1. Brucellosis

2. Introduction:
Brucellosis aka Malta fever is a zoonotic infection caused by the bacterial genus Brucella. The bacteria are transmitted from animals to humans by ingestion through infected food products, direct contact with an infected animal, or inhalation of aerosols.

3. Microbiology and etiology:
Brucellae are small, gram-negative, unencapsulated, nonsporulating, nonmotile rods or coccobacilli that can persist intracellularly. The genus Brucella includes four major clinically relevant species: B.melitensis (acquired by humans most commonly from sheep, goats, and camels), B. suis (from swine), B. abortus (from cattle or buffalo), and B. canis (from dogs).

4. Pathogenesis:
Brucellae typically enter the body through cuts and abrasions in the skin or through the gastrointestinal (GI) tract. Drugs that decrease gastric acidity may increase the likelihood of transmission via the GI route. Inhalation of infected aerosols can also lead to disease among abattoir workers.

5. Pathogenesis:
system to the regional lymph nodes, where they multiply. LPS is the major virulence factor. Brucella has a unique ability to survive in the intracellular environment by finding ways to escape from immune reaction Once the organisms gain entry, they are transported via the lymphatic

6. Pathogenesis:
Once within the bloodstream, the organisms quickly become intracellular pathogens contained within circulating polymorphonuclear cells (PMNs) and macrophages, making use of numerous mechanisms to avoid or suppress bactericidal responses. Animal data suggest that the lipopolysaccharide (LPS) coat (smooth in B melitensis, B abortus, and B suis; rough in B canis) is likely to play a role in intracellular survival, perhaps because of adenine and guanine monophosphate production, which inhibits phagosomal fusion and oxidative burst activity.

7. History:
In 1886 David Bruce ( ), a British army surgeon, isolated a cocco-bacillus that he named “Micrococcus melitensis” from the spleen of a man who had died of “Malta Fever”. This disease was endemic, but confused with other diseases, especially malaria. The average annual incidence in Malta during was 652 civilian and 605 military cases, with a death rate, respectively of 10.4% and 2.3% . The human disease was associated with people who consumed goat milk and had other close contact with goats. The organism soon was isolated from these animals. In 1897 a similar microbe was isolated from the udder of cows, and in from swine. In about 1920 the genus was renamed Brucella and its species became respectively B. Melitensis, B. Abortus, and B. Suis.

8. Epidemiology:
The true global prevalence of human brucellosis is unknown because of the imprecision of diagnosis and the inadequacy of reporting and surveillance systems in many countries. Failure of veterinary control programs due to conflict or for economic reasons contributes further to the emergence and re-emergence of disease, as seen currently in some eastern Mediterranean countries.Brucellosis is transmitted via ingestion, inhalation, or mucosal or percutaneous exposure.

9. Epidemiology:
the disease in humans is usually associated with exposure to infected animals or their products in either occupational settings (e.g., slaughterhouse work, farming) or domestic settings (e.g., consumption of contaminated foods, especially soft cheese, unpateurized milk and yoghurt). B. melitensis and B. suis have historically been developed as biological weapons by several countries and could be exploited for bioterrorism . This possibility should be borne in mind in the event of sudden unexplained outbreaks.

10. Epidemiology:
In addition, Brucella species have relatively low virulence, toxicity, and pyrogenicity, making them poor inducers of some inflammatory cytokines, such as tumor necrosis factor (TNF) and interferons. Furthermore, the bacteria do not activate the alternative complement system. Finally, they are thought to inhibit programmed cell death.

11. Clinical features:
Brucellosis almost invariably causes fever, which may be associated with profuse sweats, especially at night. In endemic areas, brucellosis may be difficult to distinguish from the many other causes of fever. B. melitensis tends to be associated with a more acute and aggressive presentation and B. suis with focal abscess induction. B. abortus infections may be more insidious in onset and more likely to become chronic. B. canis infections are reported to present frequently with acute gastrointestinal symptoms.

12. Clinical features:
Focal features or localized infections are present in the majority of patients. The most common are musculoskeletal pain and physical findings in the peripheral and axial skeleton (~40% of cases).
Osteomyelitis more commonly involves the lumbar and low thoracic vertebrae than the cervical and high thoracic spine. Individual joints that are most commonly affected by septic arthritis are the knee, hip, sacroiliac, shoulder, and sternoclavicular joints; the pattern may be one of monoarthritis or.

13. Clinical features:
polyarthritis. Osteomyelitis may also accompany septic arthritis. Neurologic involvement is common, with depression and lethargy whose severity may not be fully appreciated by either the patient or the physician until after treatment. A small proportion of patients develop lymphocytic meningoencephalitis.

14. Clinical features:
Endocarditis occurs in ~1% of cases, most often affecting the aortic valve (natural or prosthetic). Any site in the body may be involved in metastatic abscess formation or inflammation; the female breast and the thyroid gland are affected particularly often. Nonspecific maculopapular rashes and other skin manifestations are uncommon and are rarely noticed by the patient even if they develop.

15. Clinical features:
An incubation period ranges from 5 days to several months, but typically lasts several weeks, it  is followed by the development of undulating fever; sweats; increasing apathy and fatigue; and nonspecific symptoms such as anorexia, headache, myalgias, and chills. Brucella infection can cause lymphadenopathy, hepatosplenomegaly, epididymoorchitis, and focal abscess. Given the persistent fever and similar symptoms, tuberculosis is the most important differential diagnosis

16. Brucellosis and pregnancy:
Brucellosis during the course of pregnancy carries the risk of spontaneous abortion or intrauterine transmission to the infant. Brucella bacteremia can result in abortion, especially during the early trimesters, prompt diagnosis and treatment of brucellosis during pregnancy can be lifesaving for the fetus. Very rare human-to-human transmission from lactating mothers to their breastfed infants has been reported.

18. Diagnosis:
Definitive diagnosis depends on the isolation of the organism. Blood cultures are positive in 75–80% of infections caused by B. melitensis and 50% of those caused by B. abortus. Bone marrow culture should not be used routinely but may increase the diagnostic yield, particularly if antibiotics have been given before specimens are taken. CSF culture in neurobrucellosis is positive in about 30% of cases.

19. Diagnosis:
The laboratory should be alerted to a suspected diagnosis of brucellosis, as the organism has a propensity for infecting laboratory workers and must be cultured at an enhanced containment level. Serology may also aid diagnosis. In endemic areas, a single high antibody titre of more than 1/320 or a fourfold rise in titre is needed to support a diagnosis of acute infection. The test usually takes several weeks to become. Serology may also aid diagnosis. In endemic areas, a single high antibody titre of more than 1/320 or a fourfold rise in titre is needed to support a diagnosis of acute infection. The test usually takes several weeks to become positive but should eventually detect 95% of acute infections.

20. Management: prevention:
Vaccines based on live attenuated Brucella strains, such as B. abortus strain 19BA or 104M, have been used in some countries to protect high-risk populations but have displayed only short-term efficacy andhigh reactogenicity. Subunit vaccines have been developed but are of uncertain value and cannot be recommended at present. pasteurization of all milk products before consumption is sufficient to prevent non-occupational animal-to-human transmission.

21. Management: Nonpharmacological treatment
Patients are advised to avoid dairy products, especially those came from rural areas. Surgery may be indicated despite antimicrobials use properly in the following cases to complete cure:
Drainage of abscesses particularly those unresponsive to antibacterials.
Epidural abscess.
Removal of infected foreign bodies like pacemaker wire or prosthetic joints.
Resection of mycotic aneurysms.
Hepatosplenic granulomas.

22. Pharmacological treatment
The aims of antimicrobial therapy are to treat and relieve the symptoms of current infection and to prevent relapse. Focal disease presentations may require specific intervention in addition to more prolonged and antibiotic therapy. Early experience with streptomycin monotherapy showed that relapse was common; thus dual therapy with tetracyclines became the norm. This is still the most effective combination, but alternatives may be used. numerous Brucella strains show in vitro sensitivity to a whole range of antimicrobials that are therapeutically ineffective, including assorted β-lactams.

23. Drug therapy:
Moreover, the use of fluoroquinolones remains controversial despite the good in vitro activity and white-cell penetration of most agents of this class. Low intravacuolar pH is probably a factor in the poor performance of these drugs.

24. Drug therapy:
The standard strategy for the treatment of acute noncomplicated brucellosis in adults is IM streptomycin (0.75–1 g daily for 14–21 days) together with doxycycline (100 mg twice daily for 6 weeks). In both clinical trials and observational studies, relapse follows such treatment in 5–10% of cases. The usual alternative regimen is rifampin (600–900 mg/d) plus doxycycline (100 mg twice daily) for 6 weeks, relapse rate is higher with this regimen, possibly because doxycycline levels are reduced and clearance rates increased by concomitant rifampin administration.

25. Drug therapy:
Children who can’t take tetracyclines, can be given high- dose Trimethoprim-sulfamethoxazole instead (two or three standard-strength tablets twice daily for adults, depending on weight). Increasing evidence supports the use of an aminoglycoside such as gentamicin (5–6 mg/kg per day for at least 2 weeks) instead of streptomycin, although this regimen is not approved by the U.S. Food and Drug Administration. Shorter courses have been associated with high failure rates in adults. A 5- to 7-day course of therapy with gentamicin and a 3-week course of TMP-SMX may be adequate for children with uncomplicated disease.

26. Treatment of localized infections:
Bone Disease:
Doxycycline 100 mg twice daily plus rifampicin 600–900 mg once daily orally for 6 weeks plus gentamicin 5 mg/kg IV once daily for 7 days or
Ciprofloxacin 750 mg twice daily orally plus rifampicin
600–900 mg orally once daily for 3 months
Neurobrucellosis:
Doxycycline 100 mg twice daily plus rifampicin 600–900 mg
orally once daily for 6 weeks plus ceftriaxone 2 g IV twice daily
until CSF is clear (though susceptibility should be confirmed
because sensitivity to third-generation cephalosporins varies
amongst strains)

27. Endocarditis: Pregnancy Almost always needs surgical intervention plus
Doxycycline 100 mg twice daily, rifampicin 600–900 mg orally once daily and co-trimoxazole 5 mg/kg of trimethoprim component for 6 mths plus gentamicin mg/kg IV once daily for 2–4 wks
Pregnancy
Rifampicin 600–900 mg orally once daily and co-trimoxazole 5 mg/kg of trimethoprim component for 4 wks, but caution in last week of pregnancy due to displacement of bilirubin from albumin by drugs and risk of kernicterus to the fetus.