Bennett & Brachman's Hospital Infections, 5th Edition

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The Importance of Infection Control in Controlling Antimicrobial-Resistant Pathogens

Cassandra D. Salgado

Barry M. Farr

Introduction

Infection control (IC) programs were created almost four decades ago to control healthcare-associated infections (HAIs) caused by antimicrobial-resistant pathogens (ARPs) but have not succeeded in most nations. This chapter discusses the importance of using IC measures to prevent nosocomial spread of two ARPs, methicillin-resistant Staphylococcus aureus(MRSA) and vancomycin-resistant Enterococcus (VRE). Use of IC measures is important for controlling these pathogens because the measures have prevented both spread and infections [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]. An assumption will be made that preventable infections causing serious morbidity and mortality should not be allowed to continue spreading but should be controlled using available data to guide control efforts. MRSA and VRE infections have been associated with more prolonged illness, higher excess costs, and higher risk of death as compared with infections due to antibiotic-susceptible strains of the same species [132,133,134,135], and they are two of the most out-of-control pathogens in U.S. healthcare facilities (Figure 40-1) [136].

Epidemiologic Data Regarding the Risk for Colonization or Infection by Antibiotic-Resistant Pathogens

Effective prevention of any illness depends on having reliable data demonstrating modifiable risk factors. Many studies of ARP colonization and infection have identified two primary causes. The first cause appears to be clinical use of an antimicrobial. For example, before clinical use of penicillin began in the mid-1940s, resistance among clinical isolates of S. aureus was rare, but after three years of treating infections at the Hammersmith Hospital in London, about half of S. aureus clinical isolates had become resistant to penicillin and treating infections caused by them seemed to have no effect. The relationship between the use of an antimicrobial and the development of resistance has varied for different microbe-drug pairs, but clinically important antibiotic resistance usually starts showing up about a year or two after onset of widespread use of an antibiotic. This occurred with resistance to methicillin among clinical isolates of S. aureus; however, treating S. aureus infection with methicillin (or another antibiotic) will virtually never result in that strain of

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   aureusdeveloping resistance to methicillin de novo. Also, treating a patient with vancomycin will virtually never result in the patient's own strain of Enterococcusdeveloping resistance to vancomycin de novo [137,138]. By contrast, treating M. tuberculosis infection with isoniazid alone predictably results in treatment failure in about 70% of patients due to a strain with isoniazid resistance [139], the monotherapy not causing mutation to resistance but providing a selective advantage for resistant mutants and favoring their survival. Additionally, surveys have shown that 25–50% of patients in U.S. hospitals and virtually all patients in ICUs receive antimicrobial therapy [140], and many studies have confirmed the importance of exposure to antibiotics as a risk factor for nosocomial ARP colonization or infection [141,142,143,144].

The other important cause of ARP colonization or infection has been patient-to-patient spread. Spread of lethal infection via contaminated hands or clothing of healthcare workers (HCWs) has been recognized for more than a century [145,146], and transmission of ARP infections has been documented repeatedly [12,47,117,147]. Transmission among patients likely often involves transient contamination of HCWs” hands [148,149,150,151], apparel [149,152], personal equipment [153], or medical equipment that can recontaminate the HCWs” hands or serve as a fomite vector [114,149,154,155,156,157,158,159,160,161]. Clinicians moving between patients often fail to cleanse their hands [162] and almost never disinfect their clothing or personal or medical equipment between patient contacts.

Studies controlling for antimicrobial therapy have concluded that colonization pressure (i.e., the prevalence of colonization) and spread from other colonized patients is the most important predictor of a patient becoming colonized by MRSA or VRE [163,164]. Similarly, proximity to non-isolated, newly colonized patients was the most important predictor of acquiring VRE in a clonal outbreak; by contrast, proximity to VRE-colonized patients in contact isolation was not a risk factor [117]. Crowding and decreased nurse-to-patient ratios [45,46] make contamination of HCWs” hands, apparel, or equipment more likely and, thus, transmission more likely. Severe illness necessitates more touching over a longer time and usually antimicrobial therapy, each of which increases risk. In addition to transmitting MRSA or VRE from patient to patient, HCWs sometimes become colonized and transmit the organism to patients without needing to become transiently contaminated by a colonized patient [47,165,166,167]. This phenomenon has been best studied in Holland where MRSA has been rare and cultures of exposed clinicians have demonstrated that at least transient colonization occurs often enough for colonized HCWs to contribute significantly to MRSA epidemics [166].

The high frequency of antimicrobial therapy in healthcare facilities and frequent nosocomial spread of microbes from person to person give ARPs a selective advantage to survive, proliferate, and spread [11]. This means that without effective IC measures, ARP infections tend to increase to a high prevalence within a ward [45,168,169], hospital [12,19,170,171], region [147,172], and nation [136,173].

Importance of Using Infection Control to Curb Antimicrobial-Resistant Pathogens in Regard to Effectiveness

Effectiveness of Controlling Antibiotic Use to Curb MRSA and VRE

Recommendations to control antibiotic use have been made for decades [174]. This seems attractive because overuse also generates excess pharmacy and nursing costs while potentiating antibiotic resistance. Discontinuation of all antibiotic use would remove the selective advantage for ARP infections, and they likely would dwindle away, but antibiotic therapy currently is perceived as indispensable, so the only control of antibiotic use considered feasible has been limiting it to prudent, judicious usage and sometimes refraining from using one antimicrobial while substituting another. Unfortunately, the former likely still provides sufficient selective advantage to facilitate epidemic spread of ARPs such as MRSA or VRE [11,67,112]. The latter can be associated with at least transient declines in some types of antimicrobial resistance but often is accompanied by off-setting increases in another type of antimicrobial resistance [175], which has been likened to squeezing a balloon.

The Intensive Care Antibiotic Resistance Epidemiology program of the Centers for Disease Control and Prevention (CDC) included 47 hospitals, each claiming to have an antibiotic control program [176], but these hospitals may have been more interested and motivated than average, although their programs were described as less than fully

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compliant with a prior SHEA–IDSA position paper on antimicrobial control [177]. ARP infections of almost every type increased at these hospitals from 1996 to 1999 [178]. A survey of all hospitals in Virginia and North Carolina revealed that MRSA and VRE were common HAI pathogens despite the fact that about two-thirds of responding hospitals had antibiotic control programs as of 1999 [179].

One hospital used a computer algorithm to educate and advise physicians and found physicians willing to accept advice (and control) when offered by a computer program [180]. Reductions in antibiotic usage and financial savings from lower pharmacy expenditures have been reported by many programs [140,181,182,183]. Harder to document have been substantial, lasting reductions in ARP HAIs. One hospital reported that antibiotic resistance stopped increasing but did not fall to a low level [140]. Another reported that a control program was associated with a decline in C. difficile and VRE but not MRSA [183]. When piperacillin-tazobactam was substituted for ceftazidime, VRE was significantly reduced by about two-thirds in one hospital [184] and in a cancer ward [185]. By contrast, another study reported that increasing use of piperacillin-tazobactam was not consistently associated with reductions in VRE rates in four hospitals [186], and another hospital reported that reducing usage of third-generation cephalosporins by 85% was temporally associated with continually rising VRE rates [187].

Several hospitals have reported at least modest decreases in MRSA with specific changes in antibiotic usage. One switched from a third-generation cephalosporin to a first-generation cephalosporin for antimicrobial prophylaxis of surgical site infection (SSI) [188]. The second restricted use of ceftazidime and ciprofloxacin and rotated usage of other beta-lactams [189] while the third also significantly reduced use of third-generation cephalosporins and clindamycin [175]. A fourth hospital reported a significant reduction in MRSA in the first year of an antimicrobial control program [181], but then MRSA and VRE increased substantially despite continuation of the program [190].

In summary, the effects of antibiotic control on MRSA or VRE have tended to be modest as compared with the effects of preventing spread [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131] and inconsistent from one study to the next although using apparently similar methods. For this reason, despite the cardinal importance of antibiotic use, substantive, sustained control of nosocomial MRSA and VRE infections seems to require a prominent focus on controlling spread.

Effectiveness of Controlling Patient-to-Patient Spread to Curb MRSA and VRE

The most important and indisputable evidence showing that ARP infections can be controlled convincingly comes from multiple nations in Northern Europe and from the state of Western Australia, each using a similar approach to control MRSA HAI to very low levels, in some instances for decades [21,22,28,191,192,193]. Their approach has involved finding and isolating all patients suspected or known to be MRSA colonized using surveillance cultures and eradicating colonization to reduce further the reservoir for spread. Other countries in Europe and other states in Australia not using these methods routinely [194,195,196,197], have had much higher rates of MRSA HAIs (Figure 40-2) [191,192,193,198]. Also, strain typing has shown that strains considered uncontrollable (e.g., EMRSA16) by some in other European nations are well controlled in Northern European countries [44]. Such strains apparently can be well controlled in countries generally unsuccessful at controlling MRSA if (and for as long as) such measures are applied. For example, a large British hospital demonstrated tight control of MRSA for a decade using such measures [19]. EMRSA16 was introduced into that hospital on six different occasions and controlled each time, never establishing endemicity. After control measures were relaxed because of the perception that they were clinically inconvenient, however, MRSA then became endemic in that hospital and MRSA bloodstream infections (BSIs) increased from 2 and 1 during the two years before relaxation, respectively, to 18 and 74 during the two years after relaxation of control measures [19]. This increase may, in part, have been due to spread throughout the rest of the healthcare system not using such measures that resulted in increasingly frequent transfers and admissions of colonized patients.

Some suggest that Northern European control must be due to having “single payer” national health insurance, but the United Kingdom has this and one of the higher MRSA HAI rates in Europe [191,192,199]. The low rate in Western Australia and much higher rates in other Australian states show that control of MRSA HAIs has more to do with the approach to control used than with a nation's method of financing healthcare [28,193].

Others suggest that prudent antimicrobial usage by Northern European nations may explain their lower

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MRSA HAI rates than those in other European nations. Hospital usage rates reportedly have not been publicly available [200], but Denmark and Holland have had the lowest aggregate outpatient antibiotic sales of defined daily doses per 1,000 people in the population while Finland, which at the time had hospital MRSA HAI rates as low as Denmark and Holland [20,21], had a moderate rate of outpatient antibiotic sales, similar to that of the United Kingdom [200], which had a high and growing MRSA HAI rate [191,192,197,201]. If outpatient usage correlates with total antibiotic usage, as implied by the authors, this may suggest that similar measures used to control spread may be more likely to explain the similarity in MRSA HAI rates among Finland, Denmark, and Holland. Other reasons to consider that relatively low antibiotic usage may not be primarily responsible for success in controlling MRSA in Northern Europe include the facts that (1) epidemics of MRSA frequently occur in Holland when colonized patients are not suspected, cultured, and isolated [11,67], (2) nosocomial VRE epidemics can occur in Holland if colonized patients are not suspected, cultured, and isolated despite decades of restricting antibiotic use [112], and (3) methicillin-resistant S. epidermidis, not targeted for identification and isolation, has not been controlled to low levels like MRSA despite prolonged antibiotic control [22].

A recent article suggested that the key to controlling MRSA in Northern Europe may be quick eradication therapy [173], but Dutch eradication therapy usually is delayed until conditions are optimal, often after discharge [202]. Nevertheless, eradication of colonization helps prevent MRSA spread because an individual no longer colonized is one less reservoir for nosocomial spread [77,203,204], and a decolonized patient is less likely to acquire an MRSA-HAI [205,206,207,208,209]. Some regimens are more successful than others at eradicating colonization [22,210,211,212,213], and some strategies have failed to control MRSA HAIs because they facilitated spread of mupirocin-resistant MRSA strains [214,215,216,217]. Giving mupirocin only to the subset with MRSA has been associated with less mupirocin resistance than more widespread application [205,217]. Although most studies show a reduction in S. aureus and MRSA infections, these reductions have not always been statistically significant [206,218], in some instances because of transmission to and infection of previously noncolonized patients [219,220] and perhaps because a brief course of intranasal mupirocin in patients colonized at other sites often fails to eradicate colonization [15,211,212].

Eradication of colonization, although helpful, apparently is not essential to dramatically lower nosocomial MRSA spread and HAI rates [12,15,83,91], and data from scores of studies of VRE in Northern Europe, Western Australia, and elsewhere confirm that active detection and isolation of all colonized patients can control spread and infection by an ARP even when eradication is not feasible [112,115,122,221]. In addition to eradication therapy, Northern European hospitals often close wards at the first signs of epidemic spread, but multiple studies convincingly controlling MRSA or VRE spread without ward closure suggest that this also is not essential [3,33,83,91,126,221].

Are data available from outside Northern Europe and Western Australia supporting the findings cited above? We reviewed 131 studies that reported control of MRSA and/or VRE using active surveillance cultures and contact precautions [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]; four reporting simultaneous control of MRSA and VRE using this approach [33,74,81,94]. Multiple institutions reported controlling both MRSA and VRE with this approach but usually in different publications. The majority of the reported successes were not from Northern Europe or Western Australia. Ninety-seven studies described control of MRSA (67 publications in peer-reviewed journals and 30 abstract presentations at national scientific meetings) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97]. Among them, at least 50 described control of endemic spread [2,3,4,5,10,11,12,13,19,22,24,26,27,28,29,30,33,34,35,37,40,42,45,48,55,59,65,70,71,73,74,75,76,77,78,79,80,81,82,83,86,87,89,90,91,92,94,95,96,97], and 52 used MRSA decolonization protocols as an adjunctive control measure [1,2,3,7,8,9,10,11,14,15,16,17,18,22,24,25,26,27,28,29,31,34,35,36,39,40,41,42,43,44,45,46,47,48,52,53,56,57,58,59,61,62,63,64,68,69,71,72,77,80,84,89,92,93,97]. Thirty-eight studies reported control of VRE [33,74,81,94,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]. Among them, 20 described control of endemic spread [33,74,81,94,98,99,100,104,107,109,110,111,115,119,120,125,126,127,128,131], and 8 reported using antibiotic control as an adjunctive control measure [101,104,105,109,111,122,123,128]. Two of the 131 studies reported improved control while continuing surveillance cultures and isolation of colonized patients due to apparently improved use of the approach with additional education [5,99], and others reported improved control as compliance increased over time [83,91,126]. Although suboptimal, a measure of control can be achieved even in a single ward [91] or hospital [3,83,111,126] despite surrounding wards/facilities making no intervention to control the spread of MRSA or VRE.

Effectiveness of Hand Hygiene to Control MRSA and VRE

If preventing spread is acknowledged to be key to controlling ARPs such as MRSA and VRE, some may wonder whether better compliance with hand hygiene and/or use of antimicrobial hand cleansers might suffice for this purpose. Hand-hygiene noncompliance has been frequently studied [162,222,223], but the problem persists. Even Boyce and Pittet, primary authors of a guideline recommending alcohol hand-rubs and motivational campaigns to increase clinicians” compliance [224], have admitted that these did not control MRSA in their hospitals and that surveillance cultures [4,14,204] or polymerase chain reaction (PCR) of screening samples [206] and contact isolation of all colonized patients were thus added for control. Huang et al. reported that implementation of alcohol hand rubs for

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routine HCW hand hygiene between patients and a motivational campaign that increased hand-hygiene compliance from 40 to 80% was not associated with a significant change in MRSA BSI rates [83].

Another problem with the hypothesis that better compliance with hand hygiene and/or use of antimicrobial hand cleansers might suffice to control nosocomial MRSA or VRE to a very low level for a prolonged time is the lack of any examples across geographical areas with long-term control of MRSA or VRE spread with this approach. Although thousands of U.S. hospitals have been required to use standard precautions since 1996, relatively few have reported even modest control using hand hygiene without surveillance cultures and isolation [39,225,226,227,228]. By contrast, very few U.S. hospitals have reported using surveillance cultures and contact precautions for all colonized patients [179,229], yet there are many reports of control from U.S. healthcare facilities with their use [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]. Another important problem with believing that hand hygiene alone could control MRSA and VRE is that care of a colonized patient often results in contamination of a clinician's clothing [149,152], personal equipment used in the colonized patient's room (e.g., ink pen, notebook, PDA, pager, cell phone) [153], and medical equipment (e.g., stethoscope, tourniquet, sphygmomanometer cuff, reflex hammer, otoscope, ophthalmoscope, electronic thermometers, EKG leads, computer keys) [149] that can transmit contagion directly to another patient or contaminate the HCW's hands and lead to transmission. Touching environmental surfaces near a non-isolated patient often results in contamination of the HCW's hands [148], which can transmit contagion or contaminate equipment [151]. MRSA or VRE sometimes remain viable on cloth or plastic surfaces for weeks to months if not disinfected [230]. Except when a patient has been recognized to be colonized and placed in contact isolation, equipment has not traditionally been disinfected between contacts with different patients. Likewise, rooms contaminated by colonized patients can remain contaminated after routine hospital cleaning methods [231] and may require additional measures to remove contaminants [231,232]. Mathematical models based on epidemiologic data have supported the efficacy of surveillance cultures and isolation and questioned the efficacy of hand hygiene alone for controlling transmission of ARPs [233,234,235].

Even if hand hygiene cannot be relied on to control such HAIs alone, it nevertheless should help [224], and several studies have suggested better control of MRSA or VRE due to some improvement in hand hygiene although the effects often tended to be modest and control of one microbe was not always associated with control of the other [39,225,226,227,228]. For example, Larson et al. reported a significant decline in VRE in a small intervention hospital in association with improved compliance with hand washing with soap and water, but MRSA did not change significantly, and VRE went down a relative 44% in the neighboring, small, control hospital despite lack of an intervention [225]. Two studies reported control of MRSA in neonatal intensive care units (ICUs) after changing to a different antimicrobial soap for HCW hand hygiene and for antiseptic bathing all neonates in one [39,226], but both reported continuing all other IC measures, including surveillance cultures (and presumably control measures for culture-positive patients) in one [226] and gloves, gowns, cohorting, and surveillance cultures in the other [39]. It was unclear that changing from chlorhexidine to 0.3% triclosan was primarily responsible for control in the latter because only 2 months were allowed before changing to triclosan, and delayed control was also probably due to relatively infrequent surveillance cultures (i.e., only done on admission and discharge) [39]. Three years after switching from use of antimicrobial soap to use of an alcohol handrub at a VA hospital, Gordin reported a 41% relative reduction in patients with any type of new, nosocomial VRE isolate (amounting to 17 fewer patients per year for the hospital) and a 21% relative reduction in patients with new, nosocomial MRSA (amounting to 19 fewer patients per year for the hospital) [227]; because only a small fraction of all colonized patients are detected by clinical cultures, failure to do surveillance cultures made the estimate of the intervention's effect less precise than if they had been done and the reported reductions were modest compared with those achieved using active detection and contact isolation precautions [83,91,126]. Implementing use of an alcohol handrub isn't always associated with improved hand hygiene compliance [236,237]. Pittet et al. reported significantly better control of MRSA after switching to the use of an alcohol hand rub and a motivational campaign resulting in improved compliance [238], but simultaneously implemented surveillance cultures and contact precautions for every colonized patient, making the relative contribution of the changes in hand hygiene difficult to determine [14].

Studies Suggesting Isolation Is not Needed, Does not Work, or Harms Patients

Several recent publications have been used by isolation opponents to suggest that active detection and isolation are not needed to control MRSA or VRE because (1) MRSA reportedly does not spread even when colonized patients are not isolated [239], (2) isolation does not work [169], or (3) isolation harms isolated patients [240]. Nijssen et al. reported a study from an ICU where MRSA was said to be endemic, but no MRSA spread was found over 10 weeks in 2000 from nine colonized, non-isolated patients [239]. Unfortunately, Nijssen et al. failed to specify what precautions (such as standard precautions or universal barrier precautions) they used, making interpretation difficult. They also reported that the rate of clinical MRSA isolates did not change significantly over a 4-year period from 1999 through 2002 in the ICU including the study period, suggesting that MRSA really was

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not being controlled and that the small 10-week sample was not only statistically imprecise but also misleading. Other recent ICU studies confirm continuing ICU spread despite standard precautions [83,91,136,173,241] and show that MRSA clinical isolates can be significantly reduced after implementing surveillance cultures and contact precautions for all colonized patients [3], one showed a 75% reduction in MRSA BSIs in the 16 months following a phase-in period [83], and another reported continual reduction for 3 years after implementing surveillance cultures and contact precautions for all colonized patients, with the final year showing an MRSA infection rate <10% that of the year in which the intervention began [91]. These data contrast sharply with the lack of improvement over 4 years reported by Nijssen et al. not using identification and isolation [239].

Cooper et al. have authored several publications that have led some to question whether isolation can control ARPs like MRSA [169,242,243]. The first was a structured review of 46 selected studies of MRSA control, which concluded that the studies had not allowed conclusions about the efficacy of individual isolation measures but that “there is evidence that concerted efforts that include isolation can reduce MRSA even in endemic settings and …should continue to be applied until further research establishes otherwise”[242]. Then they published another study 4 months later concluding that isolation worked no better than standard precautions to control endemic MRSA [169].

The review said that 6 studies provided “stronger evidence” than the other, generally smaller 40 studies [242], presumably because there could be little question of alpha error or regression to the mean contributing to the observed outcome. Five showed success using surveillance cultures and isolation, but after a decade of control, one of the five failed after relaxing these control measures because they came to be viewed as clinically “inconvenient”[19]. Cooper et al. said that the failure of control was due to a “rise in numbers colonized on admission or change in strain rather than changed [i.e., relaxed] control measures” but offered no rationale for this conclusion [242]. After relaxation of control measures, the numbers of MRSA BSIs increased from 3 during the two years before to 92 during the two years after relaxation, respectively [19]. The sixth study reported control failure despite using surveillance cultures and contact precautions for eight years [244], but Cooper et al. failed to note that most newly identified colonization was from clinical cultures, which suggested that most colonized patients were not being identified and isolated [245]. If this occurred throughout the eight years, it likely could explain the program's failure.

Most of the other studies of surveillance cultures and isolation reported control of MRSA but were dismissed as “intermediate” or “weaker” evidence by Cooper et al, implying that they may have been flawed by chance or biased because they tended to be smaller and lacked randomization and multivariate analysis. The review, which faulted prior reviews for not being systematic and possibly missing something important, failed to note that MRSA had been controlled to exceedingly low levels in some instances for decades across multiple entire nations and the state of Western Australia, all using a similar approach, and that other European nations [191,192] and Australian states [193] not routinely using this approach had much higher MRSA rates. It also failed to note that virtually all reviewed studies reporting the use of surveillance cultures and isolation of all colonized patients demonstrated success controlling MRSA, the only apparent exceptions being the two mentioned earlier, one after relaxing control measures and the other not identifying and isolating all colonized patients. Cooper et al. suggested that a third study, said to be of “intermediate” strength, also failed to control MRSA, but this was not what the article in question said [25], and a British national guideline disagreed with Cooper, citing the study as an example of success, saying that this and “several other large outbreaks confirm that they often can be controlled and the numbers of patients colonized or infected with MRSA reduced substantially with aggressive management”[201]. It seems unlikely that virtually all of the scores of studies using surveillance cultures and isolation would report success due to some being valid and correct and the rest being invalid and incorrect.

Cepeda et al's. next article began by citing their own review discrediting prior studies reporting success controlling MRSA as “generally undertaken in response to outbreaks rather than within intensive-care units of high endemicity”[169], but many studies have reported control of MRSA using surveillance cultures and contact isolation in settings where it had been endemic for years [2,3,4,5,10,24,26,27,30,32,33,34,35,37,40,42,45,48,55,59,65,70,71,73,74,75,76,77,78,79,80,81,82,83,86,87,89,90,91,92,94,95,96,97], including multiple settings involving ICUs [3,4,24,26,27,30,70,75,76,83,91]. Many other supportive studies could be cited showing control with the same measures for endemic VRE [33,74,81,94,98,99,100,104,107,109,110,111,115,119,120,125,126,127,128,131], another ARP with similar patterns of spread and a similar selective advantage for proliferation and spread in ICUs; Hill said that “reasoning by analogy” to other conditions was an important way to get at the truth from epidemiologic studies [246].

Cepeda et al. concluded from their brief study that isolation did not reduce MRSA transmission “over and above the use of standard precautions,” but this question was not even addressed in the study. Cepeda et al. reported using the same barrier precautions in both study phases (i.e., nurses wearing disposable aprons “throughout each nursing shift” and donning gloves to turn a patient with intact skin) and using dedicated equipment for every patient (i.e., precautions very similar to contact precautions) [169]; Wilson and two of the other authors said in reply to a letter to the editor that the only thing that varied between the two study phases had been whether colonized patients were moved into an

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isolation room or not [247]. This comparatively small difference between the two study phases (i.e., moving vs. not moving colonized patients) and the brief study period both favored a negative result as did dividing the “move” phase into two separate 3-month blocks. Multiple studies reporting dramatic control with active detection and isolation showed that it took considerably longer than a 6-month intervention to achieve such results [83,91] including one that, like Cepeda, used multivariate analysis adjusting for other predictors of control [30]. Reasons for the lack of trend toward control in either study phase (i.e., despite using barrier precautions for all patients in both study phases) likely included the selection of sleeveless aprons rather than gowns as barriers and leaving HCW colonization uncontrolled in ICUs with a chronic high prevalence, likely contributing to spread in both study phases [47,165,166,167,203]. The aprons likely allowed contamination of sleeves and probably contributed to spread in both study phases. For example, when a nurse caring for one of the many MRSA patients cross covered for “nurses from adjacent bed spaces” or helped them turn their patients, sleeve contamination could spread MRSA to noncolonized patients even if hands had been washed and contaminated aprons removed, but the nurses” measured hand-hygiene rate was only 21%, and apron removal was not monitored. Nurses reportedly were wearing aprons 99% of the time when monitored, raising concern that they may have worn them “throughout each nursing shift” without removing them appropriately as needed to prevent spread. Multiple prior studies have reported MRSA spread when barriers were left on between patients [5,248,249].

Cepeda et al. called for a randomized trial to confirm their finding that isolation did not work [169], but it should be noted that (1) randomization would not have removed the problems favoring a negative result in Cepeda's study noted earlier and (2) randomization is not needed to provide a representative study sample when the approach is used for the entire patient population as in multiple countries in Northern Europe [22,191,192] and Western Australia [28]. An NIH–supported cluster-randomized trial (RCT) of MRSA and VRE control in U.S. hospitals (www.ClinicalTrials.gov, accessed April 13, 2006) is underway but should not be expected to provide definitive results; no single epidemiologic study is ever definitive. Some assume that randomized trials are much more likely to reach accurate, valid results than nonrandomized epidemiologic studies, but recent meta-analyses found that the variability of results for studies of a particular question were usually as large for randomized as for nonrandomized studies [250,251]. The reason for the similarity in variation and error rates between randomized and nonrandomized studies of a particular question may have been that randomization primarily helped prevent selection bias, just 1 of 23 types of bias listed in a recent dictionary of epidemiology, but did nothing to influence many other types of bias, nor did it reduce the probability of other types of error, such as beta error due to inadequate sample size and statistical power. A prior NIH double-blind RCT of vitamin C as therapy for common colds was believed by its authors to possibly have been biased due to unblinding of study subjects [252]. The NIH RCT of MRSA and VRE control is unblinded and thus more subject to a number of biases for this reason.

The NIH trial protocol chose not to replicate the results of the 131 prior studies showing efficacy of active detection and isolation of MRSA and/or VRE (apparently accepting these results as valid), saying that it instead sought to evaluate a previously unstudied question, comparing the effects of surveillance cultures and contact isolation of colonized patients with the effects of “enhanced standard precautions” (i.e., using alcohol hand rubs and a motivational campaign to increase hand hygiene compliance). However, a study by Huang et al. at Brigham and Women's Hospital recently compared those two approaches and found that active detection and isolation worked better than enhanced standard precautions, reporting no effect of enhanced standard precautions on MRSA BSI rates and a 75% reduction in MRSA BSIs using surveillance cultures and isolation of colonized patients [83]. Huang's study was a nonrandomized, retrospective time-series analysis, but there were multiple important differences other than randomization between the two studies nominally comparing the same measures. For example, Huang's study was much longer and obviously had ample statistical power whereas the NIH trial protocol stated that it would have 80% power only to detect a reduction at least 40% more in the isolation group than the enhanced standard precautions group. This seems inadequate given an intervention period set to last six months and a protocol provision that a study ICU could submit as little as three months of data and have that count as full participation. The lack of such rapid change in recent, eventually dramatically positive studies [83,91,30] makes an intervention period of only 3–6 months in the NIH study seem inadequate to detect a 40% reduction and makes a false negative result seem more likely. Moreover, including only one ICU from a very large hospital, doing admission cultures only on the subset likely to stay >3 days (likely representing a minority of patients in a number of participating ICUs), defining “admission culture” as one done in the first 48 hours, and sending surveillance cultures to an outside laboratory by one-day mail made a negative result seem more likely in the NIH trial than in the Huang study, which sought to culture all patients on admission in all ICUs, thus addressing spread among a much larger fraction of the hospital's high-risk patients. Each of the factors just listed is potentially important and could bias the NIH study toward finding less efficacy of surveillance cultures and isolation of colonized patients with contact precautions; in combination, they could have a major impact on study results.

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One nonrandomized study has suggested that patients isolated for MRSA were significantly more likely to suffer decubitus ulcers, falls, or fluid/electrolyte disorders than were nonisolated patients without MRSA [240]. It did not find significant increases in diagnostic, operative, anesthetic, medical procedure or adverse drug events, or mortality. Its authors emphasized that their findings would need confirmation in follow-up studies by others. Opponents of using isolation to control MRSA or VRE have cited this finding as a reason to oppose using isolation for this purpose, but nobody has objected to using isolation to contain other infections like SARS or tuberculosis that infect and kill HCWs, suggesting that they believe isolation to be acceptable for protecting HCW safety. If Stelfox's result is confirmed by additional studies, failure to care properly for isolation patients should not be tolerated by medical management and should be addressed as a quality improvement issue. It should not be used as a reason to refrain from using effective control measures and thus to allow spread of lethal infections.

Importantance of Using Infection Control to Curb Antimicrobial-Resistant Pathogens in Regard to Cost Effectiveness

Multiple studies have documented higher human and financial costs associated with MRSA or VRE HAIs than with infections due to susceptible strains of the same species [1,132,133,134,135,253,254,255,256,257], but some have questioned the cost effectiveness of using surveillance cultures to identify and isolate all colonized patients. Of 12 studies of this question found, each used different approaches, and each concluded that investing in control of spreading infection in this manner was less expensive than taking no effective measures and allowing current rates of endemic or epidemic spread [2,13,33,120,255,257,258,259,260,261,262,263]. One concluded that this was cheaper because isolation costs paradoxically declined as surveillance cultures were done to find and isolate all colonized patients because spread was curtailed and fewer patients then required isolation [263]. The other 11 generally found lower costs at least in part because of significantly lower rates of more expensive infections due to MRSA or VRE [2,13,33,120,255,257,258,259,260,261,262].

Summary

Uncontrolled spread of ARP has resulted in hundreds of thousands of patients suffering HAIs and more than 13,000 deaths in the U.S. healthcare system each year, according to a CDC estimate. Components of a successful control program include education of HCWs regarding the importance of HAIs due to ARPs, encouraging compliance with appropriate hand-hygiene methods using compliance monitoring and feedback, encouraging appropriate use of antibiotics, and, as this chapter has demonstrated, identifying all reservoirs for spread (especially colonized patients) in order to implement appropriate contact precautions. Active surveillance cultures and contact precautions for all colonized individuals have controlled MRSA and VRE infections and saved money. Efficacy has been demonstrated for both endemic and epidemic spread and at the level of the individual hospital unit, hospital, region, and nation.

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