Methicillin-Resistant Staphylococcus aureus (MRSA)

Vancomycin-Resistant Enterococci (VRE)

Multidrug-Resistant Enterobacteriaceae (MDR-E)

Clostridium difficile

Microbiological Screening and Molecular Testing

SHEA Research Network Survey

We surveyed SHEA Research Network (SRN) institutions to ascertain policies and practices for guiding duration and discontinuation of CP for MRSA, VRE, MDR-E, and C. difficile, as well as screening and testing methods (Table 1). On June 22,, June 28, and July 6, 2016, SHEA sent the survey to members of the SRN, which includes 134 individual institutions, 26% of which are outside the United States and Canada. Among them, 4 institutions opted out because they were not eligible to participate, and 7 indicated that they were unavailable to respond during the time the survey was open. The survey response rate was 70.7% (87 of 123).

TABLE 1

Survey of Institutions in the SHEA Research Network (SRN)

NOTE. CP, contact precautions; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci (VRE); CDI, Clostridium difficile infection; MDR-GNR, multidrug-resistant Gram-negative rods; CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum β-lactamase; EIA, enzyme immunoassay; PCR, polymerase chain reaction.

Of the responding institutions, 60.5% were academic medical centers, 18.4% were community teaching hospitals with academic affiliations, and 7.9% were community hospitals with no academic affiliations. The responding institutions varied in bed size and number of intensive care units (ICUs): 51–300 beds (29.7%), 301–600 beds (31.4%), 601–900 beds (16.3%), >900 beds (23.3%), and 1–3 ICUs (41.9%), 4–6 ICUs (30.2%), 7–9 ICUs (12.8%), ≥10 ICUs (14%). Overall, 94% of institutions had pediatric beds. On average, institutions reported having 1.4 hospital epidemiologists and 4.8 infection preventionists.

Individual respondents reported the following primary roles: healthcare epidemiologist (75.3%), infection committee chair (54.6%), and infection preventionist (26%). These individuals indicated that they are involved in patient care (40.3%), teaching (40.3%), clinical research (31.2%), and administration (18.9%).

More than half of the respondents identified C. difficile (56%) as the most problematic pathogen at their institution. Another 27% reported that multidrug-resistant Gram-negative rods (MDR-GNR), such as ESBL and CRE, were their highest concern. MRSA and VRE followed with 14% and 2%, respectively. Moreover, 38% of respondents reported a healthcare-associated cluster or outbreak related to C. difficile infection in calendar year 2015, followed by MDR-GNR (24%), MRSA (17%), and VRE (8%).

Most respondents reported using CP in patients colonized with MDRO: CRE (99%), MRSA (89%), VRE (90%), and other MDR-GNR (79%). All respondents reported using CP for at least 1 indication. In addition, 75% of respondents reported that their institution had a policy for discontinuing CP in patients colonized with MRSA; 61% for VRE; 32% for CRE; and 40% for other MDR-GNR. Furthermore, 25% of respondents reported using molecular methods of testing for detection of MRSA; 9% for VRE; 8% for CRE; and 5% for other MDR-GNR. The remainder reported the use of culture methods for screening.

Most respondents reported the use of screening tests for discontinuation of CP for MRSA (66%) and VRE (55%), but tests were less commonly used for discontinuing CP in patients with CRE and other MDR-GNR (29% and 26%, respectively). With regard to anatomic screening sites, the nares was the most commonly screened site for MRSA, followed by the rectum for VRE and CRE. In cases in which patients were infected with an MDRO, the original site of infection was screened frequently (45% for MRSA, 28% for VRE, 23% for CRE, and 21% for other MDR-GNR). Respondents reported using screening for discontinuing CP more frequently with MRSA and VRE (83% and 80%, respectively) than with CRE and other MDR-GNR (73% and 63%, respectively). Most commonly, 3 negative screens were required for discontinuing CP for MRSA (40%), VRE (46%), and CRE (14%). A large proportion of respondents indicated that >5 days need to elapse between screening specimen collections (30% for MRSA, 42% for VRE, 17% for CRE, and 12.7% for MDR-GNR).

The use of decolonization was reported by nearly a quarter of respondents for the purpose of discontinuing CP in MRSA (24%). A small number of institutions reported its use for eradication of VRE (3%), CRE (2%), and other MDR-GNR (2%).

Respondents reported that CP for C. difficile infection (CDI) is discontinued most frequently upon discharge (40%) or ≥24 hours after the cessation of diarrhea related to CDI (45%). Patients who are admitted with a history (within the last 6 months) of CDI are most frequently put on CP if they develop diarrhea (47%) or are managed as if they do not have a history of CDI (42%). In addition, 85% of respondents reported use of C. difficile toxin PCR for diagnosis of CDI, and 42% reported the use of enzyme immunoassay (EIA) for this purpose, suggesting that some institutions may be using both. Less than 5% of PCR and EIA users reported their use for discontinuing CP.

Current Recommendations on the Discontinuation of CP

Several states have laws supporting screening programs to identify patients with MRSA colonization, ²⁸ particularly patients viewed to be high-risk for MRSA colonization (eg, patients admitted to the intensive care unit). ²⁹ Hospitals determine where and when active surveillance should be performed and which high-risk populations and body sites are tested for colonization.Reference Calfee, Salgado and Milstone ³⁰ In addition, some hospitals perform surveillance cultures during hospitalization in predefined units to identify cases of MRSA acquisition.Reference Calfee, Salgado and Milstone ³⁰ Because colonization with MRSA can be persistent,Reference Kluytmans, van Belkum and Verbrugh ³¹ especially in high-risk populations, some previously published guidance documents recommend automatically placing patients on CP during hospitalization if they have a history of MRSA colonization or infection during prior hospital admissions,Reference Morgan, Murthy and Munoz-Price ^{5 ,} Reference Calfee, Salgado and Milstone ³⁰ thereby increasing the population in healthcare facilities who are on CP for MRSA.Reference Morgan, Murthy and Munoz-Price ⁵

There are no national guidelines pertaining to discontinuation of MRSA CP. The optimal duration of CP is unknown for patients previously colonized or infected with MRSA. Institutions often develop their own criteria for the discontinuation of CP.Reference Russell, Beekmann, Polgreen, Rubin and Uslan ^{9 ,} Reference Shenoy, Hsu, Noubary, Hooper and Walensky ^{11 ,} Reference Shenoy, Walensky, Lee, Orcutt and Hooper ³² Siegel et alReference Siegel, Rhinehart, Jackson and Chiarello ³³ suggest that if a patient has not been on antibiotics for several weeks and has at least 3 negative surveillance cultures for MRSA over the course of 1–2 weeks, this may be sufficient for discontinuing CP.

Variation exists among hospital policies for the discontinuation of CP for MRSA. Shenoy et alReference Shenoy, Hsu, Noubary, Hooper and Walensky ¹¹ conducted a survey of infection preventionists on the discontinuation of CP and found that 73% of respondents stated that their institutions had a policy for discontinuing CP for patients with a history of MRSA. However, the study found significant variation in the criteria used, and most institutions did not actively screen patients for the purpose of CP discontinuation. A survey of 55 hospitals administered by Hospital Corporation of America (HCA, Inc.), a large healthcare system in the United States, found that 68% of ICUs had a policy for discontinuing CP for MRSA.Reference Moody, Septimus and Hickok ³⁴ Additionally, 18% of the respondents to a survey administered to physicians in the Emerging Infections Network (EIN) reported that the duration of isolation for MRSA at their hospital was indefinite once a patient was positive.Reference Russell, Beekmann, Polgreen, Rubin and Uslan ⁹

Shenoy et alReference Shenoy, Kim and Rosenberg ³⁶ also conducted a randomized control trial of individuals with a history of MRSA colonization or infection at least 90 days prior to enrollment in the study and compared standard hospital practice of clinician-initiated screening using 3 sequential cultures (ie, “passive screening”) to study initiated screening for discontinuation of CP (ie, “active screening”). In the active screening arm, research staff obtained 3 sets of surveillance nasal cultures performed at least 24 hours apart, processed by both culture and PCR. Patients in both arms with 3 negative cultures who had not received antibiotics with activity against MRSA were eligible to have CP discontinued. The investigators found that in the passive screening arm, 31% of subjects had screening initiated and only 9.6% of subjects completed the series of swabs. In contrast, all subjects in the active screening arm had screenings initiated, and 74% had 3 swabs obtained to complete the series.Reference Shenoy, Kim and Rosenberg ³⁶ The negative predictive value of the first nasal swab processed by PCR was 97% compared to 3 sequential cultures. Shenoy et alReference Shenoy, Lee and Cotter ³⁷ also evaluated the use of a single PCR-based screening in an emergency department for patients with a history of MRSA prior to 90 days from that visit and who were not receiving antibiotics with activity against MRSA in the prior 48 hours. Of the patients eligible for the study, 65% were PCR negative and CP were discontinued. However, 69% of patients were not properly assessed for enrollment, demonstrating the significant challenges in implementing active screening programs for CP discontinuation, particularly in busy emergency departments.Reference Gase and Reese ³⁸

Other studies evaluating screening for discontinuation of CP used longer time intervals since the last MRSA culture for study eligibility. In a study by Vikram et al,Reference Vikram, Dumigan, Kohan, Havill, Tauman and Boyce ³⁹ individuals with no positive MRSA cultures in 6 months prior to hospital admission were screened for MRSA at multiple body sites (nares; wound if present; and if no wound, axillae and perineum) 3 consecutive times. The authors observed that only 21% of patients had 3 sets of surveillance cultures that were negative and were removed from CP. Goldsack et alReference Goldsack, DeRitter and Power ⁴⁰ collected 2 sets of nares cultures from patients readmitted to the hospital with a history of MRSA at least 1 year prior to the admission and without receipt of antibiotics in the prior 72 hours to assess continued MRSA colonization. They found that 80% of patients studied were no longer colonized with MRSA; these patients were subsequently removed from contact isolation.Reference Goldsack, DeRitter and Power ⁴⁰

Automated electronic health record systems with microbiologic data and electronic alerts may improve compliance with hospital policies for CP. In one system, discontinuation criteria are displayed to physicians when they attempt to discontinue CP, and only an infection preventionist can remove the visual alert for MRSA in the electronic health record when criteria are met per hospital protocol.Reference Quan, Cousins, Porter, Puppo and Huang ⁴¹ Carson et alReference Carson, Danford and Carson ⁴² evaluated outpatients who were not on long-term antibiotics and who had a MRSA infection at least 3 months prior to enrollment and therefore were “MRSA flagged” in the EMR. Eligible subjects had surveillance cultures obtained from the nares, axilla, inguinal area, and wound if present; if all cultures were negative, patients returned at least 7 days later for testing at these body sites a second time. They observed that 72% of outpatients in the study were no longer carriers of MRSA and were able to have the alert removed from their medical record.Reference Carson, Danford and Carson ⁴²

Duration of Colonization

Staphylococcus aureus colonization may be persistent (always present), intermittent (sometimes present and sometimes absent), or rarely occurring.Reference Kluytmans, van Belkum and Verbrugh ³¹ Studies examining individuals following hospital discharge have suggested that over time, many individuals will clear MRSA colonization, although a proportion will remain long-term carriers.Reference Scanvic, Denic, Gaillon, Giry, Andremont and Lucet ^{13 ,} Reference Robicsek, Beaumont and Peterson ^{43 ,} Reference Sanford, Widmer, Bale, Jones and Wenzel ⁴⁴ Long-term carriers of MRSA retain an increased risk of serious infection and even death due to MRSA compared to noncarriers.Reference Datta and Huang ⁴⁵ The median time to clearance of MRSA colonization is 7–9 monthsReference Scanvic, Denic, Gaillon, Giry, Andremont and Lucet ^{13 ,} Reference Marschall and Mühlemann ^{46 ,} Reference Lucet, Paoletti and Demontpion ⁴⁷ ; however, some individuals can have more prolonged carriage.Reference Robicsek, Beaumont and Peterson ⁴³ In an evaluation of children in the community over a 1-year period, 18% of children who were colonized with MRSA in the nares at enrollment remained colonized 1 year later.Reference Fritz, Krauss and Epplin ⁴⁸ In a retrospective assessment of known MRSA carriers who were readmitted to a large tertiary-care hospital, Sanford et alReference Sanford, Widmer, Bale, Jones and Wenzel ⁴⁴ observed that a proportion of readmitted carriers remained colonized for >3 years and that all patients colonized for >12 months had at least 1 positive wound culture. Similarly, Scanvic et alReference Scanvic, Denic, Gaillon, Giry, Andremont and Lucet ¹³ examined patients who were previously identified as MRSA carriers who were readmitted to the hospital and reported that those with a break in the skin at readmission were more likely to have persistent carriage of MRSA. Other factors associated with prolonged carriage of MRSA include older age, household members with MRSA colonization, need for help with daily activities, indwelling devices, a recent ICU stay, less time since the last MRSA-positive culture, longer length of stay in a healthcare facility, or residence in a long-term care facility.Reference Carson, Danford and Carson ^{42 ,} Reference Sanford, Widmer, Bale, Jones and Wenzel ^{44 ,} Reference Lucet, Paoletti and Demontpion ^{47 ,} Reference Cluzet, Gerber and Nachamkin ^{49 –} Reference Ridenour, Wong, Call and Climo ⁵⁸ In addition, colonization with MRSA at multiple body sites has been associated with prolonged carriage among patients readmitted to a university hospital.Reference Mattner, Biertz, Ziesing, Gastmeier and Chaberny ⁵⁹

Some studies have documented shorter duration of colonization. Ghosh et alReference Ghosh, Jiao, Al-Mutawa, O’Neill and Mertz ⁶⁰ examined patients with prolonged hospital stays and used active surveillance to identify patients that lose MRSA carriage. They observed a clearance rate of 11% for MRSA with a median time to clearance of 23 days, although 4 of these 19 patients were later found to be recolonized with MRSA. Cluzet et alReference Cluzet, Gerber and Nachamkin ⁴⁹ also documented a shorter duration of MRSA colonization of 21 days in individuals screened every 2 weeks following a skin infection due to MRSA. Notably, this population was younger, and most individuals received antibiotic therapy for skin infection, which could contribute to earlier clearance; 20% of individuals never cleared colonization during 6 months of follow-up. In a separate analysis, these investigators observed that 43.6% of individuals who had cleared MRSA colonization ultimately became recolonized with a median time to recurrence of 53 days.Reference Cluzet, Gerber and Nachamkin ⁶¹ In a study of patients at neurologic long-term care facilities, patients not colonized with S. aureus at admission were followed with weekly nasal surveillance cultures for a median duration of 20 weeks. The median time to clearance of MRSA colonization (acquisition of colonization until 2 consecutive nasal swabs negative for that strain) was 3 weeks.Reference Couderc, Thiébaut and Lawrence ⁶²

Challenges exist to developing a standardized definition of clearance of MRSA. Due to the heterogeneity among study designs, it is difficult to draw overarching conclusions. Prior studies showed considerable variability with respect to follow-up time, frequency of screening cultures, and definitions of what constituted MRSA clearance. Some studies included potential confounding variables, such as receipt of concomitant antibiotics or the use of decolonization regimens.Reference Shenoy, Paras, Noubary, Walensky and Hooper ⁶³ Because of variations in MRSA colonization duration, many hospitals wait at least 3 months prior to assessing an individual for clearance of MRSA colonization,Reference Shenoy, Kim and Rosenberg ³⁶ with a large proportion of hospitals requiring 3 negative specimens to document clearance of MRSA.Reference Shenoy, Kim and Rosenberg ³⁶ Published evidence indicates that most patients will remain negative for MRSA if they have 3 consecutive negative weekly surveillance cultures.Reference Huckabee, Huskins and Murray ¹²

Sites of Colonization

The anterior nares is the primary site of MRSA colonization,Reference Kluytmans, van Belkum and Verbrugh ³¹ although various extra-nasal sites are also colonized (eg, throat, axilla, inguinal area, perirectal area, and chronic wounds).Reference McKinnell, Huang, Eells, Cui and Miller ⁶⁴ Most hospital surveillance programs screen for MRSA colonization solely in the anterior nares. However, this screening may result in unrecognized extra-nasal colonization.Reference Calfee, Salgado and Milstone ³⁰ A review of 23 studies on testing for MRSA colonization estimated that extra-nasal screening increased MRSA detection by more than 33% compared to nares screening alone.Reference McKinnell, Huang, Eells, Cui and Miller ⁶⁴ It is unclear whether evaluation of extra-nasal MRSA colonization is beneficial for hospital surveillance programs or if extra-nasal colonization should be considered in a decision about discontinuation of CP. Some hospitals use nares cultures alone to confirm clearance, whereas others use additional sites of cultures to guide protocols for discontinuing CP.Reference Shenoy, Hsu, Noubary, Hooper and Walensky ¹¹ Further research is warranted in the role of extra-nasal surveillance cultures for the purpose of discontinuing CP.

Current Recommendations on the Discontinuation of CP

Early guidance suggested that CP for VRE should be discontinued after 3 negative stool cultures obtained at least 1 week apart. ⁶⁵ Subsequent guidelines from CDC and HICPAC supported this practice in the absence of uncontrolled respiratory secretions, draining wounds, or the involvement of the patient in an institutional outbreak.Reference Siegel, Rhinehart, Jackson and Chiarello ¹ Sequential testing revealed that after 3 sequential negative cultures, 35 of 37 patients (95%) remained culture negative.Reference Byers, Anglim, Anneski and Farr ²⁰ One institution, which defined VRE clearance as 3 negative stool cultures more than 3 weeks apart, found in subsequent, prospective surveillance testing that VRE recolonization occurred in 5 of 21 patients (24%) who had “cleared.”Reference Baden, Thiemke and Skolnik ¹⁴ The same authors identified 12 patients who had at least 2 VRE-positive cultures more than 1 year apart, supporting concern for prolonged colonization.Reference Baden, Thiemke and Skolnik ¹⁴

Donskey et alReference Donskey, Hoyen, Das, Helfand and Hecker ¹⁵ demonstrated that individuals who had cleared VRE colonization with 3 negative stool cultures collected at least 1 week apart had a high recurrence rate (62%) if they were exposed to antibiotics in the following year. Individuals with risk factors for VRE colonization have demonstrated recurrence,Reference Patel, Allen and Manahan ¹⁶ and recent studies suggest that a strategy of 3 weekly consecutive surveillance cultures to identify VRE clearance results in recurrence rates of 11%.Reference Henard, Lozniewski, Aissa, Jouzeau and Rabaud ⁶⁶

Duration of Colonization

Multiple studies evaluated the duration of VRE colonization and the predictive value of VRE-negative stool cultures in predicting VRE clearance. Studies on this subject have been largely retrospective and have been focused in hospital settings. A retrospective analysis of a large, multicenter study revealed that among 394 patients with VRE colonization, 76% of those admitted within 50 days of initial VRE detection remained positive for VRE, and among 126 patients admitted over 300 days from the last positive VRE culture, 20 (15.9%) remained positive in screening surveillance cultures.Reference Huang, Rifas-Shiman and Pottinger ⁶⁷ In a single-center study, 35 of 210 VRE-colonized patients cleared colonization at a mean of 49 days. Using a logistic regression model the study predicted that 40% of colonized patients would clear colonization at 100 days.Reference Goetz, Rihs, Wagener and Muder ⁶⁸ In another study, 22 of 105 VRE colonized patients remained colonized for more than 100 days.Reference Byers, Anglim, Anneski and Farr ²⁰ A recent systematic analysis pooled data on the subject from 13 studies, identifying a range of VRE clearance from 1 to 43 weeks. A logistic regression model estimated that 50% of subjects cleared colonization at 25 weeks after an initial VRE-positive stool test.Reference Shenoy, Paras, Noubary, Walensky and Hooper ⁶³ Limitations associated with most of these studies include inconsistent reporting of concomitantly administered antibiotics, variation in testing modalities (culture vs molecular methods), limited duration of follow-up, and retrospective nature of the study designs.

Several factors may influence the duration of VRE colonization and the likelihood of VRE transmission in the hospital setting. Prolonged hospitalization and intensive care unit stay have been associated with prolonged VRE colonization.Reference Byers, Anglim, Anneski and Farr ²⁰ Immunosuppressed patients may remain colonized with VRE for longer periods of timeReference Sohn, Peck and Joo ^{17 ,} Reference Henning, Delencastre and Eagan ^{18 ,} Reference Singh, Esparza, Patterson, Vogel, Patel and Gornick ⁶⁹ and may have a high rate of recurrent VRE colonization after multiple negative VRE cultures.Reference Patel, Allen and Manahan ¹⁶ Antibiotic use, specifically vancomycinReference Karki, Land and Aitchison ^{19 ,} Reference Yoon, Lee and Lee ⁷⁰ and fluoroquinoloneReference Sohn, Peck and Joo ^{17 ,} Reference Karki, Land and Aitchison ¹⁹ use, have been associated with prolonged VRE colonization. Older patients and patients receiving fluoroquinolones were more likely to transmit VRE to roommates.Reference Zhou, Moore, Eden, Tong and McGeer ⁷¹ Prior guidance suggests consideration of concurrent antibiotic use, particularly antibiotics with activity against VRE, when making decisions regarding discontinuation of CP.Reference Siegel, Rhinehart, Jackson and Chiarello ¹

Sites of Colonization

The gastrointestinal tract is the main site of VRE colonization, though VRE has been identified on the skin of patients colonized with VRE with diarrhea.Reference Beezhold, Slaughter and Hayden ⁷² Most studies investigating the duration of VRE colonization duration have used gastrointestinal tract samples,Reference Shenoy, Paras, Noubary, Walensky and Hooper ⁶³ stool samples,Reference Baden, Thiemke and Skolnik ^{14 ,} Reference Karki, Land and Aitchison ¹⁹ and perirectal and perineal swabs,Reference Byers, Anglim, Anneski and Farr ^{20 ,} Reference Huang, Rifas-Shiman and Pottinger ^{67 ,} Reference Goetz, Rihs, Wagener and Muder ^{68 ,} Reference Haverkate, Derde, Brun-Buisson, Bonten and Bootsma ⁷³ or both.Reference Huckabee, Huskins and Murray ^{12 ,} Reference Ghosh, Jiao, Al-Mutawa, O’Neill and Mertz ⁶⁰ Some studies have included surveillance cultures obtained from other sites including throat and urine samples.Reference Patel, Allen and Manahan ¹⁶ While limited, data comparing the sensitivity of rectal and perirectal cultures suggest that both are comparable.Reference Weinstein, Tallapragada, Farrel and Dembry ⁷⁴

Current Recommendations Regarding the Discontinuation of CP

The CDC HICPAC MDRO guidelines state that “In general, it seems reasonable to discontinue CP when 3 or more surveillance cultures for the target MDRO are repeatedly negative over the course of 1 or 2 weeks in a patient who has not received antimicrobial therapy for several weeks, especially in the absence of a draining wound, profuse respiratory secretions, or evidence implicating the specific patient in ongoing transmission of the MDRO within the facility.” The CDC CRE Tool Kit 2015 update states that “Currently, there is not enough evidence to make a firm recommendation about when to discontinue use of CP for infected or colonized patients; however, CRE colonization can be prolonged (>6 months). If surveillance cultures are used to decide if a patient remains colonized, >1 culture should be collected to improve sensitivity. Regardless of whether surveillance cultures are performed, the presence of risk factors for ongoing carriage or ongoing CRE exposure should be considered in the decision about discontinuing CP.” ⁷⁵

In a survey among SHEA Research Network members, among 49 respondents, CP for patients infected with ESBL-E were reportedly maintained for the duration of active illness by 8.2% of respondents, for the duration of hospitalization by 26.5%, until negative surveillance cultures were obtained by 32.7%, and indefinitely by 34.7%.Reference Drees, Pineles, Harris and Morgan ⁷⁶ Overall, 55% of respondents reported isolating patients at readmission. For those respondents requiring negative cultures for “clearance” (n=16), cultures were obtained after completion of antibiotics by 37.5% of respopndents, after hospital discharge by 25%, and within 3 months by 12.5%. Among 62 respondents regarding CRE, CP were reportedly maintained for the duration of active illness by 6.5% of respondents, for the duration of hospitalization by 12.9%, until negative surveillance cultures by 29%, and indefinitely by 43.5%. Furthermore, 72% of respondents instituted isolation at readmission for CRE. Among respondents reporting that they require surveillance cultures for CRE clearance (n=18), cultures could be obtained after completion of antibiotics by 44.4% respondents, after hospital discharge by 22.2%, within 3 months by 27.8%, and at or after 1 year by 5.6%.

In another survey of infection control practices related to MDR-E among 15 acute-care hospitals in Toronto, Canada, CP were more likely to be instituted universally for CRE patients than for ESBL-E patients for whom risk factors for transmission (eg, diarrhea, draining wounds, etc) were considered when instituting CP. For ESBL-E, CP was maintained until discharge by 5 of 15 hospitals, discontinued after 1 negative specimen by 2 of 15 hospitals, and after 3 negative specimens 1 week apart by 8 of 15 hospitals.Reference Lowe, Katz, McGeer, Muller and Group ⁷⁷ For CRE, CP was maintained until discharge by 8 of 15 hospitals, discontinued after 1 negative specimen from original positive site by 1 of 15 hospitals, after 3 negative specimens 1 week apart by 4 of 15 hospitals, and was not yet determined by 2 of 15 hospitals.

Duration of Colonization

Several studies have evaluated colonization with MDR-E longitudinally in a variety of patient populations in different countries and healthcare settings.Reference Bart, Paul, Eluk, Geffen, Rabino and Hussein ^{21 –} Reference Vehreschild, Hamprecht and Peterson ^{23 ,} Reference Titelman, Hasan and Iversen ^{78 –} Reference Lewis, Enfield, Mathers, Giannetta and Sifri ⁹⁰ Most studies were conducted in the acute-care settingReference Bart, Paul, Eluk, Geffen, Rabino and Hussein ^{21 –} Reference Vehreschild, Hamprecht and Peterson ^{23 ,} Reference Birgand, Armand-Lefevre, Lolom, Ruppe, Andremont and Lucet ^{79 –} Reference Feldman, Adler and Molshatzki ^{81 ,} Reference Weintrob, Roediger and Barber ^{83 ,} Reference Kola, Holst, Chaberny, Ziesing, Suerbaum and Gastmeier ^{85 ,} Reference Zimmerman, Assous, Bdolah-Abram, Lachish, Yinnon and Wiener-Well ^{87 ,} Reference Schechner, Kotlovsky and Tarabeia ^{89 –} Reference Kim, Han and Song ⁹¹ and identified a population of patients infected and/or colonized with MDR-E, either ESBL-E or CRE, or MDR-Enterobacteriaceae defined by resistance to multiple classes of drugs. Patients were assessed for persistence of colonization at study-specific intervals and variable durations of follow-up. The definition of “clearance” varied between a single negative screening culture,Reference Birgand, Armand-Lefevre, Lolom, Ruppe, Andremont and Lucet ^{79 ,} Reference Zimmerman, Assous, Bdolah-Abram, Lachish, Yinnon and Wiener-Well ^{87 ,} Reference Lewis, Enfield, Mathers, Giannetta and Sifri ⁹⁰ at least 2 negative screening cultures,Reference Bart, Paul, Eluk, Geffen, Rabino and Hussein ^{21 ,} Reference Vehreschild, Hamprecht and Peterson ^{23 ,} Reference Feldman, Adler and Molshatzki ^{81 ,} Reference O’Fallon, Gautam and D’Agata ⁸⁴ or at least 3 negative screening cultures swabs.Reference Löhr, Rettedal, Natås, Naseer, Oymar and Sundsfjord ^{80 ,} Reference Kola, Holst, Chaberny, Ziesing, Suerbaum and Gastmeier ^{85 ,} Reference Kim, Han and Song ⁹¹

Patient Groups at Risk for Prolonged Colonization

For ESBL-E, Phylogroup B2 and CTX-M-gr-9 were associated with ESBL-E carriage at 12 months in a Swedish cohort.Reference Titelman, Hasan and Iversen ⁷⁸ In a French university hospital, having the first positive culture on screening samples only (compared to clinical±screening samples) was associated with ESBL-E clearance at readmission.Reference Birgand, Armand-Lefevre, Lolom, Ruppe, Andremont and Lucet ⁷⁹ Similarly, among KPC-producing CRE carriers in a university hospital in Israel, the index culture being a clinical culture (vs surveillance culture) was associated with longer mean time to negativity.Reference Zimmerman, Assous, Bdolah-Abram, Lachish, Yinnon and Wiener-Well ⁸⁷ Recurrent hospitalization between the first and last culture was also associated with a longer time to clearance of CRE colonization. This finding was also reported in a case-control study of risk factors for CRE recurrence in Israel, where a shorter time between the last positive CRE culture and presumed eradication, recurrent hospitalization, and the presence of a foreign body at the time of presumed eradication were associated with CRE recurrence.Reference Bart, Paul, Eluk, Geffen, Rabino and Hussein ²¹ In another hospital-based study in Israel, persistent CRE-positive patients (n=23) were more often admitted from another hospital (59.1% vs 26.3%; P=.012) and were exposed to antimicrobials during the preceding 30 days, although the latter did not reach statistical significance (57% vs 33%; P=.059).Reference Schechner, Kotlovsky and Tarabeia ⁸⁹ In a study of CRE carriers in a university hospital in Hong Kong that employed serial quantitative detection via fecal specimens, a higher bacterial load on initial detection of CRE, and the use of cephalosporins, carbapenems, and fluoroquinolones after CRE detection were associated with persistent fecal carriage.Reference Cheng, Chan and Wong ²² In a postdischarge surveillance study in Israel, resolution of CRE carriage was more likely to occur in recent acquisitions (first positive <4 months prior to enrollment) with 29 of 75 (39%) remaining positive compared to remote positives (first positive >4 months before enrollment) with 36 of 50 (72%) remaining positive (P<.001). Furthermore, in remotely colonized patients, the presence of an invasive device and high Charlson score were associated with persistent carriage.Reference Feldman, Adler and Molshatzki ⁸¹ Among adults returning to France after traveling to tropical regions and found to carry ESBL-E, CRE, or AmpC-producing Enterobacteriaceae, travelers returning from Asia had more prolonged colonization than travelers returning from sub-Saharan Africa or Latin America, and carriers of E. coli had a lower risk of prolonged carriage than carriers of other Enterobacteriaceae species.Reference Ruppé, Armand-Lefèvre and Estellat ⁸⁶

Sites of Colonization

Generally, the lower gastrointestinal tract is considered the primary site of colonization with MDR-E, though there is no universally accepted surveillance sampling strategy. The gastrointestinal tract sampling was included in nearly all of these studies. Most studies evaluating duration of colonization with MDR-E utilized stool samples,Reference Titelman, Hasan and Iversen ^{78 ,} Reference Löhr, Rettedal, Natås, Naseer, Oymar and Sundsfjord ^{80 ,} Reference Tham, Walder, Melander and Odenholt ^{82 ,} Reference Ruppé, Armand-Lefèvre and Estellat ^{86 ,} Reference Tandé, Boisramé-Gastrin and Münck ⁸⁸ perirectal swab samples,Reference Bart, Paul, Eluk, Geffen, Rabino and Hussein ^{21 ,} Reference Birgand, Armand-Lefevre, Lolom, Ruppe, Andremont and Lucet ^{79 ,} Reference Feldman, Adler and Molshatzki ^{81 ,} Reference O’Fallon, Gautam and D’Agata ⁸⁴ or either.Reference Vehreschild, Hamprecht and Peterson ^{23 ,} Reference Kola, Holst, Chaberny, Ziesing, Suerbaum and Gastmeier ⁸⁵ Original sites of infection were tested (if still relevant) in one study,Reference Bart, Paul, Eluk, Geffen, Rabino and Hussein ²¹ and another study included cultures of samples obtained from multiple anatomic sites (ie, forehead, axillae, finger webs, groin, toe webs, and perirectal area).Reference Weintrob, Roediger and Barber ⁸³

Shedding Time

Sethi et alReference Sethi, Al-Nassir, Nerandzic, Bobulsky and Donskey ²⁵ demonstrated that 1-4 weeks after conclusion of CDI treatment with vancomycin the frequencies of skin and environmental shedding increased to 58% and 50%, respectively (Figure 1). These percentages were greater than they were at the end of CDI treatment (32% and 14%, respectively). This study suggests that skin contamination and environmental surface shedding of C. difficile often persist at the time of resolution of diarrhea, and recurrent shedding is common 1–4 weeks after therapy. These results provide support for the recommendation that CP be continued until hospital discharge if rates of CDI remain high despite implementation of standard infection control measures.

FIGURE 1

Frequency of Skin Contamination and Environmental SheddingReference Donskey, Kundrapu and Deshpande ¹¹⁶

Jinno et alReference Jinno, Kundrapu, Guerrero, Jury, Nerandzic and Donskey ²⁶ compared shedding of spores in patients with resolved CDI within the past month (the time from the end of therapy to 1 month after completion of therapy) and those with active CDI (time from diagnosis until completion of CDI treatment or until completion of 14 days of treatment in patients receiving prolonged tapering courses of vancomycin). Patients with active CDI were found to have high frequencies of positive stool, skin, and environmental cultures (100%, 63%, and 51%, respectively).Reference Jinno, Kundrapu, Guerrero, Jury, Nerandzic and Donskey ²⁶ Among the patients with resolved CDI, the frequency of positive stool, skin, and environmental cultures was significantly higher among patients cultured during the month after completion of treatment versus those cultured >1 month after treatment (50%, 46%, and 29% vs 18%, 5%, and 5%, respectively; P<.01 for each comparison). None of the patients whose CDI had resolved 6–24 months after completion of treatment had positive skin or environmental cultures. These results indicate that patients with resolved CDI may demonstrate significantly more shedding during the month following completion of treatment than those cultured >1 month following treatment.

Donskey et alReference Donskey, Sunkesula and Jencson ⁹² showed that the likelihood of carriers having a positive skin or environmental culture or positive perirectal PCR result increased as the number of colonies per swab increased. In comparison to carriers with 1–25 colonies per swab, those with ≥26 colonies per swab had significantly higher frequencies of skin shedding (1 of 10 [10%] versus 10 of 15 [67%]; P=.012) and environmental shedding (0 of 10 versus 9 [60%] of 15; P=.003) and were more likely to have positive perirectal PCR results (3 of 10 [30%] versus 14 of 15 [93%]; P=.002). The number of colonies recovered from perirectal swabs varied widely, and a low burden of colonization was associated with a low risk of skin or environmental shedding or a positive perirectal PCR result.

Shrestha et alReference Shrestha, Sunkesula, Kundrapu, Tomas, Nerandzic and Donskey ⁹³ and colleagues described the contamination of healthcare personnel (HCP) hands with C. difficile after caring for patients with resolved CDI who were no longer under CP. Patient CDI was either recent (2 days to 6 weeks after the end of CDI treatment without diarrhea) or remote (6–24 weeks after CDI treatment). Not surprisingly, the frequencies of hand contamination of HCP after contact with patients with active and recent CDI were similar. Although less common, hand contamination occurred during care of patients with remote CDI, which may support placing patients on CP for the duration of admission as well as re-admissions. Continuing CP after resolution of diarrhea may also reduce transmission.Reference Shrestha, Sunkesula, Kundrapu, Tomas, Nerandzic and Donskey ⁹³

The clinical impact of CP based on shedding might be extrapolated from studies that investigated the effect of CP on asymptomatic C. difficile carriers. Lanzas and DubberkeReference Lanzas and Dubberke ⁹⁴ used agent-based modeling to evaluate the potential effectiveness of methods targeting asymptomatic carriers to control C. difficile colonization and infection rates by screening patients at admission to detect asymptomatic C. difficile carriers and placing positive patients on CP. Scenarios simulating screening test characteristics, colonization prevalence, and type of strain present at admission were used. The investigators found on average that testing asymptomatic carriers reduced the number of new colonization cases by 40%–50% and hospital-onset CDI cases by 10%–25%, compared with the baseline scenario.

A 2016 crossover experimental study showed that placing asymptomatic carriers on CP based on universal screening on admission significantly decreased the incidence of CDI (3 hospital-associated [HA] CDI cases per 10,000 patient days) compared to a control unit (6.9 HA-CDI per 10,000 patient days; P<.001). The researchers estimate the intervention prevented approximately 63 cases.Reference Longtin, Paquet-Bolduc and Gilca ^{27 ,} Reference Longtin, Gilca and Loo ⁹⁵

Patients with C. difficile Infection

A 2009 survey of 33 acute-care hospitals in Canada identified different approaches related to the discontinuation of CP; 13 hospitals (39%) reported that CP were discontinued as soon as the patients were asymptomatic, and 19 hospitals (58%) required a period of 24–72 hours with no symptoms prior to discontinuation of CP. One hospital reported continuing CP until the end of the treatment for CDI; this hospital had the greatest percentage of positive test results (32% vs 12% for all other hospitals combined; P<.001). No respondent continued additional CP until discharge.Reference Gravel, Gardam and Taylor ⁹⁶

Johnson et alReference Johnson, Gerding and Olson ⁹⁷ performed a prospective, controlled study of the use of universal gloves on the incidence of CDI and C. difficile colonization. They found that the units in which the glove intervention was performed demonstrated a decrease of C. difficile incidence from 7.7 to 1.5 cases per 1,000 patient discharges (P=.015). Contrary to this finding, the control units without the intervention had unchanged incidence in the intervention and control phases. Colonization rates also decreased in the units undergoing the interventions (17% vs 9%; P=.029). This study suggests that the use of vinyl gloves may significantly reduce the transmission of C. difficile diarrhea and therefore should be used for the duration of hospitalization.Reference Johnson, Gerding and Olson ⁹⁷

Comparison of Molecular and Standard Methods on Sensitivity, Specificity, and Duration of Positivity

The diagnostic advantage of molecular methods (eg, PCR) is enhanced sensitivity compared to culture. Unfortunately, scientific documentation of this phenomenon has been challenged using weak study methodology. The most common methodology involves performing PCR in parallel with culture, with the latter designated as the gold standard. PCR-positive/culture-negative specimens are then retested with an “arbiter” PCR. If positive, the specimen is assigned positive screen status.Reference Yam, Siu and Ho ^{99 –} Reference Babady, Gilhuley, Cianciminio-Bordelon and Tang ¹¹⁴ This methodology (called “partial verification”) introduces bias in favor of PCR. ¹¹⁵ For MRSA, Yam et alReference Yam, Siu and Ho ⁹⁹ tested 1,246 nares swab specimens with the Lightcycler MRSA Advanced (Roche Molecular Diagnostics, Basel Switzerland), a laboratory developed test (LDT) PCR and, in parallel, cultured all specimens. The gold standard was defined as positive culture or positivity by both molecular assays. A preferable method may be to perform multiple PCR assays with similar sensitivity on all specimens using a “consensus” gold standard definition. The sensitivities of culture, Lightcycler MRSA Advanced, and the LDT were 84%, 83%, and 76%, respectively, with no apparent statistical significance.Reference Yam, Siu and Ho ⁹⁹ No similar studies were available for VRE or CRE assays.

Recently, FDA-cleared molecular methods (eg, PCR) for detecting MRSA, VRE, and CRE have become commercially available in the United States. For MRSA, commonly used assays include the Xpert MRSA XT and Xpert SA Nasal Complete (Cepheid, Sunnyvale, CA); BD MAX MRSA and BD MAX StaphSR (Becton Dickinson, Franklin Lakes, NJ); Lightcycler MRSA Advanced (Roche Molecular Diagnostics, Basel Switzerland); and the Cobas MRSA/SA Test (Roche Molecular Diagnostics). The Xpert VanA assay (Cepheid) has been cleared by the FDA to detect VRE mediated by vanA, and the Xpert CarbaR (Cepheid) detects various determinants of CRE including blaKPC, blaNDM, blaVIM, blaIMP-1 and blaOXA-48 (including OXA-48-like variants OXA-181 and OXA-232). At this time, no molecular assays that detect ESBL determinants have been cleared by the FDA.