Coxiella burnetii (Q Fever)
Authors: Thomas J. Marrie, M.D.
Microbiology
Coxiella burnetii is the etiologic agent of Q fever. It is a small Gram-negative bacterium that grows only in eukaryotic cells (38). Within these cells it multiplies in an acidic vacuole, pH 4.8. It can form a spore, which explains its ability to survive for extended periods in hostile environments and its marked resistance to physiochemical agents. C. burnetii exists in two antigenic phases, phases I and II. In animals, it exists in phase I and is extremely infectious; passage in cell culture or in embryonated eggs results in a change in surface lipopolysaccharides-phase II. This phase is much less virulent than phase I. The genome of C. burnetii strain Nine Mile Phase 1 has now been sequenced (52). It has 1,995,275 base pairs. There are many genes with potential roles in adhesion, invasion, intracellular trafficking, host-cell modulation and detoxification. The authors concluded that the obligate intracellular life style of C. burnetii may be a relatively recent innovation. This has led to multiple methods for typing the genome. Glazunova et al (12) used multispacer sequence typing to characterize 173 isolates. This resulted in three monophyletic groups.
Epidemiology
Q fever is a zoonotic disease. The epidemiology and animal reservoir varies by country. The most common animal reservoirs are cattle, sheep and goats. Cats are the primary reservoir for Q fever in Nova Scotia, Canada and occasional cases have been linked to dogs. Q fever has been reported from all continents except New Zealand and Antarctica, but the precise incidence is unknown because diagnostic tests are usually not performed and reporting of cases is not required. In the United States, 71 cases of Q fever were reported to the Centers for Disease Control in 2003.
Clinical Manifestations
Q fever has two major manifestations in man, acute and chronic infection. Acute Q fever has a variety of clinical presentations including self-limited febrile illness, pneumonia, hepatitis, meningoencephalitis, and pericarditis. Rarely it is a cause of constrictive pericarditis (4). Chronic Q fever is a much more serious illness and almost always means endocarditis, although infection of an aortic prosthesis or aneurysm is another manifestation of chronic Q fever (38). While still not adequately described in man, it is likely that Q fever during pregnancy results in chronic uterine infection with relapse during subsequent pregnancies as it does in other female mammals (27,42).
Laboratory Diagnosis
Because the illness is often nonspecific in clinical presentation, laboratory testing is necessary to confirm the diagnosis. Since most laboratories do not have the capability to isolate the organism, serologic tests are most common means of diagnosis including complement fixation and indirect fluorescent antibody tests. A four-fold rise in antibody titer is considered diagnostic. Acute Q fever is characterized by an antibody response to phase II antigen, while chronic Q fever is characterized by a higher response to phase I antigen.
Chronic Q fever (endocarditis and granulomatous hepatitis) is confirmed by: a) a complement fixation titer of 1:200 or greater to phase I antigen, or b) IgG antibody titer of 1:800 or greater by microimmunofluorescence. Both acute and chronic infections can also be diagnosed by PCR, immunochemistry, or culture of infected materials.
Pathogenesis
The mode of transmission is by inhalation of aerosols containing C. burnetii. Humans acquire the disease by direct contact with parturient animals or their placentas. The agent may be found in soil, dust, or contaminated environmental products and carried for long distances by wind. The microorganism proliferates in the lungs and then invades the bloodstream where if uncontrolled by the immune response it can infect heart valves, bone, or liver resulting in chronic disease.
SUSCEPTIBILITY IN VITRO AND IN VIVO
In many of the in vitro susceptibility studies cited below, three type strains of C. burnetii were commonly used. Strain Nine Mile was isolated from a tick, Dermacentor sp., collected near Nine Mile creek, Montana in 1935. It is a prototypic acute Q fever strain. Priscilla was isolated from a goat placenta; it is a chronic Q fever isolate. Q 212 was isolated from the brachial artery clot of a Nova Scotia, Canada, patient with Q fever endocarditis.
Determination of antimicrobial susceptibility of C. burnetii has been problematic, since it is an intracellular pathogen. Nevertheless, there is a long history of efforts to provide antimicrobial susceptibility data about C. burnetii. Three model systems have been used: chick embryos, guinea pigs, and cell cultures (60). Table 1 summarizes the results of susceptibility testing in chick embryos or guinea pigs.
In a series of studies, workers in Baca’s laboratory described a cell culture model, persistently infected L929 cells, for determining susceptibility of C. burnetii to antibiotics (1,2,49,62). The apparent advantages of the cell culture model are convenience, more-rapid test results (24-48 h vs. 1 week), and precise control of antimicrobial concentrations, which are only approximate in in vivo systems (60). What is not certain is how closely this system mimics chronic infection in man. The cells lines, L929 (mouse fibroblasts) and J774 and P388D1 (macrophage cell lines), do develop persistent infection for periods of 250 to 1400 days (60). Furthermore, these infected cells do not require addition of normal uninfected cells to maintain viable populations, yet the cell cycle is similar to that of normal uninfected cells (2).
The availability of this cell model system allowed investigators in Raoult’s laboratory in Marseille, France (28, 37) to make an observation that has major implications for the treatment of chronic Q fever. They found that phagolysosomal alkalinization with agents such as amantadine, chloroquine, or ammonium chloride increased the bactericidal effect of some antibiotics. These effects differed for different alkalinizing agents; for example, doxycycline plus amantadine resulted in weak bactericidal action, whereas combination with chloroquine or ammonium chloride resulted in strong antimicrobial activity (28). In contrast, the combination of pefloxacin and chloroquine was weakly bactericidal, whereas pefloxacin and ammonium chloride was much more effective (28). There was no correlation between phagolysosomal pH and the activity of rifampin (28).
Over the past few years there has been a suggestion that certain strains (whether defined by plasmid content or genomic profile following endonuclease digestion and pulse-field gel electrophoresis) of C. burnetii are associated with acute or chronic Q fever (15, 16, 51). There is little doubt, now that more isolates from diverse geographic areas have been studied, that there is no such association (57, 41). Yeaman and Baca (61) have shown that the plasmid content of C. burnetii isolates does not affect antimicrobial susceptibility.
Table 2 summarizes C. burnetii antimicrobial susceptibility studies in a cell culture model system. Jabrit-Aldighieri et al. (18) added another variable to the cell culture model. They used cycloheximide to block multiplication of L929 cells persistently infected with C. burnetii. This reduced the effectiveness of the two quinolones tested, compared with their effectiveness in untreated cells.
One of the important observations from C. burnetii susceptibility testing in the cell culture model is that (as might be expected) there is heterogenicity in the response of C. burnetii strains to antibiotics (40). Thus, of 13 strains tested, 6 were resistant to erythromycin, and 7 were of intermediate susceptibility. Corresponding data for pefloxacin, ofloxacin, ciprofloxacin for these 13 strains were 3/0; 1/0; 8/0; 3/0. It is also apparent from Table 2 that the Nine Mile strain ofC. burnetii is more susceptible to antibiotics than strains isolated from patients with chronic Q fever.
Lever et al (23) used vero cells and phase contrast microscopy to determine the susceptibility of C. burnetii strain Nine Mile to a variety of antibiotics. They found that doxycycline was most active, MIC 0.05 mg/L. Moxifloxacin and gatifloxacin had MICs of 1 mg/L; ciprofloxacin 2 mg/L and azithromycin > 8 mg/L. Rolain et al (48) in the L929 cell system found that moxifloxacin was bacteriostatic at 0.5 µg/mL for Nine Mile and Priscilla strains and 1 µg/mL for strain Q212. However it was not bactericidal at 4 µg/mL.
Spyridaki et al (56) converted C. burnetii to pefloxacin resistance in vitro and showed that this was associated with a nucleotide mutation leading to substitution of Glu for Lys at the position corresponding to amino acid 87 of Escherichia coli in resistant strains. Musso et al (31) found the same mutation in a strain of C. burnetii that had been converted to high level (MIC 8-16 mg/L) resistance to ciprofloxacin while no such mutation was present in isolates with low level (MIC 4 mg/L) resistance to ciprofloxacin.
ANTIMICROBIAL THERAPY
Table 3 summarizes recommendations for treatment of the various types of C. burnetii infection
Acute Q Fever (C. burnetii) Pneumonia
Based on clinical experience, doxycycline is the drug of choice for Q fever pneumonia. We recommend ciprofloxacin as second line therapy because of the in vitrosusceptibility data. Macrolides are third line therapy because of the bimodal distribution of susceptibility patterns.
Sobradillo et al. (54), Basque Country, Spain, carried out a prospective, randomized double-blind study of doxycycline and erythromycin in the treatment of pneumonia presumed to be due to Q fever. Forty-eight patients were proven by serologic studies to have Q fever; 23 received 100 mg doxycycline twice daily, and 25 received erythromycin (500 mg every 6 h) for 10 days. Fever resolution was more rapid in the doxycycline-treated group (3 ± 1.6 days vs. 4.3 ± 2 days for erythromycin-treated patients; P = .05). The erythromycin treated group had more gastrointestinal adverse effects (11 vs. 2 for the doxycycline treated patients; P <.01). By day 40, the chest radiograph was normal in 47 of the 48 patients. The authors concluded that doxycycline was more effective than erythromycin, but they recognized the self-limiting and benign nature of most cases of pneumonia due to Q fever. Kuzman et al (22) studied 64 patients with Q fever pneumonia. Twenty-two patients were treated with azithromycin (total dose 1.5 gm administered over 3 -5 days, 15 with doxycycline (100 mg bid for 10 - 14 days) and 15 received a variety of other antibiotics. The mean duration of fever was 2.5 days in the azithromycin-treated group, 2 days in the doxycycline-treated group, and 3.5 days in the patients who received other antibiotics. All patients were cured.
A retrospective review of 130 patients with Q fever pneumonia treated between 1989 and 1995 was carried out by Kofterids et al (21). Eleven patients who were treated with tetracycline became afebrile in a mean of 3 days; the 42 patients treated with erythromycin became afebrile in a mean of 4.26 days and the 28 patients treated with beta-lactam agents required 6.8 days to become afebrile. Fifteen percent of the clarithromycin treated patients were still febrile at 5 days compared with 35% of the erythromycin treated patients and none of the tetracycline treated patients. A retrospective review of 19 patients with Q fever pneumonia showed that 11 were treated with erythromycin and 8 with ß-lactam antibiotics. The erythromycin-treated group became afebrile by day 3, while only 2 of the ß-lactam-treated group were afebrile by this time (P<.005) (36). From in vitro data telithromycin is more active than erythromycin against C. burnetii (47).
The problem with all of the studies outlined in this section is that none are randomized trials. This limits the conclusion that can be drawn from these studies. In general however, treatment of acute Q fever is not a problem clinically, since most cases are unrecognized, and recovery is uneventful. However, C. burnetii may occasionally cause rapidly progressive pneumonia necessitating ventilatory support. If the recommendations of the 1993 Canadian Community Acquired Pneumonia Consensus Conference Group for treating such patients are followed, and erythromycin, rifampin, and a third generation cephalosporin are prescribed (26), the rifampin will adequately treat severe Q fever pneumonia. These recommendations have been superseded by recommendations from the Infectious Diseases Society of America (3) and the American Thoracic Society (31). Both of these groups have recommended a fluoroquinolone as an alternate choice for treatment of pneumonia requiring admission to an intensive care unit. If a fluoroquinolone is not used in this setting C. burnetii may not be treated effectively.
Followup of Patients with Acute Q Fever
Healy et al (14) described the case of a 53 year old woman who developed Q fever endocarditis 18 months following an episode of acute fever. At the time of diagnosis she was asymptomatic. This patient reported that she had had a heart murmur for 20 years. They recommend that serological monitoring be carried out every 4 months for a period of 2 years following acute Q fever and that patients with phase 1 IgG > 800 should be investigated further depending on the clinical scenario. So far there are insufficient data on which to make a firm recommendation re: followup. However there is no doubt that all patients with valvulopathy or prosthetic vascular material should undergo serological followup as recommended by Healy et al. These individuals are at high risk for development of chronic Q fever. Some authorities recommend that patients with valvulopathy who have acute Q fever should receive 12 months of doxycycline and hydroxychloroquine to prevent chronic Q fever (9).
In England and Australia about 10% of acutely ill people with Q fever have fatigue lasting more than 6 months (35); a similar finding was noted on followup of an outbreak of Q fever in Newfoundland, Canada following exposure to infected goats (14).
Chronic Q Fever Especially Endocarditis
Chronic Q fever generally means endocarditis, although osteomyelitis, sometimes hepatitis [most cases are acute] and Q fever during pregnancy are other manifestations of chronic Q fever. Endocarditis is the most serious manifestation of Q fever. There is usually a considerable delay in diagnosis, and this form of Q fever carries up to a 37% mortality rate. However with modern therapy as outline below the mortality rate has dropped to 10.5% at one centre (50).Despite this treatment of Q fever endocarditis is difficult. There are no randomized trials to provide guidance; however, by trial and error and now as a result of in vitrosusceptibility studies, we have arrived at regimens that provide (in conjunction with valve replacement) good cure rates.
At least two or more drugs active against C. burnetii should be used to treat Q fever endocarditis. Our first choice has been ciprofloxacin (750 mg twice daily, orally) plus rifampin (300 mg daily, orally). We have now treated 12 patients with this regimen, with only one failure. Therapy must be prolonged. We recommend at least 2 years, while others recommend 3 years (24). The best approach is to monitor response to treatment by determining antibody titers to phase I and phase II antigens with a microimmunofluorescence test. These antibody titers should be determined for the IgG and IgA every 3 months during treatment. Declining antibody titers reflect adequate response to treatment. When the antiphase I IgA is 1:200 or less, therapy can be stopped.
There are several reports of isolation of C. burnetii from heart valves following months to years of treatment, especially with single antimicrobial agents (24,30). Other antibiotic combinations that have been used successfully to treat Q fever endocarditis are doxycycline and cotrimoxazole (5) and doxycycline and quinolones (24). Addition of hydroxychloroquine (to alkalinize the phagolysosome) to doxycycline is effective in the treatment of chronic Q fever (41). The growing evidence suggests that hydroxychoroquine plus doxycycline should be first line treatment for Q fever endocarditis. Raoult et al (41) compared the results of treatment with doxycycline 100 mg bid and hydroxychloroquine 200 mg tid (plasma levels were measured and the dose adjusted to maintain a concentration between 0.8 and 1.2 mcg/mL) for 18 months with those of their usual regimen of doxycycline and ofloxacin. The latter patients were treated from January 1987 to May 1991 and the former group from May1991 until December 1997. Twenty-one patients received doxycycline and hydroxychloroquine -- 1 died of a surgical complication; 2 were still receiving treatment at the time of the report and 1 was being evaluated and 17 were cured. The mean duration of treatment was 31 months. In the historical comparison group (ofloxacin and doxycycline) there were 14 patients -- 1 died; 1 was still on treatment at the time of the report, 7 relapsed and 5 were cured. The doxycycline-hydroxychloroquine regimen had a significantly lower relapse rate. Doxycycline levels should also be measured as the MICs of doxycycline for C. burnetiiof 1 to 4 µg/ mL are very close to serum levels. Indeed Rolain, Mallet and Raoult found that patients with Q fever endocarditis who had > 2 fold decrease in phase I antibody levels had higher plasma doxycycline level than those of the other patients – 5.29 ± 1.75 vs 3.14 ± 1.40 µg/ mL (46). Plasma levels of doxycycline are measured using HPLC. Indeed the optimal way to manage patients with Q fever endocarditis is to isolate the organism from the heart valve, determine the MIC of doxycycline for this isolate and then measure serum levels of doxycycline. A ratio of serum level to doxycycline MIC of ≥ 1 is associated with a rapid decline in antibodies to phase 1 (45). Patients who take this regimen must be advised about the photosensitivity and retinal toxicity risks. Regular followup by an ophthalmologist is mandatory. The ability to monitor hydroxychloroquine and doxycycline blood levels is also necessary. Calza et al (6) treated one patient with Q fever endocarditis with doxycycline and chloroquine 125 mg bid for 2 years with apparent cure. In addition the doxycycline, hydroxychloroquine regimen has been found to be successful in a patient with HIV infection and Q fever endocarditis (25).
The Jarisch-Herxheimer reaction may occasionally complicate the treatment of chronic Q fever (19).
Thirteen cases of C. burnetii involving 9 aortic aneurysms and 4 vascular graft infections (53). The aneurysms involved the infrarenal aorta in 6 cases; ascending aorta in 1; thoracic aorta in 1 and suprarenal aorta in 1. The infected vascular grafts included – aortobifemoral bypass in 2 cases; abdominal aortic graft in 1 and subclavian-to-subclavian bypass graft in 1. Four (31%) died. Five (38%) developed septic pseudoaneurysms of the vascular prosthesis occurred and were adjactent to a vertebral osteomyelitis in 3 and to an aortoduodenal fistula in 2. Treatment is as for Q fever endocarditis. Surgical intervention is often required.
Chronic Q fever hepatitis is uncommon accounting for 3% of the cases of chronic Q fever in a large study from France (43).
Q Fever in Pregnancy
There are very few reports of Q fever complicating pregnancy (5, 27, 42, 44). C. burnetii has been isolated from the placenta despite treatment of the mother for Q fever during pregnancy (5, 27). Indeed, in 24 published cases of Q fever during pregnancy (3,20), C. burnetii was isolated from 12 of the 14 placentas examined. Thus in women, as in other female mammals, chronic infection of the placenta and endometrium occurs during pregnancy. This suggests that antibiotic therapy should be prolonged. In two cases (5,44), C. burnetii was isolated from the placenta despite therapy with rifampin/doxycycline and erythromycin/rifampin respectively. Until further data are available, we suggest that erythromycin/rifampin be sued to suppress (treat) C. burnetii during pregnancy and, after delivery, ciprofloxacin/rifampin or doxycycline/ciprofloxacin be given for 6 months. The infant must be monitored clinically and serologically for signs of Q fever, and a decision regarding treatment must be made on an individual basis. Clearly more data are needed before firm recommendations can be made regarding the treatment of Q fever in pregnancy. In all likelihood, however, Q fever during pregnancy is more common than is currently appreciated.
Therapy with Biological Modifying Agents
Morisawa et al (29) report use of interferon gamma to successfully treat a three year old boy with prolonged fever, abdominal pain and thrombocytopenia due toC. burnetii that could not be eradicated with conventional antibiotic therapy. Interferon gamma promotes killing of C. burnetii in monocytes through an apoptotic mechanism that is mediated by tumor necrosis factor (8).
Many patients with granulomatous hepatitis due to Q fever have a prolonged febrile illness that does not respond to antibiotics. For these individuals treatment with prednisone 0.5 mg/kg has resulted in defervescence within 2 to 15 days (7). Once defervescence has occurred the dose of steroids is tapered over the next month.
ADJUNCTIVE THERAPY
For endocarditis, valve replacement may be necessary and standard hemodynamic and clinical criteria can be applied to these patients.
ENDPOINTS FOR MONITORING THERAPY
For endocarditis, antibody titers should be monitored as described previously. Successful therapy is accompanied by decreasing antibody titers, a falling erythrocyte sedimentation rate, correction of anemia, and resolution of hypergammaglobulinemia.
VACCINES
An investigational inactivated vaccine has been used for laboratory workers. It can be obtained from the U.S. Army Medical Research Institute for Infectious Diseases in Fort Detrick, Maryland.
PREVENTION
Eradicating the reservoir to prevent outbreaks is one approach including using seronegative sheep in research facilities and minimizing contamination by aborted animal products in livestock or veterinary locales. Isolation of infected patients is unnecessary because person-to-person transmission does not exist.
References
1. Akporiaye ET, Rowatt JD, Aragon AA, Baca OG. Lysosomal response of a murine macrophage cell line persistently infected with Coxiella burnetii. Infect Immun 1983;40:1155-1162. [PubMed]
2. Baca OG, Scott TO, Akporiaye ET, DeBlassie R, Crissman HA. Cell cycle distribution patterns and generation times of L929 fibroblast cells persistently infected with Coxiella burnetii. Infect Immun 1985;47:366-369. [PubMed]
3. Bartlett JG, Dowell SF, Mandell LA, File Jr TM, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31:383-421. [PubMed]
4. Bautista-Hernandez V, Gutierrez F, Ray VG, Arribas JM, Garcia-Puente J, Casinello N, Arcas R. Constrictive pericarditis due to Coxiella burnetii. Ann Thor Surg 2004; 78: 326 – 328. [PubMed]
5. Bental T, Fejgin M, Keysary A, Rzotkiewicz S, Oron C, Nachum R, Beyth Y, Lang R. Chronic Q fever of pregnancy presenting as Coxiella burnetii placentitis: successful outcome following therapy with erythromycin and rifampin. Clin Infect Dis 1995;21:1318-1321. [PubMed]
6. Calza L, Attard L, Manfredi R, Chiodo F. Doxycycline and chloroquine and treatment for Q fever endocarditis. J Infect 2002; 45:127-129. [PubMed]
7. Crespo M, Sopena B, Bordon J, de la Fuente J, Rubianes M, Martinez-Vazquez C. Steroids treatment of granulomatous hepatitis complicating Coxiella burnetiiacute infection. Infection 1999; 27: 132-133. [PubMed]
8. Dellacasagrande J, Capo C, Raoult D, Mege JL. Interferon gamma mediated control of Coxiella burnetii survival in monocytes. The role of cell apoptosis and tumor necrosis factor. J Immunol 1999;162:2259-2265. [PubMed]
9. Fenollar F, Fournier P, Carrieri MP, Habib G, Messana T, Raoult D. Risk factors and prevention of Q fever endocarditis. Clin Infect Dis 2001; 33: 312-316. [PubMed]
10. Fernández-Guerrero JM, Aguado JM, Renedo G, Fraile J, Soriano F, de Villalobos E. Q fever endocarditis on porcine bioprosthetic valves. Ann Intern Med 1988;108:209-213. [PubMed]
11. Gikas A, Spyridaki I, Scoulica E, Psaroulaki A, Tselentis Y. In vitro susceptibility of Coxiella burnetii to linezolid in comparison with its susceptibilities to quinolones, doxycycline and clarithromycin. Antimicrob Agents Chemother 2001;45:3276-3278. [PubMed]
12. Glazunova O, Roux V, Freylikman O, Sekeyova Z, Fournous G, Tyczka J, Tokarevich N, Kovacava E, Marrie TJ, Raoult D. Coxiella burnetii genotyping. Emerg Infect Dis 2005; 11: 1211-1217. [PubMed]
13. Hatchette TF, Hayes M, Merry H, Schlech WF, Marrie TJ. The effect of C. burnetii on the quality of life of patients following an outbreak of Q fever. Epidemiol Infect 2003; 130: 491-495. [PubMed]
14. Healy B, Llewelyn M, Westmoreland D, Lloyd G, Brown N. The value of followup after acute Q fever infection. J Infect 2006; 52: e109-e112. [PubMed]
15. Heinzen R, Stiegler GL, Whiting LL, Schmitt SA, Mallavia LP, Frazier ME. Use of pulse field gel electrophoresis to differentiate Coxiella burnetii strains. In: Hechemy KE, Paretsky D, Walker DH, Mallavia LP, eds. Rickettsiology: current issues and perspectives. Ann NY Acad Sci 1990;590:504-513. [PubMed]
16. Hendrix LR, Samuel JE, Mallavia LP. Differentiation of Coxiella burnetii isolates by analysis of restriction-endonuclease-digested DNA separated by SDS-PAGE. J Gen Microbiol 1991;137:269-276. [PubMed]
17. Huebner RJ, Robinson EB. Action of streptomycin in experimental infection with Q fever. Public Health Rep 1948;63:357-362.
18. Jabarit-Aldighieri N, Torres H, Raoult D. Susceptibility of Rickettsia conorii, R. rickettsiae, and Coxiella burnetii to PD 127, 391,PD 131, 628 pefloxacin, ofloxacin, and ciprofloxacin. Antimicrob Agents Chemother 1992;36:2529-2532. [PubMed]
19. Kaplanski G, Granel B, Vaz T, Durand JM. Jarisch-Herxheimer reaction complicating the treatment of chronic Q fever endocarditis:Elevated TNF α and IL-6 serum levels. J Infect 1998; 37: 83-84. [PubMed]
20. Keren G, Keysary A, Goldwasser R, Rubinstein E. The inhibitory effect of fluoroquinolones on Coxiella burnetii growth in in vitro systems. J Antimicrob Chemother 1994;33:1254-1255. [PubMed]
21. Kofterids D, Gikas A, Spiradakis G, Psaroulakis A, Vamvakas L, Tselentis I. Clinical response to Q fever infection to macrolides. Proceedings of the IV International Conference on the Macrolides, Azalides, Streptogramins, and Ketolides. Barcelona, 1998, page 47.
22. Kuzman I, Schonwald S, Culig J, Oreskovic K, Jana Zaranic T. The efficacy of azithromycin in the treatment of Q fever: a retrospective study. Proceedings of the IV International Conference on the Macrolides, Azalides, Streptogramins and Ketolides, Barcelona, 1998; page 47.
23. Lever MS, Bewley KR, Dowsett B, Lloyd G. In vitro susceptibility of Coxiella burnetii to azithromycin, doxycycline, ciprofloxacin and a range of new fluroquinolones. Int J Antimicrob Agents. 2004; 24: 192-195. [PubMed]
24. Levy PY, Drancourt M, Etienne J, Auvergnat JC, Beytout J, Sainty JM, Goldstein F, Raoult D. Comparison of different antibiotic regimens for therapy of 32 cases of Q fever endocarditis. Antimicrob Agents Chemother 1991;35:533-537. [PubMed]
25. Madariaga MG, Pulvirenti J, Sekosan M, Paddock CD, Zaki SR. Q fever endocarditis in HIV infected patient. Emerging Infect Dis 2004; 10 : 501-504. [PubMed]
26. Mandell LA, Neiderman M, The Canadian Community Acquired Pneumonia Consensus Conference Group. Antimicrobial treatment of community-acquired pneumonia in adults: a conference report. Can J Infect Dis 1993;4:25-28.
27. Marrie TJ. Q fever in pregnancy: report of two cases. Infect Dis Clin Pract 1993;2:207-209.
28. Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm. J Infect Dis 1992;166:1097-1102. [PubMed]
29. Morisawa Y, Wakiguchi H, Takechi T, Kurashige T, Nagaoka H. Intractable Q fever treated with recombinant gamma interferon. Ped Infect Dis J 2001;20:546-547. [PubMed]
30. Muhlemann K, Matter L, Meyer B, Schopfer K. Isolation of Coxiella burnetii from heart values of patients treated for Q fever endocarditis. J Clin Microbiol 1995;33:428-431. [PubMed]
31. Musso D, Drancourt M, Osscini S, Raoult D. Sequence of quinolone resistance-determining region of gyrA gene for clinical isolates and for an in vitro-selected quinolone-resistant strain of Coxiella burnetii. Antimicrob Agents Chemother 1996;40:870-873. [PubMed]
32. Neiderman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, Dean N, File T, Fine MJ, Gross PA, Martinez F, Marrie TJ, Plouffe JF, Ramirez J, Sarosis GA, Torres A, Wilson R, Yu VL. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Crit Care Med 2001; 163: 1730 - 1754. [PubMed]
33. Ormsbee RA, Parker H, Pickens EG. The comparative effectiveness of aureomycin, terramycin, chloramphenicol, erythromycin and thiocymetin in suppressing experimental rickettsial infections in chick embryos. J Infect Dis 1955;96:162-167.
34. Ormsbee RA, Pickens EG. A comparison by means of the complement-fixation test of the relative potencies of chloramphenicol, aureomycin, and terramycin in experimental Q fever in embryonated eggs. J Immunol 1951;67:437-448.
35. Parker NR, Barralet JH, Bell AM. Q fever. Lancet 2006; 367:679-688. [PubMed]
36. Pérez-del-Molino A, Aguado JM, Riancho JA, Sampedro I, Matorras P, Gonzalez-Macias J. Erythromycin and the treatment of Coxiella burnetii pneumonia. J Antimicrob Chemother 1991;28:455-459. [PubMed]
37. Raoult D, Drancourt M, Vestris G. Bactericidal effect of doxycycline associated with lysomotropic agents on Coxiella burnetii in P388D cells. Antimicrob Agents Chemother 1990; 34: 1512-1514. [PubMed]
38. Raoult D, Marrie T. Q fever. Clin Infect Dis 1995;20:489-496. [PubMed]
39. Raoult D, Raza A, Marrie TJ. Q fever endocarditis and other forms of chronic Q fever. In: Marrie TJ, ed. Q fever--the disease. Boca Raton, FL: CRC Press, 1990:180-199.
40. Raoult D, Torres H, Drancourt M. Shell-vial assay: evaluation of a new technique for determining antibiotic susceptibility, tested in 13 isolates of Coxiella burnetii. Antimicrob Agents Chemother 1991;35:2070-2077. [PubMed]
41. Raoult D, Houpikian P, Tissot Dupont H, Riss JM, Arditi-Djiane J, Brouqui P. treatment of Q fever endocarditis. Comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychlorquine. Arch Intern Med 1999;159:167-173. [PubMed]
42. Raoult D, Stein A. Q fever during pregnancy--a risk for women, fetuses and obstetricians. N Engl J Med 1994;330:371. [PubMed]
43. Raoult D, Tissot-Dupont H, Foucault C. Q fever 1985 – 1998: Clinical and epidemiological features of 1,383 infections. Medicine (Baltimore) 2000; 79: 110-123.[PubMed]
44. Riechmann N, Raz R, Keysary A, Goldwasser R, Flatau E. Chronic Q fever and severe thrombocytopenia in a pregnant woman. Am J Med 1988;85:253-254.[PubMed]
45. Rolain JM, Boulos A, Mallet MN, Raoult D. Correlation between ratio of serum doxycycline concentration to MIC and rapid decline of antibody levels during treatment of Q fever endocarditis. Antimicrobial Agents Chemother 2005; 49: 2673-2676. [PubMed]
46. Rolain JM, Mallet MN, Raoult D. Correleation between serum doxycline concentrations and serologic evolution in patients with Coxiella burnetii endocarditis. J Infect Dis 2003; 188: 1322-1325. [PubMed]
47. Rolain JM, Maurin M, Bryskier A, Raoult D. In vitro susceptibilities of telithromycin (HMR 3647) against Rickettsia rickettsi, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella Quintana, Bartonella bacilliformis, and Ehrlichia chaffeensis. Antimicrobial Agents Chemother 2000;44:1391-1393. [PubMed]
48. Rolain JM, Maurin M, Raoult D. Bacteriostatic and bactericidal activities of moxifloxacin against Coxiella burnetii. Antimicrobial Agents Chemother 2001; 45: 301-302. [PubMed]
49. Roman MJ, Coriz PD, Baca OG. A proposed model to explain persistent infection of host cells with C. burnetii. J Gen Microbiol 1986;132:1415-1422. [PubMed]
50. Salamand AC, Collart F, Caus T, Casalta JP, Mouly-Bandini A, Monties JR, Habib G, Raoult D, Mesana TG. Q fever endocarditis: Over 14 years of surgical experience in a referral center for rickettsioses. J Heart Vavle Dis 2002; 11: 84-90. [PubMed]
51. Samuel JE, Frazier ME, Mallavia LP. Correlation of plasmid type and disease caused by Coxiella burnetii. Infect Immun 1985;49:775-777. [PubMed]
52. Seshadri R, Paulsen IT, Eisen JA, Read TD, Nelson KE, Nelson WC, Ward NL, Tettelin H, Davidsen TM, Beanan MJ, Deboy RT, Daugherty SC, Brinkac LM, Madupu R, Dodson RJ, Khouri HM, Lee KH, Carty HA, Scanlan D, Heinzen RA, Thompson HA, Samuel JE, Fraser CM, Heidelberg JF. Complete genome sequence of the Q fever pathogen Coxiella burnetii. Proc Natl Acad Sci U S A. 2003 ;100:5455-60. [PubMed]
53. Sessa C, Vokrri L, Porcu P, Maurin M, Stahl JP, Magne JL. Abdominal aortic aneurysm and Coxiella burnetii infection. Report of three cases and review of the literature. J Vasc Surg 2005; 42: 153-158. [PubMed]
54. Sobradillo V, Zalacain R, Capebastegui A, Uresandi F, Corral J. Antibiotic treatment in pneumonia due to Q fever. Thorax 1992;47:276-278. [PubMed]
55. Spirdaki G, Gikas A, Kofteridis D, Psaroulaki A, Vamvakas L, Tselentis Y. In vitro susceptibility of Coxiella burnetii to clarithromycin. Proceedings of the IV Internation Conference on the Macrolides, Azalides, Streptogramins, and Ketolides. Bracelona, 1998, page 47.
56. Spyridaki I, Psaroulaki A, Aransay A, Scoulica E. Tselentis Y. Diagnosis of quinolone-resistant Coxiella burnetii strains by PCR-RFLP. J Clin Lab Analysis 2000; 14: 59-63 [PubMed]
57. Stein A, Raoult D. Lack of pathotype specific gene in human Coxiella burnetii. Microbiol Pathog 1993;15:177-185. [PubMed]
58. Thiele D, Willems H, Kopf G, Krauss H. Polymorphism in DNA restriction patterns of Coxiella burnetii isolates investigated by pulsed field gel electrophoresis and image analysis. Eur J Epidemiol 1993;9:419-425. [PubMed]
59. Torres H, Raoult D. In vitro activities of ceftriaxone and fusidic acid against 13 isolates of Coxiella burnetii, determined using the shell vial assay. Antimicrob Agents Chemother 1993;37:491-494. [PubMed]
60. Yeaman MR, Baca OG. Antibiotic susceptibility of Coxiella burnetii. In: Marrie TJ, ed. Q fever--the disease. Boca Raton, FL: CRC Press, 1990:213-223.
61. Yeaman MR, Baca OG. Mechanisms that may account for differential antibiotic susceptibilities among Coxiella burnetii isolates. Antimicrobial Agents Chemother 1991;35:948-954. [PubMed]
62. Yeaman MR, Mitscher LA, Baca OG. In vitro susceptibility of Coxiella burnetii to antibiotics, including several quinolones. Antimicrobial Agents Chemother 1987;31:1079-1084. [PubMed]
Tables
Table 1: Summary of Results of Antimicrobial Susceptibility Testing: Coxiella burnetii Using Chick Embryo or Guinea Pig Models
| Ref | Author | Model System | Strain(s) Tested | Antibiotic(s) Tested | Results |
|---|---|---|---|---|---|
| 17 | Huebner 1948 | Chick embryos Guinea pigs | Strains from patients with acute Q fever | Streptomycin | Reduced mortality |
| 34 | Ormsbee 1951 | Embryonated eggs | Nine Mile | Aureomycin Terramycin Chloramphenicol Streptomycin Pencillin G | Most effective ↓ Least effective |
| 34 | Ormsbee 1951 | Chick embryos | Nine Mile | Terramycin Aureomycin Erythromycin Thiocymetin | Effective Effective Ineffective Effective |
| 20 | Keren 1994 | Chick embryos | Ohio 314 phase I | Minocycline Ciprofloxacin Pefloxacin Fleroxacin | Effective at 8 µg/g egg 1 µg/g egg 6 µg/g egg 1 µg/g egg |
Table 2 Summary of Results of Antimicrobial Susceptibility Testing: Coxiella burnetii Using Cell Culture Model
| Ref | Author | Cell Line | Strain(s) Tested | Antibiotics(s) Tested | Results |
|---|---|---|---|---|---|
| 20 | Keren 1994 | Vero cells | Ohio 314 | Minocycline Fleroxacin Pefloxacin Ciprofloxacin | 95% growth inhibition at 2.5 mg/L 95% growth inhibition at 10 mg/L |
| 59 | Torres 1993 | HEL cells | Nine Mile Q 212 Priscilla and 10 isolate from patients with chronic Q fever (Marseille) | Ceftriaxone Fusidic acid | Inconclusive results Authors conclude these compounds could be effective |
| 18 | Jabarit-Aldighieri 1992 | L929 cells with addition of cycloheximide | Q 212 Nine Mile 13 chronic fever Q isolates | PD 127, 391} flouro-PD 131, 628} quinolones | Both quinolones more active against Nine Mile strain than against Q212 (chronic Q fever strain), but neither drug could eliminate infection |
| 40 | Raoult 1991 | HEL cells | Nine Mile Q212 Priscilla 10 chronic Q fever isolates | Amoxicillin Amikacin Erythromycin Cotrimoxazole Pefloxacin Ciprofloxacin Chloramphenicol Tetracycline Doxycycline Minocycline Rifampin | Nine Mile more susceptible than Q212 or Priscilla; all isolates were resistant to amoxicillin and amikacin; all were susceptible to rifampin, cotrimoxazole, and tetracyclines; heterogeneity of susceptibility to fluoroquinolones, chloramphenicol, and erythromycin |
| 60 | Yeaman 1987 | L929 | Nine Mile | Penicillin G | Pencillin G, polymyxin B, |
| 47 | Rolain 2000 | HEL cells | Nne Mile Q 212, Priscilla | Telithromycin, erythromycin | MIC for telithromycin 1 mcg/ml vs 8 mcg/ml for erythromycin. |
| 62 | Yeaman 1987 | Polymyxin B Sulfamethoxazole Trimethoprim Streptomycin Gentamicin Chloramphenicol Rifampin, novobiocin Nalidixic acid Oxolinic acid Ciprofloxacin Norfloxacin Ofloxacin | sulfamethoxazole, trimethoprim, erythromycin, streptomycin, gentamicin-inactive, chloramphenicol, some activity; all others very active | ||
| 55 | Spiridacki | VERO cells | 130 isolates | Vibramycin, clarithromycin, ciprofloxacin | Clarithromycin inhibited all isolates at4 mg/L, vibramycin 2 mg/L, ciprofloxacin 8 mg/L. |
| 11 | Gikas et al | 9 isolates from Greek patients with acute Q fever | Linezolid, pefoloxacin, Ciprofloxacin, trovafloxacin, doxycycline, clarithromycin | MICs for linezolid and clarithromycin ranged from 2 to 4 mg/L. |
Table 3 Antimicrobial Treatment of Various Manifestations of C. burnetii Infection [Download PDF]
| Condition | Treatment1 | Reference |
|---|---|---|
| Acute Q fever Pneumonia | 1. Doxycycline 100 mg b.i.d. p.o. for 10 days 2. Ciprofloxacin 500 mg b.i.d. p.o. for 10 days | 54 |
| Chronic Q fever Endocarditis | 1. Doxycycline 100 mg b.i.d. p.o. plus hydroxychloroquine 200 mg t.i.d to achieve a chloroquine level of 1 mg/L 2. Ciprofloxacin 750 mg b.i.d. p.o. plus rifampin 300 mg o.d. p.o. 2 3. Doxycycline 100 mg b.i.d. p.o. plus rifampin 300 mg o.d. p.o.2 4. Doxycycline 100 mg b.i.d. p.o. plus a quinolone b | 41 Author’s recommendations, 24 41 |
| Q fever in pregnancy | 1. Erythromycin 500 mg q. 6 h p.o. plus rifampin 300 mg o.d. p.o. for the duration of the pregnancy. After delivery, ciprofloxacin 500 mg b.i.d p.o. plus rifampin 300 mg o.d. p.o. for 6 months | Author’s recommendation |
| Q fever hepatitis | Can occur as an acute or chronic form; treatment is as outlined for acute Q fever; chronic Q fever hepatitis-insufficient data to make any firm recommendations about duration of treatment; would use combination therapy as listed for endocarditis. Prednisone 0.5 mg/kg can be used in those who fail to defervesce. | 7 |
1. 1, first choice; 2, choice, etc.
2. All regimens to treat chronic Q fever must be given until IgA antiphase I antibody titer is < 1:200, this usually requires at least 2 years.
What's New
Million M, et al. Evolution from Acute Q Fever to Endocarditis Is Associated with Underlying Valvulopathy and Age and Can Be Prevented by Prolonged Antibiotic Treatment. Clin Infect Dis 2013;57:836-844.
Wegdam-Blans MCA, et al. Evaluation of Commonly Used Serological Tests for Detection of Coxiella burnetiiAntibodies in Well-Defined Acute and Follow-up Sera. Clinical Vaccine and Immunology 2012;19:1110-1115.
Wegdam-Blans MC, et al. Aneurysms, Vascular Grafts and Q Fever. In the Literature Section, Clin Infect Dis 2012;55.
Hingwe, A. Jarisch-Herxheimer reaction. 2009
guided medline search for:
Reviews
Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. The Two faces of interleukin 10 in human infectious diseases. Lancet Infectious Diseases 2006:7;557-569.
guided medline search for recent reviews
History
The Origin of the term Q Fever and Coxiella burnetii, 2013.