Rabies postexposure prophylaxis

I have been working as a float nurse in the emergency department (ED) and recently encountered patients with animal bites. What do I need to know about rabies postexposure prophylaxis?—CS, Michigan Lucas O'Brien, PharmD, and Dan Sheridan, RPh, CPPS respond—Of the world's 59 000 reported rabies deaths annually, 99% result from dog bites.1 In the United States (US), however, bats have been the predominant vector of rabies exposure since 2015, surpassing raccoons.2 The odds of surviving rabies exposure are near 100% as long as postexposure prophylaxis (PEP) is administered correctly and as soon as possible.3 As prophylaxis, the goal is to neutralize all viral particles before they can infect the central nervous system (CNS) and begin replicating.4 When the first signs and symptoms of rabies manifest (low-grade fever, pain, or paresthesia at the site of exposure), this means that the opportunity for prophylaxis has passed, and the odds of survival are incredibly low.5 If a patient seeks care immediately after rabies exposure, their survival is dependent on the health care team's proper execution of PEP. The three essential interventions of PEP are immediate wound cleansing, local infiltration of rabies immune globulin (RIG), and appropriate administration of the immunization series (see Categories of contact and recommended postexposure prophylaxis).6 Wound care Cleaning the wound is crucial to prevent both CNS rabies infection and local skin infection. The US Centers for Disease Control and Prevention (CDC) recommends gentle irrigation of the wound with soap and water or, if available, a dilute povidone-iodine solution (a virucidal agent).6 Even without the other elements of PEP, wound cleansing alone significantly reduces the risk of rabies infection.6 A bat bite wound may be difficult to locate at all, but note that direct contact with a bat (with or without an observed wound) meets severe exposure criteria.7 The CDC categorizes rabies exposures based on increasing severity.1 The categories will dictate which further steps of PEP are necessary. Wounds with more severe puncture may require debridement, antibiotics, or primary wound closure. RIG infiltration One of the most critical aspects of rabies PEP is the administration of RIG, which provides patients with passive immunity that immediately begins to neutralize the rabies virus. The first RIG with widespread use was of equine origin, but in the US, these products have been entirely replaced by human rabies immune globulin (HRIG), which has reduced the incidence of adverse reactions. Modern HRIG may be associated with local pain, dizziness, and low-grade fever, with uncommonly reported adverse effects of injection-site reactions.3,8 The CDC recommends all patients receive an HRIG dose of 20 international units (IU)/kilogram (kg).6 The only time a patient should not receive RIG after a rabies exposure is if the patient has been previously immunized against rabies, including after the third dose (Day 7) of PEP.6 These patients will already have developed initial antibodies, but they should still receive booster doses of the vaccine. If RIG is unavailable for any reason and a patient receives only their first dose of rabies vaccine on Day 1, it is recommended that they still receive RIG through the seventh day of therapy.6 The use of the local infiltration technique for giving HRIG is vital for PEP success. To prevent the rabies virus from spreading from the wound site, it is recommended to inject directly into the wound.6 As HRIG does not generate detectable titers through the whole body, the CDC recommends injecting as much of the 20 IU/kg dose into the wound and surrounding area as possible without risking compartment syndrome (although there are no recorded instances of compartment syndrome occurring with HRIG, even in space-limited tissues such as fingers and toes).9 When considering the total volume given, it is important to note that two concentrations of HRIG are currently available: 150 IU/mL and the newer 300 IU/mL. Careful consideration of the product being used is necessary to ensure the patient receives the correct dose. Due to patient-specific factors, it may not be feasible to administer the entire 20 IU/kg dose by local infiltration. In this situation, guidelines disagree on what should be done with the remaining portion. According to the CDC, any HRIG that cannot be locally infiltrated should be injected intramuscularly. The World Health Organization (WHO), however, stopped recommending distal injection of remaining HRIG in 2018, citing poor evidence of benefit, as this remainder can be conserved for use in other patients.10 - Categories of contact and recommended postexposure prophylaxis1 Categories of contact with suspect rabid animal Postexposure prophylaxis measures Category I—touching or feeding animals, animal licks on intact skin (no exposure) Washing of exposed skin surfaces, no PEP Category II—nibbling of uncovered skin, minor scratches or abrasions without bleeding (exposure) Wound washing and immediate vaccination Category III—single or multiple transdermal bites or scratches, contamination of mucous membrane or broken skin with saliva from animal licks, exposures due to direct contact with bats (severe exposure) Wound washing, immediate vaccination and administration of rabies immunoglobulin/monoclonal antibodies A recent study of one health care system showed that between 2015 and 2018, just over half of patients eligible for PEP received it correctly despite wound infiltration being recommended by the CDC since 1999.8,9 Some of this has been attributed to confusion around HRIG protocol, as some hospitals require physicians to perform wound infiltration while others permit nursing staff to do so.9 Proper clinician education on the rabies PEP protocol, including injection technique and documentation, as well as guidance from clinical experts, can help ensure that all patients receive the necessary care after a rabies exposure. Vaccine administration The third phase of PEP therapy is immunization. Several types of rabies vaccines have been developed. Both live attenuated and inactivated vaccines have been traditionally used in humans, with the latter being currently recommended due to their greater safety. Common reactions to the inactivated vaccines can include pain, erythema, edema, injection-site pruritus, fever, headache, and nausea, which can be treated with antipyretic/anti-inflammatory medications. Current CDC guidelines recommend a four-dose PEP series on Days 0, 3, 7, and 14. This four-dose series applies to all previously unvaccinated individuals, which should account for the majority of patients. The CDC references ACIP indications for preexposure prophylaxis, including occupations with high-risk animal contact, such as zookeepers, park rangers, veterinarians, and certain lab workers, or travelers to parts of the world where rabies is common and access to medical care is limited.11 This preexposure prophylaxis regimen consists of two doses on Days 0 and 7. Booster doses can be reconsidered based on titers every 6 to 36 months, depending on the individual patient's risk. If a patient has been vaccinated for rabies before, for any reason, only the first two doses of the PEP series are necessary. A fifth dose on Day 28 is recommended for immunocompromised patients. In their 2018 position statement on rabies PEP, the WHO concluded that rabies vaccines are safe and effective for pregnant patients as well, and do not interfere with the infant's development.12 The Advisory Committee on Immunization Practices likewise asserts that pregnancy is not a contraindication for rabies PEP.6 The most important interaction to remember between the PEP interventions is that rabies vaccines cannot be given in the same area of the body as RIG. For example, if HRIG was infiltrated into a bite wound on the patient's right side, then the rabies vaccine should be given in the left deltoid; any remaining HRIG should be administered in the right deltoid. If they interact with each other in the body, the immune system's natural antibody production will be inhibited.4,6 Both RIG and the first dose of rabies vaccine should be administered on Day 0 of PEP6 (most often on arrival in the ED), but great care should be taken to keep them separate. RIG and rabies vaccine should never be combined into the same syringe, and the vaccine should always be injected into the deltoid farthest anatomically from the rabies wound.9 This means that if HRIG is first injected locally and the rest of the dose intramuscularly, the remaining HRIG should be injected closer to the wound, allowing the vaccine to be administered at the distal deltoid.6 Apart from the deltoid, the CDC specifies that the anterolateral aspect of the thigh is acceptable for children, but the gluteal muscle should never be used for the administration of a rabies vaccine. Continuity of care should also be prioritized by ensuring the patient has a follow-up plan to complete the vaccine regimen upon discharge from the ED, such as at an outpatient infusion center, primary care office, or local health department.