Volume 114
Number 2
15 January 1991
Annals of Internal Medicine ARTICLES
Elimination of Coincident Staphylococcus aureus Nasal and Hand Carriage with Intranasal Application of Mupirocin Calcium Ointment David R. Reagan, MD, PhD; Bradley N. Doebbeling, MD, MS; Michael A. Pfaller, MD; Carol T. Sheetz, RN, BSN; Alison K. Houston, BS; Richard J. Hollis, MA; and Richard P. Wenzel, MD, MSc
Objective: To determine the safety and efficacy of mupirocin calcium ointment in the elimination of Staphylococcus aureus nasal and hand carriage in healthy persons. Design: A double-blind, placebo-controlled, randomized trial. Setting: Clinical research unit of a tertiary medical center. Subjects: Health care workers with stable S. aureus nasal carriage. Interventions: Subjects (n = 68) were randomly assigned to receive either mupirocin or placebo intranasally twice daily for 5 days. Measurements and Main Results: Cultures of the hands and nares were obtained at baseline and 72 hours after therapy. The nares were also cultured 1, 2, 4, and 12 weeks after therapy. Antimicrobial susceptibility testing and restriction endonuclease analysis of plasmid DNA were used to confirm strain identity. There were no serious side effects. Mupirocin decreased the frequency of S. aureus nasal carriage at each time interval: At 3 months, 71% of subjects receiving mupirocin remained free of nasal S. aureus compared with 18% of controls. This difference (53%; 95% CI, 26% to 80%) was significant (P < 0.0001). Additionally, analysis of plasmid patterns showed that 79% of subjects in the mupirocin group were free of the initial colonizing strain at 3 months. The proportion of hand cultures positive for S. aureus in the mupirocin group after therapy was lower than in the placebo group (2.9% compared with 57.6%). This difference (53%; 95 CI, 30% to 80%) was significant, after adjustment for the frequency of hand carriage at baseline (P < 0.0001). Conclusions: When applied intranasally for 5 days, mupirocin calcium ointment is safe and effective in eliminating S. aureus nasal carriage in healthy persons for up to 3 months and appears to have a corresponding effect on hand carriage at 72 hours after therapy.
O n e of the most important pathogens in the United States, Staphylococcus aureus, is the most frequent cause of surgical wound infections and the second most common cause of nosocomial pneumonias and bloodstream infections (1). Staphylococcus aureus also causes skin and soft-tissue infections, osteomyelitis, and device-related infection in the community (2). The reservoir for chronic staphylococcal carriage has been shown to be the anterior nares (3), and various oral and topical agents have been used in an attempt to decrease nasal carriage (4-6). However, recolonization typically occurs within a few weeks or months. In patients receiving hemodialysis, reduction of nasal carriage has been associated with decreased rates of infection with S. aureus (7, 8), showing that eradication of S. aureus nasal carriage may be clinically beneficial. Mupirocin (pseudomonic acid) is a naturally occurring agent produced by Pseudomonas fluorescens. Used as a topical antibiotic, it has been shown to be effective against a broad spectrum of gram-positive microorganisms, including both methicillin-resistant and methicillin-susceptible strains of S. aureus (9). Casewell and Hill (10) in England evaluated a 2% mupirocin ointment with a paraffin base for its ability to eliminate staphylococcal nasal carriage in 32 volunteers. Initial success was uniform, and 56% of subjects remained free of nasal colonization at 22 weeks. To evaluate the safety and efficacy of 2% mupirocin calcium ointment in a white, soft paraffin base in eliminating both nasal and hand carriage of S. aureus in healthy persons, we conducted a randomized, placebocontrolled, double-blind trial of mupirocin calcium ointment in health care workers.
Methods Annals of Internal Medicine. 1991;114:101-106.
Study Sample
From the University of Iowa College of Medicine and the Department of Veteran's Affairs Medical Center, Iowa City, Iowa. For current author addresses, see end of text.
Health care workers who volunteered were screened for S. aureus nasal carriage. Persons with two positive cultures within a 5-day period (stable nasal carriage) were evaluated for possible admission to the study. Screening was not done as ©1991 American College of Physicians
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part of an outbreak investigation, and rates of infection with S. aureus in our hospital were unchanged during the study period. For inclusion in the study, volunteers had to be at least 18 years of age, had to give written informed consent, and had to be able to comply with the protocol requirements. Exclusion criteria included a history of any of the following: hypersensitivity to mupirocin or paraffin; treated seasonal allergic rhinitis or nasal polyps within the previous month; an immunodeficiency state; risk factors for leukopenia; chronic cardiac, renal, or hepatic disorders; or chronic dermatitis. Subjects were ineligible for the study if they had participated in another investigational drug trial within 30 days or were receiving therapy With antibiotics, steroids, or topical intranasal preparations at the time of enrollment. Premenopausal women were excluded if they were lactating or had a positive urine pregnancy test at the time of enrollment. Study Medication Both the mupirocin calcium and the placebo ointments were similar in appearance and provided in identical 15-g tubes. Each gram of mupirocin calcium ointment contained 20 mg of mupirocin in a base of white, soft paraffin. The placebo ointment contained only white, soft paraffin. Study Design The Human Review Committee, University of Iowa, approved our study. All subjects gave a brief medical history and had a physical examination. Nasal and hand cultures were obtained. A drug assignment list was prepared by the manufacturer with randomization by blocks of four: Two subjects were assigned to each treatment arm within the block. The subjects and investigators were blinded to the allocated treatment until after the trial ended. After enrollment, subjects were issued a numbered tube of the study ointment with instructions to measure a 1-cm length of ointment onto a sterile rayon swab and apply it to the anterior nares twice daily for 5 consecutive days. After application, the nose was massaged for 1 minute to enhance local distribution of the ointment. The tubes were weighed before and after use to allow an estimate of compliance. Each subject was examined daily by one of two investigators while receiving the study ointment. Repeat examinations and cultures of subjects' hands and both anterior nares were obtained between 48 and 72 hours after finishing therapy. Follow-up nasal cultures were obtained 1 week, 2 weeks, 1 month, and 3 months after the end of therapy. Microbiologic Evaluation Nasal specimens for culture were obtained by firmly rotating a new premoistened rayon-tipped swab (Culturette II, Marion Scientific, Kansas City, Missouri) five times in each anterior naris. Both swabs were cultured directly on 5% sheep-blood agar (Baltimore Biological Laboratories, Cockeysville, Maryland). Plates were examined after 24 and 48 hours of incubation at 35 °C. Additionally, all nasal swabs taken during the follow-up period were cultured in broth media (TLSO: 5% Tween 80 [Fisher Brand, Fairlawn, New Jersey], 2% lecithin [Fisher Brand], 0.5% sodium oleate [J.T. Baker Chemical Co., Phillipsburg, New Jersey], 0.1% sodium sulfite [J.T. Baker], 0.1% proteous peptone [Difco, Detroit, Michigan], and 0.1% tryptone [Difco]). After incubation for 24 hours at 35 °C, the broth (enrichment culture) was subcultured on blood agar plates and re-examined after incubation for an additional 24 hours. Hand cultures were done as described previously (11): Each hand was immersed in a sterile plastic bag containing 30 mL of TLSO broth and agitated vigorously for 30 seconds. An aliquot (100 /LtL) of the TLSO broth was plated directly on blood agar and incubated at 35 °C for 24 hours. An additional 5 mL of the broth was incubated at 35 °C for 24 hours and processed as described for enrichment cultures. For purposes of analysis, a culture site (nares or hand) was considered positive if either the direct plate culture or the enrichment culture grew 5. aureus. Isolates were identified as S. aureus if staining showed 102
gram-positive cocci in clusters, and they were catalase and tube-coagulase positive (BBL). All S. aureus isolates were stored frozen in skim milk at - 20 °C. Susceptibility of all S. aureus isolates was determined by disk-diffusion testing using disks containing mupirocin (5 /ug), augmentin (30 /ug), and oxacillin (1 /ig) (BBL). Susceptibility testing was done according to the most recent National Committee for Clinical Laboratory Standards (NCCLS) approved standard for disk-diffusion testing (12). Plates were incubated at 35 °C for 24 hours, and break points for zone diameters of inhibition were as follows: 17 mm or less for mupirocin, 19 mm or less for augmentin, and 10 mm or less for oxacillin. Epidemiologic typing of all isolates was done by restriction endonuclease digestion of plasmid DNA (13). Stored isolates of S. aureus were plated on blood agar and incubated at 35 °C for 48 hours. Multiple colonies were removed from the plate, inoculated into 10 mL of tryptic soy broth (Difco), and incubated overnight at 35 °C. Organisms were lysed and DNA was extracted using the method of Nahaie and colleagues (14). Restriction endonuclease digestion of plasmid DNA was done with EcoRI (New England Biolabs, Boston, Massachusetts) according to the manufacturer's instructions. The DNA was digested at 37 °C for 2 hours and the restriction fragments separated by electrophoresis on 0.7% agarose gels containing ethidium bromide. Electrophoresis was done using Tris-borateEDTA (ethylenediaminetetraacetic acid) buffer at 100 volts for 4 hours. Molecular weight standards were included in each gel. The gels were photographed under ultraviolet light, and the restriction digest patterns for each isolate were then compared in a blinded fashion for similarities and differences. Isolates with similar, but not identical, EcoRI patterns were rerun on the same gel after independent digestion with Hindlll and EcoRI. Any difference in position of a major or minor band was considered meaningful. Clinical Evaluation Vital signs were assessed on entry to the study and again 48 to 72 hours after completion of treatment. A visual examination of the nasal mucosa was done at enrollment, daily during treatment, and then at 48 to 72 hours and 1 week after therapy. Any adverse occurrences were recorded. Subjects were asked to assess the ease of application, acceptability of therapy, and presence of any discomfort at the first follow-up visit. Statistical Analysis Demographic characteristics of both study groups as well as adverse events were evaluated using a two-sample /-test for each continuous variable and either a chi-square or Fisher exact test (when an expected cell value was less than five) for categorical variables. Two-tailed tests were used for all analyses. The 95% confidence intervals were calculated for the differences in response variables for the two groups. Frequencies of positive and negative responses in the treatment groups were compared using a chi-square or Fisher exact test. A Mantel-Haenszel chi-square test was done to evaluate results of post-treatment hand cultures after adjusting for the frequency of S. aureus hand carriage at baseline. The treatment groups were also compared regarding bacteriologic failure in the nose at 3 months using the chi-square test.
Analysis of Efficacy The results of bacteriologic culture for S. aureus provided the basis for evaluating the efficacy of treatment. A further analysis of the efficacy of eradication of the initial colonizing strain or strains was based on the epidemiologic typing of isolates found at follow-up visits. Strain identity was determined by antimicrobial susceptibility testing and restriction endonuclease digestion of plasmid DNA. In the evaluation of the efficacy of topical mupirocin, a negative response was defined as non-eradication of the initial strain. Non-eradication was defined by either positive cultures for the initial strain after therapy or initially negative cultures after therapy with subsequent re-isolation of the initial strain. A positive response was defined as complete failure to isolate
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S. aureus after therapy or initial failure followed by isolation of a new strain of S. aureus. Subjects were considered inevaluable if they withdrew prematurely from the study (one subject) or if they did not have follow-up cultures (no subjects).
Table 2. Side Effects in Each Study Group Sign or Symptom
Results
Table 1. Characteristics of the Two Study Groups
Mean age, y Male: Female ratio Race (white:other) Involved in patient care, % Positive medical history, % Drug allergies, % Current medications, % Normal physical examination, % Perfect compliance, % Early withdrawal from study, n Concomitant medications, % * P = 0.20 using the Student Mest. t P > 0.20.
Placebo Group (n = 33)
P Value
n(%)
We screened 311 health care workers, of whom 102 (33%) had at least one positive culture. Seventy-three (24%) were considered to have stable S. aureus nasal carriage and were further evaluated. Five subjects identified as stable nasal carriers and contacted for enrollment were excluded (2 because of an inability to comply with the follow-up schedule, 1 because of longstanding diabetes mellitus and hypertension, 1 because of chronic eczema, and 1 because of steroid use). Sixty-eight volunteers met the inclusion criteria, and 34 were randomly assigned to each treatment arm. The mean duration of documented nasal carriage was 11.6 ± 17.4 days (range, 3 to 127 days), and all had at least two positive nasal cultures within 5 days before study entry. All volunteers were health care workers: Most (84%) were actively involved in patient care in such areas as the intensive care units, burn or hemodialysis units, and inpatient wards. Subjects had a mean age of 33.5 years, and women outnumbered men by a ratio of 2.2:1. There were no statistically significant differences between treatment groups with respect to age, sex, race, involvement in patient care, significant medical history, history of drug allergies, or use of concomitant medications not prohibited by the study protocol (Table 1). During administration of mupirocin calcium ointment, subjects seldom noted significant side effects (Table 2). However, transient nasal pruritus was reported at least once by 14.7% of subjects, local burning or stinging by 3%, and dryness by 3%. The degree of such symptoms was universally mild. Examination showed mild erythema of the nasal mucosa on at least one occasion in 35% of subjects, rhinorrhea in 9%, and induration in 9%. All signs were of brief duration (24 to 48 hours) and resolved with continued therapy. The mupirocin group had a higher frequency of nasal pruritus than the placebo group (14.7% compared with 0%; P = 0.053) but a lower frequency of dryness (2.9% compared with 18.2%; P = 0.054). Regarding the frequency of other symptoms or signs, the two groups did not differ. Over-
Characteristic
Mupirocin Group {n = 34)
Mupirocin Group (n = 34)
Placebo Group (n = 34)
34.9* 0.42t 33:lt 76.5t 41.2t 26.5t 38.2t 82.4t
32.1 0.48 32:2 88.2 41.2 23.5 50.0 88.2 97.1 1 38.2
loot
Ot
38.2t
Erythema Rhinorrhea Swelling Burning or stinging Nasal pruritis Nasal dryness Other adverse experiences Any adverse experience
12(35) 3 (9) 3(9) 1 (3) 5(15) 1 (3) 7 (21)* 22 (65)
17(52) 0.13 1 (3) > 0.20 3(9) > 0.20 1 (3) > 0.20 0 (0) 0.053 6 (18) 0.054 7 (21)t > 0.20 23 (70) > 0.20
* Adverse experiences not listed: transient pharyngitis (9%), metallic taste (6%), mild rhinorrhea (3%), and nausea with malaise (3%). t Adverse experiences not listed: blood-tinged nasal secretions (12%), unpleasant odor (6%), nasal tingling sensation (6%), transient pharyngitis (3%), lethargy (3%), and intermittent arthralgias (3%).
all, adverse experiences (of any kind at any time) were recorded in 65% of subjects in the mupirocin group and 70% of subjects in the placebo group (P > 0.20). No serious side effects were noted (Table 2). Of the 68 subjects, only 1 failed to complete the study. This subject, assigned to the placebo group, left the study unexpectedly because of a death in the family and stopped applying ointment on day 3 of therapy. Follow-up cultures confirmed continued nasal colonization with S. aureus; however, he was excluded from analyses of treatment safety and efficacy because of failure to complete the study protocol. All other cultures were obtained as required by the protocol except in the cases of two subjects who were unable to report for one culture each (0.6%). Of the subjects who received mupirocin, all reported that the ointment was easy to apply and nearly all (97%) reported that its use was acceptable overall. Similar responses were noted for the placebo group (97% for both endpoints). Of 68 subjects, 64 (94%) returned their tubes of ointment at the end of the trial. Subjects receiving mupirocin used an average of 3.6 g of ointment per treatment course, whereas control subjects used a mean of 4.0 g per treatment course. Although 5 subjects in the mupirocin group used less than 1 g of ointment (mean, 0.64 g; range, 0.40 to 0.90 g), nasal carriage of S. aureus was eradicated in 4. The fifth volunteer was the only subject who failed to clear nasal carriage at 72 hours after therapy; however, this subject used only 0.40 g of ointment, suggesting inadequate compliance. Notably, the 72-hour culture in this subject was positive only on enrichment, suggesting few viable organisms. Enrichment cultures after treatment were positive in five subjects when routine cultures of the nares obtained at the same time were negative. All five subjects with positive enrichment cultures were from the treatment group, and four of five had subsequent cultures that were positive for the same strain, suggesting enhanced sensitivity of the enrichment technique. None of the enrichment cultures of hand specimens or any enrichment cultures from the placebo group were different from routine cultures. The mupirocin group showed a decrease in the pro-
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(6 of 17) than those in the mupirocin group (0 of 23). Taken together, these data suggest that elimination of nasal carriage is closely linked to elimination of S. aureus from the hands of health care workers. Discussion
Figure 1. Rates of 5. aureus nasal carriage in subjects treated for 5 days with intranasal mupirocin ( • • ) or placebo (O O). Error bars represent 95% confidence intervals for each point.
portion of patients with S. aureus nasal carriage of at 12 weeks compared with the placebo group (29% positive compared with 82% for controls; P < 0.001; CI for the difference, 26% to 80%; Figure 1). An analysis of the antibiograms and plasmid restriction endonuclease digestion patterns (Figure 2) showed that one subject in the mupirocin group had persistent S. aureus colonization, seven had initially negative cultures followed by re-isolation of the initial strain, and four subjects had subsequent isolation of a different strain. A positive response (that is, complete elimination or elimination followed by re-isolation of a different strain) was seen in 97% of subjects in the treatment group immediately after therapy, in 88% at 4 weeks, and in 79% at 12 weeks. In contrast, only 21% of the control subjects had a negative culture or had a different strain isolated at 12 weeks. Resistance to mupirocin did not develop during the study. One third of all study participants had initial hand cultures that were positive for S. aureus. The isolates were almost universally of the same plasmid type as those from the nasal culture (97%). The proportion of subjects with positive hand cultures before therapy in the mupirocin group (29.4%) was lower than in the placebo group (50.0%), but the difference was not statistically significant (P = 0.137). The frequency of positive hand cultures obtained 3 days after finishing therapy was markedly decreased in the mupirocin group (2 of 33 subjects) compared with the placebo group (19 of 33 subjects). After adjusting for the incidence of hand carriage at baseline, subjects receiving mupirocin were significantly less likely to have positive hand cultures after therapy (Figure 3). Importantly, elimination of hand carriage of S. aureus on day 3 after therapy was seen in 8 of 10 (80%) subjects with previous colonization who were treated with mupirocin. In contrast, only 3 of 16 (19%) subjects with initial hand carriage in the placebo group had negative hand cultures on day 3 after treatment. Of subjects whose hand cultures were initially negative, those in the placebo group were significantly more likely to have had positive hand cultures on day 3 after therapy 104
Our clinical trial has shown that mupirocin calcium ointment (2%) in a soft, white paraffin base is safe, well tolerated, and effective in eliminating nasal carriage of S. aureus in healthy persons over a 3-month period. The study may have important clinical implications for the control of staphylococcal infections. Many prevalence surveys of healthy persons have been reported, with S. aureus carriage rates ranging from 25% to 65%. The S. aureus nasal carriage rate of 33% in our study is within this range. Most investigators have reported that the nasal carriage is usually stable over periods of several months to years (3, 1517). The 3-month follow-up data from our study support these conclusions, because 82% of volunteers in the placebo group were persistent carriers of a single strain of 5. aureus. Some investigators have seen nasal carriage of two S. aureus strains in up to 10% of subjects, as discriminated by phage-typing (3). Our study identified 12% of subjects with more than one strain before therapy and 40% with more than one strain after ther-
Figure 2. EcoRI digests of S. aureus plasmids from three representative subjects after agarose gel electrophoresis. The first subject received placebo. Isolates from pretreatment nasal (lane 1) and hand (lane 2) cultures and the isolate from the nasal culture done 12 weeks after therapy (lane 3) show persistence of the initial strain. The second subject received mupirocin. Isolates from pretreatment nasal (lane 4) and hand (lane 5) cultures were identical. After three negative cultures, S. aureus was noted at 4 weeks (lane 6) with an identical pattern, suggesting the persistence of the initial strain. The third subject received mupirocin. The pretreatment nasal culture was positive for S. aureus (lane 7) but was followed by four negative cultures before S. aureus was again isolated (lane 8). The two plasmid patterns are different, suggesting initial nasal eradication followed by acquisition of a new strain of S. aureus. Phage lambda (A), digested with Hindlll, was used as a molecular weight standard.
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Figure 3. Comparison of rates of hand carriage of S. aureus before (P = 0.137) and after (P < 0.001) intranasal treatment with mupirocin calcium ointment (ffi). A Mantel-Haenszel chisquare test was used to compare rates of hand carriage after therapy, corrected for baseline incidence of hand carriage. (Placebo group = • . )
apy, as determined by restriction endonuclease analysis of plasmid DNA. Mupirocin has been reported by Hill and Casewell (10) to be effective in eradicating nasal carriage. In a randomized, blinded trial with 32 subjects, the application of a 2% mupirocin ointment four times daily for 5 days resulted in uniform eradication of S. aureus nasal carriage immediately after treatment. By 22 weeks, 56% of subjects were culture negative, although the number of subjects lost to follow-up was not reported. Skin carriage at the wrist or perineum was eliminated in subjects immediately after treatment. Additionally, a dramatic reduction of normal nasal flora was noted without overgrowth of gram-negative bacilli. Other investigators have reported success using mupirocin for eradication of S. aureus nasal carriage in the setting of an outbreak of infection caused by methicillin-resistant S. aureus (18-21). Previous efforts to show the safety and efficacy of alternative topical agents have not been rewarding. Topical penicillin has been ineffective in eradicating 5. aureus over periods of 1 to 3 months (5), as has topical vancomycin (22). Topical bacitracin has been suggested for eradicating S. aureus, but studies have not documented efficacy (22). Additionally, topical gentamicin has been reported to have short-term efficacy (23, 24), but concern over the possible selection of gentamicin resistance has limited extensive study of this agent. Many drugs for systemic administration have been evaluated, the most prominent of which is rifampin. Initial success has been frequent, but rifampin resistance has appeared during monotherapy (7, 25). Agents that have most frequently been used in combination with rifampin include cloxacillin and trimethoprim-sulfamethoxazole. Wheat and coworkers (26) studied medical students treated with a 10-day course of daily rifampin with or without cloxacillin every 6 hours. They reported eradication immediately after treatment in 95% to 100%, which persisted in 60% to 65% at 3 months, and in 50% at 1 year (26). These investigators also treated 12 patients on dialysis with rifampin and cloxacillin; they found an efficacy of 90% at 3 months and of 60% at 1 year. In a retrospective study of veterans, rifampin in com-
bination with trimethoprim-sulfamethoxazole and bacitracin ointment was found to be efficacious in clearing nasal carriage of methicillin-resistant S. aureus; the success rate was 85% immediately after treatment and 78% overall after an unspecified follow-up period (27). Ellison and coworkers (28) used rifampin and trimethoprimsulfamethoxazole for eradicating methicillin-resistant 5. aureus from the nares of 12 patients and reported an initial success rate of 67%. However, only two of the patients who initially responded could be followed for more than 1 month, and they both had relapses. Other experiences with rifampin have been variable (29, 30). Ciprofloxacin, with (31) or without rifampin (32), has been reported to be effective in eliminating methicillinresistant S. aureus nasal carriage from patients, although increased minimum inhibitory concentrations to ciprofloxacin were noted in one third of isolates after treatment in one study (1). Clindamycin has also been used in a few patients with success (33). Several considerations favor the use of a topical agent: relative safety compared with systemic administration and the avoidance of drugs that may have an important therapeutic role and to which bacterial resistance may develop. Although the development of resistance of S. aureus to mupirocin has been described in case reports (34-38), existing data suggest that this is uncommon. In our study, resistance to mupirocin did not develop. Other methods advocated for eradicating S. aureus nasal carriage include a whole-body antiseptic wash (39), hexachlorophene baths (40), and replacement of nasal carriage with the less virulent 502A strain (41, 42). The 502A strain requires that antistaphylococcal therapy be given before inoculation, often necessitates repetitive instillation in the nose, and can cause disease (43). Clearance of S. aureus from the hands appears to be an important finding of our study, perhaps explaining the observed decrease in infections with S. aureus in patients on hemodialysis who received rifampin after elimination of nasal carriage (7, 8). Although our observations are preliminary and deserve further study, a major benefit of the eradication of nasal carriage may be the prevention of 5. aureus infection in high-risk groups. This potential benefit should be evaluated further. The intranasal application of mupirocin calcium ointment (2%) in a white, soft paraffin base for 5 days is safe, well tolerated, and effective over a 3-month period for eradicating S. aureus nasal carriage in health care workers. This agent may represent a useful addition to therapies for limiting auto-inoculation and nosocomial spread of S. aureus. Acknowledgments: The authors thank Chi Kao, MA, for assisting in the statistical analysis and Linda Annis for assisting in data collection. Grant Support: In part by grant RR59 from the General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health, and by Beecham Pharmaceuticals. Requests for Reprints: Richard P. Wenzel, MD, MSc, Department of Internal Medicine, C-41 GH, The University of Iowa College of Medicine, Iowa City, IA 52242. Current Author Addresses: Dr. Reagan: Department of Internal Medi-
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cine, Box 21160A, James H. Quillen College of Medicine, Johnson City, TN 37614-0002. Drs. Wenzel and Doebbeling and Ms. Sheetz: Department of Internal Medicine, C-41 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Dr. Pfaller, Mr. Hollis, and Ms. Houston: Department of Pathology, 273 MRC, University of Iowa College of Medicine, Iowa City, IA 52242. References 1. Horan T, Culver D, Jarvis W, et al. Pathogens causing nosocomial infections. Preliminary data from the National Nosocomial Infections Surveillance System. Antimicrob Newslet. 1988;5:65-7. 2. Sheagren JN. Staphylococcus aureus: the persistent pathogen. N Engl J Med. 1984;310:1437-42. 3. Williams RE. Healthy carriage of Staphylococcus aureus: its prevalence and importance. Bacteriol Rev. 1963;27:56-71. 4. Wheat U , Kohler RB, White A. Prevention of infections of skin and skin structures. Am J Med. 1984;76:187-90. 5. Gould JC. The effect of local antibiotic on nasal carriage of Staphylococcus pyogenes. J Hyg. 1955;53:379-85. 6. Chow JW, Yu VL. Staphylococcus aureus nasal carriage in hemodialysis patients. Its role in infection and approaches to prophylaxis. Arch Intern Med. 1989;149:1258-62. 7. Yu VL, Goetz A, Wagener M, Smith PB, Rihs JD, Hanchett J. Staphylococcus aureus nasal carriage and infection in patients on hemodialysis. Efficacy of antibiotic prophylaxis. N Engl J Med. 1986;315:91-6. 8. Boelaert JR, De Smedt RA, De Baere YA, Godard CA, Matthys EG. The influence of calcium mupirocin nasal ointment on the incidence of Staphylococcus aureus infections in haemodialysis patients. Nephrol Dial Transplant. 1989;4:278-81. 9. Casewell MW, Hill RL. Mupirocin ("pseudomonic acid")—a promising new topical antimicrobial agent. J Antimicrob Chemother. 1987;19:1-5. 10. Casewell MW, Hill RL. Elimination of nasal carriage of Staphylococcus aureus with mupirocin (''pseudomonic acid")—a controlled trial. J Antimicrob Chemother. 1986;17:365-72. 11. Doebbeling BN, Pfaller MA, Houston AK, Wenzel RP. Removal of nosocomial pathogens from the contaminated glove. Implications for glove reuse and handwashing. Ann Intern Med. 1988;109:394-8. 12. National Committee for Clinical Laboratory Standards. Approved standard M7-A. Standard methods for dilution antimicrobial tests for bacteria which grow aerobically. Antimicrob Newslet. 1988;5:11. 13. Wachsmuth K. Molecular epidemiology of bacterial infections: examples of methodology and investigation of outbreaks. Rev Infect Dis. 1986;8:682-92. 14. Nahaie MR, Goodfellow M, Harwood CR. A rapid screening procedure for staphylococcal plasmids. J Microbiol Methods. 1984;2:7381. 15. Miles AA, Williams RE, Clayton-Cooper B. The carriage of Staphylococcus {pyogenes) aureus in man and its relation to wound infection. J Pathol Bacteriol. 1944;56:513-24. 16. Zierdt CH. Long-term Staphylococcus aureus carrier state in hospital patients. J Clin Microbiol. 1982;16:517-20. 17. Aeilts GD, Sapico FL, Canawati HN, Malik GM, Montgomerie JZ. Methicillin-resistant-Stap/ry/ococcws aureus colonization and infection in a rehabilitation facility. J Clin Microbiol. 1982;16:218-23. 18. Frank U, Lenz W, Damrath E, Kappstein I, Daschner FD. Nasal carriage of Staphylococcus aureus treated with topical mupirocin (pseudomonic acid) in a children's hospital. J Hosp Infect. 1989;13: 117-20. 19. Dacre J, Emmerson AM, Jenner EA. Gentamicin-methicillin-resistant Staphylococcus aureus: epidemiology and containment of an outbreak. J Hosp Infect. 1986;7:130-6. 20. Davies EA, Emmerson AM, Hogg GM, Patterson MF, Shields MD. An outbreak of infection with a methicillin-resistant Staphylococcus aureus in a special care baby unit: value of topical mupirocin and of traditional methods of infection control. J Hosp Infect. 1987;10: 120-8.
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21. Duckworth GJ, Lothian JL, Williams JD. Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital. J Hosp Infect. 1988;11:1-15. 22. Bryan CS, Wilson RS, Meade P, Sill LG. Topical antibiotic ointments for staphylococcal nasal carriers: survey of current practices and comparison of bacitracin and vancomycin ointments. Infect Control. 1980;1:153-6. 23. White A. The use of gentamicin as a nasal ointment. Am J Med Sci. 1964;248:52-5. 24. Williams JD, Waltho CA, Ayliffe GA, Lowbury EJ. Trials of five antibacterial creams in the control of nasal carriage of Staphylococcus aureus. Lancet. 1967;2:390-2. 25. Sande MA, Mandell GL. Effect of rifampin on nasal carriage of Staphylococcus aureus. Antimicrob Agents Chemother. 1975;7: 294-7. 26. Wheat LJ, Kohler RB, White AL, White A. Effect of rifampin on nasal carriers of coagulase-positive staphylococci. J Infect Dis. 1981;144:177-177. 27. Roccaforte JS, Bittner MJ, Stumpf CA, Preheim LC. Attempts to eradicate methicillin-resistant Staphylococcus aureus colonization with the use of trimethoprim-sulfamethoxazole, rifampin, and bacitracin. Am J Infect Control. 1988;16:141-6. 28. Ellison RT 3d, Judson FN, Peterson LC, Cohn DL, Ehret JM. Oral rifampin and trimethoprim/sulfamethoxazole therapy in asymptomatic carriers of methicillin-resistant Staphylococcus aureus infections. West J Med. 1984;140:735-40. 29. McAnally TP, Lewis MR, Brown DR. Effect of rifampin and bacitracin on nasal carriers of Staphylococcus aureus. Antimicrob Agents Chemother. 1984;25:422-6. 30. Czarlinsky DK, HaU RT, Barnes WG, Jenkins DC, Rhodes PG. Staphylococcal colonization in a newborn nursery, 1971-1976. Am J Epidemiol. 1979;109:218-25. 31. Smith SM, Eng RH, Tecson-Tumang F. Ciprofloxacin therapy for methicillin-resistant Staphylococcus aureus infections or colonizations. Antimicrob Agents Chemother. 1989;33:181-4. 32. Mulligan ME, Ruane PJ, Johnston L, Wong P, Wheelock JP. Ciprofloxacin for eradication of methicillin-resistant Staphylococcus aureus colonization. Am J Med. 1987;82:215-9. 33. Smith SM, Mangia A, Eng RH, Ruggeri P, Cytryn A. Clindamycin for colonization and infection by methicillin-resistant Staphylococcus aureus. Infection. 1988;16:95-7. 34. Baird D, Coia J. Mupirocin-resistant Staphylococcus aureus [Letter]. Lancet. 1987;2:387-8. 35. Smith GE, Kennedy CT. Staphylococcus aureus resistant to mupirocin [Letter]. J Antimicrob Chemother. 1988;21:141-2. 36. Kave J, Andrews JM, Wise R. Mupirocin-resistant Staphylococcus aureus [Letter]. Lancet. 1987;2:1472-3. 37. Rahman M, Noble WC, Cookson B. Transmissible mupirocin resistance in Staphylococcus aureus. Epidemiol Infect. 1989;102:261-70. 38. Noble WC, Rahman M, Cookson B, Phillips I. Transferable mupirocin-resistance [Letter]. J Antimicrob Chemother. 1988;22:771-2. 39. Bartzokas CA, Paton JH, Gibson MF, Graham F, McLoughlin GA. Control and eradication of methicillin-resistant Staphylococcus aureus on a surgical unit. N Engl J Med. 1984;311:1422-5. 40. Arroyo JC, Postic B. Use of 3 percent hexachlorophene baths to control patient colonization by oxacillin and aminoglycoside-resistant Staphylococcus aureus [Letter]. Am J Med. 1982;72:112,156. 41. Boris M, Sellers TF, Eichenwald HF, Ribble JC, Shinefield HR. Bacterial interference. Protection of adults against nasal Staphylococcus aureus infection after colonization with a heterologous S. aureus strain. Am J Dis Child. 1964;108:252. 42. Light U, Walton RL, Suthreland JM, Shinefield HR, Brackvogel V. Use of bacterial interference to control a staphylococcal nursery outbreak. Am J Dis Child. 1967;113:291. 43. Drutz DJ, Van Way MH, Schaffner W, Koenig MG. Bacterial interference in the therapy of recurrent staphylococcal infections. Multiple abscesses due to the implantation of the 502 A strain of staphylococcus. N Engl J Med. 1965;275:1161-5.
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Number 2
15 January 1991
Annals of Internal Medicine ARTICLES
Elimination of Coincident Staphylococcus aureus Nasal and Hand Carriage with Intranasal Application of Mupirocin Calcium Ointment David R. Reagan, MD, PhD; Bradley N. Doebbeling, MD, MS; Michael A. Pfaller, MD; Carol T. Sheetz, RN, BSN; Alison K. Houston, BS; Richard J. Hollis, MA; and Richard P. Wenzel, MD, MSc
Objective: To determine the safety and efficacy of mupirocin calcium ointment in the elimination of Staphylococcus aureus nasal and hand carriage in healthy persons. Design: A double-blind, placebo-controlled, randomized trial. Setting: Clinical research unit of a tertiary medical center. Subjects: Health care workers with stable S. aureus nasal carriage. Interventions: Subjects (n = 68) were randomly assigned to receive either mupirocin or placebo intranasally twice daily for 5 days. Measurements and Main Results: Cultures of the hands and nares were obtained at baseline and 72 hours after therapy. The nares were also cultured 1, 2, 4, and 12 weeks after therapy. Antimicrobial susceptibility testing and restriction endonuclease analysis of plasmid DNA were used to confirm strain identity. There were no serious side effects. Mupirocin decreased the frequency of S. aureus nasal carriage at each time interval: At 3 months, 71% of subjects receiving mupirocin remained free of nasal S. aureus compared with 18% of controls. This difference (53%; 95% CI, 26% to 80%) was significant (P < 0.0001). Additionally, analysis of plasmid patterns showed that 79% of subjects in the mupirocin group were free of the initial colonizing strain at 3 months. The proportion of hand cultures positive for S. aureus in the mupirocin group after therapy was lower than in the placebo group (2.9% compared with 57.6%). This difference (53%; 95 CI, 30% to 80%) was significant, after adjustment for the frequency of hand carriage at baseline (P < 0.0001). Conclusions: When applied intranasally for 5 days, mupirocin calcium ointment is safe and effective in eliminating S. aureus nasal carriage in healthy persons for up to 3 months and appears to have a corresponding effect on hand carriage at 72 hours after therapy.
O n e of the most important pathogens in the United States, Staphylococcus aureus, is the most frequent cause of surgical wound infections and the second most common cause of nosocomial pneumonias and bloodstream infections (1). Staphylococcus aureus also causes skin and soft-tissue infections, osteomyelitis, and device-related infection in the community (2). The reservoir for chronic staphylococcal carriage has been shown to be the anterior nares (3), and various oral and topical agents have been used in an attempt to decrease nasal carriage (4-6). However, recolonization typically occurs within a few weeks or months. In patients receiving hemodialysis, reduction of nasal carriage has been associated with decreased rates of infection with S. aureus (7, 8), showing that eradication of S. aureus nasal carriage may be clinically beneficial. Mupirocin (pseudomonic acid) is a naturally occurring agent produced by Pseudomonas fluorescens. Used as a topical antibiotic, it has been shown to be effective against a broad spectrum of gram-positive microorganisms, including both methicillin-resistant and methicillin-susceptible strains of S. aureus (9). Casewell and Hill (10) in England evaluated a 2% mupirocin ointment with a paraffin base for its ability to eliminate staphylococcal nasal carriage in 32 volunteers. Initial success was uniform, and 56% of subjects remained free of nasal colonization at 22 weeks. To evaluate the safety and efficacy of 2% mupirocin calcium ointment in a white, soft paraffin base in eliminating both nasal and hand carriage of S. aureus in healthy persons, we conducted a randomized, placebocontrolled, double-blind trial of mupirocin calcium ointment in health care workers.
Methods Annals of Internal Medicine. 1991;114:101-106.
Study Sample
From the University of Iowa College of Medicine and the Department of Veteran's Affairs Medical Center, Iowa City, Iowa. For current author addresses, see end of text.
Health care workers who volunteered were screened for S. aureus nasal carriage. Persons with two positive cultures within a 5-day period (stable nasal carriage) were evaluated for possible admission to the study. Screening was not done as ©1991 American College of Physicians
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part of an outbreak investigation, and rates of infection with S. aureus in our hospital were unchanged during the study period. For inclusion in the study, volunteers had to be at least 18 years of age, had to give written informed consent, and had to be able to comply with the protocol requirements. Exclusion criteria included a history of any of the following: hypersensitivity to mupirocin or paraffin; treated seasonal allergic rhinitis or nasal polyps within the previous month; an immunodeficiency state; risk factors for leukopenia; chronic cardiac, renal, or hepatic disorders; or chronic dermatitis. Subjects were ineligible for the study if they had participated in another investigational drug trial within 30 days or were receiving therapy With antibiotics, steroids, or topical intranasal preparations at the time of enrollment. Premenopausal women were excluded if they were lactating or had a positive urine pregnancy test at the time of enrollment. Study Medication Both the mupirocin calcium and the placebo ointments were similar in appearance and provided in identical 15-g tubes. Each gram of mupirocin calcium ointment contained 20 mg of mupirocin in a base of white, soft paraffin. The placebo ointment contained only white, soft paraffin. Study Design The Human Review Committee, University of Iowa, approved our study. All subjects gave a brief medical history and had a physical examination. Nasal and hand cultures were obtained. A drug assignment list was prepared by the manufacturer with randomization by blocks of four: Two subjects were assigned to each treatment arm within the block. The subjects and investigators were blinded to the allocated treatment until after the trial ended. After enrollment, subjects were issued a numbered tube of the study ointment with instructions to measure a 1-cm length of ointment onto a sterile rayon swab and apply it to the anterior nares twice daily for 5 consecutive days. After application, the nose was massaged for 1 minute to enhance local distribution of the ointment. The tubes were weighed before and after use to allow an estimate of compliance. Each subject was examined daily by one of two investigators while receiving the study ointment. Repeat examinations and cultures of subjects' hands and both anterior nares were obtained between 48 and 72 hours after finishing therapy. Follow-up nasal cultures were obtained 1 week, 2 weeks, 1 month, and 3 months after the end of therapy. Microbiologic Evaluation Nasal specimens for culture were obtained by firmly rotating a new premoistened rayon-tipped swab (Culturette II, Marion Scientific, Kansas City, Missouri) five times in each anterior naris. Both swabs were cultured directly on 5% sheep-blood agar (Baltimore Biological Laboratories, Cockeysville, Maryland). Plates were examined after 24 and 48 hours of incubation at 35 °C. Additionally, all nasal swabs taken during the follow-up period were cultured in broth media (TLSO: 5% Tween 80 [Fisher Brand, Fairlawn, New Jersey], 2% lecithin [Fisher Brand], 0.5% sodium oleate [J.T. Baker Chemical Co., Phillipsburg, New Jersey], 0.1% sodium sulfite [J.T. Baker], 0.1% proteous peptone [Difco, Detroit, Michigan], and 0.1% tryptone [Difco]). After incubation for 24 hours at 35 °C, the broth (enrichment culture) was subcultured on blood agar plates and re-examined after incubation for an additional 24 hours. Hand cultures were done as described previously (11): Each hand was immersed in a sterile plastic bag containing 30 mL of TLSO broth and agitated vigorously for 30 seconds. An aliquot (100 /LtL) of the TLSO broth was plated directly on blood agar and incubated at 35 °C for 24 hours. An additional 5 mL of the broth was incubated at 35 °C for 24 hours and processed as described for enrichment cultures. For purposes of analysis, a culture site (nares or hand) was considered positive if either the direct plate culture or the enrichment culture grew 5. aureus. Isolates were identified as S. aureus if staining showed 102
gram-positive cocci in clusters, and they were catalase and tube-coagulase positive (BBL). All S. aureus isolates were stored frozen in skim milk at - 20 °C. Susceptibility of all S. aureus isolates was determined by disk-diffusion testing using disks containing mupirocin (5 /ug), augmentin (30 /ug), and oxacillin (1 /ig) (BBL). Susceptibility testing was done according to the most recent National Committee for Clinical Laboratory Standards (NCCLS) approved standard for disk-diffusion testing (12). Plates were incubated at 35 °C for 24 hours, and break points for zone diameters of inhibition were as follows: 17 mm or less for mupirocin, 19 mm or less for augmentin, and 10 mm or less for oxacillin. Epidemiologic typing of all isolates was done by restriction endonuclease digestion of plasmid DNA (13). Stored isolates of S. aureus were plated on blood agar and incubated at 35 °C for 48 hours. Multiple colonies were removed from the plate, inoculated into 10 mL of tryptic soy broth (Difco), and incubated overnight at 35 °C. Organisms were lysed and DNA was extracted using the method of Nahaie and colleagues (14). Restriction endonuclease digestion of plasmid DNA was done with EcoRI (New England Biolabs, Boston, Massachusetts) according to the manufacturer's instructions. The DNA was digested at 37 °C for 2 hours and the restriction fragments separated by electrophoresis on 0.7% agarose gels containing ethidium bromide. Electrophoresis was done using Tris-borateEDTA (ethylenediaminetetraacetic acid) buffer at 100 volts for 4 hours. Molecular weight standards were included in each gel. The gels were photographed under ultraviolet light, and the restriction digest patterns for each isolate were then compared in a blinded fashion for similarities and differences. Isolates with similar, but not identical, EcoRI patterns were rerun on the same gel after independent digestion with Hindlll and EcoRI. Any difference in position of a major or minor band was considered meaningful. Clinical Evaluation Vital signs were assessed on entry to the study and again 48 to 72 hours after completion of treatment. A visual examination of the nasal mucosa was done at enrollment, daily during treatment, and then at 48 to 72 hours and 1 week after therapy. Any adverse occurrences were recorded. Subjects were asked to assess the ease of application, acceptability of therapy, and presence of any discomfort at the first follow-up visit. Statistical Analysis Demographic characteristics of both study groups as well as adverse events were evaluated using a two-sample /-test for each continuous variable and either a chi-square or Fisher exact test (when an expected cell value was less than five) for categorical variables. Two-tailed tests were used for all analyses. The 95% confidence intervals were calculated for the differences in response variables for the two groups. Frequencies of positive and negative responses in the treatment groups were compared using a chi-square or Fisher exact test. A Mantel-Haenszel chi-square test was done to evaluate results of post-treatment hand cultures after adjusting for the frequency of S. aureus hand carriage at baseline. The treatment groups were also compared regarding bacteriologic failure in the nose at 3 months using the chi-square test.
Analysis of Efficacy The results of bacteriologic culture for S. aureus provided the basis for evaluating the efficacy of treatment. A further analysis of the efficacy of eradication of the initial colonizing strain or strains was based on the epidemiologic typing of isolates found at follow-up visits. Strain identity was determined by antimicrobial susceptibility testing and restriction endonuclease digestion of plasmid DNA. In the evaluation of the efficacy of topical mupirocin, a negative response was defined as non-eradication of the initial strain. Non-eradication was defined by either positive cultures for the initial strain after therapy or initially negative cultures after therapy with subsequent re-isolation of the initial strain. A positive response was defined as complete failure to isolate
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S. aureus after therapy or initial failure followed by isolation of a new strain of S. aureus. Subjects were considered inevaluable if they withdrew prematurely from the study (one subject) or if they did not have follow-up cultures (no subjects).
Table 2. Side Effects in Each Study Group Sign or Symptom
Results
Table 1. Characteristics of the Two Study Groups
Mean age, y Male: Female ratio Race (white:other) Involved in patient care, % Positive medical history, % Drug allergies, % Current medications, % Normal physical examination, % Perfect compliance, % Early withdrawal from study, n Concomitant medications, % * P = 0.20 using the Student Mest. t P > 0.20.
Placebo Group (n = 33)
P Value
n(%)
We screened 311 health care workers, of whom 102 (33%) had at least one positive culture. Seventy-three (24%) were considered to have stable S. aureus nasal carriage and were further evaluated. Five subjects identified as stable nasal carriers and contacted for enrollment were excluded (2 because of an inability to comply with the follow-up schedule, 1 because of longstanding diabetes mellitus and hypertension, 1 because of chronic eczema, and 1 because of steroid use). Sixty-eight volunteers met the inclusion criteria, and 34 were randomly assigned to each treatment arm. The mean duration of documented nasal carriage was 11.6 ± 17.4 days (range, 3 to 127 days), and all had at least two positive nasal cultures within 5 days before study entry. All volunteers were health care workers: Most (84%) were actively involved in patient care in such areas as the intensive care units, burn or hemodialysis units, and inpatient wards. Subjects had a mean age of 33.5 years, and women outnumbered men by a ratio of 2.2:1. There were no statistically significant differences between treatment groups with respect to age, sex, race, involvement in patient care, significant medical history, history of drug allergies, or use of concomitant medications not prohibited by the study protocol (Table 1). During administration of mupirocin calcium ointment, subjects seldom noted significant side effects (Table 2). However, transient nasal pruritus was reported at least once by 14.7% of subjects, local burning or stinging by 3%, and dryness by 3%. The degree of such symptoms was universally mild. Examination showed mild erythema of the nasal mucosa on at least one occasion in 35% of subjects, rhinorrhea in 9%, and induration in 9%. All signs were of brief duration (24 to 48 hours) and resolved with continued therapy. The mupirocin group had a higher frequency of nasal pruritus than the placebo group (14.7% compared with 0%; P = 0.053) but a lower frequency of dryness (2.9% compared with 18.2%; P = 0.054). Regarding the frequency of other symptoms or signs, the two groups did not differ. Over-
Characteristic
Mupirocin Group {n = 34)
Mupirocin Group (n = 34)
Placebo Group (n = 34)
34.9* 0.42t 33:lt 76.5t 41.2t 26.5t 38.2t 82.4t
32.1 0.48 32:2 88.2 41.2 23.5 50.0 88.2 97.1 1 38.2
loot
Ot
38.2t
Erythema Rhinorrhea Swelling Burning or stinging Nasal pruritis Nasal dryness Other adverse experiences Any adverse experience
12(35) 3 (9) 3(9) 1 (3) 5(15) 1 (3) 7 (21)* 22 (65)
17(52) 0.13 1 (3) > 0.20 3(9) > 0.20 1 (3) > 0.20 0 (0) 0.053 6 (18) 0.054 7 (21)t > 0.20 23 (70) > 0.20
* Adverse experiences not listed: transient pharyngitis (9%), metallic taste (6%), mild rhinorrhea (3%), and nausea with malaise (3%). t Adverse experiences not listed: blood-tinged nasal secretions (12%), unpleasant odor (6%), nasal tingling sensation (6%), transient pharyngitis (3%), lethargy (3%), and intermittent arthralgias (3%).
all, adverse experiences (of any kind at any time) were recorded in 65% of subjects in the mupirocin group and 70% of subjects in the placebo group (P > 0.20). No serious side effects were noted (Table 2). Of the 68 subjects, only 1 failed to complete the study. This subject, assigned to the placebo group, left the study unexpectedly because of a death in the family and stopped applying ointment on day 3 of therapy. Follow-up cultures confirmed continued nasal colonization with S. aureus; however, he was excluded from analyses of treatment safety and efficacy because of failure to complete the study protocol. All other cultures were obtained as required by the protocol except in the cases of two subjects who were unable to report for one culture each (0.6%). Of the subjects who received mupirocin, all reported that the ointment was easy to apply and nearly all (97%) reported that its use was acceptable overall. Similar responses were noted for the placebo group (97% for both endpoints). Of 68 subjects, 64 (94%) returned their tubes of ointment at the end of the trial. Subjects receiving mupirocin used an average of 3.6 g of ointment per treatment course, whereas control subjects used a mean of 4.0 g per treatment course. Although 5 subjects in the mupirocin group used less than 1 g of ointment (mean, 0.64 g; range, 0.40 to 0.90 g), nasal carriage of S. aureus was eradicated in 4. The fifth volunteer was the only subject who failed to clear nasal carriage at 72 hours after therapy; however, this subject used only 0.40 g of ointment, suggesting inadequate compliance. Notably, the 72-hour culture in this subject was positive only on enrichment, suggesting few viable organisms. Enrichment cultures after treatment were positive in five subjects when routine cultures of the nares obtained at the same time were negative. All five subjects with positive enrichment cultures were from the treatment group, and four of five had subsequent cultures that were positive for the same strain, suggesting enhanced sensitivity of the enrichment technique. None of the enrichment cultures of hand specimens or any enrichment cultures from the placebo group were different from routine cultures. The mupirocin group showed a decrease in the pro-
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(6 of 17) than those in the mupirocin group (0 of 23). Taken together, these data suggest that elimination of nasal carriage is closely linked to elimination of S. aureus from the hands of health care workers. Discussion
Figure 1. Rates of 5. aureus nasal carriage in subjects treated for 5 days with intranasal mupirocin ( • • ) or placebo (O O). Error bars represent 95% confidence intervals for each point.
portion of patients with S. aureus nasal carriage of at 12 weeks compared with the placebo group (29% positive compared with 82% for controls; P < 0.001; CI for the difference, 26% to 80%; Figure 1). An analysis of the antibiograms and plasmid restriction endonuclease digestion patterns (Figure 2) showed that one subject in the mupirocin group had persistent S. aureus colonization, seven had initially negative cultures followed by re-isolation of the initial strain, and four subjects had subsequent isolation of a different strain. A positive response (that is, complete elimination or elimination followed by re-isolation of a different strain) was seen in 97% of subjects in the treatment group immediately after therapy, in 88% at 4 weeks, and in 79% at 12 weeks. In contrast, only 21% of the control subjects had a negative culture or had a different strain isolated at 12 weeks. Resistance to mupirocin did not develop during the study. One third of all study participants had initial hand cultures that were positive for S. aureus. The isolates were almost universally of the same plasmid type as those from the nasal culture (97%). The proportion of subjects with positive hand cultures before therapy in the mupirocin group (29.4%) was lower than in the placebo group (50.0%), but the difference was not statistically significant (P = 0.137). The frequency of positive hand cultures obtained 3 days after finishing therapy was markedly decreased in the mupirocin group (2 of 33 subjects) compared with the placebo group (19 of 33 subjects). After adjusting for the incidence of hand carriage at baseline, subjects receiving mupirocin were significantly less likely to have positive hand cultures after therapy (Figure 3). Importantly, elimination of hand carriage of S. aureus on day 3 after therapy was seen in 8 of 10 (80%) subjects with previous colonization who were treated with mupirocin. In contrast, only 3 of 16 (19%) subjects with initial hand carriage in the placebo group had negative hand cultures on day 3 after treatment. Of subjects whose hand cultures were initially negative, those in the placebo group were significantly more likely to have had positive hand cultures on day 3 after therapy 104
Our clinical trial has shown that mupirocin calcium ointment (2%) in a soft, white paraffin base is safe, well tolerated, and effective in eliminating nasal carriage of S. aureus in healthy persons over a 3-month period. The study may have important clinical implications for the control of staphylococcal infections. Many prevalence surveys of healthy persons have been reported, with S. aureus carriage rates ranging from 25% to 65%. The S. aureus nasal carriage rate of 33% in our study is within this range. Most investigators have reported that the nasal carriage is usually stable over periods of several months to years (3, 1517). The 3-month follow-up data from our study support these conclusions, because 82% of volunteers in the placebo group were persistent carriers of a single strain of 5. aureus. Some investigators have seen nasal carriage of two S. aureus strains in up to 10% of subjects, as discriminated by phage-typing (3). Our study identified 12% of subjects with more than one strain before therapy and 40% with more than one strain after ther-
Figure 2. EcoRI digests of S. aureus plasmids from three representative subjects after agarose gel electrophoresis. The first subject received placebo. Isolates from pretreatment nasal (lane 1) and hand (lane 2) cultures and the isolate from the nasal culture done 12 weeks after therapy (lane 3) show persistence of the initial strain. The second subject received mupirocin. Isolates from pretreatment nasal (lane 4) and hand (lane 5) cultures were identical. After three negative cultures, S. aureus was noted at 4 weeks (lane 6) with an identical pattern, suggesting the persistence of the initial strain. The third subject received mupirocin. The pretreatment nasal culture was positive for S. aureus (lane 7) but was followed by four negative cultures before S. aureus was again isolated (lane 8). The two plasmid patterns are different, suggesting initial nasal eradication followed by acquisition of a new strain of S. aureus. Phage lambda (A), digested with Hindlll, was used as a molecular weight standard.
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Figure 3. Comparison of rates of hand carriage of S. aureus before (P = 0.137) and after (P < 0.001) intranasal treatment with mupirocin calcium ointment (ffi). A Mantel-Haenszel chisquare test was used to compare rates of hand carriage after therapy, corrected for baseline incidence of hand carriage. (Placebo group = • . )
apy, as determined by restriction endonuclease analysis of plasmid DNA. Mupirocin has been reported by Hill and Casewell (10) to be effective in eradicating nasal carriage. In a randomized, blinded trial with 32 subjects, the application of a 2% mupirocin ointment four times daily for 5 days resulted in uniform eradication of S. aureus nasal carriage immediately after treatment. By 22 weeks, 56% of subjects were culture negative, although the number of subjects lost to follow-up was not reported. Skin carriage at the wrist or perineum was eliminated in subjects immediately after treatment. Additionally, a dramatic reduction of normal nasal flora was noted without overgrowth of gram-negative bacilli. Other investigators have reported success using mupirocin for eradication of S. aureus nasal carriage in the setting of an outbreak of infection caused by methicillin-resistant S. aureus (18-21). Previous efforts to show the safety and efficacy of alternative topical agents have not been rewarding. Topical penicillin has been ineffective in eradicating 5. aureus over periods of 1 to 3 months (5), as has topical vancomycin (22). Topical bacitracin has been suggested for eradicating S. aureus, but studies have not documented efficacy (22). Additionally, topical gentamicin has been reported to have short-term efficacy (23, 24), but concern over the possible selection of gentamicin resistance has limited extensive study of this agent. Many drugs for systemic administration have been evaluated, the most prominent of which is rifampin. Initial success has been frequent, but rifampin resistance has appeared during monotherapy (7, 25). Agents that have most frequently been used in combination with rifampin include cloxacillin and trimethoprim-sulfamethoxazole. Wheat and coworkers (26) studied medical students treated with a 10-day course of daily rifampin with or without cloxacillin every 6 hours. They reported eradication immediately after treatment in 95% to 100%, which persisted in 60% to 65% at 3 months, and in 50% at 1 year (26). These investigators also treated 12 patients on dialysis with rifampin and cloxacillin; they found an efficacy of 90% at 3 months and of 60% at 1 year. In a retrospective study of veterans, rifampin in com-
bination with trimethoprim-sulfamethoxazole and bacitracin ointment was found to be efficacious in clearing nasal carriage of methicillin-resistant S. aureus; the success rate was 85% immediately after treatment and 78% overall after an unspecified follow-up period (27). Ellison and coworkers (28) used rifampin and trimethoprimsulfamethoxazole for eradicating methicillin-resistant 5. aureus from the nares of 12 patients and reported an initial success rate of 67%. However, only two of the patients who initially responded could be followed for more than 1 month, and they both had relapses. Other experiences with rifampin have been variable (29, 30). Ciprofloxacin, with (31) or without rifampin (32), has been reported to be effective in eliminating methicillinresistant S. aureus nasal carriage from patients, although increased minimum inhibitory concentrations to ciprofloxacin were noted in one third of isolates after treatment in one study (1). Clindamycin has also been used in a few patients with success (33). Several considerations favor the use of a topical agent: relative safety compared with systemic administration and the avoidance of drugs that may have an important therapeutic role and to which bacterial resistance may develop. Although the development of resistance of S. aureus to mupirocin has been described in case reports (34-38), existing data suggest that this is uncommon. In our study, resistance to mupirocin did not develop. Other methods advocated for eradicating S. aureus nasal carriage include a whole-body antiseptic wash (39), hexachlorophene baths (40), and replacement of nasal carriage with the less virulent 502A strain (41, 42). The 502A strain requires that antistaphylococcal therapy be given before inoculation, often necessitates repetitive instillation in the nose, and can cause disease (43). Clearance of S. aureus from the hands appears to be an important finding of our study, perhaps explaining the observed decrease in infections with S. aureus in patients on hemodialysis who received rifampin after elimination of nasal carriage (7, 8). Although our observations are preliminary and deserve further study, a major benefit of the eradication of nasal carriage may be the prevention of 5. aureus infection in high-risk groups. This potential benefit should be evaluated further. The intranasal application of mupirocin calcium ointment (2%) in a white, soft paraffin base for 5 days is safe, well tolerated, and effective over a 3-month period for eradicating S. aureus nasal carriage in health care workers. This agent may represent a useful addition to therapies for limiting auto-inoculation and nosocomial spread of S. aureus. Acknowledgments: The authors thank Chi Kao, MA, for assisting in the statistical analysis and Linda Annis for assisting in data collection. Grant Support: In part by grant RR59 from the General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health, and by Beecham Pharmaceuticals. Requests for Reprints: Richard P. Wenzel, MD, MSc, Department of Internal Medicine, C-41 GH, The University of Iowa College of Medicine, Iowa City, IA 52242. Current Author Addresses: Dr. Reagan: Department of Internal Medi-
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• Volume 114 • Number 2
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