Jane E. Koehler

Recommendations for Treatment of Human Infections Caused by Bartonella Species

Members of the genus Bartonella are facultative intracellular bacteria belonging to the alpha 2 subgroup of the class Proteobacteria and are phylogenetically closely related to Brucella species (15, 73). Until 1993, only three diseases were known to be caused by Bartonella species: Carrions disease (Bartonella bacilliformis), trench fever (Bartonella quintana), and cat scratch disease (CSD; Bartonella henselae). The genus now comprises B. bacilliformis, species of the former genera Rochalimea and Grahamella (14, 18), and additional, recently described species (Table ​(Table1).1). In mammals, each Bartonella species is highly adapted to its reservoir host; the bacteria can persist in the bloodstream of the host as the result of intraerythrocytic parasitism (49). Intraerythrocytic localization of B. henselae has been demonstrated in cat erythrocytes (88), and B. bacilliformis bacilli have been observed within erythrocytes during the acute phase of Carrions disease (Oroya fever) (88). Bartonellae also have a tropism for endothelial cells, and intracellular B. henselae can be identified in endothelial cells infected in vitro (28), although intraendothelial cell bacilli have not been identified in vivo. TABLE 1. Epidemiological and clinical data for species of the genus Bartonella Bartonella species cause long-recognized diseases, such as Carrions disease, trench fever, and CSD, and more recently recognized diseases, such as bacillary angiomatosis (BA), peliosis hepatis (PH), chronic bacteremia, endocarditis, chronic lymphadenopathy, and neurological disorders (Table ​(Table2)2) (73). A remarkable feature of the genus Bartonella is the ability of a single species to cause either acute or chronic infection and either vascular proliferative or suppurative manifestations. TABLE 2. Human diseases caused by Bartonella spp. The pathological response to infection with Bartonella spp. varies substantially with the status of the host immune system. Indeed, infection with the same Bartonella species (e.g., B. henselae) can result in a focal suppurative reaction (CSD in immunocompetent patients), a multifocal angioproliferative response (BA in immunocompromised patients), endovascular multiplication of the bacteria (endocarditis), or an exaggerated inflammatory response without evidence of bacteria in patient tissues (meningoencephalitis) (86). Some of the diseases due to Bartonella species can resolve spontaneously without treatment, but in other cases, the disease is fatal without antibiotic treatment and/or surgery. The clinical situations are so different that a single treatment for all Bartonella-related diseases has not been identified, and the approach to treatment must be adapted to each species and clinical situation (49). Moreover, the database of clinical studies with a standard case definition, culture confirmation, rigidly defined disease outcomes, and patients with similar host defenses is very limited. Thus, case reports with a very limited number of subjects often serve to dictate therapy. The objective of this minireview is to summarize the antibiotic treatment recommendations for the different infections caused by Bartonella species. We have compiled the in vitro antibiotic susceptibility data and our knowledge of the in vivo efficacies of antibiotics for each clinical manifestation, and finally, we have summarized and ranked our treatment recommendations according to the Infectious Diseases Society of America (IDSA) practice guidelines (see Table ​Table5)5) (51). TABLE 5. System for ranking recommendations in clinical guidelines recommended by IDSAa

Molecular Epidemiology of Bartonella Infections in Patients with Bacillary Angiomatosis–Peliosis

BACKGROUND Bacillary angiomatosis and bacillary peliosis are vascular proliferative manifestations of infection with species of the genus bartonella that occur predominantly in patients infected with the human immunodeficiency virus. Two species, B. henselae and B. quintana, have been associated with bacillary angiomatosis, but culture and speciation are difficult, and there has been little systematic evaluation of the species-specific disease characteristics. We studied 49 patients seen over eight years who were infected with bartonella species identified by molecular techniques and who had clinical lesions consistent with bacillary angiomatosis-peliosis. METHODS In this case-control study, a standardized questionnaire about exposures was administered to patients with bacillary angiomatosis-peliosis and to 96 matched controls. The infecting bartonella species were determined by molecular techniques. RESULTS Of the 49 patients with bacillary angiomatosis-peliosis, 26 (53 percent) were infected with B. henselae and 23 (47 percent) with B. quintana. Subcutaneous and lytic bone lesions were strongly associated with B. quintana, whereas peliosis hepatis was associated exclusively with B. henselae. Patients with B. henselae infection were identified throughout the study period and were epidemiologically linked to cat and flea exposure (P< or =0.004), whereas those with B. quintana were clustered and were characterized by low income (P=0.003), homelessness (P = 0.004), and exposure to lice (P= 0.03). Prior treatment with macrolide antibiotics appeared to be protective against infection with either species. CONCLUSIONS B. henselae and B. quintana, the organisms that cause bacillary angiomatosis-peliosis, are associated with different epidemiologic risk factors and with predilections for involvement of different organs.

Reptiles, Amphibians, and Human Salmonella Infection: A Population-Based, Case-Control Study

To estimate the burden of reptile- and amphibian-associated Salmonella infections, we conducted 2 case-control studies of human salmonellosis occurring during 1996-1997. The studies took place at 5 Foodborne Diseases Active Surveillance Network (FoodNet) surveillance areas: all of Minnesota and Oregon and selected counties in California, Connecticut, and Georgia. The first study included 463 patients with serogroup B or D Salmonella infection and 7618 population-based controls. The second study involved 38 patients with non-serogroup B or D Salmonella infection and 1429 controls from California only. Patients and controls were interviewed about contact with reptiles and amphibians. Reptile and amphibian contact was associated both with infection with serogroup B or D Salmonella (multivariable odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2; P<.009) and with infection with non-serogroup B or D Salmonella (OR, 4.2; CI, 1.8-9.7; P<.001). The population attributable fraction for reptile or amphibian contact was 6% for all sporadic Salmonella infections and 11% among persons <21 years old. These data suggest that reptile and amphibian exposure is associated with approximately 74,000 Salmonella infections annually in the United States.

Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors

Bartonella spp. are facultative intracellular bacteria that cause characteristic host-restricted hemotropic infections in mammals and are typically transmitted by blood-sucking arthropods. In the mammalian reservoir, these bacteria initially infect a yet unrecognized primary niche, which seeds organisms into the blood stream leading to the establishment of a long-lasting intra-erythrocytic bacteremia as the hall-mark of infection. Bacterial type IV secretion systems, which are supra-molecular transporters ancestrally related to bacterial conjugation systems, represent crucial pathogenicity factors that have contributed to a radial expansion of the Bartonella lineage in nature by facilitating adaptation to unique mammalian hosts. On the molecular level, the type IV secretion system VirB/VirD4 is known to translocate a cocktail of different effector proteins into host cells, which subvert multiple cellular functions to the benefit of the infecting pathogen. Furthermore, bacterial adhesins mediate a critical, early step in the pathogenesis of the bartonellae by binding to extracellular matrix components of host cells, which leads to firm bacterial adhesion to the cell surface as a prerequisite for the efficient translocation of type IV secretion effector proteins. The best-studied adhesins in bartonellae are the orthologous trimeric autotransporter adhesins, BadA in Bartonella henselae and the Vomp family in Bartonella quintana. Genetic diversity and strain variability also appear to enhance the ability of bartonellae to invade not only specific reservoir hosts, but also accidental hosts, as shown for B. henselae. Bartonellae have been identified in many different blood-sucking arthropods, in which they are typically found to cause extracellular infections of the mid-gut epithelium. Adaptation to specific vectors and reservoirs seems to be a common strategy of bartonellae for transmission and host diversity. However, knowledge regarding arthropod specificity/restriction, the mode of transmission, and the bacterial factors involved in arthropod infection and transmission is still limited.

Cutaneous Vascular Lesions and Disseminated Cat-Scratch Disease in Patients with the Acquired Immunodeficiency Syndrome (AIDS) and AIDS-Related Complex

Cutaneous lesions develop frequently in patients infected with human immunodeficiency virus (HIV). We describe the clinical features of four patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex who developed angiomatous nodules involving skin and bone, 2 of whom were scratched by a cat. Some of these lesions were clinically indistinguishable from Kaposi sarcoma. When examined with Warthin-Starry staining and electron microscopy, these nodules were noted to contain numerous clumps of a bacterium. Immunoperoxidase staining with an antiserum raised against the cat-scratch disease bacillus stained these organisms in all patients. Cat-scratch disease is usually a self-limited infection, but complicated or prolonged infections have been described in both normal and immunocompromised hosts. In our patients infected with HIV, manifestations of systemic cat-scratch disease included angiomatous nodules, severe systemic symptoms of fever, chills, night sweats and weight loss, elevated erythrocyte sedimentation rate, and decreased hematocrit. Cutaneous lesions involved the face, trunk, and extremities and numbered 2 to greater than 60; osseous lesions involved the fibula, radius, femur, and tibia, and were present in two of four patients. Treatment with x-ray therapy, intralesional vinblastine, penicillin, dicloxacillin, cephradine, and nafcillin had no effect on any lesions; however, treatment with erythromycin, doxycycline, or antimycobacterial antibiotics resulted in complete and rapid resolution of the cutaneous and osseous lesions, and the accompanying signs and symptoms of systemic infection. In patients with AIDS or AIDS-related complex, angiomatous nodules should be carefully evaluated for the presence of this organism, which can be treated and cured with antibiotic agents.

Demonstration and Characterization of Opiate Inhibition of the Striatal Adenylate Cyclase

Abstract: The conditions in which Leu5‐enkephalin inhibition of striatal adenylate cyclase was observed were defined. It was determined that enkephalin inhibition was dependent on GTP. The apparent Km for GTP in opiate inhibition was determined to be 0.5 and 2 μM when 0.1 mM‐ and 0.5 mM‐ATP were used as substrate. ITP, but not CTP or UTP, could substitute for GTP in the reaction. Though the addition of monovalent cations—Na+,K+, Li+, Cs+, and choline+—stimulated striatal adenylate cyclase activity, enkephalin inhibition of striatal adenylate cyclase did not require Na+ when theophylline was used as the phosphodiesterase inhibitor. Under optimal conditions, i.e., 20 μM‐GTP and 100 mM‐Na+, Leu5‐enkephalin inhibited the striatal adenylate cyclase activity by 23–27%. When the enkephalin regulation of the cyclase activity was further characterized, it was observed that Leu5‐enkephalin inhibited the rate of the enzymatic reaction. Kinetic analysis revealed that the opioid peptide decreases Vmax values but not the Km values for the substrates Mg2+ and Mg‐ATP. Agents such as MnCl2, NaF, and guanyl‐5′‐ylimido‐diphosphate, which directly activated the adenylate cyclase, antagonized the opiate inhibition. Levorphanol and (–)naloxone were more potent than dextrorphan and (+)naloxone in inhibiting adenylate cyclase and in reversing the enkephalin inhibition, respectively. There were differences in the potencies of various opiate peptides in their inhibition of striatal adenylate cyclase activity, with Met5‐ > Leu5‐enkephalin > β‐endorphin. The opiate receptor through which the enkephalin inhibition was observed is most likely δ in nature, since in the presence of either Na+ or K+, the magnitude of the alkaloid inhibition was reduced, whereas the peptide inhibition was either potentiated or not affected.

Bacillary Angiomatosis and Bacillary Splenitis in Immunocompetent Adults

Bacillary angiomatosis and parenchymal bacillary peliosis are recently described vascular disorders associated with infection by Rochalimaea henselae and Rochalimaea quintana, which occur in patients with either human immunodeficiency virus (HIV) infection or drug-induced immune suppression [1-5]. In addition, R. henselae and R. quintana (also the agent of trench fever) are both members of the family Rickettsiaceae [1, 4, 5], and infections due to Rochalimaea species have been associated with exposure both to cats [2] and to arthropod vectors [1, 5]. We describe five patients with cutaneous bacillary angiomatosis or bacillary splenitis without evidence of HIV infection who were determined to be immunocompetent after immunologic evaluation. In three patients with both cat and cat flea exposures, infection by R. henselae was confirmed by amplification and sequencing of 16S rDNA from an infected tissue specimen. Methods Four patients with characteristic vascular lesions of cutaneous bacillary angiomatosis [1, 3] were examined. Patient 2, who lacked vascular lesions, had a 2-week history of left-sided abdominal pain, shortness of breath, low-grade fever, nausea, diarrhea, and weight loss of 3.5 kg. Results of laboratory studies included hematocrit, 0.21 (2 months before it had been 0.34); lactate dehydrogenase, 1170 U/L; total bilirubin, 53 mol/L (3.1 mg/dL); conjugated bilirubin, 24 mol/L (1.4 mg/dL); and mildly elevated hepatic transaminases and alkaline phosphatase. A computed axial tomography scan of the abdomen showed a normal liver and hypersplenism with a 4-cm2 area of focal low attenuation. The patient underwent emergency splenectomy for impending rupture. The 1100-g spleen revealed a 4.5-cm3 mottled area consistent with infarction and two 0.6-cm3 tan nodules beneath the capsular surface. Results of routine bacterial cultures were negative. In June 1991, all five patients had blood drawn for HIV culture, serologic analysis, and polymerase chain reaction studies using techniques described previously [6, 7]. In August 1991, all patients had blood drawn for immunologic evaluation, including quantitative immunoglobulins, complement, lymphocyte subset percentages, neutrophil oxidative burst [8, 9], T-lymphocyte activation studies to phytohemagglutinin, and B-lymphocyte activation studies to pokeweed mitogen [10, 11]. After their blood was drawn, patients had skin test antigens to purified protein derivative, mumps, Trichophyton, and Candida albicans placed and read at 48 hours. The diagnosis of cutaneous bacillary angiomatosis was established using defined histopathologic criteria [3]. Bacterial DNA present in the infected tissue specimen was extracted from either frozen skin biopsy tissue (Patient 4) or from sections of formalin-fixed, paraffin-embedded biopsy specimens [1, 12]. Insufficient tissue was available from Patients 1 and 3. Extracted DNA was amplified by polymerase chain reaction using primers p24E and p12B [1, 12]. Control tissues were simultaneously extracted and amplified [1]. Amplified 16S rDNA products from Patients 2, 4, and 5 were sequenced as described previously [1]. Results Only Patient 2 had a well-documented antecedent chronic illnesshereditary spherocytosis and noninsulin-dependent diabetes mellitusand no patient was receiving immunosuppressive drugs (Table 1). Idiopathic hemochromatosis was diagnosed concomitantly with bacillary angiomatosis in Patient 3. All patients responded to oral antimicrobial therapy of 4 to 6 weeks duration. Histologic examination of skin biopsy specimens from Patients 1, 3, 4, and 5 were diagnostic of bacillary angiomatosis; splenic tissue from Patient 2 showed necrotizing splenitis with fibromyxoid changes, degenerating neutrophils, and mononuclear cells in the absence of both vascular proliferation and granuloma formation. Specimens from all patients showed many bacilli on both Warthin-Starry staining and electron microscopic examination. Table 1. Characteristics of Immunocompetent Patients with Bacillary Angiomatosis and Bacillary Splenitis Amplification of the DNA extracted from infected tissue from Patients 2, 4, and 5 produced a 16S rDNA fragment of approximately 300 base pairs. The amplified DNA fragment from tissue of Patients 2 and 4 is shown in Figure 1. The sequence of this 16S rDNA fragment from Patients 2, 4, and 5 was identical to that of R. henselae [4, 12]. Figure 1. Amplification of Rochalimaea DNA. Rochalimaea henselae R. henselae Discussion We evaluated four patients with cutaneous bacillary angiomatosis and one with bacillary splenitis and found no evidence of HIV infection using a combination of sensitive HIV antibody and antigen assays, as well as viral culture and polymerase chain reaction techniques. In addition, both cellular and humoral immunity were evaluated and no abnormality was found. Because host defense mechanisms against Rochalimaea species are not well understood, defects may have been undetected by our methods. Two patients had underlying illnesses that may be associated with altered immune function, but no consistent immune defect has been associated with these conditions [13-15]. The histopathologic findings were diagnostic for bacillary angiomatosis in all four patients with cutaneous disease; tissue from Patient 2 showed necrotizing splenitis with characteristic bacillary organisms [3, 12]. Amplification and sequencing of rDNA from tissue of Patients 2, 4, and 5 confirmed that the infecting organism was R. henselae. Although we cannot speciate the bacilli seen in abundance with the Warthin-Starry stains of Patients 1 and 3, the histopathologic changes met all criteria for the diagnosis of cutaneous bacillary angiomatosis [3], a disease associated with R. henselae and R. quintana [1]. Bacillary splenitis in the absence of peliosis appears to be another manifestation of R. henselae infection. A clinical spectrum of R. henselae infection may exist, beginning with fever and bacteremia, progressing to bacillary splenitis and finally to bacillary peliosis. Differences in host immune function also may play a role in disease progression. The diagnosis of cutaneous bacillary angiomatosis and bacillary splenitis should be pursued in the immunocompetent patient when clinical or histopathologic features are suggestive. On the basis of these five patients, we recommend treatment with erythromycin or doxycycline for at least 6 weeks when the diagnosis is confirmed.

BARTONELLA-ASSOCIATED INFECTIONS

Bartonella-associated infections occur in immunocompetent and immunocompromised patients. The spectrum of diseases caused by Bartonella species has expanded and now includes cat-scratch disease, bacillary angiomatosis, bacillary peliosis, bacteremia, endocarditis, and trench fever. Most Bartonella-associated infections that occur in North America and Europe are caused by B. henselae or B. quintana. The domestic cat serves as the major reservoir for B. henselae; the reservoir for the modern day B. quintana infection remains unknown. Methods used to diagnose Bartonella-associated infections include histopathologic analysis of biopsy specimens, culture of tissue samples, blood culture, and serology. Available data on treatment of Bartonella-associated infections remain relatively sparse but would suggest that erythromycin or doxycycline provide the best responses.

Experimental and natural infection with Bartonella henselae in domestic cats

Domestic cats were experimentally infected with culture propagated Bartonella henselae by intradermal (i.d.) and intravenous (i.v.) routes. Cats were more efficiently infected by the i.d. (8/8 cats) than by the i.v. (2/16) route. Bacteremia was detected 1-3 weeks following inoculation and lasted for most cats for 1-8 months. However, one naturally infected cat was observed for 24 months and was found to be cyclically bacteremic, with bacterial levels varying one hundred fold or more from one period to another. No clinical or hematologic abnormalities were observed in any of the infected cats, even at the peak of bacteremia. Two cats that had become abacteremic were resistant to reinfection when inoculated with B. henselae a second time. Horizontal transmission through intimate contact between bacteremic and susceptible cats did not occur, and antibody positive bacteremic queens did not transmit the infection to their kittens in utero, peri-partum or post-partum. Only four of the 18 kittens acquired detectable levels of maternal antibody following nursing, which disappeared by 6 weeks of age. These studies indicate that B. henselae exists in an almost perfect host-parasite relationship with its feline host, but that most cats can ultimately rid themselves of the infection. The susceptibility of cats to intradermal infection and the lack of direct cat-cat transmission are compatible with possible arthropod vectors.

Foscarnet Therapy for Severe Acyclovir-Resistant Herpes Simplex Virus Type-2 Infections in Patients with the Acquired Immunodeficiency Syndrome (AIDS): An Uncontrolled Trial

STUDY OBJECTIVE To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Open-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection. SETTING Medical floors of acute care hospital. PATIENTS Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2. INTERVENTION Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days. MEASUREMENT AND MAIN RESULTS All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces. CONCLUSION Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.