Burkholderia pseudomallei: the unbeatable foe?

ABSTRACT

Although melioidosis has been recognized in Thailand for many years and considerable progress in term of diagnosis and treatment was achieved, B. pseudomallei is still "the unbeatable foe", for several reasons as outlined here under-recognition, high case-fatality rate, unacceptable relapse rate and a "time-bomb" for sero-positive patients. Melioidosis is largely restricted to certain geographical areas. In Thailand, it had long been considered a rare disease in Thailand until ten cases with culture-proven melioidosis were reported by Sompone Punyagupta and his associates at a meeting of the Infectious Disease Group of Thailand. Since then awareness of young physicians and laboratory personnel for melioidosis has been increased. The most dramatic consequence was seen at Sappasitprasong Hospital in Ubon Ratchathani where over 100 strains of B. pseudomallei are isolated each year. But the frequent isolation of B. pseudomallei is surprisingly restricted to some provinces in the northeast, namely Khon Kaen and Ubon Ratchathani provinces and only 1-10 cases or none from adjacent provinces. The discrepancy was well illustrated by mapping the number of isolations by province. Thus many cases of septicemic melioidosis are certain to receive inappropriate chemotherapy and nearly half of them probably leave this world without proper diagnosis in area where under-recognition unfortunately still prevails. Mortality in disseminated septicemic melioidosis used to occur in 82-87% of the patients who were treated with doxycycline, chloramphenicol, cotrimoxazole and kanamycin and in non-disseminated septicemic melioidosis about 20%. With ceftazidime therapy, the mortality rate was cut by half to 35-40%. About 50% of the patients deteriorated rapidly and died within the first few days of fever. Fatalities are related to the speed of positive results of blood culture. Accordingly, awareness of the disease, familiarity of clinical syndrome compatible with septicemic melioidosis, gram-staining of exudate to include or exclude melioidosis, are all crucial factors to lead to proper empiric chemotherapy. Since the addition of anti-cytokine and platelet activating factor receptor antagonist to current antimicrobials failed to lower the mortality rate, we need to find a new antimicrobial such as protegrin-1 which exhibits rapid microbicidal activity, especially against stationary-phase cell. We need to optimize the bactericidal action of currently used antimicrobials by examining their pharmacokinetics. With prolonged maintenance treatment with cotrimoxazole plus doxycycline or co-amoxiclav, relapse occurs in 4 to 23%. Various explanations for the relapse are the ability of the organism to produce glycocalyx, form microcolonies in damaged tissues and survive within phagocytic cells. Again, the bactericidal antimicrobial which is concentration-dependent, may be used to shorten the duration of treatment and reduce relapse. Studies so far can not relate relapse to any defect of host defense mechanism. In endemic areas, seroepidemiological surveys showed that infection, mostly latent, occurred fairly commonly since childhood as 80% of children had antibodies by the age of four years. However, clinical melioidosis is more common in the elderly which in some cases are due to reactivation of primary latent infection. Since the incubation period of the reactivation can vary from weeks to many years, a vaccine or short-course secondary chemoprophylaxis may be possible interventions for the high risk group to get rid of the "time-bomb" reactivation. The vaccine may also be used to reduce the relapse rate. We need to discover the cellular determinants which is critical to awake the host defense to the sleeping bacteria and provoke local inflammatory response to newly born bacteria before dissemination takes place again. Basic research into the pathogenic mechanisms are key to understanding how to make an effective vaccine.