title: Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Treatment 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.
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Mao-Song
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.
authors.forename: Nan-Yao
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Szu-Min
authors.initials: SM
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsin-Yun
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wang-Huei
authors.initials: WH
authors.lastname: Sheng
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
authors.forename: Kuan-Yeh
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Center for Infection Control, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shan-Ping
authors.initials: SP
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Liu
authors.affiliation: Center for Infection Control, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Ko
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan.
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Hung
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017963:Azithromycin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004275:DNA, Ribosomal / Q000737:chemistry / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000453:epidemiology*; D015658:HIV Infections / Q000150:complications; D006801:Humans; D015994:Incidence; D008297:Male; D008826:Microbial Sensitivity Tests; D010401:Penicillin G Benzathine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D012338:RNA, Ribosomal, 23S / Q000235:genetics; D013587:Syphilis / Q000175:diagnosis / Q000188:drug therapy*; D013624:Taiwan; D014210:Treponema pallidum / Q000145:classification / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D012338:RNA, Ribosomal, 23S; D017963:Azithromycin; D010401:Penicillin G Benzathine
keywords: immunomodulation; macrolide resistance; macrolides; sexually transmitted diseases; spirochetal disease