Hospitalized patients who acquire infections with antimicrobial resistant organisms are at risk for prolonged suffering, increased death rates, and higher costs than those who acquire infections with antimicrobial susceptible organisms of the same species. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) are major causes of these infections in US hospitals. Ubiquitous use of antibiotics contributes to the increasing rate of these resistant organisms; however, patient to patient spread via the hands and equipment of health care workers serves as the primary mode of transmission. To help gain control of these organisms, the Centers for Disease Control and Prevention published guidelines recommending that barrier precautions be used for patients known or suspected of being colonized with epidemiologically important organisms such as MRSA and VRE. Some patients are considered to be at high risk of becoming colonized with MRSA and VRE, including those who have been hospitalized for at least 4 days, live in a long term care facility, or are transferred between hospitals for care. In order to identify colonized patients, who serve as the reservoir for spread of these organisms, active surveillance cultures should be performed on these high-risk patients; however, most facilities have not done this.
This partnership proposes to reduce the MRSA and VRE rates in Virginia and North Carolina health care facilities agreeing to perform surveillance cultures on high-risk patients and instituting barrier precautions for patients found to be colonized or infected. We invite your interest, questions and participation in this important public health initiative. On this webpage, you will find a document explaining the process of joining the partnership, a sample algorithm explaining how to identify MRSA and/or VRE colonized patients, and sample forms for tracking the current culture status of your institution.
BACKGROUND AND SIGNIFICANCEAntimicrobial resistance was recently listed at the top of the CDC's list of emerging infectious threats to the public health and chosen by the American College of Physicians as the focus for its 2000 national meeting. Antibiotic resistant nosocomial infections have been linked to both significantly higher mortality (2-18) and significantly greater excess hospital costs(8;19-21) than occur with infections by antimicrobial susceptible strains of the same species. Transfer of genes for vancomycin resistance from VRE to other species such as S. aureus has been documented, raising concern that failure to control MRSA and VRE will make evolution of even worse pathogens like vancomycin resistant S. aureus more likely.(22)
Some studies have suggested that the higher mortality of patients with antibiotic resistant infections is merely due to a higher baseline acuity of illness,(4;23-25) but other studies accounting for baseline acuity of illness have found that the resistant strains still result in significantly higher mortality.(7;8;10;18) A recent study found that although baseline acuity of illness was very predictive of death, a trend toward higher death with VRE (than with VSE) bacteremia persisted after adjusting for baseline acuity(OR=2.07, 95%CI=0.96-4.42,p=0.063).(26) Another recent study found that 10 (50%) of 20 patients with bacteremic MRSA pneumonia treated with vancomycin died as compared with 8 (47%) of 17 patients with bacteremic MSSA pneumonia treated with vancomycin. By contrast, none of ten patients with bacteremic MSSA pneumonia treated with cloxacillin died. Multivariate analysis adjusting for underlying diseases, and the development of both septic shock and respiratory failure found vancomycin therapy (i. e., rather than cloxacillin therapy) to be an independent predictor of death.(27) A study of S. aureus bacteremia reported that 8% of MSSA cases treated with a beta lactam died, as compared with 14% of patients with MRSA treated with vancomycin, 44% of MRSA cases treated with other drugs showing in vitro susceptibility to those drugs, and 100% of 13 MRSA cases treated with drugs showing no in vitro susceptibility.(3) A study of neutropenic, bone marrow transplant patients found significantly higher mortality (46%) for patients with VRE bacteremia than for those with VSE bacteremia (0%).(13) It seems reasonable to conclude that higher case fatality rates are observed with serious MRSA and VRE infections and that this is due in part to lack of antibiotic efficacy.
Several studies have suggested that the excess costs of MRSA and VRE infections exceed those of preventing them.(28-31) These findings suggest that controlling this problem should pay important dividends over the long term. Such control has been convincingly demonstrated in Denmark where the nosocomial MRSA infection rate was decreased from 34% to <1% and kept there for the past two decades.(32) Belgium is now reportedly following this example.(33)
Studies Documenting Contamination of Clinicians' Hands, Apparel and Equipment
Spread of MRSA and VRE between patients is facilitated by the fact that clinicians' hands, equipment, and apparel are infrequently disinfected between patient contacts. A recent study documented contamination of clinicians' gloves, gowns and stethoscopes after two thirds of examinations of VRE patients whether the patient was clinically infected or asymptomatically colonized with VRE.(34) The authors concluded that such high rates of contamination suggest that patient to patient spread likely occurs via contaminated hands, apparel and equipment of clinicians unless colonized patients are identified and placed in contact isolation. Another study found that the concentration of VRE in colonic fecal contents did not differ between patients with clinical VRE infection and those with asymptomatic colonization, suggesting that the level of contagion was likely similar from the two groups.(35) This may explain why the rate of contamination of the clinicians was similar for colonized and infected patients. Ano ther study showed that gowns were frequently contaminated after care of patients with MRSA or VRE and that gowns reliably prevented contamination of clothing beneath the gown.(36) The same study showed that when a white coat was worn instead of a gown it became contaminated in two thirds of cases and that touching the coat with clean hands resulted in hand contamination.(36) A fourth study found that 65% of nurses cultured after performing morning care activities for patients with MRSA in urine or a wound had gown or uniform contamination.(37)
Studies Documenting Environmental Contamination with MRSA and VRE
Environmental contamination of the hospital rooms of patients with MRSA was documented in one study for 73% of infected patients and 69% of colonized patients.(37) The same study documented contamination of nurses' gloves with MRSA as much as 42% of the time after touching surfaces in the room without touching the patient. VRE contamination of hospital rooms and equipment has been documented in the hospital rooms of patients with VRE colonization or infection in many studies.(25;38-45) One recent study found that enterococci and staphylococci can survive for weeks to months on fabric or plastic surfaces such as are frequently found in the hospital environment.(46) Another recent study found that VRE was harder to remove by disinfection from fabric surfaces than from vinyl. One study found that 16% of surfaces in a hospital room remained culture positive for VRE after conventional disinfection but were uniformly free of VRE after a more intensive form of disinfection.(38) Another study reported control of an outbreak after an increase in the intensity of environmental disinfection, which was also associated with a decrease in the proportion of environmental cultures being found positive from 29% to 1%.(44) Environmental VRE contamination was detected in 29% of clinic exam rooms after examination of persistently colonized outpatients, suggesting that use of barrier precautions and disinfection of contacted surfaces in the exam room may be reasonable.(47)
Most MRSA and VRE Colonization Results from Spread
Nosocomial spread of pathogens from patient to patient has been documented for decades and it is thus not surprising that antibiotic resistant pathogens should follow the same pattern. Recently collected data suggest that most patients with the two most frequent antimicrobial resistant pathogens in American hospitals, MRSA and VRE, have them not because of de novo mutation to resistance, but because of spread from patient to patient.(48-53) For example, in one outbreak of MRSA in a NICU all 18 isolates were shown to be due to the outbreak strain.(48) During the 9 years after control of the outbreak no neonate had a culture positive for MRSA showing the low frequency of de novo mutation even in a population with prolonged hospital stay and frequent exposure to antibiotics. Similarly after control of a hospital outbreak of VRE in which 100% of patients in one ICU had the same strain of VRE, the ICU was then kept free of VRE for more than a year as documented by weekly cultures of all patients in the unit .(53) This occurred despite a very high prevalence of antibiotic exposure in the ICU involved and the lack of an antibiotic control program in the hospital at that time.
Community acquired MRSA infections have increased during the last decade and resulted in the deaths of four children in the upper Midwest in the last few years.(54) While some data suggest that such strains with resistance to fewer other antibiotics may be arising merely because of antibiotic exposure in the community, other studies have suggested that patients found to have community acquired MRSA tended to be patients with chronic illness requiring frequent contact with the health system in outpatient visits.(49-52) It is known that disinfection of equipment (e.g., sphygmomanometer cuffs) between patients is even less frequent in the outpatient setting than between patients in the hospital and it is unlikely that hand hygiene is more frequent in that setting. It was also shown in a recent study that patients acquiring MRSA in the hospital transmitted the same strain to 14% of their household contacts after discharge.(55)
Active Surveillance Cultures and Isolation can Prevent MRSA and VRE Infection
Many studies during the past two decades have documented that identifying and isolating patients colonized with MRSA (28;56 57 33;48;49;58) or VRE(39-41;53;59-68) can prevent nosocomial infections due to these pathogens in the absence of an antibiotic control effort (other than vancomycin restriction, which was used in a number of studies but has not been shown to be an independent predictor of control of VRE outbreaks). During one such report of a 3-year hospital-wide outbreak of MRSA, the outbreak strain came to account for 40% and 49% of all nosocomial S. aureus bloodstream infections and surgical site infections, respectively; it was then completely controlled (eradicating the MRSA strain from the hospital) by performing active surveillance cultures to identify colonized patients and placing them in contact isolation (i.e., using gown, gloves and mask for their care) with no antibiotic control measures.(57) It is important to understand that continued spread and rising rates of infection had occurred throughout the preceding 3 years when only the subset of colonized patients with clinically obvious infection were being put into such isolation. During that time most colonized and contagious patients were not recognized (i.e., like the invisible bulk of an iceberg).(57) Another study confirming these findings found that MRSA spread to other patients was reduced 16-fold when colonized patients were recognized by active surveillance cultures and placed in contact isolation (which at the time involved use of gown, gloves and mask)(48) as compared with standard precautions, which relies upon wearing gloves for touching secretions, excretions, or drainage and handwashing between patient contacts to prevent spread. These findings were in agreement with the results of a mathematical model which found that handwashing alone at a much higher rate than usually achievable in clinical settings (i.e., following 80% of patient contacts), had a negligible effect on spread of VRE because of the rate of transmission follo wing failure to wash after the remaining 20% of contacts.(69) During another study active surveillance cultures and contact isolation for colonized patients promptly contained an VRE outbreak on eight wards.(53) This study again documented that a large majority of the colonized patients would not have been detected by routine clinical specimens, leaving them unrecognized and unisolated.
Critique of Claims That CDC Guideline for Control of VRE Doesn't Work
The results of several studies have been used to suggest that the CDC Guideline for Control of VRE doesn't work because some parts of the guideline have been used without apparent benefit.(70-74) Three of these hospitals reported that they restricted use of vancomycin with no apparent effect on VRE prevalence. The PPP applicants acknowledge that vancomycin restriction has indeed had little impact on VRE prevalence. Of greater relevance to this proposal, however, are data regarding active surveillance cultures and their use for identifying and isolating colonized patients in order to prevent spread. The CDC Guideline recommends use of such cultures "for more efficient containment." One of these hospitals used no active surveillance cultures at all(70;74) and the other three used such cultures only on patients in beds on one to three hospital wards. For two of these hospitals this number of beds constituted 1.8% and 4.6% of beds, respectively, suggesting that this represented only a small fraction of t he total reservoir for VRE spread in the hospital.(71;72) One of these studies reported a high rate of VRE colonization and infection in the only ward where these control measures were being applied (an ICU), but 15% of the patients were culture positive at time of transfer to the ICU from other hospital wards and another 25% turned culture positive a mean of 7.5 days after transfer, meaning that many of these had probably already been exposed before transfer and turned culture positive after transfer due to initiation of antibiotic therapy in the ICU.(72) The other hospital performed cultures on two wards but reported hospital-wide VRE infection rates as if an intervention in two wards should affect the hospital-wide rate. The third hospital's size was not reported, but the three wards being sampled in that hospital again likely included only a small minority of VRE colonized patients. To further illustrate the issue of sampling adequacy for identifying the reservoir for spread, one need only refer to the study mentioned in the paragraph above regarding a VRE outbreak identified on eight hospital wards where 30% of initial cultures were VRE positive.(53) Had that control effort been limited to identifying colonized patients on only one to three of the eight wards experiencing epidemic spread, it seems obvious that this would have had little effect on further spread within the other 5-7 wards not being sampled. Nor would this have had any effect on spread from those 5-7 wards to the rest of the hospital via the frequent inter-ward transfers that were documented at the time of the outbreak.
One of the studies suggesting lack of effect of the VRE guideline went even further, maintaining that control was probably not possible because many different strains were observed by DNA fingerprinting, implying that spread was not the problem despite documentation of violation of isolation precautions in 44% of clinician visits to isolation rooms and lack of identification and isolation of most of the reservoir for spread.(71) While it is true that forty-five unique pulsed field gel electrophoresis (PFGE) patterns were observed among 85 isolates, there are several epidemiologic problems with their interpretation: 1) Assuming random spread of all 45 observed strains and that each patient could have only one strain, a sample size of 85 is inadequate to show all patterns of spread (i.e., being less than two per strain). A total sample size of 10 to 20 times larger than the number of strains identified would have been more appropriate for showing the amounts of spread by all strains. 2) Recognizing that each patient can in fact have multiple strains of VRE,(45;75) the study design, which did not report looking for multiple strains per patient, may have prevented showing spread for this reason as well. 3) Finally, and most importantly, this study did not report looking for transposons, mobile genetic elements that can move from strain to strain bearing a resistance gene for vancomycin resistance. In 1992 the CDC noted the polyclonality of VRE in New York City hospitals and reported that this likely meant that one or more transposons were spreading from Enterococcus to Enterococcus.(76) Patient-to-patient fecal-oral spread of VRE as documented in many studies(39-41;53;59-68) can obviously still occur with VRE bearing such a transposon, but it results in a polyclonal PFGE pattern due to transposon spread to virtually all VSE strains in all of the patients' colons. Transposon 5482 was recently found to be responsible for virtually all of the polyclonality in a VRE outbreak in a cancer hospital in Ne w York City.(77) These epidemiologic shortcomings make it impossible to conclude from the data presented that VRE was not spreading in the hospital as suggested.
Are Gowns Necessary For Preventing Spread?
For patients found to have VRE, full contact isolation with gowns has been used because of the data cited above regarding frequent contamination of clinicians' apparel when gowns were not worn and because of the many examples of documented success controlling VRE using this approach.(39-41;53;59-68) One especially pertinent study reported control of two VRE outbreaks using gloves and gowns but noted that the first outbreak had not been initially controlled when gloves alone were used for barrier precautions.(40) Another study evaluating the importance of gowns found that wearing gloves was as effective as wearing gowns and gloves for preventing spread of VRE in an intensive care unit.(72) Unfortunately, 15% of the patients were culture positive at the time of transfer to the ICU from other wards throughout the 900 bed hospital and the other 25% turning culture positive did so a mean of 7.5 days after transfer. This means that this study may have been confounded by exposures occurring before transfer else where in the hospital where colonized patients were not being detected or isolated. Such prior exposures could have resulted in positive cultures on transfer if the patient had already received antibiotics before transfer (i.e., as in the 15% positive on transfer). Prior exposure could also have resulted in "false negative" cultures on transfer among patients without prior antibiotic exposure (i.e., with subsequent conversion being documented after being started on antibiotic therapy in the ICU). The virtual necessity of antibiotic exposure for turning perirectal culture positive among patients exposed to VRE was documented in a recent study.(78) Antibiotic exposure has also been shown to be important for determining both duration of VRE culture positivity after discharge and relapse of positivity during a subsequent hospital stay.(75;79)
Does Universal Gloving Add Anything?
Data from studies at the University of Virginia (UVA) suggest that universal gloving during an outbreak can be a useful, short-term, adjunctive control measure for preventing spread from patients not yet recognized to have VRE.(80) This was felt to be a reasonable compromise measure since 1) a large majority of patients in this hospital were in fact culture negative, 2) contaminated hands likely represent the most frequent source of spread from patient to patient, and 3) universal gowning would have required significantly more time and cost.
Reasons That Antibiotic Control Alone May Be Insufficient to Control MRSA and VRE
There is clear evidence that the density of use of antimicrobials within the hospital is linked to the prevalence of bacterial resistance and that a reduction in use of some selected antimicrobials can lead to decreased prevalence of resistance in some drug-organism pairs.(81-85) The Society for Healthcare Epidemiology of American (SHEA) and the Infectious Diseases Society of America recognized the importance of judicious antibiotic use in addition to infection control when it published joint guidelines for the prevention of antimicrobial resistance in hospitals.(86)
Because the prevalence of antimicrobial therapy serves as a definite risk factor for colonization and infection by antibiotic resistant microbes, many have chosen to focus upon modifying this risk factor alone in an effort to control the problem. While much data exist that removal of a particular antimicrobial from the healthcare environment can result in a decrease in the prevalence of resistance to that drug,(81;87-89) there are other data that suggest this does not always work. For example, the greatly decreased use of penicillin over the last few decades has not resulted in a decrease in the frequency of penicillin resistant S. aureus. Likewise, a decreased use of penicillinase-resistant penicillins such as methicillin, oxacillin and nafcillin has not resulted in a lower prevalence of MRSA.(49) While most hospitals have implemented the CDC recommendation to restrict use of vancomycin, this has also had little to no effect on the prevalence of VRE colonization or infection.(71;72) One of the reasons th at this is so is that other antimicrobials also serve as risk factors for antibiotic resistant pathogens such as MRSA and VRE. For example third generation cephalosporins and metronidazole have been more important risk factors for colonization or infection with VRE in some studies than has vancomycin itself.(90-92) Of note, one study has reported a 3-fold reduction in the prevalence of VRE colonization (i.e., from 47% to 15%) using only antibiotic controls. For this purpose cefotaxime, the primary third generation cephalosporin used in a 310-bed Veterans' Affairs Hospital was reduced by 84% while clindamycin was reduced by 80%. As alternative drugs, ampicillin/sulbactam and piperacillin/ tazobactam were recommended and their use correspondingly increased.(74) While encouraging, it must be noted that the follow-up consisted of a single point prevalence study conducted on a single day six months after start of the intervention. Longer term follow-up was not felt to be appropriate because of marked downsizin g and restructuring of the patient population of the hospital according to the principal investigator.(93) It should also be noted that, while a marked improvement from the baseline rate in that hospital, the VRE prevalence of 15% achieved using major antibiotic control measures still represented a 30-fold higher rate than that maintained at the University of Virginia over a period of 3 years following control of an 8 ward outbreak using active surveillance cultures and isolation and before initiation of an antibiotic control program.(65) While vancomycin was restricted and its use reduced by half, vancomycin was not a risk factor for VRE colonization or infection at the University of Virginia and its reduction thus likely played little role in this control of VRE during the 3 years before initiation of an antibiotic control program.(53;94) Two studies have reported control of VRE using antibiotic control measures but both were also performing active surveillance cultures and using contact isolation for colo nized patients making the relative contributions of the two control measures difficult to separate.(95;96) One recent study suggested that switching from use of third generation cephalosporins to first generation cephalosporins for surgical prophylaxis in association with some new infection control measures was associated with a decline in the incidence of MRSA infections.(97) The frequency of MRSA at most hospitals using first generation cephalosporins for surgical prophylaxis during the past decade has only continued to rise, however, suggesting that this approach is certainly not a complete answer to the problem.(49)
PRELIMINARY DATA
1. Central Hypothesis
PPP will test the hypothesis that significantly increased compliance with CDC recommendations for isolation of patients colonized with MRSA and VRE will result in significantly decreased colonization and infection rates due to these pathogens. This will in turn result in less infection related morbidity, mortality and costs. This increased compliance will require recognition that detection of colonization requires active surveillance cultures in most cases.
2. Preliminary Data to Support Central Hypothesis
2.a. Failure to detect MRSA colonized patients results in continued spread while detection and isolation control the problem. A seminal study of MRSA infection at UVA showed that isolating patients recognized by results of routine clinical specimens did not stop continuing epidemic spread.(57) (cf. copy in Appendix B) After 3 years of failing control, 40% of all S. aureus BSI and 49% of all S. aureus SSI were methicillin resistant. Active surveillance cultures were then begun resulting in complete control (Figure 1). During the following decade there were low rates of MRSA at UVA using active surveillance cultures to detect and halt spread when reintroduction was noted, but MRSA rates began to increase in the 1990s due to increasing rates of transfer of colonized patients from other facilities (Figure 2).(49)
Surveillance cultures were used to control a UVA NICU MRSA outbreak to 3% colonization with 4 infections (Figure 3). Spread declined 15.6-fold with surveillance cultures and contact isolation as compared with standard precautions for unrecognized colonization (Table 1).(48) 2.b. Use of surveillance cultures and isolation to control MRSA is cost effective. 3.a. Detection and isolation of VRE colonized patients controls the problem. 4.a. Failure to detect colonized transfer patients can result in nosocomial spread. 4.b. Detecting and isolating colonized transfer patients can stop nosocomial spread. 5.a. Compliance by all facilities in a region has a more pronounced effect on infection rates.
Table 1
The costs of active surveillance cultures and isolation for controlling this outbreak were compared with the excess costs (based upon published attributable cost estimates)(19;98;99) of much a higher number of MRSA BSI in another NICU MRSA outbreak that was not as promptly controlled.(56) This suggests that preventing MRSA infection by use of this approach could be very cost effective (Figure 4).(29)
Initial control of VRE at UVA using active surveillance cultures resulted in dramatic control of an outbreak (Figure 5) and a colonization period prevalence rate < 0.5% for 3 years after control and before implementation of an antibiotic control program.(65) After 4 years of spread and infections at a 300 bed California hospital onset of use of this approach controlled the problem (Figure 5a).
Figure 5a
3.b. Use of surveillance cultures and isolation to control VRE is cost effective.
The cost to UVA of using this approach for controlling VRE over a two year period was compared with the excess costs (based upon published attributable cost estimates)(8;98;99)from a higher number of VRE BSI at a hospital of comparable size and complexity not using this preventive method, suggesting cost-effectiveness(Figure 6).(31)
Figure 6
The result of being surrounded by facilities not using this approach is shown in Figure 7 (i.e., a slowly increasing prevalence of VRE at UVA despite using active surveillance cultures and isolation). This increase implied an unrecognized reservoir for spread.
Cultures of patients transferring from other facilities confirmed the presence of a new reservoir for spread (unrecognized and unisolated VRE was found in 1.7% of hospital and 2.6% of LTCF transfers).(101) Isolation significantly decreased the rate of VRE colonization at UVA(Figure 8).(65) Unrecognized MRSA was found in 4% of hospital and 16% of LTCF transfers to UVA and isolation decreased spread.(101)
The importance of including all (4 acute and 26 long term care) facilities for controlling VRE throughout a health district using this approach was recently demonstrated in Iowa.(67) Using control measures for MRSA throughout all facilities in Denmark succeeded.(Figure 9)
Figure 9
Baseline practices and MRSA and VRE prevalence among clinical microbiology lab isolates.
In preparation for an initial PPP meeting in Richmond on 6/2/00, 128 hospitals provided data regarding their infection control practices and MRSA and VRE prevalence (Figures 10a, 10b, 10c).
Figure 10c
Prospects for PPP Compliance
After presentation of data supporting the PPP approach, 89% of those in attendance said that they felt that the data were compelling and they wanted the partnership to proceed. Of note, 15% were already using the approach and 70% said that a PPP visit and presentation would help to convince their hospital leadership to join the effort. A number of hospitals have since joined the effort.
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