A34: Antidotes in Depth

The terms “antivenom” and “antivenin” often are used interchangeably. Although the origin of the term “antivenom” is obvious, “venin” is French for venom and “antivenin” is traditionally used in certain parts of the world. Wyeth Pharmaceuticals, the maker of Crotaline and Micrurus antivenom, and Merck & Co., Inc., the maker of Latrodectus antivenom, adopted “antivenin” in the brand names for their products. Brand name recognition has largely been responsible for the use of the term “antivenin” in place of “antivenom”. In 1981, the World Health Organization determined the preferred terms for the English language to be “venom” and “antivenom.”

Of the species of spiders of medical importance in the United States, two of the most notable are Latrodectus (L. mactans, L. geometricus, L. vaiolus, L. hesperus, and L. bihopi are native, while L. geometricus was introduced) and Loxosceles. Although commercially available antivenom exists in the United States for treatment of Loxosceles envenomation, antivenom produced for South American Loxosceles spiders demonstrates cross-reactivity with North American species like L. reclusa.¹² Currently, one commercially available Latrodectus antivenom exists in the United States. Black widow spider antivenin (Merck & Co., Inc.) (Merck BW-AV) has been available in the United States since its U.S. Food and Drug Administration (FDA) approval in 1936.³ The use of this antivenom in the treatment of Latrodectus envenomations remains controversial, as mortality from these bites is low in the United States,^7,8,30,32 and complications including death following antivenom administration are rarely reported.^7,20,31 Most recently, severe production shortages have necessitated emergency release of the product by the manufacturer within 24 hours of notification of a patient with symptoms from a presumed envenomation.¹ Ongoing research and development of an F(ab′)₂ antivenom may ameliorate concerns and limitations related to potential adverse events resulting from administration of the Merck antivenom and production shortages limiting availability.¹¹

Chemistry, Preparation, and Mechanism of Action

Antivenom for spiders is prepared in a similar manner as other antivenom products by first immunizing animals with non-toxic amounts of venom.^5,25 Monkeys, horses, goats, sheep, chicken, camels, and rabbits have been used historically to source antivenom.²⁸ The animals are placed on an inoculation schedule to allow gradual production of immunoglobulins, most importantly IgG. Sufficient antibody production usually requires up to 6 weeks. Animal choice for immune serum production is more often dictated by the species availability, financial considerations, and tradition rather than scientific modeling. Horses are used by the majority of antivenom producers, since they are relatively easy to maintain, and large volumes of serum can be obtained at one time without harm. Varying efforts are made during antivenom production to remove animal proteins such as albumin. Antivenoms target, bind, neutralize, and promote elimination or redistribution of toxins from body tissues. To date, no studies have compared immune sera of different animals for human compatibility or tolerance.

The antidotal fraction of an antivenom exists as either whole IgG, Fab, or F(ab′)₂. The IgG molecule is composed of two antigen-binding fragments (Fab fragments) that are fused together and attached to the larger complement binding fragment (Fc fragment). It is the larger Fc portion that is generally considered to be the most responsible for immune mediated reactions. Digestion of the disulfide bonds of an IgG molecule with the enzyme pepsin will cleave the Fc fragment, allowing isolation of pure F(ab′)₂ fragments (two fused Fab fragments). In contrast, digestion with papain cleaves the molecule more distally such that a larger Fc portion is removed from two separate Fab fragments. Both Fab and F(ab′)₂ molecules can be isolated with affinity chromatography, and the highly antigenic Fc portion discarded. Although Fab and F(ab′)₂ are more expensive to produce than their whole immunoglobin counterparts, they are generally regarded as less allergenic and therefore safer products.

Whole IgG antivenom is the easiest and least expensive to produce. It has a molecular weight of approximately 150 kDa, and is the largest of the three antivenom types. Because of its size, it is the least filterable at the glomerulus and has the smallest volume of distribution. IgG has a longer elimination half-life than either Fab or F(ab′)₂.¹⁷

F(ab′)₂ has an intermediate size (∼100 kDa) and elimination half-life. While lowering the risk of anaphylaxis compared to whole IgG, the F(ab)₂ portion retains much of the allosteric configuration of the original IgG molecule that is lost in when Fab are formed. This configuration theoretically allows for tighter binding to venom. Fab is the smallest (∼50 kDa) antivenom molecule in size and is eliminated by the kidneys. It has the largest volume of distribution and a greater ability to reach extravascular compartments. Arachnid venoms that affect the central nervous system have low molecular weights and large volumes of distribution. Fab and F(ab)₂ based antivenoms may therefore be best suited for this function.¹⁷

Immunoglobulin based antivenoms can be given by the intramuscular (IM), intravenous, or subcutaneous route. Intravenous administration achieves rapid peak serum concentrations, and the infusion can be stopped in the event of an allergic reaction.¹⁸ Intramuscular injection has been used when intravenous access is unobtainable.

Pharmacokinetics and Pharmacodynamics

Currently, there is no published pharmacokinetic or pharmacodynamic information available on Merck BW-AV in humans or animals. Graudins and colleagues demonstrated western blot binding of L. hasselti (Red Back Spider) Antivenom (RBS-AV) to purified α-latrotoxin and similar protein bands derived from multiple widow spiders (L. mactans, L. hesperus, L. lugubris, L. tredecimguttatus, and L. hasselti). When co-mixed with the venoms from these species prior to administration, RBS-AV prevented the development of a reproducible and rapid muscle contracture of an in vitro chicken nerve-muscle preparation. A dose-response relationship was observed with varying doses of RBS-AV administration.¹⁶ This confirms a direct in vitro binding effect of RBS-AV against widow spider venoms.

Previous animal studies have demonstrated that intramuscular administration of antivenom demonstrated very low serum venom concentrations.^35,36 In these rabbit studies of intramuscular administration, F(ab′)₂ and IgG had poor bioavailability (36%–42%) and delayed time to peak concentrations of 48 to 96 hours.

Pharmacokinetic and pharmacodynamic characteristics of equine derived antivenoms may differ between species studied. Equine derived antivenom maximum concentrations were greater in cows than in horses, and steady state distribution volumes were higher in cows than in horses in one study. Similar results were observed in rabbit models.³⁷ Pharmacokinetic and pharmacodynamic parameters observed in animal models should therefore be interpreted with caution with regard to behavior of antivenoms in humans.

RBS-AV has been administered intramuscularly to treat human envenomations and clinical effectiveness equivalent to intravenous administration was previously reported.²¹ Subsequent studies, however, demonstrated the absence of RBS-AV in circulating serum up to 5 hours following intramuscular administration. Serum concentrations of RBS-AV were detected within 30 minutes of administration following intravenous administration.²⁴ These results are consistent with animal studies demonstrating little if any effect on circulating venom when antivenoms are given intramuscularly. Additional studies on the pharmacokinetic and pharmacodynamic properties of RBS-AV, Merck Black Widow Antivenom, and F(ab′)₂ black widow antivenom (in development) are needed.

Although black widow bites are associated with severe muscle pain, cramping, and autonomic disturbances, mortality remains low.^7,8,30,33 Symptomatic treatment with muscle relaxants and opioid analgesics is generally effective, although the duration of symptoms following severe envenomation may necessitate hospitalization for 1 to 2 days or more.

The use of Merck Black Widow antivenom may shorten the length of symptoms dramatically, allowing outpatient care in some cases.^{7,30,32,33,39} Studies of reported Latrodectus envenomated patients in Australia, however, have demonstrated little clinical difference between Latrodectus antivenom and placebo.²¹ In addition, anaphylaxis and other adverse events following the administration of Latrodectus antivenom are reported.^7,20,30,31

Because of low mortality and potential for adverse events following administration, some authors question the use of black widow antivenom.³⁶ Many toxicologists still believe Latrodectus antivenom is safe and effective when used appropriately, and it is generally indicated in cases of severe envenomation where muscle cramping, hypertension, diaphoresis, nausea, vomiting, and respiratory difficulty are present.⁸

Latrodectus antivenom is also reported to successfully treat priapism complicating severe envenomation.¹⁹ Although the safety of antivenom is not clearly established in the developing fetus, pregnancy is suggested as a consideration for Latrodectus antivenom administration, as the stress of severe pain and muscle cramps may have adverse fetal effects.^4,38

Antivenoms for a number of Latrodectus spiders are available worldwide (Table A34–1). A shortage of Merck antivenom prompted the finding that antivenom against L. hasseltii (RBS-AV) also neutralizes venom of L. mactans in a mouse model.¹⁰ Analatro, a polyvalent F(ab)₂, is an equine-derived antivenom created for L. mactans in both Argentina and Mexico that is currently undergoing multi-center clinical trials in Latrodectus envenomated patients in the United States.

In a review of 163 cases of presumed L. hesperus and mactans envenomations, antivenom reduced the mean duration of symptoms from 22 to 9 hours. Symptoms usually subsided within 1 to 3 hours of antivenom administration. The hospital admission rate fell from 52% in those who were managed with opioids and muscle relaxants to 12% in those patients receiving antivenom.⁷ A more recent review demonstrated pain relief in all patients receiving antivenom following symptomatic black widow envenomation.³²

A rabbit IgG based funnel-web spider (Atrax robustus and others) antivenom is available in Australia. Since the introduction of the antivenom, no deaths have been reported.²³ Complete response following administration of antivenom was reported in 97% of envenomations in one series.²²

Envenomation by the brown recluse spider Loxosceles reclusa is associated with low, but significant morbidity, particularly in the southeast United States. Anti-Loxosceles Fab blocked dermonecrosis in a rabbit model, but only if provided within 24 to 48 hours of envenomation.^15,34 Although no commercially available antivenom exists in North America for treatment of Loxosceles envenomation, antivenom produced against South American Loxosceles spiders has cross-reactivity with North American species like L. reclusa.¹² The usual late presentation of patients with necrotic lesions from spider bites make antivenom use for Loxosceles difficult to study. National laboratories in Brazil and Argentina produce antivenoms for L. reclusa, L. boneti, and L. rufescens.^5,12

Despite the apparent efficacy of antivenom, the decision to give horse serum for a disease with limited mortality should be considered. Death from bronchospasm and anaphylaxis is a rarely reported complication of whole IgG antivenom (Merck) administration,^7,20,31 as is serum sickness.⁸ Serum sickness is dose-dependent and is less likely when only 1 to 2 vials are typically administered. A detailed review of one case of death following antivenom administration⁷ demonstrates that the antivenom was inappropriately prepared (not diluted) and inappropriately administered (intravenous push rather than slow infusion) to a patient with multiple drug allergies, atopy, and asthma. Resuscitation was further complicated by the development of a pneumothorax. A second death³¹ was reported in a 37 year-old man with history of asthma who received antivenom as an infusion and developed cardiac arrest as a complication of severe anaphylaxis. He died 40 hours after presentation.³¹

In Australia, antivenom to the red-back spider (L. hasseltii, CSL Ltd.) is made by immunizing horses for production of F(ab)₂. Horse-derived F(ab′)₂ has a lower reported incidence of allergic reactions, with early allergic reactions as low as 0.5% to 0.8%. The incidence of serum sickness is reported at less than 5%.^40,41 Analatro (under evaluation) is a similar F(ab′)₂ product which would be anticipated to be a safer antivenom than the currently available Merck whole IgG product.

A review of the US National Poison Data System (NPDS) demonstrated a 3.4% rate of adverse drug reactions (ADRs) following administration of the Merck Latrodectus antivenom.³⁰ This is consistent with previously reported rates of ADRs following black widow antivenom administration.⁸ Directly attributing these complications to administration of antivenom is difficult as these patients received multiple therapies including opioids, benzodiazepines, and calcium salts preceding antivenom administration, and NPDS does not attribute an ADR to a specific therapy. Similarly, the nature of these ADRs is not described in NPDS. However, it is noteworthy that no deaths occurred in 374 instances of use and only five patients received antihistamines, suggesting acute hypersensitivity reactions to the Merck black widow antivenom to be uncommon and that this antivenom is generally safe. Similarly, a review of 96 assessable instances of black widow antivenom administration over a 10 year period in a single state similarly demonstrated a low rate of adverse reactions. Four (4%) patients in the series had adverse effects ascribed to antivenom administration. These reactions were generally mild and included myalgias, fatigue, generalized paresthesias, flushing, and urticarial rash. There were no cases of dyspnea, angioedema, bronchospasm, hypotension, or death.³² This low rate of severe adverse reactions and lack of death suggests that Merck black widow antivenom is a safe product when prepared and administered correctly to patients without underlying atopy, asthma, or drug allergies.

Black widow envenomations during pregnancy are relatively rare. Of 12,640 patients envenomated by a blackwidow spider, 97 (3%) were pregnant. When compared with nonpregnant women, no significant differences were observed in recommended or administered treatments including the use of antivenom.⁶ There are six reported cases of Loxosceles envenomations in pregnant women. They were all managed with supportive therapy including analgesics, antihistamines, and short course low dose steroids. Pregnancy outcomes were favorable in all reported cases.^2,14 Merck black widow antivenom is Pregnancy Category C. It is not known whether antivenom is excreted in human milk.

The starting dose of the Merck antivenom is one vial (2.5 mL) diluted in 50 mL of saline for intravenous administration. Although black widow spider antivenom can also be given IM, this route carries the disadvantage of slower, more erratic absorption, less control over the rate of administration, and the inability to stop the administration should an allergic reaction occur. In addition, recent studies suggest IM injection of antivenom may not yield significant serum concentrations.²⁴ For these reasons, the intramuscular route is not routinely recommended.

The initial dose of antivenom in funnel-web spider envenomation is two vials in patients with any signs or symptoms of envenomation. Patients with acute respiratory distress syndrome or decreased consciousness should receive four vials.²⁹ For severe cases, the following protocol has been suggested.²⁹ Two vials (each containing 100 mg of rabbit IgG) of antivenom are administered very slowly intravenously. The dose can be repeated in 15 minutes if no improvement occurs. The dose should be doubled for severe cases. A rapid response should occur. Administration of antivenom should be repeated until symptoms are completely reversed.¹³Atrax robustus envenomations may require multiple infusions of antivenom. The recommended dosage for children is the same as for adults.

Each vial of the Merck product contains 6000 antivenom units standardized by biologic mouse assay. Because Latrodectus venoms are virtually identical by immunologic and electrophoretic mechanisms, antivenom created for L. mactans is presumed to be effective in other species of Latrodectus as well.²⁷

Latrodectus antivenin is supplied as a white to gray crystalline powder in vials containing not less than 6000 antivenin units with thimerosal 1:10,000 added as a preservative, along with a 2.5 vial of sterile diluent for reconstitution. The antivenin must be stored and shipped at 2 to 8°C (36–46°F), but never frozen. The reconstituted antivenin color ranges from light straw to very dark iced tea, although color has no effect on potency.^2a

Emergency supplies of Lactrodectus antivenin are available for patients with symptoms due to a bite by the black widow spider within 24 hours of contacting Merck. The Antivenom Index, maintained by the Association of Zoos and Aquariums (https://www.aza.org/antivenom-index/) and accesible by the nation’s Poison Control Centers, might also serve as a resource.

• The decision to use spider antivenom must be individualized to the patient and clinical manifestations.

• Because mortality following black widow envenomation is low, antivenom is reserved for cases where symptoms are severe or do not respond to other therapies, and after a frank discussion with the patient of possible adverse effects.

• Although a large body of literature suggests that Merck black widow antivenom is safe when properly prepared and administered to patients without asthma. Adverse effects including severe anaphylaxis and death are reported.

• A new, purified F(ab)₂ black widow spider antivenom is in clinical development, but is currently unavailable.

References