1. Aetna considers outpatient intravenous antibiotic therapy medically necessary in adult and pediatric members with the diagnosis of Lyme disease only when it is based on the clinical presentation of signs and symptoms compatible with the disease and supported by a positive serologic and/or cerebrospinal fluid (CSF) titer by indirect immunofluorescence assay (IFA), Prevue Borrelia burgdorferi antibody detection assay, or enzyme-linked immunosorbent assay (ELISA), which itself is validated by a positive Western Blot Test (see CDC criteria in note* below).

   Once a definitive diagnosis of Lyme disease is established, Aetna considers outpatient intravenous antibiotic therapy medically necessary when any of the following conditions is met:

   1. Lyme arthritis which persists after failing to respond to a 4-week course of appropriate oral antibiotic therapy

   2. Moderate to severe cardiac involvement as evidenced by any of the following:

      1. A first degree heart block with P-R interval greater than 0.4 seconds
      2. Second or higher degree AV block
      3. Congestive heart failure

      4. Myopericarditis

   3. Neurologic involvement of Lyme disease (neuroborreliosis) as evidenced by any of the following:

      1. Meningitis confirmed by CSF analysis showing a lymphocytic pleocytosis with evidence of antibody production against Borrelia burgdorferi in the CSF
      2. Encephalopathy/encephalomyelitis

      3. Sensory/motor radiculoneuropathy or peripheral neuropathy (weakness and/or pain in the extremities or chest)

   4. All cases of Lyme disease in pregnant women who exhibit symptoms and signs of any of the following:

      1. Stage II Lyme disease with early dissemination documented by organ-specific manifestations of infection (cardiac, neurologic, or arthritic)

      2. Stage III late Lyme disease documented by findings of arthritis and/or neurologic complications, such as encephalomyelitis and subacute encephalitis.

2. Aetna considers initial intravenous antibiotic therapy experimental and investigational for the following indications, because the benefit of intravenous antibiotic therapy for these indications has not been established:

   1. Non-specific subjective symptoms, e.g., persistent, chronically debilitating fatigue (chronic fatigue syndrome), difficulty in concentrating, musculoskeletal pain (fibromyalgia), and headache
   2. Prophylaxis in a person who is asymptomatic and the only evidence for Lyme disease is a positive immunologic test (Elisa, IFA, or Western blot)
   3. Early Lyme disease or new-onset Lyme arthritis
   4. Flu-like syndrome (fatigue, fever, headache, mildly stiff neck, arthralgias, and myalgias)

   5. Mild cardiac involvement of Lyme disease as evidenced by any of the following:

      1. First degree heart block with P-R interval less than 0.4 seconds
      2. Transient ST-T depression, T- wave changes

      3. Left ventricular dysfunction without congestive heart failure

   6. Minor neurologic manifestations of Lyme disease (including headache, stiff neck, and irritability)
   7. Pregnant woman presenting with localized Lyme disease manifested as a single lesion of erythema migrans without any other symptoms suggestive of disseminated disease

   8. Isolated manifestations of neurologic involvement of Lyme disease (such as Bell's facial nerve palsy/paralysis).

3. Aetna considers the following diagnostic tests for Lyme disease experimental and investigational because there is inadequate scientific evidence to prove their usefulness in clinical practice:

   1. T-cell proliferation response assay
   2. Borrelia culture
   3. Polymerase chain reaction (PCR) for identification or quantification of Lyme disease (B. burgdorferi ) spirochetal DNA or RNA
   4. Urine antigen assay
   5. Serum borreliacidal assay
   6. C6 peptide ELISA assay (using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi ).

   7. Provocative testing (testing for B. burgdorferi after antibiotic provocation).

   Scheduled repeated testing for Lyme disease in a member without a change in signs and symptoms is considered not medically necessary.

4. Aetna considers a repeat 4-week course of outpatient intravenous antibiotic therapy medically necessary when the member meets all of the following criteria:

   1. The member has met the criteria for an initial course of intravenous antibiotic therapy, using lab results obtained within the past three months; and
   2. The member has completed an initial course of appropriate intravenous antibiotic therapy; and

   3. The member has objective evidence of either relapse of infection, progression of Lyme disease organ damage, and/or the finding of a new focus or type of organ damage.

   Aetna considers additional antibiotic therapy in post-treatment, persistently fatigued patients (post Lyme syndrome) experimental and investigational because intravenous antibiotic therapy has not been shown to be effective for this indication.

5. Concurrent babesiosis or cat-scratch disease is not, in and of itself, considered a medically necessary indication for long-term intravenous antibiotic therapy for Lyme disease. Long-term intravenous antibiotic therapy is generally not medically necessary in immunocompetent persons with Bartonella-associated vasculoproliferative diseases (bacillary angiomatosis-peliosis and verruga peruana) or Bartonella bacteriemia (other than Bartonella endocarditis). Intravenous antibiotic therapy may be medically necessary in persons with severe Bartonella infection, immunocompromised persons, and systemic Bartonella infection complicated by bony or parenchymal involvement or endocarditis

6. Aetna considers hyperbaric oxygen therapy experimental and investigational for the treatment of Lyme disease because its effectiveness for this indication has not been established (see CPB 172 - Hyperbaric Oxygen Therapy (HBOT)).

7. Aetna considers intravenous antibiotic therapy experimental and investigational for the treatment of Q fever because its effectiveness over oral antibiotics for this indication has not been established.

8. Aetna considers testing ticks for Borrelia burgdorferi experimental and investigational because it has not been proven to be useful for deciding if a person should receive medical treatment following a tick bite.

*Note: According to the CDC (1995), the recommended method for serologic detection of active disease or previous infection involves a two-test approach using a sensitive enzyme immunoassay (EIA) or immunofluorescent assay (IFA) followed by a Western immunoblot. All specimens positive or equivocal by a sensitive EIA or IFA should be tested by a standardized Western immunoblot.

The CDC (1995) states that when Western immunoblot is used during the first 4 weeks of disease onset (early LD), both immunoglobulin M (IgM) and immunoglobulin G (IgG) procedures should be performed. However, a positive IgM immunoblot alone is not considered sufficient evidence of active disease in a person with Lyme disease of more than one month's duration. Although the presence of IgM antibodies is useful in evaluating early disease, the CDC states that a positive IgM test result alone is not recommended for use in determining active disease in persons with illness greater than one month's duration because the likelihood of a false-positive test result for a current infection is high for these persons. The following criteria for a positive Western Blot are as adapted from the CDC (1995):

IgM immunoblot - Two of the following bands are present:

• 21/22/23/24 kDa (OspC)*
• 39 kDa (BmpA)
• 41 kDa (Fla).

or

IgG immunoblot - Five of the following bands are present:

• 18 kDa
• 21/22/23/24 kDa (OspC)*
• 28 kDa
• 30 kDa
• 39 kDa (BmpA)
• 41 kDa (Fla)
• 45 kDa
• 58 kDa (not GroEL)
• 66 kDa
• 93 kDa.

A positive serology, on its own, is not considered a medically necessary indication for antibiotic therapy for Lyme disease. According to the CDC, positive antibody tests should be correlated with symptoms to be clinically meaningful. According to the CDC (1995), if an individual with suspected early Lyme disease has a negative serology, serologic evidence of infection is best obtained by testing of paired acute- and convalescent-phase serum samples. Serum samples from persons with disseminated or late-stage Lyme disease almost always have a strong IgG response to Borrelia burgdorferi antigens.

* The apparent molecular mass of outer surface protein C (OspC) is strain dependent; thus the 21 kDa, 22 kDa, 23 kDa, and 24 kDa proteins referred to above are the same.

See also  CPB 650 - Polymerase Chain Reaction Testing: Selected Indications; CPB 369 - Chronic Fatigue Syndrome, Diagnosis; and CPB 206 - Intravenous Immunoglobulins (IVIG).

The use and duration of intravenous antibiotic therapy in Lyme disease remains controversial. Researchers are currently conducting studies to assess the optimal duration of antibiotic therapy for the various manifestations of Lyme disease. In some areas of the country, patients are being treated for months to a year or more with daily parenteral or oral antibiotics. In a randomized controlled study, Wormser et al (2003) stated that treatment of patients with early Lyme disease has trended toward longer duration despite the absence of supporting clinical trials. These investigators concluded that extending treatment with doxycycline from 10 to 20 days or adding one dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.

Randomized controlled studies of treatment of patients who remain unwell after standard courses of antibiotic therapy for Lyme have shown that repeated or prolonged courses of antibiotic therapy are not effective for such patients. Krupp et al (2003) reported that ceftriaxone therapy in patients with post Lyme syndrome (PLS) with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection. Because fatigue (a non-specific symptom) was the only outcome that improved and because treatment was associated with adverse events, these authors concluded that their findings did not support the use of additional antibiotic therapy with intravenous ceftriaxone in post-treatment, persistently fatigued patients with PLS. This in agreement with the findings of Kaplan et al (2003) who concluded that patients with post-treatment chronic Lyme disease who have symptoms (e.g., fatigue, depression) but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.  Added expense and toxicity are the only proven results of such practice. Iatrogenic problems, such as gallbladder disease, fungal infections, and other superinfections, and gastrointestinal problems, certainly increase with prolonged use of broad-spectrum antibiotics. This highlights the need for an appropriate diagnosis before subjecting the patient to antibiotic regimens.

Pfister and Rupprecht (2006) noted that the diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2 to 3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies. Moreover, Feder et al (2006) stated that antibiotic therapy for more than 8 weeks for patients with Lyme disease is not indicated. Chronic Lyme disease due to antibiotic resistant infection has not been demonstrated.  

The diagnosis of Lyme disease is valid only in a person with erythema migrans in early Lyme disease or for later stages of infection, in a person with a least one late manifestation and laboratory confirmation of infection. Laboratory support of the diagnosis of Lyme disease requires detection of specific antibodies to this tick-borne spirochete Borrelia burgdorferi in the serum, either by indirect immunofluorescence assay (IFA) or enzyme-linked immunosorbant assay (ELISA), with the latter now preferred because it is more sensitive and specific. A Western blot assay that can detect both IgM and IgG antibodies is used to confirm the diagnosis. Specific IgM antibodies appear first, usually 3-4 weeks after the infection begins, while specific IgG antibodies usually appear 6-8 weeks after the onset. An elevated IgM is a value greater than 250 mg/dl and an elevated IgG is a value greater than 1500 mg/dl. After peaking, these antibodies subsequently decline after 4-6 months of illness. The critical issue with these antibody tests is that they must be correlated with the timing of the patient's symptoms. On their own, they are meaningless.

Recent studies have suggested that the C6 ELISA assay, based on a peptide (C6) that reproduces the sequence of invariable region 6 of VlsE, the antigenic variation protein of Borrelia burgdorferi, may improve the sensitivity and standardization of immunoblots for the serologic diagnosis of Lyme disease (Marques et al, 2002; Bacon et al, 2003). In this regard, Wilske (2003) stated that it appears promising to use recombinant proteins (DbpA, VlsE, others) or synthetic peptides (the conserved C6 peptide derived from VlsE) as ELISA antigens for the diagnosis of Lyme disease. However, a recent randomized controlled study reported that C(6) antibody cannot be used to assess treatment outcome or the presence of active infection in patients with PLS (Fleming et al, 2004).

The diagnosis of Lyme neuroborreliosis must be validated with evidence of antibody production against Borrelia burgdorferi in the cerebrospinal fluid, shown by a higher titer of antibody in the cerebrospinal fluid than in the serum. The most helpful CSF test is intrathecal production of specific antibodies. This test is run on paired CSF and serum samples and distinguishes intrathecal antibody production from a positive CSF titer due to serum leakage. A ratio of cerebrospinal fluid to serum antibody of greater than 1.0 suggests local central nervous system antibody production and the presence of neuroborreliosis. With rare exceptions, a positive test documents CNS invasion by B. burgdorferi. Other CSF findings suggestive of Lyme disease include mild mononuclear pleocytosis and protein elevation. Studies that are normal or negative include the CSF glucose level, VDRL, and myelin basic protein. In North American Lyme patients, CSF oligoclonal bands and increased IgG index (very common findings in multiple sclerosis) are unusual. There are a number of experimental CSF tests that look promising (Borrelia-specific immune complexes, PCR, antigen detection), but they are available only at a few research centers and have not been validated.

According to evidence-based guidelines, polymerase chain reaction of B. burgdorferi DNA or RNA has not been validated for either the diagnosis of Lyme disease or monitoring response to therapy. PCR remains a research technique, in part because PCR can become easily contaminated, producing false-positive results. In addition, no large clinical series have been reported that assess the performance of the test in the non-research setting. American College of Physicians - American Society of Internal Medicine (ACP-ASIM) guidelines on diagnosis of Lyme disease (1997) state that PCR of serum or cerebrospinal fluid “need[s] further validation” and that “[p]ublished experience with these techniques [PCR] is insufficient to allow development of guidelines for their use.” The Centers for Disease Control and Prevention (2001) states that “PCR has not been standardized for routine diagnosis of Lyme Disease.” The National Institute of Arthritis and Infectious Disease (2001) has explained the reasons why PCR has limited utility in the diagnosis of Lyme disease: "To be sure, the polymerase chain reaction (PCR) is an extremely sensitive laboratory test that is capable of detecting very few molecules of bacterial DNA. However, the numbers of Borrelia likely to be present--if at all--in patients suspected of having Lyme disease are too small to generate sufficient amounts of bacterial DNA to be detected by this procedure."

Guidelines on treatment of Lyme disease from the Infectious Diseases Society of America (Wormser, et al., 2000) do not state any role for PCR in monitoring the treatment of patients with Lyme disease. The American Academy of Pediatrics Committee on Infectious Diseases (2003) stated: "New, more sensitive and more specific diagnostic tests, such as the polymerase chain reaction assay, which may be able to identify the presence of even small quantities of spirochetal DNA, are in development. However, physicians should be cautious when interpreting results of these investigational tests until their clinical usefulness has been proven."

Persistence of B. burgdorferi seroreactivity long after Lyme disease treatment and cure has led to excesses in therapy and attendant drug- and intravenous line-related morbidity, based on the mistaken assumption that persisting seropositivity equates with persisting infection. Laboratory tests should be employed as an adjunct in the diagnosis of Lyme disease, used only when specific symptoms suggest substantial likelihood that the disease is present. Testing as a screening tool should be discouraged.

An incorrect diagnosis of Lyme disease is often made, despite negative test results and the absence of findings suggesting Lyme disease, because the patient had symptoms compatible with Lyme disease. Some clinicians consider Lyme disease a diagnosis of exclusion, and associate any illness compatible with Lyme disease as Lyme disease. Because these patients are rarely, if ever, cured by antibiotics, this practice has contributed to an epidemic of anxiety about the chronicity of Lyme disease. The diagnosis is often supposedly confirmed by transient improvement after therapy. Oral therapy has been shown to elicit placebo responses in as many as 35% of patients undergoing oral antibiotic therapy, and rates for intravenous therapy might even be higher.

According to the American Academy of Pediatrics Committee on Infectious Diseases (2003): "The widespread practice of ordering serologic tests for patients with nonspecific symptoms such as fatigue or arthralgia who have a low probability of having Lyme disease is not recommended. Almost all positive serologic test results in these patients are false-positive results. Patients with acute Lyme disease almost always have objective signs of infection (e.g., erythema migrans, facial nerve palsy, arthritis). Nonspecific symptoms commonly accompany these specific signs but are almost never the only evidence of Lyme disease."

An incorrect diagnosis of Lyme disease can also be made even in the presence of a positive antibody test. Positive antibody tests are meaningless if not correlated with the duration of the patient's symptoms. In some instances, patients will be tested repeatedly for Lyme antibodies, until inevitably a false positive result will occur, which is then inappropriately interpreted as evidence of Lyme disease and used as justification for prolonged antibiotic therapy. The degree of clinical response associated with parenteral antibiotic treatment or decreasing serum titers do not correlate with antibiotic success and should not be used as a guide or reason for extended antibiotic administration. In general, symptoms that persist beyond a full course of parenteral antibiotic therapy generally are not due to continued infection and may actually indicate that the diagnosis is something other than Lyme disease.

An editorial summarizing the controversy surrounding the diagnosis and treatment of Lyme disease published in the New England Journal of Medicine  by the Ad Hoc International Lyme Disease Group (Feder, et al., 2007) systematically refuted the arguments behind the diagnosis and treatment of so-called chronic Lyme disease . The Ad Hoc Groupstated that "[c]hronic Lyme disease is the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections. Other examples that have now lost credibility are 'chronic candida syndrome' and 'chronic Epstein–Barr virus infection.' The assumption that chronic, subjective symptoms are caused by persistent infection with B. burgdorferi is not supported by carefully conducted laboratory studies or by controlled treatment trials. Chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatments for it is not warranted."

Whereas early Lyme disease, late Lyme disease, and post–Lyme disease symptoms/syndrome are recognized conditions, the term "chronic Lyme disease" has recently been popularized by a small number of practitioners (Feder, et al., 2007; Chang, 2007). Chronic, nonspecific symptoms (e.g., fatigue, headache, dizziness) are attributed to persistent or incurable B. burgdorferi infection, and patients are subsequently treated with long-term parenteral antibiotics.

Objective manifestations of Lyme disease include erythema migrans (the most common presentation of early Lyme disease), certain neurologic and cardiac manifestations, and pauciarticular arthritis (the most common presentation of late Lyme disease) (Chang, 2007; Feder, et al., 2007). These symptoms respond well to conventional antibiotic therapy. Symptoms of post–Lyme disease include fatigue, musculoskeletal pain, and difficulties with concentration or short-term memory following resolution of objective manifestations of infection. These symptoms are usually mild, typically resolve within months, and antibiotic therapy is not indicated; when the difficulties persist longer than 6 months, the condition is termed post–Lyme disease syndrome. Laboratory testing (usually acute- and convalescent-phase serologies) is a key component of Lyme disease diagnosis; in most cases, the testing allows clinicians to confirm evidence of current or past B. burgdorferi infection (Chang, 2007; Feder, et al., 2007).

By contrast, chronic Lyme disease is the term assigned to patients reporting chronic symptoms without objective clinical, laboratory, or epidemiologic criteria for infection (Chang, 2007; Feder, et al., 2007). They receive chronic parenteral antibiotic therapy for periods of many months to years, despite the absence of any scientific evidence to support this practice.

The Ad Hoc International Lyme Disease Group (Feder, et al., 2007) states that chronic antibiotic therapy for chronic Lyme disease has resulted in life-threatening anaphylaxis, cholecystectomy after biliary complications from ceftriaxone administration, a fatality due to candidemia from intravenous catheter infection, and other serious adverse events related to intravenous catheters.

The American Academy of Neurology (AAN)'s practice parameter on treatment of nervous system Lyme disease (Halperin et al, 2007) provided evidence-based recommendations on the treatment of nervous system Lyme disease and post-Lyme syndrome. Three questions were addressed: (i) which anti-microbial agents are effective? (ii) are different regimens preferred for different manifestations of nervous system Lyme disease? (iii) what duration of therapy is needed? These investigators analyzed published studies (1983 to 2003) using a structured review process to classify the evidence related to the questions posed. The panel reviewed 353 abstracts; yielding 112 potentially relevant articles that were reviewed, from which 37 articles were identified that were included in the analysis. The authors concluded that there are sufficient data to conclude that, in both adults and children, this nervous system infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommendation). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (Level B), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurological symptomatology, or failure to respond to oral regimens. The number of children (greater than or equal to 8 years of age) enrolled in rigorous studies of oral versus parenteral regimens has been smaller, making conclusions less statistically compelling. However, all available data indicate results are comparable to those observed in adults. In contrast, there is no compelling evidence that prolonged treatment with antibiotics has any beneficial effect in post-Lyme syndrome.

Roos (2007) provided the following comment on (AAN)'s practice parameter on treatment of nervous system Lyme disease (Halperin et al, 2007):"Misunderstanding of Lyme disease has created a demand by patients with pain, fatigue, and perceived cognitive trouble to seek prolonged parenteral treatment for Lyme disease and "post-Lyme syndrome." This study provides evidence-based recommendations for appropriate types and duration of antimicrobial therapy for neurologic Lyme disease. It also provides reassurance that the disease can be treated and highlights the lack of evidence that post-Lyme syndrome is due to active B. burgdorferi infection that would require prolonged antibiotic therapy."

Testing ticks for Borrelia burgdorferi has not been proven to be useful for deciding if a person should receive medical treatment following a tick bite.  The Centers for Disease Control and Prevention (CDC, 2005) stated that "In general, the identification and testing of individual ticks is not useful for deciding if a persons should get antibiotics following a tick bite".  The California Department of Health Services does not recommend that ticks be tested to determine if treatment is necessary because (i) testing methods vary in accuracy, (ii) the need for treatment should not be based on these test results, and (iii) tick testing results do not necessarily predict if the person bitten will get Lyme disease.  Even if an attached tick tested "negative", other undetected ticks may have attached to a person and transmitted the bacteria.  Additionally, the Rhode Island Department of Health stated that "The testing of ticks for the presence of the bacteria that causes Lyme disease has no role in the clinical diagnosis of Lyme disease".

Concurrent cat-scratch disease or babesiosis is not, in and of itself, justification for long-term antibiotic therapy for Lyme disease. Babesiosis, an infection by a protozoan parasite which in some ways resembling malaria, is most often treated with intravenous or oral clindamycin for seven days plus oral quinine, or oral atovaquone plus oral azithromycin (Gilbert, et al., 2003).

Bartonellosis (infections with Bartonella species) can create symptoms that mimic Lyme disease, and in some cases, co-infection can occur. Bartonella can create granulomatous (cat-scratch disease), bacteremic (Bartonella endocarditis, Oroya fever, and trench fever) or vasculoproliferative disease (bacillary angiomatosis-peliosis and verruga peruana). According to available guidelines, the diagnosis of both bacillary angiomatosis and cat-scratch disease rests on tissue examination (Warthin-Starry stains) and serologic tests (immunosorbant or ELISA assay). Bartonella bacteremia is diagnosed with serologic tests and confirmed by blood culture. Oroya fever may be diagnosed by examining a peripheral blood smear. According to available guidelines, most patients with cat-scratch disease do not require more than symptomatic support. A fluctuant or suppurative lymph node may benefit from needle aspiration. Antibiotic therapy should be reserved for immunocompromised individuals or those with evidence of severe or systemic disease. Available guidelines state that severe cat-scratch disease is usually treated with oral doxycycline plus rifampin or ciprofloxacin. Antibiotic therapy for cat-scratch disease should be continued for at least 14 days. The treatment of choice for bacillary angiomatosis-peliosis is either oral erythromycin or oral doxycycline. Oral azithromycin is an alternative. Available guidelines state that patients who are severely ill or unable to absorb oral medications should be treated with intravenous formulations. Rifampin should be added to the regimen for patients in the former category. Because disease relapse is otherwise so common in these immunocompromised hosts, patients should be treated for at least 3 months. Verruga lesions do not respond consistently to antimicrobial agents and sometimes require surgical resection. Bartonella bacteremia also warrants antimicrobial treatment, despite the fact that some immunocompetent hosts with B. quintana bacteremia will clear their infection spontaneously. The same drugs for treatment of bacillary angiomatosis-peliosis are recommended for primary bacteremias. All patients should be evaluated for endocarditis. According to available guidelines, oral therapy is usually sufficient for uncomplicated Bartonella bacteremia. Exceptions may include immunocompromised patients, bony or parenchymal involvement, and endocarditis, for which initial parenteral therapy may be advantageous. Treatment should be administered for at least 6 weeks and for 2 to 4 weeks in patients with and without endocarditis, respectively. Rifampin should be added to the regimen for treatment of endocarditis. Available guidelines state that patients with trench fever usually respond rapidly to oral antibiotic therapy with resolution of fever and other symptoms within 1 to 2 days. Relapses in treated patients have been well described. In patients with Oroya fever, available guidelines state that that penicillin, chloramphenicol, tetracycline, and streptomycin are effective. According to these guidelines, oral chloramphenicol for 7 or more days is the therapy of choice because of the frequent association of Salmonella infection in endemic regions. After the institution of therapy, fever generally disappears within 2 to 3 days, although blood smears may remain positive for some time.

Q fever is caused by Coxiella burnetii (C.b.), an intracellular parasitic gram-negative bacterium. The most common hosts are goats, cattle, sheep, cats, and occasionally dogs. This spore-forming microorganism reaches high concentrations in the placenta of infected animals; with aerosolization occurring during parturition. Human Q fever usually results from inhalation of contaminated aerosol. There are 3 distinct clinical syndromes of the acute form of Q fever: (i) non-specific febrile illness, (ii) pneumonia, and (iii) hepatitis. The chronic form of the disease is usually endocarditis, but occasionally it is manifest as hepatitis, osteomyelitis or endovascular infection. The pneumonic form of the disease can range from very mild to severe pneumonia requiring assisted ventilation. Diagnosis of Q fever is based on isolation of the agent in cell culture, its direct detection, namely by PCR, and serology. Detection of high phase II antibodies titers 1 to 3 weeks after the onset of symptoms and identification of IgM antibodies are indicative to acute infection. High phase I IgG antibody titers of greater than or equal to 1:800 as revealed by micro-immunofluorescence offer evidence of chronic C.b. infection. For acute Q fever, a 2-week treatment with doxycycline is recommended as the first-line therapy. In the case of Q fever endocarditis a long-term combined antibiotic therapy (e.g., doxycycline plus quinolones, or doxycycline plus hydroxychloroquine) is necessary to prevent relapses (Maurin and Raoult, 1999; Kovacova and Kazar, 2002; Marrie, 2003). There is a lack of evidence regarding the use of intravenous antibiotic therapy for patients with Q fever. A recent review (Parker et al, 2006) did not address the use of intravenous antibiotic therapy for the treatment of Q fever.