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Prospective surveillance for invasive Staphylococcus aureus and group A Streptococcus infections in a setting with high community burden of scabies and impetigo
Tropical Diseases Group, Murdoch Children’s Research Institute, Parkville, Victoria, AustraliaDepartment of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Tropical Diseases Group, Murdoch Children’s Research Institute, Parkville, Victoria, AustraliaDepartment of Paediatrics, University of Melbourne, Parkville, Victoria, AustraliaMelbourne Children’s Global Health, Melbourne Children’s Campus, The Royal Children’s Hospital, Parkville, Victoria, Australia
Ministry of Health and Medical Services, Suva, FijiWesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia
Department of Dermatology, St. Vincent’s Hospital, Darlinghurst, New South Wales, AustraliaSchool of Medicine, University of New South Wales, Kensington, New South Wales, Australia
Tropical Diseases Group, Murdoch Children’s Research Institute, Parkville, Victoria, AustraliaDepartment of Paediatrics, University of Melbourne, Parkville, Victoria, AustraliaMelbourne Children’s Global Health, Melbourne Children’s Campus, The Royal Children’s Hospital, Parkville, Victoria, Australia
Fiji has high incidence rates of invasive group A streptococcal infections and Staphylococcus aureus infections.
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Case fatality for invasive S. aureus and group A streptococcal infections was high.
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Skin infections were the most common clinical foci for both invasive S. aureus and group A Streptococcus.
Abstract
Background
Invasive Staphylococcus aureus (iSA) and group A Streptococcus (iGAS) impose significant health burdens globally. Both bacteria commonly cause skin and soft tissue infections (SSTIs), which can result in invasive disease. Understanding of the incidence of iSA and iGAS remains limited in settings with a high SSTI burden.
Methods
Prospective surveillance for admissions with iSA or iGAS was conducted at the referral hospital in Fiji’s Northern Division over 48 weeks between July 2018 and June 2019.
Results
There were 55 admissions for iSA and 15 admissions for iGAS (incidence 45.2 and 12.3 per 100,000 person-years, respectively). The highest incidence was found in patients aged ≥65 years (59.6 per 100,000 person-years for iSA and iGAS). The incidence of iSA was higher in indigenous Fijians (iTaukei) (71.1 per 100,000 person-years) compared with other ethnicities (incidence rate ratio 9.7, 95% confidence interval 3.5–36.9). SSTIs were found in the majority of cases of iSA (75%) and iGAS (53.3%). Thirteen of the 14 iGAS strains isolated belonged to emm cluster D (n = 5) or E (n = 8). The case fatality rate was high for both iSA (10.9%) and iGAS (33.3%).
Conclusions
The incidence of iSA and iGAS in Fiji is very high. SSTIs are common clinical foci for both iSA and iGAS. Both iSA and iGAS carry a substantial risk of death. Improved control strategies are needed to reduce the burden of iSA and iGAS in Fiji.
Staphylococcus aureus and group A Streptococcus (GAS) are pyogenic Gram-positive bacteria and the most common causes of impetigo and other skin and soft tissue infections (SSTIs) (
). These diseases are recognized as important causes of global morbidity and mortality with case fatality rates (CFRs) of 15–50% for invasive S. aureus (iSA) (
in: Ferretti J. Stevens D. Fischetti V. Streptococcus pyogenes: basic biology to clinical manifestations. Oklahoma Health Sciences Center,
Oklahoma City2016
). However, detailed understanding of their epidemiology and clinical impact in low- and middle-income countries remains limited.
In Fiji, an upper-middle-income country, SSTIs are highly prevalent in the community, most commonly manifesting as impetigo, with national prevalence reported at 19.6% in 2007 (
). S. aureus bacteraemia is the most commonly measured form of iSA. The incidence and CFR of iSA vary widely, depending on differences in geographic setting, health systems, socio-economic status and ethnicity (
GAS causes a wide spectrum of clinical manifestations, from impetigo and pharyngitis, to life-threatening invasive infection and postinfectious sequelae such as glomerulonephritis and rheumatic fever (
in: Ferretti J. Stevens D. Fischetti V. Streptococcus pyogenes: basic biology to clinical manifestations. Oklahoma Health Sciences Center,
Oklahoma City2016
Prospective surveillance was established for iSA and iGAS in the Northern Division of Fiji to determine the baseline burden of these diseases in the context of a larger trial (‘Big SHIFT’, Trial ID: ACTRN12618000461291), which aims to measure the impact of ivermectin-based mass drug administration on downstream complications of scabies, including iSA and iGAS.
Methods
Setting
Fiji is a South Pacific nation (population 884,887 in 2017) consisting of two main ethnicities: iTaukei or indigenous Fijian (56.8%) and Fijians of Indian Descent (37.5%) (
). Fiji was ranked 98 of 187 on the United Nations Human Development Index in 2019, placing it in the high human development category, although 28.1% of the population lives below the national basic needs poverty line, defined as a weekly income of 55.12 and 49.50 Fijian Dollars per adult in urban and rural settings, respectively (
). This study was set in the Northern Division of Fiji (population 131,914) which contains four administrative subdivisions. Surveillance was conducted at the division's referral hospital, Labasa Hospital, located in Macuata subdivision. Labasa Hospital is the only facility in the Northern Division with a microbiology laboratory, intensive care unit (ICU), and general medical and surgical services.
Case definitions and surveillance
A case of iSA or iGAS was defined as a patient with laboratory-confirmed isolation of S. aureus or GAS from a usually sterile body site (blood, cerebrospinal fluid, pleural fluid, fascia, bone, solid organ, peritoneal fluid and synovial fluid) on presentation or during admission (
). Clinicians routinely obtain blood cultures for patients who are febrile on presentation (temperature >38 °C). More specific sampling is performed when clinical foci are apparent.
This study included patients of all ages admitted to Labasa Hospital with iSA or iGAS. Patients were recruited prospectively from 16 July 2018 to 30 June 2019, with a 2-week pause from 24 December 2018 to 6 January 2019 (total 48 weeks). Study nurses reviewed results from the hospital’s microbiology laboratory and ward registers daily, and consulted with nursing and medical staff on the inpatient wards to identify cases for recruitment. Entries made to laboratory records and ward registers over the weekend were reviewed each Monday. Data were collected on patient demographics, clinical site of infection, comorbidities, culture results, management and outcomes. The presence of non-invasive SSTIs, such as cellulitis and abscesses, as diagnosed by the treating clinician was recorded. Comorbidities recorded were: type 2 diabetes mellitus, immunosuppression, heart disease, renal disease, liver disease, malignancy and chickenpox. The REDCap Mobile App (Vanderbilt University, TN, USA) was used to record data, and these were subsequently uploaded on to a secure online server hosted by Murdoch Children’s Research Institute (
Research electronic data capture (REDCap) — a metadata-driven methodology and workflow process for providing translational research informatics support.
Labasa Hospital houses the only microbiology laboratory in the Northern Division. S. aureus and GAS were identified using Gram staining and catalase testing. Other confirmatory tests included plate DNAse testing (for S. aureus) and streptococcal latex agglutination and bacitracin susceptibility (for GAS). Antibiotic susceptibility testing was undertaken using the disk diffusion methods of the Clinical and Laboratory Standards Institute. GAS isolates from a sterile site were stored at −20 °C at Labasa Hospital and transported to the laboratory at Murdoch Children’s Research Institute, where emm typing and emm cluster typing were performed using published procedures (
). As ethnicity breakdowns were unavailable from the 2017 census, denominators for ethnicity were calculated by applying Northern-Division-specific ethnicity proportions from the 2007 census to the 2017 census population. Comparisons for incidence between ethnicities were performed between the iTaukei population and other ethnicities, including Fijians of Indian Descent and other minorities. The estimated number of people with diabetes in the Northern Division was 22,991, derived by applying age-adjusted proportions from a 2011 national survey to the 2017 census population (
). The incidence rate ratio (IRR) was calculated to allow comparisons between different groups. Stata Version 15.1 (StataCorp, College Station, TX, USA) was used for statistical calculations.
Ethical considerations
Ethical approval was granted by the Fiji National Health Research Ethics Review Committee (Reference No. 2018.38.NOR) and the Royal Children’s Hospital Human Research Ethics Committee in Melbourne, Australia (Reference No. 38020). All participants (or legal guardian if participant was aged <18 years) provided written consent to be enrolled in the study. Additional written consent was obtained for typing of GAS isolates. Where no informed consent was obtained, the case was noted for incidence calculations and outcomes alone.
Results
Incidence
During the 48-week surveillance period, there were 55 admissions with iSA and 15 admissions with iGAS, equivalent to incidence rates of 45.2 per 100,000 person-years [95% confidence interval (CI) 34.0–58.8] and 12.3 per 100,000 person-years (95% CI 6.9–20.3), respectively. Of these cases, one had both iSA and iGAS (combined total of 69 admissions, incidence 56.7 per 100,000 person-years, 95% CI 44.1–71.7). Informed consent to collect clinical and demographic data was obtained for 52 (94.5%) of the iSA cases and all iGAS cases.
The incidence rates of iSA and iGAS were higher in the iTaukei population compared with other ethnicities (IRR 9.7, 95% CI 3.5–36.9 for iSA; IRR 3.2, 95% CI 0.9–17.8 for iGAS; Table 1). There was no significant difference in incidence between males and females for either iSA or iGAS (IRR 1.7, 95% CI 0.9–3.1 for iSA; 0.8, 95% CI 0.3–2.6 for iGAS; Table 1). High incidence of iSA and iGAS was observed in very young patients and elderly patients, with peak combined incidence observed in patients aged ≥65 years (122.2 per 100,000 person-years; IRR 10.3, 95% CI 2.1–97.7 compared with patients aged 25–34 years; Figure 1).
Table 1Number and incidence of invasive infections caused by Staphylococcus aureus and group A Streptococcus by sex, ethnicity, age group and type 2 diabetes status.
Figure 1Age-specific incidence of invasive infections by Staphylococcus aureus and group A Streptococcus in the Northern Division of Fiji, 15 July 2018–30 June 2019. Orange line, incidence of invasive Staphylococcus aureus; purple line, incidence of invasive group A Streptococcus; orange bars, number of invasive Staphylococcus aureus cases; purple bars, number of invasive group A Streptococcus cases.
A large proportion of cases [33 iSA (63.5%) and seven iGAS (46.7%)] were referred from facilities outside Labasa Hospital. Nineteen (36.5%) iSA cases and eight (53.3%) iGAS cases originated from within Macuata subdivision, equivalent to subdivision-specific incidence rates of 31.2 per 100,000 person-years (95% CI 18.8–48.7) and 13.3 per 100,000 person-years (95% CI 5.7–25.9), respectively. There were significant variations in the incidence of iSA and iGAS cases originating from the four subdivisions (Table S1, see online supplementary material).
Clinical characteristics
Nearly all patients had an overt clinical focus of infection; bacteraemia without focus was only observed in one case of iSA. SSTIs were the most common clinical focus of infection, observed in 75% and 53.3% of iSA and iGAS cases, respectively (Figure 2). There were no cases of infective endocarditis or toxic shock syndrome. Most patients had bacteraemia: 48 cases of iSA (92.3%) and eight cases of iGAS (53.3%). The all-age incidence rates of S. aureus bacteraemia and GAS bacteraemia were 39.4 and 6.6 per 100,000 person-years, respectively (Table S2, see online supplementary material).
Figure 2Clinical sites of infection for, invasive Staphylococcus aureus; iGAS, invasive group A Streptococcus.
Diabetes was noted in 26.9% and 46.7% of patients with iSA and iGAS, respectively. The incidence of iSA among patients with diabetes was 66.0 per 100,000 person-years, compared with 37.8 per 100,000 person-years in patients without diabetes (IRR 1.8, 95% CI 0.9–3.3). The incidence of iGAS among patients with diabetes was 33 per 100,000 person-years compared with 8 per 100,000 person-years in patients without diabetes (IRR 4.1, 95% CI 1.3–13.1; Table 1). Higher incidence of iSA and iGAS in patients with diabetes was found in all age groups ≥45 years (Table S3, see online supplementary material). All other comorbidities were not common.
Blood was the most common sterile site from which positive cultures were isolated (n = 56, 84.8%), followed by deep tissue swabs (n = 14, 21.2%) and synovial fluid (n = 9, 13.6%) for both iSA and iGAS combined (Table 2) . Methicillin-resistant S. aureus was isolated from one patient. The total number of samples collected from each sterile site and proportion that was positive for S. aureus and GAS are outlined in Table S4 (see online supplementary material).
Table 2Sites of invasive isolates for invasive Staphylococcus aureus (iSA) and group A streptococcal (iGAS) infections.
emm typing and emm cluster typing were performed on samples obtained from 14 of 15 cases with iGAS. The most common emm type was emm65.4, isolated in three cases (Table 3). All isolates except one belonged to emm cluster D (n = 5) or E (n = 8).
Table 3emm types and emm clusters of group A Streptococcus isolated from sterile sites.
Five patients (9.6%) with iSA and two patients (13.3%) with iGAS were admitted to the ICU. Paediatric cases were over-represented: four of five patients with iSA were aged <8 years, and one of the patients with iGAS was 2 years old.
Forty-one patients (78.9%) with iSA and nine patients (60%) with iGAS required surgery in the operating theatre, some on repeated occasions. The most common procedures were soft tissue incision and drainage (17 cases, 32.7%), soft tissue debridement (13 cases, 25.0%) and joint washout (12 cases, 23.1%) for iSA, and soft tissue debridement for iGAS (five cases, 33.3%, Table S5, see online supplementary material).
The median duration of intravenous antibiotics was 14 days [interquartile range (IQR) 7–16.5 days] for iSA and 10.5 days (IQR 8–20 days) for iGAS, with duration varying slightly by clinical focus (Table S6, see online supplementary material). The median length of stay in hospital was 15 days for both iSA (IQR 8–18, range 2–56 days) and iGAS (IQR 8–23, range 3–63 days).
Outcomes
Overall CFR was high. Including all 66 admissions with iSA and iGAS, 10 (14.5%) resulted in death, nine of whom were participants in the study. One of the deaths was the patient with both iSA and iGAS. There were six deaths (CFR 10.9%) among cases with iSA and five deaths (CFR 33.3%) among cases with iGAS. Among the nine participants who died, eight (88.9%) were of iTaukei ethnicity. A higher CFR was observed among patients aged ≥55 years (47.1%) compared with those aged <55 years [2%, IRR 23.1, 95% CI 3.1–1023.2; Table S5 (see online supplementary material)]. Patients with diabetes also had a higher CFR compared with patients without diabetes [IRR 8.1, 95% CI 1.5–79.4; Table S7 (see online supplementary material)].
Discussion
iSA and iGAS had a high disease burden in Fiji, with little change from comparable studies performed at the Colonial War Memorial Hospital (the national referral centre) in 2007 (
). The present data highlight that SSTIs are common foci for both iSA and iGAS. Both iSA and iGAS carry a substantial risk of death, especially iGAS with a CFR of 33%.
The incidence rates of iSA (45.2 per 100,000 person years) and iGAS (12.3 per 100,000 person years) in this population were substantially higher compared with those documented in high-income settings. Studies from North America, urban Australia and Scandinavia have reported rates of iSA between 19.0 and 33.7 per 100,000 person-years and iGAS between 3.8 and 7.6 cases per 100,000 person-years (
). In contrast, a similar epidemiologic situation appears to exist in neighbouring Pacific communities. Studies in New Caledonia have reported a very high incidence of iGAS (between 38 and 43 per 100,000 person-years), and observed that a high proportion of cases had an SSTI focus (
Clinical and microbial characteristics of invasive Streptococcus pyogenes disease in New Caledonia, a region in Oceania with a high incidence of acute rheumatic fever.
The incidence of disease was six times higher in the iTaukei population compared with people of other ethnicities in Fiji. iTaukei Fijians also appear to have higher risk of SSTIs, other GAS diseases (including rheumatic heart disease) (
). The reason for this is unclear. Disparities in the incidence of iSA and iGAS have been noted between ethnicities in other populations. In New Zealand, Maori and Pacific Islanders have 10 times higher incidence of iSA compared with the non-Maori/non-Pacific population (
). Higher annual incidence of SSTIs presenting to hospital has also been described in Australian Indigenous populations (18.9 per 1000 population) compared with non-Indigenous populations (2.9 per 1000 population) (
High burden of complicated skin and soft tissue infections in the indigenous population of Central Australia due to dominant Panton Valentine leucocidin clones ST93-MRSA and CC121-MSSA.
A major contributing factor to the high rates of iSA and iGAS in these settings is likely to be the high community burden of SSTIs. This was supported by the finding that SSTIs were the most common clinical focus of infection for both iSA (75%) and iGAS (53.3%) in this study. This was also supported by the finding that almost all iGAS isolates belonged to emm types and emm clusters that are associated with skin infections (
). The prevalence of scabies and impetigo are very high in Fiji, especially in the Northern Division, with reported rates of 28.5% and 23.7%, respectively (
High burden of complicated skin and soft tissue infections in the indigenous population of Central Australia due to dominant Panton Valentine leucocidin clones ST93-MRSA and CC121-MSSA.
A number of risk factors for iSA and iGAS were observed in this study. The highest incidence was found in the youngest and oldest age groups, particularly among those aged <5 and ≥65 years. Children comprised 90% of ICU admissions. The CFR was highest in older patients, consistent with other studies (
), likely due to the presence of underlying comorbidities, particularly type 2 diabetes which, as demonstrated in this study, resulted in higher incidence of iSA and iGAS and CFRs overall.
The emm-type profile observed in this study was diverse, even in this small sample. There was a notable absence of emm types classically described among invasive isolates in high-income countries, especially emm1 (
). This high diversity, absence of classic emm types, and predominance of skin tropic emm types and emm cluster types is consistent with previous studies of the molecular epidemiology of GAS in Fiji and surrounding Pacific island countries (
The main limitation of this study was that surveillance was limited to the referral hospital of the Northern Division, therefore providing a minimum estimate of the burden of iSA and iGAS in this population. Furthermore, some of the data on length of stay, treatment received and outcomes may have been incomplete for patients transferred back to their referring hospitals. Another reason that the study results represent a minimum estimate of iSA and iGAS in the study population is that the collection of samples from patients was determined by clinician assessment. It is possible that patients presenting to Labasa Hospital or other facilities in the Northern Division with underlying iSA or iGAS may not have had invasive samples collected, or may have had samples collected after the administration of antibiotics which may reduce the detection of bacteria using standard culture methods.
Despite the huge clinical and public health burden caused by S. aureus and GAS, there are no available vaccines against either pathogen, nor are there proven public health strategies to prevent severe infections. In settings such as Fiji, where community prevalence of impetigo is very high, it is plausible that the incidence of invasive disease could be diminished by reducing the burden of impetigo in the community. Multiple studies in the Pacific have shown that mass drug administration for control of scabies results in a marked reduction in the prevalence of impetigo (
). Determining the effect of such community-based strategies to reduce the prevalence of scabies and impetigo on the incidence of iSA and iGAS would be valuable in guiding health policy for disease prevention.
Author contributions
Conceptualization: Andrew Steer, John Kaldor, Lucia Romani, Daniel Engelman.
Data curation: Li Jun Thean, Jessica Paka, Jyotishna Mudaliar.
Funding acquisition: Andrew Steer, Margot Whitfeld, Handan Wand, Mike Kama, Joseph Kado, Lucia Romani, Natalie Carvalho.
Formal analysis: Li Jun Thean, Andrew Steer.
Investigation: Li Jun Thean, Tuliana Cua, Sera Taole, Jyotishna Mudaliar, Jessica Paka, Vika Soqo, Adam Jenney.
Project administration: Li Jun Thean, Jyotishna Mudaliar, Aalisha Sahukhan, Andrew Steer.
Supervision: Andrew Steer, Daniel Engelman, Lucia Romani, John Kaldor.
Writing original draft: Li Jun Thean.
Critical revision of the manuscript: Adam Jenney, Daniel Engelman, Lucia Romani, Handan Wand, Jyotishna Mudailar, Vika Soqo, Aalisha Sahukhan, Mike Kama, Meciusela Tuicakau, Joseph Kado, Natalie Carvalho, Margot Whitfeld, John Kaldor, Andrew Steer.
Conflict of interest
None declared.
Funding
This work was supported by funding from a project grant from the National Health and Medical Research Council of Australia (Grant No. GNT1127300).
Acknowledgements
The authors wish to thank the administrative, clinical, medical records and laboratory personnel at Labasa Hospital for their invaluable support in conducting surveillance at their facility. In particular, the authors wish to thank Dr Jaoji Vulibeci, Dr Neelesh Chand, Mr Josese Limaono and Mr Orisi Cabenatabua. The authors would also like to acknowledge the contributions of Mr Avinesh Prasad at the Fiji Bureau of Statistics and Ms Suzanna Vidmar at Murdoch Children’s Research Institute. Finally, the authors are grateful to Ciara Baker and Kristy Azzopardi at the Tropical Diseases Laboratory at Murdoch Children’s Research Institute for doing the emm typing.
Appendix A. Supplementary data
The following are Supplementary data to this article:
High burden of complicated skin and soft tissue infections in the indigenous population of Central Australia due to dominant Panton Valentine leucocidin clones ST93-MRSA and CC121-MSSA.
Research electronic data capture (REDCap) — a metadata-driven methodology and workflow process for providing translational research informatics support.
Clinical and microbial characteristics of invasive Streptococcus pyogenes disease in New Caledonia, a region in Oceania with a high incidence of acute rheumatic fever.
in: Ferretti J. Stevens D. Fischetti V. Streptococcus pyogenes: basic biology to clinical manifestations. Oklahoma Health Sciences Center,
Oklahoma City2016
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