Treatment of Q Fever Endocarditis: Comparison of 2 Regimens
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ORIGINAL INVESTIGATION Treatment of Q Fever Endocarditis Comparison of 2 Regimens Containing Doxycycline and Ofloxacin or Hydroxychloroquine Didier Raoult, MD, PhD; Pierre Houpikian, MD; Herve´ Tissot Dupont, MD; Jean Marc Riss, MD; J. Arditi-Djiane, MD; Philippe Brouqui, MD Background: Q fever endocarditis, caused by Coxiella ing this regimen only. The mean duration of therapy for burnetii, is fatal in 25% to 60% of patients. Currently, treat- cure in this group was 55 months (median, 60 months). ment with a long-term tetracycline and quinolone regi- Twenty-one patients received the doxycycline and hy- men for at least 4 years is recommended, although relapses droxychloroquine regimen: 1 patient died of a surgical are frequent. complication, 2 are still being treated, 17 were cured, and 1 is currently being evaluated. Two patients treated for Methods: Between January 1987 and December 1997, 12 months but none of the patients treated for longer than the reference treatment of Q fever endocarditis was com- 18 months relapsed. The mean duration of treatment in pared with one of doxycycline and hydroxychloroquine this group was 31 months (median, 26 months). No sig- sulfate. Patients were treated by conventional therapy un- nificant differences were observed between the 2 regi- til May 1991 and then by the new regimen. Microimmu- mens in terms of death, valve surgery, or tolerance. The nofluorescence was used for antibody-level determina- mortality rate for both regimens in this study was 5%. tion for diagnosis and follow-up. Conclusion: Prescription of the doxycycline and hy- Results: Thirty-five patients were included in the study, droxychloroquine combination for at least 18 months al- 26 males and 9 females. Of 14 patients treated with a doxy- lows shortening of the duration of therapy and reduc- cycline and quinolone combination, 1 died, 7 relapsed tion in the number of relapses. (3 were re-treated and 4 switched to the new regimen), 1 is still being treated, and 5 were considered cured us- Arch Intern Med. 1999;159:167-173 FEVER, a rickettsiosis response to phases I and II. However, caused by Coxiella bur- because of its intracellular position, C netii, was originally burnetii is difficult to eradicate, explain- described by Derrick in ing why—when the disease was 1937.1 This zoonosis is described during the 1960s and 1970s— Q widespread throughout relapses and even death occurred fre- the world and can present as either acute quently. In some series,4 two thirds of or chronic disease. Endocarditis is the the patients died. Since that time, the most serious and often fatal form of role of combined and prolonged antibi- chronic Q fever, and presents unspecifi- otic drug therapy for these patients has cally as a blood culture–negative endo- been emphasized.5-7 The current recom- From the Unite´ des Rickettsies, carditis. Diagnosis relies on nonspecific mended treatment duration is from 3 Faculte´deMe´decine, Universite´ cardiac findings, evidence of an infec- years to lifetime, even when quinolone is de la Mediterrane´e CNRS tious or inflammatory process, and added to the reference tetracycline (Drs Raoult, Houpikian, Tissot detection of specific antibodies. Coxiella therapy. This combination treatment Dupont, and Brouqui); burnetii is a strict intracellular gram- enhances patient survival,6 but the treat- Infectious Disease Units, negative bacterium. It lives and multi- ment of Q fever endocarditis is now the Hoˆpital F. Houphoue¨t Boigny plies in the phagolysosomes of infected longest of any bacterial disease, includ- (Drs Houpikian and Brouqui) cells at pH 4.8.2,3 Coxiella burnetii exhib- ing leprosy and other mycobacterial dis- and Hoˆpital Conception its a phase variation (phases I and II), eases.8 By testing C burnetii antibiotic (Dr Tissot Dupont); Ophthalmology Department, which is extremely valuable for diagno- susceptibility in a cellular model of infec- Hoˆpital Timone (Dr Riss); and sis. The serologic response of patients tion, it was previously shown that intra- Toxicology Laboratory, Hopital with acute Q fever is mainly directed cellular pH may significantly diminish Salvator (Dr Arditi-Djiane), against phase II, whereas patients with the bactericidal potency of antibiotic Marseille, France. chronic Q fever exhibit a serologic drugs.9,10 This bactericidal effect of doxy- ARCH INTERN MED/ VOL 159, JAN 25, 1999 167 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 PATIENTS AND METHODS SURVEILLANCE AND FOLLOW-UP All patients were monitored monthly with a physical ex- PATIENTS amination, blood cell count, transaminase dosage, sero- logic examination, and hydroxychloroquine plasma level Patients were treated from January 1987 to May 1991 with determination. When treatment was stopped, blood cul- doxycycline and ofloxacin and from May 1991 to Decem- tures were obtained for C burnetii and other organisms. A ber 1997 with doxycycline and hydroxychloroquine regi- cardiologist examined each patient 2 to 4 times a year, and mens. Diagnosis was performed by confirmation of C bur- an ophthalmologist (J.M.R.) performed a flash electroreti- netii infection in patients with chronic endocarditis based nogram and a fundus examination twice a year to detect on previously published criteria.12 An IgG titer of 1/1600 chloroquine accumulation.14 Patients were considered cured and an IgA titer of 1/100 directed against phase I of C bur- when IgG antibodies to C burnetii phase I were lower than netii were required for diagnosis. By using the Duke crite- 1/800 and IgM and IgA antibodies were lower than 1/50.12 ria modified for C burnetii, all these patients had a definite When these results were obtained, antibiotic drug treat- diagnosis of endocarditis.13 Treatment was prescribed ment was stopped and the patients were further moni- by 1 of us (D.R.) after receiving patient information and tored by clinical examination and blood sampling, includ- consent. ing blood cell count, serologic examination, and blood culture performed for C burnetii and other organisms.15 Pa- TREATMENT REGIMENS tients were examined monthly for the first 6 months, ev- ery 3 months for a further year, and subsequently every 6 Each patient initially received 1 tablet of doxycycline (100 months. The patients had an echocardiographic examina- mg) twice daily and 1 tablet of ofloxacin (200 mg) 3 times tion twice a year for 2 years. daily. In the study’s second stage, patients received doxy- cycline at the same dose and 1 tablet of hydroxychloro- SERUM HYDROXYCHLOROQUINE quine (200 mg) 3 times a day. Doses of hydroxychloro- CONCENTRATION DETERMINATION quine were adapted after monthly plasmatic level evaluation to maintain a concentration between 0.8 and 1.2 µg/mL. Measurement of hydroxychloroquine blood levels was per- Patients were made aware of the risks associated with over- formed by liquid chromatography as previously described16 exposure to the sun and that they should wear gloves and using a 25-cm Si 60,5 lichrospher column (Merck, Darmstadt, a hat and use protective sunscreens. Patients with an evo- Germany). The mobile phase consisted of a mixture of 20% lutive immunocompromised disease such as cancer or ac- acetonitrite and ammoniac ethanol (92/8 by volume). Sepa- quired immunodeficiency syndrome were excluded from ration was performed by means of a gradient elution. Hydroxy- the study. chloroquine and quinine, the internal standard, were extracted cycline was restored by incubating cells with chloro- diac incompetency. The 7 patients who relapsed had an quine, 1 mg/mL, which acted as a lysosomotropic alka- increase of antibody titers associated with clinical signs linizing agent and raised the pH of the phagolysosome within 6 months of treatment interruption. These fail- from 4.8 to 5.7,11 the optimal doxycycline activity being ures were observed only during the early stages of the obtained at pH 6.6. The purpose of the present study regimen. Subsequently, stable low titer of anti–phase I was to assess the clinical efficacy of the combination of antibodies had to be observed before therapy was stopped doxycyline and hydroxychloroquine on the treatment (IgG, ,800; IgA, ,50). The mean treatment duration for of Q fever endocarditis compared with a previously ini- patients considered cured was 55 months (median, 60 tiated regimen of doxycyline and ofloxacin.1,6 months). No patient relapsed when treated for longer than 4 years, and only 1 patient relapsed after 3 years of treat- RESULTS ment. However, 8 patients are still being treated or were switched to a doxycycline and hydroxychloroquine regi- Twenty-six men and 9 women were included in the study. men (Table 1). Fourteen patients were treated with a combination of Twenty-one patients were treated with a combina- doxycycline and ofloxacin (Table 1). One patient died tion of doxycycline and hydroxychloroquine and 7 relapsed and were subsequently treated with the (Table 2). One patient died 30 months after complet- same regimen (3 patients) or were switched to the new ing treatment: he underwent mitral valve replacement regimen (4 patients). Five patients were cured using this and died postoperatively of cardiac failure, although the regimen only. A total of 21 treatments using this regi- valve was sterile. All patients experienced photosensi- men were prescribed. All the patients experienced pho- tivity, mainly on the hands and nose. One patient had tosensitivity during the summer after beginning treat- an irreversible cutaneous pigmentation caused by doxy- ment. One patient had an irreversible cutaneous cyline treatment, and 1 patient had an infraclinical reti- pigmentation attributable to doxycycline use.18 No diar- nal accumulation of hydroxychloroquine that led to rhea or joint pain was reported. The patient who died withdrawal of this drug (patient 3). However, because was still receiving antibiotic drug treatment when he had the treatment was completed, it did not change the a valvular replacement and died postoperatively of car- course of the therapy.