The effect of targeted decolonization on methicillin-resistant Staphylococcus aureus colonization or infection in a surgical intensive care unit

ARTICLE IN PRESS American Journal of Infection Control ■■ (2015) ■■–■■

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Major articles

The effect of targeted decolonization on methicillin-resistant Staphylococcus aureus colonization or infection in a surgical intensive care unit Oh-Hyun Cho MD, PhD a,b, Eun Hwa Baek RN b, Mi Hui Bak PhD, RN b, Young Sun Suh MD c, Ki-Ho Park MD, PhD d, Sunjoo Kim MD, PhD e,f, In-Gyu Bae MD, PhD a,b,f, Sun Hee Lee MD, PhD g,* a Division of Infectious Diseases, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, JinJu, Republic of Korea b Infection Control Office, Gyeongsang National University Hospital, JinJu, Republic of Korea c Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, JinJu, Republic of Korea d Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Republic of Korea e Department of Laboratory Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, JinJu, Republic of Korea f Gyeongsang Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, JinJu, Republic of Korea g Division of Infectious Diseases, Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea

Key Words: Mupirocin Chlorhexidine Infection control

Background: The effect of decolonization on the control of methicillin-resistant Staphylococcus aureus (MRSA) may differ depending on intensive care unit (ICU) settings and the prevalence of antiseptic resistance in MRSA. Methods: This study was conducted in a 14-bed surgical ICU over a 40-month period. The baseline period featured active surveillance for MRSA and institution of contact precautions. MRSA decolonization via chlorhexidine baths and intranasal mupirocin was implemented during a subsequent 20-month intervention period. Pre–post and interrupted time series analysis were used to evaluate changes in the clinical incidence of hospital-acquired MRSA colonization or infection. MRSA isolates were tested for the presence of qacA/B genes and mupirocin resistance. Results: In pre–post analysis, the clinical incidence of MRSA significantly decreased by 61.6% after implementation of decolonization (P < .001). Meanwhile, interrupted time series analysis showed decreases in both the level (β = −0.686; P = .210) and trend (β = −0.011; P = .819) of clinical MRSA incidence, but these changes were not statistically significant. Of 169 MRSA isolates, 64 (37.8%) carried the qacA/B genes, and 22 (13.0%) showed either low- (n = 20) or high-level (n = 2) resistance to mupirocin. Low-level mupirocin resistance significantly increased from 0%-19.4% during the study period. Conclusion: Although decolonization using antiseptic agents was helpful to decrease hospital-acquired MRSA rates, the emergence of antiseptic resistance should be monitored. © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

* Address correspondence to Sun Hee Lee, MD, Department of Internal Medicine, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 602-739, Republic of Korea. E-mail address: [email protected] (S.H. Lee). This work was presented in part at ID week, Philadelphia, PA, October 8-12, 2014 (abstract No. 47277). Funding sources: None. Conflicts of Interest: None to report.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious infections in intensive care units (ICUs).1 Colonization with MRSA increases the risk of subsequent MRSA infections—including pneumonia and soft tissue and bloodstream infections—by 10%-30%, and creates primary reservoirs for further transmission of the pathogen within ICUs.1-3 MRSA decolonization therapy is an option when the rates of colonization and infection do not decrease when basic precautionary

0196-6553/© 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2015.12.007

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practices, including hand hygiene and contact isolation, are instituted.4 Recent studies have shown that universal decolonization with chlorhexidine, even without performance of active surveillance testing (AST) or targeted decolonization of ASTidentified MRSA carriers, may reduce the rates of MRSA acquisition, colonization, and infection.5-8 However, the widespread use of chlorhexidine and/or mupirocin has raised the concern that resistance to these antiseptic agents may increase.8-10 S aureus has 2 mechanisms of mupirocin resistance: low-level resistance (to 8-256 mg/L mupirocin) associated with mutation of the ileS gene encoding isoleucyl-tRNA synthetase, and high-level resistance (to ≥512 mg/L mupirocin) caused by acquisition of the mupA gene encoding a novel isoleucyl-tRNA synthetase.11 Mupirocin resistance in S aureus has emerged since mupirocin-based decolonization was introduced as a routine and sustained strategy to control endemic MRSA infection and transmission in some hospitals.12 Chlorhexidine-resistance involves the actions of protondependent multidrug efflux pumps encoded by plasmid-borne qacA/B genes.10 The prevalence of such genes in S aureus varies among countries, ranging from 1% in the eastern states of the United States to 80% in Brazil.13,14 In a study of 894 MRSA strains isolated in Asian countries between 1998 and 1999, the prevalence of the qacA/B genes was 32% in Korea. 15 Some studies have found that high-level mupirocin resistance, or a combination of low-level mupirocin resistance and qacA/B expression, were associated with a failure to effectively decolonize MRSA.16-18 Therefore, the efficacy of antiseptics used in decolonization procedures may vary among countries. A Korean national surveillance program (performed in 2011) showed that 64% of tertiary hospitals harbored MRSA.19 Infection control strategies should be individualized, because hospital settings differ by country, and little information is available on either the effect of decolonization on MRSA control or the prevalence of antiseptic-resistant MRSA in Korea. Targeted decolonization of MRSA carriers commenced in December 2012 in the surgical intensive care unit (SICU) of Gyeongsang National University Hospital. This was because MRSA numbers were increasing despite formalization of basic infection control practices. In the present study, we explored whether targeted decolonization successfully controlled MRSA infection or colonization, and determined the prevalence of antiseptic resistance in MRSA isolates from the SICU. METHODS Hospital setting and infection control programs The present study was conducted in a 14-bed SICU (with 2 single rooms and 3 open bays) of an 890-bed teaching hospital located in Jinju, South Korea, from April 2011 through July 2014. In this interval, we observed that both the incidence of MRSA infection and that of MRSA colonization were increasing, and targeted decolonization of MRSA carriers commenced in December 2012. To assess the efficacy of this therapy, we retrospectively analyzed data over 2 intervals of time: a baseline 20-month period (period 1) from April 2011-November 2012, and an intervention 20-month period (period 2) from December 2012-July 2014. During period 1, AST for MRSA using nasal swab samples was performed for all patients who were admitted to the SICU within 24 hours of admission. Follow-up AST was performed weekly if MRSA was identified in admission surveillance cultures; otherwise, AST was performed only on admission. Clinical culture for MRSA was requested when infections were clinically suspected. Any patient colonized or infected with MRSA was moved to a single room or a cohorted area with other MRSA patients in an open bay and managed by instituting contact precautions, until three consecutive follow-

up cultures were MRSA-negative. Contact precautions included placement of a warning post at the bedside, strict adherence to hand hygiene protocols, and the use of vinyl gowns, gloves, and dedicated medical equipment for patient care of index cases. Handwashing using an alcohol-based hand gel was encouraged, and the SICU environment was cleaned daily. On-site educational sessions, which included feedback on compliance with hand hygiene and contact precautions, and data on MRSA infection or colonization in the SICU, were given to the nursing staff and SICU physicians biweekly by an infection control team. During period 2, the following changes were made. The AST was performed on ICU admission and twice weekly until ICU discharge for all SICU patients, regardless of the MRSA culture results. Patients identified as MRSA carriers via AST or clinical culture underwent 5-day decolonization as follows: mupirocin ointment (Bactroban; GlaxoSmithKline, London, United Kingdom) was applied to the anterior nares twice a day and whole-body bathing with 2% chlorhexidine gluconate (CHG) solution (Dyna-Hex 2; Xttrium Laboratories, Mt Prospect, IL) was performed once daily. Bathing was conducted using CHG solution-soaked washcloths except for above the neck, on the perineum, or on open wounds. Bathing compliance was monitored and taught during onsite education sessions. If MRSA persisted after the first cycle of decolonization, 1 or 2 more decolonization cycles were scheduled. Follow-up MSRA surveillance culture resumed on the day after which decolonization therapy concluded. Definitions All patients admitted to the SICU with MRSA identified via surveillance or clinical culture were included in the present study. If >1 contemporaneous positive sample was obtained from the same patient, she or he was nonetheless regarded as experiencing a single MRSA episode. An admission-prevalent case was defined upon MRSA surveillance culture- or clinical culture-positivity of a sample taken less than 48 hours after SICU admission, or positivity of a sample taken during the (unbroken) period of hospitalization before admission to the SICU. An incident case was defined by a surveillance or clinical culture positive for MRSA from a sample obtained >48 hours after admission to the SICU, for patients with either a surveillance or clinical culture negative for MRSA at the time of admission or with no previous history of MRSA colonization or infection.7 A clinical-incident case was defined by a positive MRSA result according to clinical culture data alone; otherwise, the definition was the same as that of an incident case.20 The admission prevalence of MRSA was defined as the number of admissionprevalent cases per 1,000 patient-days in any given month. The incidence of MRSA was defined as the number of incident cases per 1,000 patient-days at risk of newly acquired MRSA colonization or infection in any given month. The clinical incidence of MRSA was defined as the number of clinical-incident cases per 1,000 patientdays at risk of newly acquired MRSA colonization or infection in any given month. As modifications made to the AST method before period 2 may have affected the observed incidence, we consider that comparisons of clinical incidence more reliably reveal any effect of decolonization therapy. Microbiologic methods For AST, swab samples from each patient were obtained from both anterior nares using sterile transport swabs (Copan Diagnostics, Murrieta, CA). Nasal swab specimens taken before August 2012 were processed by standard culture methods on 5% sheep blood agar plates (BD Diagnostics, Sparks, MD). After 24 hours of incubation, colonies that exhibited a morphology consistent with S aureus were processed for identification and antimicrobial susceptibility tests

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using the Vitek-2 system (bioMérieux, Durham, NC). Since August 2012, MRSA-selective agar (CHROMagar; BD Diagnostics) has been introduced for AST, and nasal swab samples were inoculated onto such plates, incubated at 35°C, and evaluated for bacterial growth after 24-48 hours. Pinkish colonies were identified as MRSA,21 and species identification was confirmed by coagulase testing using a plasma agglutination assay (BD Diagnostics) and polymerase chain reaction (PCR) detecting mecA genes. MRSA isolates obtained before decolonization therapy were tested for antiseptic resistance. This test was performed on nonduplicate patient isolates recovered from active surveillance cultures or clinical cultures. The extent of mupirocin resistance was determined using a disc-diffusion method (the discs contained 5 or 200 μg mupirocin; Oxoid, Basingstoke, United Kingdom). Low-level resistance was defined as an inhibition zone <14 mm around a 5-μg mupirocin disc and the presence of any zone around a 200-μg disc. High-level resistance was defined as the absence of any inhibition zone around the 200-μg mupirocin disc.22 PCR amplification of the mupA gene was performed, as previously described, on phenotypically mupirocin-resistant MRSA isolates; the gene confers highlevel mupirocin resistance.18 The minimal inhibitory concentrations (MICs) of chlorhexidine were determined using a broth microdilution method and a 20% CHG solution (Sigma-Aldrich, St Louis, MO); the final concentrations of the antiseptic were 0.5-32 μg/mL.23 PCR amplification of the qacA/B genes was performed as described previously.18 S aureus TS77 (qacA; RIKEN BRC, Ibaraki, Japan) and TPS162 (qacB; RIKEN BRC) served as positive controls, and S aureus ATCC 29213served as the negative control. Statistical analysis Two analytical approaches were used to assess the effect of targeted decolonization: pre–post analysis for comparing aggregated MRSA rates and interrupted time series (ITS) analysis for comparison and quantification of pre- and postintervention trends.20 In pre– post analysis, we evaluated changes in the prevalence, incidence, and clinical incidence of MRSA colonization or infection, using a Poisson regression model.20 The null hypothesis was that MRSA isolation rates were identical during the 2 periods. ITS analysis featured segmented Poisson regression in an effort to detect changes in the levels (ie, intercepts and abrupt intervention effects) and trends (ie, slopes and gradual intervention effects) of prevalence, incidence, and clinical incidence, after introduction of targeted decolonization.23,24 The segmented Poisson regression model used was: ln(λ) = β0 + β1(T) + β2(I) + β3(T*), where T was the month, I the intervention, and T* the months after intervention. In this model, β1 is the trend before intervention, β2 is the change in level, and β3 is the difference in the pre- and postintervention trend. First-order autocorrelation was explored using the DurbinWatson statistical test. Categorical variables were compared using the χ2 test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test or Student t test. All tests were 2-tailed, and P ≤ .05 was considered to indicate significance. Statistical analyses were performed with the aid of SAS for Windows, version 9.3 (SAS Institute, Chicago, IL). The study was approved by the Institutional Review Board of Gyeongsang National University Hospital. RESULTS The baseline characteristics of patients admitted to the SICU and the results of intervention during the two periods are shown in Table 1. Although the median age and the number of patients admitted to the Department of General Surgery were higher in period

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Table 1 Demographic characteristics and pre- and postintervention estimates of the prevalence and incidence of colonization or infection by methicillin-resistant Staphylococcus aureus (MRSA) during the study period

Variable Age, y Male sex Admitting department Neurosurgery General surgery Chest surgery No. of patients with hospital stays > 48 h ICU mortality Length of ICU stay, d No. of patients yielding MRSA isolates Site of MRSA isolation* Nose† Respiratory tract† Wound† Blood† Other† MRSA present on admission No. of cases Admission prevalence Incident cases of MRSA No. of cases Incidence Clinical incidence

Period 1 (n = 852)

Period 2 (n = 888)

P value

61 (48-72) 494 (58.0)

64 (52-73) 507 (57.1)

.008 .734

565 (66.3) 95 (11.2) 124 (14.6) 681 (79.9)

531 (59.8) 148 (16.7) 125 (14.1) 698 (78.6)

<.001 .001 .785 .516

148 (17.4) 5 (3-13) 168 (19.7)

166 (18.7) 5 (3-13) 140 (15.8)

.493 .446 .036

80 (47.6) 77 (45.8) 11 (6.5) 2 (1.2) 2 (1.2)

100 (71.4) 31 (22.1) 6 (4.3) 4 (2.9) 6 (4.3)

<.001 <.001 .539 .416 .148

77 (9.0) 9.6

78 (8.8) 9.7

.802 .911‡

91 (10.7) 12.0 8.6

62 (7.0) 8.4 3.3

.007 .084‡ <.001‡

NOTE. Data are presented as n (%) of admissions, median (interquartile range), or n. ICU, intensive care unit; IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus. *Multiple positive samples from the same site were considered as a single isolation. † Data are presented as n (%) of MRSA isolation sites per no. MRSA-positive patients. ‡Pre–post analysis via Poisson regression modeling.

2 than period 1, neither the median duration of SICU stay nor mortality differed significantly between the 2 periods. During period 1, a total of 852 patients were admitted to the SICU, of whom 168 (19.7%) were positive for MRSA on admission or during the SICU stay. Of these, 80 (47.6%) were identified only by AST and 23 (13.7%) by both AST and clinical culture. During period 2, a total of 888 patients were admitted to the SCIU, of whom 140 (15.8%) were positive for MRSA on admission or during the SICU stay. Of these, 100 (71.4%) were identified only by AST and 25 (17.9%) by both AST and clinical culture. The sites of MSRA isolation are shown in Table 1. Upon pre–post analysis, the admission prevalence of MRSA colonization or infection did not change significantly between the 2 periods (9.6 vs 9.7 cases per 1,000 patient-days; P = .911). However, the incidence decreased by 30.0% during period 2, and this trended toward significance (12.0 vs 8.4 cases per 1,000 patient-days; P = .084). The clinical incidence also decreased significantly (by 61.6%) from period 1 to period 2 (8.6 vs 3.3 cases per 1,000 patient-days; P < .001) (Table 1). We used ITS to evaluate the effects of targeted decolonization on MRSA colonization or infection, and the results are shown in Table 2 and Figure 1. A significant change in trend of admission prevalence was evident when the 2 periods were compared (β3, −0.095; P < .001). Although the change in the trend of MRSA incidence was insignificant (β3, −0.023; P = .529), a significant decrease in the level of incidence was observed after introduction of targeted decolonization (β2, −0.836; P = .046). However, no significant change in either the level or trend of clinical incidence was observed when the 2 periods were compared (β2, −0.686; P = .210 and β3, −0.011; P = .819).

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Table 2 Segmented regression analysis of an interrupted time series* exploring the effect of targeted decolonization during the study period

Variable Admission prevalence Preintervention trend Change in level Change in pre- to postintervention trend Incidence Preintervention trend Change in level Change in pre- to postintervention trend Clinical incidence Preintervention trend Change in level Change in pre- to postintervention trend

Regression coefficient (95% confidence interval)

P value

0.053 (0.014 to 0.092) −0.014 (−0.596 to 0.526) −0.095 (−0.150 to −0.039)

.008 .902 .001

0.036 (−0.009 to 0.081) −0.836 (−1.656 to −0.016) −0.023 (−0.094 to 0.048)

.115 .046 .529

−0.009 (−0.057 to 0.039) −0.686 (−1.760 to 0.387) −0.011 (−0.105 to 0.083)

.717 .210 .819

*The following Poisson model was used: ln(λ) = β0 + β1(T) + β2(I) + β3(Ta), where T is the month, I the intervention, and Ta the months after intervention.

Incidence of MRSA

Period 1

(b)

Period 2

Change in level β2=-0.836

Pre-intervention trend, β1=0.036

Post-intervention trend β1+β3=0.013 1

10

20

Period 1

Clinical incidence of MRSA

(a)

30

40

Period 2

β1=-0.009 β1+β3=-0.020

β2=-0.686

1

10

20

30

40

months

months

Fig 1. Changes in the rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection as revealed by segmented Poisson regression analysis by period of intervention. Changes in (A) incidence and (B) clinical incidence of MRSA (colonization or infection). The time of initiation of targeted decolonization is shown by the broken bar.

Table 3 Antiseptic-resistance frequencies of methicillin-resistant Staphylococcus aureus isolates

Antiseptic agent Chlorhexidine MIC ≥ 4 μg/mL qac A/B (+) Mupirocin Low-level resistance High-level resistance mup A (+)

Total (n = 169)

Period 1 (n = 66)

Period 2 (n = 103)

P value

108 (63.9) 64 (37.9) 22 (13.0) 20 (11.8) 2 (1.2) 4 (2.4)

38 (57.6) 31 (47.0) 1 (1.5) 0 1 (1.5) 1 (1.5)

70 (68.0) 33 (32.0) 21 (20.4) 20 (19.4) 1 (1.0) 3 (2.9)

.227 .074 <.001 <.001 .999 .999

NOTE. Data are presented as n (%). MIC, minimum inhibitory concentration.

A total of 169 MRSA isolates from nonduplicate patients underwent antiseptic-resistance testing; 37 were isolated from clinical cultures, and the remaining 132 were isolated from surveillance cultures either on admission (87 isolates) or during the SICU stay (45 isolates) (Table 3). Sixty-four (37.8%) isolates carried qacA/B genes, the presence of which was significantly associated with a chlorhexidine MIC ≥ 4.0 μg/mL (49.1% vs 18.0%; P < .001). However, the proportion of MRSA isolates with chlorhexidine MICs ≥ 4.0 μg/ mL did not change significantly over the study period (57.6% vs 68.0%; P = .227). The proportion of MRSA isolates carrying qacA/B genes decreased from 47.0% in period 1 to 32.0% in period 2 (P = .074). Overall, 22 MRSA isolates showed either low- (n = 20) or high-level (n = 2) resistance to mupirocin (the overall resistance rate was 13.0%), and

the proportion of mupirocin-resistant MRSA isolates carrying mupA genes was 2.4% over the entire study period. A significant increase in the proportion of low-level mupriocin resistance was observed when period 2 was compared with period 1 (0% vs 19.4%; P < .001). Of 22 mupirocin-resistant MRSA isolates, 12 (54.5%) contained qacA/B genes. However, mupirocin resistance was not significantly associated with qacA/B carriage (P = .101).

DISCUSSION During period 1, the rate of MRSA acquisition tended to increase trend even when basic infection control practices, including AST and contact precautions, were in effect, and we thus introduced targeted decolonization to seek to control MRSA acquisition in our SICU. Although the clinical incidence of MRSA colonization or infection significantly decreased (by 61.6%) between the 2 periods in the pre–post analysis, a nonsignificant decrease in the level or trend of the clinical incidence of MRSA was observed in ITS analysis. Considering that ITS methodology is more informative and rigorous than pre–post analysis,20 it is likely that targeted decolonization may not have been associated with the decreased clinical incidence of MRSA in this study. However, the sustained downward level and slope of the clinical incidence of MRSA in ITS analysis suggests that the influence of targeted decolonization may be positive, but our small sample size may have rendered it difficult to achieve statistical significance. Even though prevention bundles for

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ventilator-associated pneumonia did not change in the SICU during the study period, there was a significant decrease in MRSA isolates from respiratory tract cultures during period 2, which also supports a beneficial effect of targeted decolonization on the control of MRSA infection or colonization in the SICU. These results are in line with previous studies that showed a positive effect of chlorhexidine-based decolonization for MRSA carriers on decreased MRSA rates in ICUs.7,8 Ridenour et al7 reported a 52% decrease in rates of MRSA acquisition in the ICU, and Climo et al8 showed a 32% decrease in MRSA acquisition in 6 ICUs. Contrary to these studies, it is difficult to interpret whether AST alone or AST plus decolonization helped decrease MRSA rates in our study, because there were changes in AST methodology and timing before and during period 2.25 Whereas no significant change in the admission prevalence of MRSA was observed between the study periods, there was an increase in the proportion of MRSA isolates from nasal cultures (AST) during period 2. Although evidence for an influence on MRSA acquisition by increasing the frequency of AST and reducing turnaround time via introduction of chromogenic MRSA agar was lacking, these methodologic changes may have been associated with an increase in MRSA isolates from AST but a decrease in the clinical incidence of MRSA by enhancing contact isolation or decolonization.26 Recently, some studies reported that universal decolonization of ICU patients using chlorhexidine and mupirocin reduced MRSA infection or colonization more effectively than did targeted decolonization, because targeted decolonization has some drawbacks, including financial burden, increased nurse and laboratory workload associated with screening, and delayed patient throughput.5,27 However, widespread use of chlorhexidine and mupirocin raises concern about the development of resistance to these antiseptic agents. In addition, another drawback of universal decolonization is the unnecessary use of mupirocin in the 70%-80% of patients who do not carry S aureus, enhancing resistance in coagulase-negative staphylococci and creating a reservoir of resistance to MRSA.10,28 In the present study, we found that the prevalence of highlevel mupirocin resistance was low throughout the study period, but the extent of low-level resistance significantly increased during period 2. This finding is consistent with previous studies that showed that increased mupirocin use predisposes to mupirocin resistance.29 Lee et al18 reported that, in 2 Korean tertiary hospitals, the rate of low-level mupirocin resistance increased from 14% in 2006 to 22% in 2009, similar to our data. Another study, in a Canadian hospital, showed a significant increase in mupirocin-resistant isolates from 2.7%-65% for 3 years during the use of mupirocin-based nasal decolonization.30 Although an association between high-level resistance and decolonization failure is accepted, any clinical significance of low-level resistance is less well understood.12,25 In a randomized trial, Harbarth et al31 showed that low-level mupirocin resistance increased the risk of persistent S aureus carriage after decolonization. Thus, mupirocin should be used cautiously when MRSA decolonization is required.12,31 We found that the prevalence of MRSA isolates with qacA/B genes was high, peaking at 38% during our study period. In a study of 894 MRSA isolates collected in Asian countries between 1998 and 1999, the prevalence of the qacA/B genes was 32% in Korea.15 Another study found that 65% of Korean mupirocin-resistant MRSA strains carried the qacA/B genes.18 Thus, it is possible that that these genes are widely distributed in Korea, regardless of decolonization efforts. We found a significant correlation between presence of the qacA/B genes and a high chlorhexidine MIC (≥4 μg/mL), consistent with previous reports.32 However, the lack of a standardized test for assessment of susceptibility to chlorhexidine renders it difficult to assess the relationship between carriage of qacA/B and a high chlorhexidine MIC, and also to evaluate any effect of the elevated

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MIC on decolonization failure.10 Recently, some studies found that certain MRSA clones bearing qacA/B genes were at a selective advantage during decolonization, and that both the qacA/B genes and low-level mupirocin resistance were not only closely linked but also related to persistent MRSA carriage after decolonization.16,17,23 Although the finding that 54% of mupirocin-resistant MRSA isolates harbored qacA/B genes suggests a possible relationship between qacA/B genes and mupirocin resistance in this study, we could not assess the association between antiseptic resistance and decolonization failure. There were several limitations to our study. First, interventions were introduced either simultaneously or sequentially; guided by clinical necessity; and compliance with the various interventions, including hand hygiene, contact precautions, and AST, was not systematically monitored over the study period. Therefore, we could not evaluate the effects of individual interventions. Moreover, implementation of new intervention programs may have enhanced compliance with infection control measures only temporarily, yielding an immediately encouraging but later waning response.20 Second, although the ITS analysis could give more information (especially, regarding the trend of MRSA rates), this was a retrospective study in an SICU (thus not a randomized trial), and we thus could not control for several confounding factors (eg, colonization pressure and compliance with hand hygiene and contract precautions) on the observed decrease in MRSA isolation.24 Third, a change in population from a predominance of neurosurgery patients to more general surgery patients between the 2 periods is another confounding factor that may have influenced the effect of decolonization, because any effect of decolonization may be reduced in general surgery patients who often have large open wounds that can serve as sources of MRSA transmission.33 CONCLUSIONS Implementation of targeted decolonization using intranasal mupirocin and chlorhexidine baths resulted in a reduction of the clinical incidence of MRSA colonization or infection in an SICU. However, because MRSA antiseptic resistance is not uncommon, antiseptic susceptibility testing may be required to plan effective decolonization. Acknowledgments The authors thank RIKEN Bioresource Center, Japan, for providing TS77 (qacA) and TPS162 (qacB). References 1. Weber SG, Huang SS, Oriola S, Huskins WC, Noskin GA, Harriman K, et al. Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: position statement from the Joint SHEA and APIC Task Force. Am J Infect Control 2007;35:73-85. 2. Datta R, Huang SS. Risk of infection and death due to methicillin-resistant Staphylococcus aureus in long-term carriers. Clin Infect Dis 2008;47:176-81. 3. Boyce JM, Havill NL, Kohan C, Dumigan DG, Ligi CE. Do infection control measures work for methicillin-resistant Staphylococcus aureus? Infect Control Hosp Epidemiol 2004;25:395-401. 4. Calfee DP, Salgado CD, Milstone AM, Harris AD, Kuhar DT, Moody J, et al. Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:S108-32. 5. Huang SS, Septimus E, Kleinman K, Moody J, Hickok J, Avery TR, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 2013;368:2255-65. 6. Climo MW, Wong ES. Daily chlorhexidine bathing and hospital-acquired infection. N Engl J Med 2013;368:2332. 7. Ridenour G, Lampen R, Federspiel J, Kritchevsky S, Wong E, Climo M. Selective use of intranasal mupirocin and chlorhexidine bathing and the incidence of

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