities (diabetes, immune status, cigarette smoking, etc.) that could impact immune responses to vaccination. The dearth of data on preoperative and postoperative antibiotic administration is a limitation of our study. Moreover, no information on SA nasal carriage was obtained. While the literature acknowledges that SA nasal carriage is a major SSI risk, the efficacy of nasal decontamination in orthopedic surgery remains controversial.15-17 To date, the utility of anti-staphylococcal vaccines against nasal carriage has not been demonstrated.18 Vaccination would be of great interest independently of nasal carrier

Human Vaccines & Immunotherapeutics

Volume 10 Issue 12

Table 1. Patient and surgical procedure characteristics with SA SSI ORs of risk factors (fixed effects of mixed multivariate logistic regression)

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Group

Characteristics Age, median (IQRx) (years) Age by quartile (years) - number (%) 44.2 44.3-60.8 60.9-73.6 >73.6 Gender - number (%) Female Male ASA score - number (%) 1. Normal healthy 2. Mild systemic disease 3-4. At least one severe systemic disease Duration of operation (min) - number (%) 45 46-76 >76 Wound class - number (%) 1. Clean 2. Clean-contaminated 3-4. Contaminated or infected Preoperative hospital stay (days) - number (%) 2 >2 Type of surgical procedure - number (%) Simple Multiple

Total

No SSI

SA SSI

n D 238,470

n D 238,044

n D 426

n (%)

99.8%

0.2%

60.8 (44.2-73.6)

60.8 (44.2-73.6)

63.5 (50.8-75.5)

59,622 (25.0) 59,614 (25.0) 59,616 (25.0) 59,618 (25.0)

59,549 (25.0) 59,499 (25.0) 59,502 (25.0) 59,494 (25.0)

130,317 (54.6) 108,153 (45.4)

OR for fixed risk factors P

OR

95% CI

73 (17.1) 115 (27.0) 114 (26.8) 124 (29.1)

1 0.99 0.86 0.80

0.71-1.39 0.60-1.24 0.54-1.18

130,102 (54.7) 107,942 (45.3)

215 (50.5) 211 (49.5)

1 1.59

1.26-2.00