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Background The bacterium Staphylococcus aureus frequently colonizes the human skin and mucous membranes, the anterior nares being regarded as the preferred habitat. Longitudinal studies usually divide S. aureus carriers into either persistent or intermittent carriers, but because the number of samplings, the follow-up periods and the study populations differ between studies, the designation of carrier state is inconsistent (1). It has been estimated that around 20 % of a population are persistent carriers, 60 % are intermittent carriers and 20 % are non-carriers (2). S. aureus is an opportunistic pathogen that can become invasive and cause a large spectrum of infections. S. aureus is frequently the cause of skin and soft tissue infections e.g. wounds, furuncles and abscesses, and can also cause urinary tract infections and pneumonia. If it enters the bloodstream, it can lead to metastatic infections e.g. endocarditis, arthritis, osteomyelitis and meningitis. Furthermore, S. aureus is a common pathogen in surgical site infections and in infections related to foreign bodies, such as catheters and prostheses.
Antibiotic resistance in bacteria is an increasing challenge worldwide and is also seen in S. aureus. The first methicillin resistant Staphylococcus aureus (MRSA) were seen in 1961 just one year after the antibiotic methicillin was introduced (3). For several decades MRSA was mainly a hospital-associated bacterium, but since the mid 1990's it has become increasingly prevalent in the community where it often affects children and younger adults. MRSA can cause the same types of infections as the methicillin susceptible S. aureus, but often only colonizes the mucosa of the nose, throat and/or perineum. When colonization is confirmed, the person is called a carrier of MRSA and there is a risk of both a wide spectrum of infections (4) and spread of MRSA to others. The Danish Health Authority has published a National guideline on how to prevent the spread of MRSA and keep the prevalence of MRSA low in Denmark (5), especially in the health care setting. The finding of MRSA both in samples from clinical infections and in screening samples for MRSA carriage is notifiable and has to be reported to the Danish Patient Safety Authority and Statens Serum Institut, in order to monitor the number of MRSA positive persons in Denmark, potential outbreaks and risk factors for MRSA acquisition (6). Furthermore, the guideline recommends that MRSA carriers and their household members undergo a five day topical decolonization treatment consisting of nasal mupirocin ointment 2 % three times daily in the nostrils (mupirocin is an antibiotic usually active against MRSA) and chlorhexidine body wash 4 % once daily. Unfortunately, many patients are still MRSA carriers after completing the treatment and especially throat carriers are difficult to clear (7).
Routine treatment At Hvidovre Hospital, MRSA Knowledge Center, we have treated MRSA carriers routinely since 2009. Our current guideline recommends adding antibiotics to the standard regimen, clindamycin being our first line choice, on the second or third eradication attempt if the patient is a throat carrier and the isolate is clindamycin susceptible. To our knowledge, the only randomized, controlled trial including clindamycin for treatment of MRSA carriage, is a Swedish study that showed a significant effect of standard treatment plus the antibiotic rifampicin in combination with either clindamycin or sulfamethoxazole/trimethoprim compared to standard treatment alone in long-term MRSA carriers (8). As most of our patients are healthy individuals without infections, adding systemic antibiotics to the decolonization treatment must be considered thoroughly. There is a risk of side effects in the individual patient and prudent use of antibiotics in the era of a rising incidence of antimicrobial resistance is crucial to avoid selection of further resistance. Our group has recently published a retrospective study describing the MRSA treatment data of 164 patients treated in 2013 (7). The study confirmed that throat carriers had a higher treatment failure rate but adding clindamycin to the first eradication attempt did not significantly increase the success rate. However, as there had been no randomization of patients the scientific evidence is low and the fact that there are no published studies using clindamycin as the only antibiotic for MRSA throat carriers, implies the need for a randomized trial on this subject.
The current practice in the Capital Region of Denmark regarding treatment of MRSA carriers is that the patients General Practitioner (GP) is recommended to prescribe the first MRSA decolonization treatment for the patient and household members. The GP can seek expert advice from either MRSA Knowledge Center or the MRSA team at the Department of Clinical Microbiology at Herlev Hospital, depending on which hospitals' Department of Clinical Microbiology is serving the respective GP. If the patient is still MRSA carrier after completing the first treatment, the case is considered complicated and a medical doctor from either the MRSA Knowledge Center or the MRSA team at Herlev Hospital will typically discuss any further treatment plan with the patient and/or the GP.
Aim To investigate whether a significantly higher number of MRSA throat carriers become MRSA free when treated with standard topical treatment plus the antibiotic clindamycin compared to standard topical treatment and placebo at the second attempt of decolonization treatment.
Primary endpoint: MRSA negative swabs at 1 months Secondary endpoint: MRSA negative swabs after 6 months
Method and design The study will be a randomized double blinded placebo-controlled study, including patients ≥18 years old that have tested MRSA positive in their throat after completing one standard topical decolonization treatment.
MRSA patients In the Capital Region of Denmark, the number of new MRSA positive patients ≥18 years old was 855 in 2018. In around 60 % of cases, MRSA is first found in a sample from an infection (mainly skin and soft tissue infections) and approximately 75 % of these patients are MRSA carriers following the infection. Therefore, we expect to encounter approximately 700 newly diagnosed MRSA carriers per year of which around 66 % are throat carriers in their first screening sample (462 patients). Based on retrospective data, around 40 % become MRSA free after the first decolonization treatment, which means that approximately 277 of the throat carriers ≥18 years old are still MRSA positive after the first treatment. We expect that 40 % of these patients have one or more exclusion criteria and therefore end up with approximately 330 patients that fulfill the inclusion criteria within the 2-year study period. As a part of our working routine, we automatically obtain information about all MRSA culture positive samples in the lab on a daily basis. When a patient is still MRSA positive after the first decolonization attempt, the patient or the GP is either proactively or after request from the GP contacted by phone or electronic letter in order to offer a second eradication attempt.
Recruitment of study subjects The MRSA Knowledge Center at Hvidovre Hospital and the MRSA team at Herlev Hospital routinely receive control swabs from all MRSA patients in their respective uptake area. From previous contact with the patient or the patient's GP, we already have access to different information stored in our laboratory information system and/or the electronic patient's record. Based on this information, the doctors and/or infection control nurses routinely follow up upon positive MRSA samples daily at either Hvidovre Hospital or Herlev Hospital will inform the investigator about possible study subjects. The investigator will then prescreen the possible patients according to the inclusion and exclusion criteria. The prescreen includes: date of birth, initials, sex, age, MRSA positive in throat, previous decolonization attempts, known inclusion/exclusion criteria. Prescreen details on possible study subjects will be documented in an excel sheet.
Participation If the patient could be a possible participant, we will either contact the patient directly, if we have had previous contact with the patient, or we will contact the GP and ask him/her to get the patient's acceptance of us contacting them about the project. The first contact will be a short letter asking whether the patient could be interested in the project. The letter will be sent by electronic post from either the electronic patient record (Sundhedsplatformen) or secure electronic mail (eboks). In the letter, the patient is asked to contact the investigator by phone or email if he or she would like to have more information about the project. If the patient responds positively on our invitation, the patient will be informed about the possibility of entering the project, and questions will be asked according to inclusion and exclusion criteria, to determine whether the patient is eligible or not (see inclusion and exclusion criteria). If the patient does not respond to our letter within a week, we will call the patient and ask if he/she would be interested.
Additional information provided If the patient is interested in more information on the project, the participant information will be sent by electronic post to the patient and the patient will have a minimum of 48 hours to decide whether he/she is interested in learning more about the project. The patient can either contact us by phone or send an email to the investigator stating whether he/she could be interested in a personal meeting to learn more about the project. Patients that respond positively will be invited to a personal meeting at either Hvidovre Hospital or Herlev Hospital, where oral information about the trial and possible side effects will be given to the patient. The patient can bring a friend or relative at the meeting if desired. Patients will be offered 24 hours to provide oral and written informed consent in order to secure sufficient time for reflection on study participation. If a patient needs more time to consider entering the trial, more time will be given. Before signing the informed consent form, the investigator will secure that the patient has read and understood the written study information. Every possible study subject that has a personal meeting with the investigator, will be registered in REDcap, a secure web application for managing online databases.
When oral and written consent has been obtained, the subject will receive a randomized eradication package as described below, as well as a diary to fill out during the study from day 1 to 14, asking about compliance and adverse events.
Patient data Patient data will be pseudo-anonymized as each patient will receive a project number. The investigator will on another file in a locked drawer (investigator site file), as well as on a secured electronic file, only accessible for investigators, have access to the real identification of the patient (the CPR number).
Once included in the trial, one eCRF is created for each patient for collection of trial data. This will include the following data:
Project number, date of birth, age, sex, height, weight, relevant medical history/current medication, sites and dates of MRSA positive samples, prior MRSA decolonization treatments, household composition and household members MRSA carrier state, typing and resistance data of the MRSA strain and investigational results, body mass index, laboratory and investigational results. For sexually active female subjects in the reproductive age, we also record the use of contraceptives.
The CRFs will be stored in the secure web application for managing online databases 'REDCap' which is designed for non-commercial clinical research. Obtained data will be transferred manually by investigators or appointed research nurses to the CRFs.
The eCRF does not contain information on the specific treatment the patient is randomized to as the randomization is done by the pharmacist.
The treatment The subject will receive a randomized eradication package. The treatment will consist of mupirocin nasal ointment 2 %, Chlorhexidine Bodywash 4 % and either placebo capsules 2 capsules three times daily for 10 days or clindamycin 300 mg capsules 2 capsules three times daily for 10 days. Placebo and clindamycin are manufactured to look exactly alike by Glostrup pharmacy, who is also in charge of the randomization/blinding of the packages.
An emergency unblinding procedure will be established to allow investigators the option to withdraw the subject from the trial at any given time, in case of an emergency. This could be if a subject experiences serious adverse events, that could be caused by the active treatment. The pharmacist has created individual sealed and securely closed envelopes for each included subject ID available. The investigator can at any time, 24 hours a day, in case of an emergency unblind a subject, to reveal which treatment has been given. The sponsor will be notified within 24 hours.
Besides the oral treatment, the patient follows the standard treatment guidelines for MRSA decolonization.
After the treatment Thirty to sixty days after end of treatment, the subjects will routinely have MRSA control swabs taken by their GP according to the National MRSA guidelines. Subjects will be reminded about this screening test when entering the trial. If we haven't received the control swabs within 6 weeks after completing the treatment, we will send the patient an electronic reminder. The swabs are routine samples that will be handled as regular MRSA control samples in the clinical microbiology laboratory at either Hvidovre hospital or Herlev hospital and the results will be visible to both the GP and the patient at sundhed.dk.
Swab results The swab results appear automatically in the microbiology laboratory information system along with swab results of MRSA patients that are not part of the trial. If the patient is MRSA positive one month after the treatment, no further screening samples will be needed for this project. The patient will leave the trial, and if additional treatment is considered by the doctors responsible for the treatment outside the trial, the randomization will be unblinded in order to plan the most optimal treatment, without revealing the investigator about the investigation medicine given prior to the drop out.
If MRSA negative at one month, no unblinding will take place as no new treatment will be planned. The subject will have new control swabs taken at the GP six to eight months after completing the treatment. If negative swabs at 6-8 months, the patient is declared MRSA free according to the National MRSA Guidelines.
Power calculation Anticipation is 30% better eradication success rate in the group receiving standard treatment plus clindamycin compared to the group treated with standard treatment and placebo.
Power calculation shows that we will need 31 patients in each group, power being set at 80 %, and significance level at 0.05 %. It is our goal to include 40 patients in each group, as we expect that 9 patients in each group will either drop out or be non-compliant to the treatment.
Compliance Compliance is defined by having consumed more than 80 % of the oral capsules. We expect patients in both groups to be equally compliant.
Subjects are instructed to record how many capsules, if any, they have left after the treatment to monitor their compliance, in a diary handed out together with the investigation medicine. This diary should be returned as quickly as possible to the investigator, together with any leftover capsules in a prestamped envelope. If not returned 45 days after the eradication package was handed out, a reminder will be sent to the subject, about returning the diary/left over capsules.
The number of consumed tablets will be reported in the eCFR, to monitor consumption.
The returned capsules, if any, will be returned to the Glostrup pharmacy, for correct destruction.
Relevance The relevance of this trial is high. Hundreds of healthy MRSA carriers have been treated with clindamycin in the last decade without a strong scientific evidence of a better effect than standard decolonization. It is very relevant to know, whether adding clindamycin to the treatment of throat carriers is superior to the standard treatment. The outcome of this trial will help us understand the most effective way to clear throat carriers of MRSA.
Ethics In order to continue prescribing clindamycin for healthy MRSA carriers, we wish to see a significant increase in MRSA clearance higher than 30 % in the group receiving clindamycin compared to the standard treatment group.
The acceptance and approval of this study by the Regional Research Ethical Committee (appendix 6) will be obtained before initiation, and they will receive a report of the study once finished. An application will also be sent to the Danish Medicines agency. Furthermore, the study will be conducted according to ICH-GCP (guidelines for Good Clinical Practice) and monitored and inspected by the Copenhagen GCP-units, in accordance with the ethical principles, in the Declaration of Helsinki, as well as all applicable local regulatory requirements. The study will be registered at clinicaltrials.gov prior to initiation.
The treatment offered in this trial has been used for many years at MRSA Knowledge Center and the MRSA team at Herlev Hospital, without high scientific evidence for this specific indication, and is considered safe. The outcome of this study will help us determine the future recommendation for treatment of MRSA throat carriers. The patients receiving placebo in the trial, will also receive an active treatment consisting of mupirocin nasal ointment and daily chlorhexidine wash, and will be advised to follow the usual guidelines regarding cleaning their home, towels and bedlinen. The use of placebo in the trial is justified to reduce bias, when comparing the results within the two groups.
1. VandenBergh MFQ, Yzerman EPF, Van Belkum A, Boelens HAM, Sijmons M, Verbrugh HA. Follow-up of Staphylococcus aureus nasal carriage after 8 years: Redefining the persistent carrier state. J Clin Microbiol. 1999;
2. Kluytmans J., van Belkum A et Verbrugh H., Kluytmans J, van Belkum A, Verbrugh HA, Kluytmans J., van Belkum A et Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clinical Microbiology Reviews, 10 (3), 505-520. Clin Microbiol Rev. 1997;
3. Jevons MP, Coe AW, Parker MT. METHICILLIN RESISTANCE IN STAPHYLOCOCCI. Lancet. 1963;
4. Lowry FD. Review Article- Staphylococcus aureus infections. N Engl J Med. 1998;
5. Authority DH. Guidance on Preventing the Spread of MRSA. December 13. 2016. p. ISBN online: 978-87-7104-854-4.
6. Henius AE, Pedersen K, Jensen LB. Danmap 2017. 2017;
7. Bagge K, Benfield T, Westh H, Bartels MD. Eradicating MRSA carriage: the impact of throat carriage and Panton-Valentine leukocidin genes on success rates. Eur J Clin Microbiol Infect Dis. 2019;
Not yet recruiting
Hvidovre University Hospital
Published on BioPortfolio: 2019-10-01T07:55:10-0400
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