Snakebite is a neglected tropical disease with significant morbidity and mortality. Thrombotic microangiopathy (TMA) is an important but poorly understood complication of snakebite associated with acute kidney injury (AKI). Numerous treatments have been attempted based on limited evidence. We conducted a systematic review of TMA following snakebite using a pre-determined case definition of blood film red cell schistocytes or histologically diagnosed TMA. The search strategy included major electronic databases and grey literature. We present a descriptive synthesis for the outcomes of AKI, dialysis free survival (DFS), other end-organ damage, overall survival, and interventions with antivenom and therapeutic plasmapheresis (TPE). This study was prospectively registered with PROSPERO (CRD42019121436). Seventy-two studies reporting 351 cases were included, predominantly small observational studies. Heterogeneity for study selection, design, reporting and outcomes were observed. The commonest envenoming species were hump-nosed vipers (Hypnale spp.), Russell’s viper (Daboia russelii) and Australian brown snakes (Pseudechis spp.). The prevalence of TMA was at least 5.4% in proven and probable Hypnale bites, and 10–15% of Australian elapid envenomings, AKI occurred in 94% (293/312) of TMA cases, excluding case reports. The majority of cases with AKI required dialysis. Included prospective and retrospective cohort studies reporting interventions and renal outcomes showed no evidence for benefit from antivenom or TPE with respect to DFS in dialysis dependant AKI. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment for quality of accumulated evidence for interventions was low. The major complication of TMA following snakebite is AKI. AKI improves in most cases. We found no evidence to support benefit from antivenom in snakebite associated TMA, but antivenom remains the standard of care for snake envenoming. There was no evidence for benefit of TPE in snakebite associated TMA, so TPE cannot be recommended. The quality of accumulated evidence was low, highlighting a need for high quality larger studies.

Burkholderia pseudomallei is endemic in northern Australia, with cases of melioidosis most commonly occurring during the wet season in individuals with diabetes, hazardous alcohol use, and chronic kidney disease. Pneumonia is the most common presentation and the majority of patients are bacteraemic—however, infection may involve almost any organ, with the skin and soft tissues, genitourinary system, visceral organs, and bone and joints affected most commonly. Central nervous system involvement is rarer, but has a high attributable mortality. Increased awareness of the disease amongst healthcare providers, ready access to appropriate antibiotic therapy and high-quality intensive care services has resulted in a sharp decline in the case fatality rate over the last 20 years. Further improvement in clinical outcomes will require a greater understanding of the disease′s pathophysiology, its optimal management, and more effective strategies for its prevention.

A recent modeling study estimated that there could be as many as 20,000 human melioidosis cases per year in Indonesia, with around 10,000 potential deaths annually. Nonetheless, the true burden of melioidosis in Indonesia is still unknown. The Indonesia Melioidosis Network was formed during the first melioidosis workshop in 2017. Here, we reviewed 101 melioidosis cases (99 human and two animal cases) previously reported and described an additional 45 human melioidosis cases. All 146 culture-confirmed cases were found in Sumatra (n = 15), Java (n = 104), Kalimantan (n = 15), Sulawesi (n = 11) and Nusa Tenggara (n = 1). Misidentification of Burkholderia pseudomallei was not uncommon, and most cases were only recently identified. We also evaluated clinical manifestations and outcome of recent culture-confirmed cases between 2012 and 2017 (n = 42). Overall, 15 (36%) cases were children (age <15 years) and 27 (64%) were adults (age ≥15 years). The overall mortality was 43% (18/42). We conducted a survey and found that 57% (327/548) of healthcare workers had never heard of melioidosis. In conclusion, melioidosis is endemic throughout Indonesia and associated with high mortality. We propose that top priorities are increasing awareness of melioidosis amongst all healthcare workers, increasing the use of bacterial culture, and ensuring accurate identification of B. pseudomalleiand diagnosis of melioidosis.

Background Scabies is listed as a neglected tropical disease by the World Health Organization. Crusted scabies affects vulnerable and immunosuppressed individuals and is highly contagious because of the enormous number of Sarcoptes scabiei mites present in the hyperkeratotic skin. Undiagnosed and untreated crusted scabies cases can result in outbreaks of scabies in residential facilities and can also undermine the success of scabies mass drug administration programs. Methods and principal findings Crusted scabies became a formally notifiable disease in the Northern Territory of Australia in 2016. We conducted a 2-year prospective study of crusted scabies cases notified between March 2016 and February 2018, with subsequent follow up for 22 months. Demographics, clinical and laboratory data, treatment and outcomes were analysed, with cases classified by severity of disease. Over the 2-year study period, 80 patients had 92 episodes of crusted scabies; 35 (38%) were Grade 1 crusted scabies, 36 (39%) Grade 2 and 21 (23%) Grade 3. Median age was 47 years, 47 (59%) were female, 76 (95%) Indigenous Australians and 57 (71%) from remote Indigenous communities. Half the patients were diabetic and 18 (23%) were on dialysis for end-stage kidney failure. Thirteen (16%) patients had no comorbidities, and these were more likely to have Grade 3 disease. Eosinophilia was present in 60% and high immunoglobulin E in 94%. Bacteremia occurred in 11 episodes resulting in one fatality with methicillin-susceptible Staphylococcus aureus bacteremia. Two other deaths occurred during admission and 10 others died subsequent to discharge consequent to comorbidities. Treatment generally followed the recommended guidelines, with 3, 5 or 7 doses of oral ivermectin depending on the documented grade of crusted scabies, together with daily alternating topical scabicides and topical keratolytic cream. While response to this therapy was usually excellent, there were 33 episodes of recurrent crusted scabies with the majority attributed to new infection subsequent to return to a scabies-endemic community. Conclusions Crusted scabies can be successfully treated with aggressive guideline-based therapy, but high mortality remains from underlying comorbidities. Reinfection on return to community is common while scabies remains endemic.

The Tier 1 select agent Burkholderia pseudomallei is an environmental bacterium that causes melioidosis, a high mortality disease. Variably present genetic markers used to elucidate strain origin, relatedness and virulence in B . pseudomallei include the Burkholderia intracellular motility factor A ( bimA ) and filamentous hemagglutinin 3 ( fhaB3 ) gene variants. Three lipopolysaccharide (LPS) O-antigen types in B . pseudomallei have been described, which vary in proportion between Australian and Asian isolates. However, it remains unknown if these LPS types can be used as genetic markers for geospatial analysis within a contiguous melioidosis-endemic region. Using a combination of whole-genome sequencing (WGS), statistical analysis and geographical mapping, we examined if the LPS types can be used as geographical markers in the Northern Territory, Australia. The clinical isolates revealed that LPS A prevalence was highest in the Darwin and surrounds (n = 660; 96% being LPS A and 4% LPS B) and LPS B in the Katherine and Katherine remote and East Arnhem regions (n = 79; 60% being LPS A and 40% LPS B). Bivariate logistics regression of 999 clinical B . pseudomallei isolates revealed that the odds of getting a clinical isolate with LPS B was highest in East Arnhem in comparison to Darwin and surrounds (OR 19.5, 95% CI 9.1–42.0; p <0.001). This geospatial correlation was subsequently confirmed by geographically mapping the LPS type from 340 environmental Top End strains. We also found that in the Top End, the minority bimA genotype bimA Bm has a similar remote region geographical footprint to that of LPS B. In addition, correlation of LPS type with multi-locus sequence typing (MLST) was strong, and where multiple LPS types were identified within a single sequence type, WGS confirmed homoplasy of the MLST loci. The clinical, sero-diagnostic and vaccine implications of geographically-based B . pseudomallei LPS types, and their relationships to regional and global dispersal of melioidosis, require global collaborations with further analysis of larger clinically and geospatially-linked datasets.

Human-to-human transmission of the melioidosis bacterium, Burkholderia pseudomallei , is exceedingly rare, with only a handful of suspected cases documented to date. Here, we used whole-genome sequencing (WGS) to characterize one such unusual B. pseudomallei transmission event, which occurred between a breastfeeding mother with mastitis and her child. Two strains corresponding to multilocus sequence types (STs)-259 and -261 were identified in the mother’s sputum from both the primary culture sweep and in purified colonies, confirming an unusual polyclonal infection in this patient. In contrast, primary culture sweeps of the mother’s breast milk and the child’s cerebrospinal fluid and blood samples contained only ST-259, indicating monoclonal transmission to the child. Analysis of purified ST-259 isolates showed no genetic variation between mother and baby isolates, providing the strongest possible evidence of B. pseudomallei human-to-human transmission, probably via breastfeeding. Next, phylogenomic analysis of all isolates, including the mother’s mixed ST-259/ST-261 sputum sample, was performed to investigate the effects of mixtures on phylogenetic inference. Inclusion of this mixture caused a dramatic reduction in the number of informative SNPs, resulting in branch collapse of ST-259 and ST-261 isolates, and several instances of incorrect topology in a global B. pseudomallei phylogeny, resulting in phylogenetic incongruence. Although phylogenomics can provide clues about the presence of mixtures within WGS datasets, our results demonstrate that this methodology can lead to phylogenetic misinterpretation if mixed genomes are not correctly identified and omitted. Using current bioinformatic tools, we demonstrate a robust method for bacterial mixture identification and strain parsing that avoids these pitfalls.

The purpose of this study was to quantify the adverse effects from oral eradication therapy for melioidosis, which is usually with high dose trimethoprim-sulfamethoxazole for 3-6 months. Methods: This retrospective cohort study reviewed side effects from oral eradication therapy in patients presenting with first episode culture-confirmed melioidosis in the tropical north of Australia's Northern Territory between 1st October 2012 and 1st January 2017. Results: 234 patients presented for the first time with culture-confirmed melioidosis. Of these, 16 (6.8%) died during the intensive phase treatment and 6 (2.6%) did not have complete treatment at Royal Darwin Hospital. Of the remaining 212 patients, 203 (95.8%) were initially prescribed trimethoprimsulfamethoxazole as oral eradication therapy, 6 (2.8%) were prescribed doxycycline and 3 (1.4%) had no eradication therapy. Of the 203 prescribed trimethoprim-sulfamethoxazole, 61 (30.0%) experienced adverse effects, which necessitated a cessation, a change in antibiotic or reduction in dose. Conclusions: In patients treated for melioidosis in northern Australia there are high rates of adverse effects from oral trimethoprim-sulfamethoxazole, frequently necessitating a change in therapy or a reduction in dose. Given the side effects and low rates of oral therapy completion in our region we emphasise the importance of the prior often prolonged intensive phase intravenous therapy and using weight based trimethoprim-sulfamethoxazole dosing for eradication therapy.

Background: Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of patients with venom-induced consumption coagulopathy (VICC) following snakebite. Acute kidney injury (AKI) is the commonest end-organ manifestation of TMA. The epidemiology, diagnostic features, outcomes, and effectiveness of interventions including therapeutic plasma-exchange (TPE), in snakebite-associated TMA are poorly understood. Methods: We reviewed all patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project (2004-2018 inclusive), a prospective cohort study, from 202 participating Australian hospitals across the country. TMA was defined as anemia with schistocytosis. Results: 2069 patients with suspected snakebite were enrolled, with 1158 (56.0%) systemically envenomed, of which 842 (72.7%) developed VICC, from which 104 (12.4%) developed TMA. Of those systemically envenomed, TMA occurred in 26% (13/50) taipan, 17% (60/351) brown, and 8% (16/197) tiger snakebites. Thrombocytopenia was present in 90% (94/104) of TMA cases, and a further eight (8%) had a > 25% decrease in platelets from the presentation. Patients with TMA were significantly older than non-TMA patients with versus 41 [24-55] years, median [IQR], p < 0.0001). AKI developed in 94% (98/104) of TMA patients, with 34% (33/98) requiring dialysis (D-AKI). There were four deaths. In D-AKI TMA cases, eventual dialysis-free survival (DFS) was 97% (32/33). TPE was used in five D-AKI cases, with no significant difference in DFS or time to independence from dialysis. >90-day follow-up for 25 D-AKI cases (130 person-years) showed no end-stage kidney disease but 52% (13/25) had ! stage 3 chronic kidney disease (CKD). Conclusion:Our findings support a definition of snakebite-associated TMA as anemia with schistocytosis and either thrombocytopenia or >25% drop in platelet count. AKI occurring with snakebite-associated TMA varied in severity, with most achieving DFS, but with a risk of long-term CKD in half. We found no evidence of benefit for TPE in D-AKI.