Staphylococcal Infections
Conditions
Keywords
mupirocin, prevention and control, s. aureus
Brief summary
The purpose of this study is to determine if mupirocin 2% in polyethylene glycol (PEG) ointment \[Treatment Arm\] is effective in preventing moderate to severe re-infection with Staphylococcus aureus compared with treatment with polyethylene glycol (PEG) ointment \[Placebo Arm\].
Detailed description
Treatment of staphylococcal carriage with the topical antibiotic, mupirocin, has led to decreased infections in some hemodialysis patients and intensive care unit (ICU) patients. However, most of these studies were not placebo controlled and only certain subsets of patients benefited. Relapse of colonization, generally within 90 days after treatment is stopped, presumably with increased risk of infection, approaches 50%. Continuous use of mupirocin on daily, three times weekly, or weekly basis has resulted in increased resistance to the drug. Despite this lack of evidence, the use of mupirocin has become commonplace because it is perceived as an effective and simple means to prevent infection. In a National Institutes on Aging/Claude D. Pepper Older Americans Independence Center (NIA/OAIC)-sponsored proposal, we found that a 2 week treatment regimen with mupirocin ointment was effective in decolonizing older chronically ill nursing home residents of S. aureus when compared with placebo ointment. Decolonization began to decline by 3 months post-treatment, and resistance occurred only once in 52 treated patients. That study was not powered to detect differences in infection between the 2 study groups; the end point was eradication of colonization. However, a trend towards reduction in staphylococcal infection with mupirocin was seen. In addition, there were more therapeutic failures in residents who were colonized with methicillin-resistant S. aureus (MRSA) than methicillin-sensitive S. aureus (MSSA). We hypothesize that intermittent treatment with mupirocin ointment every 3 months may be an effective means of preventing recolonization and infection with S. aureus. We propose to study a patient population that has already had treatment for severe S. aureus infection and is at significant risk for a subsequent infection. Patients will receive mupirocin 2% polyethylene glycol (PEG) ointment \[Treatment Arm\] or polyethylene glycol (PEG) ointment \[Placebo Arm\] for 14 days every 3 months. The effect of these two regimens on S. aureus re-infection, re-colonization, and development of mupirocin resistance will be assessed.
Interventions
The impact of the treatment arm versus placebo arm on development of new (recurrent) S. aureus infection will be assessed as the primary end point. Change in S. aureus strains (MSSA versus MRSA) will be assessed as the secondary end point.
DRUGPolyethylene Glycol Ointment [Placebo]
The impact of the treatment arm versus placebo arm on development of S. aureus re-infections will be assessed as the primary end point. Change in S. aureus strains (MSSA versus MRSA) will be assessed as the secondary end point.
Sponsors
University of Michigan
Trinity Health Michigan
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All patients who receive care at Ann Arbor VA Medical Center, University of Michigan Medical Center, or St. Joseph Mercy Hospital, Ypsilanti who have been hospitalized for documented S. aureus infection will be eligible for enrollment. Staphylococcal infections may be community or hospital-acquired. Patients with S. aureus infection will be identified on a daily basis with the assistance of the Infection Control Practitioner, the Clinical Microbiology Laboratory, the Infectious Diseases Consultation Services, and Infectious Diseases physicians caring for patients in their offices. * Patients will provide written informed consent. The patient's guardian or next of kin will be contacted for informed consent in the event that the patient is incapable of doing so.
Exclusion criteria
* Patients who are unable to cooperate with treatment or follow-up. * Patients who are not likely to survive beyond one month or those who are transferred back to another acute care hospital. * Patients who require treatment with rifampin will be excluded since this drug is effective in decolonization of some staphylococcal carriers. * Patients with known hypersensitivity to mupirocin ointment or polyethylene glycol base. * Patients with ulcers obviously related to pressure will be excluded because they are frequently large, difficult to keep clean, and infections are difficult to diagnose. * Patients with small vascular or neuropathic ulcers \< 3 cm in circumference and \< 2 cm in depth may be enrolled. * Pregnant women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Re-infection With S. Aureus | 18 months | During the study, patients with prior well-documented infections with Staphylococcus aureus who developed new signs and symptoms of infection, met standardized clinical criteria for infection, and had S. aureus isolated on culture were considered to have re-infection with S. aureus. The number of S. aureus re-infections were compared in the mupirocin ointment (Treatment Arm) versus polyethylene glycol ointment (Placebo Arm) for all participants enrolled in the study and in participants who completed each study time point (visit) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acquisition of New S. Aureus Strains | 18 months | In the Mupirocin Ointment (Treatment) and Polyethylene Glycol (Placebo) Arms, S. aureus isolates (MSSA or MRSA) that caused infection prior to enrollment in the study were compared with S. aureus infecting isolates (MSSA or MRSA) that occurred during the study (re-infections). Infecting isolates that were found to be MRSA at enrollment and MRSA during the study were considered to be the same strain; this same strain definition was also applied to MSSA isolates. Infecting isolates that changed from MRSA at enrollment to MSSA during the study (or vice versa) were considered to be different strains. |
Other
| Measure | Time frame | Description |
|---|---|---|
| S. Aureus Re-infections (New or Recurrent) | 18 months | The anatomic site of each S. infection at enrollment and S. aureus re-infection that occurred during the study was compared. S. aureus isolated from a different site of infection than at baseline was considered to represent a new infection. Isolation of S. aureus from the same site as the baseline infection was considered to represent a recurrent infection. |
Countries
United States
Participant flow
Recruitment details
Patients with a history of documented infection with Staphylococcus aureus cared for at Veterans Affairs Ann Arbor Healthcare System, University of Michigan Medical Center, St. Joseph Mercy Hospital (Ypsilanti, MI), and Pittsburgh VA Medical Center from April 2005-August 2012.
Pre-assignment details
Patients who met study criteria and signed an informed consent were enrolled and randomized to treatment with mupirocin 2% in polyethylene glycol (PEG) ointment or treatment with a placebo (polyethylene glycol) ointment
Participants by arm
| Arm | Count |
|---|---|
| Mupirocin Ointment (Treatment) Mupirocin 2% in polyethylene glycol (PEG) ointment applied topically to nares and/or wounds for 14 days every 3 months for up to 18 months (Treatment Group). | 83 |
| Polyethylene Glycol Ointment (Placebo) Polyethylene glycol (PEG) ointment applied topically to nares and/or wounds for 14 days every 3 months for up to 18 months (Placebo Group). | 63 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 25 | 12 |
| Overall Study | Protocol Violation | 9 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Polyethylene Glycol Ointment (Placebo) | Total | Mupirocin Ointment (Treatment) |
|---|---|---|---|
| Age, Continuous | 57.9 years | 57.2 years | 56.7 years |
| Baseline S. aureus Infection Strain MRSA Infection at Baseline | 43 participants | 96 participants | 53 participants |
| Baseline S. aureus Infection Strain MSSA Infection at Baseline | 20 participants | 50 participants | 30 participants |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 4 Participants |
| Sex: Female, Male Male | 54 Participants | 133 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 83 | 0 / 63 |
| serious Total, serious adverse events | 1 / 83 | 2 / 63 |
Outcome results
Primary
Re-infection With S. Aureus
During the study, patients with prior well-documented infections with Staphylococcus aureus who developed new signs and symptoms of infection, met standardized clinical criteria for infection, and had S. aureus isolated on culture were considered to have re-infection with S. aureus. The number of S. aureus re-infections were compared in the mupirocin ointment (Treatment Arm) versus polyethylene glycol ointment (Placebo Arm) for all participants enrolled in the study and in participants who completed each study time point (visit)
Time frame: 18 months
Population: Re-infections with S. aureus, new or recurrent, were noted for all patients enrolled in the study and for patients who completed each study visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | Completed visit 0 baseline [n=79,60] | 0 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | completed visit 4 (9 mo) [n=38,37] | 3 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | Completed visit 2 (3 mo) [n=54,46] | 2 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | completed visit 5 (12 mo) [n=37,37] | 0 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | Completed visit 1 (2 wks) ([n=72,54] | 1 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | completed visit 6 (15 mo) [n=36,33] | 1 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | completed visit 3 (6 mo) [n=44,38] | 2 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | completed visit 7 (18 mo) [n=34,31] | 1 participants with S. aureus re-infection |
| Mupirocin Ointment (Treatment) | Re-infection With S. Aureus | All enrolled participants [n=83,63)] | 10 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | completed visit 7 (18 mo) [n=34,31] | 1 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | All enrolled participants [n=83,63)] | 11 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | Completed visit 0 baseline [n=79,60] | 0 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | Completed visit 1 (2 wks) ([n=72,54] | 0 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | Completed visit 2 (3 mo) [n=54,46] | 3 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | completed visit 3 (6 mo) [n=44,38] | 4 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | completed visit 4 (9 mo) [n=38,37] | 1 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | completed visit 5 (12 mo) [n=37,37] | 0 participants with S. aureus re-infection |
| Polyethylene Glycol Ointment (Placebo) | Re-infection With S. Aureus | completed visit 6 (15 mo) [n=36,33] | 2 participants with S. aureus re-infection |
Comparison: Our null hypothesis was that no significant effect of mupirocin ointment (treatment) on S. aureus re-infection would be seen at 18 months compared with placebo ointment. Based on prior studies, we estimated that 198 participants would need to be enrolled assuming a 20% dropout rate; 84 participants per arm would be required to detect a 66% decrease in re-infection from 30% to 10% with a significance level alpha of 0.05 and a power of 0.9.p-value: 0.356Chi-squared
Secondary
Acquisition of New S. Aureus Strains
In the Mupirocin Ointment (Treatment) and Polyethylene Glycol (Placebo) Arms, S. aureus isolates (MSSA or MRSA) that caused infection prior to enrollment in the study were compared with S. aureus infecting isolates (MSSA or MRSA) that occurred during the study (re-infections). Infecting isolates that were found to be MRSA at enrollment and MRSA during the study were considered to be the same strain; this same strain definition was also applied to MSSA isolates. Infecting isolates that changed from MRSA at enrollment to MSSA during the study (or vice versa) were considered to be different strains.
Time frame: 18 months
Population: Participants with S. aureus re-infection who acquired a new strain during the 18 month study period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mupirocin Ointment (Treatment) | Acquisition of New S. Aureus Strains | Same strain baseline & Re-infection | 10 participants |
| Mupirocin Ointment (Treatment) | Acquisition of New S. Aureus Strains | MRSA Baseline & Re-Infection | 8 participants |
| Mupirocin Ointment (Treatment) | Acquisition of New S. Aureus Strains | MSSA Baseline & Re-Infection | 2 participants |
| Polyethylene Glycol Ointment (Placebo) | Acquisition of New S. Aureus Strains | Same strain baseline & Re-infection | 10 participants |
| Polyethylene Glycol Ointment (Placebo) | Acquisition of New S. Aureus Strains | MRSA Baseline & Re-Infection | 10 participants |
| Polyethylene Glycol Ointment (Placebo) | Acquisition of New S. Aureus Strains | MSSA Baseline & Re-Infection | 0 participants |
Other Pre-specified
S. Aureus Re-infections (New or Recurrent)
The anatomic site of each S. infection at enrollment and S. aureus re-infection that occurred during the study was compared. S. aureus isolated from a different site of infection than at baseline was considered to represent a new infection. Isolation of S. aureus from the same site as the baseline infection was considered to represent a recurrent infection.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mupirocin Ointment (Treatment) | S. Aureus Re-infections (New or Recurrent) | All Re-Infections | 10 participants |
| Mupirocin Ointment (Treatment) | S. Aureus Re-infections (New or Recurrent) | Re-infections Different Anatomic Site | 7 participants |
| Polyethylene Glycol Ointment (Placebo) | S. Aureus Re-infections (New or Recurrent) | All Re-Infections | 11 participants |
| Polyethylene Glycol Ointment (Placebo) | S. Aureus Re-infections (New or Recurrent) | Re-infections Different Anatomic Site | 6 participants |