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Introduction: In our study, we aimed to evaluate the epidemiological features of brucellosis and the efficacy of different treatment options in patients with various organ involvements., Methodology: Patients diagnosed with brucellosis and treated in two different centers between 2009 and 2019 were retrospectively screened and evaluated regarding epidemiological and clinical features, laboratory findings, and treatment responses., Results: The study included 297 complete-data patients (76% of rural patients were farmers). Farming (76%) and raw dairy (69%) were the main transmission methods. Most patients (98.6%) had positive tube agglutination tests. Ninety-two patients' blood and bodily fluid cultures grew Brucella spp. The incidence of leukopenia was 18.8%, thrombocytopenia 10.7%, anemia 34.3%, and pancytopenia 4.3%. Doxycycline and rifampicin were the major treatments, with streptomycin utilized in osteoarticular patients. Pregnant women with neurobrucellosis took ceftriaxone and trimethoprim-sulfamethoxazole. After one year, 7.1% of patients relapsed. Doxycycline + streptomycin and doxycycline + rifampicin had similar relapse rates (p = 0.799). The double- and triple-antibiotic groups had identical recurrence rates (p = 0.252)., Conclusions: In uncomplicated brucellosis cases doxycycline + streptomycin and doxycycline + rifampicin treatments were equally effective. Again, there is no statistical difference in relapse development rates between double and triple combination treatments in uncomplicated brucellosis cases. Relapsed patients generally miss follow-ups, interrupt therapy, have osteoarticular involvement, and get short-term treatment. Patients with focused participation should be thoroughly checked at diagnosis and medicine, and treatment should be lengthy to prevent relapses., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Mustafa Arslan, Barış Ertunç, Muhammed Emin Düz, Elif Menekşe, Burak Yasin Avci, Ecem Avci, Gürdal Yilmaz.)

Brucellosis remains one of the major zoonotic diseases worldwide. As a causative agent of brucellosis, it has many ways to evade recognition by the immune system, allowing it to replicate and multiply in the host, causing significant harm to both humans and animals. The pathogenic mechanism of Brucella has not been elucidated, making the identification of drug targets from the pathogenic mechanism a challenge. Metalloenzymatic targets and some protein targets unique to Brucella are exploitable in the development of inhibitors against this disease. The development of specific small molecule inhibitors is urgently needed for brucellosis treatment due to the antibiotic resistance of Brucella . This review summarizes the research on small molecule inhibitors of Brucella , which could be instructive for subsequent studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Brucellosis is an endemic zoonotic disease caused by Brucella species, which are intramacrophage pathogens that make treating this disease challenging. The negative effects of the treatment regime have prompted the development of new antimicrobials against brucellosis. A new treatment modality for antibiotic-resistant microorganisms is the use of nanoparticles (NPs). In this study, we examined the antibacterial activities of silver and gold NPs (SNPs and GNPs, respectively), the resistance developed by Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) strains and the toxicity of both of these NPs in experimental rats. To test the bactericidal effects of the SNPs and GNPs, we used 22 multidrug-resistant Brucella isolates (10 B. melitensis and 12 B. abortus). The minimal inhibitory concentrations (MICs) of both types of NPs were determined utilizing the microdilution technique. To test the stability of resistance, 7 B. melitensis and 6 B. abortus isolates were passaged ten times in culture with subinhibitory concentrations of NPs and another ten times without NPs. Histopathological analysis was completed after rats were given 0.25, 0.5, 1, and 2 mg/kg NPs orally for 28 consecutive days. The MIC values (μg/ml) of the 10-nm SNPs and 20-nm GNPs against B. melitensis were 22.43 ± 2.32 and 13.56 ± 1.22, while these values were 18.77 ± 1.33 and 12.45 ± 1.59 for B. abortus, respectively. After extensive in vitro exposure, most strains showed no resistance to the 10-nm SNPs or 20-nm GNPs. The NPs and antibiotics did not cross-react in any of the evolved Brucella strains. SNPs and GNPs at doses below 2 mg/kg were not harmful to rat tissue according to organ histopathological examinations. However, a greater dose of NPs (2 mg/kg) harmed all of the tissues studied. The bactericidal properties of NPs are demonstrated in this work. Brucella strains develop similar resistance to SNPs and GNPs, and at low dosages, neither SNPs nor GNPs were hazardous to rats., Competing Interests: The authors have declared that no competing interests exist.

Background: Brucellosis is a worldwide zoonotic disease that causes serious public health problems. This study aimed to identify Brucella strains isolated from various clinical samples by conventional and molecular methods and to determine antimicrobial susceptibilities against doxycycline (DOX), streptomycin (STR), ciprofloxacin (CIP) and rifampicin (RIF) by the gradient strip (E test) test method., Methods: A total of 87 Brucella strains isolated from various clinical specimens between 2004 and 2018 were included in this study. While four of the 87 strains included in the study were identified only at the genus level, the remaining 83 strains were identified at the species level by the Real-Time Multiplex PCR (M-RT-PCR) method and conventional methods were used for biotyping., Results: According to molecular identification results, 83 strains were identified as B. melitensis by the M-RT-PCR method, with 82 strains identified as Brucella melitensis biovar (bv) 3 and one as B. melitensis bv 1 according to the conventional biotyping method. Among the antibiotics studied, CIP was found to be the most active agent according to the minimum inhibitory concentrations (MIC) 90 values. This was followed by DOX and STR, respectively. While all of the isolates were sensitive to CIP, DOX and STR, 18 (20.7%) strains were found to be moderately susceptible to RIF, with the highest values of MIC 50 and MIC 90 ., Conclusions: In our study, all strains were identified as B. melitensis. DOX, STR, CIP and RIF used in the treatment of brucellosis were found to be effective.

Introduction: Brucellosis is a zoonotic disease caused by Brucella spp. affecting multiple body systems and may lead to complications. Saudi Arabia is a country where brucellosis is endemic. This study aimed to describe the epidemiological characteristics of uncomplicated brucellosis and to assess outcomes of different antibiotic regimens., Methodology: A retrospective cohort study in a Saudi tertiary academic medical center. Adults with confirmed uncomplicated brucellosis between January 2008 and December 2018 who received antibiotics were included. The primary endpoint was clinical cure. Secondary endpoints included all-cause mortality and length of stay., Results: Fifty-four patients met the inclusion criteria and were included in the study. Twenty five patients received a combination of doxycycline, rifampin, and aminoglycoside (group 1), whereas 29 patients received doxycycline and rifampin (group 2). There was no significant difference between the two groups in clinical cure, all-cause mortality, length of stay, and end of therapy parameters, including temperature, white blood cells count, C-reactive protein levels, and erythrocyte sedimentation rates., Conclusions: Due to lack of differences in clinical outcomes, mortality, length of stay, and end of therapy parameters between the two groups, a regimen comprising two, rather than three, agents can be sufficient for uncomplicated brucellosis. This finding conforms to previous studies. Therefore, replacing rifampin with an aminoglycoside for its presumed superior efficacy as per the World Health Organization's guidelines is not substantiated by our study. Further studies with a larger sample size are required to confirm these findings., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Rawan O Al-Madfaa, Mai A Alalawi, Lana O Basudan, Shahad F Alhejaili, Khalid Eljaaly, Tariq A Madani, Abrar K Thabit.)

A study was conducted to examine the prevalence of brucellosis (in animal farms) in the vicinity of Islamabad and Rawalpindi. A total of 170 milk samples were collected randomly from several farmhouses. The collected milk samples were initially screened by a Brucella selective medium. The bacterial isolates grown on the selective medium were subjected to biochemical identification for further confirmation of Brucella species. Among the tested samples, 28 (16.4%) were found positive for selective medium and 14 (8.2%) were found positive after biochemical confirmation. The antimicrobial susceptibility of several antibiotics performed by the disc-diffusion method did not yield any significant findings. Encapsulating antimicrobial drugs in unilamellar niosomes is an effective approach to treat the endemic infection. In this study, the antimicrobial activity of niosome-encapsulated levofloxacin is compared with free drug. The drug-encapsulating and empty niosomes were synthesized by using two surfactants Tween 80 and Span 40. Niosomal characterization included electron microscopy, dynamic light scattering, and zeta potential. The encapsulation efficiency was found to be 78% and 74% for Span 40 and Tween 80 niosomes, respectively. The antibacterial activity of niosomal levofloxacin was evaluated against the identified Brucella species and the antimicrobial activity of the free drug was increased many folds after encapsulation. In this study, levofloxacin niosomes were successfully synthesized against Brucellosis., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: To determine blood Brucella DNA loads between brucellosis patients and those without brucellosis., Methods: The patient group included 350 brucellosis patients. The control was composed of 200 subjects without brucellosis. The extracted DNA from blood was tested by quantitative polymerase chain reaction (qPCR). The cutoff value was determined by receiver operating characteristic curve analysis. A portion of the brucellosis patients were monitored by qPCR during therapy., Results: The detection limit of qPCR was between 1E+01cfu/μL and 1E+08cfu/μL. The standard curve R 2 reached 0.998. The cutoff value was 4E+01cfu/μL, which was determined by comparison of the patient group and the control. The qPCR assay had a specificity of 100% and a sensitivity of 93.14%. The monitoring results showed that the Brucella DNA load decreased in most patients during the first 4 weeks of treatment. One patient with bad treatment compliance showed a rebound., Conclusions: The qPCR results were in accordance with the course of brucellosis in the clinic. The DNA load often reflects the situation of the Brucella-infected patient. The cutoff value provides an important reference of infection. This qPCR-based method can be used to assist in the diagnosis of brucellosis and to adjust the therapy., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brucellosis in pregnant women is reported to be associated with obstetric complications (OCs), and adequate data for human brucellosis during pregnancy are largely lacking. We performed this multicenter retrospective cross-sectional study to evaluate the epidemiology, clinical course, treatment responses, and outcomes of brucellosis among pregnant women. The study period comprised a 14-year period from January 2002 to December 2015. All consecutive pregnant women diagnosed with brucellosis in 23 participating hospitals were included. Epidemiological, clinical, laboratory, therapeutic, and outcome data along with the assessment data of the neonate were collected using a standardized questionnaire. Data of 242 patients were analyzed. The OC rate was 14.0% (34/242) in the cohort. Of the 242 women, 219 (90.5%) delivered at term, 3 (1.2%) had preterm delivery, 15 (6.2%) aborted, and 5 (2.1%) had intrauterine fetal demise. Seventeen (7.0%) of the newborns were considered as low birth weight. Spontaneous abortion (6.1%) was the commonest complication. There were no maternal or neonatal deaths and pertinent sequelae or complications were not detected in the newborns. Splenomegaly (p = 0.019), nausea and/or vomiting (p < 0.001), vaginal bleeding (p < 0.001), anemia (blood hemoglobin < 11 g/dL; p < 0.001), high level of serum aspartate aminotransferase (> 41 IU/L; p = 0.025), oligohydramnios on ultrasonography (p = 0.0002), history of taking medication other than Brucella treatment during pregnancy (p = 0.027), and Brucella bacteremia (p = 0.029) were the significant factors associated with OCs. We recommend that pregnant women with OC or with fever should be investigated for brucellosis if they live in or have traveled to an endemic area.

Brucellosis is a debilitating febrile illness caused by an intracellular Brucella. The disease is distributed in humans and animals widely, especially in developing countries. Ten species are included in the genus Brucella nowadays; four species of them are pathogenic to humans, which make brucellosis a zoonosis with more than 500,000 new cases reported annually. For human brucellosis, the most pathogenic species is B. melitensis followed by B. suis, while B. abortus is the mildest type of brucellosis. The infection mechanism of Brucella is complicated and mostly relies on its virulence factors. The therapy of the disease contains vaccination and antibiotic. However, there are some defects in currently available vaccines such as the lower protective level and safety. Thus, safe and efficient vaccines for brucellosis are still awaited. The dual therapy of antibacterial is effective in the treatment of brucellosis if a rapid and exact detection method is found., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Leptospira , Brucella , and Borrelia are major agents of zoonotic disease, causing high morbidity and, in some cases, significant mortality in humans. For all three genera, prompt diagnosis and appropriate antimicrobial therapy are required to prevent the development of chronic, debilitating illness. Leptospira spp. are intrinsically resistant to several antimicrobial classes; however, there is little evidence in the literature for development of acquired resistance to antimicrobial agents used for clinical treatment of acute leptospirosis. For Brucella infections, there are numerous reports of relapses following therapy, but it is unclear whether this is due to sequestration within infected sites (e.g., bone) or the development of acquired resistance. Brucella have maintained their susceptibility to doxycycline and rifampicin, which in combination remain the most common treatments of brucellosis in humans. In vitro induced point mutations are described as imparting resistance to rifampicin ( rpoB ) and fluoroquinolones ( gyrA ). The clinical significance of these mutations is unclear. For Borrelia burgdorferi , although acquired resistance to some antimicrobial agents has been described, resistance due to bacterial persister cells surviving in the presence of antimicrobial, with no apparent increase in the MIC of the organism, have been recently described. Of the remaining veterinary fastidious pathogens, Lawsonia intracellularis is the most interesting from an antimicrobial resistance perspective because it can only be grown in cell culture, making in vitro susceptibility testing challenging. MIC testing has been undertaken on a small number of isolates, and some differences in susceptibility to macrolides have been demonstrated between isolates obtained from different regions.

Diffuse spinal arachnoiditis in neurobrucellosis is a rare manifestation. We report a boy aged 17, presenting with hearing impairment and recurrent vomiting for 18 months, weight loss for 12 months, dysphagia, dysarthria, hypophonia for 6 months, and gait unsteadiness for 5 months. He had bilateral 5th (motor) to 12th cranial nerve palsy, wasting and weakness of limbs, fasciculations, absent tendon reflexes, and positive Babinski's sign. Cerebrospinal fluid (CSF) showed raised protein and pleocytosis. Magnetic resonance imaging (MRI) showed extensive enhancing exudates in cisterns and post-contrast enhancement of bilateral 5th, 6th, 7th, and 8th nerves. Spine showed clumping with contrast enhancement of the cauda equina roots and encasement of the cord with exudates. Serum and CSF were positive for anti- Brucella antibodies. He showed significant improvement with antibiotics. At 4 months follow-up, MRI demonstrated near complete resolution of cranial and spinal arachnoiditis. It is important to recognize such rare atypical presentations of neurobrucellosis.

Objective: To investigate the antimicrobial susceptibility of Brucella and to provide a scientific basis for rational drug use and effective treatment of patients with brucellosis. Methods: A total of 41 Brucella strains were isolated from the blood of patients with brucellosis in 5 counties and 2 districts in Yuxi City, China from 2014 to 2016. The susceptibility to 23 antimicrobial drugs was tested using Kirby-Bauer (K-B) disk diffusion method and the sizes of antimicrobial rings were recorded. The susceptibility testing results were interpreted according to the Drug Susceptibility Testing Guideline (2009 version) . Results: The susceptibility rate of Brucella was 100.00% to ofloxacin, ciprofloxacin, levofloxacin, and amikacin and >90% to cefotaxime, cefepime, imipenem, doxycycline, cefoperazone, minocycline, tobramycin, rifampicin, cefoperazone/sulbactam, and chloramphenicol. The high resistance to aztreonam and ampicillin was observed (87.80% and 41.46%). Doxycycline-intermediate strains, rifampicin-intermediate strains, and rifampicin-resistant strains were identified. Conclusion: Doxycycline and rifampicin are commonly used in the treatment of brucellosis, but doxycycline/rifampicin-intermediate and-resistant strains have been identified. The susceptibility of Brucella to fluoroquinolones and cephalosporins was high, so the two drugs can be considered in the treatment of brucellosis.

Brucellosis is a worldwide zoonotic disease and still continuous to be a major public health problem. In this study, it was aimed to identify the Brucella strains to the species level isolated from blood cultures, and to determine the rate of antimicrobial susceptibility against eleven antibacterial agents. A total of 106 Brucella spp. strains were included in the study, which were isolated from blood cultures in University of Health Sciences, Konya Training and Research Hospital, Medical Microbiology Laboratory between January 2011 and June 2013. Identification of the isolated strains were mainly based on conventional methods. In vitro antibacterial susceptibilities of azithromycin, ciprofloxacin, doxycycline, gentamicin, levofloxacin, moxifloxacin, rifampicin, streptomycin, tetracycline, tigecycline, and trimethoprim/sulfamethoxazole, were evaluated by using the gradient (E-test, bioMerieux, France) strip method. The bacterial suspensions adjusted to 0.5 McFarland turbidity was inoculated to Mueller Hinton agar plates, supplemented with 5% sheep blood, and E-test strips of selected antibacterial were applied. The plates were incubated in ambient air 48 hours at 37ºC and Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 were used as quality control strains for antimicrobial susceptibility testing. Minimum inhibitors concentration (MIC) values were interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines for slow-growing bacteria such as Haemophilus spp. Of the 106 Brucella spp. strains included in to the study, 90 were identified as Brucella melitensis, and 16 were Brucella abortus. MIC90 values of azithromycin, ciprofloxacin, doxycycline, gentamicin, levofloxacin, moxifloxacin, rifampicin, streptomycin, tetracycline, tigecycline, and trimethoprim/sulfamethoxazole were determined as 1 µg/ml, 0.25 µg/ml, 0.19 µg/ml, 0.25 µg/ml, 0.19 µg/ml, 0.75 µg/ml, 0.25 µg/ml, 0.75 µg/ml, 0.38 µg/ml, 0.64 µg/ml, and 0.19 µg/ml respectively. According to MIC90 values, gentamicin, moxifloxacin, and trimethoprim/sulfamethoxazole, were the most effective antibacterial agents. All the Brucella strains were sensitive to all the tested antibacterial agents except rifampicin. Only six isolates showed intermediate susceptibility to rifampicin. With regard to fluoroquinolones, the most active antibacterial agent was moxifloxacin, followed by ciprofloxacin and levofloxacin. In our study, no resistance was found for the classically recommended antibacterial agents used in the treatment of Brucella species in our hospital but antibiotic susceptibility patterns of Brucella spp. may vary geographically. As a result it was concluded that, the antimicrobial susceptibilities of Brucella species should be determined and controlled periodically to avoid the possible development of resistance problems in the future.

Brucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.

Aims: To discuss together the novel cases of Brucella infections in frogs with the results of published reports to extend our current knowledge on 'atypical' brucellae isolated from amphibians and to discuss the challenges we face on this extraordinary emerging group of pathogens., Methods and Results: Since our first description, an additional 14 isolates from four different frog species were collected. Novel isolates and a subset of Brucella isolates previously cultured from African bullfrogs were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), Fourier transform-infrared (FT-IR) spectroscopy and broth microdilution susceptibility testing. MALDI-TOF MS worked very efficiently for an accurate bacterial identification to the genus level. Within the cluster analysis, 'atypical' brucellae grouped distant from Brucella melitensis and were even more separated by FT-IR spectroscopy with respect to their geographical origin. Minimum inhibitory concentrations of 14 antimicrobial substances are provided as baseline data on antimicrobial susceptibility., Conclusions: The case history of Brucella infections in amphibians reveals a variety of pathologies ranging from localized manifestations to systemic infections. Some isolates seem to be capable of causing high mortality in zoological exhibitions putting higher demands on the management of endangered frog species. There is considerable risk in overlooking and misidentifying 'atypical' Brucella in routine diagnostics., Significance and Impact of the Study: Brucella have only recently been described in cold-blooded vertebrates. Their presence in frog species native to Africa, America and Australia indicates a more common occurrence in amphibians than previously thought. This study provides an extensive overview of amphibian brucellae by highlighting the main features of their clinical significance, diagnosis and zoonotic potential., (© 2016 The Society for Applied Microbiology.)

The brucellosis is an actual zoonotic disease in many countries, Russia included. The complexity of individual prognosis of disease and choice of tactics of maintenance of patients is explained by heterogeneity of clinical manifestations of brucellosis and different rate of progression of organs pathology. Despite of low mortality, this pathology quite often results in disability of patient. The frequent transition of acute process into chronic one (40-60%), probability of development of primary chronic brucellosis determines interest of researchers to issues of immunopathogenesis of this disease. The article presents review of achievements in studies of polymorphism of genes of gamma-interferon in the given area.

We describe a simple protocol to inactivate the biosafety level 3 (BSL3) pathogens Brucella prior to their analysis by matrix-assisted laser desorption ionization-time of flight mass spectrometry. This method is also effective for several other bacterial pathogens and allows storage, and eventually shipping, of inactivated samples; therefore, it might be routinely applied to unidentified bacteria, for the safety of laboratory workers., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Brucellosis, a worldwide zoonosis, is linked to reproductive problems in primary hosts. A high proportion of Brucella-positive hooded seals (Cystophora cristata) have been detected in the declined Northeast Atlantic stock. High concentrations of polychlorinated biphenyls (PCBs) have also been discovered in top predators in the Arctic, including the hooded seal, PCB 153 being most abundant. The aim of this study was to assess the pathogenicity of Brucella pinnipedialis hooded seal strain in the mouse model and to evaluate the outcome of Brucella spp. infection after exposure of mice to PCB 153. BALB/c mice were infected with B. pinnipedialis hooded seal strain or Brucella suis 1330, and half from each group was exposed to PCB 153 through the diet. B. pinnipedialis showed a reduced pathogenicity in the mouse model as compared to B. suis 1330. Exposure to PCB 153 affected neither the immunological parameters, nor the outcome of the infection. Altogether this indicates that it is unlikely that B. pinnipedialis contribute to the decline of hooded seals in the Northeast Atlantic., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Three culture media (Brucella agar, Farrell medium, and CITA) were compared for their effectiveness in inhibiting contamination and for isolating Brucella spp. One hundred lymph nodes from pigs (n = 50) and wild boars (n = 50) with lymphadenitis were collected in slaughterhouses in the State of São Paulo and were assessed on these three selective media for Brucella spp. All of the samples were negative for Brucella spp. on the three culture media. On the agar medium, fungal (70 plates) and Gram-positive bacterial (59 plates) contaminants were observed; in the CITA medium, the absence of fungal and Gram-positive bacteria on 15 plates was observed; no bacterial or fungal growth was observed on the Farrell media. The results demonstrated that the CITA and Farrell media inhibited the growth of contaminants better than the Brucella agar.

Background: Brucellosis poses a significant public health problem in Mediterranean countries, including Egypt. Treatment of this disease is often empirical due to limited information on the antibiotic susceptibility profiles of Brucella spp. in this region of the world. The aim of this study was to determine the antibiotic susceptibility profiles of Brucella blood isolates in Egypt, a country endemic for brucellosis., Methods: Brucella spp. isolates were identified from the blood cultures of acute febrile illness (AFI) patients presenting to a network of infectious disease hospitals from 1999-2007. Minimum inhibitory concentrations were determined for tetracycline, gentamicin, doxycycline, trimethoprim-sulfamethoxazole, streptomycin, ceftriaxone, ciprofloxacin and rifampin using the E-test. Interpretations were made according to Clinical and Laboratory Standards Institute (CLSI) guidelines., Results: A total of 355 Brucella spp. isolates were analyzed. All were susceptible to tetracycline, doxycycline, trimethoprim-sulfamethoxazole, streptomycin and ciprofloxacin; probable resistance to rifampin and ceftriaxone was observed among 277 (64%) and 7 (2%) of the isolates, respectively. Percentages of isolates showing probable resistance to rifampin were significantly lower before 2001 than in the following years (7% vs. >81%, p < 0.01)., Conclusions: Despite the high burden of brucellosis in Egypt and frequent empirical treatment, isolates have remained susceptible to the majority of tested antibiotics. However, this is the first report of high rates of probable resistance to rifampin among Brucella isolates from Egypt. Patients should be closely monitored while following standard treatment regimens. Continued surveillance, drug susceptibility studies and updated CLSI interpretive criteria are needed to monitor and update antibiotic prescribing policies for brucellosis.

No data on whether brucellar meningitis or meningoencephalitis can be treated with oral antibiotics or whether an intravenous extended-spectrum cephalosporin, namely, ceftriaxone, which does not accumulate in phagocytes, should be added to the regimen exist in the literature. The aim of a study conducted in Istanbul, Turkey, was to compare the efficacy and tolerability of ceftriaxone-based antibiotic treatment regimens with those of an oral treatment protocol in patients with these conditions. This retrospective study enrolled 215 adult patients in 28 health care institutions from four different countries. The first protocol (P1) comprised ceftriaxone, rifampin, and doxycycline. The second protocol (P2) consisted of trimethoprim-sulfamethoxazole, rifampin, and doxycycline. In the third protocol (P3), the patients started with P1 and transferred to P2 when ceftriaxone was stopped. The treatment period was shorter with the regimens which included ceftriaxone (4.40 ± 2.47 months in P1, 6.52 ± 4.15 months in P2, and 5.18 ± 2.27 months in P3) (P = 0.002). In seven patients, therapy was modified due to antibiotic side effects. When these cases were excluded, therapeutic failure did not differ significantly between ceftriaxone-based regimens (n = 5/166, 3.0%) and the oral therapy (n = 4/42, 9.5%) (P = 0.084). The efficacy of the ceftriaxone-based regimens was found to be better (n = 6/166 [3.6%] versus n = 6/42 [14.3%]; P = 0.017) when a composite negative outcome (CNO; relapse plus therapeutic failure) was considered. Accordingly, CNO was greatest in P2 (14.3%, n = 6/42) compared to P1 (2.6%, n = 3/117) and P3 (6.1%, n = 3/49) (P = 0.020). Seemingly, ceftriaxone-based regimens are more successful and require shorter therapy than the oral treatment protocol.

Objectives: To determine risk factors in children for the acquisition of Brucella, clinical presentation, treatment, and disease outcomes., Methods: A retrospective multicenter chart review was undertaken of children identified with brucellosis from 1986 to 2008 at three tertiary care centers in Chicago, Illinois, USA. The charts were reviewed for data regarding risk factors for acquisition, clinical presentation, and outcomes., Results: Twenty-one charts were available for review. The median age was 6.5 years (range 2-14 years); 62% were female. Ethnic background was 67% Hispanic and 24% Arabic. Risk factors included travel to an endemic area (86%), particularly Mexico, and consumption of unpasteurized milk products (76%). Common findings included fever (95%), bacteremia (86%), elevated liver transaminases (80%), constitutional symptoms (76%), splenomegaly (60%), and hepatomegaly (55%). Relapse occurred in three of six subjects started on single drug treatment, but in only one of 15 subjects who started on two or more drugs (p=0.053). No relapses occurred in children whose initial therapy included rifampin or those administered three-drug regimens., Conclusions: Brucella is an infrequent pathogen but should be considered in children with compatible epidemiologic and clinical characteristics. Blood cultures should be obtained, and initial therapy with two or more drugs may decrease the risk of relapse., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Brucellosis is a worldwide zoonosis with a huge economic impact on animal husbandry and public health. The diagnosis of human brucellosis can be protracted because the disease primarily presents as fever of unknown origin with unspecific clinical signs and symptoms. The isolation rate of the fastidious etiologic agent from blood cultures is low, and therefore laboratory diagnosis is mainly based on serologic and molecular testing. However, seronegative brucellosis patients have been described, and antibody titers of diagnostic significance are difficult to define. Whether the molecular detection of Brucella DNA in clinical samples should be followed by long-term antibiotic treatment or not is also a matter of debate. The aim of this article is to review and discuss the implications of laboratory test results in the diagnosis of human brucellosis on disease therapy.

Bacteriological diagnosis of brucellosis is performed by culturing animal samples directly on both Farrell medium (FM) and modified Thayer-Martin medium (mTM). However, despite inhibiting most contaminating microorganisms, FM also inhibits the growth of Brucella ovis and some B. melitensis and B. abortus strains. In contrast, mTM is adequate for growth of all Brucella species but only partially inhibitory for contaminants. Moreover, the performance of both culture media for isolating B. suis has never been established properly. We first determined the performance of both media for B. suis isolation, proving that FM significantly inhibits B. suis growth. We also determined the susceptibility of B. suis to the antibiotics contained in both selective media, proving that nalidixic acid and bacitracin are highly inhibitory, thus explaining the reduced performance of FM for B. suis isolation. Based on these results, a new selective medium (CITA) containing vancomycin, colistin, nystatin, nitrofurantoin, and amphotericin B was tested for isolation of the main Brucella species, including B. suis. CITA's performance was evaluated using reference contaminant strains but also field samples taken from brucella-infected animals or animals suspected of infection. CITA inhibited most contaminant microorganisms but allowed the growth of all Brucella species, to levels similar to those for both the control medium without antibiotics and mTM. Moreover, CITA medium was more sensitive than both mTM and FM for isolating all Brucella species from field samples. Altogether, these results demonstrate the adequate performance of CITA medium for the primary isolation of the main Brucella species, including B. suis.

Purpose: Brucellosis is a worldwide zoonotic disease and still constitutes a major public health problem. In the study we claimed to identify Brucella species from clinical samples of patients with active brucellosis from Van region of Eastern Anatolia and to determine in vitro antimicrobial susceptibilities of these strains to commonly used anti-Brucella agents and a possible new alternative tigecycline., Materials and Methods: A total of 56 Brucella isolates were enrolled the study and the identification of the isolates were based on conventional methods. In vitro activities of antimicrobials were evaluated by the E test method., Results: All isolates were identified as B. melitensis. MIC(90) values of doxycycline, streptomycin, rifampin, trimethoprim-sulfamethoxazole and tigecycline were 0.064 mg/L, 1 mg/L, 2 mg/L, 0.125 mg/L and 0.094 mg/L, respectively. Tigecycline had low MIC(50) and MIC(90) values against all B. melitensis strains; the highest MIC observed was 0.25 μg/mL., Conclusion: Our data suggest that tigecycline can be a therapeutic alternative option for the treatment of brucellosis.

Brucella are resistant to polymyxin B (PB), but their relative susceptibility to PB and its derivative, colistin (COL) has not been rigorously or systematically studied. Comparative susceptibility of Brucella reference strains, vaccine strain RB51, and Brucella isolates from marine mammals to these two cationic peptides were determined by Etest. Vast differences among Brucella species were found in susceptibility to both PB and COL. Brucella demonstrated similar pattern of relative susceptibility to PB as that of COL, but they were less susceptible to COL. Both B. melitensis and B. suis were the least susceptible to polymyxins and rough strains were more susceptible to both PB and COL than the smooth except for the BvrR mutant. Strains were generally less susceptible to PB when cultured in CO(2) rather than ambient air; some became more susceptible in acidified medium. Results show that environment cultural conditions must be considered when selecting for CO(2)-independent strains of Brucella especially the vaccine strain RB51 on selective media containing PB. Our observations extend basic knowledge of the differential resistance of Brucella to polymyxins., (Published by Elsevier Ltd.)

Background: The standard agglutination (SAT) and 2-mercaptoethanol (2-ME) tests are usually used in the follow-up of treated cases of human brucellosis. The purpose of this study was to monitor the levels of these tests, two years after clinical cure in cases of brucellosis., Methods: From April 2003 to September 2008, 175 clinically cured cases of brucellosis (103 males, 72 females) were evaluated. Diagnosis of brucellosis was established with a SAT of > or =1:320 and a 2-ME of > or =1:80, with clinical symptoms and signs compatible with brucellosis. SAT and 2-ME were retested at the end of therapy and at 3-monthly intervals for two years. Serologic cure was considered in the event of a SAT titer decrease to < or =1:160 or a 2-ME decrease to<1:80., Results: The mean age of study patients was 31 +/- 13.5 years. At 6, 12, 18, and 24 months after treatment, SAT titers > or =1:320 were seen in 41 (23.4%), 22 (12.6%), 7 (4%), and 6 (3.4%) cases, respectively, whereas 2-ME titers > or =1:80 were seen in 51 (29.1%), 24 (13.7%), 12 (6.9%), and 8 (4.6%) cases, respectively. The probability of serologic cure for patients with SAT titers < or =1:640 was higher than for those >1:640 (95% confidence interval (CI) 2.5-3.47, p=0.023). The probability of serologic cure for patients with 2-ME titers < or =1:320 was higher than for those >1:320 (95% CI 2.48-3.5, p=0.04)., Conclusions: SAT and 2-ME may be found in significant titers in less than 5% of clinically treated cases after two years. Serologic cure for both tests with lower titers were higher than with higher titers., (Copyright 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Worldwide, human brucellosis is the most common zoonotic disease and it has gained increasing interest because of the potential use of Brucella as a biological weapon. Monotherapy for brucellosis is associated with a high relapse rate and dual therapy in different combinations is more efficacious. The combination regimen of intramuscular streptomycin with an oral tetracycline resulted in fewer relapses than the doxycycline-rifampin combination in meta-analysis and prospective studies, although the use of doxycycline and rifampin is a reasonable choice in certain conditions. Longer duration and triple antimicrobial therapy appear to improve outcome and prevent relapses, especially in patients with focal disease. Recently, the use of gentamicin-loaded microparticles and the use of new antibiotics, such as tigecycline, may hold future promise. In addition, there are a few studies of the enhanced effect of immune response stimulators, such as levimasole and IFN-2, in the treatment of brucellosis. The development of an effective subcellular Brucella vaccine would be an important step forward to curtail the disease. However, currently and for the near future, only the control of animal disease is possible using vaccine strategies.

Infection with Brucella spp. continues to pose a human health risk globally despite strides in eradicating the disease from domestic animals. Brucellosis has been an emerging disease since the discovery of Brucella melitensis by Sir David Bruce in 1887. Although many countries have eradicated B. abortus from cattle, in some areas B. melitensis and B. suis have emerged as causes of this infection in cattle, leading to human infections. Currently B. melitensis remains the principal cause of human brucellosis worldwide including India. The recent isolation of distinct strains of Brucella from marine mammals as well as humans is an indicator of an emerging zoonotic disease. Brucellosis in endemic and non-endemic regions remains a diagnostic puzzle due to misleading non-specific manifestations and increasing unusual presentations. Fewer than 10% of human cases of brucellosis may be clinically recognized and treated or reported. Routine serological surveillance is not practiced even in Brucella - endemic countries and we suggest that this should be a part of laboratory testing coupled with a high index of clinical suspicion to improve the level of case detection. The screening of family members of index cases of acute brucellosis in an endemic area should be undertaken to pick up additional unrecognised cases. Rapid and reliable, sensitive and specific, easy to perform and automated detection systems for Brucella spp. are urgently needed to allow early diagnosis and adequate antibiotic therapy in time to decrease morbidity / mortality. The history of travel to endemic countries along with exposure to animals and exotic foods are usually critical to making the clinical diagnosis. Laboratory testing is indispensable for diagnosis. Therefore alertness of clinician and close collaboration with microbiologist are essential even in endemic areas to correctly diagnose and treat this protean human infection. Existing treatment options, largely based on experience gained > 30 years ago, are adequate but not optimal. In our experience, an initial combination therapy with a three drug-regimen followed by a two-drug regimen for at least six weeks and a combination of two drugs with a minimum of six weeks seems warranted to improve outcome in children and adult patients respectively with laboratory monitoring. A safe and effective vaccine in humans is not yet available. Prevention is dependent upon the control of the disease in animal hosts, effective heat treatment of dairy produce and hygienic precautions to prevent occupational exposure. This review compiles the experiences and diagnostic and treatment paradigms currently employed in fighting this disease.

Polymerase chain reaction (PCR) was applied to confirm the diagnosis of brucellosis and to study its clearance in response to the standard treatment regimen with doxycycline and rifampin at hospitals in Callao and Lima, Peru. The PCR confirmed the diagnosis in 23 (91.7%) patients with brucellosis including 12 culture-confirmed cases. For patients treated at the hospital in Callao, PCR was positive for all samples collected during and at the conclusion of treatment and for 76.9% of follow-up samples collected on average 15.9 weeks after completion of treatment. For patients treated at the hospital in Lima, PCR tests were positive for 81.8% of samples collected during treatment, for 33.3% of samples collected at the conclusion of treatment, and for > or = 50% of samples collected at first, second, and third post-treatment follow-up. Thus, Brucella DNA may persist in the serum weeks to months after completion of the standard treatment regimen.

Brucellosis is a highly contagious bacterial zoonosis that affects millions of people worldwide. Brucella is highly infectious, especially when aerosolized. The infection induces severe protracted diseases, which are both debilitating and incapacitating, hence, Brucella melitensis has been considered a potential biological warfare agent. In the battle against Brucella, it is crucial to know its chemical-structure and biochemistry-metabolic characteristics. It is well known that Brucella, as well as many other intracellular bacterial pathogens, has evolved to survive and even proliferate within monocytes and macrophages cells. Depending on the route of entry (complement, Fc, lectin or fibronectin receptors), the fate of the bacteria will vary; it may even segregate from the endocytic route towards the endoplasmic reticulum. This intracellular "non regular" behaviour of Brucella makes treatment difficult. Most antibiotics, although effective in vitro, do not actively pass through cellular membranes, or, once inside, may not reach the discrete intracellular niche where the bacteria is hidden. Therefore, complete eradication of the microorganisms is difficult to achieve, and the incidence of relapses is rather high. Taking these data into consideration, this review will evaluate the past, current and new trends in the control of brucellosis, paying special attention to the drug delivery systems as potential vectors for targeting these intracellular sites where the organisms are located.

The global burden of human brucellosis remains enormous. Existing treatment options, largely based on experience gained > 30 years ago, are adequate but not optimal. The evolving understanding of the pathophysiology of the disease may augment in designing and evaluating alternative approaches that may prove to be superior. Current alternative approaches such as co-trimoxazole-containing regimens, should be widely evaluated as being more cost-effective. New methods of delivery such as gentamicin-loaded microparticles, neutralisation of the environment where Brucella resides and use of novel antibiotics such as tigecycline may be of importance in the future. The role of immunomodulation, widely but inconsistently applied in 'chronic' brucellosis, should be further evaluated in all disease stages to define if it is of any use. The development of a subcellular vaccine would be an important step forward although one has to take into account the multiple interactions between Brucella and the immune system, various technical problems and the lack of funds. Reviewing existing attempts at the development of such a vaccine, the authors conclude that a trivalent subcellular vaccine may be needed for adequate efficacy.

The efficacy and tolerability of three different combination treatment regimens in human brucellosis were compared in 118 uncomplicated patients enrolled in a prospective study between May 1997 and December 2002. Brucellosis was diagnosed using standard clinical and microbiological findings. Patients with central nervous system involvement, spondylitis, endocarditis or children under 16 years of age were excluded from the study. Patients were randomly assigned to receive 400 mg of ofloxacin plus 600 mg of rifampicin (OR, n = 41), 200 mg of doxycycline plus 600 mg of rifampicin (DR, n = 45) or 1g intramuscularly streptomycin (administered for three weeks) plus 200 mg doxycycline (DS, n = 32) daily for 6 weeks. All patients were followed up at least 6 months after cessation of therapy. There was no statistical difference between the groups on relapse rates and clinical response to the treatment (P>0.05). Five patients in OR (12.8%), six patients in DR (14.3%) and three patients in DS groups (9.7%) suffered relapse. The side-effects were seen in eight (19.5%), 21 (46.7%) and eight (25.0%) patients of OR, DR and DS groups, respectively. The use of combination therapy of ofloxacin plus rifampicin for 6 weeks was found to be as effective as DR and DS. The side-effects of therapy in OR and DS groups was less severe than in the DR group.

Treatment of uncomplicated brucellosis in humans utilises a variety of anti-biotic combinations, applied to a series of important pathogenetic and clinical parameters. The currently recommended treatment regimens have not been surpassed by newer compounds, and various therapeutic strategies utilising these compounds cannot be adequately evaluated due to the absence of large, multi-centre, multinational trials. The review focuses on the basic principles of brucellosis treatment, the properties of the various regimens used, the results of trials involving them, and the questions raised about the efficacy of these regimens in certain clinical situations.

In many parts of the world, brucellosis has significantly decreased, but it is still a problem in some regions of Turkey. Totally, 11 Brucella strains isolated from the blood cultures of patients with presumptive diagnosis of brucellosis were identified to species and biovar level. For species identification, (i) CO2 requirements of isolates; (ii) detection of urease activation; (iii) detection of H2S production; (iv) dye sensitivities (thionine and basic fuchsin); (v) susceptibility to Brucella phage and (vi) agglutination with monospecific antisera (A and M) were performed. Ten out of 11 isolates were identified as B. melitensis biovar 3 and one out of 11 were identified as B. melitensis biovar 1. The sensitivity of isolates to antibiotics was determined by the E-test. All isolates were found to be sensitive to doxycycline, rifampin, ciprofloxacin and cephtriaxone. Only one out of 11 isolates was found to be semi-sensitive to trimethoprim/sulfamethoxazole (cotrimoxazole)., (Copyright (c) 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The primary objective of the study was to determine the prevalence of brucellosis and the antimicrobial susceptibility pattern of local Brucellae isolates in the Infectious Diseases Hospital, Kuwait., Subjects and Methods: A single serum sample was collected from each of 1,836 patients of different nationalities from January 2000 to December 2001. Any patient with a provisional diagnosis of fever or brucellosis had a standard tube agglutination (STA) test for the quantitation of Brucella antibodies. Blood cultures were done in 166 of 455 patients with significant STA titers, using the Bactec system. Antimicrobial susceptibility testing of 123 isolates of Brucella spp. was done against 8 antimicrobial agents., Results: A total of 455 serum samples (24.8%) having an STA titer of > or =1:160 were presumptively diagnosed as cases of brucellosis. The peak isolation was in April and May. Brucella spp. were isolated from 123 blood cultures (74.1%). The blood culture isolation rate was significantly higher in patients with an STA titer of >/=1:1,280 than in those with an STA titer of

MIC50 and MIC90 values of doxycycline, rifampicin, ciprofloxacin, trimethoprim-sulphamethoxazole and ceftriaxone for 42 blood isolates of Brucella species were determined using the Etest. Thirty-seven isolates were identified as B. melitensis and five as B. abortus. Doxycycline had the lowest and rifampicin the highest MIC50 values. Four strains were non-susceptible to rifampicin, and one strain was resistant to trimethoprim-sulphamethoxazole. There is no significantly important resistance problem for antibiotics targeted against Brucella species in Turkey. However, since rifampicin is commonly used for prevalent diseases such as tuberculosis, the regional susceptibility pattern of rifampicin should be assessed periodically.

In order to evaluate the efficacy and tolerability of a high intravenous dose of rifampin plus oral minocycline (administered daily for 3 weeks) for the treatment of acute brucellosis, we retrospectively reviewed the outcome of 239 consecutive patients (135 adults and 104 children) diagnosed and treated over a 17-year period in Italy. The combination used resulted in 100% response and a relapse rate lower than 2%. Fifty-two (30 adults and 22 children) (29.8%) complained of mild adverse effects including an increase in aspartate aminotransferase (>250 IU) observed in 12 cases and considered related to rifampin and in 11 cases a reversible hyperpigmentation of the tongue attributed to minocycline. A randomized prospective comparative study should be performed to confirm our encouraging results.

Microparticles, containing an antigenic complex from Brucella ovis (HS), were evaluated for vaccine purposes against brucellosis. They were prepared by the double emulsion solvent evaporation method using two different polyesters, poly-lactide-co-glycolide acid (75:25; RG 756) and poly-epsilon-caprolactone. The encapsulation efficiency and release of HS from the microparticles, their capacity to be phagocytosed and also their toxicity on murine monocytes J774.2 were investigated. Both polymers lead to smooth and spherical sub-5 microm particles, with approximately 30% of the antigen initial dose encapsulated. SDS-PAGE and immunoblot of extracted antigens confirmed that the apparent molecular weight and antigenicity remained unaltered after the encapsulation procedure. However, the in vitro release of the antigens differed among them. The release profile for PLGA microparticles was continuous, whereas PEC ones released the antigens in a triphasic release pattern. Phagocytosis was clearly influenced by the hydrophobicity of the polymer, increasing in the case of PEC microparticles. Toxicity assay showed that both types of microparticles induced similar levels of mitochondrial damage. In conclusion, HS-PEC microparticles could be used as an effective vaccine against brucellosis, as the antigen is released in boosters and they are greatly phagocytosed by macrophages.

Brucella pathogens are highly susceptible in vitro to pefloxacin, lomefloxacin, meropenem and azithromycin. High efficacy of these drugs was demonstrated for experimental brucellosis treatment, azithromycin being the most active. Meropenem and azithromycin implementation resulted in more rapid and full normalization of the bactericidial and energy systems of the experimental animals peripheral blood cells.

In vitro efficacy of tetracyclines, aminoglycosides, fluoroquinolones, rifampin and macrolides and their combinations against four Brucella canis and two B. melitensis strains isolated from dogs was evaluated by means of inhibition tests: minimal inhibitory concentration (MIC) and fractional inhibitory concentrations (FIC) and by bactericidal tests: minimal bactericidal concentrations (MBC) and kill-time experiments. In inhibition studies, tetracyclines showed the lowest MICs of all compounds tested (0.06-0.50 mg/l). However, doxycycline did not inhibit growth of B. canis D-519 strain at concentrations lesser than 1 mg/l. Most strains were resistant to macrolides. Chequerboard MIC titrations showed synergy between enrofloxacin and aminoglycosides against B. canis RM 6/66 reference strain and between doxycycline and streptomycin against B. canis D-519 strain. Combinations of tetracyclines and aminoglycosides were at the limit of synergy for B. canis RM 6/66 strain (FIC = 0.56). Combination of doxycycline and rifampin seemed to be antagonistic against B. canis M-strain (FIC = 3). Other combinations studied were indifferent or additive against all other strains. In bactericidal studies, aminoglycosides, fluoroquinolones and rifampin showed bactericidal activity at 1-4 x MIC but tetracyclines or macrolides did not kill brucellae below 8 x MIC. Results of kill-time experiments indicated that streptomycin was the antimicrobial agent tested which more rapid killed brucellae. In most cases, doxycycline did not kill brucellae in 96 h of incubation. Which using rifampin alone, some inocula of B. canis strains RM 6/66, D-519 and M- showed regrowth after 24 h of incubation. Retesting of these regrowing brucellae showed an increased MIC indicating development of phenotypic resistance. Testing of antimicrobial combinations in kill-time experiments indicated synergy between enrofloxacin and streptomycin and antagonism between rifampin and doxycycline both for B. canis RM 6/66 strain.

The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a Brucella melitensis experimental infection in a mouse model. Animals were infected with 2 x 10(4) to 4 x 10(4) CFU of B. melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days. Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy. Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice. RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained. DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured. All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls. These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B. melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis. The results also appear to support the clinical superiority of combination drug therapy over monotherapy.

Intravenously injected recombinant human interleukin-1 alpha (IL-1 alpha) given to mice 4 h before infection with Brucella abortus 19 depressed the growth of bacteria in the spleen and liver. However, the same dose (10(5) U) or a 10-fold higher dose was not able to decrease numbers of bacteria when given to chronically infected mice. IL-1 injected into normal mice induced a dramatic increase 2 h later in colony-stimulating activity in serum, measured by bone marrow proliferation, and in colony-stimulating factor 1, measured by radioimmunoassay. Colony-stimulating factor levels declined but remained higher than normal for at least 12 h. The early peak stimulation was not observed in chronically infected mice, but the more prolonged elevation was. As a result of IL-1 treatment, the number of colony-forming cells, especially in the spleen, was increased in normal and acutely or chronically infected mice. Myeloperoxidase staining of newly formed monocytes and polymorphonuclear cells in the spleen revealed an increase in the number of these cells in normal and acutely infected mice as a result of IL-1 treatment, but there was no increase in the already high numbers in chronically infected mice. The relationship between these observations and the basis of chronic infection are discussed.

The most effective, least toxic chemotherapy for human brucellosis is still undecided. In vitro, the antibiotics most active against Brucella include the tetracyclines, the aminoglycosides, the aminopenicillins, some cephalosporins, trimethoprim-sulfamethoxazole, erythromycin, rifampin, and some new fluorinated quinolones. Because Brucella species are facultative intracellular parasites, the penetration of drugs into and within phagocytes and phagosomes can be problematic and can best be studied in experimental animals or tissue cultures. In humans, the effectiveness of various regimens of chemotherapy has been compared best in acute bacteremic infections by assessment of the control of symptoms, bacteremia, complications, and relapses. The standard therapy against which all other therapies have been judged is a combination of tetracycline and streptomycin, which is almost universally effective but fails to prevent relapse in 10% of cases. A combination of oral doxycycline and rifampin is convenient and currently popular; it is highly effective, with an average relapse rate of only 8.4%. Trimethoprim-sulfamethoxazole is less effective in controlling bacteremia and other manifestations: in collected series, 5.7% of cases did not respond and 12% relapsed. Drug-resistant Brucella strains are rarely a cause of therapy failure. Localized brucellosis poses special problems, often requiring surgery in addition to prolonged combined chemotherapy.