Date of Award

2016

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Georgina Gethin

Second Supervisor

Professor Hilary Humphreys

Keywords

Honey, MRSA

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an endemic pathogen of public health concern in Ireland, as in many other health systems. For the nasal clearance of MRSA, the site that is often colonised in humans, the antibiotic mupirocin remains one of the most successful topical antibiotics to date. However, increasing bacterial resistance to mupirocin and limited effective alternate antibiotic options necessitate the need for unconventional approaches to eradicate nasal MRSA. Colonisation is a precursor for infection, and infections due to MRSA are associated with a greater risk of treatment failure, increased patient mortality and higher costs.

Natural honey has been used by many traditional systems of medicine as a healing agent. In modern medicine, it is used as a wound healing agent. A recent Cochrane review reports that honey appears to heal partial thickness burns more quickly than conventional treatment, and infected post-operative wounds more quickly than antiseptics and gauze.

Interest in an alternative agent for nasal decolonisation of MRSA led the researcher to the pilot study that employed medical grade honey (MGH). The results of the pilot study were encouraging which lead to the conduct of a clinical study ‘Natural Honey to Eradicate Nasal MRSA (NHNMRSA) a Randomised Control Trial (RCT)’. Patients were recruited from Beaumont Hospital to the single centre open label RCT, which investigated the comparative efficacy of nasal decolonisation of MRSA using MGH and mupirocin 2% nasal application.

Patient characteristics, including age, gender, comorbidity, dependency of care, presence of invasive and indwelling devices, skin integrity, colonisation with multi-resistant drug resistant organisms, MRSA status on study enrolment, past decolonisation attempts and mupirocin use, as well as infection prevention and control practices during the study period were assessed, to determine the impact if any, on the outcome of intervention on nasal MRSA. The data were then analysed to establish the correlation, if any, between the outcomes of the and between the intervention and control groups. The relationship between nasal as well as non-nasal MRSA colonisation was assessed, in addition to other factors that are previously reported as factors associated with failed decolonisation.

Five specific objectives formed the foundation of the RCT, the key findings of which are summarised. The first objective a literature review on mupirocin resistance (MR), presented a comprehensive picture on the prevalence of MR, which ranges from 1% - 81%, associated chlorhexidine resistance, which ranges from 0.6% - 91%, as well as multi drug resistance among MRSA isolates. The emergence of high-level MR amongst coagulase negative Staphylococci (CoNS) isolates indicates an expanding reservoir of plasmids encoding MR, which can be transferred to other CoNS strains as well as to S. aureus including MRSA. HLMR and resistance to other antibiotics amongst CoNS curtails the oral antibiotic options for prolonged treatment of prosthetic infections with CoNS. Resistance to mupirocin and chlorhexidine limits the options for patients who may benefit from MRSA suppression or decolonisation therapy. Alternative agents such as octenidine dihydrochloride, polyhexanide, ethanol (70%), sodium hypochlorite, lysostaphin, omiganon pentahydrochloride, natural honey, tea tree oil, silver and bacteriophages have been investigated with varying success for MRSA decolonisation. However, therapeutic trials of alternative agents that show some promise must be further evaluated in clinical trials before they can be recommended for use in clinical practice.

In the RCT, robust comparability of the study participants in the intervention and control groups was confirmed on univariate analysis. The univariate analysis also confirmed that none of the patient variables analysed was of statistical significance on the patient outcome, i.e. eradication of nasal MRSA. On an intention to treat (ITT) analysis, 18 (36%) in the intervention group and 25 (50%) in the control group were decolonised of nasal MRSA. A c2 test was performed to assess the difference in the rate of decolonisation of MRSA between the intervention and control group. There was no statistically significant difference between the two groups (c2=1.999, p=0.157). On a per-protocol (PP) analysis,in the intervention group 18 (43%) participants and in the control group 25 (57%) participants were decolonised of nasal MRSA, however, a c2- test showed no significant difference (c2=1.675, p=0.196). Based on the ITT and PP analysis, as there was no statistical significance difference in the outcome of nasal MRSA decolonisation between the intervention and control groups, the null hypothesis was not rejected. On multivariate logistic regression, concomitant non-nasal MRSA colonisation was significantly associated, (c2=7.241, p=0.008) with persistent nasal MRSA. In addition, altered skin integrity and the application of more than two courses of mupirocin 2% nasal ointment prior to RCT enrolment were also associated with persistent nasal carriage of MRSA. However the less than anticipated number of patients enrolled in the study impacted on the power to detect significant differences between the intervention and control groups.

The third objective was to determine and compare bacterial susceptibility to mupirocin and changes over time from first identification to completion of the RCT. Of the historic, baseline and final isolates, mupirocin susceptibility (MS) was 91%, 88% and 77% respectively. The prevalence of MR progressively increased from the time initially identified to the end of the study, 8% on first time identification, 12% at study enrolment, and 23% at the end of study. New acquisition of MR amongst RCT participants was 10% and of all the cases who newly acquired MR, 75% were HLMR. The acquisition of MR necessitates the monitoring of MS amongst MRSA isolates, risk assessment, the judicious use of mupirocin as well as the use of alternative agents for MRSA decolonisation.

Laboratory investigations of MRSA isolates and assays to determine antimicrobial efficacy of MGH together formed the fourth study objective. The MRSA isolates were characterised using spa typing and compared where available, at three time points; historic, baseline and on study completion. Of the baseline and persistent MRSA isolates (143), 26 different spa types were identified. The common spa types were; t032, 59 (41%), t515, 19 (13%), t127, 17 (11.8%) and t4599, 10 (7%). Based on the spa types, a sequence-type (ST) could be inferred for 110 (77%) isolates. The common STs were ST22, 91 (63.6%), followed by ST1, 17 (11.8%), and one isolate each of the ST5 and ST8 type. In summary, the spa type of the carriage isolates did not appear to influence the outcome of the nasal decolonisation. Persistent colonisation with the same spa type was evident even over relatively long time-spans. However, replacement of the colonising spa type was also identified.

The minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) of MGH (test honey) was determined using laboratory assays. The MIC determined using the agar well diffusion method demonstrated antibacterial activity of test honey at 5% and higher concentrations for the clinical and reference MRSA isolates. Using the broth micro-dilution method to differentiate bactericidal or bacteriostatic action, it was established that the MIC and MBC of the test honey were both 12.5% to the MRSA isolates tested. The findings are in concordance with reports by other investigators who have reported MIC at concentrations of 4% and higher to antibacterial honey.

The participant’s perception on MRSA carriage and their experience following the use of MGH and mupirocin 2% was evaluated which formed the basis of the fifth objective. An adapted brief illness perception questionnaire (BIPQ) that composed of nine elements was utilised to collate patient perceptions of MRSA. In summary the participants perceived MRSA colonisation as a chronic condition and that it did not have serious consequences on their daily lives. They were in general emotionally detached from the condition and few had MRSA related symptoms. Although most participants felt they had limited or no control over carriage, decolonisation was considered beneficial, indicating the importance attached to treatment/control of MRSA. The survey result shows a sub-optimal understanding of MRSA among 40% of patients that necessitates measures to target improving knowledge about MRSA. Such an intervention should enable patients to understand MRSA acquisition and transmission as well as adherence to treatment/decolonisation, potentially leading to better outcomes.

A Likert scale type rating was used in the product experience questionnaire (PEQ) to collate participants' experiences of MGH cream and mupirocin nasal application. In the investigative group, most patients (95%) concurred that Medihoney™ Derma Cream was easy to apply, not sticky (90%), did not lead to a runny nose (85%) and they did not experience an unpleasant sensation (95%). Based on the participants’ response it could be inferred that Medihoney™ Derma Cream may be applied to the human nasal passages with minimal undesirable effects. In the control group, most respondents (87%) concurred that mupirocin 2% nasal ointment was easy to apply, but it was sticky (20%), and a runny nose was experienced by 33% of respondents. Almost all (95%) respondents agreed that they did not experience any unpleasant sensation following its application. Overall the patients’ preferred choice was a natural alternative to an antibiotic, if available, for MRSA decolonisation.

The NHNMRSA RCT, I believe, is the first study that has used MGH for nasal MRSA decolonisation. The RCT results offer potential but larger and multisite studies must be conducted to confirm the results to facilitate the development of MGH as an alternate agent for nasal decolonisation of MRSA.

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Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland, 2016.

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