Phylodynamic signatures in the emergence of community-associated MRSA.

Community-associated, methicillin-resistant Staphylococcus aureus (MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 y. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole-genome sequencing data for the Australian sequence type (ST) ST93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (Re) and sustained transmission (Re > 1) coincided with spread of progenitor methicillin-susceptible S. aureus (MSSA) in remote northern Australian populations, dissemination of the ST93-MRSA-IV genotype into population centers on the Australian East Coast, and subsequent importation into the highlands of Papua New Guinea and Far North Queensland. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associated S. aureus lineages from America, Asia, Australasia, and Europe. Surges in Re were observed at the divergence of antibiotic-resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed among drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA in the late 20th century was driven by a combination of antibiotic-resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

Phylodynamic Inference of Bacterial Outbreak Parameters Using Nanopore Sequencing.

Nanopore sequencing and phylodynamic modeling have been used to reconstruct the transmission dynamics of viral epidemics, but their application to bacterial pathogens has remained challenging. Cost-effective bacterial genome sequencing and variant calling on nanopore platforms would greatly enhance surveillance and outbreak response in communities without access to sequencing infrastructure. Here, we adapt random forest models for single nucleotide polymorphism (SNP) polishing developed by Sanderson and colleagues (2020. High precision Neisseria gonorrhoeae variant and antimicrobial resistance calling from metagenomic nanopore sequencing. Genome Res. 30(9):1354-1363) to estimate divergence and effective reproduction numbers (Re) of two methicillin-resistant Staphylococcus aureus (MRSA) outbreaks from remote communities in Far North Queensland and Papua New Guinea (PNG; n = 159). Successive barcoded panels of S. aureus isolates (2 × 12 per MinION) sequenced at low coverage (>5× to 10×) provided sufficient data to accurately infer genotypes with high recall when compared with Illumina references. Random forest models achieved high resolution on ST93 outbreak sequence types (>90% accuracy and precision) and enabled phylodynamic inference of epidemiological parameters using birth-death skyline models. Our method reproduced phylogenetic topology, origin of the outbreaks, and indications of epidemic growth (Re > 1). Nextflow pipelines implement SNP polisher training, evaluation, and outbreak alignments, enabling reconstruction of within-lineage transmission dynamics for infection control of bacterial disease outbreaks on portable nanopore platforms. Our study shows that nanopore technology can be used for bacterial outbreak reconstruction at competitive costs, providing opportunities for infection control in hospitals and communities without access to sequencing infrastructure, such as in remote northern Australia and PNG.

The epidemiological transition in Papua New Guinea: new evidence from verbal autopsy studies.

BACKGROUND: Recent economic growth in Papua New Guinea (PNG) would suggest that the country may be experiencing an epidemiological transition, characterized by a reduction in infectious diseases and a growing burden from non-communicable diseases (NCDs). However, data on cause-specific mortality in PNG are very sparse, and the extent of the transition within the country is poorly understood. METHODS: Mortality surveillance was established in four small populations across PNG: West Hiri in Central Province, Asaro Valley in Eastern Highlands Province, Hides in Hela Province and Karkar Island in Madang Province. Verbal autopsies (VAs) were conducted on all deaths identified, and causes of death were assigned by SmartVA and classified into five broad disease categories: endemic NCDs; emerging NCDs; endemic infections; emerging infections; and injuries. Results from previous PNG VA studies, using different VA methods and spanning the years 1970 to 2001, are also presented here. RESULTS: A total of 868 deaths among adolescents and adults were identified and assigned a cause of death. NCDs made up the majority of all deaths (40.4%), with the endemic NCD of chronic respiratory disease responsible for the largest proportion of deaths (10.5%), followed by the emerging NCD of diabetes (6.2%). Emerging infectious diseases outnumbered endemic infectious diseases (11.9% versus 9.5%). The distribution of causes of death differed across the four sites, with emerging NCDs and emerging infections highest at the site that is most socioeconomically developed, West Hiri. Comparing the 1970-2001 VA series with the present study suggests a large decrease in endemic infections. CONCLUSIONS: Our results indicate immediate priorities for health service planning and for strengthening of vital registration systems, to more usefully serve the needs of health priority setting.

Holistic care of complicated tuberculosis in healthcare settings with limited resources.

In recent years, most of the focus on improving the quality of paediatric care in low-income countries has been on improving primary care using the Integrated Management of Childhood Illness, and improving triage and emergency treatment in hospitals aimed at reducing deaths in the first 24 hours. There has been little attention paid to improving the quality of care for children with chronic or complex diseases. Children with complicated forms of tuberculosis (TB), including central nervous system and chronic pulmonary TB, provide examples of acute and chronic multisystem paediatric illnesses that commonly present to district-level and second-level referral hospitals in low-income countries. The care of these children requires a holistic clinical and continuous quality improvement approach. This includes timely decisions on the commencement of treatment often when diagnoses are not certain, identification and management of acute respiratory, neurological and nutritional complications, identification and treatment of comorbidities, supportive care, systematic monitoring of treatment and progress, rehabilitation, psychological support, ensuring adherence, and safe transition to community care. New diagnostics and imaging can assist this, but meticulous attention to clinical detail at the bedside and having a clear plan for all aspects of care that is communicated well to staff and families are essential for good outcomes. The care is multidimensional: biomedical, rehabilitative, social and economic, and multidisciplinary: medical, nursing and allied health. In the era of the Sustainable Development Goals, approaches to these dimensions of healthcare are needed within the reach of the poorest people who access district hospitals in low-income countries.

Clinical management of diarrhoea in children.

Diarrhoea is one of the commonest reasons children require health care in Papua New Guinea (PNG). Acute watery diarrhoea is the commonest form, and is due to viruses. Oral rehydration solution, zinc and continued breastfeeding are highly effective treatments that can be delivered in homes and health facilities. Antibiotics are not useful in acute watery diarrhoea--they make it worse. Deaths from acute watery diarrhoea should be rare if basic curative services are available. Persistent diarrhoea (lasting longer than 14 days) is commonly associated with other co-morbidities, including malnutrition, anaemia, HIV (human immunodeficiency virus) infection, parasite (such as Giardia) or worm infections and environmental enteropathy. Educating parents on handwashing, food preparation, water purification, improvements in sanitation and the home environment, breastfeeding, nutrition and immunization are essential in preventing diarrhoea. Cholera appeared in PNG in 2009, causing over 500 deaths in all age groups. Cholera emerged because of limited access to safe, clean drinking water and poor sanitation. Addressing these will have beneficial effects not only on cholera but also on all causes of diarrhoea and many other common childhood infections.

Pigbel in the 21st century: still here, and still in need of an effective surveillance system.

Pigbel remains a likely significant cause of morbidity and mortality in the highlands of Papua New Guinea (PNG), two decades after the administration of pigbel vaccination ceased. There is a need for an effective surveillance program for pigbel to better understand the disease burden and to target communities for preventive strategies. This paper reviews the epidemiology, pathogenesis, recent history and current data on the burden of pigbel in PNG. We propose a surveillance program based on clinical recognition of likely cases and laboratory confirmation using an ELISA assay for Clostridium perfringens type C beta-toxin. Research aimed at validating this approach in the clinical setting is outlined.

In search of pigbel: gone or just forgotten in the highlands of Papua New Guinea?

Throughout the 1960s and 1970s, pigbel (enteritis necroticans) was the most common cause of death in children over the age of 1 year in hospitals in the highlands of Papua New Guinea (PNG). There has been recent widespread perception that after the successful vaccination program in the 1980s the disease virtually disappeared. A new vaccine is now available, but disease burden information is conflicting: despite almost no pigbel being reported from major hospitals there have been many reports of the disease from outlying health centres. This study aimed to provide information on the disease burden of pigbel in PNG, so that appropriate vaccine policy decisions could be made. We conducted a 12-month prospective study of all cases of acute abdomen in children presenting to 38 health facilities, 29 health centres and 9 hospitals in the highlands. Children were eligible for inclusion if they were aged 1-12 years and had abdominal pain of less than 2 weeks' duration. A standardized case definition of pigbel was used to distinguish cases of acute abdominal pain very likely to be due to pigbel from cases very likely to be accounted for by other diagnoses (such as gastroenteritis, typhoid, dysentery, intussusception, urinary tract infection and others). A total of 119 cases of acute abdomen were reported from 17 of the 38 health facilities involved. Of these 119 cases 11 met the criteria for pigbel and a further 8 were probable cases. There were 4 deaths among the 119 children with acute abdomen: 2 from definite pigbel, 1 from probable pigbel and the other due to complications of measles. In 2002 pigbel was the cause of between 9% and 16% of presentations with acute abdominal pain in children in the PNG highlands. The overall disease burden of pigbel was relatively small (19 definite or probable cases and 3 deaths in 12 months). However, there was substantial geographical clustering of cases: more than 50% of the definite cases occurred in children living within three electorates on the Western Highlands-Enga provincial border, no more than 40 km from each other. This study will be useful in planning pigbel vaccine policy and future surveillance.

Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial.

BACKGROUND: Pneumonia is the most frequent cause of child mortality in less-developed countries. We aimed to establish whether the combination of benzylpenicillin and gentamicin or chloramphenicol would be better as first-line treatment in children with severe pneumonia in Papua New Guinea. METHODS: We did an open randomised trial in which we enrolled children aged 1 month to 5 years of age who fulfilled the WHO criteria for very severe pneumonia and who presented to hospitals in two provinces. Children were randomly assigned to receive chloramphenicol (25 mg/kg 6 hourly) or benzylpenicillin (50 mg/kg 6 hourly) plus gentamicin (7.5 mg/kg daily) by intramuscular injection. The primary outcome measure was a good or an adverse outcome. FINDINGS: 1116 children were enrolled; 559 children were treated with chloramphenicol and 557 with benzylpenicillin and gentamicin. At presentation the median haemoglobin oxygen saturation was 71% (IQR 57-77) for those allocated chloramphenicol and 69% (55-77) for those allocated penicillin and gentamicin. 147 (26%) children treated with chloramphenicol and 123 (22%) treated with penicillin and gentamicin had adverse outcomes (p=0.11). 36 children treated with chloramphenicol and 29 treated with penicillin and gentamicin died. More children treated with chloramphenicol than penicillin and gentamicin represented with severe pneumonia within 1 month of hospital discharge (p=0.03). INTERPRETATION: For children with severe pneumonia in less-developed countries the probability of a good outcome is similar if treated with chloramphenicol or with the combination of benzylpenicillin and gentamicin.