16th century it was sometimes found to be sufficient to halt development of the disease when applied to ulcers as an inunction or when inhaled as a suffumigation. Once the disease had gained a strong foothold, however, the amounts and forms of mercury necessary to control its development exceeded the human body's ability to tolerate it, and the treatment became worse and more lethal than the disease. Nevertheless, medically directed mercury poisoning became widespread through the 17th, 18th, and 19th centuries in Europe, North America, and India. Mercury salts such as mercury (II) chloride were still in prominent medical use as late as 1916, and considered effective and worthwhile treatments. Early infections The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of intramuscular benzathine benzylpenicillin. The bacterium is highly vulnerable to penicillin when treated early, and a treated individual is typically rendered non-infective in about 24 hours. Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects, these are not recommended for pregnant women. Resistance to macrolides, rifampicin, and clindamycin is often present. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment. It is recommended that a treated person avoid sex until the sores are healed. In comparison to azithromycin for treatment in early infection, there is lack of strong evidence for superiority of azithromycin to benzathine penicillin G. Late infections For neurosyphilis, due to the poor penetration of benzathine penicillin into the central nervous system, those affected are given large doses of intravenous penicillin G for a minimum of 10 days. If a person is allergic to penicillin, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks. Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred. Serologic cure can be measured when the non-treponemal titers decline by a factor of 4 or more in 6–12 months in early syphilis or 12–24 months in late syphilis. Jarisch–Herxheimer reaction One of the potential side effects of treatment is the Jarisch–Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate. It is caused by cytokines released by the immune system in response to lipoproteins released