The goals of pharmacotherapy are to stop toxin production within the wound, to neutralize unbound toxin, and to control disease manifestations. Drugs used to treat muscle spasm, rigidity, and tetanic seizures include sedative-hypnotic agents, general anesthetics, centrally acting muscle relaxants, and neuromuscular blocking agents. Antibiotics are used to prevent multiplication of Clostridium tetani, thus halting production and release of toxins. Antitoxins are given to neutralize unbound toxin.
These agents are used to eradicate clostridial organisms in the wound, which may produce tetanus toxin. They are administered to patients with clinical tetanus; however, their efficacy is questioned. Penicillin G was long considered the drug of choice, but metronidazole is now considered the antibiotic of choice.
Although tetracyclines are an alternative in patients who have a history of serious allergic reactions to penicillin or metronidazole (eg, urticaria, anaphylaxis), strong consideration should be given to desensitizing the patient to penicillin before resorting to alternative agents. Large doses of antibiotic are recommended to favor diffusion into the devitalized tissue.
Metronidazole is active against various anaerobic bacteria and protozoa. It appears to be absorbed into cells, and intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death. A 10- to 14-day course of treatment is recommended. Some consider it the drug of choice in tetanus because of its safety profile, efficient penetration into wounds and abscesses, and negligible central nervous system (CNS) excitation.
Penicillin G is a bactericidal antibiotic that binds to and inhibits penicillin-binding proteins, which are transpeptidases that cross-link peptidoglycans, the final step in bacterial cell wall synthesis. Inhibition of cell wall synthesis and autolytic enzyme activation are responsible for its bactericidal action on dividing bacteria.
A 10- to 14-day course of treatment is recommended. Large intravenous (IV) doses of penicillin may cause hemolytic anemia and neurotoxicity. Cardiac arrest has been reported in patients receiving massive doses of penicillin G potassium. Patients with renal failure are particularly at risk.
Doxycycline inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. A 10- to 14-day course of treatment is recommended.
Erythromycin is a bacteriostatic agent that inhibits protein synthesis by binding to the 50S subunit of bacterial ribosomes. It is not the drug of choice for tetanus but may be used when the drugs of choice cannot be administered for some reason.
Clindamycin is a bacteriostatic agent that binds to the 50S ribosomal subunit. It is not the drug of choice for tetanus and may be used only if the drugs of choice cannot be used.
Tetracycline is a bacteriostatic agent that inhibits protein synthesis. It is not the drug of choice for tetanus and may be used only if the drugs of choice cannot be used.
Vancomycin is a bactericidal agent that inhibits cell wall and RNA synthesis. It is not the drug of choice for tetanus and may be used only if the drugs of choice cannot be used.
Sedative-hypnotic agents are the mainstays of tetanus treatment. Benzodiazepines are the most effective primary agents for muscle spasm prevention and work by enhancing gamma-aminobutyric acid (GABA) inhibition. Diazepam is the most frequently studied and used drug. Lorazepam is an effective alternative. Phenobarbital is another anticonvulsant that may be used to prolong the effects of diazepam. Other agents used for spasm control include baclofen, dantrolene, short-acting barbiturates, and chlorpromazine.
Diazepam modulates the postsynaptic effects of GABA-A transmission, thereby increasing presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and hypothalamus to induce a calming effect. It is also an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders. Diazepam rapidly distributes to other body fat stores. To avoid adverse effects, individualize dosage and increase it cautiously.
Rapidly distributes to other body fat stores. Twenty minutes after initial IV infusion, serum concentration drops to 20% of Cmax.
Individualize dosage and increase cautiously to avoid adverse effects.
Midazolam is a shorter-acting benzodiazepine sedative-hypnotic that is useful in patients requiring acute or short-term sedation. It also has amnestic and antiepileptic effects.
Lorazepam is a sedative hypnotic with a short onset of effects and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the central nervous system, including the limbic and reticular formation. The drug is an excellent choice when the patient needs to be sedated for longer than 24 hours.
The drug dosage must be small enough to ensure that respirations are not depressed. If the patient is already on a ventilator, higher dosages may provide the desired sedation.
Skeletal Muscle Relaxants
Skeletal muscle relaxants can inhibit both monosynaptic and polysynaptic reflexes at spinal level, possibly by hyperpolarization of afferent terminals. Benzodiazepines are used to control muscle spasms and to provide sedation. Dantrolene and baclofen may also be considered for severe spasticity and may assist with shortening duration of artificial ventilation. The use of propofol has been proposed.
Baclofen, a central muscle relaxant, is a presynaptic GABA-B receptor agonist that may induce hyperpolarization of afferent terminals and inhibit both monosynaptic and polysynaptic reflexes at spinal level. It lessens flexor spasticity and hyperactive stretch reflexes of upper motor neuron origin.
Baclofen is well absorbed, with an average oral bioavailability of 60% and a mean elimination half-life of 12 hours. Steady state is reached within 5 days with multiple dose administration. Metabolism occurs in the liver (through P450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites are produced. Elimination is through renal excretion.
For intrathecal (IT) administration, a pump is implanted subcutaneously (SC), and a catheter is implanted in the subarachnoid space of the spinal canal (where the medication is administered). Less medication is needed, and systemic effects are decreased. This agent is reported to be effective in about 20% of patients; it appears to be of dramatic benefit in as many as 30% of children with dystonia, though the benefit not always sustained.
Dantrolene stimulates muscle relaxation by modulating skeletal muscle contractions at a site beyond the myoneural junction and by acting directly on the muscle. It may reduce painful cramping and detrimental muscle tightening. It is not approved by the US Food and Drug Administration (FDA) for use in tetanus but has been described in a small number of case reports.
Dantrolene acts peripherally at muscle fiber rather than at the neural level; it reduces muscle action potential–induced release of calcium and also affects intrafusal and extrafusal fibers and spindle sensitivity. It has no action on smooth or cardiac muscle tissue. Dantrolene induces release of calcium ions into the sarcoplasmic reticulum, subsequently decreasing the force of excitation coupling.
Dantrolene is preferred for the cerebral form of spasticity; it is less likely to cause lethargy or cognitive changes, as baclofen and diazepam do. It can be administered either orally or IV. The IV form is much more expensive and should be reserved for patients unable to take oral medications. Most patients respond to dosages of 400 mg/day or less. The drug is eliminated in urine and bile.
General Anesthetics, Systemic
These agents stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents the initiation and transmission of nerve impulses, thereby producing the local anesthetic effects.
Propofol is a phenolic compound that elicits a sedative-hypnotic effect. It is used for induction and maintenance of anesthesia or sedation. It has also been shown to have anticonvulsant properties.
Antitoxins are used to neutralize any toxin that has not reached the CNS. They are used for passive immunization of any person with a wound that might be contaminated with tetanus spores.
TIG is used to prevent tetanus and to treat patients with circulating tetanus toxin. It provides passive immunity. TIG should be used to treat all patients with active tetanus, in combination with other supportive and therapeutic treatments. Should also be used to prevent tetanus in patients with inadequate or unknown immunization status after an acute injury. Administration should begin as soon as the clinical diagnosis of tetanus is made.
Neuromuscular Blocking Agents
Neuromuscular blocking agents inhibit the transmission of nerve impulses at neuromuscular junctions of skeletal muscles or autonomic ganglia.
Vecuronium is a prototypical nondepolarizing neuromuscular blocking agent that reliably results in muscular paralysis. For maintenance of paralysis, a continuous infusion may be used. Infants are more sensitive to neuromuscular blockade activity, and though the same dose is used, recovery is prolonged by 50%. This drug is not recommended for use in neonates.
Vaccines, Inactivated, Bacterial
Active immunization increases resistance to infection. Vaccines consist of microorganisms or cellular components that act as antigens. Administration of the vaccine stimulates the production of antibodies with specific protective properties. Administer tetanus toxoid vaccine for wound prophylaxis if the vaccine history is unknown or if fewer than 3 tetanus toxoid immunizations have been administered.
DTaP may be administered into the deltoid or midlateral thigh muscles in children and adults. In infants, the preferred site of administration is the midlateral thigh muscles.
This vaccine promotes active immunity to diphtheria, tetanus, and pertussis by inducing the production of specific neutralizing antibodies and antitoxins. It is indicated for active booster immunization for tetanus, diphtheria, and pertussis prevention for persons aged 10-64 years. It is the preferred vaccine for adolescents scheduled for booster.
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