Staphylococcus aureus colonization and infection Optimizing MRSA decolonization and addressing challenges in S. aureus bacteremia management Annette Westgeest
Staphylococcus aureus colonization and infection Optimizing MRSA decolonization and addressing challenges in S. aureus bacteremia management Annette Claire Westgeest
Staphylococcus aureus colonization and infection: optimizing MRSA decolonization and addressing challenges in S. aureus bacteremia management © 2024, Annette Westgeest, The Netherlands Cover design: Claire Ohlenschlager Layout: Maaike Swets and Annette Westgeest Printed by: Ridderprint Financial support for the printing of this thesis: Wetenschapsfonds HagaZiekenhuis ISBN: 978-94-6506-170-2
Staphylococcus aureus colonization and infection Optimizing MRSA decolonization and addressing challenges in S. aureus bacteremia management Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Leiden, op gezag van rector magnificus prof.dr.ir. H. Bijl, volgens besluit van het college voor promoties te verdedigen op donderdag 19 september 2024 klokke 16.00 uur door Annette Claire Westgeest
Promotores: Prof. dr. M.G.J. de Boer Prof. dr. L.G. Visser Copromotores: Dr. M.M.C. Lambregts Dr. E.F. Schippers Promotiecommissie: Prof. dr. J.T. van Dissel Prof. dr. J.G. van der Bom Prof. dr. J.A.J.W. Kluytmans UMC Utrecht Dr. L.E. Visser Erasmus MC en HagaZiekenhuis
1 Part I 2 3 4 5 Part II 6 7 8 9 10 11 Introduction and outline of the thesis Optimization of MRSA decolonization Exploring the barriers in the uptake of the Dutch MRSA ‘search and destroy’ policy using the cascade of care approach Eradication of community-onset MRSA carriage: a narrative review Complicated carriage with methicillin-resistant Staphylococcus aureus: evaluation of the effectiveness of decolonization regimens advised in the Dutch national guideline Genetic determinants in MRSA carriage and their association with decolonization outcome Challenges in S. aureus bacteremia management Global differences in the management of Staphylococcus aureus bacteremia: no international standard of care Acute kidney injury in Staphylococcus aureus bacteremia Persistent MRSA bacteremia: host, pathogen and treatment The association of female sex with management and mortality in patients with Staphylococcus aureus bacteremia Female sex and mortality in patients with Staphylococcus aureus bacteremia: a systematic review and meta-analysis Summary and general discussion Nederlandse samenvatting Acknowledgements List of publications Curriculum Vitae Table of contents 9 20 22 40 62 80 108 110 142 156 190 212 248
Chapter 1 Introduction and outline of the thesis
10 Chapter 1 Introduction and outline of the thesis Staphylococcus aureus is a fascinating pathogen. The Gram-positive spherically shaped bacterium is generally considered as the most virulent member of the Staphylococcus genus [1]. It adopted its name in the 1880s from the combination of the Greek words staphyle (bunch of grapes), kokkos (berry), and the Latin word aureum (gold), representing the appearance of the colonies on blood agar plates [2, 3]. As a human commensal, it colonizes more than half of the population, either intermittently or persistently [4]. Colonized persons are often asymptomatic and can be colonized in the anterior nares, throat, groin, skin, intestine, and other body sites. In only a minority, S. aureus causes disease – often caused by the individual’s colonizing strain [5]. S. aureus is the causative agent of common and relatively benign infections such as folliculitis and impetigo. On the other end of the clinical spectrum, it is the causative agent of severe invasive infections such as endocarditis, spondylodiscitis, and bacteremia (Figure 1), and even the leading cause of mortality by bloodstream infections worldwide [6]. Figure 1. A glimpse of the spectrum of clinical manifestations of Staphylococcus aureus The variability in both colonization and invasive infection of S. aureus is the result of a complex interplay between host, pathogen, and environment. Many aspects of these interactions are largely unexplained. Susceptibility of the host is, among other factors, influenced by age, immune response and genetic make-up. Although predisposing factors in the host have been identified, it remains impossible to predict who will be colonized, who will develop disease and in whom this disease will be severe.
11 General Introduction 1 Concerning the pathogen, S. aureus is capable of colonizing healthy individuals as well as causing catastrophic disease in many different animal hosts, including humans. It produces various virulence and immune evasion factors, interfering with the immune system of the host and preventing it from effectively warding off recurrent infections [7]. S. aureus has unique features, such as the ability to cause metastatic infections throughout the human body, mainly facilitated by the expression of surface proteins that mediate adhesion, and the tendency to persist in the bloodstream despite appropriate antibiotics. Besides, the pathogen has the ability to form biofilms leading to chronic device infections [8], and to produce multiple exotoxins, some of which are accountable for toxic shock syndrome and food poisoning [9]. Environmental factors are of influence on the variability of S. aureus as well, such as the prevalence in the community and the timely initiation of effective treatment. A major additional complicating factor is the capacity of S. aureus to develop antimicrobial resistance. Antimicrobial resistance and Staphylococcus aureus Antimicrobial resistance has significantly increased over the past decades, and is now in the top ten public health threats facing humanity, as declared by the World Health Organization (WHO) [10]. As a natural evolutionary response to antimicrobial exposure, bacteria develop resistance to antibiotics through multiple different mechanisms [11]. For S. aureus, the most relevant resistance mechanism is by acquiring a mecA gene through horizontal transfer of a mobile genetic element designated staphylococcal cassette chromosome mec (SCCmec), leading to methicillin resistance. The mecA gene encodes for a specific penicillin binding protein (PBP2a), which crosslinks bacterial peptidoglycans and has low affinity for beta-lactam antibiotics, causing resistance to almost all antibiotics within this class [12]. Methicillin-resistant S. aureus (MRSA) was first described in the early 1960s, shortly after the introduction of the antibiotic methicillin [13]. However, modern molecular phylogenetics suggest that MRSA emerged already by natural selection in the pre-antibiotic era and was further selected for by the widespread use of penicillin since the 1940s. Methicillin only provided better selective pressure for the bacterium to spread [14, 15]. Responsible for over 100,000 deaths in 2019, MRSA is currently the leading cause of mortality attributable to antimicrobial resistance in the world [16]. As a major actor in the field of antimicrobial resistance, MRSA also serves as an indicator for antimicrobial resistance in the global sustainable development goals of the United Nations [17].
12 Chapter 1 Despite the high prevalence and global burden of S. aureus, many questions remain unanswered with respect to the management and risk factors of both colonization and invasive infection. Research is continuously ongoing in order to unravel the complexities of this extraordinary pathogen and the diseases it causes in humans. This thesis aims to address the optimization of MRSA decolonization and some of the frequently encountered challenges in S. aureus bacteremia management (Figure 2). Figure 2. Graphical summary of thesis
13 General Introduction 1 Outline of the thesis Optimization of MRSA decolonization Colonization with S. aureus is a risk factor for developing subsequent infections. For bloodstream infections, this results from an endogenous infection source, reflected by identical isolates cultured from the blood and nares of patients with S. aureus bacteremia. Colonization with MRSA increases infection risk even more than colonization with methicillin-susceptible S. aureus (MSSA), in both patients and healthy individuals [18-21]. Decolonization therapy has been proven to reduce S. aureus infections, although the evidence for infection reduction outside of hospital settings is limited [22-24]. In the Netherlands, the MRSA prevalence is one of the lowest in the world [25]. This low prevalence is, next to the restricted use of antibiotics, to a large part ascribed to our ‘search and destroy’ policy [26, 27]. The policy consists of screening and preemptive isolation of patients at risk for MRSA carriership when hospitalized, and subsequent decolonization treatment when persistent carriership is found [28]. The aim of this policy is to minimize MRSA colonization in order to prevent transmission and infection. The effectiveness of the ‘search and destroy’ policy depends on several consecutive steps. First of all, MRSA carriers need to be identified. The second step includes the initiation of eradication treatment. We evaluated barriers in these first steps of MRSA eradication care in chapter 2. The third and final step involves the effectiveness of decolonization treatments, and is addressed in the next two chapters. Despite being notorious for nosocomial transmission and hospital outbreaks, MRSA with onset in the community has emerged over the past decades and has become endemic in large parts of the world [29, 30]. In chapter 3, we reviewed the evidence on individual decolonization strategies for MRSA, with particular emphasis on community-onset MRSA. The Dutch guideline for MRSA eradication distinguishes between uncomplicated and complicated carriership [31]. Complicated carriership is defined as extra-nasal MRSA colonization, colonization with active skin lesions, foreign body material with connection to exterior, or previous failure of eradication treatment. Active skin lesions are recommended to be treated and foreign body material with connection to exterior to be removed before initiation of eradication treatment. Extra-nasal MRSA carriership is recommended to be treated with the combination of topical therapy and two systemic antimicrobial agents. However, which combination of systemic anti-staphylococcal antibiotics is most effective in MRSA eradication has not been clarified yet [32]. In chapter 4, the effectiveness of different MRSA decolonization
14 Chapter 1 treatments for complicated MRSA carriage is analyzed. Another potential influencing factor on effective decolonization is the genetic composition of the MRSA strain, as well as the host [33]. The complex genetic host-pathogen interaction in MRSA decolonization is relatively undiscovered, but is starting to gain interest as a result of the rapid developments in the field of molecular biology, especially whole genome sequencing. Chapter 5 describes an explorative study on genomic characteristics of MRSA isolates that are associated with decolonization failure. Challenges in Staphylococcus aureus bacteremia management S. aureus bacteremia (caused by both MSSA and MRSA) is a highly variable disease affecting a heterogenous patient population. Consequently, the disease course varies greatly, ranging from transient uncomplicated bacteremia to disseminated infection, metastatic infections or persistent bacteremia despite appropriate antimicrobial therapy. All combined, the incidence of S. aureus bacteremia is estimated at 30 per 100,000 person years, and the overall 90-day mortality amounting to 20-30% [34, 35]. In the past decades the disease has been extensively studied, learning us that infectious disease consultation, follow-up blood cultures, and routine echocardiography all improve patients’ outcomes [36, 37]. However, many challenges in the optimal management of S. aureus bacteremia remain. Different strategies are practiced throughout the world regarding optimal antibiotic regimen, oral switch therapy, treatment duration and defining persistence. Chapter 6 describes the results of a survey of over 2,000 clinicians from 71 countries and 6 continents, about their treatment practices. It focuses on identifying global variation in management, diagnostics, and definitions of S. aureus bacteremia. In clinical practice, a frequent complication in patients with S. aureus bacteremia is acute kidney injury. The complexity of this phenomenon lies in the combination of the diverse etiology – including prerenal, toxic/drug-related, immune-mediated, tubulointerstitial nephritis, and postrenal pathophysiology – and the lack of diagnostic tests to differentiate between them. Moreover, acute kidney injury has a significant impact on patient management and outcome [38]. Still, knowledge on acute kidney injury in S. aureus bacteremia is limited. In chapter 7, we evaluated the incidence, reversibility and risk factors for the development of acute kidney injury in patients with S. aureus bacteremia. As mentioned before, S. aureus has the ability to persist in the bloodstream despite adequate antimicrobial treatment. Persistent bacteremia has been associated with increased mortality compared to those whose bacteremia promptly resolves [39, 40].
15 General Introduction 1 Although very rare in countries with low MRSA prevalence such as the Netherlands, persistent MRSA bacteremia is relatively common in the United States [41]. A variety of host and pathogen factors are potentially associated with persistence, and few alternative therapeutical options for persistent bacteremia have gradually evolved over time. We reviewed the literature on persistent MRSA bacteremia in chapter 8. S. aureus bacteremia affects both males and females around the globe. Females have a lower a priori risk of acquiring S. aureus bacteremia compared to males, and represent approximately 40% of the S. aureus bacteremia population [42]. Although less frequently affected, some previous studies reported an increased mortality risk of up to 30% in females with S. aureus bacteremia as compared to males [43, 44]. However, other studies did not find a sex inequality in mortality, or even a higher mortality in males in a subgroup of patients with more comorbidities [45, 46]. Thus, the impact of female sex on outcome among patients with S. aureus bacteremia remained unclear. Chapter 9 describes our study on sex-differences in mortality, patient characteristics, disease aspects and management, in a large cohort of over 3,000 S. aureus bacteremia patients. In chapter 10, a systematic review and metaanalysis was conducted to determine the true association of female sex and mortality in S. aureus bacteremia. The results of this thesis are summarized and discussed in chapter 11.
16 Chapter 1 References 1. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone Elsevier; 2010. 2. Ogston, A., Micrococcus Poisoning. J Anat Physiol, 1882. 17(Pt 1): p. 24-58. 3. Rosenbach, AJ. Mikro-Organismen bei den Wund-Infections-Krankheiten des Menschen. Wiesbaden, J.F. Bergmann, 1884 4. Wertheim, H.F., et al., The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis, 2005. 5(12): p. 751-62. 5. von Eiff, C., et al., Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med, 2001. 344(1): p. 11-6. 6. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet, 2022. 400(10369): p. 2221-2248. 7. Howden, B.P., et al., Staphylococcus aureus host interactions and adaptation. Nat Rev Microbiol, 2023. 21(6): p. 380-395. 8. Arciola, C.R., D. Campoccia, and L. Montanaro, Implant infections: adhesion, biofilm formation and immune evasion. Nat Rev Microbiol, 2018. 16(7): p. 397-409. 9. Oliveira, D., A. Borges, and M. Simões, Staphylococcus aureus Toxins and Their Molecular Activity in Infectious Diseases. Toxins (Basel), 2018. 10(6). 10. WHO factsheet antimicrobial resistance 11. Holmes, A.H., et al., Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 2016. 387(10014): p. 176-87. 12. Peacock, S.J. and G.K. Paterson, Mechanisms of Methicillin Resistance in Staphylococcus aureus. Annu Rev Biochem, 2015. 84: p. 577-601. 13. Jevons, M.P., “Celbenin”-resistant Staphylococci. Br Med J. 1961;1:124–5 14. Harkins, C.P., et al., Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol, 2017. 18(1): p. 130. 15. Larsen, J., et al., Emergence of methicillin resistance predates the clinical use of antibiotics. Nature, 2022. 602(7895): p. 135-141. 16. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet, 2022. 399(10325): p. 629-655. 17. United Nations. The Sustainable Development Goals Extended Report 2022. 3: Good health and well-being. Available from https://unstats.un.org/sdgs/report/2022/extendedreport/Extended-Report_Goal-3.pdf. 18. Ellis, M.W., et al., Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis, 2004. 39(7): p. 971-9. 19. Quezada Joaquin, N.M., et al., Long-term risk for readmission, methicillin-resistant Staphylococcus aureus (MRSA) infection, and death among MRSA-colonized veterans. Antimicrob Agents Chemother, 2013. 57(3): p. 1169-72. 20. Safdar, N. and E.A. Bradley, The risk of infection after nasal colonization with Staphylococcus aureus. Am J Med, 2008. 121(4): p. 310-5. 21. Davis, K.A., et al., Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its effect on subsequent MRSA infection. Clin Infect Dis, 2004. 39(6): p. 776-82.
17 General Introduction 1 22. Perl, T.M., et al., Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med, 2002. 346(24): p. 1871-7. 23. van Rijen, M., et al., Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database Syst Rev, 2008. 2008(4): p. Cd006216. 24. Bode, L.G., et al., Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med, 2010. 362(1): p. 9-17. 25. WHO Regional Office for Europe/European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2022 – 2020 data. Copenhagen: WHO Regional Office for Europe; 2022. 26. Vos, M.C., et al., 5 years of experience implementing a methicillin-resistant Staphylococcus aureus search and destroy policy at the largest university medical center in the Netherlands. Infect Control Hosp Epidemiol, 2009. 30(10): p. 977-84. 27. Wertheim, H.F., et al., Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission in the Netherlands: the value of search and destroy and restrictive antibiotic use. J Hosp Infect, 2004. 56(4): p. 321-5. 28. Dutch Working Party on Infection Prevention (WIP) (2017) MRSA hospitals. 29. Stefani, S., et al., Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int J Antimicrob Agents, 2012. 39(4): p. 273-82. 30. Baud, O., et al., First outbreak of community-acquired MRSA USA300 in France: failure to suppress prolonged MRSA carriage despite decontamination procedures. Eur J Clin Microbiol Infect Dis, 2014. 33(10): p. 1757-62. 31. Dutch Working Party on Antibiotic Policy (Stichting Werkgroep Antibiotica Beleid [SWAB]). 2012. Guideline for the treatment of MRSA carriage. Secretariaat SWAB, Nijmegen, the Netherlands. 32. Ammerlaan, H.S., et al., Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis, 2009. 48(7): p. 922-30. 33. Parsons, J.B., et al., Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment. Antibiotics (Basel), 2023. 12(3). 34. Jernigan, J.A., et al., Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012-2017. N Engl J Med, 2020. 382(14): p. 1309-1319. 35. Bai, A.D., et al., Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis. Clin Microbiol Infect, 2022. 28(8): p. 1076-1084. 36. Yousaf, A., G.L. Baird, and L. Mermel, Association of Infectious Disease Consultation With Clinical Outcomes in Patients With Staphylococcus aureus Bacteremia at Low Risk for Endocarditis. Open Forum Infect Dis, 2018. 5(7): p. ofy142. 37. Holland, T.L., C. Arnold, and V.G. Fowler, Jr., Clinical management of Staphylococcus aureus bacteremia: a review. Jama, 2014. 312(13): p. 1330-41. 38. Holmes, N.E., et al., Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia. BMC Infect Dis, 2018. 18(1): p. 107. 39. Minejima, E., et al., Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes. Clin Infect Dis, 2020. 70(4): p. 566-573. 40. Kuehl, R., et al., Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis, 2020. 20(12): p. 1409-1417.
18 Chapter 1 41. Holland, T.L., A.S. Bayer, and V.G. Fowler, Persistent Methicilin-Resistant Staphylococcus aureus Bacteremia: Resetting the Clock for Optimal Management. Clin Infect Dis, 2022. 75(9): p. 1668-1674. 42. Tong, S.Y., et al., Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev, 2015. 28(3): p. 603-61. 43. Smit, J., et al., Gender differences in the outcome of community-acquired Staphylococcus aureus bacteraemia: a historical population-based cohort study. Clin Microbiol Infect, 2017. 23(1): p. 27-32. 44. Mansur, N., et al., Does sex affect 30-day mortality in Staphylococcus aureus bacteremia? Gend Med, 2012. 9(6): p. 463-70. 45. Forsblom, E., et al., Comparison of patient characteristics, clinical management, infectious specialist consultation, and outcome in men and women with methicillin-sensitive Staphylococcus aureus bacteremia: a propensity-score adjusted retrospective study. Infection, 2018. 46(6): p. 837-845. 46. Kang, C.K., et al., Gender affects prognosis of methicillin-resistant Staphylococcus aureus bacteremia differently depending on the severity of underlying disease. Eur J Clin Microbiol Infect Dis, 2018. 37(6): p. 1119-1123.
19 General Introduction 1
Part I Optimization of MRSA decolonization
Antibiotics. 2022 Sep 8;11(9):1216. Annette C. Westgeest, Emile F. Schippers, Martijn Sijbom, Leo G. Visser, Mark G. J. de Boer, Mattijs E. Numans, Merel M. C. Lambregts, on behalf of the MRSA Network Holland West Exploring the barriers in the uptake of the Dutch MRSA ‘search and destroy’ policy using the cascade of care approach Chapter 2
24 Chapter 2 Abstract The Dutch ‘search and destroy’ policy consists of screening patients with an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) carriership and subsequent decolonization treatment when carriership is found. Decolonization therapy of individual MRSA carriers is effective. However, the effectiveness of the national ‘search and destroy’ policy is dependent on the entire cascade of care, including identification, referral, and subsequent treatment initiation in MRSA carriers. The aim of this study was to evaluate the leakages in the cascade of MRSA decolonization care. We assessed familiarity with the ‘search and destroy’ policy and the barriers in the uptake of MRSA eradication care using a questionnaire among 114 Dutch general practitioners. The main reasons for treatment were planned hospital visits, occupational reasons, and infections. The main reasons for refraining from eradication treatment were unfamiliarity with the ‘search and destroy’ policy and the assumption that MRSA carriership is often self-limiting. To optimize the continuity of the cascade of care, interventions should be aimed at supporting general practitioners and facilitating treatment and referral. Introduction Antimicrobial resistance is a global health threat that causes millions of deaths [1]. The WHO has declared that antimicrobial resistance is one of the top ten global public health threats facing humanity [2]. Methicillin-resistant Staphylococcus aureus (MRSA) is a major actor in the field of antimicrobial resistance. In 2019, 100.000 deaths and 3.5 million disability-adjusted life-years (DALYs) were attributable to infections with MRSA [3]. Colonization with MRSA leads to increased infection rates of up to 25% [4–6]. Colonization and infection rates are known to vary throughout the world. Historically, in the Netherlands, MRSA infection rates are low. Less than 5% of invasive Staphylococcus aureus isolates are resistant to methicillin. Together with the Nordic European countries, the Dutch prevalence of MRSA is the lowest in the world [7]. The estimated nasal colonization rate in the Dutch population is 0.03–0.17%, compared to 0.9–1.5% in the US [8]. The healthcare system in the Netherlands has executed a national ‘search and destroy’ policy since 1988, which is outlined in the guidelines of the Dutch Working Party on Infection Prevention (WIP) [9]. The policy consists of the screening and preemptive isolation of patients with an increased risk of MRSA carriership when hospitalized
25 Barriers in the uptake of MRSA ‘search and destroy’ 2 and subsequent decolonization treatment when persistent carriership is found [10– 12]. Examples of an increased risk are preceding events such as hospitalization in a country where MRSA is endemic, or a confirmed MRSA-carrying household contact. The aim of the policy, which is endorsed by the Dutch health council, is to keep the MRSA prevalence and the associated disease burden low [13]. Cost-effectiveness was confirmed in the years thereafter, with an estimated saving of up to EUR 400 per hospital per year [10,14]. As part of this ‘search and destroy’ policy, decolonization treatment in MRSA carriers has proven to be an effective preventive strategy in reducing infection and hospitalization rates [15]. The success rate of decolonization treatment, defined as three consecutive negative MRSA swabs from nose, throat, and perineum, is as high as 86% [16]. However, the effectiveness of the policy is also dependent on the initial identification of carriership and the initiation of treatment. Therefore, the effectiveness of the national policy relies on the correct execution of several consecutive steps in a so-called cascade of care and involves several healthcare professionals. In HIV care, a similar approach was taken and led to the clarification of the culprits in the uptake of combination anti-retroviral therapy (cART) [17]. Following this example, this approach was applied to tuberculosis and hepatitis C [18,19]. We hypothesize that the same approach is applicable to MRSA decolonization care as well (Figure 1). Within the MRSA decolonization cascade of care, individuals may be lost, which is referred to as leakage, and is analogous to the cART roll-out strategies. Understanding at which steps this leakage occurs will provide information to optimize MRSA eradication strategies [20]. The aim of our current study was to evaluate the leakages within the cascade of MRSA decolonization care and the main reasons for them. We carried out a questionnaire study amongst general practitioners (GPs) to gain insight into their familiarity with the ‘search and destroy’ policy and to evaluate barriers in the uptake of MRSA eradication care. The knowledge generated will help to determine specific targets that can be addressed to keep MRSA prevalence low and to contribute to a reduced burden of antimicrobial resistance.
26 Chapter 2 Figure 1. Conceptual graphic of the cascade of care in MRSA decolonization. Legend: The first column addresses the total number of MRSA carriers in the Netherlands. The second column represents the proportion of carriers that is diagnosed. The third column addresses the MRSA carriers that are diagnosed and undergo eradication treatment. The last column represents the success rate of complicated MRSA eradication treatment. In every step of this conceptual cascade of care, there is the potential for leakage. As this figure represents a conceptual model, the columns are not quantified. Methods The questionnaire study was executed in primary care as GPs hold a central position in the Dutch healthcare system. All Dutch citizens are registered with a general practitioner (GP), who is the first point of contact in case of illness and acts as a gatekeeper to secondary care. With regard to MRSA carriership, the GPs are often the first healthcare professionals to be in contact with patients at risk or to detect MRSA carriership. Questionnaire development and distribution The regional MRSA Network developed a questionnaire that was reviewed by a panel consisting of a general practice specialist and an infectious disease specialist (Supplementary File S1). The questionnaire included 14 questions on the ‘search and destroy’ policy, the screening of risk patients, the difference between complicated
27 Barriers in the uptake of MRSA ‘search and destroy’ 2 and uncomplicated carriership, and eradication therapy. Two case vignettes were included to assess daily practice (Box 1). The target population consisted of GPs in the Netherlands. The questionnaire was hosted on Formdesk, a web-based survey platform, and was distributed via different networks of GPs and newsletters from participating hospitals. The majority of the recipients were situated in the western part of the Netherlands. There was the possibility of responding anonymously. The questionnaire was accessible between 7 March 2022 and 13 June 2022. Descriptive statistics were used to summarize the data derived from the Formdesk software. Box 1. Case vignettes. Legend: Two clinical case vignettes were included in the questionnaire. Case A describes a patient with uncomplicated carriership. Case B describes a patient with complicated carriership. The guideline recommends treatment with topical therapy in case A and treatment with additional (systemic) antibiotics in case B. Definitions The Dutch national guideline on the treatment of MRSA carriers recommends different eradication treatments depending on the type of carriership. Uncomplicated MRSA carriership is defined as having all of the following features: (i) the presence of MRSA exclusively located in the nose, (ii) no active infection with MRSA, (iii) in vitro sensitivity for mupirocin, (iv) the absence of active skin lesions, (v) the absence of foreign material that connects an internal body site with the outside (e.g., urine catheter or external fixation material), and (vi) no previous failure of decolonization treatment. All other cases are considered to be complicated colonization [21]. Uncomplicated carriership is treated with topical therapy (mupirocin topically applied to the nares and disinfecting shampoo) and hygienic measures. In the case of complicated MRSA carriage, additional systemic antimicrobial therapy with a combination of two antibiotic agents is recommended. Furthermore, the guideline recommends the screening of household contacts (and sometimes pets) and the simultaneous treatment of colonized household contacts [21]. Case A: A 26 years-old healthy male was admitted in the hospital during a holiday in Spain because of a trauma. After returning in the Netherlands, you perform culture swabs from, throat and perineum. The nasal culture is positive for MRSA. There are no skin lesions. There are no hospital visits planned. Case B: A 56 years-old male with a history of heart failure and chronic kidney disease, was screened for MRSA carriership by you following a hospital admission. He is MRSA positive in nose, throat and perineum.
28 Chapter 2 Results The questionnaire was completed by 114 Dutch GPs. The majority of the GPs (98/114, 86%) performed screening for MRSA carriership. Recent admission to a hospital abroad was more often considered to be the reason for screening in older patients with comorbidity (89/114, 78%) compared to younger patients without comorbidity (77/114, 68%). A previous infection with MRSA was considered to be a reason for screening by 55/114 (48%) of the GPs and a positive household contact by 39/114 (34%) of the GPs. The majority of the respondents, 98/114 (86%), reported having 1-3 new MRSA cases per year. Fifteen GPs (15/114, 13%) stated that they had never had a single patient in his/her practice. The median prevalence of MRSA carriers per practice was 2 (interquartile range 0–4). With regard to the familiarity with the explicit ‘search and destroy’ policy in the Netherlands, 98/114 (86%) of the GPs indicated that they were not familiar with this policy. Initiation of eradication therapy and/or referral for treatment Almost half of the GPs (52/114, 46%) estimated that <20% of the MRSA carriers in their practice received eradication therapy. With respect to the indication for eradication treatment, most of the GPs (58/114, 51%) stated that only specific MRSA carriers should be eligible for eradication treatment, namely if there is a specific reason (e.g., frequent hospital visits) (58/58, 100%), if the patient is a healthcare worker with clinical duties (52/58, 90%), if the patient has an infection with MSRA (42/58, 72%), or if the patient insists on treatment (10/58, 17%). The most important reasons to refrain from eradication therapy were: the potentially self-limiting nature of MRSA carriership (59%), unfamiliarity with the Dutch ‘search and destroy’ policy (25%), the burden of treatment for the patient (23%), the lack of any recommendation being known GP protocols (18%) and the patients’ explicit request not to be treated (18%) (Table 1).
29 Barriers in the uptake of MRSA ‘search and destroy’ 2 Table 1. The attitude of GPs towards indication for treatment of MRSA carriership. Frequency n/n (%) Indication for eradication treatment In all MRSA carriers 18/114 (16) In selected cases 58/114 (51) Planned/expected hospital visits 58/58 (100) Infections with MRSA 42/58 (72) Occupational reason (e.g., healthcare worker) 52/58 (90) Patients’ request 10/58 (17) In none of the MRSA carriers 1/114 (1) Unknown 37/114 (32) Reasons to refrain from treatment * Potential self-limiting nature of MRSA carriership 57/96 ** (59) Unfamiliarity with the policy 24/96 (25) Treatment burden for patients 22/96 (23) Lack of recommendation in the GP guideline 17/96 (18) Patients’ request 17/96 (18) Absence of benefit for the patient 11/96 (11) Sense of incompetence to guide a treatment 10/96 (10) Absence of benefit for the society 5/96 (5) Costs for the patient 4/96 (4) Other *** 19/96 (20) Legend: Indications for MRSA eradication according to Dutch general practitioners and reasons not to initiate treatment or refer for treatment. * Multiple answers possible. ** Eighteen GPs who answered in the previous question that all MRSA carriers have an indication for eradication treatment were not asked for reasons to refrain from treatment. *** Other reasons mentioned in free text: not a task for the GP, assumption of no curation, never considered, patient in palliative setting. GP = general practitioner. Forty-four respondents (44/114, 39%) had treated patients with (complicated or uncomplicated) MRSA carriership themselves—in all cases or in selected cases. When treating a patient for MRSA carriership, 10/44 (23%) of the responding GPs included the screening and treatment of household contacts in the initial treatment attempt, 5/44 (11%) included the household contacts only after a failed treatment attempt, and 12/44 (27%) never included household contacts. Other GPs (17/44, 39%) stated that they asked an expert for advice. The most important reasons to refrain from referring an MRSA carrier to the hospital were unfamiliarity with the existence of MRSA outpatient clinics (55/114, 48%), feeling competent in the self-performance of treatment (19/114, 17%), and the absence of this recommendation in the guideline (17/114, 15%) (Table 2).
30 Chapter 2 Table 2. Treatment of MRSA carriers. Frequency n/n (%) Estimated proportion of carriers in a GP practice that receive treatment * <20% 52/114 (46) 20–40% 8/114 (7) 40–60% 11/114 (10) 60–80% 12/114 (11) 80–100% 25/114 (22) Unknown 6/114 (5) Treatment by GP or referral to hospital Treatment by GP in all cases 12/114 (11) Referral to a hospital in all cases 40/114 (35) Treatment by GP in selected cases 32/114 (28) Uncomplicated carriership 23/32 (72) Patient preference for GP treatment 9/32 (28) Other 8/32 (25) None of the above 27/114 (24) Reasons not to refer to a hospital ** Unfamiliar with the existence of MRSA outpatient clinics 55/114 (48) Competent in self-performance 19/114 (17) Lack of recommendation in GP protocol 17/114 (15) Patients’ request not to be referred 13/114 (11) Costs for the patient *** 13/114 (11) Administrative burden of a referral 3/114 (3) Other **** 33/114 (29) Unknown 10/114 (9) Legend: * Estimation of the proportion of known MRSA carriers in the practice that are receiving eradication therapy or have received eradication treatment in the past. ** Multiple answers possible. *** In the Netherlands, the health insurance charges the patient an obligatory deductible excess for hospital care. **** Other reasons mentioned in free text were: consultation of specialist is sufficient, never considered, palliative settings, refusal of hospital, or not specified. GP = general practitioner. Two cases were presented in the questionnaire: case A was the description of a young patient with an uncomplicated carriership, and case B was a case of a complicated carriership (Box 1). Of the respondents, 40/114 (35%) were aware of the difference between ‘complicated’ versus ‘uncomplicated’ MRSA colonization. Respectively, 37 (33%) and 3 (3%) of the GPs would refrain from treatment in case A and B, 15 (13%) and 56 (49%) would refer the patient to a hospital for treatment, and 29 (25%) and 31 (27%) would first consult a specialist. Of the GPs that would initiate treatment in these cases themselves (17 in case A and 14 in case B), the treatment prescription was in accordance with the treatment guideline for 12/17 (71%) in case A (uncomplicated carriership) and for 8/14 (57%) in case B (complicated carriership). In both cases, four
31 Barriers in the uptake of MRSA ‘search and destroy’ 2 GPs (24%, 29%) indicated to add or refrain from systemic antibiotics where this was not in accordance with the guideline (Supplementary File S2). Discussion The main finding of this study is that there is significant leakage in the cascade of MRSA decolonization care. Firstly, the vast majority of the responding GPs are not familiar with the explicit ‘search and destroy’ policy. Secondly, when evaluating a patient with MRSA carriage, many assumptions are made to refrain from eradication treatment. Thirdly, eradication treatment is not always in accordance with the guideline. The conceptual steps of the cascade of MRSA colonization care are visualized in Figure 1. For optimal effect of the strategy, adherence to each consecutive step is crucial. Based on our findings, the uptake of decolonization care in the Netherlands, as part of the ‘search and destroy’ policy, is not flawless. All subsequent process steps in the cascade have the potential for improvement. We summarized the main leakages of the cascade and the possible solutions in Table 3. The most apparent opportunity for the improvement of its implementation is through expanding familiarity with the ‘search and destroy’ policy. All three steps in the cascade could benefit from the training/education of both the patients and the professionals. In addition, incorporating the policy in the GP practice guidelines should be considered in order to support the entire process from screening to successful eradication. The current national MRSA decolonization guideline is primarily targeted at medical specialists, and the recommendations for screening and treatment have not yet been translated to the Dutch GP guidelines [22]. At the patient level, financial barriers exist that could be targeted by waving the excess fee for MRSA decolonization care. Despite the described leakages in the identification and treatment of MRSA carriership, the MRSA prevalence is low in our country compared to surrounding countries. The estimated nasal colonization rate in the Netherlands was 0.03–0.17% in 2010–2017 [23]. It is generally accepted that this is largely attributed to the ‘search and destroy’ policy [11,24-27]. The policy seems to be effective, despite the leakages we found in the decolonization cascade. The effectivity of the policy as a whole is only partly determined by the uptake of screening and decolonization therapy. Another important arm of the ‘search and destroy’ policy—the preemptive isolation of patients at risk—was not assessed in the current study. There has been debate about the rigorous ‘search and destroy’ policy in the past. Up to the present day, it is the subject of discussion whether healthy carriers that do not have any connections with hospital healthcare should be treated [21]. This is reflected in our results, where the GPs were less inclined to treat a young healthy MRSA carrier compared to an older patient with comorbidity. Although this is a leak in the cascade of care, not
32 Chapter 2 treating this subset of MRSA carriers is justifiable as stated in the Dutch guideline. Overall, the last report of the Dutch health council to the Ministry of Health in 2006, advising the continuation of the ‘search and destroy’ policy, is still valid [13]. Efficacy and cost-effectiveness have been demonstrated in the past [10,14]. The semi recent history of the United Kingdom is an extra confirmation of the effectiveness of this approach. In the UK, a similar strict MRSA policy was carried out in the 1980s. After the policy was tempered in the 1990s, the percentage of methicillin resistance in Staphylococcus aureus bacteremia increased steeply from <2% to >30% [28,29]. This percentage is now lower due to rigorous measures on hygiene and the mandatory reporting of MRSA, as part of a major public health infection prevention campaign [30]. To our knowledge, this study is the first to map the MRSA cascade of care. Although the methodology does not enable the quantification of the leakage within the different cascade steps, it does provide specific targets for the optimization of the cascade. The central position of GPs in the healthcare system is a characteristic of the Netherlands. However, the targets for optimization and proposed interventions could be translated to settings where GPs do not hold a central position, with a greater focus on hospitals. A limitation of the study is the fact that all results were self-reported. Answers are subject to bias, and potential targets may have been missed. Furthermore, the majority of the respondents were from one region in the Netherlands, which is mainly an urbanized area. In regions with more agriculture and more livestock-associated MRSA, knowledge about MRSA and attitudes towards MRSA carriership may differ [31]. Another limitation is the fact that the response rate was unknown as a result of the various ways (e.g., newsletters) that the questionnaire was distributed. Assuming that the GPs with an affinity with MRSA were more inclined to respond, bias would be in favor of an overall knowledge of the policy. We believe that the identified barriers are valid, even if the response rate were to be relatively low. Conclusions In conclusion, the results of this survey and the derived cascade of care reveal that there are barriers in the uptake of the ‘search and destroy’ MRSA policy in the Netherlands. Low health-provider familiarity with the policy, lack of GP guidelines on the topic, and financial constraints are key factors. To optimize the continuity of the cascade of care, interventions should be aimed at supporting healthcare professionals in the execution of the ‘search and destroy’ policy. Eventually, this will be beneficial both on the population level and for the individual patient.
33 Barriers in the uptake of MRSA ‘search and destroy’ 2 Table 3. Leakages in cascade of MRSA decolonization care and possible solutions. Legend: Causes of leakages in the cascade of MRSA decolonization care derived from the questionnaire and possible solutions devised by the MRSA Network. GP = general practitioner.
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