Animal Bites and Rabies From: TRAVEL MEDICINE ADVISOR Paul P. Roberts, MD,MSc Formerly Director of the Tropical Medicine and Infectious Disease Clinic, University of Washington, Seattle, the author 's private practice is devoted to infectious diseases and tropical/travel medicine. Animal bites are common. Between one half and one percent of Americans sustain bites each year. Some of these bites are medically trivial; others are severe and immediately life-threatening. Most bites fall into a broad middle zone in which serious consequences are related to infectious complications. For this reason, early therapy heavily influences resulting morbidity from a given bite. Although bite wound complications have been reported in travelers, a systematic survey of travel-related animal bites has never been conducted. Therefore, the principles of animal-bite management in international travelers must be inferred from what is known about domestically acquired bites. Epidemiology The 70 to 80 million dogs and cats in the United States (along with a scattering of other species) inflict one to two million bites to humans annually. The public health impact of these bites is substantial; each year, they account for approximately 1% of emergency department visits and more than 10,000 hospitalizations. Of bites severe enough to come to medical attention, about 85% are inflicted by dogs and 10% by cats. Data are sparse regarding factors that predispose a given animal to attack. Large dogs are obviously more likely than small ones to cause significant bites; pit bulls are responsible for a large proponion of dog-bite fatalities. Strays inflict only about 10% of dog bites, although how this figure compares with the number of strays in the total dog population is not known. However, considering the infrequent contact of stray dogs with humans, the percentage of bites inflicted by strays is clearly disproportionate. Most dog bites are from domestic dogs; in about one sixth of all events, the victim is the owner. Approximately two thirds of dog-bite victims are under age 25; one third are younger than 10. Children are not only over represented but also are more likely to sustain severe or facial bites. These tendencies are easily explained by the facts that children are less prudent in their relationships with dogs, closer to the size of a dog, and less able to defend themselves. Most dog-bite victims are male, and most cat-bite victims are female. Infectious Complications Animal-bite wounds, like human-bite wounds, are prone to infection. The pathogens involved tend to reflect (with some distortion) the oral flora of the biting animal. Not all mouth flora are virulent, and fresh bite wounds often contain a greater variety of bacteria compared with clinically infected wounds. Bite wound pathogens can also derive from the victim's skin flora, from soil, or from other environmental sources. Rabies, tetanus, and other special cases of bite-wound infection are discussed later in this chapter. A number of factors influence the likelihood of infection. Compared with dog bites, cat bites are more prone to infection. The likelihood that a cat bite will become infected is 20-50%; for a dog bite, the likelihood is only 3-5%. Bites to the hand (or bites involving joints) are significantly more infection-prone than those elsewhere on the body. In contrast, bites to the face are less likely to become infected. As might be expected, puncture wounds and wounds containing devitalized tissue are infection-prone. Although the influence of host factors has not been statistically defined, diabetes mellitus, vascular or Iymphatic compromise, alcoholism, asplenia, extremes of age, and other immunocompromising conditions almost certainly predispose bite victims to wound infection and systemic complications. Finally, the first Animal bites are common. Between one half and one percent of Americans sustain bites each year. Some of these bites are medically trivial; others are severe and immediately life-threatening. Most bites fall into a broad middle zone in which serious consequences are related to infectious complications. For this reason, early therapy heavily influences resulting morbidity from a given bite. Although bite wound complications have been reported in travelers, a systematic survey of travel-related animal bites has never been conducted. Therefore, the principles of animal-bite management in international travelers must be inferred from what is known about domestically acquired bites. Epidemiology The 70 to 80 million dogs and cats in the United States (along with a scattering of other species) inflict one to two million bites to humans annually. The public health impact of these bites is substantial; each year, they account for approximately 1% of emergency department visits and more than 10,000 hospitalizations. Of bites severe enough to come to medical attention, about 85% are inflicted by dogs and 10% by cats. Data are sparse regarding factors that predispose a given animal to attack. Large dogs are obviously more likely than small ones to cause significant bites; pit bulls are responsible for a large proportion of dog-bite fatalities. Strays inflict only about 10% of dog bites, although how this figure compares with the number of strays in the total dog population is not known. However, considering the infrequent contact of stray dogs with humans, the percentage of bites inflicted by strays is clearly disproportionate. Most dog bites are from domestic dogs; in about one sixth of all events, the victim is the owner. Approximately two thirds of dog-bite victims are under age 25; one third are younger than 10. Children are not only overrepresented but also are more likely to sustain severe or facial bites. These tendencies are easily explained by the facts that children are less prudent in their relationships with dogs, closer to the size of a dog, and less able to defend themselves. Most dog-bite victims are male, and most cat-bite victims are female. Infectious Complications Animal-bite wounds, like human-bite wounds, are prone to infection. The pathogens involved tend to reflect (with some distortion) the oral flora of the biting animal. Not all mouth flora are virulent, and fresh bite wounds often contain a greater variety of bacteria compared with clinically infected wounds. Bite wound pathogens can also derive from the victim's skin flora, from soil, or from other environmental sources. Rabies, tetanus, and other special cases of bite-wound infection are discussed later in this chapter. A number of factors influence the likelihood of infection. Compared with dog bites, cat bites are more prone to infection. The likelihood that a cat bite will become infected is 20-50%; for a dog bite, the likelihood is only 3-5%. Bites to the hand (or bites involving joints) are significantly more infection-prone than those elsewhere on the body. In contrast, bites to the face are less likely to become infected. As might be expected, puncture wounds and wounds containing devitalized tissue are infection-prone. Although the influence of host factors has not been statistically defined, diabetes mellitus, vascular or Iymphatic compromise, alcoholism, asplenia, extremes of age, and other immunocompromising conditions almost certainly predispose bite victims to wound infection and systemic complications. Finally, the first aid and medical care given soon after the bite certainly influence whether infection will follow. Characteristics of bite wound infection vary according to the biting species. Cat bites are likely to involve a single microbial species, usually Pasteurella multocida. This organism is also the pathogen that is most commonly isolated from infected dog bites; however, staphylococci and a variety of other bacterial species are also found with significant frequency in dog-bite wounds (~see Table 1). As in human-bite wounds, infection in dog-bite wounds is often polymicrobial and involves anaerobes. On occasion, cat bites may also involve the organisms listed in Table 1. Table 1. Frequent Pathogens in Infected Dog-bite Wounds Note: Base treatment on Gram's stain, culture, and in vitro sensitivities Pasteurella multocida Staphylococcus aureus Sraphylococcus epidermidis Corynebacterium species Acinetobacter calcoaceticus Pseudomonas aeruginosa Enterohacter species Streptococcus species including enterococci Capnocytophaga canimorsus ~F-2) llj EF-4 MS Eikenella corrodens Anaerobes: Bacleroides species Anaerobic streptococci, Peptococcus, Peptostreptococcus Fusobacterium species Clostridwm species It should be noted that cat bites and scratches can transmit plague, tularcmia, and cat-scratch disease; dog bites have been known to cause infection with Blastomyce.s dermatitidis and Mycobacteriumfortuitum. Other biting animals have characteristic pathogens as well (see Table 2). For example, rodents (including domestic hamsters, gerbils, and guinea pigs) may transmit Streptobacillus moniliformis and, less commonly, Spirillum minor (the two agents of rat-bite fever), as well as P. multocida. Rat bites have transmitted leptospirosis. Monkey bites can transmit hepatitis A, tuberculosis, or B-virus (a virulent herpesvirus formerly known as Herpes virus simiae). Although plague and blastomycosis have been observed to occur only in endemic areas and spirillary rat-bite fever occurs mostly in Asia, the other bite-associated infections are cosmopolitan. In the animal-bite victim who appears to have a systemic infection, two bacterial pathogens, Capnocytophaga canimorsus (forrnerly DF-2) and P. multocida, deserve special consideration. C. canimorsus causes systemic sepsis, sometimes fulminant, in a large proportion of the cases in which it is isolated (usually in immunocompromised patients). P. multocida, a particularly virulent pathogen even in normal hosts, may cause rapidly advancing cellulitis within hours of a bite, as well as Iymphangitis, osteomyelitis, softtissue abscesses, or metastatic infections such as meningitis, brain abscess, and distant septic arthritis. Table 2. Pathogens Associated with Bites of Animals other than Dogs and Cats Animal Pathogen Treatment Rodents P. multocida Penicillins, tetracyclines, IV cephalosporins Streptobacillus moniliformis Penicillin, tetracycline, streptomycin Spirillum minor Penicillin, tetracycline Leptospira interrogans Penicillins, tetracyclines, cefotaxime Primates Hepatitis A Prophylactic immune globulin B-virus Acyclovir, gancyclovir M. tuberculosis Depends on origin of strain Seals Unknown agent of "seal finger" Tetracycline Snakes "Fecal flora" including Bacteroides Base on Gram's stain, culture, and fragilis, Clostridium perfringens, sensitivities Salmonella species, and Arizona hinshawii Primary Care of Bite Wounds Although a number of controversies remain concerning bite wound management, the underlying principles of care are the same as those for management of contaminated wounds. Because flora of fresh wounds correlate poorly with subsequent infection, there usually is no reason to culture a fresh, clinically uninfected wound. The risk of rabies exposure should be evaluated and tetanus immunity verified. Because all bite wounds are prone to tetanus, a tetanus toxoid booster should be given if five or more years have passed since the last booster. In addition, if a victim has not completed the primary series of three toxoid shots (or does not know whether the series is complete), 250 IU of tetanus immune globulin (TIG) should be given at a site remote from the toxoid injection. More aggressive use of TIG is recommended wher~ wounds are highly tetanus-prone. Such wounds include those that cannot be completely debrided of necrotic tissue, those that are contaminated with fecal material, or those presenting late with established infection. TIG may be indicated for a victim with a high-risk wound who has completed a primary series but has not had a booster within 10 years. A larger dose (up to 500 IU) is warranted for high-risk wounds in patients who have received fewer than three toxoid shots in the past. All animal-bite wounds should be cleaned aggressively. If rabies exposure is possible, a detergent disinfectant solution should be used. For other bites, a disinfectant without detergent (such as povidone iodine solution) is preferable, because detergent is damaging to tissues. Scrubbing should be followed by copious, high-pressure irrigation with saline using a large-bore (14gauge) blunt needle and syringe. Exploration should then address whether the wound involves tendon, joint, bone, or cartilage; wounds involving any of these structures are at greater risk for subsequent complications. Any devitalized tissue should be debrided. (Some practitioners sharply debride even wounds without devitalized tissue whenever possible.) The decision to close a bite wound is based primarily on the risk of infection. Because facial wounds are relatively unlikely to become infected, and cosmetic results are important, they are usually closed. If a facial wound is old or infected at the time of presentation, delayed primary closure may be possible after debridement and several days of antibiotic therapy. Tape closure is slightly less infection-prone than suturing. Because bites on the hand become infected more often than bites elsewhere on the body, suturing bite wounds to the hand should be the exception rather than the rule. Because of their greater risk of infection, cat bites are less suitable than dog bites for suturing; of course, cat bites tend to be smaller and therefore are less likely to need closure. Wounds extending to tendon, joint, bone, or cartilage are usually best left open (or closed later). Puncture wounds seldom should be closed. Persons with infected wounds require antibiotic therapy, which should be guided by Gram's stain and culture, as well as by lists of pathogens known to be associated with various biting animals. For severe infections, penicillin should be part of the initial antibiotic regimen whenever possible; it is the drug of choice for both P. multocida and the so-called alphanumeric gram-negatives. The antistaphylococcal penicillins are less active against these pathogens, but amoxicillin/clavulanate (Augmentin), ampicillin/sulbactam (Unasyn) and ticarcillin/clavulanate (Timentin) extend the penicillin spectrum to cover Staphylococcus aureus and most anaerobes. Selected parenteral cephalosporins such as cefuroxime and ceftriaxone are also active against the alphanumerics, P. multocida, and S. aureus. Oral cefuroxime axetil has significant activity in vitro against both P. multocida and S. aureus, but no clinical trials of this agent have been published. The role of prophylactic antibiotics in treating uninfected wounds is less certain. Controlled clinical trials have yielded contradictory results, probably because meticulous wound care is more important than drug therapy. However, a substantial risk of infection remains even after cleansing, irrigation, and debridement. Therefore, antibiotic prophylaxis seems reasonable for persons with bite wounds associated with a risk of infection that is perceptibly above the mean. Candidates for prophylaxis include persons at high risk for infection, such as those with diabetes mellitus, liver disease, asplenia, HIV infection, alcoholism, organ transplants, and other immunocompromising conditions. Other situations in which prophylactic antibiotic treatment might be warranted include cat bites, bites to the hand, bites more than eight hours old at presentation, and puncture wounds or large wounds with extensive crush injury, in which thorough debridement and irrigation are not possible. One clear requirement of the antibiotic selected is that it cover P. multocida. For cat bites, this is probably the only consideration, and penicillin (or amoxicillin) is the drug of choice. Tetracycline and doxycycline are good alternatives for nonpregnant women and older adolescents. Limited data suggest that ciprofloxacin may also be effective, but this drug is not recommended for pregnant women or persons younger than 18 years. The next-best drugs for young children are cefuroxime axetil, cefixime, or erythromycin, although published clinical experience with these and other oral agents is limited. For bites inflicted by other animals (including dogs, the most frequent offenders), the spectrum of potential pathogens is broader; the incidence of staphylococci and coliforms is significant (see Table 1). Nevertheless, no regimen has empirically been shown to be better than penicillin alone or dicloxacillin alone. These microbiologic considerations have led some physicians to prefer amoxicillin/ clavulanate (Augmentin), cefuroxime axetil, penicillin plus an oral first-generation cephalosporin (e.g., cephalexin), or penicillin plus dicloxacillin. Care of Animal Bites Optimal care for animal bites calls for considerable medical sophistication as well as supplies that are impractical for most travelers to obtain and carry. All travelers should have immunity to tetanus before embarking, but appropriate preparation in other respects depends on the proposed trip. For travelers who will have ready access to medical care throughout a trip, simply advising them that bite wounds will likeiy require medical care may be sufficient. However, travelers who will spend a significant amount of time more than eight hours from a medical facility should be prepared to give themselves first aid. They should know at least the fundamentals of wound care (including direct pressure for hemostasis and the importance of aggressive cleansing) and carry an antimicrobial soap containing povidone iodine, chlorhexidine, or hexachlorophene. Travelers who will be beyond the reach of medical care for extended periods need more intensive preparation. At least one member of a party traveling to a remote location should have formal training in first aid and should be equipped with the following: € A sophisticated manual, such as Medicine for Mountaineering (Wilkerson JA (ed): ed 3. Seattle, The Mountaineers, 1985.) € Surgical soap € Dressing supplies € Irrigation equipment € Wound closure tape (or suturing equipment if a member of the party is trained in its use) € One or more general-purpose antibiotics Because wound care is likely to be suboptimal in remote locations, and treatment for infection difficult to obtain, travelers to these areas should also take along a five-day course of prophylactic antibiotics for significant bite wounds. The selection will be limited by logistics. Amoxicillin/ clavulanate is a good choice for wounds in general, as well as for its utility in urinary and respiratory tract infections. Doxycycline, erythromycin, ciprofloxacin, penicillin, dicloxacillin, and trimethoprim/ sulfamethoxazole all have theoretical disadvantages for wound care (see Table 3), although some of them have other redeeming applications. Table 3. Characteristics of Some Antibiotics with Contingency Applications for Travelers Remote from Medical Care Drug Advantages Disadvantages Penicillin Inexpensive; narrow Narrow spectrum; limited spectrum; no agent proven range of applications better for bites. Amoxicillin/clavulanate Broad spectrum; good for Expensive; frequent side skin and soft tissue infections effects. (SSTI), urinary tract infections (UTI), and lower respiratory tract infections (LRI). Dicloxacillin Good for SSTI; no agent proven Narrow spectrum; poor better for bites; inexpensive; P. multocida coverage; narrow spectrum. limited range of applications. Doxycycline Inexpensive; good for Poor gram-positive and gastrointestinal infections anaerobic coverage; (Gl) and some uncommon photosensitivity; unsuitable infections; applications in for children and malaria prophylaxis; infrequent pregnant women. dosing. Ciprofloxacin Broad spectrum; good for UTI Expensive; only fair for gram and Gl; can be used for SSTI positives; unsuitable for and LRI; infrequent dosing. children and pregnant women. Erythromycin Inexpensive; good for SSTI Frequent side effects; poor and LRI; narrow spcctrum. P. multocida coverage. Trimethoprim/ Inexpensive; good for UTI and Poor P. multocida coverage; sulfamethoxazole Gl; can be used for SSTI and only fair for gram-positives, LRI; infrequent dosing. sulfa allergies. Cehalexin Good for SSTI, UTI, and LRI. Expensive; poor P. multocida coverage. Rabies Rabies, a viral zoonosis capable of infecting a wide range of vertebrate species, is a special case of bite wound infection. Rabies is an encephalitis. Its predilection for the lower parts of the brain presumably accounts for the bizarre behavioral aspects of the disease, including hydrophobia and aggressive or phobic rages, as well as autonomic dysfunction that may cause hypersalivation (foaming at the mouth), perspiration, temperature dysregulation, lacrimation, cardiac arrhythmias, priapism, and spontaneous orgasm. When the spinal cord is affected before the brain, the result is ascending myelitis or "dumb rabies," which may be indistinguishable from Guillain-Barre syndrome and difficult to diagnos in countries (such as the US) where rabies is rare and clinical suspicion is low. During infection, the virus is present in most body fluids, but the highest titer is found in saliva; hence, the aggressive rages that characterize rabies infection in many species contribute to its transmission via bite wounds. After inoculation, there is a variable lag time during which the virus replicates in the muscle tissue around the wound. At the end of this lag time, the virus crosses the neuromuscular junction into neurons, to be transported proximally into the central nervous system (CNS). When CNS infection has occurred, the disease invariably pursues a fatal course. The only way to prevent rabies after exposure is to induce immunity capable of aborting the infection before the virus attains an immunologically privileged location in the nervous system. Although human rabies has been almost completely controlled in the US, it still occurs with \substantial frequency elsewhere in the world. Its importance for international travelers is therefore disproportionate to its significance in North America. In the second half of the 1980s, the incidence of human rabies in the US was 0.004 cases per million population. In many developing countries, particularly Asia, the incidence is hundreds of times greater (see Tables 4 and 5). In the past decade, most cases of human rabies in the US have been acquired abroad. The US is not rabies-free, however; thousands of cases are documented in animals every year. One fact accounting for the rarity of human rabies in developed countries is that the distribution of animal rabies is almost entirely in wild animals that have little contact with humans (see Figure I). In developing countries, by contrast, rabies is relatively common in domestic animals (see Figure 2), thus leading to vastly higher rates of human rabies. The other main factor accounting for lower rates of human rabies in developed countries is the high quality and availability of post-exposure prophylaxis, even for low-risk exposures. Table 4. Incidence of Human Rabies in Selected Countries Country Incidence per million population U.S. 0.004 South Africa 0.1 Argentina 0.2 Indonesia 0.4 Turkey 0.8 Colombia 0.9 Mexico 1.2 Brazil 1.2 Ghana 1.8 Zimbabwe 2.2 Morocco 2.4 Ecuador 3.1 Honduras 3.3 Nepal 3.7 Thailand 7.6 Sri Lanka 10.3 Ethiopia 12.6 India 28.8 Sources: WHO (Bull WHO 64:883, 1986), CDC (MMWR 36 (suppl.3S):lS-27S, 1987). ---------------------------------------------------------------------------- Table 5. Areas Recently Free of Human and Animal Rabies North Amcrica and Caribb~an: Anguilla, Antigua and Barbuda, Bahamas, Barbados, Bermuda, Cayman Islands7 Dominica, Guad~loupe, Jamaica, Martinique, Montserrat, Netherlands Antilles (Aruba, Bonaire, Curacao, Saba, St. Maarten, St. Eustatius), Redonda, St. Christopher (St. Kitts) and Nevis, St. Lucia, St. Martin, St. Pierre and Miquelon, St. Vincent, Turks and Caicos, Virgin Islands (U.K. and U.S.). (Rabies persists in Haiti, Dominican Republic, Grenada, and other Caribbean countries not listed above.) South America: Uruguay. Europe: Bulgaria, Cyprus, Faro~ Isl;lnds, Gibraltar, Iceland, Ireland, Malta, Norway, Pottugal, Sweden, United Kingdom. Africa: Mauritius. Asia: Bahrain, Brunei Darussalam, Japan, Kuwait, Malaysia, Maldives, Oman, Singapore, Taiwan. Pacific: American Samoa, Australia, Belau, Cook Islands, Federated States of Micronesia (Kosrae, Ponape, Truk, Yap), Fiji, French Polynesia, Guam, Kiribati, New Caledonia, New Zealand, Niue, Northet~ Mariana Islands, Papua New Guinea, Samoa, Solomon Islands, Tonga, Vanuatu. Rabies Vaccines Only one rabies vaccine, the Merieux Institute human diploid cell vaccine (HDCV), is available in the US; the exception is Michigan, which manufactures its own alternative, rabies vaccine adsorbed (RVA). In the rest of the world, many differcnt vaccines are used. Technologically, these vaccines span the entire history of rabies immunization, and some are not much more sophisticated than the onc Pasteur developed using the spinal cords of rabid rabbits. Because they are much less expensive than HDCV, thcse primitive vaccines arc still used in many poor countries and represcnt an additional hazard for the traveler. The earliest and least expensive vaccines, made from ncrvous system tissue of infected animals, are Semple vaccine, Fermi vaccine, and nerve tissue vaccine, among others. All of these have the unfortunate side effect of occasionally immunizing the recipient against myelin basic protein, resulting in potentially fatal iatrogenic autoimmune encephalomyelitis. The next level of sophistication in vaccine preparation involves use of suckling mice. Because the brains of these mice are not myelinated, autoimmune neurologic disease is less frequent. Side effects are further reduced by growing the virus in duck eggs. Although these refinements help prevent adverse vaccine reactions, the biggest drawback of the primitive vaccines is their lack of efficacy (see Table 6). They are demonstrably better than no vaccine at all but are only about 60-80% effective at preventing rabies when given after exposure, even when used in conjunction with rabies immune globulin (RIG). Recently, a new generation of rabies vaccines has been developed. These vaccines are produced in tissue cultures; the HDCV currently used in the US is the prototype. Serious toxicity is rare with these vaccines, and their immunogenicity is an order of magnitude higher than that of the primitive vaccines. When post-exposure HDCV is administered in conjunction with human RIG using optimal technique, the protective efficacy approaches 100%, and serious toxicity is very rare. Other tissue culture vaccines (grown in Vero cells, chick embryo cells, hamster kidney cells, etc.) are almost as effective, but clinical experience with them is limited. Therefore, the most important consequence of the primitive rabies vaccines is that the exposed traveler receiving one of them may assume that he or she is adequately protected and neglect to pursue obtaing HDCV. When specific details about a vaccine are not available, tissue-culture-derived vaccines usually can be distinguished from unacceptable vaccines by the dosing schedule used for post-exposure prophylaxis. Primitive vaccines are given daily for two or three weeks, whereas tissue-culturederived vaccines are given in five doses over a month (sometimes with a sixth dose at 90 days). An alternative regimen used in some areas calls for eight small doses on day 0, four doses on day 7, and one dose on each of days 28 and 90. Table 6. Characteristics of Rabies Vaccines in Use Worldwide Type of vaccine Effcacy Neuroparalytic accidents Semple (adult animal nerve tissue) 60-80% 1/200-1/1600 Suckling mouse brain 60-80% 1/8000 Duck embryo 60-80% 1/30,000 Human diploid cell (HDCV) ~100% < 1/2,000,000 Rabies Immune Globulin Post-exposure rabies prophylaxis should include RIG as well as vaccine, because of the limited time period during which immunity sufficient to prevent the virus from reaching the CNS can be achieved. Experiments have conflrmed that RIG augments the clinical efficacy of rabies vaccine, and globulin is always given with post-exposure prophylaxis in the US. Half the RIG isinfiltrated around the fresh wound, if possible (this may not be practical for a hand or face wound); the other half is injected elsewhere (but not in the same limb in which the vaccine was injected). Early RIG preparations were usually made from horse or mule serum. The advent of safe and effective vaccines has made it possible to hyperimmunize human donors. Human RIG is now available for post-exposure prophylaxis, thus avoiding the problem of serum sickness. Again, there is a big discrepancy between the standards of practice in developed countries and those in developing countries. All RIG is expensive, and human RIG is many times more expensive than equine RIG. Therefore, many countries with limited health care resources offer RIG only for exceptionally high-risk exposures; often, only equine RIG is available. Nevertheless, the reported risk of serum sickness (at least for equine RIG of French or Swiss manufacture) is only about 1%, which is much lower than that historically associated with horse serum in this country. No difference in efficacy between equine and human RIG has been described, and using some immune globulin is clearly better than using none at all. Most RIG offered worldwide, whether equine or human, is manufactured in developed countries with adequate control to prevent contamination with blood-borne viruses. It is not known, however, whether human immunoglobulin preparations manufactured in developing countries are completely safe with respect to HIV. Pre-Exposure Rabies Prophylaxis Pre-exposure rabies immunization can provide partial protection; however, because it is not 100% reliable, immediate booster immunization is required in case of exposure. Nevertheless, preexposure prophylaxis offers several benefits for individuals whose risk of exposure to rabies is significant. First, by priming the immune system against the rabies virus, prophylaxis facilitates response to a subsequent booster. This effect could be critically important in a number of situations, such as when treatment is delayed by prolonged evacuation, when only primitive vaccines are available, or when exposure is severe (e.g., face and scalp wounds, which predispose to very rapid onset of rabies and vaccine failure). Second, prophylaxis allows reduced intensity of necessary post-exposure treatment (i.e., 2 instead of S doses of vaccine are required, treatment duration is a week rather than a month, and RIG is not is needed). Finally, pre-exposure prophylaxis protects against inapparent exposure, such as that involving mucous membranes. The number of rabies cases for which no exposure can be established is increasing. Pre-exposure prophylaxis is expensive enough that it is not cost-effective for most travelers. However, travelers who might be expected to benefit (see Table 7~ can be identified on the basis of exposure risk and the risk that post-exposure treatment will be suboptimal. Pre-exposure prophylaxis is generally appropriate only for a traveler going to an area where rabies is endemic; this includes most of the developing world. Risk is highest in India, Sri Lanka, Thailand, and the less developed countries of Asia and Africa. Childhood is an important risk factor, because children are more likely than adults to approach dogs (or even wild animals), more likely to have mucous membrane exposure to animal saliva, more likely to be bitten, more likely to sustain a head bite, and less likely to recognize potential exposure and respond to it promptly. In some areas, 40% of all human rabies occurs in children under 14 years. Therefore, pre-exposure rabies prophylaxis should be seriously considered for any child traveling for prolonged periods (e.g., one month or more) to a rabies-endemic country. The accessibility of medical care while traveling should also be considered. An adult traveler who will always have ready access to modern medical facilities can probably do without preexposure prophylaxis. Travelers to areas where tissue-culture-derived rabies vaccine and R~G may not be obtainable within 24 hours are candidates for pre-exposure immunization, and those who will face delays of two or more days should usually be vaccinated. Certain activities, such as occupational animal contact or spelunking, predispose travelers to rabies exposure. Most animal observation activities (i.e., visiting a game preserve) do not involve excessive rabies risk, but veterinary, zoological, and animal-control activities do. Cave exploration has led to human rabies even without direct animal contact, probably via the aerosolized body fluids of bats. Travelers who will do extensive walking or bicycling in rural areas are obviously more likely to be exposed, compared with persons visiting urban areas. Finally, the level of risk is proportional to the duration of stay in a high-risk area. For visits of less than a week, immunization is seldom, if ever, necessary. For visits of a month or more, it is often indicated. Pre-exposure immunization may be offered to travelers who anticipate long-term residence in a high-risk area, simply because of the possibility of inapparent exposure. Pre-exposure vaccination comprises three doses given on days 0, 7, and 28. The traditional regimen calls for 1.0 ml of vaccine given intramuscularly into the deltoid muscle on each of those days. Because the vaccine is expensive, however, it is now customary to use smaller doses (0.1 ml) administered intradermally. Although the low-dose, intradermal regimen results in an immune response slightly less than that of the intramuscular regimen, it provides adequate protection in most circumstances. In certain cases, the extra safety margin of the high-dose, intramuscular regimen is called for. When the vaccinee is currently taking chloroquine, which partially suppresses the response, and when exposure may occur within 30 days after the last shot of theseries, the higher dose should be used. Either HDCV or RVA can be used for high-dose immunization; only HDCV is used for low-dose immunization. Travelers receiving pre-exposure prophylaxis must understand that appropriate measures (including booster immunization and aggressive wound care with a detergent disinfectant) are still required if they are subsequently exposed to rabies. Travelers who have received rabies immunization with HDCV in the past do not need booster doses for subsequent travel unless they will be at exceptionally high risk (i.e., exploring caves, handling animals on a regular basis, or having no access to post-exposure medical care). These high-risk travelers should be given a single booster dose of vaccine if more than two years have elapsed since vaccination. Travelers who have received non-tissue-culture-derived vaccines in the past generally should be treated as though they have never been immunized, unless their serologic response was documented. Table 7. Factors Calling for Consideration of Pre-exposure Rabies Prophylaxis for Travelers 1. Degree of risk in desti~ation country. 2. Age less than 16 years. 3. Risk of exposure in a location more than 24 hours' travel from modern medical carc. 4. Occupational animal contact. 5. Spelunking. 6. Extensive walking or hicycling in rural areas. 7. Duration of stay. Post-Exposure Rabies Prophylaxis In the US, where a uniform protocol for immunization has been adopted (see Table 8), the only difficult part of post-exposure rabies prophylaxis is deciding whether exposure has occurred. If the source animal is a bat or wild carnivore (especially a skunk, fox, raccoon, coyote, or bobcat), it should be presumed rabid unless it can be killed and proved not to be rabid by immunohistologic examination of thebrain. (Killing the animal by blows to the head can make this study impossible.) If the biting animal is a healthy domestic dog or cat, it shouId be quarantined and observed for 10 days. With extremely rare exceptions, that is the upper limit on the time a rabid dog or cat will excrete virus before falling ill. This method of observation cannot be used for wild animals or domestic ones other than dogs and cats, because the clinical features and time course of rabies are not as well-defined for other species. Strays, unwanted animals, or animals developing symptoms suggestive of rabies should be killed and an autopsy performed for evidence of rabies infection. For other animals, including livestock, rodents, rabbits, and hares, the risk is generally limited but varies regionally. Thus, consultation with local or state public health officials is in order. The same is true of dogs or cats that escape and cannot be observed or examined. Rabies vaccine and RIG are generally stocked by the pharmacies of hospitals providing emergency care. If supplies of these biologics cannot be located, the fastest results can usually be obtained by contacting local or state health departments, which often maintain lists of pharmacies carrying them. Alternative contacts are the CDC Division of Viral Diseases (daytime phone 404 639-3095; night phone, 404-639-2888) and the Merieux Institute Inc. (outside Florida, 800-327-2842; in Florida, 305-593-9577). When a traveler who has been exposed to rabies abroad returns home, the practitioner may be faced with difficult questions regarding the adequacy of therapy given abroad. The extreme case is that of no therapy at all, which raises the question of how long after exposure anything can be gained by post-exposure therapy. The answer to this question is not known. Certainly, treatment is more effective the sooner it is given, but rabies can have an incubation period of a year or longer; therefore, immunization, even monnhs after exposure, is reasonable. At the other extreme is the patient with documentation of HDCV having been administered in the deltoid muscle on days 0, 3, 7, 14, and 28 with a concurrent dose of RlG; this therapy can be considered adequate. Between these two scenarios are many possible combinations of vaccines, RIG, injection sites, and timing of doses. Therefore, it is usually best to consult a rabies expert in the local or state health department to help evaluate the adequacy of previous treatment and decide what to do next. When in doubt, the safest course is to draw serum for a rabies-neutralizing antibody titer by the rapid fluorescent focus inhibition test (RFFIT). While awaiting the result, therapy should be started using the standard post-exposure regimen and continued unless documentation of an adequate antibody titer is received. Table 8. Post-Exposure Rabies Prophylaxis Always clean wound thoroughly with disinfectant soap and water. For persons previously immunized with HDCV or RVA; (prior irnmunization with other vaccines is taken into consideration only if adequate antibody response was docurnented): Rabies vaccine 1.0 ml IM in deltoid on each of days O and 3. No rabies immune globulin. For all other persons: Rabies immune globulin 20 lU/kg, half infiltrated at the site of the bite, the other half given IM at a site remote from vaccine administration; plus rabies vaccine 1.0 ml IM in deltoid on each of days O,3,7, 14,and28. The same doses are used for infants and children. Advice to Travelers Travelers to rabies-endemic areas should understand the following principles: 1. In many developing countries, rabies remains a significant risk and can be transmitted by the saliva of domestic dogs and cats, wild carnivores, bats, and sometimes livestock. Even vaccinated animals can transmit rabies. 2. Individuals at significant risk, including children, spelunkers, those who will have poor access to modern medical care, those who will be handling animals, and those traveling for prolonged periods, are candidates for pre-exposure rabies prophylaxis; they should understand that treatment is still necessary if exposure occurs. 3. Rabies exposure consists of contamination of a wound or mucous membranes (the eyes or the inside of the nose or mouth) with saliva of a rabid animal. Simply being in the presence of, or even petting, a rabid animal does not cause exposure. However, claw wounds and scratches might lead to infection. 4. In case of rabies exposure, the wound should be washed vigorously with a detergent disinfectant, and the victim should seek immunization . 5. After rabies exposure, victims who have not been previously immunized with one of the modern vaccines should always receive rabies immune globulin, preferably human, in addition to rabies vaccine. If possible, half the globulin should be injected~ around the wound. 6. In many places, primitive rabies vaccines that are poorly protective and have serious side effects are still used. These include Semple vaccine, Fermi vaccine, nerve tissue vaccine, suckling mouse brain vaccine, and duck egg vaccine. The feature they have in common is once-a-day dosing. The traveler should do whatever is necessary to get, instead, one of the tissue-culture derived vaccines, which are given as five shots spaced out over a month. The nearest US or Canadian embassy medical department often will have HDCV and RIG available for emergency use in rabies-endemic countries. 7. Rabies vaccine shots should be given in the deltoid (upper arm), never the buttock. RIG can be injected in the buttock, usually in two divided doses (when feasible, one of the doses should be injected around the wound instead). Selected References Baer GM, Fishbein DB: Rabies post-exposure prophylaxis. NEnglJMed 1987;316:1270-1272. Callaham M: Controversies in antibiotic choices for bite wounds. Ann Emerg Med 1988;17:1321-1330. Centers for Disease Control. Rabies prevention: United States, 1984. MMWR 1984;33:393402. Centers for Disease Control: Guidelines for prevention of Herpes virus simiae (B virus) infection in monkey handlers. MhlWR 1987;36:680-689. Feder HM, et al: Review of 59 patients hospitalized with animal bites. Pediatr Infect Dis J 1987;6:24-28. Research toward rabies prevention. Rev Infect Dis 1988;10(Supplement 4):S573-S815. Trott A: Care of mammalian bites. Pediatr Infect Dis J 1987;6:8-10. Underman AE: Bite wounds inflicted by dogs and cats. Vet Clin North Am [Small Anim Practice~ 1987;17:195-205.