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1048 SECTION 13: Infectious Diseases With good aseptic technique, prophylactic antibiotics are not recommended prior to invasive procedures such placement of as central lines.35  RISK OF ENDOCARDITIS RECURRENCE Nearly 5% of patients with a single episode of endocarditis have repeat or relapse of endocarditis. Risk factors for repeat endocarditis include IV drug use and hemodialysis. 50 Repeated episodes of endocarditis may require valvular repair or replacement.39 REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 156-7 Prophylaxis Against Endocarditis for Highest-Risk Patients Procedure Patient Characteristics Antibiotic Agent Dose Dental procedures involving manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa Able to take oral antibiotics Amoxicillin 2 grams PO, 30–60 min before procedure Unable to take oral medication Ampicillin 2 grams IM or IV, 30–60 min before procedure Cefazolin or ceftriaxone 1 gram IM or IV, 30–60 min before procedure Allergic to penicillins or ampicillin Cephalexin 2 grams PO, 30–60 min before procedure Clindamycin 600 milligrams PO, 30–60 min before procedure Azithromycin or clarithromycin 500 milligrams PO, 30–60 min before procedure Unable to take oral medication and allergic to penicillins or ampicillin Cefazolin or ceftriaxone 1 gram IM or IV, 30–60 min before procedure Clindamycin 600 milligrams IM or IV, 30–60 min before procedure Procedures on infected skin, skin structure, or musculoskeletal tissue Non–methicillin-resistant strain of Staphylococcus or β-hemolytic Streptococcus suspected Dicloxacillin 2 grams PO, 30–60 min before procedure Cephalexin 2 grams PO, 30–60 min before procedure Patients unable to tolerate a β-lactam or who are known or suspected to have an infection caused by a methicillin-resistant strain of Staphylococcus Vancomycin 1 gram IV, 30–60 min before procedure Clindamycin 600 milligrams IM or IV, 30–60 min before procedure Other procedures (respiratory; GI; GU; noninfected dermatologic or musculoskeletal procedures) Prophylaxis not indicated contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause. 3 In the United States, tetanus is a reportable disease, aggregated through the National Notifiable Diseases Surveillance System. Improved childbirth practices, widespread immunization programs for children, decennial tetanus boosters for adults, mechanization of agriculture, and use of chemical fertilizers rather than animal manure have all resulted in a >95% decline in the annual incidence of tetanus in the United States since 1947. 4 From 2009 to 2015, 197 tetanus cases were reported in the United States, with 16 deaths. 4 Most patients who develop tetanus have inadequate immunity to the disease. Due to wan ing immunity and failure to receive routine boosters, only 31% of Americans >70 years old have adequate tetanus immunity. 5 Tetanus among children and neonatal tetanus are uncommon. The case fatality rate is approximately 8%, and patients >55 years of age account for all deaths. 3,4 Most cases of tetanus in the United States are associated with an acute wound. Puncture, contaminated, infected, or devitalized wounds account for approximately 70% of tetanus cases. Although less com mon, chronic wounds and dental abscesses are also associated with the disease.

years of age account for all deaths. 3,4 Most cases of tetanus in the United States are associated with an acute wound. Puncture, contaminated, infected, or devitalized wounds account for approximately 70% of tetanus cases. Although less com mon, chronic wounds and dental abscesses are also associated with the disease. Diabetics and injection drug users have an increased risk of contracting tetanus. 3,6 Two thirds of patients who develop tetanus do not seek medical care for their initial wound. Of those who do seek initial treatment and later develop tetanus, up to 95% do not receive appropriate therapy. PATHOPHYSIOLOGY Clostridium tetani is a motile, nonencapsulated, anaerobic gram-positive rod; it produces toxins that cause tetanus. C. tetani exists in either a vegetative or spore-forming state. The spores are ubiquitous in soil and animal feces and can survive on environmental surfaces for years. CHAPTER Tetanus Alan X. You Donna L. Carden Joel Moll INTRODUCTION AND EPIDEMIOLOGY Tetanus is uncommon in the United States, but worldwide estimates are approximately 100,000 cases per year, with a mortality rate of 35% to 40%. 1,2 The Centers for Disease Control and Prevention defines tetanus as a syndrome of acute onset of hypertonia and/or painful muscular Tintinalli_Sec13_p0997-1100.indd 1048 8/2/19 8:12 PM

uncommon in the United States, but worldwide estimates are approximately 100,000 cases per year, with a mortality rate of 35% to 40%. 1,2 The Centers for Disease Control and Prevention defines tetanus as a syndrome of acute onset of hypertonia and/or painful muscular Tintinalli_Sec13_p0997-1100.indd 1048 8/2/19 8:12 PM CHAPTER 157: Tetanus 1049 In agricultural areas, adults may harbor the organism; spores are found in many places, including on skin or in contaminated heroin.6,7 C. tetani is usually introduced into a wound in the spore-forming, noninvasive state but can germinate into the toxin-producing, vegetative form if tis sue oxygen tension is reduced. Crushed or devitalized tissue, a foreign body, or the development of infection favors the growth of the toxinproducing form of C. tetani. 7,8 C. tetani produces two exotoxins: tetanolysin, which facilitates growth of the bacterial population; and tetanospasmin, a powerful neurotoxin responsible for all of the clinical manifestations of tetanus. Tetanospas min reaches the nervous system by hematogenous spread of the exo toxin to peripheral nerves and by retrograde intraneuronal transport. Tetanospasmin does not cross the blood–brain barrier, but retrograde intraneuronal transport of the exotoxin enables tetanospasmin to gain access to the CNS. Tetanospasmin prevents the release of the inhibitory neurotransmitters glycine and γ-aminobutyric acid from presynaptic nerve terminals, releasing the nervous system from its normal inhibitory control. Loss of inhibition may also affect the preganglionic sympathetic neurons, resulting in sympathetic overactivity and high circulating catecholamine levels. 7-10 CLINICAL FEATURES Tetanus results in generalized muscular rigidity, violent muscular contractions, and autonomic nervous system instability. 8 Wounds that become contaminated with toxin-producing C. tetani are often punc ture wounds, but contaminated wounds range from deep lacerations to minor abrasions. 3 No wound exists in up to 10% of patients with tetanus. Tetanus can also develop after surgical procedures, otitis media, or abortion and can develop in injection drug users from contaminated heroin and in neonates through infection of the umbilical stump. 6,11 The incubation period for tetanus ranges from <24 hours to >1 month. Short incubation periods are associated with severe disease and a poor prognosis. Clinical tetanus comes in three forms: generalized, cephalic, and local. Generalized tetanus accounts for about 80% of cases. The most frequent presenting complaints of patients with generalized tetanus are pain and stiffness in the masseter muscles (“lockjaw”). Nerves with short axons are first involved, with symptoms in the facial muscles; later, descending progression to the muscles of the neck, trunk, and extremities occurs. The transition from muscle stiffness to rigidity leads to the development of trismus and the characteristic facial expression called risus sardonicus (sardonic smile). Reflex convulsive spasms and tonic muscle contractions are responsible for the development of dysphagia, opisthotonic flexing of the arms, clenching of the fists, and extension of the lower extremities. Spasms can last for 3 to 4 weeks. Recovery depends on regrowth of axonal nerve terminals and may take months. 8 Complications of tetanus include rhabdomyolysis and longbone fractures secondary to violent muscle contractions. The mental status is normal, an important consideration in differentiating tetanus from other disorders ( Table 157-1). Patients remain conscious and alert unless laryngospasm or contraction of respiratory muscles results in respiratory compromise. Aspiration pneumonia is present in 50% to 70% of autopsied cases.

ions. The mental status is normal, an important consideration in differentiating tetanus from other disorders ( Table 157-1). Patients remain conscious and alert unless laryngospasm or contraction of respiratory muscles results in respiratory compromise. Aspiration pneumonia is present in 50% to 70% of autopsied cases. 7,8 Autonomic dysfunction and a hypersympathetic state including tachycardia, labile hypertension, profuse sweating, hyperpyrexia, and increased urinary excretion of catecholamines occur during the second week of clinical generalized tetanus. 8-10 Neonatal tetanus , a form of generalized tetanus, develops in infants born to inadequately immu nized mothers, frequently after unsterile treatment of the umbilical cord stump. 11 Infants with neonatal tetanus are weak, irritable, and have an inability to suck. Symptoms are evident by the second week of life.11 Cephalic tetanus follows injuries to the head or occasionally otitis media and results in dysfunction of the cranial nerves, most commonly the seventh. It has a poor prognosis. Local tetanus displays muscle rigidity in proximity to the site of injury and usually resolves completely after weeks to months. Local tetanus may progress to the generalized form of the disease. Approximately 1% of these cases are fatal. 7,8 DIAGNOSIS Tetanus is a clinical diagnosis. In the United States, 96% of tetanus cases occur in those with unknown or inadequate immunization history.3 The elderly, those on hemodialysis, and the immunocompromised often have inadequate immunity. 12,13 There are no laboratory tests to diagnose tetanus, although serum antitoxin titers of >0.01 IU/mL are usually protec tive. An immunochromatographic dipstick test allows rapid assessment of immunity, with an 88% sensitivity and 98% specificity; it may be useful in regions with high disease incidence. 14 However, tetanus can occur in patients with protective levels of antitetanus antibodies.15 Wound culture is of limited value because C. tetani may be cultured from wounds in the absence of clinical disease and may not be recovered in patients with documented tetanus. Table 157-1 provides the differential diagnosis of tetanus. Strychnine poisoning most closely mimics the clinical picture of generalized tetanus. TREATMENT Treatment is supportive (Table 157-2). Identify and debride the wound to improve the oxidation-reduction potential of infected tissue, remove spores, and prevent further toxin production. Provide tetanus immuni zation because the disease does not result in immunity. Admit patients with tetanus to the intensive care unit. Respiratory compromise requires immediate neuromuscular blockade and intuba tion. Minimize environmental stimuli to prevent the precipitation of reflex convulsive spasms.  TETANUS IMMUNOGLOBULIN Human tetanus immunoglobulin neutralizes circulating tetanospas min and toxin in the wound but not toxin already fixed in the nervous system. Even though tetanus immunoglobulin does not reduce clinical symptoms of tetanus, it may reduce mortality. 16 For postexposure prophylaxis, a single dose of 250 units (4 units/kg in children) IM given in the anterolateral thigh or deltoid is recommended. For the treatment of clinical tetanus, the optimal dose of tetanus immunoglobulin is unknown, but 3000 to 6000 units IM is the usual recommended dose, administered in a separate syringe and opposite the site of tetanus toxoid administration. A portion of the dose is optimally given in and around the wound.

recommended. For the treatment of clinical tetanus, the optimal dose of tetanus immunoglobulin is unknown, but 3000 to 6000 units IM is the usual recommended dose, administered in a separate syringe and opposite the site of tetanus toxoid administration. A portion of the dose is optimally given in and around the wound. 7 Intrathecal administration of tetanus immunoglobulin does not appear to have advantages over standard IM delivery.17 Give tetanus immunoglobulin before wound debridement because exotoxin may TABLE 157-1 Differential Diagnosis of Tetanus Disorder Comments Strychnine poisoning See Chapter 201, “Pesticides.” Dystonic reaction (phenothiazines, metoclopramide) See Chapter 180, “Antipsychotics.” Hypocalcemic tetany See Chapter 17, “Fluids and Electrolytes.” Malignant neuroleptic syndrome See Chapter 180, “Antipsychotics.” Serotonin syndrome See Chapter 178, “Atypical and Serotonergic Antidepressants.” Stiff person syndrome Centrally mediated motor hyperexcitability with persistent and intense spasms, particularly of the proximal lower limbs and lumbar paraspinal muscles. Peritonsillar abscess See Chapter 246, “Neck and Upper Airway.” Peritonitis See Chapter 71, “Acute Abdominal Pain.” Meningeal irritation (bacterial meningitis, subarachnoid hemorrhage) See Chapter 174, “Central Nervous System and Spinal Infections,” and Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage.” Rabies See Chapter 158, “Rabies.” Temporomandibular joint disease See Chapter 243, “Face and Jaw Emergencies.” Tintinalli_Sec13_p0997-1100.indd 1049 8/2/19 8:12 PM

hnoid hemorrhage) See Chapter 174, “Central Nervous System and Spinal Infections,” and Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage.” Rabies See Chapter 158, “Rabies.” Temporomandibular joint disease See Chapter 243, “Face and Jaw Emergencies.” Tintinalli_Sec13_p0997-1100.indd 1049 8/2/19 8:12 PM 1050 SECTION 13: Infectious Diseases be released during wound manipulation. Repeated doses of tetanus immunoglobulin are unnecessary because the half-life is 28 days.  ANTIBIOTICS Antibiotics have limited utility; when used, metronidazole, 500 milligrams IV every 6 to 8 hours, is the antibiotic regimen of choice. 18-20 Penicillin can theoretically potentiate the effects of tetanospasmin, but no clinical data show an adverse effect in use.  MUSCLE RELAXANTS Tetanospasmin prevents neurotransmitter release at inhibitory inter neurons, so tetanus therapy aims at restoring normal inhibition. The benzodiazepines are centrally acting inhibitory agents used for this purpose. Diazepam is the preferred benzodiazepine for treatment of tetanus because of cost and availability. Another option is midazolam, a water-soluble agent, administered as a continuous infusion in cases that require large doses of benzodiazepines. 21 Intrathecal baclofen has some effect in the treatment of tetanus but is not recommended as routine therapy. 17,21  NEUROMUSCULAR BLOCKADE Prolonged neuromuscular blockade aids in control of ventilation, mus cular spasms, secondary fractures, and rhabdomyolysis. Succinylcholine can be given early for emergency airway control, whereas vecuronium is a good option for prolonged blockade because of minimal cardiovas cular side effects.  TREATMENT OF AUTONOMIC DYSFUNCTION One randomized controlled trial in 256 patients with severe tetanus demonstrated that magnesium sulfate reduced autonomic instability and muscle spasm in the disease. 9 Magnesium sulfate also reduces urinary catecholamine excretion in patients with severe tetanus. 10 However, a meta-analysis failed to show a benefit of magnesium sulfate on tetanus mortality, and the effect of the drug on duration of intensive care unit and hospital stay and need for ventilatory support was unclear. Adrenergic blocking agents may reduce the autonomic dysfunction of severe tetanus. A short-acting β-blocker such as esmolol, or a combined α- and β-adrenergic blocking agent such as labetalol, are options. Morphine sulfate reduces sympathetic α-adrenergic tone and central sympathetic efferent discharge and produces peripheral arteriolar and venous dilatation. 8 Clonidine, a central α 2-receptor agonist, may reduce the sympathetic hyperactivity that causes autonomic dysfunction and thereby provide better control of crises. TETANUS IMMUNIZATION Patients who recover from tetanus must receive active immunization, because infection does not confer immunity and vaccination is the only means of disease prevention. Give adsorbed tetanus toxoid (0.5 mL) IM at the time of presentation and at 6 weeks and 6 months after injury. In patients with incomplete vaccinations, with tetanus-prone wounds and more than 5 years from previous vaccination, or with any wounds more than 10 years from vaccination, use tetanus-diphtheria if ≥7 years old. 24 Use diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) for patients <7 years of age. 25 Because of the recent increase in the incidence of pertussis, adults should receive a single lifetime dose of Tdap (tetanus toxoid with lower doses of diphtheria and acellular pertussis than DTaP) to replace one tetanus-diphtheria booster. 25 Adolescents should also receive a single dose of Tdap, preferably at 11 to 12 years of age. 26 An inadvertent dose of DTaP in an adult would count as the single lifetime dose of Tdap.

of Tdap (tetanus toxoid with lower doses of diphtheria and acellular pertussis than DTaP) to replace one tetanus-diphtheria booster. 25 Adolescents should also receive a single dose of Tdap, preferably at 11 to 12 years of age. 26 An inadvertent dose of DTaP in an adult would count as the single lifetime dose of Tdap. The revised Advisory Committee on Immunization Practices guide lines recommend administering a dose of Tdap during each pregnancy, irrespective of the patient’s prior history of receiving Tdap or interval since last injection, to maximize the maternal antibody response and passive antibody levels in the newborn. 27 Tdap may be given at any point during pregnancy, with optimal timing between 27 and 36 weeks of gestation unless treating a specific wound. For women who have never received Tdap, it should be given to the mother immediately postpartum. Table 157-3 summarizes the guidelines for tetanus immunization and tetanus prophylaxis in wound management. 25 Patients with human immunodeficiency virus infection or severe immunodeficiency who have contaminated wounds should also receive tetanus immunoglobu lin, regardless of their tetanus immunization history. 28 Only about 60% of patients with an acute injury who seek medical care receive appropriate tetanus wound prophylaxis. 3 Table 157-2 summarizes the management of tetanus. Adverse reactions following tetanus immunization include erythema, induration, and pain at the injection site. Local reactions are common and usually self-limited. Exaggerated local reactions (Arthus reactions) occur occasionally and involve extensive pain and swelling of the entire TABLE 157-2 Treatment of Tetanus Respiratory management Sedation and neuromuscular blockade with succinylcholine or vecuronium for intubation and ongoing mechanical ventilation Immunotherapy Tetanus immunoglobulin, 3000–6000 units IM opposite side of the body from tetanus toxoid, with at least a portion around the wound site and Tetanus toxoid (DTaP or Td/Tdap depending on age), 0.5 mL IM at presentation, and 6 wk and 6 mo after presentation Wound care Wound debridement Antibiotic therapy Metronidazole, 500 milligrams IV every 6 h. Penicillin can theoretically potentiate the effects of tetanospasm. Muscle relaxation Diazepam preferred Management of autonomic dysfunction Magnesium sulfate, 40 milligrams/kg IV loading, then 2 grams/h (1.5 grams/h if ≤45 kg) continuous infusion to maintain blood level of 2.0–4.0 mmol/L Labetalol, 0.25–1.0 milligram/min continuous IV infusion Morphine sulfate, 0.5–1.0 milligram/kg/h Clonidine, 300 micrograms every 8 h by nasogastric tube Abbreviations: DTaP = diphtheria and tetanus toxoids and acellular pertussis vaccine; Tdap = tetanus toxoid with lower doses of diphtheria and acellular pertussis than DTaP; Td = tetanus-diphtheria. TABLE 157-3 Summary Guide to Tetanus Prophylaxis in Wound Management Clean, Minor Wounds All Other Wounds* History of Adsorbed Tetanus Toxoid (doses) Tdap or † IM TIG, 250 units IM Tdap or † TIG, 250 units IM Unknown or less than 3 Yes‡ No Yes Yes 3 or more§ No¶ No Yes# No Abbreviations: DTaP = diphtheria and tetanus toxoids and acellular pertussis vaccine; DT = diphtheriatetanus toxoids; Td = tetanus-diphtheria; Tdap = tetanus toxoid with lower doses of diphtheria and acellular pertussis than DTaP; TIG = tetanus immunoglobulin. *For example, wounds >6 hours old, contaminated with soil, saliva, feces, or dirt; puncture or crush wounds; avulsions; wounds from missiles, burns, or frostbite. †DTaP for children <7 years of age (DT if pertussis vaccine is contraindicated); Td for persons ≥7 years of age. A single booster dose of Tdap is recommended for adolescents and adults to replace 1 Td booster. ‡The primary immunization series should be completed.

s; avulsions; wounds from missiles, burns, or frostbite. †DTaP for children <7 years of age (DT if pertussis vaccine is contraindicated); Td for persons ≥7 years of age. A single booster dose of Tdap is recommended for adolescents and adults to replace 1 Td booster. ‡The primary immunization series should be completed. Three doses total are required, with the second dose given at least 4 weeks after the first dose and the third dose given 6 months later. §If only three doses of fluid toxoid have been received, then a fourth dose of absorbed toxoid should be given. ¶Yes, if >10 years since last dose. #Yes, if >5 years since last dose. Boosters more frequent than every 5 years may predispose to side effects. Tintinalli_Sec13_p0997-1100.indd 1050 8/2/19 8:12 PM