Pathogenicity and treatment of Bartonella infections.

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Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

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Review

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Pathogenicity and treatment of Bartonella infections

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Emmanouil Angelakis, Didier Raoult ∗ URMITE UMR 6236, CNRS-IRD, Faculté de Médecine et de Pharmacie, 27 Bd. Jean Moulin, 13385 Marseille cedex 05, France

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a r t i c l e

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a b s t r a c t

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Article history: Received 20 March 2014 Accepted 30 April 2014

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Keywords: Bartonella spp. Treatment Pathogenicity

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Introduction

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Bartonella spp. are responsible for emerging and re-emerging diseases around the world. The majority of human infections are caused by Bartonella henselae, Bartonella quintana and Bartonella bacilliformis, although other Bartonella spp. have also been associated with clinical manifestations in humans. The severity of Bartonella infection correlates with the patient’s immune status. Clinical manifestations can range from benign and self-limited to severe and life-threatening disease. Clinical conditions associated with Bartonella spp. include local lymphadenopathy, bacteraemia, endocarditis, and tissue colonisation resulting in bacillary angiomatosis and peliosis hepatis. Without treatment, Bartonella infection can cause high mortality. To date, no single treatment is effective for all Bartonella-associated diseases. In the absence of systematic reviews, treatment decisions for Bartonella infections are based on case reports that test a limited number of patients. Antibiotics do not significantly affect the cure rate in patients with Bartonella lymphadenopathy. Patients with Bartonella spp. bacteraemia should be treated with gentamicin and doxycycline, but chloramphenicol has been proposed for the treatment of B. bacilliformis bacteraemia. Gentamicin in combination with doxycycline is considered the best treatment regimen for endocarditis, and erythromycin is the first-line antibiotic therapy for the treatment of angioproliferative lesions. Rifampicin or streptomycin can be used to treat verruga peruana. In this review, we present recent data and recommendations related to the treatment of Bartonella infections based on the pathogenicity of Bartonella spp. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Bartonella spp. are intracellular bacteria that cause prolonged intraerythrocytic bacteraemia in their hosts and are typically transmitted by haematophagous insects such as phlebotomine sandflies, human body lice and cat fleas, or via animal scratches and bites [1]. To date, more than 30 Bartonella spp. and several Candidatus spp. have been isolated from humans as well as from wild and domestic animals around the world (Table 1) [2,3]. The suspected role of ticks in the transmission of Bartonella spp. is supported by direct and indirect evidence [4–6]. A wide range of mammals serve as reservoirs for Bartonella spp., but humans are the only known reservoir for Bartonella bacilliformis and Bartonella quintana [1]. Bartonella henselae, B. quintana and B. bacilliformis are responsible for the majority of infections in humans [1,7]. The ability to cause acute or chronic infections and vascular proliferative or suppurative manifestations is a remarkable feature of Bartonella spp. The severity of clinical manifestations correlates with the patient’s

∗ Corresponding author. Tel.: +33 4 91 38 55 17; fax: +33 4 91 83 03 90. E-mail address: [email protected] (D. Raoult).

immune status. As a result, Bartonella spp. can persist in the blood of their hosts resulting in intraerythrocytic parasitism [1], and they are responsible for a number of diseases including Carrion’s disease, cat-scratch disease (CSD), chronic lymphadenopathy, trench fever, chronic bacteraemia, endocarditis, bacillary angiomatosis, peliosis hepatis and neurological disorders [1]. Without treatment, Bartonella infections are associated with high mortality and the potential for relapse due to the existence of an intraerythrocytic phase that may provide a protective niche for the bacteria [7]. Owing to the variety of known clinical manifestations and localisations of Bartonella spp., no single treatment exists for all Bartonella-associated diseases. As a result, treatment approaches must be adapted to each species and clinical situation (Fig. 1) [1,7]. Moreover, clinical studies that include a standard case definition, culture confirmation, rigidly defined disease outcomes, and patients with similar host defences are limited. Clinical data related to the treatment of Bartonella infections are primarily based on case reports that test a limited number of patients. As a consequence, current recommendations for the treatment of Bartonella infections are based primarily on the clinical course and the immunological status of the patient and rely less on the infective species. The objective of this review is to present recent

http://dx.doi.org/10.1016/j.ijantimicag.2014.04.006 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Please cite this article in press as: Angelakis E, Raoult D. Pathogenicity and treatment of Bartonella infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.04.006

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Table 1 Bartonella spp. reported to date: epidemiological and clinical data. Bartonella spp.

First cultivation

Rabbit

Endocarditis, lymphadenopathy Not described

1909

Human/sandfly Rat Cow Ruminant

Oroya fever and verruga peruana Not described Not described Not described

Wild rabbit (Oryctolagus cuniculus) Gray kangaroo (Macropus giganteus) Human

Alsace, France

1999

Queensland, Australia

2007

Bodensee, Germany Bissy, France Chizé, France

2000 2002 2002

Loire-Atlantique and Nord, France

2004

B. henselae

Mouse (Apodemus spp.) Cow Roe deer (Capreolus capreolus) Domestic cattle (Bos taurus) Cat Mottle-tailed rat (Rattus leucopus) Woodland mammal (Microtus agrestis) Endocarditis patient Woodland mammal (Clethrionomys glareolus) Cat

B. koehlerae

Domestic cat

B. peromysci B. phoceensis B. queenslandensis

Mouse (Peromyscus spp.) Wild rat (Rattus norvegicus) Grassland melomys (Melomys spp.) Human

B. bacilliformis B. birtlesii B. bovis (B. weissii) B. capreoli B. chomelii B. clarridgeiae B. coopersplainsensis B. doshiae B. elizabethae B. grahamii

B. quintana

B. rattimassiliensis B. rattiaustraliensis B. rochalimae B. schoenbuchensis B. talpae B. tamiae B. taylorii B. tribocorum B. vinsonii subsp. arupensis B. vinsonii subsp. berkhoffii B. vinsonii subsp. vinsonii B. washoensis B. weissii Candidatus spp. B. mayotimonensis B. melophagi B. ancashi B. merieuxii B. antechini B. thailandensis

Not described

1996 2008

Cat/cat flea

Queensland, Australia

Lymphadenitis Not described

UK

1995

Rat

Not described

USA UK

1993 1995

Rat Rat, insectivore

Endocarditis, neuroretinitis Neuroretinitis

1990

Cat/cat flea

California, USA

1999

Cat

1995 2004 2008

Mice

Marseille, France Queensland, Australia

Lymphadenitis, endocarditis, bacillary angiomatosis, bacillary peliosis, Parinaud’s oculoglandular, neuroretinitis, osteomyelitis, arthropathy, bacteraemia with fever Endocarditis, lymphadenitis Not described Not described Not described

1920

Human/body louse

Trench fever, endocarditis, bacillary angiomatosis, lymphadenitis Not described Not described

Rat (R. norvegicus) Tunney’s rat (Rattus tunneyi) Human

Marseille, France Queensland, Australia

2004 2008

USA

2007

Wild roe deer (C. capreolus) Mole Human Woodland mouse (Apodemus spp.) Wild rat (R. norvegicus) Cattle rancher

Germany Khon Kaen, Thailand UK

2001 1995 2008 1995

France USA

1998 1999

Dog, rodent/ticks

Dog Vole (Microtus pennsylvanicus) Human Domestic cat

USA

1995 1946

Dog/ticks Vole/vole ear mite

Not described Bacteraemia, fever, endocarditis Endocarditis Endocarditis, bacteraemia

USA USA

2000 2000

Fleas Deer, elk, beef, cattle

Myocarditis, meningitis Not described

Human Sheep

France USA

2010 2004

Human Canids Fleas and ticks Rodents

Peru Iraq Australia Thailand

2013 2012 2011 2009

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data and recommendations related to the treatment of Bartonella infections based on the pathogenicity of Bartonella spp.

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Pathogenicity of Bartonella spp.

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Human disease(s)

Area, country

B. australis

59

Reservoir host/vector

Mammal B. alsatica

56

Year of description

In humans, the infection cycle of Bartonella spp. is initiated by colonisation of the primary niche [8,9]. In this stage, the infection is

Ruminant/deer ked Mole Rat

Sheep ked (Melophagus ovinus)

Bacteraemia, fever, splenomegaly Not described Not described Febrile illness Not described

Endocarditis Bacteraemia Verruga peruana Not described Not described Not described

usually controlled by the immune system and the clinical manifestations are characterised by local lymphadenopathy (i.e. associated with B. henselae, B. quintana and Bartonella alsatica) [1,10,11]. However, under certain poorly defined circumstances, the commensal relationship between reservoir-adapted Bartonella spp. and the host is imperfect, resulting in a stealth pathogen strategy [12]. As a result, Bartonella spp. are rapidly cleared from the blood after


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Fig. 1. Pathogenicity and treatment of Bartonella infections. BA, bacillary angiomatosis; PH, peliosis hepatis.

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the initial inoculation but can reappear in the bloodstream in a synchronous infection wave after 4 or 5 days [8]. In this stage, the bacteria (primarily B. bacilliformis and B. quintana) adhere to and invade erythrocytes, facilitating a short period of intracellular replication. The clinical manifestations of this intraerythrocytic stage are Oroya fever (i.e. for B. bacilliformis infection) or trench fever (i.e. for B. quintana infection). Bartonella spp. can subsequently colonise secondary foci, particularly vascularised tissues such as heart valves (i.e. as in endocarditis caused by B. quintana, B. henselae and other Bartonella spp.), the liver and the spleen (i.e. as in peliosis hepatis caused by B. henselae) as well as cooler areas of the body such as the vascular bed of the skin (i.e. as in verruga peruana caused by B. bacilliformis and Candidatus Bartonella ancashi [13] or bacillary angiomatosis caused by B. henselae and to a lesser extent B. quintana) [9,14]. Bartonella spp. can circulate in the blood for the remaining lifespan of the infected erythrocyte. As a result, bacteraemia can last for several weeks to months [9,15]. This chronic bacteraemia is asymptomatic or has few symptoms [16]. Local manifestations of Bartonella spp. infection in immunocompetent individuals Transmission of Bartonella to humans via scratches or bites can result in a wide range of clinical symptoms. These manifestations are primarily determined by the status of the immune system of the infected human. Immunocompetent humans typically develop CSD, which is a self-limiting but long-lasting swelling of the lymph nodes that drain the primary inoculation site. Bartonella henselae and, to a lesser extent, B. alsatica and B. quintana have been reported as agents of lymphadenitis [10,17,18]. Patients typically present with a gradual regional lymphadenitis which is accompanied by a papule that develops in the scratch line after ca. 3–10 days and can persist for a few days or for as long as 2–3 weeks [19]. The

presence of B. henselae in the skin papule was initially proposed by Wear et al. [20] and subsequently confirmed by immunohistochemical staining of the lymph nodes and skin biopsies of patients with CSD [21,22]. We recently isolated B. henselae from the inoculation sites of three patients after cat scratches [23] and from the scalp eschars of patients with scalp eschar and neck lymphadenopathy after tick bite (SENLAT) [6]. After 1–2 weeks, one or more regional lymph nodes that drain the primary inoculation site gradually enlarge. Lymph node enlargement can persist for months, with some cases exhibiting prolonged enlargement for as long as 12–24 months. The characteristic histological change in CSD is an inflammatory granulomatous process with central microabscess surrounded by a ring of macrophages and rare giant cells (Fig. 2). Immunopathogenesis is assumed to play an important role in this lymph node enlargement because B. henselae has only been isolated from the lymph nodes in a small number of cases [18,24]. In experimental animal models, B. henselae was eliminated within a few days to 1 week after systemic (i.e. intraperitoneal or intravenous) infection [25]. Moreover, B. henselae-infected dendritic cells produce cytokines (e.g. interleukin-10) and chemokines (e.g. CXCL13) locally, contributing to the formation of the characteristic B-cell- and neutrophil-rich CSD granulomata [26]. In mice, B. henselae-induced lymphadenopathy was altered by immune cell recruitment and enhanced B-lymphocyte proliferation [25].

Treatment of local manifestations CSD responds poorly to antibiotic treatment (Table 2). Collipp treated children with CSD and found that the necessary duration of treatment with trimethoprim/sulfamethoxazole (SXT) was between 7 days and 16 days [28]. Margileth retrospectively tested 18 antibiotics for the treatment of 268 patients with typical CSD and found that the duration of illness for the patients who received no


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Table 2 Pathogenicity and treatment of Bartonella spp. infections. Pathogenicity

Bartonella agent

Clinical manifestation

Treatment

Local manifestations

B. henselae, B. quintana, B. alsatica, B. clarridgeiae

Lymphadenitis

No treatment

Atypical CSD

Neuroretinitis Hepatosplenic

Intracellular erythrocyte parasitism

B. bacilliformis

Oroya fever

Pregnancy

Endocarditis

Angioproliferative lesions

B. quintana

Trench fever

B. henselae, B. rochalimae, B. vinsonii subsp. arupensis, B. vinsonii, B. melophagi B. quintana, B. henselae, other Bartonella spp.

Bacteraemia

B. bacilliformis, B. ancashi

Verruga peruana

B. quintana, B. henselae

Endocarditis

Bacillary angiomatosis, bacillary peliosis

Uncomplicated Complicated Relapses

Doxycycline (200 mg/day) and rifampicin (600 mg/day) Rifampicin (20 mg/kg/day) alone or with gentamicin (3 mg/kg/day) Chloramphenicol (50 mg/kg/day for 3 days and then 25 mg/kg/day until completion of 14 days) Chloramphenicol (50–100 mg/kg/day) and penicillin G (50 000–100 000 IU/kg/day) Gentamicin (3 mg/kg/day for 2 weeks) and doxycycline (200 mg/day for 4 weeks) Gentamicin (3 mg/kg/day for 2 weeks) and doxycycline (200 mg/day for 4 weeks) Gentamicin (3 mg/kg/day for 2 weeks) and doxycycline (200 mg/day for 6 weeks) Rifampicin (10 mg/kg/day) (maximum total daily dose 600 mg/day for children) Streptomycin (15–20 mg/kg/day) Erythromycin (2 g/day) or doxycycline (200 mg/day) Doxycycline (200 mg/day) with rifampicin (600 mg/day) Erythromycin (2 g/day) or doxycycline (200 mg/day)

Duration

Reference [31]

4–6 weeks

[36,37]

4–6 weeks

[39]

2 weeks

[7,48,67,70]

2 weeks

[70]

6 weeks

[62]

6 weeks

[62]

6 weeks

[81]

2–3 weeks

[27,70]

2–3 weeks

[31,67]

3 months

[7,91,92]

3 months

[7,91,92]

4–6 months

[35,96]

CSD, cat-scratch disease.

130 131 132 133 134 135

antibiotics was 14.5 weeks [29]. However, in patients who received rifampicin, gentamicin, ciprofloxacin or SXT, the mean duration of adenopathy was 9 weeks prior to therapy and 2.8 weeks after therapy; rifampicin was the most effective regimen [29]. Bass et al. found that the initial lymph node volume decreased significantly faster in patients treated with azithromycin than in patients treated

with placebo. However, after 30 days of treatment, no significant differences in the rate or degree of resolution were observed between the two groups [30]. Available data do not support the use of antibiotics for the treatment of CSD. Moreover, a recent meta-analysis study that included randomised controlled trials and observational studies demonstrated that antibiotics failed to significantly affect the cure rate or the time required to achieve a cure [31]. In addition, it remains unclear whether antibiotic treatment of localised CSD reduces the risk of developing systemic disease. When CSD lymph nodes suppurate, needle aspiration is likely to be the best treatment, with patients typically reporting reduced pain within 24–48 h. If fluid re-accumulates, needle re-aspiration may be required [32]. Large painful lymph nodes can be surgically removed, and in cases of long-lasting lymphadenopathy patients should be reassured that the adenopathy is benign and will likely subside spontaneously within 2–4 months [32]. Management consists of treatment with analgesics for pain and prudent follow-up.

Atypical cat-scratch disease and treatment

Fig. 2. Characteristic histological change in the lymph node with cat-scratch disease: inflammatory granulomatous process with central microabscess surrounded by a ring of macrophages and rare giant cells (haematoxylin/eosin, original magnification ×100).

Atypical CSD occurs in a minority of cases (5–14%), with most of these patients suffering from severe systemic symptoms that indicate a disseminated infection [33,34]. Patients with atypical CSD have prolonged fever for >2 weeks, myalgia, arthralgia/arthropathy, malaise, fatigue, weight loss, splenomegaly and Parinaud’s oculoglandular syndrome [35]. Parinaud’s oculoglandular syndrome appears to be the most common ocular complication of CSD and affects ca. 5% of symptomatic patients.


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155 156 157 158 159 160 161 162



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No data are available regarding the benefits of specific antimicrobial therapy for immunocompetent patients with atypical presentations of CSD. For patients with neuroretinitis, the combination of 100 mg of doxycycline twice daily with 300 mg of rifampicin twice daily appears to promote disease resolution, improve visual acuity, decrease optic disk oedema and decrease the duration of disease [36,37]. In contrast, Rosen et al. proposed that Bartonella neuroretinitis is self-limited and requires no antibiotic therapy for management [38]. The same combination of doxycycline and rifampicin is also suggested for the treatment of Bartonella encephalopathy [7]. Finally, 20 mg/kg/day rifampicin alone or in combination with gentamicin or SXT should be considered for hepatosplenic CSD [39].

Intracellular erythrocyte parasitism of Bartonella spp. Bartonella spp. cause long-lasting intraerythrocytic bacteraemia in their mammalian reservoirs [1]. Humans serve as the reservoir host for B. bacilliformis and B. quintana and infection with these agents results in chronic intraerythrocytic bacteraemia. However, only B. henselae and B. quintana have been demonstrated to establish chronic intraerythrocytic bacteraemia in humans [9]. Animal models of intraerythrocytic infection have been established for several bartonellae, and data related to the characteristics and course of intraerythrocytic bacteraemia are similar for all of these models [8,40–42]. Models indicated that 5 days after intravenous inoculation of Bartonella tribocorum, large numbers of these agents were released from the inoculation niche into the bloodstream [8,43]. In the bloodstream, B. tribocorum adhered to mature erythrocytes, indicating that the bacteria become competent for erythrocyte interaction during colonisation of the primary site [8,43]. After adhesion to erythrocytes, B. tribocorum invades and replicates intracellularly until a critical density is reached. The number of intracellular bacteria remains static for the remaining lifespan of the infected erythrocytes, which is indistinguishable from that of uninfected erythrocytes [8]. During this intraerythrocytic bacteraemia, antibodies are unlikely to function against infected erythrocytes as the lifespan of these cells is similar to that of uninfected erythrocytes [8,40]. In rats, the intraerythrocytic bacteraemia caused by B. tribocorum subsides spontaneously after ca. 10 weeks [8]. A similar duration of bacteraemia is observed in other experimental models of Bartonella infection [44].

Bartonella bacilliformis intracellular pathogenicity within erythrocytes Bartonella bacilliformis causes an essentially asymptomatic intraerythrocytic infection similar to that caused by other Bartonella spp. [1]. Bartonella bacilliformis causes massive haemolysis of infected erythrocytes, resulting in a frequently fatal haemolytic anaemia (i.e. Carrion’s disease) [1]. Approximately one-third of patients with Carrion’s disease present with opportunistic infections due to infections with non-typhoid Salmonella, Shigella dysenteriae, Enterobacter, Pseudomonas aeruginosa, Staphylococcus aureus and Pneumocystis jirovecii or re-activation of tuberculosis, toxoplasmosis and histoplasmosis [45]. Specific genetic variants of B. bacilliformis might account for the marked variability in mortality and morbidity that is observed in outbreaks [46]. The mortality of Carrion’s disease can reach 85% in untreated patients, particularly if the infection is complicated by other diseases such as salmonellosis [47]. Young children are the most affected people in endemic areas, likely due to the presumed protective immunity that develops after repeated infections [48].

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Bartonella quintana intracellular pathogenicity within erythrocytes Bartonella quintana is the agent of trench fever, which is characterised by the synchronous release of bacteria at intervals of ca. 5 days. This five-day cycle is triggered by re-infection of the primary niche by bacteria that are released at the end of each cycle [1]. In patients with trench fever, B. quintana can also be present extracellularly, in mature erythrocytes or in erythroblast cells [49]. The clinical manifestations of B. quintana bacteraemia range from asymptomatic infection to severe life-threatening disease. A sudden onset of fever associated with headache, shin pain and dizziness that lasts 1–3 days is observed after an incubation period of 2–3 weeks [50]. Although fatal cases have not been reported, the disease may persist for 4–6 weeks and result in prolonged disability. Relapses may occur years later and, in some cases, bacteraemia may exist with no clinical signs [1]. Bacteraemia caused by other Bartonella spp. Other Bartonella spp. have been isolated from individual patients with bacteraemia. Bartonella henselae and Bartonella koehlerae bacteraemia were recently documented in two epithelioid haemangioendothelioma patients from Australia [51]. Bartonella henselae bacteraemia has also been reported in patients from the USA [52,53]. Bartonella tamiae was also isolated from human patients with febrile illness from Thailand [54], and Bartonella rochalimae was isolated from a woman with bacteraemia, fever and splenomegaly [55]. Moreover, bacteraemia with fever caused by Bartonella vinsonii subsp. arupensis was reported in a cattle rancher [56] and in patients from Thailand [57]. Bartonella vinsonii subsp. berkhoffii and Candidatus Bartonella melophagi have also been reported to cause bacteraemia in humans [58,59]. Utilisation of the Bartonella Alphaproteobacteria growth medium (BAPGM) platform facilitated the isolation and molecular detection of Bartonella spp., including B. vinsonii subsp. berkhoffii genotypes I and II and B. koehlerae [53,60]. Finally, a novel Bartonella sp. related to Candidatus Bartonella volans was also reported as an agent of bacteraemia in humans [61]. Treatment of Bartonella bacteraemia The intracellular residence of Bartonella spp. offers protection both from host defence mechanisms and from antibiotics (Table 2). Obligate or facultative intracellular bacteria must be killed to avoid relapses. The enhanced activities of doxycycline and gentamicin and careful evaluations are required for patients with long-term relapses. For the treatment of B. quintana bacteraemia, Foucault et al. [62] reported that the combination of 3 mg/kg/day gentamicin for 2 weeks and 200 mg/day doxycycline for 4 weeks was more effective for treating bacteraemia in homeless patients than either no treatment or the use of ␤-lactams or doxycycline alone [62]. Another study demonstrated that eradication of bacteraemia was achieved in all homeless patients who were treated with a combination of gentamicin and doxycycline [63]. Because gentamicin is bactericidal for bacteria once they are released from erythrocytes, this drug should be administered to infected patients for ≥5 days to enable a cure [64]. Doxycycline is not bactericidal but has been shown to penetrate erythrocytes [62]. In summary, patients with Bartonella spp. bacteraemia should be treated with 3 mg/kg body weight of gentamicin once daily for 2 weeks in combination with 200 mg of doxycycline daily for 4 weeks. Bartonella quintana bacteraemia may cause hidden endocarditis, and people with existing heart valve abnormalities should be monitored extensively. Finally, a meta-analysis demonstrated that treatment of patients with


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Bartonella bacteraemia with gentamicin and doxycycline increases the cure rate [31]. In the absence of prospective studies related to the treatment of bacteraemia caused by other Bartonella spp., the regimen used for B. quintana should be employed. No controlled clinical trials related to the treatment of Carrion’s disease have been performed and the interpretation of results is difficult. In an epidemic of Oroya fever in the Peruvian Andes, all patients treated with chloramphenicol survived; in contrast, the mortality among untreated patients was 88% [65]. In addition, chloramphenicol was the most frequently used antibiotic among a cohort of 518 patients in Caraz, Peru [66]. Moreover, good resolution was observed for the majority of patients with B. bacilliformis bacteraemia who were treated with chloramphenicol alone or chloramphenicol in combination with another antibiotic such as penicillin, ampicillin, cefalexin, dicloxacillin, clindamycin, SXT, gentamicin or ceftriaxone [67]. However, patients in whom >80% of erythrocytes were colonised by B. bacilliformis failed to respond to treatment. As a result, many of these patients died from complications [67]. SXT, macrolides (e.g. roxithromycin), and norfloxacin have also been used successfully in some patients [68]. A 500 mg dose of oral ciprofloxacin twice daily for 14 days was also used successfully in patients with Carrion’s disease [69]. Traditionally, patients who suffer from Oroya fever without complications have been treated with 500 mg of ciprofloxacin for 10 days; in patients younger than 7 years of age, the regimen is 10 mg/kg divided into two doses [70]. However, in vitro evidence suggests that ciprofloxacin is inadequate for the treatment of B. bacilliformis bacteraemia [71–73]. Thus, we believe that this treatment regimen should be removed from the current guidelines. An initial dose of 50 mg/kg/day chloramphenicol for the first 3 days and a subsequent dose of 25 mg/kg/day until the completion of 14 days of treatment has been proposed as the best regimen for the treatment of B. bacilliformis bacteraemia [7,48,67,70] (Table 2). During pregnancy, treatment should be 50–100 mg/kg/day chloramphenicol and 50 000–100 000 IU/kg/day penicillin G for 14 days. A combination of ciprofloxacin and chloramphenicol was also proposed because this regimen has the advantage of treating potential infections with Salmonella spp. and Haemophilus influenzae [70]. Moreover, red blood cell transfusions in the amount of 10–20 mL/kg can be useful when the haematocrit is 90% of patients require valvular surgery [77]. Bartonella endocarditis causes significant destruction of the valves; this destruction is characterised by mononuclear cell inflammation, extensive fibrosis, large calcifications and small vegetations (Fig. 3) [78]. Moreover, more than one-half of patients with Bartonella endocarditis have pre-existing valvular diseases that could lead to the development of degenerative changes, particularly fibrosis, calcification and chronic inflammation, independent

Fig. 3. Immunohistochemical detection of Bartonella quintana in a heart valve (monoclonal antibody and haematoxylin counterstain, original magnification ×400).

of the infective process [78]. In Bartonella spp. endocarditis, the bacteria are observed extracellularly in dense immunopositive clusters that are located primarily in vegetations and intracellularly within the cytoplasm of neutrophils and macrophages [79]. Treatment of Bartonella endocarditis Patients with Bartonella endocarditis have a higher death rate and undergo valvular surgery more frequently than patients with endocarditis caused by other pathogens [77]. In a series of patients from France, patients who received an aminoglycoside for ≥14 days were more likely to survive than those who received a shorter duration of therapy [80]. Moreover, the recovery rate was lower in patients who received doxycycline only or doxycycline in combination with other non-aminoglycoside antibiotics than in patients who received aminoglycosides [80]. In addition, fluoroquinolone compounds were not more effective than other antibiotic regimens, and ␤-lactams without aminoglycosides failed to exhibit a higher efficacy than other antibiotics [80]. Finally, a recent meta-analysis demonstrated that treatment with gentamicin and ceftriaxone in the presence or absence of doxycycline was not significantly more effective than other antibiotic combinations [31]. Patients with suspected or confirmed Bartonella endocarditis should be treated with 3 mg/kg/day gentamicin for 2 weeks in combination with 200 mg of doxycycline daily for 6 weeks [81] (Table 2). The American Heart Association consensus treatment for infective endocarditis is ceftriaxone and gentamicin with or without doxycycline when Bartonella is suspected, and doxycycline and gentamicin when Bartonella endocarditis is confirmed [82]. Ceftriaxone can be also effective against other bacteria with the potential to cause culture-negative endocarditis. In patients allergic to penicillin, a tetracycline or macrolide should be used and treatment should be continued for a minimum of 4 weeks. Angioproliferative lesions caused by Bartonella spp. Infection with B. bacilliformis, B. quintana or B. henselae can lead to marked vasoproliferation, which manifests clinically as the formation of vascular tumours [83]. Candidatus Bartonella ancashi was also recently associated with angioproliferative lesions in a patient from Peru [84]. Bartonella spp. are observed in close association with proliferating endothelial cells, and bacterial eradication by antibiotic treatment results in tumour regression [85]. These


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7

Fig. 4. Warthin–Starry silver stain of a bacillary angiomatosis (original magnification ×1000). Fig. 5. Warthin–Starry silver stain of a peliosis hepatis (original magnification ×1000). 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428

vascular tumours form via a complex sequence of morphogenetic events that result in blood vessel formation via the sprouting of pre-existing vessels. Growth of these tumours depends on the continuous presence of bacteria in the tumour lesions [83]. The lesions contain proliferating endothelial cells, bacteria and mixed infiltrates of macrophages/monocytes and polymorphonuclear neutrophils (Fig. 4). The bacteria are present as aggregates both surrounding and within endothelial cells, indicating that the vascular endothelium represents a target tissue for intracellular and extracellular colonisation in vivo [85]. These vasoproliferative lesions are indicative of chronic inflammation. An acute inflammatory reaction triggered by the Bartonella-infected endothelium may be crucial for initiating chronic inflammation. In general, an acute inflammatory response is thought to induce a mediator cascade that activates the endothelium, resulting in the release of proinflammatory chemo-attractants and the sequential establishment of receptor–ligand interactions between the activated endothelium and circulating polymorphonuclear neutrophils [43]. Inoculation of B. quintana or B. henselae into endothelial cells increased the lifespan of the cultured cells and leads to morphological changes [86]. Moreover, these angiogenic effects were associated with increased production of vascular endothelial growth factor (VEGF) by B. henselae-infected carcinoma and monocytic cell lines [87,88]. Bartonella angiogenesis typically manifests as either sarcomalike skin lesions, which are known as verruga peruana (i.e. in association with B. bacilliformis and Candidatus Bartonella ancashi) or bacillary angiomatosis (i.e. in association with B. quintana and B. henselae), or as a cystic form in the liver and spleen, which is referred to as peliosis hepatis and primarily associated with B. henselae [48,89]. Immune status is a key risk factor for these lesions as they are rarely reported in immunocompetent patients and are much more common in immunocompromised patients who are infected with B. henselae and B. quintana [90,91]. Bacillary angiomatosis caused by both species is characterised by vasoproliferative skin lesions that resemble Kaposi’s sarcoma, which is caused by human herpes virus 8 in acquired immunodeficiency syndrome (AIDS) patients. Bartonella henselae is also responsible for peliosis hepatis, which is defined as a vascular proliferation of sinusoidal hepatic capillaries that creates blood-filled spaces; however, this condition also affects the spleen, abdominal lymph nodes and bone marrow (Fig. 5) [35]. In contrast, verruga peruana is not dependent on the patient’s immune status as the state of partial immunosuppression that develops at the end of Oroya fever favours the eruption of vasoproliferative lesions; this event marks the beginning of the verruga peruana phase of infection [19].

Treatment of angioproliferative lesions Erythromycin is the drug of first choice for the treatment of patients with bacillary angiomatosis. Even a single 250 mg oral dose of erythromycin sterilises blood cultures and eliminates subcutaneous lesions [7,92]. However, the antibacterial effects of erythromycin cannot explain the disappearance of subcutaneous lesions. Erythromycin is believed to modulate Bartonella-induced pathological angiogenesis [89]. The anti-angiogenic effect of erythromycin on microvascular endothelial cells plays an important role in the treatment of the angioproliferative lesions caused by Bartonella spp. [89]. An experimental model revealed that HMEC-1 cell proliferation induced by wild-type B. quintana or by the erythromycin-resistant mutant was significantly inhibited by erythromycin. In contrast, doxycycline and gentamicin failed to exert such an effect [89]. As a result, the effectiveness of erythromycin against the angioproliferative lesions of Bartonella spp. was proposed to be based primarily on the combined anti-angiogenic and anti-inflammatory effects of erythromycin [89]. Another study demonstrated that macrolides were the most effective drugs in patients suffering from bacillary angiomatosis or peliosis hepatis, and none of the patients treated with a combination of rifampicin and erythromycin relapsed [93]. In contrast, relapses have been frequently observed in immunocompromised patients who received a short duration of therapy [93]. Although treatment with doxycycline has also been consistently successful [91], a human immunodeficiency virus (HIV) patient was reported to relapse after a 4-week course of therapy with doxycycline; this patient was cured after an additional 8 weeks of treatment with the same drug [94]. Treatment failure has been reported when using nafcillin, dicloxacillin and cefalexin [7]. Moreover, several relapses have been reported after treatment of angioproliferative lesions using amoxicillin, aminoglycosides or SXT [95–97]. Relapses in the bone and skin have been reported frequently, primarily when antibiotics are administered for 21 days was necessary for a large proportion of patients [66].


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8 473 474

475

ARTICLE IN PRESS

Finally, a combination of sultamicillin and deflazacort was effective for the treatment of a 12-year-old girl with verruga peruana [100]. Bartonella quintana and B. henselae angioproliferative lesions

492

A 500 mg dose of erythromycin four times daily for 3 months is the first-line antibiotic therapy for the treatment of angioproliferative lesions (Table 2). In patients with serious infections, 100 mg of erythromycin or doxycycline twice daily in combination with 300 mg of rifampicin twice daily is proposed. A meta-analysis of a study of HIV patients suffering from bacillary angiomatosis revealed no statistically significant differences between erythromycin and doxycycline [31]. Hepatic lesions improve after several months of treatment, but cutaneous lesions exhibit improvement after 4–7 days of treatment and resolve after ca. 1 month of treatment [7,101]. A 2-month antibiotic regimen is the minimum duration of treatment in immunocompromised patients [95]. Patients who relapse after the recommended treatment should be retreated with 500 mg of erythromycin four times daily or 100 mg of doxycycline twice daily for 4–6 months. Patients with repeated relapses should receive antibiotic therapy as long as they remain immunocompromised [35,96]

493

Bartonella bacilliformis angioproliferative lesions

476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491

499

The recommended treatment for verruga peruana is 10 mg/kg/day rifampicin for 14–21 days [48,70] (Table 2). Streptomycin can be used as an alternative treatment as this drug exhibits a nearly 100% cure rate [68]. A meta-analysis revealed no significant differences between rifampicin and streptomycin treatment [31].

500

Candidatus Bartonella ancashi angioproliferative lesions

494 495 496 497 498

501 502

503

Azithromycin was successfully used for the treatment of verruga peruana caused by Candidatus Bartonella ancashi [13,84]. Conclusion

525

Bartonella spp. are responsible for acute and chronic diseases and vascular manifestations. The diversity of reported clinical manifestations is dependent on the infecting species of Bartonella and on the immune status of the patient. Bartonella spp. infections present a treatment challenge because of the persistence of the infection; frequent relapses occur due to the existence of an intraerythrocytic phase that provides a protective niche for the bacteria. Unfortunately, no systematic reviews are available that summarise and appraise the evidence related to treatment decisions for infections caused by Bartonella spp. To date, only two randomised clinical trials have been reported for the treatment of Bartonella; one of these studies evaluated patients with CSD [30] and the other study evaluated adult patients with chronic bacteraemia caused by B. quintana [63]. As a result, treatment of Bartonella infections must be adapted based on whether the disease is in the acute or chronic form and based on the infecting Bartonella sp. Moreover, well designed randomised clinical trials are needed to compare different options for the treatment of Bartonella spp.-related emerging and re-emerging infections. Funding: None. Competing interests: None declared. Ethical approval: Not required.

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Pathogenicity of the enterococcus in surgical infections.

Pathogenicity mechanisms and host response during oral Candida albicans infections.

Pathogenicity of Propionibacterium acnes in mixed infections with facultative bacteria.

Pathogenicity of Candida albicans auxotrophic mutants in experimental infections.

Bartonella spp. infections in rodents of Cambodia, Lao PDR, and Thailand: identifying risky habitats.

Infections and cardiovascular disease: is Bartonella henselae contributing to this matter?

A review of trichuriasis, its incidence, pathogenicity and treatment.

Microbial pathogenicity and host defense mechanisms--crucial parameters of posttraumatic infections.

Bartonella clarridgeiae and Bartonella vinsonii subsp. berkhoffii exposure in captive wild canids in Brazil.

Treatment of respiratory infections.

Bartonella henselae infections in an owner and two Papillon dogs exposed to tropical rat mites (Ornithonyssus bacoti).

Bartonella-Associated Transverse Myelitis.

Anaerobic infections: diagnosis and treatment.

Evolutionary history of rat-borne Bartonella: the importance of commensal rats in the dissemination of bacterial infections globally.

Prophylaxis and Treatment of Herpetic Infections.

Prevention and treatment of neonatal nosocomial infections.

Treatment of Chlamydia trachomatis infections.

[Infections during antirheumatic treatment].

Ceftriaxone in treatment of serious infections. Urinary tract infections.

Lack of transplacental transmission of Bartonella bovis.

Development and characterisation of highly antibiotic resistant Bartonella bacilliformis mutants.

Detection of Bartonella quintana in African body and head lice.

Dental Infections: Their Diagnosis and Treatment.

Diversity and phylogenetic relationships among Bartonella strains from Thai bats.