US Pharm. 2013;38(5):39-52.
ABSTRACT: Acute tetanus is a preventable disease that could be fatal if not immediately treated. Tetanospasmin, a neuromuscular exotoxin released by Clostridium tetani, causes generalized rigidity and spasms. It is imperative to admit patients to rule out other etiologies and provide appropriate medical interventions. For acute cases, pharmacists in ICUs could promote best practices and uses of medications, which include sedative hypnotics, neuromuscular blocking agents, and antibiotics. The most recent need for tetanus prophylaxis in the United States arose after a natural disaster, Hurricane Sandy. Pharmacists should continue to promote public health information and counsel patients to remain updated with their vaccinations.
The hallmark symptoms of tetanus (i.e., generalized rigidity and convulsive spasms) are caused by tetanospasmin, a neuromuscular exotoxin released by Clostridium tetani.1,2 It is prudent that health care professionals identify the various risk factors and treatment modalities for tetanus, as well as promote techniques for prevention.2,3
Tetanus occurs in dense populations, especially in hot, damp climates with soil rich in organic matter.1 Spores of C tetani are widespread in the feces and intestines of animals (e.g., chickens, cattle, horses).1 In agricultural areas, manure-treated soil could contain large numbers of spores, and a significant number of human adults may harbor the organism.1
In 2004, there were approximately 163,000 deaths worldwide attributed to tetanus in World Health Organization (WHO) member countries.4 In the United States, the CDC utilizes a National Notifiable Disease Surveillance System (NNDSS) to collect data from authorities and report trends via the Morbidity and Mortality Weekly Report (MMWR).5 Since 1947, the rate of tetanus cases and deaths has declined due to the continuous use of tetanus antitoxin for wound management, tetanus toxoid-containing (TT) vaccines for prevention, TT boosters every decade, and a near elimination of neonatal tetanus (FIGURE 1).6 Some cases of tetanus in adults still occur, particularly in patients who have no history of receiving a TT vaccine or are injection drug users (IDUs).6-8
C tetani is a gram-positive, obligate anaerobic bacillus that produces spores.1,9 During growth and development, the bacillus has multiple flagella and generates two exotoxins, tetanospasmin (i.e., tetanus toxin) and tetanolysin (unknown importance).9 During further maturation, the bacillus loses its flagella and develops a terminal spore.1,9 These spores are able to germinate indefinitely, particularly due to high resistance to heat and usual antiseptics (e.g., ethanol, formalin).1,9 They become noninfectious if treated with hydrogen peroxide, iodine, glutaraldehyde, or autoclaving at 121°C (249.8°F) and 103 kPa (15 psi) for 10 to 15 minutes.1,9 Although C tetani grows at 37°C (98.6°F) under strictly anaerobic conditions, culture results do not provide much diagnostic value.9
C tetani is usually transmitted through contaminated wounds (apparent/unapparent or major/minor), including but not limited to deep puncture wounds (e.g., splinters, unsterile injections), burns, animal bites, surgeries, and dental procedures.1 C tetani disseminates via the circulatory system (blood and lymphatics), and, although infectious, tetanus is not contagious.1
Tetanospasmin is one of the most potent known toxins, with an estimated minimum human lethal dose of 2.5 ng per kilogram of body weight.1 It is a zinc-dependent matrix metalloproteinase that irreversibly degrades synaptobrevin-2, a protein needed for docking neurotransmitter vesicles (containing gamma-aminobutyric acid [GABA] and glycine) with their release sites on the presynaptic membrane.9-13 Preventing exocytosis of inhibitory transmitters sustains muscular rigidity by increasing firing rates of motor neurons, and leads to spastic paralysis.9,13 Additionally, tetanospasmin affects the autonomic nervous system, leading to a hypersympathetic state secondary to failed inhibition of the adrenal release of catecholamines (e.g., epinephrine, norepinephrine).9
Four types of clinical tetanus have been described in the literature: generalized (most common), localized (uncommon), cephalic (rare), and neonatal (highest worldwide mortality, but very rare in the U.S.).1,9
In generalized tetanus, after an initial injury and inoculation with C tetani, the bacteria incubate for about 8 days (range 3-21 days).1 Shorter incubation and symptom-onset periods are associated with a poorer prognosis.9 Tetanus is manifested by descending signs and symptoms and requires inpatient admission.1,9 The first sign is trismus (masseter rigidity or lockjaw), which may be followed by neck stiffness, dysphagia, abdominal muscle rigidity, and risus sardonicus (increased tone of orbicularis oris).1,9 Patients also exhibit generalized spasms (i.e., arm flexion and leg extension) often triggered by sensory stimuli (therefore requiring dark, quiet rooms), and experience severe pain without losing consciousness.9 Acute spasms may occur frequently and last up to 4 weeks.1,9 Autonomic dysfunction occurs several days after the onset of spastic symptoms and causes a hypersympathetic state (e.g., hypertension and tachycardia).1,9 Despite immediate medical interventions, complete recovery could take months and is prolonged if patients experience complications (e.g., nosocomial infections).1,9
In the differential diagnosis for tetanus, the majority of cases could be determined through clinical observation.1,9 Laboratory testing of serum and urine could be used to exclude conditions resembling tetanus (e.g., strychnine poisoning); regardless, initial therapy should be instituted immediately.1,9 Immunized patients usually have serum antitoxin antibody levels >0.01 IU/mL, but this does not always preclude the development of clinical tetanus.1,9,14 Wound cultures for C tetani do not provide much utility because anaerobic cultures are frequently negative and positive cultures fail to indicate if the organism contains tetanospasmin or if it is present without disease in patients with immunity.1,9
It is important to note that neck stiffness secondary to neuroleptic or antipsychotic drugs (e.g., haloperidol, risperidone) almost always involves lateral head turning (whereas tetanus does not), and improves with anticholinergic drugs (e.g., diphenhydramine, benztropine).1,9 In addition, while certain dental infections could lead to trismus, they do not produce any other symptoms of tetanus.1,9
The multimodal approach to the inpatient treatment of acute, generalized tetanus includes providing supportive care as well as neutralizing and removing the source of tetanospasmin.2,9,14-18 Several protocols exist in the literature, but they are tailored to each institution’s location and population, so a unified protocol does not exist.9,15 Pharmacists should verify whether their institution has a protocol outlined. Management of tetanus involves ventilatory support, passive and active immunizations, control of muscle spasms and rigidity, antibiotics, and agents to minimize sympathetic overactivity (TABLE 1).2,9,14-24
Passive immunity with human tetanus immune globulin (HTIG) is indicated to neutralize circulating tetanospasmin, particularly in patients with an unclean wound and an unknown or <3-dose TT vaccination history.1,19 Recommended dosages range from 250 units in neonates to 500 units in adults administered IM.14,18 Dosages of HTIG ranging from 3,000 to 5,000 units have also been reported.1 While intrathecal HTIG also results in decreased spastic duration and ventilatory demands, its use is concerning due to thimerosol and immunoglobulin aggregates.9,17
Active immunization with a TT vaccine (tetanus-diphtheria toxoid or Td) is indicated in the same subset of patients.1,19 In patients with a ≥3-dose TT vaccination history, Td is indicated if the wound is clean and 10 years have elapsed (or an unclean wound and 5 years have elapsed) since the last dose.1 In each scenario, Tdap (Td-acellular pertussis) could be provided instead of Td if patients ≥7 years of age have not previously received Tdap.1 Tetanus toxoid without diphtheria may be used if patients are allergic to diphtheria toxoid.9,15
Antibiotics must be combined with cleaning, draining, or excising of dirty wounds or abscesses.9,14 While cephalosporins, tetracyclines, macrolides, clindamycin, carbapenems, chloramphenicol, and vancomycin exhibit in vitro activity against C tetani, they are not recommended as first-line agents.9,18 Penicillin G 100,000-200,000 IU kg/day (in 2-4 divided doses) IV/IM was historically used, but is no longer favorable due to GABA antagonism (potentiates tetanospasmin, worsening muscle rigidity and spasms).9,14,17,18 Metronidazole is currently the drug of choice, dosed at 500 mg IV every 6 hours in adults for 7 to 10 days (up to 14 days).3,9,14-18 Compared to penicillin G, metronidazole has greater penetration in wounds and abscesses, leading to better survival, shorter hospitalizations, and decreased disease progression.9,14
Magnesium sulfate is currently the first-line drug for sympathetic overactivity in tetanus. Labetalol, propranolol, esmolol, morphine, fentanyl, and clonidine are alternatives.9,14,17,18 Doses of each agent depend on the patient’s hemodynamic state.9,14,17,18 Because nonselective beta-blockers have led to mixed outcomes, esmolol is recommended.9,14,17,18 Opioids reduce sympathetic tone in the cardiovascular system, and could be combined with benzodiazepines for sedation.9,14,17,18 Clonidine and magnesium decrease adrenal norepinephrine release.14,17,18
Immunization with a TT vaccine (0.5mL IM) is still the only safe and effective method for preventing tetanus, as the acute infection does not invoke active immunity.1,2,9,14-20 Current recommendations from the CDC are summarized in TABLE 2.1,25-30 Tetanus vaccines could cause local, self-limiting reactions (e.g., pain, erythema), but rarely lead to systemic symptoms (e.g., anaphylaxis, urticaria, peripheral neuropathy, Guillain-Barré syndrome).1
Natural disasters, such as Hurricane Sandy, are also compelling reasons for tetanus prophylaxis.31-35 After October 29, 2012, relief workers put themselves at risk for contracting C tetani since they could have suffered cuts or deep wounds from storm debris.36 In New York state, pharmacists were only permitted to administer influenza, pneumococcal, and herpes zoster vaccines to adults.37 On November 9, 2012, New York’s governor signed an executive order to temporarily permit pharmacists to administer Td and Tdap vaccines to adults in affected areas.31-34,38 Relief workers were strongly encouraged to visit pharmacies and clinics to remain updated with their vaccines.35
Tetanus continues to be a rare but life-threatening disease, and acute cases should be managed within the ICU setting. It is important to understand that along with other health care professionals, pharmacists in the inpatient and outpatient settings should continue to promote vaccinations and educate patients on strategies for preventing tetanus.
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24. Girgin NK, Iscimen R, Gurbet A, et al. Dexmedetomidine sedation for the treatment of tetanus in the intensive care unit. Br J Anaesth. 2007;99:599-600.
25. Lam S, Jodlowski TZ. Vaccines for older adults. Consult Pharm. 2009;24:380-391.
26. CDC. FDA approval of expanded age indication for a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. MMWR Morb Mortal Wkly Rep. 2011;60:1279-1280.
27. CDC. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2012;61:468-470.
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30. Wolfe RM. Update on adult immunizations. J Am Board Fam Med. 2012;25:496-510.
31. Temporary suspension and modification of statutes and regulations to expand access to tetanus immunizations during the state disaster emergency. State of New York Executive Chamber. November 9, 2012. www.governor.ny.gov/executiveorder/68. Accessed December 24, 2012.
32. Governor Cuomo signs executive order to allow pharmacists, EMTs, and dentists to help administer tetanus vaccines in areas affected by Hurricane Sandy. Governor’s Press Office. November 10, 2012. www.governor.ny.gov/press/111012vaccines. Accessed December 24, 2012.
33. Kouadio IK, Aljunid S, Kamigaki T, et al. Infectious diseases following natural disasters: prevention and control measures. Expert Rev Anti Infect Ther. 2012;10:95-104.
34. Goodman B. Hurricane Sandy’s health woes continue. Medscape. November 30, 2012. www.medscape.com/viewarticle/775433. Accessed December 24, 2012.
35. WHO. Current Recommendations for Treatment of Tetanus During Humanitarian Emergencies: WHO Technical Note. Geneva, Switzerland: WHO; January 2010. http://whqlibdoc.who.int/hq/2010/WHO_HSE_GAR_DCE_2010.2_eng.pdf. Accessed December 24, 2012.
36. Mangano and Eisenstein offer tetanus vaccine for Hurricane Sandy relief workers. Nassau County Executive. December 7, 2012. www.nassaucountyny.gov/agencies/CountyExecutive/NewsRelease/2012/12-5-2012b.html. Accessed December 24, 2012.
37. Regulations of the commissioner: part 63, pharmacy. University of the State of New York, New York State Education Department. October 15, 2012. www.op.nysed.gov/prof/pharm/part63.htm#immunization. Accessed December 24, 2012.
38. NY pharmacists allowed to administer tetanus shots in Sandy’s wake. November 21, 2012. U.S. Pharmacist Weekly News Update. www.uspharmacist.com/weekly_news_update/story/37669. Accessed December 24, 2012.
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