Approach

Most people (up to 60%) infected with Coxiella burnetii remain asymptomatic.[2][38] For many who experience symptoms, the acute infection is mild and self-limiting, and spontaneously resolves within 2 weeks.[5][38] However, patients who are symptomatic should be treated with oral antibiotics for 14 days. Endocarditis and other persistent focalised infections require long-term antibiotic therapy. As many as 65% of patients with untreated endocarditis may die of the disease.[1][2] With prolonged combination therapy (doxycycline plus hydroxychloroquine) in patients with endocarditis, mortality is less than 5% at 5 years.[84]

Treatment should be initiated based on clinical suspicion alone and should not wait for results of confirmatory tests.

Acute infection

Acute infections are usually mild and self-limiting, lasting 2 to 14 days. Treatment is not recommended for patients with acute infection without valvulopathy who are asymptomatic before medical visit. However, if the patient is symptomatic, antibiotic therapy may shorten the duration of the disease. Treatment is most effective if given within the first three days of symptom onset.[33]​ Oral doxycycline for 14 days is the recommended treatment as it is the most effective antibiotic for C burnetii infections and has been shown to decrease hospitalisation rate.[26][33]​​[53][85]​​​​​ If the patient cannot tolerate doxycycline, then other antibiotics may be used (e.g., moxifloxacin, clarithromycin, rifampicin, or trimethoprim/sulfamethoxazole).[2][86]

Systemic fluoroquinolone antibiotics such as moxifloxacin may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[87]

  • Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability).

  • Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.

The patient should be advised to rest in bed and drink plenty of fluids. Antitussives can be used for cough, but paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for fever and any discomfort are not recommended as paracetamol can worsen the liver involvement and NSAIDs can worsen the infection.

In patients with acute infection, high levels of immunoglobulin G (IgG) anticardiolipin (aCL) antibodies (i.e., ≥75 GPLU [G antiphospholipid units]) have been associated with valvulopathy, vegetation (in acute endocarditis), and progression to chronic endocarditis and thrombosis.[55][57][71][77] The immunomodulatory drug hydroxychloroquine can prevent the thrombogenic effects of antiphospholipid antibodies.[88][89][90][91] Hydroxychloroquine can also reduce the risk of developing persistently positive antiphospholipid antibodies and lupus anticoagulant.[92][93] Therefore, combination treatment with doxycycline plus hydroxychloroquine is recommended for patients with IgG aCL antibodies ≥75 GPLU. Patients should be given this combination therapy until IgG aCL antibody levels are reduced to <75 GPLU. Patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency should not receive hydroxychloroquine.

Patients with acute infection and significant valvulopathy have a very high risk of endocarditis, which can be fatal if left untreated. In these patients, a 12-month course of antibiotic prophylaxis with combination doxycycline plus hydroxychloroquine is recommended. One study found this combination treatment to be highly effective in preventing endocarditis in such at-risk patients.[45] This prophylaxis is also recommended for patients with a history of vascular graft or aneurysm who have a negative 18F-fluorodeoxyglucose (FDG) PET/CT scan during acute infection.

Patients with acute infection and severe immunodeficiency (e.g., transplant patients, patients undergoing chemotherapy or corticosteroid therapy, patients with HIV and <200 CD4+ T cells, and patients with haematological malignancy) are at high risk of developing persistent focalised infections, such as endocarditis.[94] Doxycycline alone is recommended for these patients. Hydroxychloroquine is not recommended in these patients. In those with long-term immunodeficiency, long-term doxycycline is recommended until the immunosuppression has resolved, since infection can reactivate several months after primary infection in those who are immunocompromised.

Several medications (e.g., doxycycline, fluoroquinolones) may not be recommended in pregnant patients. Long-term (≥5 weeks) trimethoprim/sulfamethoxazole therapy protects against obstetric complications, including intrauterine death, spontaneous abortion, and premature delivery.[26][95]​ The alternative treatment for pregnant patients who are allergic to trimethoprim/sulfamethoxazole is azithromycin.[96] After delivery, mothers with acute infection should be evaluated for risk of persistent focal infection and managed accordingly.

C burnetii is found in maternal breast milk; therefore, breastfeeding is not recommended in infected patients. To confirm if breastfeeding should be stopped, a PCR for C burnetii could be performed on the maternal breast milk.

Persistent focalised infection

Common persistent focalised infections include endocarditis (up to 70% of cases) and vascular infection (e.g., aneurysm, vascular prosthetic infection).[2] The recommended treatment for endocarditis is oral doxycycline plus hydroxychloroquine for 18 months in patients with native valve endocarditis, or for 24 months in those with prosthetic valve endocarditis or with foreign body-related C burnetii endocarditis (e.g., from a cardiovascular implantable electronic device/pacemaker).[2][5][97][84][26] Valve replacement surgery should be considered for all patients with infective endocarditis who have haemodynamic compromise. Antibiotics should be prolonged in absence of good serological outcome (i.e., two-fold decrease in dilution titre of phase I IgG and absence of phase II IgM at 1 year).[84] In this case, monitoring should continue and drug levels should be repeatedly measured to verify therapeutic drug levels. An expert opinion should be obtained if therapeutic drug levels are achieved without improvement in serological outcomes. 

Endocarditis may be diagnosed in patients with severe heart valve disease (generally in a cardiac surgery unit) who have phase I IgG levels as low as 1:200.[73][79] In this specific context (i.e., cardiac surgery and vascular surgery and very low serological titres between 1:200 and 1:400), treatment of endocarditis and vascular infection must be prescribed, even in the absence of infectious symptoms or absence of a positive PCR, since mortality risk is high if left untreated.

If the patient has an implanted artificial pacemaker device, an 18F-FDG PET/CT scan is recommended.[98] If the scan shows high FDG uptake on the pacemaker device, the pacemaker pocket should be changed after 1 month of treatment with combination doxycycline plus hydroxychloroquine has been completed. If the scan shows high FDG uptake on the intracavitary leads, there is no immediate need for removal; a repeat 18F-FDG PET/CT scan should be performed after 2 months of treatment. Expert opinion is required if high FDG uptake persists on the scan.

Vascular infections are a very important challenge in C burnetii infection treatment because antibiotics do not prevent vascular rupture. The recommended treatment for vascular infections is oral doxycycline plus hydroxychloroquine for 18 months in patients without vascular prosthetic material, or for 24 months in those with vascular prosthetic material, followed by surgical removal of infected vascular tissue or infected vascular prosthetic material after 3 to 4 weeks of treatment, unless surgery is urgently required. Surgery is associated with an improved prognosis.[99] Therefore, routine surgical resection of infected vascular tissue/prosthetic material is required.[99]

In severely immunocompromised patients (e.g., transplant patients, patients receiving chemotherapy or corticosteroid therapy, patients with HIV and <200 CD4+ T cells, or patients with haematological malignancy) with C burnetii endocarditis or vascular infection, long-term doxycycline alone is recommended.

For all persistent focalised infections and acute infections with valvulopathy, monthly serological and drug monitoring is of critical importance and associated with therapeutic success.[100][101][102] Doxycycline should be maintained at 5-10 mg/L and hydroxychloroquine at 0.8 to 1.2 mg/L.[103] The main causes of treatment failure and relapse are lack of monthly drug monitoring, insufficient levels of drug in the plasma, and absence of surgery in patients with vascular infections.

[Figure caption and citation for the preceding image starts]: Algorithm for the diagnosis and management of C burnetiiinfection. TTE: transthoracic echocardiography; IgG aCL: IgG anticardiolipin antibodies; 18 F-FDG PET/CT: 18F-fluorodeoxyglucose PET combined with CT Eldin C, et al. Clin Microbiol Rev 2017; used with permission [Citation ends].com.bmj.content.model.Caption@7dac6732

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