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In this paper, a few important aspects about brucellosis are discussed. The main etiologic agent Brucella strains is characterized both morphologically and metabolically, in which the B. melitensis it the most common cause of human brucellosis. Brucellosis is transmittable from animals to human via the consummation of animal products such as dairy and cheese. Moreover, the infection mechanism is fully described which can be simplified as the secretion of endotoxin by Brucella enable itself to infect host cells. Accordingly, the strategies of treatments were found out were the listed below:
intramuscular streptomycin: 750 mg to 1g daily for 14 to 20 days; cooperate with doxycycline :100 mg twice a day; for 6 weeks.
rifampin : 600 to 900 mg/d; plus dexycycline : 100 mg twice daily ; for 6 weeks.
Nevertheless, the fluoroquinolone monotherapy may lead to a poor complicance of treatment, which is believed can be optimized by the molecular modification.
Brucellosis is a bacterial zoonosis transmitted indirectly to humans from infected animals, dominantly homebred ruminants and swine (Aragon et al., 1996). Due to the remittent character, the disease is normally known as Malta fever. With some exceptional few countries which have been eradicated from the animal host, it distributes world-widely(Billard et al., 2005). Despite brucellosis is commonly known as an acute febrile disease, the clinical manifestations of it can be fairly various, and definitive marks or signs indicating the diagnosis is insufficiency(Billard et al., 2005).
In the simplest case, it starts as influenza like along with fever reaching 38 to 40â„ƒ. Back, arms and legs pains are unusually severe, however, sweating and fatigue are significant(Celli, 2006). The counting of leukocyte tends to be regular or slightly reduced, along with a relative lymphocytosis. Upon on physical examination, splenomegaly may be the only observed. If the disease is not treated, the symptoms may continue for 2-4 weeks(Goldstein et al., 1992).
Brucellae are tiny, gram-negative coccobacilli that do not from spores and can not motile. They grow in an aerobic condition; in spite of some species require carbon dioxide supplication for primary isolation. Brucella strains normally show positive catalase activity, but have a variable activities of oxidase activity and rease activity, as well as the H2S production(Jimenez de Bagues et al., 2005). The main nomen species of Brucella and their biovars are differentiated according to selective inhibition of growth containing dyes, for example, thionon and basic fuchsin. A series of Brucella-phages can also be used for typing smooth and rough Brucellae(Kahl-McDonagh and Ficht, 2006).
Brucellosis of human beings is mainly introduced by Brucella strans, a bacterial genus considered is composed of a single species, Brucella melitensis, with several biologic variants would display certain host preferences(Moreno et al., 1984). For the sake of convenience, the traditional classification into nomen species is still in general use; this scheme, which closely follows the epidemiologic patterns of the infection, recognized B. melitensis, as known as the most common cause of disease in humans symptomatically and the main sources are camels, goats&sheep. Brucellae bacterias are spread in huge amount in the urine, milk, and pregnant products of infected animals(Porte et al., 2003). As a consequence, farmers, veterinarians, abattoir workers, and laboratory personnel have been in the occupational risk of brucellosis(Rolan et al., 2009). Direct contaction of animals or their secretion via abrasions and cuts of skin, or by inhalling infected aerosols or inoculating into the conjunctival asc of the eyes, or ingesting unpasteurized dairy products can be regular transmission pathways to human beings(Trevejo et al., 2001).
The determine factors of Brucella pathogenicity have not been fully described, and the mechanisms of brucellosis clinical manifestations are uncompleted well known(Vemulapalli et al., 1998). The survival strategy of Brucella is focus on the processes that to live inside of monocytic cells. The smooth Brucella lipopolysacchride, possessing an unusual O-chain component, as well as endotoxin activity which plays a vital role in pyrogenicity. Within the non-immune host, it resist to phagocytosis and serum killing (Young, 1995). Specific exotoxins have not been isolated, however, the identified proteins which regulate intracellular trafficking and survival are secreted from the IV type of secretion(Zhan and Cheers, 1998). This system is activated by low pH, working together with Brucellae produced acid-stable proteins thus facilitating its survival in phagosomes and depressing activation of the oxidative burst. Macrophage apoptosis and phagosome-lysosome fusion are also suppressed(Aragon et al., 1996). To achieve resistant to defensins, by producing a Cu-Zn superoxide dismutase and reactivating oxygen intermediates, resistance of Virulent Brucellae increased (Billard et al., 2005).
Comparison of typhoid fever & brucellosis how bacteria access into the lymphatics and start replication inside of regional lymph nodes had been done by Spink. Followed by localization of bacteria within organs rich in elements of the reticuloendothelial system, for example, bone marrow, spleen and liver, Hematogenous dissemination occured(Young, 1995). Reticuloendothelial system localization also explains many of the clinical complications of brucellosis involving these organs. Brucellae ingested by mononuclear phagocytes also survive and replicate initially(Kahl-McDonagh and Ficht, 2006). Intracellular survival within smacrophages is facilitated by the inhibition of phagosome-lysosome fusion by soluble products of Brucellae and the production of a number of stress-induced proteins(Moreno et al., 1984). The eventual elimination of virulent Brucellae depend on the activation of macrophages through the development of Th 1-type cell-mediated immunity. Cytokines that appear to contribute to the anti-brucella activity of activated macrophages include TNF-Î± or TNF-Î³, or both, as well as IL-1 and IL-12(Goldstein et al., 1992).
Genetic studies in various animals have shown that resistance to intracellular pathogens is polygenic; however, single genes are recognized to have a major effect on immune-mediated resistance(Zhan and Cheers, 1998). Selected breeding of cattle has yielded evidence for the genetic determination of resistance to bovine brucellosis. Moreover, the data suggest that resistance is reflected in immunoglobulin allotypes and in differences in the ability of macrophages to control the replication of B. abortus in vitro(Celli, 2006).
S-LPS are the main determinant of Brucellae virulence and dominate response of antibody. Humoral antibodies to S-LPS confer short-term protection as shown by passive transfer experiments using monoclonal andpolyclonal antibodies. Antibodies to S-LPS are also used for diagnosis when bacterial isolation is unsuccessful(Billard et al., 2005). Avariety of serologic tests have been used to measure antibodies to Brucella, the earliest of which was the serum agglutination test(SAT) devised by Wright and Smith in 1897. The SAT can measure the total of agglutinating antibodies but does not distinguish between immunoglobulin isotypes(Moreno et al., 1984). The SAT was modified by adding 2-mercaptoethanol to differentiate agglutination by IgG antibodies and showed that their presence correlated well with active infection. The combination of SAT and 2-mercaptoethanol test results have shown as a useful protocol to monitor the course of brucellosis as well as responses to therapy(Porte et al., 2003). The application of the enzyme-linked immunosorbent assay has make it possible to measure the immune response in brucellosis more accurately. It was shown that IgM antibodies appear within the first week of infection and are for the second week, lowed by a switch to IgG synthesis after the second week. In time, titers of IgM antibodies decline, and with treatment, titer of IgG antibodies also fall consistent with recovery. A failure of the IgG titer to decline is prognostic of relapse of chronic infection(Trevejo et al., 2001).
Serologic tests employing S-LPS can detect antibodies to the principal nomen species owing to common epitopes; however infection with B. canis a naturally rough species requires monospecific antigen. Currently, there is interest in cytoplasmic protein antigens present in both smooth and rough strains that could be used for diagnostic purposes(Zhan and Cheers, 1998).
The roughly goals of therapy for brucellosis are to cure current infections and relieve symptoms and prevent further relapse. Surgical intervention with tailored and prolonged antibiotic therapies are demanded for presentations(Aragon et al., 1996). Moreover, tuberculosis should be excluded, to prevent emerging of resistance-the strategy have to be tailored to exclude monotherapy specifically with agents active against tuberculosis or to include a full antitubeculous regimen.
The "gold standard" of treatment for adualt brucellosis is intramuscular streptomycin( 750 mg - 1g daily, for 14 - 22 days) together with doxycycline (100 mg twice a day for 6 weeks). In these two clinical trials of studies, relapse occurs after such treatment in the percentage of 5 to 10 of total(Celli, 2006). The common alternative regimen (recommended by World Health Organization) is rifampin, which is 600 -- 900 mg per day, plus dexycycline, which is 100 mg twice daily for 6 weeks. In the cases of trial, the failure rate is around 10%, but it can rise up to 20% in many nontribal situations, mainly because doxycycline levels are retraction. Patients with low tolerance ( usually children and pregnant women) can be treated with high dose TMP-SMX alternatively (2 or 3 standard-strength tablets twice daily for adults, depending on weight)(Porte et al., 2003).
It is not necessary to carry out vitro drug sensitivity tests on isolated strains of Brucella for human therapy(Rolan et al., 2009). Many clinical experiences have shown that tetracycline is right choice for the treatment of brucellosis. In severe illness tetracycline can be used together with streptomycin. The alternative for tetracycline is chloramphenicol(Ugalde et al., 2000).
As was show in vitro tests, tetracycline antibiotics are the most effective drugs which inhibits 96% of organisms in a concentration of 0.021ug per ml. In comparison, chloramphenicol is about 100 times less active than tetracycline. And streptomycin is not effective clinically, due to its ability to enter the cells in which Brucella are living(Pasquali et al., 2003).
TREATMENT FAILURE-POOR COMPLICANCE
Previously experience with streptomycin monotherapy for brucellosis indicated that relapse happened all the time; therefore dual-therapy of tetracyclines and streptomycin become the altermative. Until now, they are the most effective drugs, but alternatives could be supplied with rifampin. By carrying out vitro tests, the efficacy of antimicrobial cab be predicted.(Rolan et al., 2009). The efficacy of fluoroquinolone monotherapy has been disappointing; with a high relapses rate. For grow-ups who has critical non-focal brucellosis a 6-week duration of therapy together with two antimicrobial agents is necessary. Therapy for focal & complex disease is necessitated over 3 months (Trevejo et al., 2001). Insisting on the therapeutic treatment is very significant, perish compromise underlies most cases of failure. It is good to have a 6-week course of treatment and prevention of relapse in children, but this point has not yet been proved in prospective studies(Zhan and Cheers, 1998).
Evidences are accumulated and shown alternatives can be used instead of cstreptomycin. Netilmicin or gentamicin can be used about 5 to 6 mg/kg per day for two weeks at least. (A shorter treatment of adults comes with high failure.) A 5 to 7 days treatment with gentamicin (as well as a course of TMP-SMX for 3 weeks) is sufficient for children (Moreno et al., 1984). Early examinations using fluoroquinolone monotherapy was completely fail, and extra amount of dose ofloxacin --410 mg 2times/day; or ciprofloxacin --500 mg 2 times /day, together with rifampin for 1 and half months, may become an acceptable alternative to the other regimens for adults with same duration of treatments(Rolan et al., 2009).
Severely neurologic disease caused by Brucella requires extended period of treatment (i.e., for 6 to 12 months), normally come with ceftriaxone. Brucella associated endocarditis are usually supplied with three drugs for cure: amonoglycoside, tetracycline, and rifampin; Treatments are usually lasted for half an year, and it is difficult to define its clinical end points(Ugalde et al., 2000). For most cases, surgery is still needed. No evidence shown the prophylaxis after exposure to brucellae laboratorial, as well as live with infected animals.
The major authorities recommended that the administration of rifampin as well as doxycycline for 3 weeks after exposure with low risk(for example, non-specific lab accidents); 6 weeks after a long period of time exposure to aerosol or injected material(Young, 1995).
Relapse occurs frequently up to 30% of negative compromised patients. Hence clinically patients should be followed by 2 years of later detecting for relapse, which is the same therapeutic treatments with extended course (Ugalde et al., 2000).
Patients' health and body weight are much more helpful that serology in guiding lack of relapse. After the successful treatment, the IgG antibody levels can still remain in the diagnostic range for the following 2 years.
IgG antibody levels detected by SAT and variants of this test can remain in the diagnostic range for over 2 years after successful treatment. Complement fixation titers generally fall to normal in 1 year. Patients could be reinfected after exposure to bacteria repeatedly due to the weakened imunity. Only a tiny portion of patient died from Brucellosis. Regarding to the patient who die for Brucellosis, cardiac failure was involved; in more rare cases, death is a consequence of neurologic involvement(Billard et al., 2007). Recovery from Brucellosis is slow; even it has a low mortality rate.
It can be concluded that the effective treatment strategy regards to brucellosis has been working on most patients. The most effective drug is tetracycline examined clinically. The dual therapy including tetracycline provides alternative regimen for special human groups. However, the relapse of brucellosis after successful treatment of poor compliance patients is required to examine IgG antibody regularly in the next 2 years. In a word, the combination regimens are helping increasing number of people get rid of brucellosis.