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Prevention of Staphylococcus aureus infections among surgical patients: Beyond traditional perioperative prophylaxis

Trish M. Perl, MD, MSc, Baltimore, Md

Background. Health care-related infections cause signicant patient morbidity and mortality rates and add excess costs that frequently are not reimbursed. Staphylococcus aureus has long been recognized as an important pathogen in human disease and is the most common cause of nosocomial infections. Method. The objective of this review of the English language literature and a MEDLINE search was to describe recent advances in the prevention of S aureus health care-related infections that are attributable to patients endogenous colonization. The ecologic niche of S aureus is the anterior nares and nasal carriage increases the risk of the development of a surgical-site, lower respiratory tract, or bloodstream infection. S aureus carriers have a 2- to 9-fold increased risk of the development of a surgical-site or intravenous catheter infection. Results. Three treatment strategies may eliminate nasal carriage: locally applied antibiotics or disinfectants, systemic antibiotics, and bacterial interference. Among these strategies, locally applied or systemic antibiotics are used most commonly. Nasal ointments or sprays and oral antibiotics have variable efcacy, and their use frequently results in antimicrobial resistance among S aureus strains. Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S aureus nasal carriage. In a recently published randomized, double-blind, placebocontrolled trial to determine whether intranasal mupirocin reduced the rate of S aureus-infected surgicalsite and other S aureus health care-related infections; 4% of S aureus nasal carriers who received mupirocin acquired S aureus health care-related infections compared with 7.7% of S aureus nasal carriers who received placebo (P = .02). The S aureus surgical-site infection rate was not reduced signicantly, but carriers who received mupirocin before cardiothoracic or general surgery operations had almost 50% fewer S aureus surgical-site infections than carriers who received placebo. In this setting resistance rarely has been reported. Conclusions. Given the importance of S aureus nosocomial infections and the increased risk of S aureus nasal carriage in patients with health care-related infections, investigators must study cost-effective strategies to further prevent certain types of health care-related infections or nosocomial infections that occur in specic settings. One potential strategy is to decrease or eliminate S aureus nasal carriage among certain patient populations or in certain healthcare settings. (Surgery 2003;134:S10-7.)
From the Departments of Medicine and Pathology, the Division of Infectious Diseases, The Johns Hopkins Medical Institutions; the Department of Epidemiology, The Johns Hopkins School of Medicine; the Bloomberg School of Public Health; and the Department of Hospital Epidemiology and Infection Control, The Johns Hopkins Hospital, Baltimore, Md

MORE THAN 40 MILLION PATIENTS undergo operations annually in the United States.1 Up to 20% of these
Sponsored by the Ofce of Continuing Medical Education at Excerpta Medica and supported by an educational grant from GlaxoSmithKline. Reprint requests: Trish M. Perl, MD, MSc, Department of Hospital Epidemiology and Infection Control, 425 Osler, The Johns Hopkins Hospital, 600 North Wolfe St, Baltimore, MD 21287. 2003, Mosby, Inc. All rights reserved. 0039-6060/2003/$30.00 + 0 doi:10.1016/S0039-6060(03)00391-X

patients acquire at least 1 health care-related infection in the postoperative period.2 The Centers for Disease Control and Prevention estimates that nosocomial infections contribute to 0.7% to 10.1% of deaths and cause 0.1% to 4.4% of deaths that occur in hospitals.3 These infections are associated with signicant morbidity and mortality rates, double the length of hospital stay, and increase the cost of health care in the United States by $5 to $10 billion annually.4,5 Several studies have demonstrated that surgical-site infections prolong hospital stay by 6.5 to 7.4 days and comprise 42%

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Table I. Nasal decolonization: potential agents/ strategies


Systemic antibiotics Rifampin Trimethoprim/sulfamethoxazole Ciprooxacin Combinations of systemic antibiotics TMP/SMX and rifampin Minocycline and rifampin Systemic and local antibiotics TMP/SMX and bacitracin Rifampin and bacitracin Local antimicrobials and antiseptics Bacitracin Mupirocin Povidone-iodine Chlorhexidine Bacterial interference 502 A Phages

Table II. Nasal decolonization failures: reasons and agents


Decolonization failures Nares not decolonized Nares recolonized quickly Agents Gentamicin Vancomycin Neomycin Bacitracin Chlorhexidine Quinolones Clindamycin Cephalexin Erythromycin

of extra charges that are attributed to nosocomial infections.3,6 Under systems that use a capitated reimbursement structure such as diagnostic-related groups, the costs that are related to nosocomial infections frequently are not recovered and thus represent a loss to the institution or health care system.7 Leape et al8,9 estimate that surgical-site infections account for 14% of adverse events and may cause patient morbidity that will last up to 6 months. Staphylococcus aureus causes 25% of health carerelated infections and contributes substantially to the morbidity and costs of hospital stays.4,10,11 The source of many of these infections is thought to be the patients endogenous ora.12-14 The ecologic niche of S aureus is the anterior nares, and 25% to 30% of individuals are infested with colonies of infection at a given time.12-14 Numerous studies have linked S aureus nasal carriage with an increased S aureus infection risk.12-14 Patients who are carriers are at higher risk of the acquisition of staphylococcal infections after invasive medical or surgical procedures than are persons who do not carry this organism.12-14 Compared with noncarriers, S aureus carriers are 2 to 9 times more likely to acquire surgical-site infections.12-14 Several studies have shown that patients who are admitted to an intensive care unit setting with S aureus colonization intranasally are at increased risk of the development of nosocomial infections.15-18 Over the years, investigators have evaluated several methods to decolonize the anterior nasal passages (Table I). The use of locally applied and oral antimicrobials has been limited by their

inability to penetrate the nasal epithelia or because organism resistance develops quickly after the use of these agents to render them ineffective (Table II). In addition, some clinical failures have occurred because the nares recolonize quickly, which limits the usefulness of these agents to prevent the development of infection. Currently, local antimicrobial agents are the most promising because they are easy to apply, because high levels of antimicrobial agent are delivered to the nasal epithelia, because they work rapidly, and because they appear effective for a long period of time. ELIMINATION OF S AUREUS NASAL CARRIAGE In populations in which S aureus carriage is identied, the elimination of nasal carriage may eradicate the source of infection whether in an individual patient or from an outbreak. When considering any prophylactic therapy, several issues should be considered. The agent must be easy to use, safe to use, and effective in eliminating S aureus carriage rapidly. It should be effective for a prolonged period of time, be cost-effective, and limit the chance of antimicrobial resistance. Three approaches to eliminate nasal carriage have been studied adequately and include the use of bacterial interference, systemic antimicrobials, and locally applied antimicrobial agents or disinfectants. Although a staphylococcal vaccine has been developed, it is efcacious in decreasing infections but may not decolonize the anterior nares.19 Bacterial interference. One of the earliest strategies that was studied to eradicate S aureus nasal carriage was bacterial interference, which was used successfully to control S aureus outbreaks and to treat patients with recurrent furunculosis.20-24 A minimally pathogenic strain of S aureus, 502A,

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was placed in a persons nares to prevent colonization from more virulent strains.23 This therapeutic attempt failed as patients became recolonized with their original endogenous S aureus strain, and some patients experienced serious infections that were caused by the implanted S aureus 502A.25-27 Systemic and local antimicrobials and disinfectants. Subsequently, several systemic antibiotics and combinations of antibiotics were studied generally in medical patients to evaluate whether they decolonize S aureus from the anterior nares.12,28,29 Of the studied combinations, those combinations that include rifampin alone or with trimethoprim-sulfamethoxazole or minocycline appeared to be the most efcacious.12,28,29 However, many investigators have noted the emergence of resistance primarily with rifampin, which limits its usefulness in large patient populations or patients whose condition may require multiple applications. The results of studies that have evaluated nasal ointments or sprays, which often are combined with skin disinfectants, have been disappointing because the agents that were tested have not proved to be efcacious; and antimicrobial resistance has emerged rapidly.30-35 In these studies, bacitracin (a locally applied antimicrobial agent) was evaluated alone or in combination with rifampin.12 The combination of oral antimicrobials and locally applied agents appears more effective. For example, in a 1986 publication, Chow and Yu35 reported the results of a randomized clinical trial among patients who underwent hemodialysis and demonstrated that rifampin with intranasal bacitracin decolonized S aureus from the anterior nares more effectively than bacitracin alone or vancomycin. In this study population, vancomycin was no more effective than no therapy. However, no study evaluated whether these antimicrobials, alone or in combination, decolonize the anterior nares of surgical patients. Mupirocin. Another agent, mupirocin calcium ointment (pseudomonic acid), is a newer topical antimicrobial agent with a broad-spectrum antimicrobial activity against many Gram-positive organisms that included S aureus, methicillinresistant S aureus (MRSA), S aureus strains with intermediate susceptibility to vancomycin, and vancomycin-resistant S aureus. It has a unique mechanism of action whereby the drug binds to isoleucyl transfer RNA synthetase.36 Mupirocin that is applied intranasally has rare side effects, most of which are mild. In studies in health care workers, mupirocin effectively decolonizes the anterior nares.37,38 Reagan

et al38 performed a randomized, double-blind, placebo-controlled study in 311 health care workers and found that mupirocin ointment eliminated 97% of S aureus nasal carriage within 24 hours. Six months later, more than 50% of the health care workers from whom cultures were processed previously did not grow S aureus. In addition, mupirocin decreased the S aureus that was carried on the hands of health care workers from 58% in the placebo recipients to 3% among mupirocin recipients. A substantial portion of health care workers who received mupirocin remained decolonized 3 months after it was applied.38 Next, investigators asked whether decolonizing S aureus from the anterior nares translated into decreasing S aureus infections in high-risk patients. Initial studies in patients who were undergoing hemodialysis and those patients who were receiving chronic ambulatory peritoneal dialysis showed that decolonizing the anterior nares prevented S aureus infections, thereby decreasing complications and costs of medical care.39-46 For example, among patients who were undergoing hemodialysis, Boelaert et al41 showed that mupirocin reduced the S aureus nasal carriage rate and subsequent S aureus bloodstream infection rate by 4.26-fold. Mupirocin use in surgical patients. Once the association between S aureus nasal carriage and the subsequent development of S aureus surgicalsite infections was established, several investigators13 studied whether decolonizing S aureus nasal carriers before surgery decreases the risk of the development of S aureus surgical-site infections. Kluytmans et al47 compared 983 patients who were undergoing cardiothoracic surgery who belonged to an historic cohort with 1003 patients who were treated with mupirocin and noted a decrease in S aureus surgical-site infection rate. The 116 patients who unintentionally were not treated were considered as a concurrent control group. The surgical-site infection rate decreased from 7.3% in the historic control group to 2.8% in the intervention group (P < .0001; relative risk, 0.33; 95% CI, 0.21-0.52). Not unexpectedly with this study design, the surgical-site infection rate decreased in the control group that was not treated, which suggests that other unmeasured factors contributed to the decrease in surgical-site infections. More recently, Cimochowski et al48 compared 992 consecutive patients who underwent cardiac surgery who did not receive mupirocin with 854 prospectively followed patients who were treated preoperatively with intranasal mupirocin. The surgical-site infection

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rate decreased from 2.7% (27/992 patients) to 0.9% (8/854 patients; P = .005). Among diabetic patients, the surgical-site infection rates decreased from 5.1% (14/277 patients) to 1.9% (5/266 patients; P = .04). These investigators estimated the cost of a deep surgical-site infection to be between $40,000 and $120,000.48 Gernaatvan der Sluis et al49 performed an unblinded intervention trial and compared 1044 patients who underwent orthopedic procedures and who were treated with mupirocin with 1260 historic control subjects and reviewed whether the elimination of S aureus nasal carriage decreased surgical-site infections. Surgical-site infections decreased from 2.7% (34/1260 patients) in the untreated group to 1.3% (14/1044 patients) in patients who received mupirocin (P = .02). S aureus surgical-site infection rates among these patients decreased from 1.1% to 0.7% (P = .3). All of these studies suffer from a less robust methodologic study design because they were unblinded and did not account for other unmeasured interventions. Importantly, none of the investigators reported the resistance of S aureus to mupirocin. Mupirocin and the risk of S aureus study. A randomized, placebo-controlled clinical trial, the Mupirocin and the Risk of S aureus study50 evaluated whether preoperative intranasal application of mupirocin nasal ointment would decrease the rate of S aureus surgical-site infections and S aureus nosocomial infections. The study enrolled 4030 adults who underwent elective and nonemergent cardiothoracic, general, oncologic-gynecologic, and neurosurgical operative procedures at the University of Iowa Hospitals and Clinics and the Veterans Affairs Medical Center in Iowa City, Iowa. Intranasal mupirocin was compared with a placebo vehicle and applied to each anterior naris twice daily for up to 5 days before the operative procedure. Patients were followed for 25 to 35 days after their operations to determine whether they acquired S aureus infections, dened with Centers for Disease Control-based criteria.51 Surgeons followed standard clinical practices and used standard prophylactic antimicrobial regimens. Of the 3864 patients (95.9%) who were included in the intent-to-treat analysis, 1933 patients received mupirocin, and 1931 patients received placebo. The demographic and surgical characteristics, preoperative functional status, number and types of underlying diseases, and types of surgical procedures were similar among the 2 groups, except that patients who received placebo were more likely

to have had renal disease (17.4%) than the patients who received mupirocin (14.9%; P = .04). Of the 3864 patients, 889 patients (23%) were colonized with S aureus. Mupirocin eliminated S aureus carriage in 1604 patients (83%) who received mupirocin; 81% among those patients received 3 to 5 doses, and 93% among those patients received 6 or more doses (P < .001). Posttherapy nasal carriage rates remained virtually unchanged among placebo recipients. Of the patients who were included in the analysis, 438 patients (11.3%) acquired nosocomial infections (11.3% of the patients who received mupirocin and 11.4% of the patients who received placebo). The surgicalsite infection rates in the mupirocin and placebo arms were 7.9% and 8.5%, respectively. The S aureus surgical-site infection rate was 2.3% among mupirocin recipients and 2.4% among placebo recipients. Among the 17 nasal carriers who received mupirocin and who acquired S aureus nosocomial infections, 16 patients had surgical-site infections, and 1 patient had a bloodstream infection. Among the 34 carriers who were treated with placebo, 26 patients had surgical-site infections; 4 patients had bloodstream or catheter infections, and 4 patients had lower respiratory tract infections. Among placebo recipients, the odds of an S aureus nasal carrier acquiring an S aureus surgical-site infection were 4.5 times that of a noncarrier (95% CI, 2.5-8.2; P < .001). The rate of S aureus nosocomial infections, in carriers, at any site was 49% lower (95% CI, 0.250.92; P = .02) among mupirocin recipients than among placebo recipients (3.8% vs 7.6%, respectively). Among patients who underwent general surgical procedures, the nosocomial S aureus infection rate in nasal carriers was 49% lower among those who received mupirocin (7.7% vs 3.9%; odds ratio, 2.1; 95% CI, 0.9-4.8; P = .07). Among patients who underwent cardiothoracic surgery, the nosocomial S aureus infection rate in carriers was 66% lower in patients who received mupirocin (4.7% vs 13.8%; odds ratio, 3.2; 95% CI, 0.9 to 14.4; P = .06). Mupirocin reduced the rate of S aureus surgicalsite infections for all procedures, although not signicantly. The true impact of mupirocin could not be evaluated on individual procedures because of the small numbers in the subgroup. Overall, mupirocin decreased S aureus surgical-site infections by 38% (3.6% vs 5.8%; odds ratio, 2.9; 95% CI, 0.8-3.4; P = not signicant). Among carriers who underwent general surgical procedures, the rate of S aureus surgical-site infections in the mupirocin group (3.6%) was 45% lower than that

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in the placebo group (6.6%; odds ratio, 2.9; 95% CI, 0.8-4.8; P = not signicant). Among S aureus carriers who underwent cardiothoracic surgical procedures, the S aureus surgical-site infection rate was 53% lower among mupirocin recipients (4.7%) than among placebo recipients (8.8%; odds ratio, 1.9; 95% CI, 0.5-9.39; P = not signicant). Of the 39 patients who acquired S aureus surgical-site infections and paired S aureus isolates were available, 84.6% of the patients had identical isolates from the nares and the infected surgicalsite, based on molecular ngerprinting. Of the 1021 S aureus patient isolates that were tested for in vitro susceptibility to mupirocin, 6 isolates (0.6%) were resistant to mupirocin. Minimum inhibitory concentrations of the resistant strains ranged from 16 to 2048 lg/mL. Cost-effectiveness of the elimination of S aureus nasal carriage. To evaluate the cost-effectiveness of eliminating S aureus nasal carriage, one must consider the cost of the infection that was prevented (includes inpatient and outpatient medical and surgical therapy), the indirect costs, and the costs of the cultures and the therapy that was used to eradicate S aureus nasal carriage. Most published studies that address the issue of whether elimination of S aureus nasal carriage is cost-effective have focused on 1 drug, mupirocin ointment. Because S aureus infections, especially nosocomial infections, are estimated to be so expensive, in all cases these studies have shown mupirocin to be cost-effective.10,11,48 For example, Boelaert et al41 estimated that the use of mupirocin ointment saved the health care system more than $700 per infection that was prevented. Furthermore, Bloom et al52 estimated that, based on certain assumptions, the potential annual savings to Medicare could be $784,000 to $1,117,000 per 1000 hemodialysis patients if mupirocin prophylaxis was implemented. Few data are available for patients in a surgical setting. VandenBergh et al53 estimated the attributable cost of a surgical-site infection after cardiac surgery and then estimated the cost-effectiveness of prophylactic treatment with preoperative intranasal mupirocin ointment. Each surgical-site infection that was prevented saved the institution more than $16,633. The risk of mupirocin: Mupirocin resistance. Mupirocin resistance is increasing, and rates appear higher in Europe where mupirocin has been used longer than in the United States. Deshpande et al54 reviewed the SENTRY Antimicrobial Surveillance Study data and reported that, among bloodstream isolates, mupirocin resistance among

S aureus isolates varied by geographic area from 1.9% to 5.6%. Investigators who have used the agent selectively among high-risk patient populations (such as those patients who underwent dialysis) report low rates of resistance development.41,42,46 When used intranasally for short courses (twice daily for 5 days), mupirocin resistance has been reported rarely.47,48,50 However, resistance has been reported when mupirocin has been applied to large surfaces (such as wounds or when used for long periods of time) in a single institution.55-58 Although mupirocin ointment has been used successfully to abort many S aureus and MRSA outbreaks in hospitals, chronic care and long-term care facilities, and specialty clinics, at least 1 hospital reported that widespread mupirocin use led to signicant increases in mupirocin resistance. Miller et al59 found that extensive use of mupirocin correlated with increasing resistance among MRSA strains from 2.7% in 1990 to 65% in 1993. CONCLUSIONS S aureus is an important cause of healthcareassociated infections at all sites. Among surgical patients, these infections are associated with signicant morbidity and mortality rates. Given the morbidity and mortality rates that are associated with nosocomial infections, especially those caused by S aureus, strategies to prevent such infections are important for patient safety. With the epidemiologic association between S aureus nasal carriage and the development of S aureus surgical-site infections and other S aureus nosocomial infections, investigators have realized that prevention strategies to decolonize nasal carriage and eliminate infections would be a tremendous enhancement to care. Early studies with oral antimicrobials and local antibiotic and antiseptic agents were disappointing. Several agents were ineffective, and others that were effective had a limited duration of activity. A combination of 2 systemic antibiotics was most effective. However, antimicrobial resistance emerged quickly. A newer local agent, mupirocin, was studied in patients who were undergoing dialysis, and the initial results suggested not only that it effectively decolonized the anterior nares but also that it decreased the subsequent risk of the development of serious S aureus infections. The strategy was reported to be safe for patients and cost-effective for health care providers and insurers. Because of the initial success of these studies and the properties of this antimicrobial agent, additional work was under-

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taken to assess the efcacy of mupirocin in surgical patients. Importantly, in the surgical population, a randomized, double-blind, placebo-controlled trial showed that mupirocin decolonized the anterior nares of patients and decreased S aureus nosocomial infections in patients who were colonized with S aureus.50 Several sets of investigators have shown that preoperative mupirocin decreased surgical-site infections and S aureus surgical-site infections; however, these studies had methodologic aws.13,48,49 In a randomized, doubleblind, clinical trial, mupirocin did decrease S aureus infections among colonized patients, but the decreases were not statistically signicant. Despite these promising data, an additional randomized clinical trial should be performed among surgical patients to identify the patients who would benet the most from the prophylactic use of mupirocin, to identify the appropriate dosing regimen, and to determine whether such treatment is truly costeffective. At this point, the selective use of mupirocin prophylaxis is thought not to cause widespread resistance. However, this product has been used in a limited fashion, and the impact of widespread use may not be measured adequately with the current data. In this era of patient safety and costcontainment, interventions that prevent morbidity and death and decrease costs deserve serious evaluation.

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