Jarisch‐Herxheimer reaction among HIV‐positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy

Abstract

IntroductionThe Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated.MethodsIn HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance.ResultsThe overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the macrolide resistance mutation (A2058G). In subgroup analyses confined to the 75 patients infected with T. pallidum lacking resistance mutation, a statistically significantly lower risk for the Jarisch-Herxheimer reaction following azithromycin treatment was noted.ConclusionsTreatment with azithromycin was associated with a lower risk for the Jarisch-Herxheimer reaction than that with benzathine penicillin G in HIV-positive patients with early syphilis. Previous benzathine penicillin G therapy for syphilis decreased the risk, whereas higher RPR titres increased the risk, for the reaction.

The Jarisch–Herxheimer reaction in syphilis: could molecular typing help to understand it better?

“…It is also important that especially young doctors recognize this reaction not to be confused even with neurosyphilis in the light of the current epidemic of syphilis in Europe. Concerning treatment, it has been shown that there is a difference between the incidence of JHR depending on the antibiotic used, being it most frequently with penicillin compared with azithromycin or doxycycline, also observed by us. This fact has been explained by the bacteriostatic effect of the tetracycline with a slower release of toxic substances in the bloodstream …”

“…4,5 Probably, this discrepancy might be more related to the limitations of those studies than to the putative changes in the capacity of the bacteria to cause the reaction. Our and other's findings that prior syphilis reduces the risk for JHR 6,8 might suggest that the antibiotic administered (mostly The Jarisch-Herxheimer reaction in syphilis penicillin) during that episode prevents the occurrence of the reaction following another exposure to the same treatment. To explain this, Yang et al 6 suggested that desensitization may occur, considering the theory that JRH could be a hypersensitivity reaction.…”

“…Contemporary studies show that the incidence of JHR in syphilis varies around 9–31%, being the most frequent in secondary syphilis . It has also been related to higher RPR titres and it seems to be less probable when the patients have been previously treated with penicillin for previous syphilis or are being treated with azithromycin or doxycycline . HIV co‐infection has not been associated with increased frequency of JHR reaction …”

Jarisch-Herxheimer reaction in a patient with syphilis and human immunodeficiency virus infection

“…Aurean D'Eça Júnior [1] , Lívia dos Santos Rodrigues [2] and Luciana Cavalcante Costa A 29-year-old HIV-infected Brazilian man presented syphilis symptoms; infection was detected using Venereal Disease Research Laboratory (VDRL) reagent (1:512). Penicillin 7,200,000 IU (intramuscular) was prescribed as 3 weekly doses of 2,400,000 IU.…”

“…Clinical symptoms disappeared after 24 hours; the lesions regressed within 48 hours ( Figure C). Jarisch-Herxheimer reaction a febrile inflammatory reaction, frequently occurs after the first chemotherapy dose during spirochetal disease treatment 1 . Its clinical manifestations include fever, sweating, headache, hypotension, and worsening of cutaneous lesions.…”