Does adjunctive clindamycin have a role in Staphylococcus aureus bacteremia? A protocol for the adjunctive treatment domain of the S. aureus Network Adaptive Platform (SNAP) randomized controlled trial.

INTRODUCTION: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and is recommended in many guidelines, but there is limited evidence underpinning this. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leucocidins (e.g., Panton-Valentine Leucocidin (PVL), toxic shock syndrome toxin 1 (TSST-1), exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multi-center adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either five days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard of care antibiotics. Most participants with SAB (within 72hr of index blood culture and not contraindicated) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and PVL-positive isolate.

Group A Streptococcus Primary Peritonitis in Children, New Zealand.

Group A Streptococcus (GAS) primary peritonitis is a rare cause of pediatric acute abdomen (sudden onset of severe abdominal pain); only 26 pediatric cases have been reported in the English language literature since 1980. We discuss 20 additional cases of pediatric primary peritonitis caused by GAS among patients at Starship Children's Hospital, Auckland, New Zealand, during 2010-2022. We compare identified cases of GAS primary peritonitis to cases described in the existing pediatric literature. As rates of rates of invasive GAS increase globally, clinicians should be aware of this cause of unexplained pediatric acute abdomen.

An Update on Pediatric Acute Hematogenous Osteomyelitis in New Zealand - A Decade on.

INTRODUCTION: New Zealand (NZ) has high rates of pediatric acute hematogenous osteomyelitis (AHO) with males and children of Pasifika and Maori ethnicity overrepresented. AIMS: To update the incidence of Pediatric AHO over 10 years, identifying trends in presentation, organisms, treatment, and outcomes. METHODS: A 10-year retrospective review of children aged 6 weeks to 15 years admitted with Pediatric AHO across two centers from 2008 to 2017. Demographic data, features of presentation, investigations, management, and complications were collected. Incidence was calculated from census data. Data were compared with our osteomyelitis database from the previous decade. (1). RESULTS: 796 cases were identified. The incidence was 18 per 100,000 per annum. The average age was 7.7 years. Pasifika and Maori children are overrepresented (57%). 370 children (51%) came from low socioeconomic areas. Methicillin-sensitive Staphylococcus aureus was the most common pathogen (87%). Methicillin-resistant Staphylococcus aureus (MRSA) rates are low (4.4%). Forty-four (5.5%) children were admitted to the Pediatric Intensive Care Unit (PICU) with 9% mortality. The mean duration of antibiotics was 40 days. 325 children (41%) had surgery. Chronic infection has increased from 1.7% to 5.7%. CONCLUSIONS: NZ has high rates of AHO, however, the incidence has decreased from the previous decade. Males, those in low socioeconomic areas, Pasifika and Maori have high disease burden. The use of MRI as a diagnostic modality has increased. Future studies should focus on improving treatment via prospective analysis and reporting long-term morbidity to improve outcomes for children with severe disease and reduce rates of chronic infection.

Pediatric Staphylococcus aureus Bacteremia: Clinical Spectrum and Predictors of Poor Outcome.

BACKGROUND: Staphylococcus aureus is a common cause of bacteremia, yet the epidemiology and predictors of poor outcome remain inadequately defined in childhood. METHODS: ISAIAH (Invasive Staphylococcus aureus Infections and Hospitalizations in children) is a prospective, cross-sectional study of S. aureus bacteremia (SAB) in children hospitalized in Australia and New Zealand over 24 months (2017-2018). RESULTS: Overall, 552 SABs were identified (incidence 4.4/100 000/year). Indigenous children, those from lower socioeconomic areas and neonates were overrepresented. Although 90-day mortality was infrequent, one-third experienced the composite of: length of stay >30 days (26%), intensive care unit admission (20%), relapse (4%), or death (3%). Predictors of mortality included prematurity (adjusted odds ratio [aOR],16.8; 95% confidence interval [CI], 1.6-296.9), multifocal infection (aOR, 22.6; CI, 1.4-498.5), necrotizing pneumonia (aOR, 38.9; CI, 1.7-1754.6), multiorgan dysfunction (aOR, 26.5; CI, 4.1-268.8), and empiric vancomycin (aOR, 15.7; CI, 1.6-434.4); while infectious diseases (ID) consultation (aOR, 0.07; CI .004-.9) was protective. Neither MRSA nor vancomycin trough targets impacted survival; however, empiric vancomycin was associated with nephrotoxicity (OR, 3.1; 95% CI 1.3-8.1). CONCLUSIONS: High SAB incidence was demonstrated and for the first time in a pediatric setting, necrotizing pneumonia and multifocal infection were predictors of mortality, while ID consultation was protective. The need to reevaluate pediatric vancomycin trough targets and limit unnecessary empiric vancomycin exposure to reduce poor outcomes and nephrotoxicity is highlighted. One in 3 children experienced considerable SAB morbidity; therefore, pediatric inclusion in future SAB comparator trials is paramount to improve outcomes.

Diagnosis and management of paediatric Clostridioides difficile infection in a tertiary centre: A prospective audit.

AIM: The optimisation of diagnosis and management of paediatric Clostridioides (formerly Clostridium) difficile (C. difficile) infection (CDI) has importance on multiple levels, from individual patient to population disease management and infection control. This study aimed to evaluate current practice at a paediatric tertiary hospital against Australasian Society for Infectious Diseases 2016 guidelines. METHODS: Prospective audit was undertaken. All positive C. difficile tests (by two step immunoassay then polymerase chain reaction) over 6 month period were reviewed for appropriateness of testing, including review of clinical characteristics and treatment of appropriately requested positive tests (CDI cases). Consecutive test requests for C. difficile over 2 month period were reviewed for appropriateness of testing. RESULTS: Of 70 consecutive test requests, 64 met laboratory criteria for processing. Of these, 31 (48%) out of 64 were asymptomatic or had clinically insignificant or laxative-associated diarrhoea. Overall, 44 (63%) out of 70 were deemed inappropriate requests. Of 45 positive tests, 17 (38%) were appropriately requested. Amongst inappropriate requests, 13 (46%) out of 28 were treated; those aged >2 years were significantly more likely to be treated (P < 0.05). Thirteen children were treated unnecessarily. Only one out of seven positive tests in infants (<1 year) was appropriately requested. Haematology/oncology patients accounted for 41% of cases. Treatment was in accordance with guidelines in 58% of cases. CONCLUSIONS: Inappropriate testing for C. difficile and variable clinical response to positive tests have sequelae including unnecessary antibiotics for hospitalised children. Areas for improvement have been identified and this study confirms the need for establishment of national paediatric CDI guidelines with increased awareness of these by clinicians.

Compliance with perioperative prophylaxis guidelines and the use of novel outcome measures.

Postoperative wound infections represent an important source of morbidity and mortality in children. Perioperative antibiotic prophylaxis has been shown to decrease the risk of developing infections and hospital guidelines surrounding antibiotic use exist to standardize patient care. Despite supporting evidence, rates of compliance with guidelines vary. Quality improvement initiatives have been introduced to improve compliance with intraoperative antibiotic guidelines. Thorough infection surveillance, including antibiotic provision in presurgical checklists, computerized voice antibiotic administration prompts, and national feedback systems are now increasingly common. Few studies have been conducted investigating the effectiveness of prophylactic antibiotics in children. Outcome measures such as morbidity and mortality and return to the operating room can be used to examine the relationship between antibiotic use and patient outcome but these measures are limited in that they occur infrequently or are subjective and difficult to measure. Metrics such as days alive out of hospital and length of hospital stay may be useful alternatives for ongoing monitoring of infections and identifying improvements in patient outcomes. Guidelines on antibiotic prophylaxis have facilitated an increase in the correct provision of perioperative antibiotics and a reduction in the incidence of postoperative infection. Measures of patient outcome such as days alive out of hospital and length of hospital stay are easy to collect and calculate but further work is needed to confirm the utility of these measures for monitoring infection rates.

Public health action following an outbreak of toxigenic cutaneous diphtheria in an Auckland refugee resettlement centre.

Global forced displacement has climbed to unprecedented levels due largely to regional conflict. Degraded public health services leave displaced people vulnerable to multiple environmental and infectious hazards including vaccine preventable disease. While diphtheria is rarely notified in New Zealand, a 2 person outbreak of cutaneous diphtheria occurred in refugees from Afghanistan in February 2015 at the refugee resettlement centre in Auckland. Both cases had uncertain immunisation status. The index case presented with a scalp lesion during routine health screen and toxigenic Corynebacterium diphtheriae was isolated. A secondary case of cutaneous diphtheria and an asymptomatic carrier were identified from skin and throat swabs. The 2 cases and 1 carrier were placed in consented restriction until antibiotic treatment and 2 clearance swabs were available. A total of 164 contacts were identified from within the same hostel accommodation as well as staff working in the refugee centre. All high risk contacts (n=101) were swabbed (throat, nasopharynx and open skin lesions) to assess C. diphtheriae carriage status. Chemoprophylaxis was administered (1 dose of intramuscular benzathine penicillin or 10 days of oral erythromycin) and diphtheria toxoid-containing vaccine offered regardless of immunisation status. Suspected cases were restricted on daily monitoring until swab clearance. A group of 49 low risk contacts were also offered vaccination. Results suggest a significant public health effort was required for a disease rarely seen in New Zealand. In light of increased worldwide forced displacement, similar outbreaks could occur and require a rigorous public health framework for management.

Early-onset neonatal group B streptococcus sepsis following national risk-based prevention guidelines.

BACKGROUND: Neonatal infection with group B streptococcus (GBS) is an important cause of infant mortality. Intrapartum antibiotics reduce early-onset GBS sepsis, but recommendations vary as to whether they should be offered following antenatal screening or based on risk factors alone. We aimed to determine the incidence of early-onset GBS sepsis in New Zealand five years after the publication of national risk-based GBS prevention guidelines. MATERIALS AND METHODS: Prospective surveillance of early-onset GBS sepsis (defined as infection in the first 48 h of life) was undertaken between April 2009 and March 2011 through the auspices of the New Zealand Paediatric Surveillance Unit as part of a survey of infection presenting in the first week of life. RESULTS: There were 29 cases of confirmed early-onset GBS sepsis, including one case of meningitis, giving an incidence rate of 0.23 per 1000 (95% CI 0.16-0.33) live births. Three infants (10.3%) died. In 16 cases (55%), a maternal risk factor qualifying the mother for intrapartum antibiotics was present, but only five (31%) received this intervention. A retrospective review of the major hospital laboratory databases for this period identified two additional cases. A secondary sensitivity analysis taking account of these cases provided an estimated national incidence of 0.26 (95% CI 0.18-0.37) per 1000 live births. CONCLUSIONS: Ten years after a similar survey and five years after promoting a single, risk-based prevention protocol nationally, the incidence of early-onset GBS disease in New Zealand has more than halved, but opportunities remain to further reduce the rate.

Improved paediatric antimicrobial prescribing with a smartphone application: a before and after interventional study.

INTRODUCTION: Children have a high consumption of antimicrobials that require complicated decision-making by prescribers. Despite this, antimicrobial stewardship (AMS) interventions are often not translated into paediatric medicine. Script is a smartphone application (app) launched in Auckland, New Zealand to support decision-making for antimicrobial prescribers. The aim was to improve adherence to existing local clinical guidelines for both adult and paediatric infections. METHODS: Inpatient and emergency department antimicrobial prescriptions were prospectively collected and evaluated for guideline adherence. Baseline prescribing data were collected and compared with prescribing at 4 months and 1 year after the app was launched. Prescriptions were graded as 'appropriate' or 'inappropriate' by investigators. Grading was done blinded to timing of the prescription relative to the intervention. RESULTS: Following the launch of the Script app, guideline adherence significantly increased from 241 of 348 (69%) antimicrobial prescriptions graded as appropriate during the baseline period to 301 of 359 (83%) after 4 months (p<0.0001). This improvement from baseline was sustained at 1 year with 263 of 323 (81%) adherence (p<0.001). At 1 year, this improvement could be demonstrated separately for medical, surgical and emergency department prescriptions. CONCLUSION: There was a significant and sustained improvement in adherence to paediatric antimicrobial guidelines following the introduction of a prescribing support app. The need to seek guidance for antimicrobial doses due to the age-based and weight-based calculations in paediatrics may mean that AMS interventions such as decision support and prescribing tools are particularly well suited to paediatric prescribing.

Multisystem Inflammatory Syndrome in New Zealand Children.

New Zealand (NZ) initially adopted an elimination approach to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pre-Omicron variant, the NZ pediatric population was immunologically naïve to SARS-CoV-2. This study, utilizing national data sources, describes the NZ incidence of multisystem inflammatory syndrome in children (MIS-C) following infection with the Omicron variant. MIS-C incidence was 1.03 of 100,000 age-specific population and 0.04 of 1000 recorded SARS-CoV-2 infections.

Whole genome sequencing and molecular epidemiology of paediatric Staphylococcus aureus bacteraemia.

OBJECTIVES: The role Staphylococcus aureus antimicrobial resistance genes and toxins play in disease severity, management and outcome in childhood is an emerging field requiring further exploration. METHODS: A prospective multisite study of Australian and New Zealand children hospitalised with S. aureus bacteraemia (SAB) occurred over 24 months (2017-2018). Whole genome sequencing (WGS) data were paired with clinical information from the ISAIAH cohort. RESULTS: 353 SAB isolates were sequenced; 85% methicillin-susceptible S. aureus ([MSSA], 301/353) and 15% methicillin-resistant S. aureus ([MRSA], 52/353). There were 92 sequence types (STs), most commonly ST5 (18%) and ST30 (8%), grouped into 23 clonal complexes (CCs), most frequently CC5 (21%) and CC30 (12%). MSSA comprised the majority of healthcare-associated SAB (87%, 109/125), with principal clones CC15 (48%, 11/21) and CC8 (33%, 7/21). Panton-Valentine leukocidin (PVL)-positive SAB occurred in 22% (76/353); predominantly MSSA (59%, 45/76), community-onset (92%, 70/76) infections. For community-onset SAB, the only microbiological independent predictor of poor outcomes was PVL positivity (aOR 2.6 [CI 1.0-6.2]). CONCLUSION: From this WGS paediatric SAB data, we demonstrate the previously under-recognized role MSSA has in harbouring genetic virulence and causing healthcare-associated infections. PVL positivity was the only molecular independent predictor of poor outcomes in children. These findings underscore the need for further research to define the potential implications PVL-producing strains may have on approaches to S. aureus clinical management.

Invasive group A streptococcal infection and vaccine implications, Auckland, New Zealand.

We aimed to assess the effect of invasive group A streptococcal (GAS) infection and the potential effects of a multivalent GAS vaccine in New Zealand. During January 2005-December 2006, we conducted prospective population-based laboratory surveillance of Auckland residents admitted to all public hospitals with isolation of GAS from normally sterile sites. Using emm typing, we identified 225 persons with confirmed invasive GAS infection (median 53 years of age; range 0-97 years). Overall incidence was 8.1 cases per 100,00 persons per year (20.4/100,000/year for Maori and Pacific Islanders; 24.4/100,000/year for persons >65 years of age; 33/100,000/year for infants <1 year of age). Nearly half (49%) of all cases occurred in Auckland's lowest socioeconomic quintile. Twenty-two persons died, for an overall case-fatality rate of 10% (63% for toxic shock syndrome). Seventy-four percent of patients who died had an underlying condition. To the population in our study, the proposed 26-valent vaccine would provide limited benefit.

Surveillance of pediatric parapneumonic effusion/empyema in New Zealand.

AIM: The incidence of childhood empyema has been increasing in some developed countries despite the introduction of pneumococcal vaccination. This study aimed to document the incidence, bacterial pathogens, and morbidity/mortality of parapneumonic effusion/empyema in New Zealand. METHODS: A prospective study of 102 children <15 years of age requiring hospitalization with parapneumonic effusion/empyema between May 1, 2014 and May 31, 2016 notified via the New Zealand Paediatric Surveillance Unit. Parapneumonic effusion/empyema was defined as pneumonia and pleural effusion persisting ≥7 days, and/or any pneumonia, and pleural effusion necessitating drainage. Notifying pediatricians completed standardized questionnaires. RESULTS: Annual pediatric parapneumonic effusion/empyema incidence was 5.6/100,000 (95% confidence interval [CI]: 4.7-6.9). Most children (80%) required surgical intervention and 31% required intensive care. A causative organism was identified in 71/102 (70%) cases. Although Staphylococcus aureus (25%) and Streptococcus pneumoniae (25%) infection rates were equal, prolonged hospitalization and intensive care admission were more common in children with S. aureus PPE/E. Maori and Pasifika children were over-represented at 2.2 and 3.5 times, their representation in the New Zealand pediatric population. Pneumococcal vaccination was incomplete, with only 61% fully immunized and 30% unimmunized. Haemophilus influenzae type b vaccine uptake was near complete at 89/94 (95%), with influenza immunization only 3/78 (4%). CONCLUSIONS: New Zealand has a high incidence of pediatric complicated parapneumonic effusion/empyema with significant morbidity. S. aureus was a significant cause of severe empyema in New Zealand, particularly for Maori and Pasifika children. Improvements in vaccine coverage are needed along with strategies to reduce S. aureus disease morbidity.

Epidemiology and Mortality of Staphylococcus aureus Bacteremia in Australian and New Zealand Children.

IMPORTANCE: Staphylococcus aureus bacteremia (SAB) in children causes significant morbidity and mortality, but the epidemiology in children is not well characterized. OBJECTIVE: To describe the epidemiology of SAB in children and adolescents younger than 18 years from Australia and New Zealand. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study, using data from the Australian New Zealand Cooperative on Outcomes in Staphylococcal Sepsis cohort for 1153 children with SAB from birth to less than 18 years in pediatric and general hospitals across Australia and New Zealand, collected between January 1, 2007, and December 31, 2012. Multivariate analysis was performed to identify risk factors for mortality. Incidence calculations were calculated separately for Australasian children younger than 15 years using postcode population denominator data from Australian and New Zealand census data. MAIN OUTCOMES AND MEASURES: Demographic data, hospital length of stay, principal diagnosis, place of SAB onset (community or hospital), antibiotic susceptibility and principal antibiotic treatment, and 7- and 30-day mortality. RESULTS: Of the 1153 children with SAB, complete outcome data were available for 1073 children (93.1%); of these, males accounted for 684 episodes (63.7%) of SAB. The median age was 57 months (interquartile range, 2 months to 12 years). The annual incidence of SAB for Australian children was 8.3 per 100 000 population and was higher in indigenous children (incident rate ratio, 3.0 [95% CI, 2.4-3.7]), and the incidence for New Zealand children was 14.4 per 100 000 population and was higher in Maori children (incident rate ratio, 5.4 [95% CI, 4.1-7.0]). Community-onset SAB occurred in 761 cases (70.9%), and 142 cases (13.2%) of the infections were methicillin-resistant S aureus (MRSA). Bone or joint infection was most common with 348 cases (32.4%), and endocarditis was uncommon with 30 cases (2.8%). Seven- and 30-day mortality rates were 2.6% (n = 28) and 4.7% (n = 50), respectively. Risk factors for mortality were age younger than 1 year; Maori or Pacific ethnicity; endocarditis, pneumonia, or sepsis; and receiving no treatment or treatment with vancomycin. Mortality was 14.0% (6 of 43) in children with methicillin-susceptible S aureus (MSSA) treated with vancomycin compared with 2.6% (22 of 851) in children treated with alternative agents (OR, 6.1 [95% CI, 1.9-16.7]). MRSA infection was associated with increased length of stay but not mortality. CONCLUSIONS AND RELEVANCE: In this large cohort study of the epidemiology of SAB in children, death was uncommon, but the incidence was higher for infants and varied by treatment, ethnicity, and clinical presentation. This study provides important information on the epidemiology of SAB in children and risk factors for mortality.

The prevention of early-onset neonatal group B streptococcus infection: New Zealand Consensus Guidelines 2014.

AIMS: Group B streptococcal (GBS) disease is the leading cause of early-onset neonatal sepsis in New Zealand. Disease follows vertical transmission of GBS from the mother, which can largely be prevented by intravenous intrapartum antibiotics. A 2004 New Zealand guideline recommended using clinical risk factors to identify mothers who would qualify for intrapartum antibiotics. An expert multidisciplinary group met to reconsider these guidelines in the light of a two year survey of the incidence of early onset GBS neonatal sepsis. METHODS: Representatives from the New Zealand College of Midwives, the Fetus and Newborn Committee of the Paediatric Society of New Zealand, the Royal New Zealand College of General Practitioners, the New Zealand Committee of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, the New Zealand sub-Committee of the Australasian Society of Infectious Diseases, and the Canterbury Home Birth Association met to review the literature and the most recent New Zealand data. RESULTS: The multidisciplinary group noted that the estimated incidence of early-onset GBS sepsis had halved over a 10-year period to be 0.26 per 1,000 live births in 2009-11 and that there were missed opportunities for preventing GBS infection. Consensus was reached that adoption of a national guideline on prevention and management of early onset GBS neonatal sepsis by all practitioners and District Health Boards would have the greatest potential to further reduce the incidence. CONCLUSION: A risk-based GBS prevention strategy continues to be recommended as being the most clinically and cost effective for the New Zealand context. Universal routine antenatal GBS screening is not recommended.

Infective endocarditis in New Zealand children 1994-2012.

BACKGROUND: New Zealand is a developed country with high incidence of bacterial infections and postinfectious sequelae including rheumatic heart disease. We sought to describe the clinical and microbiology features of children with infective endocarditis (IE) between 1994 and 2012. METHODS: Retrospective review of patients <16 years identified from hospital records. RESULTS: In total 85 episodes occurred in 82 children and 68 (80%) were classified as Definite IE and 17 as Possible IE according to modified Duke criteria. From Pacific Island countries, 13 cases were referred. There were 72 children who originated in New Zealand, of whom 52% were either indigenous New Zealand Maori or Pacific migrants. The median age at diagnosis was 7 (0-15) years. Of the 85 cases, 51 (60%) had congenital heart disease 10 children with rheumatic heart disease developed IE. Of the 85 cases, 35 (41%) met our criteria for healthcare-associated IE. 39/85 underwent surgery for IE. As direct result of IE, 4 (4.7%) children died and 9% of survivors had neurologic sequelae. Attributable in-hospital mortality was 4.7%. Staphylococcus aureus was the most common organism, accounting for 26 episodes (30.6%). Other notable pathogens included Corynebacterium diphtheriae (10 cases, 11.8%) and Streptococcus pyogenes (7 cases, 8.2%). In 6 episodes, the microbiologic diagnosis was made by 16S ribosomal RNA testing of excised cardiac tissue. CONCLUSIONS: Congenital heart disease was the major risk factor for IE; however, rheumatic heart disease is also an important risk factor in New Zealand, with implications for local endocarditis prophylaxis recommendations. In addition to a high burden of healthcare-associated and staphylococcal IE, pathogens such as C. diphtheriae and S. pyogenes occurred. 16S ribosomal RNA testing is a useful tool to determine the etiologic agent in culture-negative IE.