The development of snake antivenoms more than a century ago should have heralded effective treatm... more The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.An international, multidisciplinary collaboration provides a mechanism to fund evaluation of existing antivenoms and production of new antivenoms using improved antigens. This donorfunded, regulated process would deliver safe, effective free antivenoms to snakebite victims.► Snakebite is arguably the most neglected of all the neglected tropical diseases. ► A global shortage of accessible, safe, effective antivenoms is a major barrier to improving snakebite treatment. ► Greater deployment of proteomic, and other techniques could produce improved antivenoms. ► A multi‐disciplinary, multi‐centre collaboration to improve access to safe, effective antivenoms is proposed.
Background: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyur... more Background: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyuranus scutellatus, inflicts a large number of bites that, in the absence of antivenom therapy, result in high mortality. Parenteral administration of antivenoms manufactured in Australia is the current treatment of choice for these envenomings. However, the price of these products is high and has increased over the last 25 years; consequently the country can no longer afford all the antivenom it needs. This situation prompted an international collaborative project aimed at generating a new, low-cost antivenom against O. scutellatus for PNG. Methodology/Principal Findings: A new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab’)2 monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A2 activities of the venom of O. scutellatus from PNG. The F(ab’)2 antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A2 activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab’)2 antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG. Conclusions/Significance: The new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab’)2 antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.
The development of snake antivenoms more than a century ago should have heralded effective treatm... more The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and newantivenoms formeeting urgent regional needs.We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary,multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.
Snakebite envenoming is a neglected public health challenge of compelling importance in many regi... more Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens (snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent. (i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by theWorld Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming.
Lancet 2010; 375: 89–91:
Panel: Key initiatives
• Community education about improved prevention a... more Lancet 2010; 375: 89–91: Panel: Key initiatives • Community education about improved prevention and preclinical care on the basis of the specific needs of different regions, consistent advocacy, and comprehensive community engagement • Improved injury surveillance, and advocacy for making snake bite a notifiable disease so that reporting becomes mandatory at local, national, and regional levels • Further clinical and basic research with focus on an improved understanding of injury mechanisms and optimisation of interventions • Systematic approaches to improve medical management, education, and training of medical and paramedical personnel, focusing on the specific needs of different regions (teaching materials should be developed by those with first-hand experience of treating snake bites) • Functional support for the prequalification of antivenoms (the only specific antidote for envenoming), research to improve their safety and clinical eff ectiveness, and storage conditions and hence shelf life • Promotion of rehabilitation and prevention of disability through engagement with established stakeholders in this field so that the physical, economic, and psychological handicaps resulting from snake bite are kept to a minimum • Build effective public health policy and governance frameworks, and create innovative fi nancing bridges to enable programmes to be put into practice
Pseudonaja textilis is a widespread and common snake in eastern parts of Australia, but its distr... more Pseudonaja textilis is a widespread and common snake in eastern parts of Australia, but its distribution in New Guinea is poorly understood, and the origin of the New Guinea populations and its timing have been the subject of much speculation. Phylogenetic analysis of mitochondrial DNA sequences from three New Guinea populations of P. textilis indicates that New Guinea was colonised from two independent eastern and western migration routes most likely in the Pleistocene. One dispersal event from northern Queensland led to the populations in eastern New Guinea (Milne Bay, Oro and Central Provinces, Papua New Guinea), whereas another, from Arnhem Land to central southern New Guinea, led to the populations from the Merauke area, Indonesian Papua. The results are consistent with the effects of Pleistocene sea level changes on the physical geography of Australasia, and are thus suggestive of a natural rather than anthropogenic origin of the New Guinea populations. The taxonomic status of the New Guinean populations is discussed.
Objective: To examine antivenom use, premedication, early adverse reactions and patient outcomes ... more Objective: To examine antivenom use, premedication, early adverse reactions and patient outcomes after snake bite in rural Papua New Guinea. Design: Retrospective chart analysis of all admissions for snake bite with documented antivenom use at 11 rural health facilities from January 1994 to June 2004. No formal protocol was followed and there was no attempt at randomisation or blinding of prophylaxis. Results: Antivenom use was documented in 136/1881 (7.2%) snake bite admissions and most (121/136: 88.9%) received a single vial. CSL Polyvalent antivenom was administered to 112/136 (82.4%). One hundred and eleven patients (81.6%) happened to have been given premedication with adrenaline and/or promethazine and/or hydrocortisone. Early adverse reactions were reported in 25 patients (18.4%) including 23 treated with polyvalent antivenom. Intravenous test doses of antivenom were given to 32 patients, none of whom had a positive test result. Subsequent adverse reactions occurred in 9 of these 32 (28.1%) patients. One death may have been attributable to anaphylaxis after polyvalent antivenom. Reaction rates were significantly (pp0.005) lower in adrenaline premedicated patients (7.7%) compared to patients premedicated without adrenaline (28.3%) and unpremedicated patients (28.0%). Adrenaline premedication caused no detectable changes in vital signs. The case fatality rate was 9.6% (13/136 patients). Conclusions: Polyvalent antivenom is the main treatment for envenomation in rural health centres, and early adverse reactions are common. Adrenaline premedication appears to significantly reduce acute adverse reaction rates. Premedication with promethazine and/or hydrocortisone without adrenaline did not reduce early adverse reactions.
The Australian snake fauna is unique in harbouring more venomous species than non-venomous ones. ... more The Australian snake fauna is unique in harbouring more venomous species than non-venomous ones. Although taxonomic research on the elapid snakes of Australia goes back to the late 18th century, in stark contrast to other developed regions of the world (e.g. the continental USA), Australian snake taxonomy is very much in its infancy. Despite this, or perhaps because of this, the taxonomy of Australian snakes has been extraordinarily controversial, and many of the taxonomists involved correspondingly colourful. In this review, we explore the sometimes-tortured history of the taxonomic exploration of the venomous snake fauna of Australia, looking at some of the more colourful and notable contributors and highlighting systematic pitfalls that persist even today.
Abstract
We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—deat... more Abstract We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
Objective: Fatal snakebites at Port Moresby General Hospital (PMGH), Papua New Guinea (PNG), were... more Objective: Fatal snakebites at Port Moresby General Hospital (PMGH), Papua New Guinea (PNG), were examined to identify interventions that may improve patient survival. Design: Retrospective case series. Subjects and setting: Inpatients at PMGH who presented with snakebite, had evidence of envenomation, and died as inpatients between 1 January 1992 and 31 December 2001. Outcome measures: Number and cause of fatalities; ventilation bed-days; antivenom timing, dose and price. Results: 87 deaths occurred among 722 snakebite admissions to the intensive care unit (ICU). Of these 722 patients, 82.5% were ventilated, representing 45% of all ventilated ICU patients and 60% (3430/5717) of all ICU ventilator bed-days. The median duration of ventilation in fatal snakebite cases was significantly less than in non-fatal cases for children (3.0 v. 4.5 days) and adults (3.0 v. 5.0 days). The case-fatality rate for children (14.6%) was significantly greater than that for adults (8.2%). Sixty fatalities were examined in detail: 75% received blood products; 53% received antivenom (mostly a single ampoule of polyvalent), but only 5% received antivenom 4 hours post-bite. Major causes of death included respiratory complications (50%), probable intracerebral haemorrhage (17%), and renal failure (10%). Antivenom unit costs increased significantly over the decade; in 2000 an ampoule of polyvalent antivenom was 40-fold more expensive in PNG than in Australia on a gross domestic product (A$) per capita basis. Conclusions: Management of severe snakebite is a major challenge for PMGH. Improved antivenom procurement and use policies (including increased use of appropriate monovalent antivenoms), combined with targeted snakebite education interventions (community- and hospital-based), are key interventions to reduce the ongoing toll from snakebite.
Nine cases of serious envenomation following bites by Papuan taipans Oxyuranus scutellatus canni ... more Nine cases of serious envenomation following bites by Papuan taipans Oxyuranus scutellatus canni are presented. Eight cases were fatal with contributing factors such as delayed presentation with advanced symptoms, incorrect antivenom administration, failure to recognise key indications of envenoming, lack of antivenom, and delayed administration of correct antivenom. The survival of a single patient was greatly assisted by prompt recognition of coagulopathy as a symptom of envenoming, followed by administration of appropriate antivenom and careful patient monitoring using available techniques such as the 20WBCT protocol. A consistent approach to management incorporating strategies such as early recognition of envenomation, prompt pressure immobilisation, precise ongoing clinical assessment and early treatment with appropriate antivenom may improve the prognosis of envenomed patients.
The development of snake antivenoms more than a century ago should have heralded effective treatm... more The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.An international, multidisciplinary collaboration provides a mechanism to fund evaluation of existing antivenoms and production of new antivenoms using improved antigens. This donorfunded, regulated process would deliver safe, effective free antivenoms to snakebite victims.► Snakebite is arguably the most neglected of all the neglected tropical diseases. ► A global shortage of accessible, safe, effective antivenoms is a major barrier to improving snakebite treatment. ► Greater deployment of proteomic, and other techniques could produce improved antivenoms. ► A multi‐disciplinary, multi‐centre collaboration to improve access to safe, effective antivenoms is proposed.
Background: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyur... more Background: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyuranus scutellatus, inflicts a large number of bites that, in the absence of antivenom therapy, result in high mortality. Parenteral administration of antivenoms manufactured in Australia is the current treatment of choice for these envenomings. However, the price of these products is high and has increased over the last 25 years; consequently the country can no longer afford all the antivenom it needs. This situation prompted an international collaborative project aimed at generating a new, low-cost antivenom against O. scutellatus for PNG. Methodology/Principal Findings: A new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab’)2 monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A2 activities of the venom of O. scutellatus from PNG. The F(ab’)2 antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A2 activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab’)2 antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG. Conclusions/Significance: The new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab’)2 antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.
The development of snake antivenoms more than a century ago should have heralded effective treatm... more The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and newantivenoms formeeting urgent regional needs.We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary,multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.
Snakebite envenoming is a neglected public health challenge of compelling importance in many regi... more Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens (snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent. (i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by theWorld Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming.
Lancet 2010; 375: 89–91:
Panel: Key initiatives
• Community education about improved prevention a... more Lancet 2010; 375: 89–91: Panel: Key initiatives • Community education about improved prevention and preclinical care on the basis of the specific needs of different regions, consistent advocacy, and comprehensive community engagement • Improved injury surveillance, and advocacy for making snake bite a notifiable disease so that reporting becomes mandatory at local, national, and regional levels • Further clinical and basic research with focus on an improved understanding of injury mechanisms and optimisation of interventions • Systematic approaches to improve medical management, education, and training of medical and paramedical personnel, focusing on the specific needs of different regions (teaching materials should be developed by those with first-hand experience of treating snake bites) • Functional support for the prequalification of antivenoms (the only specific antidote for envenoming), research to improve their safety and clinical eff ectiveness, and storage conditions and hence shelf life • Promotion of rehabilitation and prevention of disability through engagement with established stakeholders in this field so that the physical, economic, and psychological handicaps resulting from snake bite are kept to a minimum • Build effective public health policy and governance frameworks, and create innovative fi nancing bridges to enable programmes to be put into practice
Pseudonaja textilis is a widespread and common snake in eastern parts of Australia, but its distr... more Pseudonaja textilis is a widespread and common snake in eastern parts of Australia, but its distribution in New Guinea is poorly understood, and the origin of the New Guinea populations and its timing have been the subject of much speculation. Phylogenetic analysis of mitochondrial DNA sequences from three New Guinea populations of P. textilis indicates that New Guinea was colonised from two independent eastern and western migration routes most likely in the Pleistocene. One dispersal event from northern Queensland led to the populations in eastern New Guinea (Milne Bay, Oro and Central Provinces, Papua New Guinea), whereas another, from Arnhem Land to central southern New Guinea, led to the populations from the Merauke area, Indonesian Papua. The results are consistent with the effects of Pleistocene sea level changes on the physical geography of Australasia, and are thus suggestive of a natural rather than anthropogenic origin of the New Guinea populations. The taxonomic status of the New Guinean populations is discussed.
Objective: To examine antivenom use, premedication, early adverse reactions and patient outcomes ... more Objective: To examine antivenom use, premedication, early adverse reactions and patient outcomes after snake bite in rural Papua New Guinea. Design: Retrospective chart analysis of all admissions for snake bite with documented antivenom use at 11 rural health facilities from January 1994 to June 2004. No formal protocol was followed and there was no attempt at randomisation or blinding of prophylaxis. Results: Antivenom use was documented in 136/1881 (7.2%) snake bite admissions and most (121/136: 88.9%) received a single vial. CSL Polyvalent antivenom was administered to 112/136 (82.4%). One hundred and eleven patients (81.6%) happened to have been given premedication with adrenaline and/or promethazine and/or hydrocortisone. Early adverse reactions were reported in 25 patients (18.4%) including 23 treated with polyvalent antivenom. Intravenous test doses of antivenom were given to 32 patients, none of whom had a positive test result. Subsequent adverse reactions occurred in 9 of these 32 (28.1%) patients. One death may have been attributable to anaphylaxis after polyvalent antivenom. Reaction rates were significantly (pp0.005) lower in adrenaline premedicated patients (7.7%) compared to patients premedicated without adrenaline (28.3%) and unpremedicated patients (28.0%). Adrenaline premedication caused no detectable changes in vital signs. The case fatality rate was 9.6% (13/136 patients). Conclusions: Polyvalent antivenom is the main treatment for envenomation in rural health centres, and early adverse reactions are common. Adrenaline premedication appears to significantly reduce acute adverse reaction rates. Premedication with promethazine and/or hydrocortisone without adrenaline did not reduce early adverse reactions.
The Australian snake fauna is unique in harbouring more venomous species than non-venomous ones. ... more The Australian snake fauna is unique in harbouring more venomous species than non-venomous ones. Although taxonomic research on the elapid snakes of Australia goes back to the late 18th century, in stark contrast to other developed regions of the world (e.g. the continental USA), Australian snake taxonomy is very much in its infancy. Despite this, or perhaps because of this, the taxonomy of Australian snakes has been extraordinarily controversial, and many of the taxonomists involved correspondingly colourful. In this review, we explore the sometimes-tortured history of the taxonomic exploration of the venomous snake fauna of Australia, looking at some of the more colourful and notable contributors and highlighting systematic pitfalls that persist even today.
Abstract
We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—deat... more Abstract We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
Objective: Fatal snakebites at Port Moresby General Hospital (PMGH), Papua New Guinea (PNG), were... more Objective: Fatal snakebites at Port Moresby General Hospital (PMGH), Papua New Guinea (PNG), were examined to identify interventions that may improve patient survival. Design: Retrospective case series. Subjects and setting: Inpatients at PMGH who presented with snakebite, had evidence of envenomation, and died as inpatients between 1 January 1992 and 31 December 2001. Outcome measures: Number and cause of fatalities; ventilation bed-days; antivenom timing, dose and price. Results: 87 deaths occurred among 722 snakebite admissions to the intensive care unit (ICU). Of these 722 patients, 82.5% were ventilated, representing 45% of all ventilated ICU patients and 60% (3430/5717) of all ICU ventilator bed-days. The median duration of ventilation in fatal snakebite cases was significantly less than in non-fatal cases for children (3.0 v. 4.5 days) and adults (3.0 v. 5.0 days). The case-fatality rate for children (14.6%) was significantly greater than that for adults (8.2%). Sixty fatalities were examined in detail: 75% received blood products; 53% received antivenom (mostly a single ampoule of polyvalent), but only 5% received antivenom 4 hours post-bite. Major causes of death included respiratory complications (50%), probable intracerebral haemorrhage (17%), and renal failure (10%). Antivenom unit costs increased significantly over the decade; in 2000 an ampoule of polyvalent antivenom was 40-fold more expensive in PNG than in Australia on a gross domestic product (A$) per capita basis. Conclusions: Management of severe snakebite is a major challenge for PMGH. Improved antivenom procurement and use policies (including increased use of appropriate monovalent antivenoms), combined with targeted snakebite education interventions (community- and hospital-based), are key interventions to reduce the ongoing toll from snakebite.
Nine cases of serious envenomation following bites by Papuan taipans Oxyuranus scutellatus canni ... more Nine cases of serious envenomation following bites by Papuan taipans Oxyuranus scutellatus canni are presented. Eight cases were fatal with contributing factors such as delayed presentation with advanced symptoms, incorrect antivenom administration, failure to recognise key indications of envenoming, lack of antivenom, and delayed administration of correct antivenom. The survival of a single patient was greatly assisted by prompt recognition of coagulopathy as a symptom of envenoming, followed by administration of appropriate antivenom and careful patient monitoring using available techniques such as the 20WBCT protocol. A consistent approach to management incorporating strategies such as early recognition of envenomation, prompt pressure immobilisation, precise ongoing clinical assessment and early treatment with appropriate antivenom may improve the prognosis of envenomed patients.
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Papers by David Williams
Methodology/Principal Findings: A new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab’)2 monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A2 activities of the venom of O. scutellatus from PNG. The F(ab’)2 antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A2 activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab’)2 antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG.
Conclusions/Significance: The new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab’)2 antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.
snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new
approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and
snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach
brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the
suitability of current and newantivenoms formeeting urgent regional needs.We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom
drought in Africa and Asia: first by establishing a multidisciplinary,multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.
(a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae.
(b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories.
(c) Increasing the capacity of low-income countries to produce specific immunogens (snake venoms) locally, and to perform their own quality control of antivenoms.
(d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible.
(e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries.
(f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials.
(g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country.
(h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.
(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities.
(j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion.
Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by theWorld Health Organization, will help to
alleviate the enormous burden of human suffering inflicted by snakebite envenoming.
Panel: Key initiatives
• Community education about improved prevention and preclinical care on the basis of the specific needs of different regions, consistent advocacy, and comprehensive community engagement
• Improved injury surveillance, and advocacy for making snake bite a notifiable disease so that reporting becomes mandatory at local, national, and regional levels
• Further clinical and basic research with focus on an improved understanding of injury mechanisms and optimisation of interventions
• Systematic approaches to improve medical management,
education, and training of medical and paramedical personnel, focusing on the specific needs of different regions (teaching materials should be developed by those with first-hand experience of treating snake bites)
• Functional support for the prequalification of antivenoms (the only specific antidote for envenoming), research to improve their safety and clinical eff ectiveness, and storage conditions and hence shelf life
• Promotion of rehabilitation and prevention of disability through engagement with established stakeholders in this field so that the physical, economic, and psychological handicaps resulting from snake bite are kept to a minimum
• Build effective public health policy and governance frameworks, and create innovative fi nancing bridges to enable programmes to be put into practice
Design: Retrospective chart analysis of all admissions for snake bite with documented antivenom use at 11 rural health facilities from January 1994 to June 2004. No formal protocol was followed and there was no attempt at randomisation or blinding of prophylaxis.
Results: Antivenom use was documented in 136/1881 (7.2%) snake bite admissions and most (121/136: 88.9%) received a single vial. CSL Polyvalent antivenom was administered to 112/136 (82.4%). One hundred and eleven patients (81.6%) happened to have been given premedication with adrenaline and/or promethazine and/or hydrocortisone. Early adverse reactions were reported in 25 patients (18.4%) including 23 treated with polyvalent antivenom. Intravenous test doses of antivenom were given to 32 patients, none of whom had a positive test result. Subsequent adverse reactions occurred in 9 of these 32 (28.1%) patients. One death may have been attributable to anaphylaxis after polyvalent antivenom. Reaction rates were significantly (pp0.005) lower in adrenaline premedicated patients (7.7%) compared to patients premedicated without adrenaline (28.3%) and unpremedicated patients (28.0%). Adrenaline premedication caused no detectable changes in vital signs. The case fatality rate was 9.6% (13/136 patients).
Conclusions: Polyvalent antivenom is the main treatment for envenomation in rural health centres, and early adverse reactions are common. Adrenaline premedication appears to significantly reduce acute adverse reaction rates. Premedication with promethazine and/or hydrocortisone without adrenaline did not reduce early adverse reactions.
We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
Design: Retrospective case series.
Subjects and setting: Inpatients at PMGH who presented with snakebite, had evidence of envenomation, and died as inpatients between 1 January 1992 and 31 December 2001.
Outcome measures: Number and cause of fatalities; ventilation bed-days; antivenom timing, dose and price.
Results: 87 deaths occurred among 722 snakebite admissions to the intensive care unit (ICU). Of these 722 patients, 82.5% were ventilated, representing 45% of all ventilated ICU patients and 60% (3430/5717) of all ICU ventilator bed-days. The median duration of ventilation in fatal snakebite cases was significantly less than in non-fatal cases for children (3.0 v. 4.5 days) and adults (3.0 v. 5.0 days). The case-fatality rate for children (14.6%) was significantly greater than that for adults (8.2%). Sixty fatalities were examined in detail: 75% received blood products; 53% received antivenom (mostly a single ampoule of polyvalent), but only 5% received antivenom 4 hours post-bite. Major causes of death included respiratory complications (50%), probable intracerebral haemorrhage (17%), and renal failure (10%). Antivenom unit costs increased significantly over the decade; in 2000 an ampoule of polyvalent antivenom was 40-fold more expensive in PNG than in Australia on a gross domestic product (A$) per capita basis.
Conclusions: Management of severe snakebite is a major challenge for PMGH. Improved antivenom procurement and use policies (including increased use of appropriate monovalent antivenoms), combined with targeted snakebite education interventions (community- and hospital-based), are key interventions to reduce the ongoing toll from snakebite.
Methodology/Principal Findings: A new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab’)2 monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A2 activities of the venom of O. scutellatus from PNG. The F(ab’)2 antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A2 activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab’)2 antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG.
Conclusions/Significance: The new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab’)2 antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.
snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new
approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and
snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach
brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the
suitability of current and newantivenoms formeeting urgent regional needs.We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom
drought in Africa and Asia: first by establishing a multidisciplinary,multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.
(a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae.
(b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories.
(c) Increasing the capacity of low-income countries to produce specific immunogens (snake venoms) locally, and to perform their own quality control of antivenoms.
(d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible.
(e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries.
(f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials.
(g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country.
(h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.
(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities.
(j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion.
Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by theWorld Health Organization, will help to
alleviate the enormous burden of human suffering inflicted by snakebite envenoming.
Panel: Key initiatives
• Community education about improved prevention and preclinical care on the basis of the specific needs of different regions, consistent advocacy, and comprehensive community engagement
• Improved injury surveillance, and advocacy for making snake bite a notifiable disease so that reporting becomes mandatory at local, national, and regional levels
• Further clinical and basic research with focus on an improved understanding of injury mechanisms and optimisation of interventions
• Systematic approaches to improve medical management,
education, and training of medical and paramedical personnel, focusing on the specific needs of different regions (teaching materials should be developed by those with first-hand experience of treating snake bites)
• Functional support for the prequalification of antivenoms (the only specific antidote for envenoming), research to improve their safety and clinical eff ectiveness, and storage conditions and hence shelf life
• Promotion of rehabilitation and prevention of disability through engagement with established stakeholders in this field so that the physical, economic, and psychological handicaps resulting from snake bite are kept to a minimum
• Build effective public health policy and governance frameworks, and create innovative fi nancing bridges to enable programmes to be put into practice
Design: Retrospective chart analysis of all admissions for snake bite with documented antivenom use at 11 rural health facilities from January 1994 to June 2004. No formal protocol was followed and there was no attempt at randomisation or blinding of prophylaxis.
Results: Antivenom use was documented in 136/1881 (7.2%) snake bite admissions and most (121/136: 88.9%) received a single vial. CSL Polyvalent antivenom was administered to 112/136 (82.4%). One hundred and eleven patients (81.6%) happened to have been given premedication with adrenaline and/or promethazine and/or hydrocortisone. Early adverse reactions were reported in 25 patients (18.4%) including 23 treated with polyvalent antivenom. Intravenous test doses of antivenom were given to 32 patients, none of whom had a positive test result. Subsequent adverse reactions occurred in 9 of these 32 (28.1%) patients. One death may have been attributable to anaphylaxis after polyvalent antivenom. Reaction rates were significantly (pp0.005) lower in adrenaline premedicated patients (7.7%) compared to patients premedicated without adrenaline (28.3%) and unpremedicated patients (28.0%). Adrenaline premedication caused no detectable changes in vital signs. The case fatality rate was 9.6% (13/136 patients).
Conclusions: Polyvalent antivenom is the main treatment for envenomation in rural health centres, and early adverse reactions are common. Adrenaline premedication appears to significantly reduce acute adverse reaction rates. Premedication with promethazine and/or hydrocortisone without adrenaline did not reduce early adverse reactions.
We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
Design: Retrospective case series.
Subjects and setting: Inpatients at PMGH who presented with snakebite, had evidence of envenomation, and died as inpatients between 1 January 1992 and 31 December 2001.
Outcome measures: Number and cause of fatalities; ventilation bed-days; antivenom timing, dose and price.
Results: 87 deaths occurred among 722 snakebite admissions to the intensive care unit (ICU). Of these 722 patients, 82.5% were ventilated, representing 45% of all ventilated ICU patients and 60% (3430/5717) of all ICU ventilator bed-days. The median duration of ventilation in fatal snakebite cases was significantly less than in non-fatal cases for children (3.0 v. 4.5 days) and adults (3.0 v. 5.0 days). The case-fatality rate for children (14.6%) was significantly greater than that for adults (8.2%). Sixty fatalities were examined in detail: 75% received blood products; 53% received antivenom (mostly a single ampoule of polyvalent), but only 5% received antivenom 4 hours post-bite. Major causes of death included respiratory complications (50%), probable intracerebral haemorrhage (17%), and renal failure (10%). Antivenom unit costs increased significantly over the decade; in 2000 an ampoule of polyvalent antivenom was 40-fold more expensive in PNG than in Australia on a gross domestic product (A$) per capita basis.
Conclusions: Management of severe snakebite is a major challenge for PMGH. Improved antivenom procurement and use policies (including increased use of appropriate monovalent antivenoms), combined with targeted snakebite education interventions (community- and hospital-based), are key interventions to reduce the ongoing toll from snakebite.