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In 2020–2022, infectious diseases were the major causes of infection and death globally. Many viral and bacterial diseases are starting to emerge/reemerge frequently. The zoonotic infections were reported to be dominant in a few decades. Now the holistic one-health approach is the need of the hour to tackle the emerging and reemerging pathogens by extensive and heedless use of antimicrobials, lack of novel antimicrobials, and unavailability of appropriate vaccines increased the severity of pathogens. Brucellosis is a well-known zoonotic disease also called undulant fever, Malta fever, Mediterranean fever, etc. Many components of the genus Brucella will be discussed in this chapter, namely pathogenesis, genes/proteins responsible for diseases in animal and humans, available treatment options, drug resistance phenomenon, etc.
*Address all correspondence to: grdnikhil@gmail.com
1. Introduction
In developing and underdeveloped world, communicable diseases are the key cause of illness and death. Among the wide range of infectious diseases, bacterial infectious diseases are concerned due to prevalence of the drug resistance [1]. After the Industrial Revolution, about 350 infectious emerging/reemerging pathogens evolved since 1940 [2]. The majority of these events are linked with animals [3]. Recently, accelerated climatic, demographic, and technological changes due to anthropogenic activities have transformed the risks associated with infectious diseases [4]. Due to limited treatment options, these resistant bacteria put an extra burden and cost and boost infection severity many times [5]. Gram-negative bacteria are one of the major cause of neglected tropical diseases [6].
Human brucellosis poses serious challenges for scientists and clinicians to understand the pathogenic mechanisms of Brucella spp., identification of severity markers for disease progression, regimen for treatment, and developmental progress of advanced treatment arsenals [7]. Brucellosis is a zoonotic disease that manifests systemic symptoms by involving several organs [8]. Major causes of infection were reported to be consumption of raw dairy products and occupational contact. Brucella, a gram-negative coccobacillus reported as a slow grower in vitro [9]. Six species of brucella are so far reported to cause infection in humans [10]. With the backdrop of neglected tropical diseases and a traditional biological weapon make these bacteria a serious health issue [8]. It was the subject of vast bioweapon research topics in the past and a category B pathogens [8]. This book chapter was conceptualized on the prevalent strain, epidemiology, virulence, pathogenesis, genes/proteins responsible for diseases in animals and humans, available treatment options, drug resistance phenomenon, etc. This book chapter summarizes current knowledge of the pathogenic mechanisms, therapeutic options, and the situation of developing countries regarding human brucellosis.
Nature has created the planet in such a way that the health of all the creatures, that is, humans, animals, and environment are linked with the health of each other [11]. The interaction among them is not always of benefit but also has some negative influences on animals, plants, environment as well as on humans. Zoonoses are a great example of this. Etymologically, the word zoonosis has been picked up from the Greek dictionary and is made up of the union of two words, that is., zoon, which means animal, and nosos, meaning disease or illness or unwellness [12].
Zoonoses are those diseases in humans that are acquired by direct or indirect communication with infected animals [13]. In other words, zoonoses are the diseases that are gifted from infected wild animals to human in order to interfere or grab their natural habitat (as these animals are the natural home for various pathogens and these pathogens rarely cause diseases in them). The pathogens responsible for zoonosis could either be bacteria, viruses, protozoa, or parasites [3].
Humans can screw up with these pathogens either by direct contact, indirect contact, or through vectors. When a person gets infected after contact with the blood, saliva, urine, mucous, feces, or other fluids of infected animal, then it is considered as direct transmission of disease, for example, Ebola virus disease (EVD) [14]. Person can fall for zoonotic disease even after not having any direct interaction with infected animals but living in the area where infected animals live or contact with fomites are other means of infection. Besides this, zoonoses also transmit from the consumption of food that is derived from the infected animals, for example, milk, milk products, and meat, which is called foodborne zoonosis, for example, brucellosis [4]. Many vectors, such as mosquitoes, fleas, mites, and ticks, play a crucial role in the transmission of diseases from animals to other animals and human, for example, Japanese encephalitis, plague, scrub typhus, etc. [15, 16, 17].
One health is a collaborative, multisectoral, and transdisciplinary approach and is built to collaborative work of all disciplines of health (human, animal, and environment) only for the sake of health regardless of their disciplines to attain an optimal yield of health [18]. According to one health approach, the health of human has a direct link with the health of animals and their shared environment. In other words, the healthier the animal and environment are, the healthier humans will be (Figure 1).
Figure 1.
One health concept.
About 1415 species of pathogens have so far been identified by researchers that are causing diseases in human beings. Of those 1415, 868 (61%) are zoonoses and 75 (12%) are emerging infectious diseases (EIDs). EIDs are cases of infectious diseases with a significant increment of their incidence in past two decades [19, 20]. According to WHO, among all the emerging infectious diseases, 75% are zoonotic in nature. Besides emerging infectious diseases (EIDs), reemerging infectious diseases (REIDs) are also reported as a threat to human beings. REIDs are pathogenic diseases with a sudden rise after a significant decline in infections [21].
Brucellosis, a zoonosis, which is transmitted directly or indirectly to humans by infected animals. Many names have been given in the past to the diseases on the basis of the name of the place where it was endemic, or whom it is infecting, that is, animal or human, or on the name of any event that was going at that time or on the name of its discoverer. These names are remittent fever (body temperature above normal all day), undulant fever (wave pattern body temperature, that is, sudden rise and fall), Mediterranean fever, Maltese fever, Gibraltar fever, Crimean fever, goat fever, and Bang’s disease [9].
Brucellae are gram-negative, non-capsulated, aerobic, intracellular, and nonmotile bacteria. They are very small in size (0.5–0.7 × 0.6–1.5 μm) and coccobacillus in shape [22]. Brucella cells do not have plasmids instead, they possess two circular chromosomes of different sizes. The larger chromosome is of 2.1 Mb and the smaller one is of 1.2 Mb. Hence, they are known to have 3.3 Mb average genome size (Figure 2). The members of the genus Brucella belong to the family Brucellaceae, class α-proteobacteria and order Rhizobiales. Morphologically, they are non-flagellated and cannot move but, in some species, genome sequencing has confirmed the presence of flagellar genes. Functionally, the flagellum is known for the motility of the organism but here in the genus Brucella they act as a virulence factor [23, 24, 25].
Figure 2.
A typical Brucella cell.
Sir David Bruce had discovered the bacteria in the eighteenth century but in reality, the genus Brucella came into existence in the early nineteenth century. To know, what made this journey too long, it is necessary to contemplate its historical background.
Marston, a British army physician of Malta Island, in 1859 segregated a Mediterranean remittent fever from other different prevalent fevers. When Sir David Bruce (pathologist and microbiologist) was in his service at Malta, a British soldier died due to Malta fever. He then started his study on patients who were died with Malta fever in the year 1866–1867. During this period, he successfully isolated an organism from the spleen of the cadaver and established a relation between this organism and Marston’s described fever in 1887 [26]. Because the bacteria seem very small and round in shape so Bruce’s assistant, Surgeon Captain Matthew Louis Hughes named the organism Micrococcus melitensis and to disease undulant fever [27]. But the source of the bacteria was still hidden and it was first described by the Maltese scientist and archeologist Themistocles Zammit in 1905. According to him the bacteria causing Malta fever in Maltese is actually coming from the consumption of infected goat milk [28].
On the other hand, in 1897, independent of Bruce work, Danish veterinarian Bernhard Bang, isolated rod-shaped bacteria that were causing a spontaneous abortion in cows and named the disease Bang’s disease. He classified the bacteria as bacillus. This was another species of Brucella known as Brucella abortus [29].
In 1906, Alice C. Evans, a bacteriologist in America, during her study on the etiological agent of Bang’s disease, she realized there was no difference between Bruce’s cocci and bang’s bacillus. Then she finds they are neither coccus nor bacillus, that is, they are not two different organisms but one coccobacillus. Evans then changed the bacteria’s name from Micrococcus to Brucella in 1920 in the honor of Bruce’s work [30].
Scientists have discovered a total of 12 species in genus Brucella till date [31]. All of them have some definite host with whom they reside and spread disease. Moreover, some species also have biovars. Biovars are the subdivision of the species in which strains of a species differ biochemically and physiologically from each other. B. melitensis, B. abortus, and B. suis contain 3, 7, and 5 biovars, respectively. Earlier, B. abortus was known to have 8 biovars but later it was found that the biovar 7 is actually the combination of the biovar 3 and 5. Hence, they are now considered to have only 7 biovars [32].
Prior, it was known that terrestrial mammals are the only reservoir of this bacteria. However, it is also infecting aquatic mammals was came to light in 1994 when one of its strains was found in the aborted fetus of a marine bottlenose dolphin (Tursiops truncatus). Afterward, many other species were isolated from the marine mammals [33, 34]. The details of the Brucella species known till date are given below.
Brucella melitensis: They are distributed globally and are highly pathogenic for humans. Sheep and goats are their usual host. However, they can also infect camels and cattle. Brucella melitensis has three biovars. In isolation, species form smooth colony on a culture plate that defines bacteria possess a smooth type of Lipopolysaccharide (LPS) [31].
Brucella abortus: Infection caused by B. abortus differs from other species because it has the capability to become chronic. Cattles are their preferred host but they can also infect other mammals such as camel, Bison, horse, and elk. B. abortus contains seven biovars. Their pathogenicity to humans is high but less than B. melitensis. Along with the respiratory or oral route, B. abortus can also transmit through arthropods like ticks. They are also distributed worldwide [35].
Brucella suis: It was discovered in 1929 by Huddleson and is the first strain that was used as a biological weapon in 1952 in the United States [8, 10]. They are divided into five biovars, that is, 1 to 5. All biovars are highly specific to their host. Biovars 1 and 3 are concerned with infecting humans and are highly pathogenic and virulent. However, biovar 2 has nothing to do with human infection. Biovars 1, 2, and 3 are known to infect members of the family Suidae. Moreover, Biovar 2 is also known to infect Hares along with Suidae [36].
Brucella ovis: This species was first found in New Zealand by M. B. Buddle while searching for the cause of abortion and epididymitis in ovine or sheep and named the organism as B. ovis in 1956. Sheep are their preferred host and organisms are responsible for epididymitis in them. They are non-pathogenic to humans and have no biovars. Members of the species have rough LPS makes them less virulent. Stable flies (Stomoxys calcitrans) are another source of transmission of infection [37].
Brucella neotome: It was first isolated from desert wood rats (Neotoma lepida) in the United States of America (USA) in year 1957. Earlier, it was known that they do not infect humans and are non-pathogenic like some other species. Later, after about 60 years, its zoonotic nature was revealed. At present, no biovars have been discovered for this species [38].
Brucella canis: This strain was first isolated from aborted tissues of Beagle (a breed of dog) and vaginal discharge of canines in the year between 1966 and 1967. However, B. canis is a common cause of brucellosis in dogs but in a small proportion of cases other species, such as B. melitensis, B. abortus, or B. suis, have also been seen for causing the disease. Disease in dogs is concerned with the reproductive disorder while in humans it is concerned with febrile syndrome and/or with some organ manifestation [39].
Brucella ceti: They are the first Brucella strain known to infect aquatic animals. It was first isolated in 1994 from aborted fetus of a bottlenose dolphin [33]. They specifically infect members of the infraorder cetacea (whales, dolphins, and porpoises).
Brucella pinnipedialis: Another brucella strain from the Scottland was discovered in the same year in which B. ceti was discovered from the stranded harbored seal (Phoca vitulina) and was named B. pinnipedialis [40].
Brucella microti: It was first isolated in the late twentieth century from common voles (Microtus arvalis) in South Moravia, Czech Republic [41]. Unlike other species, it lives in soil [42].
Brucella inopinata: It was first recognized in the women with breast transplants showing symptoms of brucellosis. A Brucella strain (BO1T) was isolated from her breast transplant wound in the year 2010 and was called B. inopinata [43].
Brucella papionis: Two strains (F8/08-60(T) and F8/08-61) were discovered in the year 2014 for the first time in primates (baboons) that were facing stillbirth and named B. papionis [44].
Brucella vulpis: Two isolates (strains F60T and F965) in the year 2016 from the mandibular lymph node of red fox (Vulpes vulpes) were discovered in Austria. Hence, they were named B. vulpis [45].
Brucellosis is distributed almost every corner of the earth but it is commonly found in Mediterranean countries, the Middle East, India, Mexico, Central Asia, and Central and South America. Brucellosis is a notifiable disease in most of countries (Figure 3) [46]. The prevalence of infection with B. melitensis has the highest prevalence in the world than other species. The incidence of Brucella cases in developing countries is comparably higher than in developed countries due to poor health infrastructure, unprotected farm practices, etc. According to the data analysis of the incidence of brucellosis 2017, Kenya, Yemen, Syria, and Greece are ranked 1st, 2nd, 3rd, and 4th, respectively. However, Sweden, Finland, Germany, the United Kingdom, and Belgium are Brucella-free countries but they still report few cases [47, 48].
Figure 3.
Brucella endemic areas.
Any person can get infected with bacteria but people at higher risk are those who live in direct exposure to animals due to their occupation. This includes veterinarians, slaughterhouse workers, meat packers, laboratory workers, and animal hunters. Transmission among humans with a human is rare but possible. A breastfeeding mother can pass the infection to their child, an infected blood or tissue donor to its accepter. Moreover, sexual transmission is extremely rare but cases like this also exist [49].
Brucellar infection in animals is associated with sterility and abortion. However, in humans, brucellosis can represent with simple flu-like illness (fever, malaise, fatigue, joint and back pain, etc.) to severe organ manifestation. Hepatic abscess (hepatic brucelloma), spinal brucellosis, neuro-brucellosis, myocarditis, pneumonitis, and ocular involvement are the other complications that have been seen in chronic brucellar infection [50, 51, 52, 53, 54]. Among 12, only 4 species, that is, B. melitensis, B. suis, B. abortus, and B. canis are responsible for the above-described complication in humans and the rest of them do not infect humans but their respective animal hosts.
The mortality rate due to brucellosis is very low but the rate of infection is really high. The infectious dose of brucellosis is very low and varies between 10 and 100 bacteria. However, the time taken by bacteria to show first symptom after getting infected (incubation period) is very high, that is, 5 days to 6 months but the average period is between two and 4 weeks [55].
Virulence is concerned with the ability of the organism that define its destructiveness. Brucella has several virulence factors that help them to invade the host cell, causing illness, and to protect them from the host immune response. The reported virulence factors of this pathogen are lipopolysaccharide (LPS), base excision repair (BER), cyclic β-1-2-glucans (CβG), superoxide dismutase (SOD) and catalase, type IV secretion system (T4SS), cytochrome oxidase, urease, alkyl hydroperoxide reductase (AhpC, AhpD), BvrR/BvrS system, nitric oxide reductase (NorD), and Brucella virulence factor A (BvfA) [56, 57, 58, 59, 60, 61, 62].
9.1 Lipopolysaccharide (LPS)
Being the weak inducer of the host inflammatory response, Brucellar LPS plays a major role in virulence [63]. In gram-negative bacteria, lipid A, O-antigen, and core sugar are the three components of LPS. Two structural variants of Brucella were reported based on the structure of LPS. The first one is smooth strains of Brucella which possess a complete LPS structure with O-antigen chain and the other one carries LPS which does not possess O-antigen chain and is called a rough strain of bacteria [64].
The structure of LPS of brucellae differs from the LPS of other gram-negative bacteria and thus their LPS is regarded as nonclassical LPS which is less pyrogenic in nature when compared to other classical types of LPS-bearing bacteria (e.g., enterobacteria). The presence of diaminoglucose in place of glucosamine and longer acyl group in lipid A made the brucellar LPS unconventional [65]. Also, in Brucella, lipid A does not connect to the core by ester and amide bonds but by amide bonds.
The structure of S-LPS of the smooth strain of Brucella composed of.
I) Lipid A (two types aminoglycose, fatty acids besides β-hydroxymiristic acid); II), the core which is made up of quinovosamine, glucose, and mannose and III) O-chains with 4-formamido-4,6-dideoxymannose. However, R-LPS of Brucella strain contains every content as smooth strain except O-chain [48, 65, 66].
9.2 Reactive oxygen and nitrogen-based regulators
9.2.1 Superoxide dismutase (SOD) and catalase
When Brucella enters to reside into the macrophage cell, the macrophages then start producing reactive oxygen intermediates (ROIs). These oxygen intermediates (hydrogen peroxide, superoxide, and hydroxyl radical) are extremely destructive in nature. They can stop bacterial replication or even kill the bacteria. Enzymes, superoxide dismutase (SOD), and catalase are produced by Brucella to get protection against ROIs. SOD is a metalloenzyme. Some species of Brucella contain two types of SOD (SodA and SodC). SodA is cytoplasmic and contains Mn as cofactor. Whereas, SodC is periplasmic and contains Cu, Zn as cofactor. SOD converts superoxide into hydrogen peroxide and oxygen. However, catalase is responsible for the breakdown of hydrogen peroxide into water and oxygen [48, 67].
9.2.2 Alkyl hydroperoxide reductase (AhpC, AhpD)
These enzymes are used by the bacteria as a defense system for the detoxification of reactive oxygen and nitrogen, which facilitates their survival in the environmental stress produced by the host immune system [68, 69].
9.2.3 Nitric oxide reductase (NorD)
It is another mechanism of the bacteria that saves them from the scarcity of oxygen in the macrophage cell. NorD is a defensive enzyme of the organism against nitric oxide (NO) toxicity (innate immune response to the infection). Nitric oxide metabolizes by the bacteria in the presence of any four types of reductases, that is, Nar–nitrate reductase, Nir–nitrite reductase, Nos–nitrous oxide reductase, and Nor–nitric oxide reductase into nitrous oxide (N2O) that favors their establishment inside the cell [48, 70].
9.2.4 Cytochrome bd oxidase
Brucellae are aerobes which means oxygen is a necessary condition for their growth but there is a scarcity of oxygen in macrophage cells (targeted host cells). Cytochrome bd oxidase functions to manage oxygen shortage inside the host cell and makes the intracellular environment suitable for their multiplication [48].
9.3 Type IV secretion system (T4SS)
Type IV secretion systems (T4SS), a channel of large protein complexes that transport proteins and protein-DNA complexes across the cell membrane. The T4SS of Brucella in vivo neither help them in invasion, infection dissemination, and in developing early infection but they are meant for the persistence of infection [71].
9.4 Cyclic β-1-2-glucans (CβG)
Synthesis of Cyclic β-1-2-glucans is another strategy of Brucella to protect themselves from the host defense mechanism and to make their persistence for a long duration. Functionally, CβG prevents the fusion of phagosome to lysosome and in this way Brucella saves them from acidic, microbicidal, and hydrolytic activity of lysosome [72].
9.5 Urease
Urease is a metalloenzyme that works for the protection of bacteria when it enters the body through the digestive route. The high acidic environment of the digestive tract can cause trouble in their survival. Hence, by using the enzyme urease, they decompose urea to ammonium and carbonic acid, which raises the pH of the surrounding to make the environment suitable for their existence until they enter into the target cells. Almost every species of Brucella produces urease except B. ovis [61, 73].
9.6 Brucella virulence factor A (BvfA)
BvfA is very unique and only found in the genus Brucella but is essentially required for the virulence of B. suis. It is a small periplasmic protein that is used to establish an intracellular replication niche [74].
9.7 Base excision repair (BER)
The damage in the DNA of the bacteria due to oxidation in the macrophage cells, is fixed by base excision repair (BER) with the help of the enzyme exonuclease III [48, 57].
9.8 BvrR/BvrS system
BvrR/BvrS, the two-component regulatory system of Brucella controls cell invasion and their survival inside the host cell. It prevents phagosome fusion to lysosome, which enables them to replicate. This system is essential for the virulent nature of B. abortus [75].
Microorganisms that enter the host have to fight with various protective mechanisms of the host. In the case of Brucella, when they enter the phagocytes they have to meet with several unpleasant ambience and then some (10%) who win the fight for survival (initial phase of infection) linger rest die [71]. However, brucellae possesses several strategies to evade from host defense system.
Brucella can infect diverse categories of cells, whether they are professional phagocytes (macrophages and dendritic cells), nonprofessional phagocytes (placental trophoblast and epithelial cells), or other blood cells like RBCs and other WBCs. However, Brucella does not replicate inside RBCs and lymphocytes but they play a role in bacterial dispersal [76]. Brucellae expertise in the survival and multiplication inside the macrophages capacitate them to cause chronic infection and persisting complications [72].
The process of brucellar infection starts with the adherence of bacterial cells to the host cell and ends with the dispersal of bacteria in other organs of the host body. Brucella has many adhesion proteins called adhesins that assist them in the process of adherence with the host cell. It has been observed that brucellae holds several different adhesin molecules for different host cell types [77]. The adhesins of Brucella, their respective host cell types and the receptors used by the bacteria are mentioned in Table 1.
Fibronectin, hyaluronic acid, fetuin, type I collagen
Table 1.
List of brucellar adhesins and their respective host cell type and receptors.
After the adherence, internalization takes place. Brucella uses a zipper-like mechanism to enter inside the macrophage cell. Internalization of smooth or virulent Brucella species occurs through the lipid rafts present on the macrophage cell. On the other hand, internalization of rough or avirulent species does not occur through lipid rafts but normally by the process of phagocytosis hence they get connected rapidly with the lysosome resulting destruction of the bacteria which shows that lipid raft is a necessary condition for the survival of early stage of bacteria in the host cell [78, 79].
Internalization results in wrapping of the bacteria in a vesicle. This wrapped structure is now called phagosomes or Brucella-containing vacuoles (BCV).
Normally, phagocytes engulfed bacteria to destroy them with the help of lysosome but brucellae prefers to reside and grow inside macrophages. In the process of invasion, several Toll-like receptors (TLRs) provide security to the organism from cytokines by checking the intracellular signaling associated with the activation of transcription of nuclear factor kappa B (NF-kB) [48, 71].
At first, the 5 minutes old BCVs fuse with early endosomes and form early BCV (eBCV), which is marked by early endosomal antigen 1 (EEA1), Rab5 (GTP-binding protein), and transferrin receptor (TfR) marker. Brucella perpetuates fusion with late endosomes to form late BCVs, which is characterized by the markers lysosomal-associated membrane proteins (LAMP1), RILP, and Rab7 [80].
The avirulent one, that is, Brucella strain with R-LPS will now merge with lysosome to form phagolysosome (Figure 4A). Lysosomes contain reactive oxygen species (ROS), nitric oxide (NO), and antimicrobial peptides which are released inside the phagolysosome to destroy the invading bacteria [48, 63, 81].
Figure 4.
A. Intracellular life cycle of an avirulent strain of Brucella showing formation of eBCV and late BCV and finally destruction of the bacteria by lysosome of the host cell. 4B. Intracellular life cycle of a virulent strain of Brucella showing how it manages to escape from the host protection system and makes way to reach ER for growth and replication. Repeated replication results tightening of vacuole which ultimately erupts into the blood stream, from where infection reaches to other cells and organs.
Contrary to this the virulent Brucella strains (with S-LPS) resist fusion with lysosome by secreting a lysozyme-like protein (muramidase) coded by SegA gene. This SegA protein prevents eBCVs from becoming late BCVs and its encounter with lysosome by changing intracellular trafficking [82]. Moreover, brucellar T4SS plays an important role in keeping away the BCVs from the host immune response. The early BCVs now interact with the endoplasmic reticulum (ER) to form replicative BCVs (rBCV) which are characterized by several ER markers, namely calnexin, calreticulin, and Sec61β (Figure 4B) [79]. Bacterial virulence factor, cyclic β-1-2-glucans (CβG) assists BCVs in combining with ER. Brucella continues to multiply in ER and gradually acquires the autophagic feature. Although proteins ULK1, Beclin 1, ATG14L, and PI3-kinase activity are prerequisites for the formation of autophagic BCV (aBCV) [83]. When the macrophage cells become too small for the growing number of the brucellae, it bursts and with this bacterial dissemination occurs in the bloodstream and from there they spread to other cells or tissues [84].
11. Treatment of human brucellosis
There is currently no approved vaccine against brucellosis in humans. Thus, the administration of effective antibiotics for a sufficient duration is a crucial component in the treatment of all forms of human brucellosis. The appropriate antibiotic therapy is effective in treating uncomplicated acute brucellosis. However, due to their intracellular location in reticuloendothelial cells and their preferred sites (e.g., bone), most antibiotics cannot reach the site of action. Doxycycline, rifampin, quinolones (ciprofloxacin or ofloxacin), trimethoprim/sulfamethoxazole (TMP–SMX), and aminoglycosides (gentamicin or streptomycin), are the antibiotics used to treat human brucellosis [85]. Antibiotics of the tetracycline group, especially doxycycline is the first-line drug to treat brucellosis due to its longer half-life and fewer adverse effects. It is widely accessible, reasonably priced, and exhibits good intracellular and excellent activity in the acidic phagolysosomal environment [86]. Another effective first-line medication is rifampin, which has good bactericidal activity, good penetration in phagocytic cells, and many-fold increases in anti-brucellar activity at low pH levels [87]. Quinolones are reported to be the alternative of first-line drugs due to have excellent intracellular penetration and high tissue concentration but poor bactericidal activity in an acidic intracellular environment makes them inferior [88]. Tetracycline, streptomycin, and other medications with teratogenic potential are not recommended for treating children below 8 years of age, patients with co-morbidities and pregnant women. In these vulnerable groups, rifampicin and third-generation cephalosporins are recommended to treat brucellosis [89].
TMP-SMX exhibits acceptable in vitro activity, suitable tissue, and intracellular penetration. Nevertheless, it is only recommended to treat pregnant patients and children younger than 8 years [89]. In addition, streptomycin, an aminoglycoside medication, can be used to treat brucellosis in addition to tetracycline or doxycycline. It has been reported that the combination of these antibiotics kills Brucella at a higher rate than either medication acting alone. Thus, to treat brucellosis in humans, the World Health Organization (WHO) recommends a double or triple combination of antibiotics [90].
Treating brucellosis-related central nervous system disorders presents a special set of difficulties because high concentrations of antibiotics in the CSF must be achieved [91]. The blood-brain barrier is not effectively crossed by aminoglycosides or tetracyclines. Hence, in addition to the standard treatment of doxycycline plus streptomycin, the use of antibiotics with the ability to enter the central nervous system, such as rifampicin or co-trimoxazole, is advised. While the optimal duration of treatment for neurobrucellosis remains undetermined, most authorities recommend a minimum of 6–8 weeks of treatment, with the possibility of extending this period based on clinical response. Currently, ceftriaxone shows promise as a combination therapy option for certain brucellar complications, such as endocarditis and neurobrucellosis [92].
12. Antimicrobial resistance in Brucella
Relapses of brucellosis following treatment are common, with rates ranging from 5 to 15 percent in mild cases [93]. Treatment failure is also relatively common. Globally, brucellosis-endemic regions (such as Malaysia, Egypt, Qatar, China, and African countries) have recently seen the emergence of multidrug-resistant in Brucella against rifampicin, streptomycin, azithromycin, ciprofloxacin, tetracycline, vancomycin, etc. [94, 95]. In vitro induced point mutations in rpoB and gyrA genes are described as imparting resistance to rifampicin and fluoroquinolones, respectively [96, 97]. However, the clinical significance of these mutations is yet not clear. Moreover, the introduction of mutations in genes of RND-type efflux pumps in vitro generates the multidrug resistance phenotype of B. suis having resistance to ampicillin, norfloxacin, ciprofloxacin, tetracycline, and doxycycline [98, 99]. Recently, cephalosporin-resistant B. melitensis was isolated from clinical samples in China. Further, whole genome sequencing (WGS) of these isolates showed that more than 50% of antibiotic resistance genes were associated with efflux pumps [89].
13. Brucellosis control in animals
Antibiotics used as a primary prevention in domesticated animals contribute to the enhancement of bacterial resistance and have a significant impact on their dissemination throughout the food supply chain [100]. Thus, the treatment of animal brucellosis is not recommended due to its ineffectiveness and inability to completely prevent the carriage of the causative agent. Since humans can easily contract the disease from animals, thus animal-brucellosis control programs can aid in the eradication of human brucellosis. Animal brucellosis can be prevented with two widely used vaccines [101]. To prevent brucellosis in cattle, the most widely used and first vaccine for the disease is the live attenuated B. abortus strain 19 (S19 vaccine). A live attenuated strain of B. melitensis Rev. 1 (Rev.1 Vaccine) is the best vaccine to prevent brucellosis in goats and sheep. Nevertheless, they had certain disadvantages, including the induction of abortion in animals that were pregnant, their virulence to humans, the development of anti-Brucella antibodies that interfered with serodiagnosis, and the development of antibiotic resistance against brucellosis treatment [101]. Due to their high safety levels when compared to traditional live-attenuated vaccines, engineered live-attenuated vaccines based on virulence gene deletions have proven to be the most effective method for creating new vaccines with minimal residual virulence among vaccines using new technologies. Different kinds of these vaccines are being developed based on various deletions in virulence genes of B. melitensis and B. abortus, leading to a considerable reduction in the pathogen’s ability to cause disease and to develop an increased immune-protective response [102]. Thus, these may be a potential vaccine candidate for human use as well.
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Written By
Shahzadi Gulafshan, Rajeev Singh, Manoj M. Murhekar and Gaurav Raj Dwivedi
Submitted: 21 December 2023Reviewed: 07 February 2024Published: 26 June 2024
Open access peer-reviewed chapter
