There are several factors to consider when assessing whether to adopt a new intervention. Often, new literature or growing literature around a strategy with a strong rationale for positive impact can propel hospitals to adopt that strategy, especially in the case of a perceived need. The balance between early adoption before definitive clinical trials versus adoption after definitive trials must be determined based on local needs and culture.
The results of the REDUCE MRSA Trial provide strong evidence in support of universal decolonization to reduce MRSA and other pathogens in adult ICUs. In assessing the quality of evidence underpinning a new strategy, well-conducted, randomized controlled trials provide the highest level of certainty about the effects of an intervention. The REDUCE MRSA Trial has the following high quality features:
- Randomized controlled trial.
- Large scale trial. The trial involved 43 hospitals and 74 ICUs.
- Pragmatic application. The intervention was applied to all adult ICU patients. This means that the intervention was studied in the way it would generally be applied to patients for quality improvement purposes.
- Pragmatic implementation. The decolonization strategy was implemented by the same hospital staff and processes usually responsible for quality improvement campaigns. This means that it was rolled out in a manner that reflects how most hospitals would implement this strategy.
- Generalizable approach. Unlike many studies of hospital-based interventions which are conducted in major academic centers, the REDUCE MRSA was conducted in mostly community hospitals. Although the study was conducted in facilities owned by a single hospital system (the Hospital Corporation of America), the results of this trial are likely to be widely applicable.
Comparison to current best practice. Sometimes trials compare an intervention to older strategies that are no longer considered best practice. The REDUCE MRSA Trial compared two decolonization strategies to a strategy of high compliance ICU MRSA screening and contact precautions and showed superiority.
- Evidence-based intervention. While the combination of universal mupirocin plus chlorhexidine gluconate (CHG) had not been studied prior to the REDUCE MRSA Trial, there are several other studies that have supported the use of universal chlorhexidine bathing alone. These include multicenter clinical trials1,2 and single-center observational studies.3-5
Once the evidence is well-understood, it is important to assess the likely gains that the hospital will attain if the universal decolonization strategy from the REDUCE MRSA trial is adopted. Since this trial has an impact on adult ICU bloodstream infection rates and MRSA clinical cultures, the following baseline assessments are recommended:
- Determining ICU bloodstream infection rates. The REDUCE MRSA Trial showed a 44 percent reduction in all-cause bloodstream infections when baseline rates were 4 to 6 per 1,000 attributable ICU days. These are total bloodstream infection rates from all causes, not just those limited to central line infection bloodstream events. It may be helpful to estimate the expected impact should universal decolonization be adopted in the hospital. Census data and data from the clinical microbiology laboratory are needed for this estimate.
- Comprehensive Estimate: The infection measure used in the REDUCE Trial was the number of ICU patients with bloodstream infections attributed to the ICU area (numerator) divided by the number of attributable ICU days (denominator). Attribution to an ICU is defined by the CDC as events that occur more than 2 days after ICU admission through 2 days after ICU discharge. Specifically, the number of attributable ICU bloodstream infections within a reasonable length of time (i.e., 1 year) should be divided by the number of attributable ICU patient days in that same year.
ICU bloodstream infection rates should be obtained from positive blood cultures occurring more than 2 days after ICU admission through 2 days after ICU discharge. To avoid having persistent bacteremia count as multiple events, allow only one event per patient. Two positive blood cultures should be required for skin commensals to be considered an infection. This is consistent with CDC guidance.6,7 Denominators should include patient days beginning from day 3 of an ICU stay through 2 days beyond ICU discharge if the patient remains hospitalized.
To change the calculated rate into a rate per 1,000 patient days, simply multiply rate (number of events/denominator of ICU patient days) by 1,000 = total events per 1,000 ICU patient days.
- Simplified Estimate: If the comprehensive estimate is too difficult to obtain, a simplified estimate can be made by identifying all ICU patients who have a positive blood culture within their ICU stay and dividing that number by total ICU patient days. As a reminder, the desired estimate is ICU bloodstream infections from all causes, not just those limited to central line infection bloodstream events.
- Determining MRSA clinical cultures. The universal decolonization strategy of the REDUCE MRSA Trial also reduced MRSA clinical cultures attributable to the ICU by 37 percent. It may be of value to estimate the benefit to reducing MRSA burden in the ICU. This can be estimated in one of two ways:
- Comprehensive estimate: The percent of ICU patients that have any MRSA clinical cultures within a reliable window of time (e.g., 1 year).
- Alternative estimate: The percent of ICU patients that harbor MRSA (based upon a MRSA flag or tag in the medical record). Use a reliable window of time (e.g., 1 year).
- Calculate rates for each adult ICU. For the ICU outcomes above, knowing the rate for each of the hospital's adult ICUs may help in several ways. It provides a baseline on which to assess improvement following implementation. It may identify adult ICUs most in need of an intervention strategy or those most likely to have important gains due to universal decolonization. In addition, if a staged roll out is desired, it may identify ICUs that could be good candidates (e.g., due to high rates) for a pilot evaluation to learn any hospital-specific logistical issues that need to be overcome before rolling the intervention out to all adult ICUs.
Decision to Implement
Once the evidence has been reviewed and baseline data on ICU MRSA burden and ICU bloodstream infections have been collected, the information should be used to determine the need for universal decolonization based on the following criteria:
- The strength of the evidence that this intervention will impact care in the hospital. This includes the magnitude of impact found in published studies, and similarities of the hospital to the patient populations studied. The latter includes case mix, hospital type, and whether the comparator groups in the studies reflect current infection prevention standards at the hospital.
- The amount of ICU MRSA burden (prevalence, incidence, and infection rate) and all-pathogen bloodstream infections found in adult ICUs and the hospital leadership's desire and need to target these outcomes for improvement. Importantly, these data can also be used for internal benchmarking to assess the impact of the intervention once a decision to implement has been made.
- Alignment with existing guidance and position statements from national committees and societies, survey requirements for accreditation, and State laws. As evidence increases on prevention of health care-associated infections, legislative and regulatory requirements may change. It is important to know State legislative mandates and accreditation requirements, as well as guidance provided by the CDC and other national societies related to health care-associated infections.8-12
Assessing the Intervention Scope
- Experience with successful implementation of prior strategies can help guide the type of roll out. Hospitals with robust experience in rolling out ICU strategies may be able to engage in a full simultaneous roll out. In addition, hospitals with considerable prior experience with chlorhexidine bathing due to preoperative bathing or other reasons may be able to perform an all-ICU roll out.
- Reasons for an initial single ICU pilot roll out may include:
- Working out logistics and training with a single ICU before expanding to all ICUs.
- Strong champion in one ICU but uncertain support in other ICUs. Success in one ICU could help drive additional support and adoption.
- Concern about cost. Hospital leadership would like to see returns on a single ICU before expanding to others.
Hospitals will differ on whether they wish to adopt an intervention based on published trial results or await guidance from the CDC or national societies. Higher rates of ICU bloodstream infection and MRSA burden may help drive decisionmaking.
Assessing the Timing of the Decolonization Intervention
Once the evidence-base is understood and baseline rates have been defined, it is important to assess whether the timing is right for a new intervention. Considerations for timing include:
- Urgency related to high bloodstream infection rates or high MRSA prevalence.
- National guidance or regulatory standards.
- Other recent campaigns or new educational training for staff. Does this intervention fit with an ongoing ICU campaign? If not, is there a better time in the near future to adopt this when ICU staff and educators have the time and availability for another campaign? Is there a scheduled training update for clinical staff to which this could be easily added?
- It may be best to avoid launching new campaigns over the holidays unless all collective stakeholders determine that it is the most appropriate time.
Garnering Institutional Support
Once the rationale, baseline data, and timing support the implementation of universal ICU decolonization, it is important to ensure institutional support. Key elements of ensuring institutional support include the following:
- Develop a brief overview statement (go to Appendix C for an example). Select pieces of the above rationale, your hospital rates for outcomes, and comments on timing.
- Business Case: Develop a business case for hospital leadership. Basic steps needed to develop a business case for infection prevention strategies have been well described by Perencevich and colleagues.13
- For universal ICU decolonization, the business case will require the following:
- Number of annual hospital-specific ICU bloodstream infections (see above). As a reminder, since universal decolonization resulted in a 44 percent reduction in bloodstream infections from all causes in the REDUCE MRSA Trial, the proper estimate is broader than estimates limited to central line infection bloodstream events.
- Estimated cost of an ICU-attributable bloodstream infection of $18,000 ($7,000-$29,000) based on several commonly cited sources.14-17
- Number of annual patient days in the adult ICUs that will be adopting universal decolonization as an estimate of the number of baths to be given.
- Number of annual ICU admissions as an estimate of the number of mupirocin courses to be given.
- Hospital-specific cost of chlorhexidine bathing product (each bath).
- Hospital-specific cost of a 5-day course of mupirocin (or the average length of ICU stay, if shorter than 5 days).
- If able to evaluate hospital throughput, consider adding cost estimates for reduction in hospital length-of-stay due to prevention of 44 percent of bloodstream infections, as well as reductions in gown and glove use due to reduction in contact precautions associated with screening. Formal cost effectiveness analyses are being pursued for the REDUCE MRSA Trial.
- For universal ICU decolonization, the business case will require the following:
- Stakeholder Support: Broach and review overview statement and nursing protocol (Appendix D) with key stakeholders, such as the Chief Medical Officer, Chief Nursing Officer, Director of Infection Control and Prevention, Director of Quality Improvement, and the Chair of the Critical Care Committee. Key stakeholders should include high position personnel that are able to offer institutional support for the implementation of the protocol. The order of approaching these key stakeholders will depend on the culture, standard processes, and existing relationships at the hospital, but they should all be included in the decisionmaking process.
- Infection Prevention Program: The hospital Infection Prevention and Control program may be one of several groups to initiate this safety effort. If so, it will be important for the initiator to ensure that the entire Infection Prevention program (e.g., hospital epidemiologist, director of infection prevention, infection preventionist providing support to adult ICUs) is fully supportive, understands the above rationale, and can speak to this endeavor.
- ICU Directors (nursing, physician): The hospital intensivist team may be another group to initiate this campaign and is essential for support. The nursing and medical director can provide critical support and insight to the process and important logistical considerations for universal decolonization, such as bathing shift, recommended bathing time, approach to developing an ICU standardized protocol, successful method for roll out, and concurrent campaigns.
- Purchasing: The purchasing department can provide not only the current hospital-specific cost of certain products, but may be able to engage in price negotiations due to anticipated increases in the amount of products purchased.
- Hospital Administration and Leadership: Support is required from the Chief Executive Officer, Chief Medical Officer, and Chief Nursing Officer to have a successful campaign. Advance preparation of the business case (including anticipated product costs and cost-savings due to prevention of bloodstream infections), description of supporting stakeholders within the hospital, and implementation strategy are important.
Common Stakeholder Questions
Common stakeholder questions regarding universal decolonization should be anticipated. These include the following:
- What is the evidence for universal decolonization?
Go to the first section of Appendix B.
- What is the hospital's need for this intervention?
Refer to the earlier section on assessing the need for the intervention. The response to this question should include consideration of hospital rates of MRSA and bloodstream infection, national guidelines, regulation, and any relevant State legislation.
- What is the cost of this intervention and how is it justified?
Refer to the earlier section on developing a business case.
- Who is supportive of this intervention?
Be prepared to demonstrate support from key stakeholders as described above.
- Is universal decolonization just about reducing MRSA?
No. In fact, the REDUCE MRSA Trial found that the best strategy for reducing bloodstream infections due to all pathogens was universal decolonization consisting of daily chlorhexidine and up to 5 days of mupirocin in all ICU patients. This strategy reduced all-cause bloodstream infections by 44 percent, and it was significantly better than either targeting decolonization to MRSA carriers or actively screening for MRSA to enhance time to contact precautions. Since chlorhexidine is broadly active against most bacteria and some fungi, there is a strong basis for reducing infections due to all pathogens.
- What is the added benefit of mupirocin over the daily chlorhexidine baths?
There are several reasons to pursue universal decolonization using a combination of chlorhexidine plus mupirocin in adult ICUs.
- Staphylococcus aureus is the number one cause of health care-associated infections in the United States. It is the most common cause of ventilator-associated pneumonia, the most common cause of surgical site infection, and the second most common cause of central line associated bloodstream infection. This includes both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains.18
- The nose is the major reservoir of S. aureus. Evidence supports use of mupirocin as an essential component of eradication and, because of the nasal reservoir, suggests that eradication of MRSA and MSSA is better with mupirocin than with chlorhexidine alone.19,20
- Even among hospitals where ICU screening for MRSA is currently occurring or is mandated by State law, it is important to recognize that MSSA is a major pathogen. Nationally, MSSA accounts for 45-55 percent of S. aureus health care-associated infections.18 A single nasal screening is only 70-80 percent effective in detecting S. aureus in the nose.
- Are there specific formulations of chlorhexidine and mupirocin that should be used?
There have not been direct comparisons of the effectiveness of different formulations in reducing infection. However, the significant reduction in bloodstream infection and MRSA clinical cultures achieved in the REDUCE MRSA trial was based on the use of 2% chlorhexidine cloths and a paraffin-based nasal mupirocin ointment. Theoretically, methods that deliver an equivalent amount of active decolonizing agent to the skin and nose should be effective. However, it is worth noting that the method of application may have appreciable effects on achieving appropriate concentrations of chlorhexidine on the skin. Prior evidence suggests that no-rinse applications of chlorhexidine using a 2% cloth achieve significantly higher concentrations of chlorhexidine on the skin than applications of 4 percent with rinsing. In addition, attention to skin coverage in applying CHG is critical. Shower-based liquid applications have been shown to result in gaps in skin antisepsis compared to cloth-based applications.21
- Should we be concerned about producing antimicrobial resistance?
The benefits and potential risks should be weighed with any strategy. As with all antimicrobials, we must be vigilant about antimicrobial resistance. Some discussion points include:
- Because chlorhexidine is an antiseptic used for decolonization but not to treat active infection, resistance to this agent will not result in the loss of an antimicrobial for therapy.
- Mupirocin ointment is used for decolonization but is also used for topical treatment of some infections. Under some circumstances, extensive use of nasal mupirocin might favor the emergence of strains resistant both to mupirocin and to unrelated antimicrobials.
- Evidence for emergence of antimicrobial resistance during the use of mupirocin is mixed. The literature has reported evidence of increased mupirocin resistance with broad use of mupirocin,22,23 increased resistance to mupirocin in the absence of broad use of mupirocin,24 and no increase in resistance with broad use.25-29 Thus, surveillance by researchers and national surveillance systems will be important in monitoring resistance. Alternative agents for use in place of mupirocin are also being studied.
- Additional analysis is being conducted as part of the REDUCE-MRSA trial to determine if resistance has developed in the ICUs that have implemented this protocol.
- Since mupirocin resistance is not routinely tested by microbiology laboratories, most hospitals will not have local data to guide their decision. If the hospital does have these data for the ICU, they can be used to guide the use of this agent.
- Chlorhexidine resistance has been rarely reported in the United States. However, it is important to ensure that bathing is done properly and according to protocol to provide the best chance of removing harmful bacteria from the skin.
- Aren't some bacteria good for us? Will this strategy remove good bacteria?
Even usual bacteria on the skin can become harmful during hospitalization. The use of lines and devices, as well as surgical wounds and other breaks in the skin, result in a higher chance that our normal body bacteria can enter sterile places and produce infection during high-risk periods. Thus, universal decolonization is being advocated during the ICU stay to remove bacteria from the body because of the high-risk setting.
Identifying Unit Champions
For each ICU that will adopt this strategy, it is important to identify nursing and physician champions who are well-respected by their peers and can speak in strong support of the intervention. Unit champions differ from key stakeholders in that they are personnel that are routinely staffing or providing oversight within the ICUs such as the Medical Director or Nurse Manager/Director. Unit champions should be able to
- Promote the intervention and serve as a peer leader for this intervention.
- Speak to the rationale of universal decolonization during ICU rounds, nursing huddles, and ICU teaching sessions.
- Provide baseline and followup data on intervention targets, such as MRSA burden and ICU infections.
- Provide adherence data on use of decolonizing products and bathing checks.
- Encourage high compliance among unit staff. Highly compliant and consistent application is essential to the success of this strategy.
Finalizing the Protocol and Obtaining Committee Approvals
Using the provided protocol (Appendix D), make edits to reflect the usual hospital infrastructure by which mupirocin and chlorhexidine can be used in a standardized protocol for the ICU. We encourage you to use all steps of the protocol as written, since this was the trial protocol that demonstrated significant effectiveness in reducing MRSA clinical cultures and bloodstream infections due to all pathogens.
In finalizing the protocol, elements should include:
- Discussion with nursing leadership, pharmacy, and the ICU medical directors about the best way to implement universal decolonization using a hospital protocol. Options include a standardized nursing protocol or an ICU admission order set.
- The use of mupirocin will need a physician order, which some hospitals have arranged by having standing orders under the ICU medical director's name or the Chief Medical Officer's name. Others place it in a standing admission order set that is activated when the admitting ICU physician places admission orders. The best mechanism will be hospital-dependent and requires discussion.
- Pharmacy and supply chain staff will need to confirm the best way for documentation and re-stocking to occur.
Most hospitals have required committees for approval of standing nursing protocols and standing order sets. Such committees may include, but are not limited to, the Critical Care Committee and the Medical Executive Committee. Identifying the committee approval process for the hospital will be important. Scheduling for presentation to these committees will be essential to the planning and timing of this intervention.
Set Launch Date
A launch date should be set that accounts for the following:
- Timing of committee approvals.
- Timing required for product stocking and compatibility assessment (see below).
- Timeline required for educational training, including possible computer-based training modules, presentations to nurse manager forums, nursing staff meetings, and medicine or critical care grand rounds or other ICU physician forums.
- Sequence of timing for expansion if sequential roll out to multiple ICUs is planned.
- Other competing campaigns and holidays.
Stock Product and Address Compatibility Issues
Once the protocol is approved by the required committees and is scheduled for launch, the following launch details should be addressed.
- Stocking the products: Preparations for adequate stocks of mupirocin and chlorhexidine should be made. If chlorhexidine cloths are used, mechanisms for warming should be addressed.
- Compatibility: Replacing bathing products that are incompatible with chlorhexidine (certain soaps, lotions, and skin barrier products will inactivate chlorhexidine and negate the antiseptic effect) with ones that are compatible. Compatibility should be discussed with the manufacturers of all skin products used in the ICU.
Formulate Education and Training Plans
- Education and training: Education and training should be planned with nurse managers, nurse educators, infection prevention, and the ICU medical directors. Options include a brief computer-based training module for nurses and nursing assistants, train-the-trainer sessions, and discussions at nursing huddles, plus presentations at critical care or medicine grand rounds. The following resources are provided in this protocol:
- Instructional materials for computer-based training modules.
- Frequently asked questions.
- Just-in-time training document.
- Do and don't factsheet.
- CHG bathing wall poster.
Assuring Adherence and Reinforcing Training
As with any campaign, it is important to provide regular assessments of adherence to intervention protocols. In this protocol, we provide the "Bathing Skills Assessment" tool for observing bathing practice and asking key questions to ensure understanding. For example, a small number of baths could be observed in the weeks post-implementation. This could be done by the ICU nursing director, facility nurse educator, or a designee. The frequency of sample observations (weekly, monthly) should be tailored to the results of these assessments (i.e., more frequent observations if protocols are not fully adhered to or if understanding appears limited; less frequent if highly compliant).
Nurse training can be reinforced with the following, which are provided in this protocol (Appendix E):
- Instructional materials for computer based training modules.
- Frequently asked questions by staff.
- Just-in-time training document.
- Do and don't factsheet.
- CHG bathing wall poster.
2. Milstone AM, Elward A, Song X, et al. Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicenter, cluster-randomized, crossover trial. Lancet 2013; epub ahead of print.
3. Popovich KJ, Hota B, Hayes B, et al. Effectiveness of routine patient cleansing with chlorhexidine gluconate for infection prevention in the medical intensive care unit. Infect Control Hosp Epidemiol 2009; 30(10):959-63.
4. Climo MW, Sepkowitz KA, Zuccotti G, et al. The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial. Crit Care Med 2009; 37(6):1858-65.
5. Bleasdale SC, Trick WE, Gonzalez IM, et al. Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients. Arch Intern Med 2007; 167(19):2073-9.
6. Centers for Disease Control and Prevention. National Healthcare Safety Network. Surveillance for central-line associated bloodstream infecitons (CLABSI). Available at http://www.cdc.gov/nhsn/acute-care-hospital/clabsi/index.html.
7. Centers for Disease Control and Prevention. CDC/NHSN protocol clarifications. Available at http://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf (PDF File, 280 KB).
8. Healthcare Infection Control Practices Advisory Committee (HICPAC). Various publications. Available at http://www.cdc.gov/hicpac/pubs.html.
9. Society for Healthcare Epidemiology of America (SHEA). Guidelines and resources. Available at http://www.shea-online.org/GuidelinesResources/Guidelines.aspx.
10. Society for Healthcare Epidemiology of America (SHEA). Featured topics in HAI prevention. Available at http://www.shea-online.org/HAITopics/FeaturedTopicsinHAIPrevention.aspx.
11. Society of Critical Care Medicine. Clinical guidelines. Available at http://www.learnicu.org/Pages/Guidelines.aspx.
12. American Association of Critical Care Nurses. Practice alert: bathing the adult patient. Available at http://www.aacn.org/wd/practice/content/practicealerts/bathing-adult-patient-practice-alert.pcms?menu=practice.
15. Scott RD. The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/hai/pdfs/hai/scott_costpaper.pdf (PDF File, 835 KB).
16. Warren DK, Quadir WW, Hollenbeak CS, et al. Attributable cost of catheter-associated bloodstream infections among intensive care patients in a nonteaching hospital. Crit Care Med 2006 Aug;34(8):2084-9.
18. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013; 34(1):1-14.
19. Harbarth S, Dharan S, Liassine N, et al. Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1999 June; 43(6):1412–16.
20. Wendt C, Schinke S, Wurttemberger M, et al. Value of whole-body washing with chlorhexidine for the eradication of methicillin-resistant Staphylococcus aureus: a randomized, placebo-controlled, double-blind clinical trial. Infect Control Hosp Epidemiol 2007; 28:1036-43.
21. Edmiston CE, Krepel CJ, Seabrook GR, et al. Preoperative shower revisited: can high topical antiseptic levels be achieved on the skin surface before surgical admission? J Am Coll Surg 2008; 207:233–9.
22. Ridenour G, Lampen R, Federspiel J, et al. Selective use of intranasal mupirocin and chlorhexidine bathing and the incidence of methicillin-resistant Staphylococcus aureus colonization and infection among intensive care unit patients. Infect Control Hosp Epidemiol 2007; 28:1155-61.
24. Jones JC, Rogers TJ, Brookmeyer P, et al. Mupirocin resistance in patients colonized with methicillin-resistant Staphylococcus aureus in a surgical intensive care unit. Clin Infect Dis 2007 Sep 1; 45(5):541-7.
25. Harbarth S, Dharan S, Liassine N, et al. Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin resistant Staphylococcus aureus. Antimicrob Agents Chemother 1999; 43:1412-6.
27. Ellis MW, Griffith ME, Dooley DP, et al. Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother 2007; 51: 3591-8.
28. Jones JC, Rogers TJ, Brookmeyer P, et al. Mupirocin resistance in patients colonized with methicillin-resistant Staphylococcus aureus in a surgical intensive care unit. Clin Infect Dis 2007; 45:541-7.