Drug formulations
Embolictoxic reactions to penicillin depot formulations were first described in patients with syphilis. The symptoms include fear of death, confusion, acoustic and visual hallucinations, and possibly palpitation, tachycardia, and cyanosis.
Generalized seizures or twitching of the limbs have been observed in children and adults. As a rule, the symptoms abate and disappear within several minutes to an hour. They rarely persist for up to 24 hours. If a cardiovascular reaction with a fall in blood pressure occurs simultaneously with typical symptoms, a combination with anaphylactic shock must be considered.
Such reactions have been called “pseudo-anaphylactic reactions” or “acute non-allergic reactions”, “panic attack syndrome,” and “acute psychotic reactions”. In several countries, the term “Hoigne syndrome” is used. The frequency of such reactions is about 1-3 reactions per 1000 intramuscular injections of penicillin G procaine, the usual dose being about 0.6-1.2 million units.
Eight of 920 patients with venereal diseases had a definite toxic-like reaction with a dose of 4.8 million units of penicillin G procaine, corresponding to about one in 120 patients. In a series of 7700 intramuscular injections with only 400 000 units of penicillin G procaine, there was not one episode.
The mechanism is probably embolic, as has been shown in one case at autopsy, in which emboli of benzathine penicillin crystals were found in the lungs. Some reports suggest that the procaine component may be especially important.
Plasma procaine ester-ase activity was low in patients with systemic toxic reactions. The same symptoms occurred in three patients after erroneous administration of penicillin G procaine by intravenous infusion, but also in two after procaine-free antihistamine penicillin was injected intramuscularly. However, observations of similar symptoms with a procaine-free antihistamine penicillin argue against a central role of the procaine component.
Drug administration route
Intramuscular injection of high doses of depot formulations of penicillins can lead to painful swelling, especially when over 600 000-1 000 000 units are given at a single site. Such reactions occurred in two of 878 patients (0.2%) with intramuscular penicillin G procaine.
Arthus phenomenon seems to be rare. Nicolau syndrome (embolia cutis medicamentosa) is a very rare complication of intramuscular injections, in which there is extensive necrosis of the injected skin area, perhaps due to accidental intra-arterial and/or para-arterial injection. It usually occurs in children: in a review of 102 patients, 80 were under 12 years of age.
Complications can include everything from an ischemic syndrome with local necrosis of the skin, subcutaneous tissue, and muscle, often combined with vascular and nervous system involvement, intestinal and renal hemorrhage, necrosis of the entire leg, and even paraplegia from spinal cord damage.
Necrosis of the forearm has been described in two patients after inadvertent intra-arterial administration of dicloxacillin. Special emphasis should be put on the precautionary measures to be taken when injecting long-acting penicillins or other drugs in crystalline suspensions intramuscularly. Repeated intramuscular injections into the thighs of newborns and infants can cause severe and widespread muscular contractures of the quadriceps femoris. In some cases, penicillin was implicated.