Bartonella Infection: Treatment and Drug Resistance

Silpak Biswas; Jean-Marc Rolain

Future Microbiol. 2010;5(11):1719-1731.

Abstract and Introduction

Abstract

Bartonella species, which belong to the α-2 subgroup of Proteobacteria, are fastidious Gram-negative bacteria that are highly adapted to their mammalian host reservoirs. Bartonella species are responsible for different clinical conditions affecting humans, including Carrion's disease, cat scratch disease, trench fever, bacillary angiomatosis, endocarditis and peliosis hepatis. While some of these diseases can resolve spontaneously without treatment, in other cases, the disease is fatal without antibiotic treatment. In this article, we discuss the antibiotic susceptibility patterns of Bartonella species, detected using several methods. We also provide an overview of Bartonella infection in humans and animals and discuss the antibiotic treatment recommendations for the different infections, treatment failure and the molecular mechanism of antibiotic resistance in these bacteria.

Introduction

The genus Bartonella was named after AL Barton, who was the first person to describe the intraerythrocytic bacterium Bartonella bacilliformis in 1909. Bartonella are facultative intracellular Gram-negative bacteria that belong to the α-2 subgroup of Proteobacteria. Based on 16S rRNA-encoding gene similarity, Bartonella is closely related to Brucella and Agrobacterium.^[1,2]

Until 1993, only three diseases were known to be caused by Bartonella species: Carrion's disease, caused by Bartonella bacilliformis; trench fever, caused by Bartonella quintana; and cat scratch disease (CSD), caused by Bartonella henselae.^[1,3] Currently, there are more than 30 Bartonella species, and several Candidatus species that have been isolated from humans and wild and domestic animals globally.

In mammals, each Bartonella species is highly adapted to its host reservoir, and the bacteria can persist in the bloodstream of the host as a result of intraerythrocytic parasitism.^[4] The intraerythrocytic localization of B. henselae has been demonstrated in cat erythrocytes, and B. bacilliformis bacilli have been observed within erythrocytes during the acute phase of Carrion's disease (Oroya fever).^[5] The intraerythrocytic presence of B. quintana has also been previously demonstrated in people with asymptomatic bacteremia using confocal microscopy.^[6]

Members of the genus Bartonella cause historically well known diseases, including Carrion's disease, trench fever, CSD, bacillary angiomatosis, peliosis hepatis (PH), chronic bacteremia, endocarditis, chronic lymphadenopathy and neurological disorders.^[2]

The role of Bartonella species as human and domestic animal pathogens is becoming increasingly important. Clinical diseases caused by Bartonella infections, and the treatment of these diseases with antibiotics, are challenging in many instances.

This article focuses on Bartonella infections in humans, domestic pets and other animals, and discusses the antibiotic treatments and drug resistance for these infections.

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Table 1. Molecular mechanisms underlying the resistance of *Bartonella* species to different antibiotics.
Bartonella species	Antibiotics	Resistance mechanisms (candidate genes)	Ref.
Bartonella henselae	Erythromycin	A2058G^† (23S rRNA) A2059G (23S rRNA) C2611T (23S rRNA) G71R (L4 protein) G71R and H75Y (L4 protein)	[107]
	Azithromycin	A2058G (16S rRNA)	[112]
	Gentamicin	A1408G^‡ (16S rRNA)	[113]
	Pradofloxacin	S83V (gyrA)	[112]
	Enrofloxacin	S83V (gyrA)	[112]
	Ciprofloxacin	S83A (gyrA)	[102]
Bartonella bacilliformis	Erythromycin	A2058G (23S rRNA)	[109]
	Ciprofloxacin	D87N, S83A (gyrA)	[102,109,124]
	Rifampicin	S531F (rpoB)	[109]
Bartonella quintana	Erythromycin	GRARHSSAR^§ (L4 protein)	[110]
	Rifampicin	S83A (gyrA)	[126]
	Ciprofloxacin	S531F (rpoB)	[102]

^†Heterozygous mutation at position 2058 of the domain V of 23S rRNA encoding gene.
^‡Double peak A/G.
^§Insertion of the 9 aa between aa R71 and aa A72.

Table 2. Antibiotic treatment recommendations for infections caused by *Bartonella* species.
Bartonella disease	Adults	Children
Cat scratch disease	No recommendation Azithromycin if extensive lymphadenopathy	No recommendation Azithromycin if extensive lymphadenopathy
Carrion's disease (Oroya fever)	Chloramphenicol + β-lactam or ciprofloxacin	Chloramphenicol + β-lactam or ciprofloxacin or chloramphenicol or doxycycline + gentamicin
Carrion's disease (Verruga peruana)	Doxycycline + gentamicin or streptomycin	Rifampin
Trench fever and chronic bacteremia	Doxycycline + gentamicin	Unknown
Bacillary angiomatosis	Erythromycin or doxycycline	Erythromycin
Peliosis hepatis	Erythromycin or doxycycline	Erythromycin
Endocarditis	Doxycycline + gentamicin or Ceftriaxone + gentamicin ± doxycycline	Unknown

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Executive Summary

Bartonella infection in animals

The domestic cat serves as the carrier for Bartonella henselae and Bartonella clarridgeiae and usually remain healthy.
Clinical features in infected cats included generalized or localized peripheral lymphadenomegaly, short periods of fever and mild neurologic signs.
Bartonella vinsonii subsp. berkhoffii , Bartonella quintana , B. clarridgeiae , Bartonella elizabethae and Bartonella rochalimae have been identified as pathogenic for dogs.
The clinical symptoms of Bartonella infection in dogs ranges from chronic subclinical infections to protracted illness accompanied by lethargy and weight loss.
Bartonella infections are also reported in horses, in some domestic and wild ruminants, and in wild rodents.

Human bartonellosis

Bartonella bacilliformis is the etiologic agent of Carrion's disease. The acute form of the disease is known as Oroya fever and the chronic form is known as verruga peruana.
B. quintana , the agent of trench fever in humans, also causes bacillary angiomatosis, a vascular proliferative lesion observed in immunocompromised individuals, most often due to acquired immunodeficiency syndrome.
B. quintana has also been demonstrated to cause chronic bacteremia in homeless people.
B. henselae is the primary etiologic agent of cat scratch disease, which seems to be the most common Bartonella infection in people today.
B. quintana , B. henselae , B. elizabethae , B. vinsonii subsp. berkhoffii , B. vinsonii subsp. arupensis , Bartonella alsatica and Bartonella koehlerae have been associated with endocarditis in patients with existing valvulopathies.
Bartonella tamiae was isolated from human patients from Thailand with febrile illness and Bartonella rochalimae was isolated from a woman with bacteremia, fever and splenomegaly.

Antibiotic treatment against bartonellosis

Based upon in vitro testing, bacteria of the genus Bartonella are susceptible to many antibiotics. However, in vitro sensitivity results do not consistently correlate with in vivo patient data.
No regimen of antibiotic treatment has been proven effective in controlled studies with long-term follow-up for definitively eliminating Bartonella infections in cats or dogs.
Fluoroquinolones alone, or in combination with amoxicillin, have also showed positive therapeutic response in dogs.
Doxycycline in combination with gentamicin is the recommended treatment for endocarditis.
Cat scratch disease does not typically respond to antibiotic therapy.
Erythromycin is the antibiotic of choice for bacillary angiomatosis and peliosis hepatis.

Drug resistance against Bartonella infection

An in silico genome analysis study revealed a natural mutation at position 83 of the quinolone-resistance determining region (Ser 83→Ala) of the gyr A gene for three Bartonella species ( B. bacilliformis , B. quintana and B. henselae) conferring an intrinsic heterogeneity of susceptibility against fluoroquinolones.
In Bartonella spp. different mutations have been reported in the 23S rRNA-encoding gene and ribosomal protein L4 by in vitro studies in erythromycin-resistant mutants.
Gentamicin-resistant strain of B. henselae was also obtained in vitro .
Fluoroquinolone-resistant strains of Bartonella were also obtained in vitro with different mechanisms of resistance in the gyr A gene.
Amino acid substitutions in RNA polymerase and ropB point mutations have been demonstrated after in vitro selection of rifampin-resistant strains of B. bacilliformis and B. quintana .

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Bartonella Infection: Treatment and Drug Resistance

Abstract and Introduction

Abstract

Introduction

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