Which is the most appropriate strategy for nasal screening and Staphylococcus aureus decolonization in total hip arthroplasty patients?


 Background: To reduce periprosthetic joint infection after total hip arthroplasty (THA), several nasal screening and decolonization strategies for methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) have been performed. These include universal decolonization (UD; i.e., no screening and decolonization for all patients), universal screening and target decolonization (US; i.e., screening for all patients and decolonization for bacterial positive patients), and target screening and decolonization (TS; i.e., screening and decolonization for high-risk populations only). Although TS is the most cost-effective strategy, useful risk factors must be identified. The purpose of this study was to evaluate the presence of predictive factors that enable the TS strategy to be successfully implemented and to compare the costs of each strategy.Methods: A total of 1654 patients scheduled for primary or revision THA (1464 women, 190 men; mean age 64 years) were screened prior to surgery for bacterial colonization of the nasal mucosa. Risk factors for positive MRSA and MRSA/MSSA tests were analyzed according to the following parameters: sex, age ≥80 years, body mass index ≥30 kg/m2, antibiotic use within 3 years, corticosteroid use, serum albumin <3.5 g/dL, glomerular filtration rate <50 mL/min, presence of brain, thyroid, cardiac or pulmonary disease, diabetes, asthma, and smoking habit. The average cost of each strategy was calculated.Results: In total, 29 patients (1.8%) tested positive for MRSA and 445 (26.9%) tested positive for MRSA/MSSA. No parameters were identified as independent risk factors for MRSA and only female sex was identified as a risk factor for MRSA/MSSA (p=0.003; odds ratio: 1.790; 95% confidence interval: 1.210-2.640). The average cost of each strategy for eradicating MRSA was 1641.3 yen for UD, 285.8 yen for US, and 252.3 yen for TS.Conclusions: No useful predictive parameters for implementing the TS strategy were identified. Based on cost implications, US is the most cost-effective strategy for THA patients.


Background
Total hip arthroplasty (THA) is a common surgical procedure, and the number of such procedures performed is expected to increase with increasing aging of society [1]. Although THA is an effective procedure with a low complication rate, periprosthetic joint infection (PJI) following THA is a devastating complication. PJI from Staphylococcus aureus leads to increased mortality, duration of hospitalization, and cost [2,3], and therefore prevention and control strategies for PJI caused by methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) are critical for both patient safety and cost reduction.
One of the most important factors in reducing infections is identifying and eradicating nasal bacterial colonization prior to surgery. Previous studies have shown that preoperative nasal decolonization for MRSA/MSSA in THA patients can reduce the risk of surgical site infection (SSI), which can lead to PJI [4,5]. However, various screening and decolonization strategies have been reported: universal decolonization (UD), which involves no screening and decolonization of all patients [6,7]; universal screening and target decolonization (US), which involves screening for all patients and decolonization for MRSA or MRSA/MSSA-positive patients [4,5,8,9]; and target screening and decolonization (TS), which involves screening for high-risk populations only and decolonization for MRSA or MRSA/MSSA-positive patients [10]. Controversy remains as to the most appropriate strategy.
Although UD can signi cantly reduce the prevalence of MRSA/MSSA carriers without a waiting period for screening results [7], the protocol has problems of higher cost and the development of resistant strains [11]. US can reduce sampling error rates and offers a cost-effective screening method [4,5]. One option to reduce the cost of screening is to implement TS based on certain 'risk factors'. However, this strategy requires determining these risk factors with appropriate sensitivity and speci city. According to Dave et al., the TS method failed to detect half of the MRSA-positive cases in their study [8]. Thus, clarifying whether proper predetermined factors are correlated with the risk of MRSA/MSSA carrier status is important in TS. Moreover, although nancial considerations are crucial for implementing nasal screening and decolonization, few reports have compared the costs of these three strategies.
The purpose of this study was to investigate whether it is possible to determine the predictive factors for successful implementation of the TS strategy with MRSA/MSSA carriers, and to clarify the most costeffective strategy for patients who undergo THA surgery. group. Risk factors for positive MRSA and MRSA/MSSA tests were analyzed according to the following parameters: sex, age at time of surgery (≥80 or <80 years), body mass index (BMI: ≥30 or <30 kg/m 2 ), antibiotic use within 3 years before surgery, previous or present corticosteroid use, serum albumin (<3.5 or ≥3.5 g/dL), glomerular ltration rate (GFR: <50 or ≥50 mL/min), presence or not of brain, thyroid, cardiac or pulmonary disease, diabetes, asthma, and smoking habit. Screening and decolonization costs for each strategy were calculated.

Methods
Fisher's exact test was used for univariate analysis to identify risk factors for MRSA and MRSA/MSSA, and stepwise logistic regression was used for multivariate analysis.

Risk factors for MRSA
In total, 29 cases (1.8%) were classi ed in the MR+ group and 1625 in the MR− group. Univariate analysis found no signi cant difference between the proportion of females in the MR+ group relative to all females (25 vs. 1464) and relative to all males (4 vs. 190 Similarly, as shown in Table 1, no signi cant differences were found between age ≥80 and <80 years, BMI ≥30 and <30 kg/m 2 , antibiotic use within 3 years or not, corticosteroid use or not, serum albumin<3.5 and ≥3.5 g/dL, GFR<50 and ≥50 mL/min, presence of brain, thyroid, cardiac, or pulmonary disease or not, presence of diabetes or not, presence of asthma or not, and smoking habit or not.
Multivariate analysis revealed no parameters as independent risk factors.

Risk factors for MRSA/MSSA
In total, 445 cases (26.9%) were positive for MRSA/MSSA. Therefore, the number of patients in the MS+ group was 445, with 1209 in the MS− group. From univariate analysis, the proportion of females in the MS+ group relative to all females (411 vs. 1464) was signi cantly higher than relative to all males (34 vs. 190) (28.1% vs. 17.9%, p=0.003; OR: 1.790; 95%CI: 1.205-2.724). No signi cant difference was seen with any other parameters (Table 2.).
According to multivariate analysis, only female sex (p=0.003; OR: 1.790; 95%CI: 1.210-2.640) was an independent risk factor for the presence of MRSA/MSSA with a sensitivity of 0.924, speci city of 0.129.

Calculation of costs
For the UD strategy, all patients needed mupirocin ointment, which costs 1641.3 yen for every 3-gram product in Japan. Therefore, the cost of the UD strategy is 1641.3 yen per person.  Table 3).

Incidence of SSI or PJI
A total of 1522 cases (92.0%) were observed in the more than 2 years of follow-up. There were 6 cases of super cial SSI. Pathogens were 1 case of MRSA, 1 of methicillin-resistant coagulase-negative Staphylococcus, 2 of MSSA, and 2 of methicillin-sensitive coagulase-negative Staphylococcus. Among these patients, SSI pathogens of 1 MSSA case and 1 methicillin-sensitive coagulase-negative Staphylococcus case were matched with nasal bacteria. There were no cases of deep incisional SSI. Other than these, there were no cases of PJI during the follow-up period.

Discussion
In this study, no risk factors for MRSA were identi ed and the risk factor for MSSA/MRSA carriage was female sex only. As for MSSA/MRSA carrier status, speci city of female sex as a risk factor was 0.129.
Because of low speci city, implementing the TS strategy considering this risk factor would require screening a considerable number of patients-amounting to 88.5% of all patients-with 4 of 29 (13.8%) MRSA-positive cases and 34 of 445 (7.6%) MRSA/MSSA-positive cases being overlooked. Thus, this parameter is not useful and no suitable risk factor for the TS strategy was identi ed.
Previous studies have attempted to clarify various risk factors including male sex, white race, obesity, asthma [12], diabetes [13], and renal disease [14] for both MSSA and MRSA colonization, but opinions remain divided. While smoking was described as a risk factor in one study [15], it was found to have no relationship with MSSA/MRSA colonization in other studies [1,12]. De Wouters et al. reported although Belgian guidelines recommend TS for MRSA carriage on admission for high-risk populations only (age > 80 years; inpatient admission in the previous 6 months; past history of MRSA colonization; living in a nursing or residential home; exposure to invasive devices; chronic wounds or skin lesions; working in healthcare; and being in contact with farm animals), there was no correlation between identi ed MRSA carriers and these risk factors [16]. In the present study, when female sex was applied as a risk factor for TS, the average costs of US vs TS per person were 285.8 vs 252.3 yen (decolonization for MRSA-positive cases) and 698.6 vs 635.3 yen (decolonization for MRSA/MSSA-positive cases), so TS could reduce costs only by about 10% compared with US. As such, no useful predictive factors that enable the successful implementation of TS were identi ed and the strategy was also not that cost-effective.
The UD strategy is advocated in clinical units with a high risk of MRSA infections, such as intensive care units and emergency units, because it can protect patients during a period of vulnerability to infection and it can prevent delayed decolonization pending the results of screening [7]. However, in cases of elective surgery like arthroplasty, there is no urgency that requires UD, because patients are not particularly vulnerable and the waiting period for screening results is irrelevant. Moreover, UD as empiric therapy is not recommended because of the risk of increasing bacterial resistance [11]. Prior mupirocin use was reported to increase the risk of mupirocin resistance in MRSA carriers by 9 fold [17]. According to Graber and Schwartz, failure of decolonization may be the result of increased mupirocin resistance [18]. Another disadvantage of UD is nancial burden. In this study, mupirocin ointment at 1641.3 yen/product is needed to implement UD for all patients and this excludes personnel costs. In the United States, Stirton et al. reported the cost of empiric treatment with mupirocin for all patients as an estimated $24.65 per patient (equivalent to 2711.5 yen at 110 yen to 1 US Dollar), which included the personnel costs for instruction on mupirocin application [19].
The incidence of deep SSI in THA was reported as 1.1% [20], and the prevalence of revision THA due to PJI was reported as 0.4% following primary procedures and 1.6% following revision hip arthroplasty [21].
Bozic and Ries reported a longer duration of hospitalization with revision arthroplasty for infection than with aseptic loosening (28.2 vs 8.1 days, p<0.001) as well as higher total hospital cost ($96,166 vs $34,866, p<0.001) and higher outpatient charges ($48,348 vs $16,411, p<0.001) [22]. The cost of care for treatment of deep SSI caused by methicillin-resistant strains was estimated at $107,264 compared with $68,053 when caused by sensitive strains [2]. These amount to extremely high costs of revision arthroplasty due to infection.
Regarding SSI after total joint arthroplasty, MRSA and MSSA were reported as the most common pathogens [23]. Colonization of the nares occurs at higher rates compared with other body surfaces, and 65% of cases of MRSA colonization were detected in the nares [24]. There are three general sources of infection: endogenous, exogenous, and hematogenous [25]. Nasal carriage of Staphylococcus aureus is thought to be endogenous to patients and is a well-established risk factor for SSI or PJI. The risk of SSI following orthopaedic surgery was reported as 6.9 times higher among patients with preoperative MRSA nasal colonization [ The effectiveness of US for reducing SSI following THA has been widely reported. According to Nixon et al., implementing the US strategy for MRSA eradication reduced the cost of care, considering the enormous costs saved incurred by revision arthroplasty and prolonged admission due to infection [9].
Hacek et al. implemented US for 1495 cases of total joint arthroplasty with decolonization for MRSA/MSSA-positive patients and reported reduced SSI compared with 583 non-screened or decolonized control cases (0.77 vs 1.7 %, p≤0.1) [4]. Pofahl et al. reported that the SSI rate of US with decolonization for MRSA-positive patients was signi cantly lower than that of no-intervention controls (0 vs 0.30 %, p=0.04) for total joint arthroplasty [5]. Thus, implementing US can reduce the SSI rate, costs related to revision arthroplasty, and hospitalization duration.
In this study, no risk factors were identi ed for MRSA carriers and only female sex was identi ed, albeit with low speci city, for MRSA/MSSA carriers. Thus, no risk factors that can help target TS were identi ed. Also, TS was determined not to be as cost-effective as US. UD, which is suitable for intensive care units and emergency units, is over 5 times more expensive than US for eradicating MRSA. US would be a more cost-effective strategy than UD for THA patients whose screening results can be waited for. Therefore, overall, US is considered to be the most cost-effective strategy with reduced sampling error rates for THA patients.
There are several limitations in this study. First, the study population included few patients with extremely high risk such as age > 90 years, poorly controlled diabetes, and currently undergoing dialysis. Also, few of the patients were living in nursing or residential homes, which are considered sources of communityacquired infection. Second, there might be differences among countries. In this study, we attempted to identify risk factors for nasal bacterial carriage in a Japanese population, but different results might be obtained elsewhere. Further investigation is needed to clarify the risk factors for other countries. Third, in the calculation of costs, workloads differ in terms of giving instructions about applying ointment, collecting samples, and identifying the bacterial species. Also, personnel costs would differ considerably depending on the methods used and the insurance systems in place in each country. As such, personnel costs were not included in this study. Finally, there were only 6 cases of super cial SSI, 4 of which the causative pathogens did not match the nasal bacteria, and there were no cases of PJI in the 2-year followup period. Therefore, the relationship between nasal bacterial carriage and SSI or PJI remains unknown.

Conclusions
No predictive factors for nasal carriage of MRSA and MRSA/MSSA, which are useful for implementing the TS strategy, were identi ed. The cost of UD is more than 5 times that of US or TS for eradicating MRSA, and TS can reduce costs by about 10% only compared with US. Taking these ndings together, the US strategy is considered to reduce sampling errors and to be the most cost-effective strategy to implement for THA patients.    Figure 1 Calculation of screening cost The average total cost for screening was 257.0 yen/person.