Invasive Methicillin-resistant S. Aureus Infection Research Articles

S. aureus Surveillance and Decolonization Associated with Decreased MRSA, but not MSSA, Infections in the Neonatal ICU

Background: Invasive Staphylococcus aureus infections cause significant morbidity and mortality in neonatal intensive care unit (NICU) infants.1 Colonization (asymptomatic carriage in the nose, skin, or gut) is a risk factor for subsequent invasive infection (e.g., pneumonia, bone infections, bloodstream infections, etc.). Active surveillance and decolonization measures for S. aureus-colonized infants have been associated with decreased invasive infection rates. 2-4 Methods: A methicillin-resistant S. aureus (MRSA) surveillance and decolonization program, consisting of admission and weekly MRSA nasal cultures followed by intranasal mupirocin plus chlorhexidine baths for colonized infants, was implemented in our level IV NICU with 150 beds in 2006.5 Due to poor compliance with decolonization protocols5, existing practices were reviewed and multiple interventions to increase compliance were implemented in 2018. These renewed efforts included revision of the existing MRSA decolonization protocol, updating the associated electronic medical record order set, re-education of unit staff, and weekly review by the Infection Prevention (IP) and NICU leadership teams to ensure the decolonization protocol was followed for newly colonized infants. Mean MRSA bloodstream infection (BSI) rates were calculated quarterly pre- (January 2014-December 2017) and post- (January 2018-December 2023) implementation of renewed efforts and compared via unpaired t-test. In July 2020 a similar methicillin-susceptible S. aureus (MSSA) surveillance and decolonization program was implemented with an associated revision of existing documents, education campaign, and weekly review of infants with new MSSA colonization. Mean MSSA BSI rates pre- (July 2018-June 2020) and post- (July 2020-December 2023) implementation were compared via unpaired t-test. Results: Renewed implementation of MRSA surveillance and decolonization was associated with a sustained decrease in the mean MRSA BSI rate (Figure 1): 0.10 per 1000 patient-days pre-implementation, 0.03 post-implementation (p=0.02). Following implementation of MSSA surveillance and decolonization, there was no statistically significant change in the mean MSSA BSI rate (Figure 2): 0.20 per 1000 patient-days pre-implementation, 0.15 post-implementation (p=0.32). Conclusions: Implementation of a robust MRSA surveillance and decolonization program in the NICU was associated with a sustained decrease in invasive MRSA infections. No change in invasive MSSA infection rates was observed following implementation of a similar protocol for MSSA. Additional research is needed to better understand the role of MSSA surveillance and decolonization in the NICU.

Dysfunctional accessory gene regulator (agr) as a prognostic factor in invasive Staphylococcus aureus infection: a systematic review and meta-analysis

The accessory gene regulator (agr) locus of Staphylococcus aureus is a quorum-sensing virulence regulator. Although there are many studies concerning the effect of dysfunctional agr on the outcomes of S. aureus infection, there is no systematic review to date. We systematically searched for clinical studies reporting outcomes of invasive S. aureus infections and the proportion of dysfunctional agr among their causative strains, and we performed a meta-analysis to obtain estimates of the odds of outcomes of invasive S. aureus infection with dysfunctional versus functional agr. Of 289 articles identified by our research strategy, 20 studies were meta-analysed for crude analysis of the impact of dysfunctional agr on outcomes of invasive S. aureus infection. Dysfunctional agr was generally associated with unfavourable outcomes (OR 1.32, 95% CI 1.05–1.66), and the impact of dysfunctional agr on outcome was more prominent in invasive methicillin-resistant S. aureus (MRSA) infections (OR 1.54, CI 1.20–1.97). Nine studies were meta-analysed for the impact of dysfunctional agr on the 30-day mortality of invasive S. aureus infection. Invasive MRSA infection with dysfunctional agr exhibited higher 30-day mortality (OR 1.40, CI 1.03–1.90) than that with functional agr. On the other hand, invasive MSSA infection with dysfunctional agr exhibited lower 30-day mortality (OR 0.51, CI 0.27–0.95). In the post hoc subgroup analysis by the site of MRSA infection, dysfunctional agr was associated with higher 30-day mortality in MRSA pneumonia (OR 2.48, CI 1.17–5.25). The effect of dysfunctional agr on the outcome of invasive S. aureus infection may vary depending on various conditions, such as oxacillin susceptibility and the site of infection. Dysfunctional agr was generally associated with unfavourable clinical outcomes and its effect was prominent in MRSA and pneumonia. Dysfunctional agr may be applicable for outcome prediction in cases of invasive MRSA infection with hardly eradicable foci such as pneumonia.

Liposomal mupirocin holds promise for systemic treatment of invasive Staphylococcus aureus infections

Staphylococcus aureus is a major cause of severe invasive infections. The increasing incidence of infections caused by antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA), calls for exploration of new approaches to treat these infections. Mupirocin is an antibiotic with a unique mode of action that is active against MRSA, but its clinical use is restricted to topical administration because of its limited plasma stability and rapid degradation to inactive metabolites. Mupirocin was identified by a machine learning approach to be suitable for nano-liposome encapsulation. The computational predictions were verified experimentally and PEGylated nano-liposomal formulation of mupirocin (Nano-mupirocin) was developed. The aim of this study was to investigate the efficacy of this formulation when administered parenterally for the treatment of S. aureus invasive infections. Nano-mupirocin exhibited prolonged half-life of active antibiotic and displayed superior antimicrobial activity against S. aureus than free mupirocin in the presence of plasma. Parenteral application of Nano-mupirocin in a murine model of S. aureus bloodstream infection resulted in improved antibiotic distribution to infected organs and in a superior therapeutic efficacy than the free drug. Parenterally administered Nano-mupirocin was also more active against MRSA than free mupirocin in a neutropenic murine lung infection model. In addition, Nano-mupirocin was very efficiently taken up by S. aureus-infected macrophages via phagocytosis leading to enhanced delivery of mupirocin in the intracellular niche and to a more efficient elimination of intracellular staphylococci. The outcome of this study highlights the potential of Nano-mupirocin for the treatment of invasive MRSA infections and support the further clinical development of this effective therapeutic approach.

Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants.

Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity and longer hospital stays, but data on the burden of S aureus disease in hospitalized infants are limited. To compare demographics and mortality of infants with invasive methicillin-resistant S aureus (MRSA) and methicillin-susceptible S aureus (MSSA), to determine the annual proportion of S aureus infections that were MRSA, and to contrast the risk of death after an invasive MRSA infection with the risk after an invasive MSSA infection. Multicenter retrospective study of a large, nationally representative cohort at 348 neonatal intensive care units managed by the Pediatrix Medical Group. Participants were 3888 infants with an invasive S aureus infection who were discharged from calendar year 1997 through calendar year 2012. Invasive S aureus infection. The incidence of invasive S aureus infections, as well as infant characteristics and mortality after MRSA or MSSA infection. The 3888 infants had 3978 invasive S aureus infections (2868 MSSA and 1110 MRSA). The incidence of invasive S aureus infection was 44.8 infections per 10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from calendar year 1997 through calendar year 2006 and has moderately decreased since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections (n = 237) died before hospital discharge than infants with invasive MRSA infections (n = 110). The proportions of infants who died after invasive MSSA and MRSA infections were similar at 237 of 2474 (9.6%) and 110 of 926 (11.9%), respectively (P = .05). The adjusted risk of death before hospital discharge was similar after invasive MSSA and MRSA infections (risk ratio, 1.19; 95% CI, 0.96-1.49). The risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA infection and infants with invasive MRSA infection. Infant mortality after invasive MRSA and MSSA infections is similar, but MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S aureus infection should include MSSA in addition to MRSA.

Efficacy of the decolonization of methicillin-resistant Staphylococcus aureus carriers in clinical practice.

BackgroundNasal and extra nasal carriage of methicillin-resistant S. aureus (MRSA) is a pre-existing condition that often leads to invasive MRSA infection, as MRSA colonization is associated with a high risk of acquiring MRSA infection during hospital stays. Decolonization may reduce the risk of meticillin-resistant Staphylococcus aureus (MRSA) infection in individual carriers and prevent transmission to other patients.MethodsA retrospective cohort study was conducted to evaluate the effectiveness of two decolonization protocols for newly diagnosed MRSA carriage in hospitalized patients and to assess the impact of decolonization on the rate of MRSA infection. The study population consisted of all patients diagnosed as MRSA-positive between January 2006 and June 2010.Patients diagnosed as carriers were designated as requiring contact precautions by the hospital infection control team. The standing order protocol of the hospital pertaining to decolonization procedures was then applied, and all newly diagnosed patients were administered one of the two decolonization treatments outlined in the hospital protocol, with the exception of MRSA respiratory carriers (MRSA obtained from sputum or other lower respiratory tract samples). The two decolonization treatments consisted of the application of intranasal mupirocin 2 % and washing with chlorhexidine soap (40 mg/mL) (mupi/CHX) or application of intranasal povidone-iodine and washing with povidone-iodine soap (PVPI), with each treatment lasting for 5 days.Success was determined by at least three successive nose swabs and throat and other screened site swabs that tested negative for MRSA before patient discharge.ResultsA total of 1150 patients admitted to the hospital were found to be infected or colonized with MRSA. Of the 1150 patients, 268 were prescribed decolonization treatment. 104 out of 268 patients (39 %) were successfully decolonized. There was no significant success after two decolonization failures.MRSA infection rate among the successes and failures were 0.0 and 4.3 %, respectively [P = 0.04].ConclusionsOur results fit well with the prescription of decolonization based on local strategy protocols but reflect a low rate of successful treatment.Although the success rate of decolonization was not high in our study, the effectiveness of decolonization on the infection rate, justifies the continuation of this strategy, even if a marginal cost is incurred.

Antibiotics and Staphylococcus aureus—more than meets the MIC

The discovery of penicillin in 1928 and its subsequent introduction into clinical practice in 1941, heralded a new era in the treatment of serious bacterial infections, including those caused by Staphylococcus aureus . This organism causes a wide range of infections in humans, with bloodstream infection and endocarditis being the most serious and potentially devastating. However, despite the discovery of antibiotics, S. aureus continues to cause a significant burden of illness around the world, with a high mortality rate for invasive disease [1]. One of the reasons for this is the ability of the organism to continually evolve and adapt to new environments, including antibiotic exposures, resulting in the ongoing accumulation of antibiotic resistance [2]. Remarkably, penicillin-resistant S. aureus was detected within 1 year of the clinical use of penicillin, and the progressive acquisition of antibiotic resistance in S. aureus since that time, particularly methicillin-resistant S. aureus (MRSA), has severely impacted the available antibiotic armamentarium. As an example of how serious this problem is, over the past 10 years, there have been more deaths from invasive MRSA infection than human immunodeficiency virus infection in the USA [3], yet MRSA comprises less than half of all S. aureus infections. In day-to-day practice, clinicians rely on susceptibility results from the diagnostic microbiology laboratory to guide appropriate antimicrobial therapy for their patients. Most susceptibility tests performed in these laboratories rely on in vitro phenotypic methods, where the test organism is exposed to different concentrations of antibiotic and the impact on growth of the organism is determined. Performance and interpretation guidelines for these assays are provided by regulatory authorities such as the Clinical and Laboratory Standards Institute, and European Committee on Antimicrobial Susceptibility Testing. The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will completely inhibit the growth of an organism after a defined period of incubation, usually 18 to 24 h, and is used by diagnostic microbiology laboratories to define antimicrobial susceptibility or resistance. All clinicians are aware, andmedical students are taught, not to use an antibiotic to treat a bacterial infection if the report from the microbiology laboratory indicates it is resistant to that antibiotic. There is, however, a limitation to the current methods for antimicrobial susceptibility testing—they are performed in vitro and therefore do not measure other potentially important factors influencing the in vivo activity of the agent. Aside from antibiotics, other significant contributors to the clearance of bacterial infections are the innate immune system factors including host defense peptides (HDPs) and neutrophils. Host defense peptides have received increasing attention in the scientific literature because of their antimicrobial activity against a wide range of pathogens, including drugresistant bacterial strains [4]. These amphipathic cationic peptides are naturally occurring antimicrobials produced by a variety of cell types such as epithelial cells and phagocytes [5], and while they have direct antimicrobial activity against human pathogens and cancer cells in vitro, they are increasingly recognized as important immunomodulators in vivo [6]. B. P. Howden (*) Austin Centre for Infection Research (ACIR), Infections Diseases Department, and Department of Microbiology, Austin Health, Heidelberg, Melbourne, Australia e-mail: Benjamin.Howden@austin.org.au

Characteristics of invasive Staphylococcus aureus infections in three regions of Korea, 2009-2011: a multi-center cohort study

BackgroundDespite the importance of invasive Staphylococcus aureus (ISA) infection, its overall burden in non-selected populations has only been defined in a small number of studies in Europe and North America. To define the characteristics of ISA infections in Korea, we conducted a multi-center cohort study to estimate population-based incidence rates.MethodsWe conducted a multicenter prospective cohort study at nine university-affiliated active-surveillance core centers (ASCs) in three regions of Korea. To cover all available clinical microbiologic laboratories, we classified the laboratories in these regions into three groups according to their clinical environment as: 1) Nine ASCs, 2) Five major commercial laboratories and 3) Forty-four acute-care hospital-affiliated microbiology laboratories. We requested all the laboratories to report prospectively their numbers of cases of S. aureus isolated from normally sterile sites. Detailed clinical information was collected about the cases in the nine ASCs.ResultsFrom 1 July 2009 to 30 June 2011, a total of 1,198 cases of ISA infection were identified at the nine ASCs, including 748 (62%) methicillin-resistant S. aureus (MRSA) infections. Most (81%) ISA infections were healthcare-associated (HCA): 653 (55%) hospital-onset and 322 (27%) community-onset. 223 (19%) were community-associated infections. The most common primary diagnosis was catheter-associated infection (225 cases, 19%). Respiratory tract infection (160, 13%), skin & soft tissue (152, 13%) and bone & joint infections (120, 10%) were also common. 30-day and 12-week mortality rates were 25.6% (262/1,024) and 36.5% (314/860), respectively. Complications, including metastatic infection within 12 weeks, occurred in 17.8% of ISA infections. The most common site of metastatic infection was the lung (9.8%, 84/860). Based on the total of 2,806 observed cases of ISA infection, estimated annual rates of ISA and invasive MRSA infections were 43.3 and 27.7 per 100,000 populations, respectively.ConclusionsOur data provide important information about the clinical characteristics of ISA infections. We estimate that over 21,000 ISA infections and 13,000 invasive MRSA infections occurred in Korea in 2010.

Detection of methicillin-resistant Staphylococcus aureus with high-level resistance to mupirocin

Staphylococcus aureus with high-level mupirocin resistance has rarely been isolated in Japan. We detected methicillin-resistant S. aureus (MRSA) with high-level mupirocin resistance (HLMR-MRSA; MIC ≥1,024μg/ml) in a surveillance program of invasive MRSA infection in the Minami Ibaraki Area of Japan. The other 177 strains surveyed in the program showed susceptibility or low-level resistance to mupirocin. The HLMR-MRSA strain, named 115, was isolated from the blood of a patient with peripheral venous catheter-associated infection. The patient had not received administration of mupirocin before the isolation of strain 115. Another HLMR-MRSA strain, named 257, was recovered from the patient's sputum obtained 1year after the infection. Close relatedness between genotypes of strains 115 and 257 indicated persistent colonization of strain 115 on the patient. In contrast, no HLMR-MRSA was detected in materials submitted from other inpatients treated in the same wards during the same period, demonstrating that horizontal transmission of HLMR-MRSA did not occur.

Staphylococcus aureus bacteraemia: a major cause of mortality in Australia and New Zealand

To document the types of, and mortality from, Staphylococcus aureus bacteraemia in Australia and New Zealand, and determine factors associated with mortality. Prospective observational study in 27 independent or hospital pathology laboratories in Australia (24) and New Zealand (3), employing a web-based database to prospectively record demographic features, selected risk factors, principal antibiotic treatment and mortality data on all patients with positive blood cultures for S. aureus from June 2007 to May 2008. 30-day all-cause mortality. 1994 episodes of S. aureus bacteraemia were identified, and complete 30-day follow-up data were available for 1865. Most episodes had their onset in the community (60.8%; 95% CI, 58.7%-63.0%). Methicillin-resistant S. aureus (MRSA) caused 450 episodes (24.1%; 95% CI, 22.2%-25.9%), and 123 of these (27.3%) had a susceptibility profile consistent with community-associated MRSA. All-cause mortality at 30 days was 20.6% (95% CI, 18.8%-22.5%). On univariate analysis, increased mortality was significantly associated with older age, European ethnicity, MRSA infection, infections not originating from a medical device, sepsis syndrome, pneumonia/empyema, and treatment with a glycopeptide or other non-beta-lactam antibiotic. On multivariable analysis, independent predictors of mortality were age, sepsis syndrome, pneumonia/empyema, device-associated infection with a secondary focus, left-sided endocarditis, and treatment with a glycopeptide such as vancomycin, but not MRSA infection. S. aureus bacteraemia is a common infection in both the community and hospitals in Australia and New Zealand, and is associated with appreciable mortality. Invasive MRSA infection may be more life-threatening, partly because of the inferior efficacy of the standard treatment, vancomycin. National web-based surveillance of S. aureus bacteraemia and its outcomes is not only important but also easily achievable.

Methicillin‐ResistantStaphylococcus aureus:An Evolving Clinical Challenge

Staphylococcus aureus infections particularly infections with methicillin-resistant S. aureus (MRSA) strains in their practices. One only has to look at stories in the national and local media about outbreaks of MRSA infection to appreciate how widespread MRSA has become. Recently, Klevens et al. [1], using data from the Active Bacterial Core surveillance system of the Emerging Infections Program Network of the Centers for Disease Control and Prevention, estimated that, in the United States during 2005, there were 94,360 invasive MRSA infections and 18,650 related in-hospital deaths. Clearly, there is a compelling need to better understand the pathogenesis, prevention, and treatment of such infections. Serious infections due to MRSA, such as endocarditis, pneumonia, and bacteremia, have become more prevalent in the hospital setting. Perhaps more importantly, MRSA infections are now quite commonplace among previously healthy individuals with no or limited exposure to health care settings. So-called communityacquired MRSA (CA-MRSA) infections

Treatment Strategies for Methicillin-Resistant Staphylococcus aureus Infections in Pediatrics

Staphylococcus aureus is an important pathogen that frequently causes clinical disease in children. A wide array of illnesses can be caused by this common pathogen ranging from non-invasive skin infections to severe, life-threatening sepsis. Additionally, as antibacterials have been used to eradicate S. aureus, it has developed resistance to these important therapeutic agents. Methicillin-resistant S. aureus (MRSA) has become an increasing problem in pediatric patients over the past decade. In this review, we discuss the epidemiology, pathogenesis, and treatment options available in treating MRSA infections in children. Specifically, we address the importance of abscess drainage in the treatment of skin and soft tissue infections, the most common clinical manifestation of MRSA infections, and highlight the various agents that are available for treating this common infection. In severe, life-threatening invasive MRSA infections the primary therapeutic option is vancomycin. In cases of MRSA toxic shock syndrome the addition of clindamycin is necessary. In other invasive MRSA infections, such as pneumonia and musculoskeletal infections, the empiric treatment of choice is clindamycin. Finally, newer agents and additional treatment options are discussed.

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Vancomycin for Staphylococcus aureus therapy of respiratory tract infections: the end of an era?

In 1991, Karchmer [1] raised several key issues related to the pathogenesis and optimal treatment of Staphylococcus aureus infections. The main issue concerned the role of vancomycin in treating serious or invasive methicillin-sensitive S. aureus ( MSSA) and methicillinresistant S. aureus (MRSA) infections. He recognized and envisaged the current global epidemic of MRSA infections in hospitals [2], and to a lesser extent the community [3], and concluded that ‘there is an urgent need for effective alternatives to vancomycin for the treatment of MRSA infections’. Since then we have emerging evidence, a recent meta-analysis, that in patients with S. aureus -related bacteraemia, MRSA is an independent risk factor for higher mortality compared with MSSA bacteraemia [4]. This adds further support to the ongoing debate about the virulence of MRSA infections compared with MSSA and the need for optimal antibiotics at the onset of treatment. The reality, a decade later, is the occurrence of a broad range of serious and invasive MRSA infections, often in vulnerable patients in ‘high risk’ clinical settings [5]. The need to treat many of these patients empirically with a view to ‘covering’ the most likely offending pathogens is perceived to be high if the critical therapeutic window of opportunity for optimal antibiotic therapy is not to be missed. The undesirable consequences of not getting the ‘right drug, to the right patient, in the right dose at the right time’ are clear [6]. The rapid laboratory and clinical capability of predicting patients likely to be infected with MRSA continues to improve but is by no means ideal [7,8]. Additionally, we are witnessing the concurrent rise in S. aureus strains that exhibits glycopeptide-intermediate susceptibility from several countries including Japan, France and US that has been subject to recent review [9]. For example, strains with MIC to vancomycin of 4 mg/l have caused clinical infections that failed to respond to vancomycin therapy. Traditionally, when the effectiveness of an antimicrobial agent in serious infections is considered, there has been an overemphasis on the need for bactericidal activity as a pre-requisite for a good outcome. Many of us now accept that local tissue penetration should be considered of equal importance. This is particularly important when looking at treatment options for staphylococcal infections, especially in tissues such as lung or the endovascular lining. Vancomycin is still regarded as the ‘gold-standard’ therapy for serious or invasive MRSA infections. Considering Karchmer’s concerns of a decade ago, we examine what more have we learnt about vancomycin treatment and summarize the emerging evidence for new or combination therapies. Vancomycin is bactericidal and appears to exert its effect by binding to the precursor units of peptidoglycan synthesis inhibiting the transpeptidase reaction. It exhibits concentration-independent bactericidal action against susceptible bacteria and is more bactericidal in aerobic conditions. This effect is exerted without a lag period but acts only on multiplying organisms and with a post-antibiotic effect of about 2 h. Against MSSA, it is a less active agent than b-lactams [1,10 /12] by virtue of being more slowly and incompletely bactericidal compared with equivalent concentrations of a b-lactam. A recent illustration of this phenomenon in clinical practice was demonstrated by Tam et al. [13] in haemodialysis patients with MSSA bacteraemia. This study revealed that persistent bacteraemia 24 h after therapy was significantly greater (37% vs. 25%, P /0.05) in patients initially treated with vancomycin compared with those with a b-lactam. Additionally, in patients with MSSA endocarditis and related bacteraemia, there * Corresponding author. Tel.: /44-1382-660-111; fax: /44-1382816-178. E-mail address: dilip.nathwani@tuht.scot.nhs.uk (D. Nathwani). International Journal of Antimicrobial Agents 21 (2003) 521 /524