Scott A. Weinstein

A review of the natural history, toxinology, diagnosis and clinical management of Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) poisoning

Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) are potentially lethal plants after ingestion. Poisoning by these plants is a common toxicological emergency in tropical and subtropical parts of the world and intentional self-harm using T. peruviana is prevalent in South Asian countries, especially India and Sri Lanka. All parts of these plants are toxic, and contain a variety of cardiac glycosides including neriifolin, thevetin A, thevetin B, and oleandrin. Ingestion of either oleander results in nausea, vomiting, abdominal pain, diarrhoea, dysrhythmias, and hyperkalemia. In most cases, clinical management of poisoning by either N. oleander or T. peruviana involves administration of activated charcoal and supportive care. Digoxin specific Fab fragments are an effective treatment of acute intoxication by either species. However, where limited economic resources restrict the use of such Fab fragments, treatment of severely poisoned patients is difficult. Data from case reports and clinical studies were reviewed to identify treatments supported by evidence for the management of poisoning by N. oleander and T. peruviana.

A review of the epidemiology, diagnosis and evidence-based management of Mycoplasma genitalium

Mycoplasma genitalium is attracting increasing recognition as an important sexually transmitted pathogen. Presented is a review of the epidemiology, detection, presentation and management of M. genitalium infection. Accumulating evidence suggests that M. genitalium is an important cause of non-gonococcal, non-chlamydial urethritis and cervicitis, and is linked with pelvic inflammatory disease and, possibly, obstetric complications. Although there is no standard detection assay, several nucleic acid amplification tests have >95% sensitivity and specificity for M. genitalium. To date, there is a general lack of established protocols for screening in public health clinics. Patients with urethritis or cervicitis should be screened for M. genitalium and some asymptomatic sub-groups should be screened depending on individual factors and local prevalence. Investigations estimating M. genitalium geographic prevalence document generally low incidence, but some communities exhibit infection frequencies comparable to that of Chlamydia trachomatis. Accumulating evidence supports an extended regimen of azithromycin for treatment of M. genitalium infection, as data suggest that stat 1 g azithromycin may be less effective. Although data are limited, azithromycin-resistant cases documented to date respond to an appropriate fluoroquinolone (e.g. moxifloxacin). Inconsistent clinical recognition of M. genitalium may result in treatment failure and subsequent persistence due to ineffective antibiotics. The contrasting nature of existing literature regarding risks of M. genitalium infection emphasises the need for further carefully controlled studies of this emerging pathogen.

Replies to Fry et al. (Toxicon 2012, 60/4, 434-448). Part A. Analyses of squamate reptile oral glands and their products: A call for caution in formal assignment of terminology designating biological function.

To the Editor: We read with interest the contribution entitled, “The structural and functional diversification of the Toxicofera reptile venom system” by B. G. Fry and colleagues. This review article recounts the previous contributions of the authors, presents the authors’ views of the terminology regarding “venom” and Duvernoy’s glands as well as the relevant application of the authors’ interpretations of their phylogenetically based data. The paper also includes dismissal of our concerns and/or recommended cautions about the premature, broad use of the term “venomous” when not supported by evidence of function. In their paper, the authors included some of our published views in total, while others were only partly stated and taken out of context, not mentioned, or in our view, misinterpreted. While refutation of the views presented in the paper requires detailed argument, there are some fundamentals that arise from the paper. Firstly, at the centre of contention is the definition of “venom” and, by extension, “venom glands”. Not only is such definition central to the science of toxinology, but it also has important secondary consequences. If an animal is labelled as “venomous” this can affect the way it is considered by society, the restrictions that are placed on it and the study of the animal, and the attitude, at a community level, towards conservation of the animal. As some readers of Toxicon will know, at the governmental level there are increasing restrictions on the movement and study of anything labelled as a toxin or venom, most recently affecting the study of toxins from cone snails. Although the biological/functional definition of “venom” (see ahead) has nothing to do with medical relevance, the conversely inaccurate labelling of an animal as “non-venomous” can carry serious secondary consequences. These are practical considerations providing a meaningful perspective that cannot be ignored. Secondly, there is the concept of science and the scientific method versus speculation or opinion that can become embedded as scientifically accepted “fact”. As “evidence” will always be selective and partial, it is subject to interpretation based on both the views of the investigators and the selective data being considered by them. Due to these considerations, we recognize that the use of the term, “evidence”, including our employment of it here, has inherent limitations that require further information in order to ascertain a complete objective fact or concept. Thirdly, there is the issue of experimental confirmation, the concept that any new discovery, before formal acceptance, should stand the test of independent experimental confirmation, and be reproducible. Consensus will evolve and change over time, as new information and understanding become available and individual scientists exercise their right to argue in favour of a new consensus. However, they should not, in our opinion, declare they have unilaterally developed a new imposed consensus and “abandoned” specific terminology without broad formal acceptance. In our opinion the paper by Fry et al. (2012) is both premature and non-consensual in its attempt to redefine “venom”, based on its origin (i.e. phylogenetics) rather than by function. Many genes are common, in whole or part, across diverse taxa, doubtless reflecting evolutionary origins, but it is the way each organism has utilised the gene product, in a functional sense, that has traditionally determined the definition of venom and what is “venomous”. The limits we place on a definition clearly affect inclusion/exclusion criteria and rightly are the subject of scientific debate and consensus. Without such care in terminology, humans might be defined as “venomous” (see ahead). Here, we present in detail our disagreement with Fry et al. (2012) regarding the definition of “venom” and “venomous”:

Local envenoming by the Western hognose snake (Heterodon nasicus): A case report and review of medically significant Heterodon bites

A case of clinically significant local envenoming resulting from a bite inflicted by a Western hognose snake, Heterodon nasicus, is described. The patient was bitten while offering a juvenile mouse to a captive snake. The snake maintained a grip on the patients arm (left anticubital fossa) for several minutes. The bite resulted in marked edema, ecchymoses, lymphadenopathy, cutaneous signs suggestive of mild cellulitis and blister formation. There were no systemic effects. Recovery was complete after approximately five months. Several documented Heterodon sp. bites with significant clinical effects are reviewed. This common xenodontine colubrid must be considered capable of inflicting medically significant bites. It is currently unclear whether the pathological changes associated with these bites are due to specific Duvernoys secretion components, Type I hypersensitivity or a combination of these. The influence of the feeding response on the severity of clinical effects is considered as is the discrepancy between experimentally verified pharmacological activities of Duvernoys secretions from Heterodon sp. and medical sequelae of documented bites. Although hognose snakes may uncommonly produce medically significant bites, they should not be considered dangerous or venomous. Captive specimens should be handled carefully, particularly when offered food.

Recent perspectives in the diagnosis and evidence-based treatment of Mycoplasma genitalium.

Mycoplasma genitalium is a globally important sexually transmitted pathogen. Men infected with M. genitalium frequently present with dysuria, while women may present with or without urogenital symptoms. In some populations, M. genitalium is significantly associated with HIV-1 infection, and is also an etiological agent in pelvic inflammatory disease. However, there is insufficient evidence to establish a causative role of the organism in obstetric complications, including tubal factor infertility. Although several nucleic acid amplification tests offer rapid, sensitive methods for detecting M. genitalium, there is no standardized assay. Available evidence supports treatment of M. genitalium infections with an extended regimen of azithromycin and resistant strains respond to moxifloxacin. Accumulating evidence indicates growing fluoroquinolone resistance, including against moxifloxacin, emphasizing the need for new therapeutic strategies to treat M. genitalium infections.

Ventricular bigeminy following a cobra envenomation

Context. Envenoming by some species of cobras (Naja species) may include cardiotoxic effects including various dysrhythmias. However, dysrhythmias leading specifically to ventricular bigeminy have not been previously documented. We report a case of cardiotoxicity and the development of ventricular bigeminy following a cobra envenomation. Case details. The patient was a 23-year-old man who presented to an emergency department following an alleged cobra bite. There was transient episode of nausea, vomiting, hypotension and tachycardia. The ECG showed infrequent ventricular ectopics that progressed to ventricular bigeminy and persisted even after the vital signs normalized. Complete resolution and resumption of normal sinus rhythm occurred following an empirical administration of monovalent antivenom against Naja kaouthia venom. The patient was discharged after 24 hours of uneventful observation. Discussion. The patients concomitant local effects, episodic cardiovascular instability and evolution of ventricular bigeminy support the likelihood of a venom-induced disease. Ventricular bigeminy can develop following a cobra envenomation. Thorough clinical evaluation, close serial observation of vital signs and early continuous cardiac monitoring are important in Naja spp. bites.

An instructive case of presumed brown snake (Pseudonaja spp.) envenoming

Abstract Context. Several species of medically important Australian elapid snakes are frequently involved in human envenoming. The brown snake group (Pseudonaja spp., 9 species) is most commonly responsible for envenoming including life-threatening or fatal cases. Several Pseudonaja spp. can inflict human envenoming that features minor local effects, but may cause serious systemic venom disease including defibrination coagulopathy, thrombocytopenia, micro-angiopathic hemolytic anemia (MAHA) and, rarely, paralysis. Pseudonaja envenoming is typically diagnosed by history, clinical assessment including occasional active clinical bleeding noted on physical examination (e.g. from venipuncture sites, recent cuts, etc.), and laboratory detection of coagulopathy (prolonged activated partial thromboplastin time [APTT]/INR, elevated D-dimer, afibrinogenemia and thrombocytopenia). Lack of verified identity of the envenoming snake species is a common problem in Australia and elsewhere. Identification and confirmation of the envenoming Australian snake taxon is often attempted with enzyme sandwich immunoassay venom detection kits (SVDKs). However, the SVDK has limited utility due to unreliable specificity and sensitivity when used to detect venoms of some Australian elapids. Antivenom (AV) remains the cornerstone of treatment, although there is debate concerning the recommended dose (1 vs. 2 or more vials) necessary to treat serious Pseudonaja envenoming. Envenomed patients receiving timely treatment uncommonly succumb, but a proportion of seriously envenomed patients may exhibit clinical or laboratory evidence of myocardial insult. Case details. An 88-year-old woman presented her dog to a veterinarian after it had sustained a bite by a witnessed snake, reportedly an eastern brown snake (Pseudonaja textilis, Elapidae). The woman became suddenly confused, and lost consciousness at the veterinary office. After transport to hospital, she denied any contact with the snake, but developed large haematomas at intravenous (i.v.) catheter insertion sites; blood tests revealed a severe defibrination coagulopathy, consistent with envenoming by a brown snake. An SVDK-tested urine sample was negative. A non-contrast CT of her head showed a minor subacute infarction of the left corona radiata. A twelve-lead ECG was normal, but her troponins were mildly elevated (39 ng/L). A diagnosis of brown snake envenoming was made and she received 2 vials of brown snake AV i.v., without adverse incident. Thirty min post AV her Glasgow Coma Score (GCS) had improved from 13 to 15 (normal). At 3.5 h post AV all bleeding from i.v. sites ceased, although her troponin T level peaked at 639 ng/L, supporting a diagnosis of non-ST elevated myocardial infarction (NSTEMI). Discussion. Severe brown snake envenoming may occur in the absence of a perceived bite, and AV is temporally associated with improvement in clinical findings and coagulopathy. However, severe envenoming by this species can be complicated by cardiovascular events that in the circumstance of incomplete or absent history may confuse the primary diagnosis and affect patient outcome.

Reply to Vikrant and Verma about “Monitor Lizard Envenoming”

We read with concern the case report by S. Vikrant and B.S.Verma (Renal Failure online early DOI: 10.3109/0886022X.2013.868223), claiming a bite from a monitorlizard caused systemic envenoming and fatal renal failure. Inthe patient’s location a variety of venomous snakes exist,including Russell’s viper (Daboia russelii), envenoming bywhich would certainly be able to cause the constellation ofeffects and outcome experienced by this patient. Snakebitecauses at least an estimated 45,000 fatalities in India everyyear

The pharmacotherapy for pit viper envenoming in the United States: A brief retrospective on roots, recurrence, and risk

The report by Bush and colleagues ( “ Comparison of F(ab ’ ) 2 versus Fab antivenom (AV) for pit viper envenomation: A prospective, blinded, multicentre, randomized clinical trial ” ) 1 in this issue of Clinical Toxicology presents the results of a controlled Phase-3 study comparing the therapeutic effi ciency of two Fab AVs, equine-derived F(ab ’ ) 2 and ovine-derived Fab (Fig. 1), for treating pit viper (crotaline) envenomation. The study was conducted at 18 clinical sites and included envenoming attributed to at least 12 identifi ed crotaline species with the majority (102) of bites ascribed non-specifi cally as “ rattlesnake ” or “ unidentifi ed ” bites. Most of the 114 patients ultimately included in the three study groups (F(ab ’ )2/F(ab ’ ) 2 , F(ab ’ ) 2 /placebo, and Fab/ Fab) exhibited characteristics reasonably representative of commonly encountered envenomed patients in the US, for example, predominantly white males with a median age between 32.9 and 45.6 years. Children aged less than 10 years, and mostly in the F(ab ’ ) 2 /F(ab ’ ) 2 group, were also included. The study by Bush et al. (2014) 1 provides encouraging support for the clinical effi ciency of F(ab ’ ) 2 AV against North American pit viper venoms, as their study reports a notably lower percentage of patients who experienced late coagulopathy when respectively comparing the F(ab ’ ) 2 /placebo (5.3%) and F(ab ’ ) 2 /F(ab ’ ) 2 (10.3%) groups with the Fab/Fab (29.7%) group. Also, although the overall adverse event incidence was similar in the F(ab ’ ) 2 /F(ab ’ ) 2 and Fab/Fab groups, adverse events associated with coagulopathy or hemorrhage (e.g., petechiae and gingival bleeding) were reported in 8.1 – 9.3% of those in the F(ab ’ ) 2 /placebo and F(ab ’ ) 2 /F(ab ’ ) 2 groups in comparison to 24.4% in the Fab/Fab group. Of the nine patients who reportedly experienced serious adverse events, two-thirds were in the F(ab ’ ) 2 /F(ab ’ ) 2 group, but the authors indicate that all of these were not associated with the AVs, and provide several examples supporting their assertion. There were no reported life-threatening anaphylactic reactions in any of the groups. The authors thus reported an absolute risk reduction of 19.5% (F(ab ’ ) 2 /F(ab ’ ) 2 ) to 24.5% (F(ab ’ ) 2 /placebo), thereby

Reply to Isbister and Page: Further discussion of an illuminated case of presumed brown snake (Pseudonaja spp.) envenoming

In commenting about our reported case of presumed brown snake (Pseudonaja spp.) envenoming, Isbister and Page opined that some of our statements were not ‘‘evidence based’’. We strongly disagree that we ‘‘left the reader and the patient in the dark about the diagnosis’’. As stated, the circumstances and presentation strongly supported the diagnosis, as did the demonstrable improvement of the patient’s clinical condition and laboratory tests following administration of brown snake antivenom (BSAV). We also outlined the problems with venom immunoassays, and would not have hinged our diagnosis on the results of a given assay. Our overriding concern was managing the patient who showed signs of clinical decline. To the best of our knowledge, their recommended venom assay is not a real-time test, independently verified or commercially available, and so is not practical for management of acute cases across Australia. Our view that a single vial of BSAV is a ‘‘precariously narrow strategy’’ is based on individual clinical experience with a substantial number of cases. We support the principle of evidence-based medicine, as a set of recommendations derived from the combined evaluation of the best external clinical evidence, individual clinical experience/expertise and patient values, as well as expectations. The authors state that their studies demonstrate that ‘‘one vial’’ of BSAV is ‘‘more than sufficient for all brown snake bites’’ and that ‘‘low concentrations of venom detected post-AV are in fact bound venom’’. The authors’ study does not include all possible clinical circumstances including patient co-morbidities that could complicate effects of a prolonged defibrinating coagulopathy. The complications that occurred in our patient are a good example of this, thus our entitling it ‘‘an instructive case’’. The possible role of venom variability and related effects in patients is another unpredictable factor. It must be noted that one of the authors (GI) has also suggested, based on a computer-modeled analysis of selected cases, that ‘‘antivenom has little or no benefit’’ for treating Australian elapid coagulopathic envenoming. Also, while the authors’ data have suggested the presence of bound venom in their post-envenoming assays, recent transcriptomic analyses suggest that Pseudonaja spp. venom contains at least 113 different toxin transcripts, and this should raise questions about which and proportionally how many expressed components are ‘‘bound’’, and what is the in vivo fate/metabolism of many clinically relevant toxins and isotoxins. Although, our patient did not specifically report chest pain and cardiac monitoring remained unremarkable, her troponin levels suggested a NSTEMI (our precise words were, ‘‘consistent with a NSTEMI’’). NSTEMI in some patients (e.g. geriatric patients and women) may present atypically, for example as syncope, or fatigue. Her advanced age, hypertension, hyperlipidemia and smoking histories are all traditional risk factors for NSTEMI. Our patient had no evidence of pulmonary embolism, sepsis or any other significant cause for the markedly abnormal Troponin T, other than myocardial insult. The key term ‘‘infarction’’ is warranted as the designation for this patient’s clinical status because the clinical evidence was consistent with a recent consensus definition. The early pro-thrombotic effects of the consumption coagulopathy likely precipitated the myocardial insult. The patient was not a candidate for acute interventional therapy because of her coagulopathy and the absence of ischemic changes, as well as clinical improvement post-BSAV. A recent NSTEMI management guideline also suggested that, in all but the highest-risk patients, immediate cardiac catheterization or other interventional therapy does not offer benefit over initial medical stabilization and subsequent early cardiac catheterization/intervention Address for correspondence Scott A. Weinstein, PhD, MBBS, MD, Toxinology Department, Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia. Tel: +61 8 8 161 8044. E-mail: herptoxmed@msn.com Received 28 August 2015; revised 3 September 2015; accepted 14 September 2015.