Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this systematic review is to determine whether the use of mupirocin nasal ointment in patients with identified S. aureus nasal carriage reduces S. aureus infection rates.
Background
Staphylococcus aureus (S. aureus) is the leading nosocomial (hospital infection) pathogen in hospitals throughout the world. Infection with S. aureus is associated with substantial morbidity and mortality ‐ a trend that is increasing due to the widespread dissemination of methicillin‐resistant S. aureus (MRSA) (NNIS 2004). MRSA is not more pathogenic (disease‐causing) than S. aureus, but therapy is more problematic.
Staphylococcal infections occur regularly in hospitalized patients and can have severe consequences including postoperative wound infections, nosocomial pneumonia, and catheter‐related bacteremia (bacteria in the blood that can cause disease, e.g. endocarditis, elsewhere in the body) (Kaplowitz 1988; Kluytmans 1997; Kluytmans 1995; Yu 1986; Yzerman 1996). A recent study of over seven million hospital admissions in the US estimated that 0.8% of all patients suffered from infection with S. aureus, corresponding to a total of nearly 300,000 patients in US hospitals in 2003. After controlling for confounders (i.e. applying appropriate statistical techniques), the annual impact in the US was estimated to be 2.7 million additional days in hospital, US$9.5 billion excess costs, and at least 12,000 in‐patient deaths (Noskin 2005). Since the consequences of these infections are immense, effective prevention strategies are essential.
Traditionally, control of S. aureus has been focused on preventing cross‐infection between patients (Pittet 2000), however, it has been shown repeatedly that a large proportion of nosocomial S. aureus infections originate from the patients' own flora (non‐pathogenic bacteria normally present on the patient) (Kluytmans 1995; Von Eiff 2001; Wertheim 2004). Nasal carriage (presence in the nose) of S. aureus is now considered a well defined risk factor for subsequent infection in various groups of patients, including those on dialysis; with cirrhosis of the liver; undergoing surgery; and with intravascular devices or in intensive care (Kluytmans 1997; Mangram 1999).
Three approaches to the elimination of carriage of this bacterium are available: local application of antibiotics or disinfectants; administration of systemic antibiotics; and the harnessing of bacterial interference through active culturing of a minimally‐pathogenic strain of S. aureus. (Bacterial interference is the term given to the effect that different micro‐organisms can have on each other when they are present simultaneously. This interference can result in partial or complete inhibition of one micro‐organism ‐ desired in this case ‐ though sometimes activity may be increased.) Mupirocin nasal ointment (applied to the nose twice daily for five days) has often been used to eradicate carriage because of its effectiveness, safety, ease of use and low cost. Mupirocin can be used for the eradication of both S. aureus and MRSA, although MRSA resistance for mupirocin has been shown (Henkel 1999). As a result of these findings, several interventional studies have hoped to reduce rates of infection by eradicating nasal carriage (Kluytmans 1997). Recent technological advances in rapid diagnostics have provided the ability to detect nasal carriage of S. aureus within hours rather than days (Francois 2003; Paule 2004). This will enable pre‐emptive treatment of carriers only, which will enhance the efficacy of prophylaxis.
Objectives
The objective of this systematic review is to determine whether the use of mupirocin nasal ointment in patients with identified S. aureus nasal carriage reduces S. aureus infection rates.
Methods
Criteria for considering studies for this review
Types of studies
We will include prospective randomized controlled trials (RCTs) evaluating nasal mupirocin in the prevention of S. aureus infections in nasal S. aureus carriers.
Types of participants
Studies of nasal carriers of S. aureus (both methicillin‐resistant and methicillin‐sensitive) that are using hospital services (either as inpatient or outpatient) will be included. We will include studies of patients from any population, gender, and age. Nasal carriage must be identified by microbiological culture techniques.
Types of interventions
We will include trials in which nasal carriers of S. aureus are treated with mupirocin ointment intranasally. Control groups may be treated with a placebo, receive no treatment or alternative topical treatment.
We will exclude studies that have systemic antibiotics or active colonization as a comparator.
Types of outcome measures
Primary outcome
S. aureus infection rate ‐ determined according to well‐defined criteria (for example to Centers for Disease Control (CDC) guidelines). The infection rate consists of the number of infected patients per study group. Any infection caused by both methicillin‐resistant and methicillin‐sensitive S. aureus will be included.
Secondary outcomes
Where reported, the following outcomes will also be recorded:
1. Time to infection.
2. Mortality.
3. Adverse events.
4. Infection rate caused by other micro‐organisms than S. aureus
Search methods for identification of studies
We will systematically search the following electronic databases for relevant trial reports:
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The Cochrane Central Register of Controlled Trials (CENTRAL, latest issue);
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Cochrane Wounds Group Specialized Register;
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EMBASE (January 1980 to date);
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MEDLINE (January 1980 to date).
Search strategy for CENTRAL:
1. MUPIROCIN single term (MeSH)
2. mupirocin
3. pseudomonic acid
4. bactroban
5. (#1 or #2 or #3 or #4)
6. nasal
7. intranasal
8. (#6 or #7)
9. (#5 and #8)
The search will not be limited by language. Citations within identified studies will be searched.
The authors, who are experts in this field with a long lasting interest in this subject, will search their personal archives, including the abstracts from major scientific meetings (Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and The Society for Healthcare Epidemiology of America (SHEA)).
Unpublished trials and unfinished studies will be identified by contacting researchers and manufacturers of mupirocin, and by searching several electronic databases (SIGLE, ASLIB Index, mRCT, USA Clinical Trials).
Data collection and analysis
Study selection
Titles and abstracts of studies retrieved from the search process will be independently assessed by two authors (JK, MvR) for their eligibility for inclusion in the review. Studies that are clearly ineligible will be discarded. Full versions of all potentially relevant studies will be obtained and independently assessed for inclusion by two authors. Disagreements will be resolved by discussion or by reference to a third author (MB). When more than one published report of a trial exists, all publications will be considered and maximal data will be extracted. However, only a single set of data will be used in any meta‐analysis. If data are missing from reports, then attempts will be made to contact the authors to obtain the missing information.
Data extraction
Types of information and data extracted will include the following:
1. Study authors.
2. Year of publication.
3. Country where study performed.
4. Study design (RCT).
5. Patient population.
6. Baseline characteristics of participants per treatment group (gender, age, and prevalence of co‐morbidity such as diabetes).
7. Length, dose and timing of mupirocin treatment.
8. Methods used for identifying micro‐organisms.
9. Criteria used for identifying infections / definition of infection used.
10. Withdrawals (per group with numbers and reasons).
11. Numbers of S. aureus nasal carriers in mupirocin‐ and placebo‐treated patients.
12. Number of nosocomial S. aureus infections among mupirocin‐ and placebo‐treated patients.
13. Healthcare setting.
Study quality
The quality of the included studies will be assessed independently by JK and MvR without blinding to authorship or journal using the checklist developed by the Cochrane Renal Group. The results of the validity criteria will be summarised in a table and be taken into account in the conclusions and discussion.
Quality checklist
All included trials will be assessed for quality using a quality checklist that considers the following points:
1. Allocation concealment
Trials will be awarded the following grades for allocation concealment:
A = Adequate: a randomization method described that would not allow an investigator/participant to know or influence an intervention group before an eligible participant entered the study.
B = Unclear: trial states that it is 'randomized', but no information on the method used is available.
C = Inadequate: inadequate method of randomization used, such as alternate medical record numbers or unsealed envelopes; or any information in the study that indicated that investigators or participants could influence the intervention group.
2. Blinding
The following points will be graded as 'yes' for present, 'no' for absent, and 'not stated' if the relevant information is not stated in the trial report:
a. Blinding of investigators.
b. Blinding of participants.
c. Blinding of outcome assessor.
d. Blinding of data analysis.
The above will be considered not to have been blinded if the treatment group can be identified in > 20% of participants because of any side effects of the treatment.
3. Intention‐to‐treat analysis:
This will evaluate whether participants were analyzed in the groups to which they were originally randomized, and will be graded as:
Yes ‐ specifically stated by authors that intention‐to‐treat analysis was undertaken, and this was confirmed on study assessment.
Yes ‐ not specifically stated, but confirmed on study assessment.
No ‐ not reported, and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomized were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)
No ‐ stated, but not confirmed upon study assessment.
Not stated.
4. Completeness of follow up
Percent of participants excluded or lost to follow up will be recorded.
Statistical assessment
Primary and secondary outcomes of the studies will be analyzed for each study individually, and, where appropriate combined across studies.
Infection rates and mortality will be expressed as relative risk (RR) with 95% confidence intervals (CI). In the first instance, data from all studies will be pooled in a forest plot using the random‐effects model. Levels of heterogeneity will be analyzed using the chi‐square test and the I2 statistic (Higgins 2002; Higgins 2003). Values of I2 over 50% indicate a substantial level of heterogeneity. If heterogeneity is detected the studies will be presented in a narrative summary. Subgroup analyses are planned where obvious differences exist between the included study groups; these differences may exist in the following variables: age, healthcare setting (for example surgical versus non‐surgical), or length, timing, and dose of treatment.
Time to infections will be analyzed as continuous data using mean differences and 95% CI.
Adverse events will be described
