Randomized trial of doxycycline versus josamycin for Mediterranean spotted fever

The in vitro bacteriostatic activity of clarithromycin, a new macrolide derivative, against Rickettsia rickettsii, Rickettsia conorii, and "Rickettsia israeli" was determined by the plaque assay and the dye uptake assay. Both bacteriostatic and bactericidal activities of clarithromycin against the Nine Mile, Q212, Priscilla, and ME9 strains of Coxiella burnetii were evaluated by using three cell culture systems. Clarithromycin showed improved antibacterial activity compared with that of erythromycin. A bacteriostatic activity was obtained at concentrations below the reported maximum concentration of clarithromycin in human serum (about 4 ,ug/ml) for all tested rickettsiae. MICs ranged from 1 to 2 ,ug/ml for the three Rickettsia species and from 1 to 4 ,ug/ml for the C. burnetii strains. No bactericidal activity against C. burnetii was obtained when clarithromycin was used at 4 ,ug/ml.Rickettsia rickettsii is the etiologic agent of Rocky Mountain spotted fever, Rickettsia conorii is the etiologic agent of Mediterranean spotted fever (MSF), and "Rickettsia israeli" is responsible for a spotted fever without "tache noire" in Israel (20,21). Coxiella burnetii is the etiologic agent of Q fever, a widely distributed zoonosis. C. burnetii infections may present as an acute disease, such as hepatitis, pneumonitis, and self-limited febrile illness, or a chronic disease, mainly endocarditis. Bacteria of the genera Rickettsia and Coxiella are obligate intracellular pathogens, the former being located in the cytoplasm (16,42,45) and the latter being located in the phagolysosomes (1, 22) of infected host cells.Tetracyclines remain the antibiotics of choice for the treatment of rickettsial diseases, with chloramphenicol and the fluoroquinolones used as alternative drugs (27,32,33,37,46). However, severe forms of Rocky Mountain spotted fever and MSF have been described (38, 44), especially when appropriate antibiotic treatment was delayed. Whereas acute C. burnetii infections respond to antibiotic therapy with tetracyclines, chronic C. burnetii infections are hard to cure, and we have previously demonstrated that the antibiotic compounds used against C. burnetii have no in vitro bactericidal activity (25). On the other hand, because of potential adverse effects, tetracyclines and fluoroquinolones are not recommended for use during pregnancy and childhood, and chloramphenicol may be responsible for aplastic anemia.Erythromycin is considered not to be a reliable treatment for diseases caused by R conorii (33). Authors have emphasized the susceptibility heterogeneity among different strains of C. burnetii to macrolides, which may explain why erythromycin may be considered effective or not effective in treating Q fever (31a). More recently, in vitro experiments have shown that the macrolides josamycin and roxithromycin are effective against R. conorii and R. rickettshi (13,35 4 ,ug/ml (9, 19) and that it is highly concentrated within eukaryotic cells (2). MATERIALS AND METHODSAntibiotic preparation. Clarithromycin (Abbott Labora...

Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

In vitro susceptibilities of spotted fever group rickettsiae and Coxiella burnetti to clarithromycin

Maurin

Raoult

1993

“…Because of their potential adverse effects, all of these compounds are not recommended during pregnancy and childhood. In these cases, some macrolides, such as josamycin, have been successfully used (2). The screening of antirickettsial activity of new antibiotics is currently done in embryonated eggs or in cultured cells.…”

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confidence: 99%

In vitro susceptibilities of Coxiella burnetii, Rickettsia rickettsii, and Rickettsia conorii to the fluoroquinolone sparfloxacin

Raoult¹,

Brès²,

Drancourt³

et al. 1991

In vitro susceptibilities of Rickettsia nckettsu, Rickettsia conoru, and CoxieUa burneti to the new fluoroquinolone sparfloxacin (AT4140; RP 64206) were determined. Plaque and dye uptake assays were used to measure the MICs against R. rickettsii and R. conoru. The susceptibifities of C. burnetii Nine Mile and Q 212 were determined in two acute-infection models and In two chroni-infection models. The MICs were 0.125 to 0.25 ,ug/ml for R. ,ickeffsu and 0.25 to 0.5 pg/ml for R. conoriu. Sparfloxacin (1 pg/ml) cured cells recently infected with C. burnetW Nine Mile and Q 212 within 4 to 9 days and cured multiplying, persistently infected cels within 10 days, As prevousl described with other fluoroquinolones (D. Raoult, M. Drancourt, and G. Vestris, Antimicrob. Agents Chemother. 34:1512Chemother. 34: -1514Chemother. 34: , 1990, sparfRoxacin failed to cure cells persistently infected with C. burnelii and blocked from dividing with cycloheximide. As determined by the dye uptake assay, no cellular toxicity was noted with spariloxacin at up to 128 gAg/mI. These results are consistent with those previously obtained with fluoroquinolones (D. Raoult, M. Yeaman, and 0. Baca, Rev. Infect. Dis. ll[Suppl. 5]:S986, 1989), although sparfloxacin may be slightly more active.Rickettsia rickettsii and Rickettsia conorii are the etiologic agents of Rocky Mountain spotted fever and Mediterranean spotted fever, respectively. These bacteria are antigenically (9) and genetically closely related and share the morphological characteristics and biochemical compositions of gramnegative bacteria. Both rickettsiae are strict intracellular pathogens, living free in the cytoplasm of infected host cells.

“…In vitro studies have shown that rifampin, the fluoroquinolones, and some macrolides have good activity against R. conorii (7,8); however, of these, only josamycin has proven efficacy in vivo (9). Although josamycin has been commercially available for years in some countries (e.g., France, Switzerland, Austria, Italy, South Africa, and Spain), it is unavailable in many others.…”

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confidence: 99%

Randomized Trial of Clarithromycin for Mediterranean Spotted Fever

Antón

Muñoz

Travería

et al. 2016

The classic antibiotic treatment for Mediterranean spotted fever (MSF) is based on tetracyclines or chloramphenicol, but chloramphenicol's bone marrow toxicity makes tetracyclines the treatment of choice. However, it is convenient to have alternatives available for patients who are allergic to tetracyclines, pregnant women, and children <8 years old. We conducted a randomized clinical trial to compare clarithromycin with doxycycline or josamycin in the treatment of MSF. Forty patients were evaluated (23 male; mean age, 39.87 years); 13 patients were aged <14 years. Seventeen patients received clarithromycin, and 23 received doxycycline or josamycin. The interval between the onset of symptoms and the start of treatment was 4.04 ؎ 1.70 days in the clarithromycin group versus 4.11 ؎ 1.60 days in the doxycycline/josamycin group (P ‫؍‬ not significant [NS]). Time to the disappearance of fever after treatment was 2.67 ؎ 1.55 days in the clarithromycin group versus 2.22 ؎ 1.35 days in the doxycycline/ josamycin (P ‫؍‬ NS). The symptoms had disappeared at 4.70 ؎ 2.25 days in the clarithromycin group versus at 4.75 ؎ 3.08 days in the doxycycline/josamycin (P ‫؍‬ NS). There were no adverse reactions to treatment or relapses in either group. In conclusion, clarithromycin is a good alternative to doxycycline or josamycin in the treatment of MSF. Mediterranean spotted fever (MSF) is a spotted fever group rickettsiosis. Caused by Rickettsia conorii, MSF is endemic in the Mediterranean area. Clinically, MSF is characterized by fever, exanthema, and the inoculation eschar known as tache noire. MSF affects people of both sexes and all ages (1-3).Antibiotic therapy helps prevent progression to severe disease and the associated mortality (4). Classic antibiotic therapy consists of tetracyclines or chloramphenicol, although the use of chloramphenicol in developed countries is limited by its bone marrow toxicity (5).Both in vitro and in vivo studies have shown that doxycycline is highly efficacious in this group of rickettsiosis. Even short-course treatments with doxycycline are highly effective (6). Nevertheless, it would be useful to have alternative treatments for patients allergic to tetracyclines, pregnant women, and children Ͻ8 years old.In vitro studies have shown that rifampin, the fluoroquinolones, and some macrolides have good activity against R. conorii (7, 8); however, of these, only josamycin has proven efficacy in vivo (9). Although josamycin has been commercially available for years in some countries (e.g., France, Switzerland, Austria, Italy, South Africa, and Spain), it is unavailable in many others. Thus, it would be useful to have another antibiotic that can be obtained in most countries to treat MSF.Several studies showed that clarithromycin and its metabolite 14-hydroxyclarithromycin have excellent in vitro activity against R. conorii and Rickettsia rickettsii (10-12), and these results were confirmed in clinical studies, where clarithromycin was efficacious and safe in treating children with spotted fever group...