Ehrlichia and Anaplasma species (Ehrlichiosis)
Authors: Johan S. Bakken M.D., F.A.C.P., J. Stephen Dumler M.D.
Ehrlichioses and anaplasmosis are tick-borne zoonoses caused by rickettsia-like bacteria, and characteristic infectious syndromes have been recognized in mammals as well as humans (16,38, 101, 125). Patients typically present with acute onset fever and nonspecific symptoms following tick exposure or tick-bite. The diagnosis requires a high index of suspicion and is frequently made retrospectively.
Microbiology
Members of the genera Ehrlichia and Anaplasma belong to the family Anaplasmataceaethat also includes two other genera, Neorickettsia and Wolbachia (31, 49, 141, 147). Ehrlichiaand Anaplasma species are obligate intracellular, Gram-negative cocco-bacilli that exert tropism predominantly for mammalian mononuclear and polymorphonuclear leukocytes (10, 15, 47, 55,113). Ehrlichia chaffeensis and Anaplasma phagocytophilum, but not Ehrlichia ewingii, can be cultured in vitro by employing specific mammalian cell lines.
Epidemiology
All Ehrlichia and Anaplasma species cause veterinary infections, and require an arthropod host (hard-shelled tick) for parts of their life cycles (106). Three Anaplasmataceae species are currently known to cause human disease (48,55,113,144) and two of these cause human infections in the United States. Ehrlichia chaffeensis causes human monocytotropic ehrlichiosis (HME) (65,114), whereas Anaplasma phagocytophilum causes human granulocytotropic anaplasmosis (HGA) (9, 15, 16, 49). Both illnesses have been primarily described in the United States; HGA occurs globally, and HME could also have a worldwide distribution (148). E. ewingiiis reported to infect granulocytes in a limited number of patients, most of who were infected with HIV or were treated with immunosuppressive medication (38). E. ewingii causes a clinical syndrome indistinguishable from HME or HGA. Ehrlichiosis and anaplasmosis most often result from tick-bites (10, 30, 47, 113). However, accidental or occupational exposure to infected blood from infected animals (20) or through direct transfusion of or contact with infected human blood-products have been described as potential sources of infection (9, 28, 43, 88, 96, 152). Recently Pritt and coworkers described 3 patients from the Upper Midwest who presented with nonspecific febrile illness following tickbite. Laboratory workup indicated that all three patients were infected with a novel Ehrlichia agent genetically similar to Ehrlichia muris. Amplification and sequence analysis indicated that each was infected with an Ehrlichia species genetically similar toEhrlichia muris (121).
A fourth species Neorickettsia (Ehrlichia) sennetsu causes Sennetsu fever, a mononucleosis-like illness, which occurs in patients from the Far East, Malaysia, and most recently in Laos, who ingested infected fish (31, 111, 144). Wolbachia species that are endosymbionts of nematodes have been implicated as pathogenetically important components that drive inflammation in human filariasis (137).
Clinical Manifestations
HME and HGA cause similar symptoms and cannot be reliably distinguished on clinical grounds (15, 46, 48, 113). A provisional diagnosis may be made by the recognition of characteristic clinical signs and symptoms (55, 142). High fever and shaking chills accompanied by severe headache and generalized myalgias usually begin 1-2 weeks after tick exposure or a tick bite (11, 15, 16, 47, 55, 61, 68, 141, 144). The physical examination is typically non-revealing, although a nonspecific rash has occasionally been described for patients who present with HME (55, 59, 67, 144). The clinical severity of human ehrlichiosis and anaplasmosis ranges from mild to severe infection with occasional fatal outcome, reported fatality rates have ranged from 1.3-5.0% in published case series (15, 46, 48, 60, 66, 113, 114, 144). Impairment of the cellular immune system, whether from immunosuppressive therapy or underlying disease, predisposes to more severe disease, increases death-rates and delays recovery from HME (49, 98, 115, 116, 128,136) as well as HGA (13,135, 140).
Laboratory Diagnosis
Associated but nonspecific laboratory changes often include leukopenia, thrombocytopenia, mild elevation of serum hepatic transaminase activities, and elevated C-reactive protein (CRP) values (9,14,15,19, 60, 61, 66, 112, 113, 114, 151).
The diagnosis should be suspected in patients who are found to have characteristic intra-cytoplasmic inclusions (morulae) in peripheral blood leukocytes. However, the sensitivity of blood-smear evaluation is low and specific laboratory tests are usually required to confirm the diagnosis. These tests include indirect fluorescent antibody (IFA) seroconversion or seroreversion in convalescence, PCR amplification of species-specific DNA in acute phase blood, in vitrocultivation of the bacteria in cell culture, or a combination of these tests (3,9, 15, 18, 19, 46,60, 61, 66, 74, 112, 113, 114, 142, 143, 151). It is important to recognize that many infected patients may present with non-specific fever, and absence of diagnostic laboratory clues such as morulae in peripheral blood leukocytes does not rule out the diagnosis (3, 12, 15, 46, 66, 113,143, 144). Patients suspected of having HME should be started on empiric treatment with an appropriate antibiotic agent as soon as possible, since the prognosis is inversely related to duration of symptoms before antibiotic therapy is instituted (33, 53, 60, 66, 77, 113, 114, 142,143). The same recommendation applies to patients with suspected HGA and ehrlichiosis caused by E. ewingii, but published experience is limited and not as clear-cut as with HME (9, 10, 15,142, 143).
Pathogenesis
Pathologic studies of tissues from patients with HME (48, 50) and HGA (97) show widespread perivascular lympho-histiocytic infiltrates without vasculitis, and leukopenia and thrombocytopenia most likely occur as a consequence of peripheral sequestration, consumption or direct destruction. Elevated concentrations of IFN-γ and interleukin-10 are present in patients infected with A. phagocytophilum, and alterations in cytokine responses could play important roles in the clinical manifestations of or recovery from human granulocytic ehrlichiosis (54, 90,91, 122).
SUSCEPTIBILITY TESTING IN VITRO AND IN VIVO
All clinically relevant Ehrlichia and Anaplasma species appear to be susceptible to tetracycline drugs and their derivatives (31, 32, 33, 82, 92, 104. 105, 126, 142). Ehrlichia andAnaplasma species are obligate intracellular pathogens and in vitro susceptibility testing of these agents must utilize biologic assays, although there is no current role for susceptibility testing in the clinical management of patients. E. chaffeensis and A. phagocytophilum grow relatively slowly in vitro and at variable rates (3, 40, 74, 81), and methods for susceptibility testing have not been standardized. Thus, published in vitro results may not be directly comparable. No data exist from controlled clinical trials comparing the effect of specific antibiotic drugs for the treatment of HME or HGA. Most treatment recommendations have therefore been based on in vivosusceptibility testing in animal models, as well as experiences with empiric antibiotic therapy and treatment outcome data in humans.
In Vitro Testing
Only a handful of studies have been published on the in vitro susceptibility of Ehrlichia-species to antibiotic drugs. Rikihisa and Jiang (126) tested a single strain of the equine pathogenNeorickettsia risticii cultured in murine P388D1 macrophage cells and showed that demeclocycline and doxycycline were very active (MIC50 < 0.01 µg/ml). Rifampin and tetracycline were less active (MIC50 0.45-0.9 µg/ml and 1-10 µg/ml, respectively). Erythromycin and nalidixic acid were ineffective in eliminating the bacteria in macrophages, and chloramphenicol was not tested.
Brouqui and Raoult tested a single N. sennetsu isolate (Miyayama strain) using the P388D1 cell line, and noted MIC values of 0.125 µg/ml for doxycycline and ciprofloxacin, and 0.5 µg/ml for rifampin, respectively (32). In a separate experiment, a single strain of E. chaffeensis was grown in a DH82 canine malignant histiocytic cell line (33). Both doxycycline and rifampin were rapidly bactericidal, and MBC values in the extracellular culture medium were less than 0.5 and 0.125 µg/ml, respectively. Penicillin, chloramphenicol, ciprofloxacin, erythromycin, co-trimoxazole, and gentamicin were inactive against E. chaffeensis with MIC values ranging from 4-40 µg/ml. Brouqui and Raoult later tested the canine pathogen E. canis, propagated in the DH82 cell line. Both tetracycline and doxycycline effectively eliminated ehrlichiae from the cytoplasm of infected cells (31). Penicillin, erythromycin, chloramphenicol, gentamicin, and co-trimoxazole were all ineffective.
Klein et al. determined the antibiotic susceptibility for three A. phagocytophilum strains using the continuous HL-60 human promyelocytic cell line for bacterial propagation (92). Doxycycline and rifampin both demonstrated significant activity (MIC values of 0.25 and 0.5 µg/ml, respectively). Trovafloxacin was also very active (MIC, <0.125 µg/ml). Ciprofloxacin and chloramphenicol exerted bacteriostatic effect at 2 and 8 µg/ml, respectively, but neither drug was bactericidal at clinically achievable serum levels. A. phagocytophilum was resistant to co-trimoxazole, clindamycin, erythromycin, azithromycin, and beta-lactam drugs.
More recently, Horowitz et al. tested six A. phagocytophilum isolates from New York State (82). All of the isolates were susceptible to doxycycline (MIC and MBC, < 0.125 µg/ml), rifampin (MIC and MBC, < 0.125 µg/ml), ofloxacin (MIC and MBC, < 2.0 µg/ml), levofloxacin (MIC and MBC, < 1.0 µg/ml), and trovafloxacin (MIC and MBC, < 0.032 µg/ml). Their findings were confirmed by Maurin et al. who examined eight separate A. phagocytophilum strains collected from various regions of the United States (105). Doxycycline and rifampin were both highly active, each with MIC values of <0.03 µg/ml, respectively. Levofloxacin was somewhat less active and MIC values ranged from 0.06 to 0.5 µg/ml. Neither erythromycin nor azithromycin demonstrated clinical activity (MIC > 16 µg/ml for each drug, respectively).
Ehrlichia ewingii has not yet been grown successfully in vitro, thus there have been no published antibiotic susceptibility studies involving this species.
In summary, doxycycline, tetracycline derivatives, and rifampin are highly active drugs against E. risticii, E. canis, N. sennetsu, E. chaffeensis, and A. phagocytophilum judged by in vitro susceptibility studies (Table 1). Chloramphenicol, somewhat surprisingly, appears to have no demonstrable in vitro activity against these organisms despite excellent in vivo activity against closely related rickettsial agents (3, 143, 144). Ciprofloxacin is inactive against E. chaffeensis, but is somewhat active against A. phagocytophilum, albeit at concentrations that may be difficult to achieve in serum or infected leukocytes. Trovafloxacin is no longer licensed for use in the USA, and it is currently unknown whether other recently marketed fluoroquinolone drugs have any useful activity against clinically important Ehrlichia or Anaplasma species. Members of the Ehrlichiagenus, including E. chaffeensis and E. canis, are naturally resistant to fluoroquinolone drugs, and Maurin et al. has shown that the genetic basis for the resistance relates to the substitution of serine with an alanine residue at positions 77 and 79 in the fluoroquinolone-resistance determining region of DNA gyrase (GyrA) (104). Similar changes were not detected in GyrA for A. phagocytophilum, N. sennetsu and Neorickettsia risticii which may explain why ciprofloxacin and trovafloxacin were active in vitro against these organisms (104, 105).
In Vivo Testing
Kobayashi et al. tested the efficacy of various antibiotics against N. sennetsu in a mouse model, and found that chlortetracycline and tetracycline were highly effective (93). Erythromycin, penicillin and chloramphenicol were not effective, even at very high serum concentrations. Tetracycline and various tetracycline derivatives have been used successfully to treat canine ehrlichiosis, but penicillin, sulfonamides and chloramphenicol have all been ineffective (35). Delayed institution of tetracycline therapy resulted in chronic E. canis infections in both mice and dogs ( 78, 86). Chronic ehrlichiosis has not been recognized in humans with the single exception of a 68-year old man who developed persistent E. chaffeensis infection despite prolonged tetracycline therapy (53). There was no information to suggest that the patient was immunocompromised prior to the ehrlichia infection. Prospective clinical trials of antibiotic treatment for human ehrlichioses or anaplasmosis have been not been published to date.
ANTIMICROBIAL THERAPY
Sennetsu Fever
Sennetsu fever is a self-limited illness that is not known to occur in the United States. The illness often resolves without antibiotic therapy, and the prognosis is excellent. Fatal outcomes have never been described (32, 106, 143, 144). Tetracycline hydrochloride or doxycycline hyclate are both highly effective and when prescribed should be administered for at least 7 days (143, 144).
Human Monocytic Ehrlichiosis
Most published literature to date recommend tetracycline drugs and their derivatives as the preferred agents for treatment (8, 29, 43, 60, 61, 66, 101, 113, 114, 127, 130, 143, 144, 150). HME is a moderately severe illness that frequently resolves even without antibiotic therapy after a variable time-course, which can last from a few days to several weeks. However, some patients, especially those who are actively immunosuppressed, developed a severe illness or died from fulminant ehrlichiosis. Several patients died from opportunistic infections that could have developed as a consequence of ehrlichia-associated immunosuppression (23, 102, 115, 116). It is generally accepted that all patients with suspected or confirmed ehrlichiosis should be treated, since it may be very difficult to identify and distinguish those patients who will have a mild self-limited illness from patients who go on to develop severe or even fatal illness (113, 114, 143,144). Furthermore, delayed treatment is associated with more severe illness (66, 119).
Doxycycline is used in preference to tetracycline in most cases because of superior pharmacokinetic properties and lesser frequency of adverse gastrointestinal reactions (7, 10, 70). Tetracycline hydrochloride or doxycycline hyclate should be administered orally or by intravenous route and continued for at least three days after fever has abated (3, 8, 29, 58, 62, 64, 66, 80,117, 118, 127, 130, 143, 144, 146, 148). Other authors have advocated that tetracycline should be administered for 7-14 days (47, 61). Both doxycycline and other tetracycline derivatives exert their effect rapidly, and most patients resolve fever and feel markedly improved within 24 to 48 hours after beginning treatment (27, 47, 58, 60, 61, 66, 76, 113, 114). In fact, failure to improve within 48 hours after initiation of tetracycline or doxycycline therapy for presumed human monocytotropic ehrlichiosis should raise questions of whether the diagnosis is correct.
At least 170 patients have been treated successfully with doxycycline or tetracycline for HME since 1987 (60, 61, 63, 66, 69, 79, 124, 129, 133). Fishbein reported a case series of 237 patients who had HME and found that those patients who were treated with either a tetracycline drug or chloramphenicol had significantly shorter intervals of fever and days to complete recovery than patients who were treated with other antibiotics (66). Only a few individuals, many of whom were children, were treated with chloramphenicol. In the latter group chloramphenicol was associated with a significantly longer interval to defervescence of fever as compared to those treated with tetracycline alone (66). Abramson and Givner advocate the use of tetracycline for the treatment of presumed Rocky Mountain spotted fever regardless of age (1), and similar arguments are voiced for treatment of patients who have HME (58, 148). The American Academy of Pediatrics has recommended doxycycline as the first line of therapy for all forms of ehrlichiosis as well as the clinically similar infection Rocky Mountain spotted fever (5).
Clinical relapse of canine tropical pancytopenia after completed therapy is well described in dogs when tetracycline therapy has been instituted late in the course of infection (36, 125). Although post-treatment relapse has not been described in human patients to date, four patients with documented HME died either while receiving doxycycline therapy or some time after the completion of therapy (53, 60, 66). In each of the fatal cases, tetracycline therapy was started late (day 9 or later), and two of the patients died more than 50 days after doxycycline or tetracycline therapy had ended. One of these patients had immunohistologic evidence of E. chaffeensis in tissue at autopsy (53). There was insufficient information reported about the other two patients to determine whether they died while receiving tetracycline therapy (60, 66). Thus, although a tetracycline derivative or doxycycline should be considered the drugs of choice for acute HME, the prognosis can worsen proportionally with delayed initiation of therapy. Dual infections by Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, and E. chaffeensis are occasionally reported among patients from the southeastern United States; these patients have been treated successfully with doxycycline (132). Chloramphenicol is active againstRickettsia species, including R. rickettsii. Chloramphenicol has been advocated as an alternative agent for treatment of HME and rickettsial infections for patients who are either intolerant or have contraindications to tetracycline therapy (24, 26, 42, 44, 61, 63, 66, 73, 76). Forty-one of 47 reported patients (87.2%) were treated with chloramphenicol for HME since 1987 (25, 26, 42,44, 53, 61, 63, 66, 74, 76, 123). Resolution of fever and clinical symptoms occurred within two days after therapy had begun in the majority of the responders, but some patients had fever for more than seven days. Six patients (12.8%) failed to improve with chloramphenicol therapy, and 3 of these patients died (53, 60, 66). HME usually resolves spontaneously after 1 to several weeks of clinical symptoms, even in the absence of specific antibiotic treatment (66, 112, 114). Furthermore, both E. chaffeensis and E. canis are resistant to chloramphenicol in vitro (31, 33,34). Thus, the efficacy of chloramphenicol and the role this drug should play in the treatment of HME remains undefined. Patients who are treated with chloramphenicol and fail to respond promptly to treatment should be treated with doxycycline hyclate or tetracycline hydrochloride for definitive treatment.
Tetracyclines are deposited into developing teeth and bone during the early stages of calcification. Administration of these drugs is therefore relatively contraindicated for children and pregnant women (7, 70). Doxycycline binds less to calcium than other tetracyclines; thus, the potential for adverse effects is lower than the other tetracycline drugs. Since ehrlichiosis may be fatal in untreated patients, doxycycline is recommended for treatment of children (6, 7, 51, 58,70, 76, 77, 87, 131, 141, 145) and pregnant women (134). Doxycycline hyclate should be administered for as short a period of time as possible, perhaps no longer than 3 days after fever has resolved, to minimize the risk of adverse effects (6, 58, 141, 145).
There are no published reports that describe the outcome of rifampin treatment for HME, but E. chaffeensis appears to be highly susceptible to this drug in vitro (31). Thus, rifampin may be a suitable alternative drug for treatment of children under the age of 8 years, pregnant women, and patients who are allergic to tetracycline or doxycycline.
The use of adjunctive corticosteroid therapy to minimize inflammatory manifestations in HME has not been tested objectively in any clinical evaluations. However, at least several complications of E. chaffeensis have responded favorably when corticosteroids have been added to appropriate antibiotic treatment, including in patients with severe meningoencephalitis and ARDS (56, 118). In contrast, high dose corticosteroid therapy has been implicated as a risk factor for fulminant infection (103).
Human Granulocytic Anaplasmosis
Most published recommendations for therapy of human granulocytic anaplasmosis are based on the treatment response to doxycycline hyclate (2, 4, 16, 17, 19, 31, 71, 74, 75, 85, 89,95, 99, 108, 109, 120, 138, 149). Bakken described several patients with acute HGA who failed to respond to cefazolin, cefotaxime, gentamicin, or erythromycin; all patients rapidly resolved their infection after doxycycline hyclate therapy was initiated (16). Thirty-four of 41 patients diagnosed with HGA at the Duluth Clinic, Duluth, MN were treated with doxycycline hyclate for an average of 13 days (11). One of these patients was severely immunocompromised from previous splenectomy and ongoing prednisone therapy for chronic lymphocytic leukemia. He started doxycycline hyclate treatment on day 14 of the acute illness, but died of fungal pneumonia 5 days after doxycycline therapy had begun. Hardalo described a patient who died a week after completing doxycycline hyclate therapy (75). Autopsy examination of both these patients failed to demonstrate any evidence of A. phagocytophilum in blood or tissues.
There is limited experience with use of doxycycline in children (3, 79, 57, 83, 94, 110,130) and during pregnancy (83) for the treatment of HGA. Doxycycline was used successfully to treat a 5-year old boy who had simultaneous infection with Borrelia burgdorferi and HGA (110). Horowitz et al. reported a 39-week pregnant woman who became symptomatic with HGA during parturition (83). She delivered a healthy infant and recovered uneventfully with doxycycline therapy which was started 5 days after parturition. She was well eight months later. Her infant was diagnosed with HGA on the sixth day of life and the authors speculated that the infection occurred via transplacental transmission. The infection resolved promptly with doxycycline and the baby recovered uneventfully after five days of intravenous doxycycline therapy. Recently a 38-year old female was diagnosed with HGA 10 days after she had delivered a healthy baby (39). While breastfeeding she was treated with doxycycline for two weeks, and both mother and baby were well at later follow-up examination.
Goodman et al. used chloramphenicol to treat a 64-year-old man who had acute HGA (74). The patient had previously developed laryngeal edema after tetracycline therapy. Fever resolved and abnormal laboratory values promptly returned to baseline following chloramphenicol administration. Chloramphenicol is inactive against A. phagocytophilum in vitro (22, 82, 92,105). Furthermore, chloramphenicol is ineffective for treatment of horses infected with A. phagocytophilum (100). The efficacy of chloramphenicol for treatment of HGA must therefore be questioned.
Rifampin appears to be very active against A. phagocytophilum in vitro, but the published clinical experience with rifampin is limited. Recently rifampin was used successfully to treat two women who developed HGA during the third trimester of pregnancy (37). Both patients recovered clinically, completed 7 days of rifampin therapy, and delivered healthy babies at term. There was no evidence of infection in the infants at subsequent follow-up examinations. Krause et al. recently described two young children with HGA who were successfully treated with rifampin (94). There is no published experience about the use of clarithromycin, azithromycin, ciprofloxacin, or recently released fluoroquinolones for treatment of HGA.
In summary, in vitro studies and clinical experience confirms that doxycycline hyclate should be considered the treatment of choice for patients who have human granulocytotropic anaplasmosis (3, 4, 9, 10, 84, 92, 105, 143, 144). The American Academy of Pediatrics continues to recommend doxycycline as the preferred antibiotic choice for treatment of HGA and other human ehrlichioses (5). Tetracycline hydrochloride should also work well but clinical data to substantiate this recommendation for humans is limited. Patients with HGA can be coinfected with B. burgdorferi (10, 15, 43, 45, 48, 52, 108, 139); under these circumstances the recommended length of therapy is 10 to 14 days to provide adequate coverage for Lyme borreliosis (10, 16, 19, 46, 48, 110).
In the absence of clinical experience with alternative drugs that are active in vitro, it is difficult to provide definitive treatment recommendations at this time for children younger than 8 years of age, pregnant women, and individuals known to be hypersensitive to tetracycline drugs (5, 10, 15, 19, 58). Rifampin has demonstrated excellent in vitro activity against A. phagocytophilum and probably represents an effective and safe alternative treatment choice, but clinical experience is limited. Newer fluoroquinolones may hold promise as alternative agents for treating HGA; however, fluoroquinolones are currently not recommended for use in children and pregnant women, and there is no published information about their clinical efficacy in the literature. The questionable in vitro activity of chloramphenicol against A. phagocytophilum as well as many veterinary ehrlichiae, and several reports of failure when used for the treatment of patients with HME make it difficult to recommend chloramphenicol for treatment of HGA.
No clinical information exists on the utility of adjunctive corticosteroid therapy for suppression of inflammatory manifestations of HGA.
ENDPOINTS FOR MONITORING THERAPY
Human ehrlichioses and anaplasmosis are, for the most part, self-limited illnesses that resolve even without specific antimicrobial therapy. Doxycycline leads to rapid defervescence of fever and marked improvement of clinical symptoms 24 to 48 hours after initiation of therapy (4,16, 19, 38, 43, 60, 66, 74, 113, 114). Nonspecific laboratory abnormalities usual returned to the normal range within 7 days. Seroconversion evidenced by a > 4-fold change in the concentration of specific serum antibodies is typically observed after 14 to 28 days for most patients. Persistently elevated antibody titers should be interpreted as evidence of past infection rather than as proof of ongoing or unresolved infectious process (3, 15, 18, 46, 48, 143).
VACCINES
There are currently no experimental or commercially available vaccines for prevention of human or veterinary ehrlichiosis or anaplasmosis.
PREVENTION
Avoidance of tick-bites is the key to prevention. Daily inspections of skin areas and immediate removal of attached ticks probably reduces the risk of transfer of bacteria from the tick to the mammal host (41). Additional preventive measures include the use of long-legged, light-colored pants tucked inside the socks, 30% N,N-diethyl-m-toluamide (DEET) skin spray and permethrin clothing spray (15, 46, 48, 66, 143, 148).
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Tables
Table 1. In vitro Susceptibility and Clinical Efficacy of Selected Antibiotic Drugs Used for the Treatment of Ehrlichial Infections. Susceptible Breakpoint Values have not been Established for Ehrlichiae and Anaplasmae.
| Ehrlichial species | Mammal host | Antibiotic drug | MIC (µg/ml) | In vitro susceptibility | Clinical efficacy | Clinical failure | Key References* |
|---|---|---|---|---|---|---|---|
| E. canis | Canids | DOXY | 2 | Yes | Yes | Yes† | Buhles 1974 Brouqui 1993* Iqbal 1994 |
| CHLOR | > 4 | No | No | Yes | |||
| N. risticii | Equines | DOXY | 0.03 | Yes | No¶ | Unknown¶ | Rikihisa 1989* |
| TCN | 0.03 | Yes | Yes | No | |||
| CHLOR | ND | No | Unknown | Unknown | |||
| RIF | 0.45* | Yes | Unknown | Unknown | |||
| N. sennetsu | Humans | DOXY | 0.25 | Yes | Yes | No | Brouqui 1990* McDade 1990 Fine 1994 |
| CHLOR | >4 | No | No | Unknown | |||
| RIF | 0.5 | Yes | Unknown | Unknown | |||
| E. chaffeensis | Humans | DOXY | <0.5 | Yes | Yes | Yes | Maeda 1987 Eng 1990 Brouqui 1992* Fishbein 1994 Dumler 1995 |
| CHLOR | >16 | No | Possible | Yes | |||
| RIF | 0.125 | Yes | Unknown | Unknown | |||
| A. phagocytophila | Humans Canids Ungulates | DOXY | 0.25 | Yes | Yes | No | Dumler 1995 Wormser 1995 Bakken 1996 Goodman 1996 Greig 1996 Horowitz 1998* Klein 1997* Maurin 2002* |
| CHLOR | 8 | No | Possible | Unknown | |||
| RIF | <0.125-0.5 | Yes | Yes | Unknown |
ND not done, DOXY doxycycline, CHLOR chloramphenicol, RIF rifampin, TCN tetracycline or oxytetracycline
MIC minimum inhibitory concentration
* Published in vitro antibiotic susceptibility test results
† Late therapy has resulted in chronic infections
¶ Doxycycline is toxic to horses in therapeutic concentrations
Table 2. Antibiotic Recommendations
1. Doxycycline hyclate: Effective
Adults: 100 mg orally or intravenously at 12 hour intervals.
Children: 4.4 mg/kg/day orally or intravenously in two divided doses.
Duration of therapy HME: 7-10 days, or at least 3 days after fever has abated.
Duration of therapy HGE: 14 days.
Duration of therapy Sennetsu fever: 7-10 days.
Duration of therapy E. ewingii infection. 7-10 days, or at least 3 days after fever has abated.
2. Tetracycline hydrochloride: Effective
Adults: 500 mg orally in four divided doses.
Children: 25-50 mg/kg/day orally in two to four divided doses, or
0.6-1.2 g/m2/day in two to four divided doses.
Duration of therapy: As for doxycycline hyclate.
3. Rifampin: Probably effective
Adults: 300 mg orally twice daily.
Children: 10 mg/kg/day orally twice daily.
Maximum individual dose 300 mg each.
Duration of therapy: Unknown (7-10 days?)
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