Abstract
Abstract
Background:
Mupirocin nasal ointment may be prescribed for decolonization prior to surgical procedures, especially for carriers of methicillin-resistant Staphylococcus aureus (MRSA). The approved regimen for decolonization of S. aureus from the anterior nares is twice daily for 5 d (10 doses). We performed a two-center, randomized, open-label study to compare the utility of six and 10 doses for decolonization of S. aureus.
Methods:
Patients expecting to undergo surgery were screened for S. aureus nasal carriage approximately three weeks prior to the procedure. Those found to be positive were offered enrollment in the study. In the first arm (n=41), patients were randomized to receive 2, 3, or 5 d (six or 10 doses) of treatment prior to their operation. Their anterior nares were swabbed for culture and S. aureus polymerase chain reaction (PCR) during the decolonization therapy period as well as for four weeks after surgery. In the second arm (n=60), all patients were given 5 d (10 doses) of nasal mupirocin treatment, and the patient's anterior nares were swabbed for culture and S. aureus PCR for four weeks after surgery. Data from six of the patients were excluded from analysis because of failure to submit swabs after operation. All S. aureus isolates were tested for susceptibility to mupirocin and the presence of the mecA gene to detect MRSA.
Results:
In Arm 1, 16 patients received 10 doses of mupirocin, 18 received six doses (twice daily for 3 d), and 7 received six doses (thrice daily for 2 d). In the second arm, all patients received 10 doses of mupirocin (twice a day for 5 d). Overall, 89.5% patients who received 10 doses of mupirocin remained decolonized for at least four weeks after surgery versus 68.0% of patients who received six doses (p=0.016). There was no difference between arms 1 and 2 for those given mupirocin twice daily for 5 d.
Conclusion:
The ten-dose regimen is superior to any six-dose regimen for de-colonizing S. aureus from the anterior nares of patients and for maintaining the decolonized state for at least four weeks after therapy.
S. aureus is one of the most common causes of surgical site infection (SSI). Because 25%–30% people carry S. aureus in their anterior nares, either intermittently or persistently, a possible link between S. aureus colonization and SSI has been explored [9]. It is well demonstrated that detection and subsequent nasal decolonization can lower significantly The risk of infection several fold for patients undergoing surgery [10–12].
Mupirocin, a naturally occurring antibacterial agent, has antibacterial activity against many gram-positive cocci, including S. aureus (both MSSA and MRSA strains). Using mupirocin for decolonization in hemodialysis patients reduces S. aureus disease [13]. Thus, it is postulated that by reducing nasal carriage of S. aureus, the overall rate of healthcare-associated infection can be reduced [14], decreasing costs, morbidity, and the mortality rate.
The current U.S. Food and Drug Administration (FDA)-approved dosing regimen for mupirocin nasal ointment is twice daily for 5 d (http://us.gsk.com/products/assets/us_bactroban_nasal.pdf). For many hospitals, the average length of stay for their patients is <5 d. Thus, decolonization regimens started in the hospital would need to be completed at home, which would increase the chances of non-compliance. Therefore, a shorter regimen, if effective, could be useful. The primary object of this study was to determine the minimum number of doses of 2% mupirocin calcium nasal ointment needed to eradicate S. aureus carriage from the nasal passages of carriers of this organism for at least four weeks. Because most disease after surgery that is prevented by mupirocin decolonization occurs in the first few weeks after operation, it is likely some persistence of S. aureus elimination is useful to avoid direct contamination of the surgical incision by a patient rubbing his or her nose and then scratching the area of the surgical incision. Therefore, the secondary objective was to assess the rate of S. aureus re-colonization in patients who had S. aureus eradicated from the anterior nares and to determine the similarity, if any, by pulsed field gel electrophoresis (PFGE) testing of the initial colonizing strain and the re-colonizing/infecting strain in patients who are initially colonized, had colonization eradicated, and then were re-colonized or infected with S. aureus intra-nasally or at a distant site.
Materials and Methods
Approvals
The NorthShore University HealthSystem Research Institute Institutional Review Board (Evanston, IL) approved this study.
Study sites
Two academic centers with diverse patient populations participated in this research. NorthShore University HealthSystem at the time of this study was a three-hospital academic institution with a total of 800 inpatient beds located in the northern suburbs of Chicago, Illinois. Denver Health Medical Center is an academic public health hospital and Level I trauma center located in downtown Denver, Colorado.
Test method
Double-headed nasal swabs were collected from patients about to undergo elective orthopedic surgery and were screened for S. aureus nasal carriage by real-time polymerase chain reaction (PCR) [15] and culture at 2–3 wks prior to surgery. To be eligible for the study, each patient had to be 18 years of age or older, had to have a screening test that was positive for S. aureus, and agreed to comply with the study protocol (described later). Patients who were known or suspected to have hypersensitive reactions to mupirocin or glycerin esters, patients who had received intranasal administration of mupirocin ointment within 3 mos prior to the first dose of study medication, patients who had received more than 24 h of systemic antibacterial therapy within 14 d prior to the first dose of the study medication; and patients known to have a S. aureus infection within 1 mo prior to randomization were excluded from the study. Only patients who signed a consent form were enrolled.
Design of the intervention
Arm 1
Patients were randomized into three groups:
1: Intranasal mupirocin calcium ointment 2% twice daily for 5 d; 2: Intranasal mupirocin calcium ointment 2% twice daily for 3 d; 3: Intranasal mupirocin calcium ointment 2% three times daily for 2 d.
Those randomized to group 3 were limited to patients already admitted to the hospital.
Once enrolled, patients were instructed in the study procedures, and then study medications along with sterile double-headed swabs were provided during a clinic visit or shipped to the patient's home with written instructions on how to apply the medication and collect swabs. The subjects were told to begin the mupirocin decolonization so that their last dose would be administered the evening before the operation. Patients were instructed to swab their anterior nares prior to each intranasal mupirocin ointment application up to the day before their scheduled operation. Post-surgery nasal swabs were collected at 24 h, two weeks, three weeks, and four weeks. All swabs, along with the used mupirocin drug tubes, were shipped to the research laboratories in a self-addressed envelope that was provided to each patient.
Laboratory testing methods
For culture at NorthShore, one of the paired swabs was plated on colistin–nalidixic acid (CNA) agar and incubated at 35°C for 48 h. Any colony that resembled S. aureus was tested using the Staphaurex latex agglutination test (Remel, Lenexa, KS). If positive, methicillin resistance was detected by Kirby-Bauer testing using a standardized oxacillin disk diffusion method as well as a real-time PCR assay developed in-house [16]. Susceptibility to mupirocin was tested using a mupirocin E-test and Kirby-Bauer using a mupirocin disk, both following the Clinical and Laboratory Standards Institute (CLSI) guidelines [17], and an in-house mupirocin real-time PCR assay. For culture at Denver, one of the paired swabs was plated on mannitol salt agar (BD, Franklin Lakes, NJ) and incubated overnight at 35–37°C. Any yellow colonies were subcultured onto a blood agar plate. Gram-positive cocci in clusters from the blood agar plate were tested for the presence of catalase and coagulase after 24 h of incubation. Isolates that were both catalase and coagulase positive were inoculated onto selective agar containing oxacillin 6 mcg/mL. Those with no growth after 24 h on the oxacillin plate were reported as MSSA, and isolates that showed growth after 24 h were considered MRSA. The PCR testing from the second swab at both sites was done as described by Paule et al. [15].
Arm 2
The procedure for this arm of the study was modified on the basis of the initial results from Arm 1 showing inferiority of the 3 d bid and 2 d tid regimens to the 5 d bid protocol in eradicating S. aureus carriage. Thus, in arm 2, only the 5 d bid regimen was evaluated.
Testing for S. aureus re-colonization
Patients were instructed to swab their anterior nares at 24 h, two weeks, three weeks, and four weeks after surgery.
During Arm 1, a total of 630 patients were swabbed for study entrance screening. Of these 179 (28.4%) carried S. aureus, of which 5 (2.8%) were MRSA. For Arm II, 283 patients were swabbed for potential study entry; 98 (34.63%) carried S. aureus, of which 5 (5.1%) were MRSA.
PFGE typing
At NorthShore, ten pairs of S. aureus were recovered before and after mupirocin therapy where genomic DNA was available for typing by PFGE. In this procedure, the DNA was digested with SmaI, resulting in fragments ranging from 50 to 500 kilobases. The DNA banding patterns of each isolate were compared visually to determine if they were genetically related [18] and were interpreted as described by Tenover et al. [19].
Statistical analysis
Comparison of the results in the two treatment arms was done using the Fisher exact test with two-tailed analysis.
Results
There were 101 patients enrolled in the study, and six were excluded from the analysis because they failed to submit their swabs after operation (three from arm 1 [5-d therapy] and three from arm 2). Of the 95 evaluable patients, there were 41 in arm 1 and 54 in arm 2. Of the 41 patients in arm 1, 16 were in group 1, with one patient colonized with MRSA; 18 in group 2 with two patients having MRSA (one mupirocin susceptible and one resistant); and 7 patients in group 3, all of whom were colonized with MSSA. In Arm 2, of the 54 patients enrolled, only one was colonized with MRSA on pre-surgery screening but was decolonized at all time points after surgery. The number and percentage of patients decolonized at 24 h and two, three, and four weeks after mupirocin therapy for all groups is shown in Table 1. Patient swabs that were not returned or could not be evaluated for any reason were excluded from the calculation for each particular time point.
Sample times where from one to six patients did not submit a swab.
Sample times where one or two swab cultures were overgrown with mold and could not be interpreted.
Sample times when all patients submitted samples and all cultures were evaluable.
Note: The difference between ten doses and six doses (all results for ten doses and six doses combined) is not significant at day 1; the difference is significant at two weeks (p<0.001), three weeks (p=0.002), and four weeks (p=0.016).
PFGE typing
Of the ten pairs of pre- and post-treatment isolates that were typed, all 10 patients were colonized initially with MSSA; six patients re-acquired their original strain, and the other four had post-treatment strains that were distinct from their original strains. Interestingly, one patient was newly colonized with MRSA, suggesting a small risk of MRSA acquisition after decolonization where MRSA is prevalent.
Discussion
Our data indicate had that a ten-dose regimen of mupirocin left fewer patients remaining colonized with S. aureus for at least four weeks after treatment than does the six-dose regimen (p=0.016) and thus is the preferred treatment. Our results suggest that completing a full 5-d bid course would be important to maximize success of eradication of S. aureus nasal carriage for those at risk for all tested times more than 1 d after operation [4,10].
The PFGE data relating to re-colonization imply that patients who re-acquire S. aureus become colonized with a new strain a minority of the time; they are more likely to become re-colonized by their own strain (60%). The reasons could be that, along with the anterior nares, these patients were colonized in other body areas that were not tested in this study, leading to re-colonization by their original strain from these other sites [20,21], or that they are living where their strain is found in others or the environment, thus leading to eventual re-colonization. One patient lost the original strain of MSSA and was re-colonized with MRSA, suggesting that control of MRSA in the hospital is important for surgical patients being decolonized prior to operation.
Our study had some limitations. The data set is relatively small, but it is important that the 5-d, ten-dose regimen was significantly more effective at removing S. aureus colonization from the nares for at least four weeks—long enough to protect recent surgical incisions from self-contamination by the patient. Also, although the study sites were both academic medical centers, the patients enrolled were of the same type as cared for at any hospital where elective orthopedic surgery is performed, so we believe the data are generalizable widely.
Several studies have been done to show the efficacy of mupirocin versus a placebo or another topical ointment for eradication of S. aureus from the anterior nares [22–25]; however, to our knowledge, there is no other investigation that compared the effectiveness of different dosing regimens for mupirocin application on persistance of S. aureus decolonization. Our study showed that 10 doses of mupirocin was more effective than fewer doses for eradication of S. aureus from the anterior nares of colonized patients in the four-week post-operative period (p=0.016). Decolonization has been demonstrated to reduce post-operative surgical site infection by several-fold in patients at our organization [11], as well as by a large, prospective, multicenter, blind trial [10]. Our data indicate that the minimum regimen to be used twice-daily application of mupirocin to the anterior nares for 5 d, as is currently recommended for the FDA-approved product.
Footnotes
Research Support and Author Disclosure Statement
This research was supported by an investigator-initiated grant from GlaxoSmithKline.
No conflicting financial interests exist for any of the authors other than the grant funding provided to CP and LRP.