November 2017 FAQs
November 2017 FAQs Heading link
What is the evidence for decolonization with an alcohol-based nasal antiseptic?
What is the evidence for decolonization with an alcohol-based nasal antiseptic?
Approximately 15% to 30% of healthy individuals in the United States are nasally colonized with methicillin-sensitive Staphylococcus aureus (MSSA) and 1% to 3% are colonized by methicillin-resistant S. aureus (MRSA).1 Colonization often precedes infection and can result in significant morbidity and mortality.2 Nasal carriers of S. aureus have a 2- to 12-fold increased risk of subsequent infection.3 Decolonization is a process used to decrease or eliminate bacteria and is used as a means of prevention for healthcare-associated infections (HAIs).1 Decolonization may be done with a method intended to reduce all pathogens or it may be aimed at reducing a specific pathogen. There are a variety of agents available for decolonization with nasal mupirocin and chlorhexidine baths being the mainstay for MRSA decolonization.
Decolonization has been shown to be particularly useful in certain populations including surgical patients. Although universal decolonization (e.g., decolonization provided to all surgical patients) is effective, screening for S. aureus and selective decolonization may be preferred. Selective decolonization in patients who are to undergo cardiothoracic or orthopedic surgery has been shown to decrease hospital costs.4 Decolonization with nasal mupirocin and chlorhexidine body wash has been shown to decrease the incidence of S. aureus surgical site infections.5
There are a number of clinical practice guidelines to aid in the decision of when and how to decolonize. The Infectious Diseases Society of America (IDSA) guidelines for the treatment of MRSA infections recommend considering decolonization in patients with recurrent skin or skin structure infections or when there is ongoing transmission among close contacts.6 The recommended regimen in these guidelines is nasal decolonization with mupirocin twice daily for 5 to 10 days with or without skin antiseptic solution (e.g., chlorhexidine) for 5 to 14 days or dilute bleach baths. The American Society of Health-System Pharmacists (ASHP) provides guidelines for antimicrobial prophylaxis in surgery.7 They recommend against universal decolonization. However, selective decolonization with intranasal mupirocin is recommended for all patients with documented S. aureus colonization who are undergoing orthopedic or cardiac procedures. The guidelines recommend surveillance for susceptibility of S. aureus isolated from surgical site infections when mupirocin is used for decolonization. The Society for Healthcare Epidemiology of America (SHEA) provides guidance on strategies to prevent surgical site infections in acute care hospitals.8 These guidelines recommend screening and decolonization similar to the ASHP guidelines; however, they do acknowledge that there is conflicting data on the effectiveness of rapid screening for MRSA followed with decolonization on the rate of surgical site infections due to S. aureus. Routine preoperative decolonization with mupirocin without screening is not currently recommended by these guidelines.
Methods of Nasal Decolonization
Mupirocin remains the gold standard agent for S. aureus nasal decolonization, but the concern for resistance demands alternate options.1,2 Mupirocin overuse is contributing to increased resistance and mupirocin-resistant MRSA strains.1,4,9 There are data supporting the use of other nasal decolonizing agents such as povidone-iodine and alcohol-based antiseptics. Povidone-iodine is a skin antiseptic with activity against both gram-positive and gram-negative bacteria.1 It has been shown to be effective against MRSA and mupirocin-resistant MRSA. A challenge with povidone-iodine solutions is the inactivation of its antibacterial effect by nasal secretions.1,10
Alcohol-based antiseptics have bactericidal activity against both gram-positive and gram-negative bacteria including multidrug resistant organisms.11 Nozin nasal sanitizer is an alcohol-based antiseptic that has been shown to decrease nasal bacterial colonization. Nozin is 62% alcohol with a number of inactive ingredients including jojoba, orange oil, coconut oil, lauric acid, benzalkonium chloride, and vitamin E. It is formulated as a popswab ampule to facilitate nasal application. Nozin has been shown to have a potential role in decolonization throughout a healthcare facility.11-13
Nozin nasal sanitizer has been studied in healthcare professionals and orthopedic surgery patients.12,13 A randomized controlled trial by Steed and colleagues aimed to decrease nasal S. aureus carriage in healthcare professionals at an urban health center.12 Mullen and colleagues investigated the role of perisurgical nasal decolonization with Nozin in spine surgical patients and their affiliated nursing staff.13 These studies are summarized in the Table.
Table. Clinical efficacy of an alcohol-based nasal antiseptic (Nozin).12,13
Study design and duration
Patients and regimen
DB, PC, RCT
Subjects assessed and cultures taken at time 0 and followed for 10 hours
Nasal application of test preparation at time 0 with reapplications 4 and 8 hours later
39 HCPs with S. aureus nasal colonization
Excluded HCPs with upper respiratory disease,a antibiotic use 2 weeks before or during study, allergy to citrus oil, cigarette smoker
Intervention: saturated sterile swab with 5 drops of alcohol-based nasal sanitizer or matching placebo inside the vestibular surfaces of both nostrils
- S. aureus colonies declined from 756 ± 338 CFU at baseline to 30 ± 12 CFU at end of 10 hour study period (p<0.001 compared with placebo)
- Mean 82% decline (median = 99%)
- Total bacteria CFU reduction from 1200 ± 379 at baseline to 167 ± 70 at end of 10 hour study period
- Mean 71% decline (median =91%)
- S. aureus colonies increased from 562 ± 255 to 1239 ± 838 CFU
- Total bacteria CFU also increased from baseline
- Single daily treatment with Nozin nasal sanitizer is effective in reducing nasal colonization by S. aureus and other potentially pathogenic bacteria in HCPs.
Data collected 9 months prior to nasal antiseptic intervention and 15 months post-intervention
1073 spine surgery patients
Pre-intervention: CHG bathing and surgical site decolonization with or without nasal mupirocin
Intervention: alcohol-based nasal sanitizer application by trained staff preoperatively and patient postoperatively for 5 to 7 days with continued CHG bathing
Mean change in S. aureus infection rates: 1.76 to 0.33 infections per 100 surgeries represented an 81.3% statistically significant decline from baseline (p=0.036)
- Adoption of alcohol-based nasal antiseptic protocol by the spine surgery group resulted in decreased S. aureus SSI from baseline over a 15 month intervention period.
Abbreviations: CFU=colony forming units; CHG=chlorhexidine gluconate; DB=double-blind; HCPs = healthcare professionals; PC=placebo-controlled; RCT=randomized controlled trial; SSI=surgical site infection.
aRespiratory disease: chronic rhinitis/sinusitis, seasonal allergies, or upper respiratory infections in previous 4 weeks.
These studies support a potential role of Nozin nasal sanitizer in decolonization. Steed et al studied the efficacy and safety of Nozin in healthcare professionals, a population that is known to be colonized by S. aureus anywhere from 20 to 40%.12 Although this study found Nozin to be safe and effective, the study has a number of limitations. First, the sample size (n=39) was very small and the intervention was not compared to mupirocin or other decolonization strategies. Second, although the formulation of Nozin incorporates moisturizing agents to decrease irritation, the short duration of this study is not enough to assess nasal irritation/dryness or other potential adverse reactions. In addition, the 3 times daily application may not be realistic for busy healthcare professionals.
The study by Mullen and colleagues focused on surgical patients and staff, a setting where decolonization has been shown to be beneficial in decreasing infection rates.13 This study was an observational study in a large number of patients that did find a decreased incidence of S. aureus infections after implementation of a structured decolonization strategy including Nozin. A primary limitation of this trial is that there was inconsistent use of mupirocin prior to the Nozin intervention so it is impossible to determine whether routine mupirocin decolonization would have decreased infection rates to the same degree as Nozin.
Colonization by pathogens can result in a significant cost burden and increases in morbidity and mortality as a result of active infection. Decolonization has been shown to decrease the incidence of HAIs by decreasing or eliminating bacterial load. In the case of nasal colonization with S. aureus, mupirocin is the standard nasal decolonization agent. Nozin has been studied in select populations and appears to be safe and effective for nasal decolonization, but widespread replacement of mupirocin is not yet warranted. Larger, more robust studies are needed to determine the place of Nozin in decolonization strategies.
- Septimus EJ, Schweizer ML. Decolonization in prevention of healthcare-associated infections. Clin Microbiol Rev. 2016;29(2):201-222.
- McConeghy KW, Mikolich DJ, LaPlante KL. Agents for the decolonization of methicillin-resistant Staphylococcus aureus. Pharmacotherapy. 2009;29(3):263-280.
- Nair R, Perencevich EN, Blevins AE, Goto M, Nelson RE, Schweizer ML. Clinical effectiveness of mupirocin for preventing Staphylococcus aureus infections in nonsurgical settings: a meta-analysis. Clin Infect Dis. 2016;62(5):618-630.
- Humphreys H, Becker K, Dohmen PM, et al. Staphylococcus aureus and surgical site infections: benefits of screening and decolonization before surgery. J Hosp Infect. 2016;94(3):295-304
- Hetem DJ, Bootsma MC, Bonten MJ. Prevention of surgical site infections: decontamination with mupirocin based on preoperative screening for staphylococcus aureus carriers or universal decontamination? Clin Infect Dis. 2016;62(5):631-636.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infections Diseases Society of America for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011:52(3):e18-e55.
- Bratzler DW, Dellinger P, Olsen KM. et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283.
- Anderson DJ, Podgorny K, Berrios-Torres S, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(6):605-627.
- Poovelikunnel T, Gethin G, Humphreys H. Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA. J Antimicrob Chemother. 2015:70(10):2681-2692.
- Rezapoor M, Nicholson T, Tabatabaee RM, Chen AF, Maltenfort MG, Parvizi J. Povidone-iodine-based solutions for decolonization of nasal staphylococcus aureus: a randomized, prospective, placebo-controlled study. J Arthroplasty. 2017;32(9):2815-2819.
- Nozin website. https://www.nozin.com. Accessed October 4, 2017.
- Steed LL, Costello J, Lohia S, Jones T, Spannhake EW, Nguyen S. Reduction of nasal Staphylococcus aureus carriage in health care professionals by treatment with a nonantibiotic, alcohol-based nasal antiseptic. Am J Infect Control. 2014;42(8):841-846.
- Mullen A, Wieland HJ, Wieser ES, Spannhake EW, Marinos RS. Perioperative participation of orthopedic patients and surgical staff in a nasal decolonization intervention to reduce Staphylococcus spp surgical site infections. Am J Infect Control. 2017;45(5):554-556.
Kathryn Mundi, Pharm.D.
PGY-1 Pharmacy Resident
University of Illinois at Chicago
The information presented is current as September 1, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
What evidence supports combining insulin and other antidiabetic medications in adults with type 1 diabetes?
What evidence supports combining insulin and other antidiabetic medications in adults with type 1 diabetes?
Type 1 diabetes is an endocrine condition that accounts for 5% to 10% of all cases of diabetes and is characterized by autoimmune destruction of pancreatic beta cells.1 Without beta cells, the pancreas cannot produce insulin and the body’s ability to regulate blood glucose levels is impaired. Beta-cell destruction also prevents the secretion of amylin, a hormone that usually functions to suppress inappropriate glucagon secretion and causes satiety by slowing gastric emptying.
Patients with type 1 diabetes require lifelong exogenous insulin therapy to prevent hyperglycemia-induced events such as ketoacidosis and long-term microvascular and macrovascular complications.1,2 Patients who do not achieve glycemic control despite well-titrated basal-bolus insulin regimens may benefit from combination therapy. Metformin has been used in patients with type 1 diabetes to decrease insulin resistance, with subsequent reductions in insulin doses, glycated hemoglobin (A1C) levels, weight, and total cholesterol.2,3 Recent studies have also combined sodium-glucose cotransporter-2 (SGLT-2) inhibitors with insulin therapy in patients with type 1 diabetes, since SGLT-2 inhibitors block resorption of glucose in the kidneys and decrease glucose levels in an insulin-independent manner.3
Some patients may need help regulating glucagon levels and gastric emptying patterns in the absence of endogenous amylin. Pramlintide, a synthetic amylin analogue, has a Food and Drug Administration-approved indication as an adjunct to insulin therapy in patients with unpredictable postprandial glucose levels caused by erratic gastric emptying.2,4 There has been a growing interest in using other medications that affect glucagon secretion and regulation in patients with type 1 diabetes. For example, glucagon-like peptide 1 (GLP-1) receptor agonists suppress inappropriate postprandial glucagon secretion and slow gastric emptying. Dipeptidyl peptidase 4 (DPP-4) inhibitors prevent the breakdown of GLP-1 and reduce postprandial glucagon levels.
Guidance documents from the American Diabetes Association mention that the use of GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors in patients with type 1.2,4 This article summarizes the available evidence with GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors in combination with insulin therapy in adult patients with type 1 diabetes.
Several small studies have investigated the efficacy of GLP-1 agonists or DPP-4 inhibitors in adult patients with type 1 diabetes.5-12 Some of these studies found no difference in A1C levels or other markers of glucose control, likely due to small sample sizes.8-10 An 8-week crossover study (n=20) with sitagliptin 100 mg daily found a reduction in A1C of 0.27% compared to placebo after controlling for the insulin dose.5 An open-label study with sitagliptin 100 mg daily or exenatide 5 mcg twice daily found reductions in A1C of 0.4% and 0.5%, respectively, with combination therapy compared to insulin alone, but combination therapy was started in patients with newly-diagnosed type 1 diabetes which may not mimic current clinical practice.7
Neither of the 2 largest studies support the use of GLP-1 agonists or DPP-4 inhibitors to improve long-term glucose control compared to placebo.6,11 A randomized, double-blind, parallel group, 20-week study compared sitagliptin 100 mg daily to placebo in 141 patients with type 1 diabetes.6 After 16 weeks, there was no difference in A1C levels, insulin doses, or body weight between sitagliptin and placebo despite significantly lower post-meal GLP-1 levels with sitagliptin. Another randomized, double-blind, placebo-controlled trial in 100 adults with type 1 diabetes and body mass index >25 kg/m2 compared liraglutide (dose titrated to 1.8 mg daily) and placebo for 24 weeks.11 The primary endpoint, change in A1C at 24 weeks, was not significantly different between liraglutide and placebo, although there were significant reductions in bolus insulin doses (-5.8 units, 95% confidence interval [CI] -10.7 to -0.8, p=0.0227), body weight (-6.8 kg, 95% CI -12.2 to -1.4, p=0.0145), and hypoglycemic events (rate ratio 0.82, 95% CI 0.74 to 0.90) with liraglutide. Postprandial glucagon and GLP-1 concentrations were similar between groups.
There are few studies with SGLT-2 inhibitors in patients with type 1 diabetes. A 4-week study with empagliflozin 2.5 mg, 10 mg, or 25 mg once daily added to insulin in 75 patients with type 1 diabetes found significant reductions in A1C levels compared to placebo (-0.35% to -0.49%, p<0.05); total daily insulin doses and body weight were also significantly reduced.13 It is unknown whether these differences would persist with longer-term treatment. Additional trials with empagliflozin for up to 52 weeks (EASE-2 and EASE-3) are underway.14 A small randomized study (n=30) evaluated 12 weeks of dapagliflozin 10 mg daily added-on to the combination of insulin and liraglutide.12 Compared to placebo, A1C decreased by 0.66% (p<0.01) and basal insulin doses were significantly lower (-0.72 units, p<0.05); however, urine ketones were significantly increased (p<0.05) and 2 patients in the dapagliflozin group experienced diabetic ketoacidosis.
Two larger studies support the use of SGLT-2 inhibitors in combination with insulin in patients with type 1 diabetes.15,16 A multicenter, randomized, double-blind, placebo-controlled trial in 833 patients found that dapagliflozin 5 mg and 10 mg significantly lowered A1C levels after 24 weeks compared to placebo (-0.42%, 95% CI -0.56% to -0.28%, p<0.0001 and -0.45%, 95% CI -0.58% to -0.31%, p<0.0001, respectively).15 Hypoglycemia occurred at a similar rate (about 80%) in all 3 groups. This trial is ongoing and 52-week results are forthcoming. A randomized, double-blind trial in 351 patients who received canagliflozin 100 mg or 300 mg found that both doses reduced A1C more than placebo (-0.29% and -0.25%, respectively) at 18 weeks.16 Rates of hypoglycemia were similar between groups, but diabetic ketoacidosis was more common with canagliflozin 100 mg and 300 mg vs placebo (4.3%, 6%, and 0%, respectively).
Overall, current data is conflicting regarding the benefit of GLP-1 agonists and DPP-4 inhibitors in combination with insulin in patients with type 1 diabetes, but the strongest evidence does not support their use in this setting.6,11 In contrast, 2 randomized trials found statistically significant decreases in A1C levels with dapagliflozin and canagliflozin compared to placebo.15,16 Adding an SGLT-2 inhibitor to insulin improved A1C levels by 0.25% to 0.45% more than placebo. This modest benefit must be weighed against the risk of ketoacidosis without hyperglycemia (euglycemic diabetic ketoacidosis), which is cautioned against in the product labeling for SGLT-2 inhibitors.2 Recommendations are lacking regarding the appropriate A1C level at which combination therapy should be started. Another limitation of combination therapy is that adding a second agent has only been compared to placebo, not to increasing the insulin dose. Overall, there is insufficient data to recommend routinely combining insulin with other antidiabetic agents in patients with type 1 diabetes.
- Triplitt CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146065891. Accessed October 9, 2017.
- American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Suppl 1):S64–S74.
- Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia. 2010;53(5):809-820.
- Chiang JL, Kirkman MS, Laffel LM, Peters AL; Type 1 Diabetes Sourcebook Authors. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care. 2014;37(7):2034-2054.
- Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK. Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med. 2011;28(10):1176-1181.
- Garg SK, Moser EG, Bode BW, et al. Effect of sitagliptin on post-prandial glucagon and GLP-1 levels in patients with type 1 diabetes: investigator-initiated, double-blind, randomized, placebo-controlled trial. Endocr Pract. 2013;19(1):19-28.
- Hari Kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin in new onset type 1 diabetes: a randomized, open label study. Diabetes Res Clin Pract. 2013;100(2):e55-e58.
- Sarkar G, Alattar M, Brown RJ, Quon MJ, Harlan DM, Rother KI. Exenatide treatment for 6 months improves insulin sensitivity in adults with type 1 diabetes. Diabetes Care. 2014;37(3):666-670.
- Zhao Y, Yang L, Xiang Y, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014;99(5):E876-E880.
- Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-week treatment with liraglutide as add-on to insulin in normal-weight patients with poorly controlled type 1 diabetes: a randomized, placebo-controlled, double-blind parallel study. Diabetes Care. 2015;38(12):2250-2257.
- Dejgaard TF, Frandsen CS, Hansen TS, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4(3):221-232.
- Kuhadiya ND, Ghanim H, Mehta A, et al. Dapagliflozin as sdditional treatment to liraglutide and insulin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2016;101(9):3506-3515.
- Pieber TR, Famulla S, Eilbracht J, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17(10):928-935.
- U.S. National Library of Medicine. Clinicaltrials.gov website. https://clinicaltrials.gov/. Accessed October 24, 2017.
- Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587(17)30308-X.
- Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose ctransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258-2265.
The information presented is current as of October 2, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
What is the appropriate management of rabies exposure?
What is the appropriate management of rabies exposure?
Rabies is a fatal, acute viral disease that causes encephalitis, coma, and death.1,2 Around the world, approximately 40,000 to 70,000 people die annually from rabies.2,3 Fortunately, in the United States ~2 deaths per year are caused by rabies compared to 100 deaths reported per year in the 1990s.4 Although rabies-related death is significantly lower in the United States, exposure to rabies still occurs. It is estimated that approximately 23,000 people are exposed to rabies and receive post-exposure prophylaxis annually.5
Rabies is an RNA virus which belongs to the Rhabdoviridae family and Lyssavirus genus.5 The rabies virus is found in the saliva of rabid animals and most reported cases of rabies are primarily related to animal bites.1,2 Domesticated animals, such as dogs, or wild animals, such as bats, skunks, raccoons, or foxes, can transmit rabies to humans. While most rabies exposures in countries outside of the United States are associated with dog bites, exposure to rabies in the United States is most commonly associated with bats (see Table 1).6 The transmission of rabies occurs when the saliva from a rabid animal is introduced into the broken flesh or mucous membranes of the host. However, there are many other routes of rabies transmission, such as inhalation, tissue/organ transplant, or the handling of infected carcasses.
Unprotected physical contact with bats is considered a high risk for infection because the rabies virus transmitted by bats can multiply in epidermal cells. Typically, the rabies virus replicates slowly in muscle tissue and enters the central nervous system (CNS) through retrograde transport via the neurons.7 The rabies virus can rapidly multiply in the CNS and spread to other organs. The incubation period of the rabies virus is 1 to 3 months but can range from less than a week to years. Once a human is infected with rabies, the virus can be transmitted to other humans via saliva (eg, kissing or sharing food) because the rabies virus can shed abundantly in the saliva 2 weeks before the onset of symptoms.7,8
Table 1. Most frequently reported rabid species in rabies cases9
Active rabies infection invokes fear not only because of its deadly outcome but also because of the symptomatology itself.2 The symptoms associated with rabies can present in 2 forms, encephalitic (furious) or paralytic (dumb) rabies.6,7 Although both types of rabies will eventually lead to death if untreated prior to the development of symptoms, furious rabies is more prevalent and death can occur within 5 to 7 days, whereas paralytic rabies is relatively less common and death can occur within 11 days. Prodromal symptoms of rabies include fevers, flu-like symptoms, gastrointestinal disturbances, pruritus, and neuropathic pain.6 The cardinal symptoms of rabies include initial weakness, fluctuating consciousness (eg, general arousal, hyperexcitability, lucid periods), hydrophobia, aerophobia, inspiratory spasms, and signs of autonomic dysfunction (eg, hypersalivation, piloerection, and cardiac arrhythmias), coma, and death.6,7 Paralytic rabies closely mimics Guillain-Barre syndrome but can be differentiated because paralytic rabies can progress to myoedema, and coma.6 In addition to determining whether the patient had physical contact with a rabid animal, diagnostic tests such as reverse transcription and polymerase chain reaction (RT-PCR), serum antibody testing, cerebrospinal fluid analysis or a biopsy of the nape of the neck or brain can help diagnose rabies.7
Rabies is a preventable disease when appropriate precautions are applied and with the use of pre- and post-exposure prophylaxis.8 However, for patients with active rabies symptoms, there is no available cure and treatment typically includes palliative care.2,7 In cases of known or suspected exposure, post-exposure prophylaxis management involves wound cleaning, vaccination, and human rabies immunoglobulin (HRIG).10 Without previous or timely administration of the vaccine, mortality is nearly 100%.
Pre-exposure prophylaxis against rabies should be considered for biologists who work with the rabies virus, veterinarians, agriculturists, wildlife officers, animal control, bat handlers, or people who plan to travel to areas where rabies is widespread, especially in areas where dog rabies is common.11 The Centers for Disease Control and Prevention (CDC) stratifies pre-exposure recommendations based on the risk frequency of exposure (eg, continuous, frequent, infrequent, or rare). There are 2 rabies vaccines available in the United States, human diploid cell vaccine (HDCV) [Imovax® Rabies] and purified chick embryo cell vaccine (PCEC) [RabAvert®].12,13 Both vaccines have indications for pre- and post-exposure prophylaxis. The rabies vaccine is administered intramuscularly into the deltoid muscle, which is considered the only acceptable site for administration, except in younger children where the outer aspect of the thigh can be used. The vaccine should never be administered in the gluteal area. Both vaccines are administered as 1 mL doses given on days 0, 7 and 21 or 28. For people who are likely to be continuously or frequently exposed to rabies, the CDC recommends serological testing and a booster vaccination if the titers are low.11 It is important to note that patients who are exposed to rabies after receipt of the pre-exposure vaccine will still require additional therapy.
Recommendations to initiate post-exposure prophylaxis in patients depends on the type of exposure (see Table 2).14 Post-exposure prophylaxis is indicated for healthcare workers only if contact occurs between the infected patient’s saliva, tears, or nervous tissue and the mucous membranes or open skin of the healthcare provider.8,14 Post-exposure prophylaxis should be started immediately if exposed to rabid dogs, cats, or ferrets. It is recommended to consider immediate prophylaxis if unprotected physical contact occurs with wild animals such as skunks, raccoons, foxes, and bats.
Table 2. Recommendations for post-exposure prophylaxis against rabies.14
Evaluation and disposition of animal
Post-exposure prophylaxis recommendations
Dogs, cats, ferrets
Healthy and available for 10 days observation
Persons should not begin prophylaxis unless animal develops clinical signs of rabies.
Rabid or suspected rabid
Immediately begin prophylaxis.
Unknown (e.g., escaped)
Consult public health officials.
Skunks, raccoons, foxes, and most other carnivores, bats
Regarded as rabid unless animal proven negative by laboratory tests
Consider immediate prophylaxis.
Livestock, small rodents (rabbits and hares), large rodents (woodchucks and beavers), and other mammals
Consult public health officials. Bites from squirrels, hamsters, guinea pigs, gerbils chipmunks, rats, mice, other small rodents, rabbits, and hares rarely require
antirabies postexposure prophylaxis.
Post-exposure prophylaxis against rabies involves the use of the rabies vaccine plus human rabies immune globulin [HRIG].14 The regimen for the rabies vaccine for post-exposure prophylaxis differs from that for pre-exposure prophylaxis, as does the recommendations on whether to administer HRIG (see Table 3). Human rabies immune globulin is given on the same day as the initial dose of the rabies vaccine, but if delayed, it can be administered up to the seventh day after exposure. The HRIG works by neutralizing the virus before it invades the nervous system.15 There are 2 HRIG preparations available, Imogam® and HyperRAB®. The dose of HRIG used for post-exposure prophylaxis is 20 IU/kg.15,16 Depending on the site and number of wounds, the full dose of HRIG is infiltrated into the area(s) around the wound(s). If there is HRIG remaining after infiltrating the wound(s) the remaining HRIG is injected intramuscularly at a site distant from the site of the vaccine injection. The remaining HRIG dose should be administered intramuscularly into the deltoid or lateral thigh muscle, but it should not be injected into the gluteal region because it can damage the sciatic nerve.
Table 3. Rabies vaccination for post-exposure prophylaxis14
Human Rabies Immune globulin*
Days since exposure
0, 3, 7, 14
0, 3, 7, 14, 28
Previous post-exposure prophylaxis
Do not administer
Received pre-exposure prophylaxis series
Previously documented rabies antibody titers [considered adequate]
*Only 1 dose is required.
¥ Can be administered up to the 7th day since the initial day of exposure
In the United States and Puerto Rico, a total of 23 cases of rabies in humans were documented by the CDC since January 2008, and only 2 people survived.4 A list of the cases and case reports (if provided) are available here. The management of active rabies is normally supportive care since currently, there are no effective treatment options once the clinical signs and symptom manifest. If the infection is identified in the very early stages, the use of aggressive treatment with rabies vaccine, HRIG, ribavirin, interferon, and ketamine can be considered.10 When used for the aggressive treatment of rabies, the rabies vaccine is given via multiple-site intradermal injections to accelerate the immune response compared to the intramuscular route, which can take up to a week to produce a detectable response. Since immunoglobulin typically does not cross the blood-brain barrier, it is unknown if administration of HRIG would clear an active rabies infection. Monoclonal antibodies demonstrated efficacy in rodent models, but none are currently available for human use.
Rabies is a fatal disease if is it not immediately recognized and treated with preventative measures.1 Although the number of rabies-related deaths has drastically declined in the United States because of animal vaccinations, a concern still remains for the exposure to rabies from bats.4 Since bats have tiny teeth that barely leave a bite mark, bat bites can go unnoticed and unprotected physical contact can lead to the development of rabies in humans.17 Often, encounters with bats occur at night when they enter a bedroom while a person is sleeping.8 Upon waking up it is difficult for the person to recall or determine the extent of contact with the bat or determine if a healthcare provider should be notified.
People living in areas where bats have the potential to enter homes should be educated about the proper and safe removal of the bats, and the need for a medical evaluation if any suspected contact with a bat occurs.17 The Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention recommends post-exposure prophylaxis for people in the same room as a bat including those who were in a deep sleep at night, an unattended child, a disabled person or an intoxicated person. Furthermore, ACIP recommends that persons with direct contact with a bat (eg, touching or landing on the person) where a bite or scratch cannot be ruled out should also receive post-exposure prophylaxis.
1. Koury R, Warrington SJ. Rabies. In. StatPearls. Treasure Island, FL: StatPearls Publishing; 2017. https://www.ncbi.nlm.nih.gov. Accessed October 23, 2017.
2. Davis BM, Rall GF, Schnell MJ. Everything you always wanted to know about rabies virus (but were afraid to ask). Annu Rev Virol. 2015;2(1):451-471.
3. Rabies. Centers for Disease Control and Prevention website. https://wwwnc.cdc.gov/travel/diseases/rabies. Updated May 16, 2016. Accessed October 18, 2017.
4. Rabies in the U.S. Centers for Disease Control and Prevention website. https://www.cdc.gov/rabies/location/usa/index.html. Updated April 22, 2011. Accessed October 18, 2017.
5. Rupprecht CE, Briggs D, Brown CM, et al; Centers for Disease Control and Prevention. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep 2010;59((RR-2)):1-9.
6. Hemachudha T, Ugolini G, Wacharapluesadee S, Sungkarat W, Shuangshoti S, Laothamatas J. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol. 2013;12(5):498-513.
7. DynaMed [database online]. Ipswich, MA: EBSCO Information Services; 2017. http://www.dynamed.com. Accessed October 22, 2017.
8. Harrist A, Styczynski A, Wynn D, et al. Human rabies – Wyoming and Utah, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(21):529-533.
9. Wild Animals. Centers for Disease Control and Prevention website. https://www.cdc.gov/rabies/location/usa/surveillance/wild_animals.html. Updated July 5, 2017. Accessed October 19, 2017.
10. Jackson AC, Warrell MJ, Rupprecht CE, et al. Management of rabies. Clin Infect Dis. 2003;36(1):60-63.
11. Preexposure Vaccinations. Centers for Disease Control and Prevention website. https://www.cdc.gov/rabies/specific_groups/travelers/pre-exposure_vaccinations. Updated April 22, 2016. Accessed October 19, 2017.
12. Imovax [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2016.
13. RabAvert [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
14. Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention. Human rabies prevention–United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008;57(RR-3):1-28.
15. HyperRAB S/D [package insert]. Research Triangle Park, NC: Grifols Therapeutics Inc; 2017.
16. Imogam Rabies-HT [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2014.
17. Dato VM, Campagnolo ER, Long J, Rupprecht CE. A systematic review of human bat rabies virus variant cases: Evaluating unprotected physical contact with claws and teeth in support of accurate risk assessments. PLoS One. 2016;11(7):e0159443.
The information presented is current as of October 25, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.