- Email: [email protected]
S20.2 Role of immunotherapy in TB
$38
@eakers' Abstracts ~International Journal of Antimicrobial Agents 26S (2005) S1 $63
can also be used for inpatients, although they lestrict mobility in active patients. Drag stability can also be an issue, as the [3 lactam needs to be stable for 24 hours, the usual interval for a bag/pump change, and at room or skin temperature. Most ~3-1actams are stable, but imipenem and benzylpenicillin are not. Continuous infusion should be considered ill'St-line when prolonged (i>2 weeks) high-dose 13-1actam therapy is required, such as is encountered with some deep staphylococcal infections, or for facilitating early discharge when changing to oral therapy is not recommended. It can also be applied in other settings where optimizing bactericidal activity is felt to be important, such as sepsis in ICU patients and febrile neutropenia. Its role in endocm'ditis treatment is controversial.
S19.5 The Pharmacokinetics and Pharmacodynamics of Anti-Malarials: A New Approach in the Treatment of Malaria: The Philippine Experience Ma. Dorina G. BUSTOS. Research Institute for TroFical Medicine, Alabang~ Metro Manila, Philippines Tile emel~gence of tile problem of malaria drug iesistance wm'ldwide has led to a better understanding of tile relationsliip between the phH'macoldnetics mid phamlacodynamics of Hltimalafials, with the aim of improving the way in wliich we use these anti-parasitic agents. Understanding clinical pharmacokineties facilitates the design of the most appropriate dosage regimen, explains the reason for treatment failures and unexpected side effects, and elucidates the mechanism of drug interaction especially in combination therapy. In antimalarial treatment, for complete radical cure to be acliieved, it is essential that drug concentrations exceed the minimum inliibitoC¢ concentration (MIC) until the last parasite has been cleared from the blood. Antimalarials also differ in their inhibitory effects on the parasite asexual stages: chloroquine (CQ) acts more rapidly than sulfadoxine pyrimethamine (SP) against tile mid- to late trophozoite stage. Tile duration of treatment using &atgs with a short or long elimination halflife should be considered in relation to tile 48-hour parasite asexual cycle, effectively covering at least 2 parasite cycles and tile residuum of parasites in circulation. Like all other countries in the region, the Philippines was faced with a dilemma some 5 years ago of what treatment regimen to use following confirmed reports of high levels of treatment failures with CQ and SP monotherapy against Plasmodium falciparum malaria. Tile combination CQ+SP was an alternative, with SP still effective in several parts of tile
country. Hence the efficacy and kinetics of CQ+SP given sequentially or simultaneously were investigated in malaria patients in Palawan province. Results showed that the sequential regimen CQ given over 3 days followed by a tingle dose SP on Day 4 was well tolerated, had minimum fide effects and was as efficacious as CQ and SP given fimultHreously on Day 0. The simultaneous administration showed a shorter parasite and fever clearance time and parasite elimination halflffe. Both regimens achieved effective therapeutic concentrations in the serum, without much inter-individual variation in drug concentrations of tile 4 compounds chlm'oquine, des-ethylchlm'oquine (active metabolite), sulfadoxine and pyrimethamine.
$20. Tuberculosis: Immunology and Therapy $20.1 Immunology of TB W. Henry BOOM. Case Western Reserve ~;>ziversi~, Cleveland, OH, USA
M. tubereulosis remains one of the most successful human pathogens. The ability ofM. tubereulosis to elicit vigorous acquired immune responses and use of the macrophage as primary ceB to infect, suggest that the organism has evolved multiple strategies to survive and persist in the face of innate and acquired immune responses. Persistence of M. tuberculosis in othel;vise healthy persons is one of the hallmarks of this Ol~gHtism. Survival and persistence require not only resistance to microbicidal mechanisms of phagocytes but also avoidance of recognition by multiple T ceB subsets. The acquired immune response to M. tuberculosis requires participation by multiple T cells subsets. These include not only a central role for MHC-II restricted CD4+ T cells, but also MHC-I restricted CD8+, gamma-delta and CD-1 lestdcted T cells. These diverse T cell populations recognize a wide range of mycobacterial antigens, but share overlapping functions such as secretion of IFN ~ and TNF ~ CTL function, and ability to provide cob contact dependent help to macrophages. How T cell responses are regulated in vivo and their robs in different stages of M. tuberculosis infection mid in protective immunity remain to be detemfined. Better understanding of how M. tuberculosis avoids recognition and elimination by T cell mediated immunity is also necessary to improve detection and elimination of latent infection. Answers to these questions wiB impact on vaccine development as web as the understanding of the host-pathogen inteiaction in M. tuberculosis infection.
$20.2 Role of Immunotherapy in TB Douglas B. LOWRIE. National tnstirate for Medical Research, London, UK
Background: Tuberculosis is a disease that is driven by the acquired immune response to the tubercle bacillus, Mycobacterium tubereulosis. From the very earliest days, soon after the discovery of the bacterium by Robert Koch, it has been apparent that ff one attempts to achieve cure by stimulating acquired immunity, the disease can be made worse. Discussion: Scientific investigations have not yet been able to separate the effecter components of protective immunity from the effecter components of pathology, let alone define the regulatoc¢ pathways that deteixnine the balance between the two. Therefore it should come as no surprise that attempts to devise practical immunotherapeutie interventions to add on to conventional chemotherapy can sometimes find ways of exacerbating disease. The issue is not that it happens, or that it is not always predictable from our limited knowledge, but that it is vasiable under seemingly controlled conditions in laboratmy mice. This is hindering progress. Furthermore, the few clinical trials of potential immunotherapeutic agents that have been reported, such as interferon gamma, intedeukin 2 and heat killed M. vaeeae, have shown little evidence of benefit. However, we should not be discouraged. On the positive side, it has now been established in a number of independent studies in mice that dramatic therapeutic benefit can indeed be obtained by immune stimulation. Hitherto it had been far from clear that protection and pathology could in fact be separated. Much of this advance has come from studies of DNA vaccines and the results and implications will be discussed.
@eakers' Abstracts ~International Journal of Antimicrobial Agents 26S (2005) S1 $63
can also be used for inpatients, although they lestrict mobility in active patients. Drag stability can also be an issue, as the [3 lactam needs to be stable for 24 hours, the usual interval for a bag/pump change, and at room or skin temperature. Most ~3-1actams are stable, but imipenem and benzylpenicillin are not. Continuous infusion should be considered ill'St-line when prolonged (i>2 weeks) high-dose 13-1actam therapy is required, such as is encountered with some deep staphylococcal infections, or for facilitating early discharge when changing to oral therapy is not recommended. It can also be applied in other settings where optimizing bactericidal activity is felt to be important, such as sepsis in ICU patients and febrile neutropenia. Its role in endocm'ditis treatment is controversial.
S19.5 The Pharmacokinetics and Pharmacodynamics of Anti-Malarials: A New Approach in the Treatment of Malaria: The Philippine Experience Ma. Dorina G. BUSTOS. Research Institute for TroFical Medicine, Alabang~ Metro Manila, Philippines Tile emel~gence of tile problem of malaria drug iesistance wm'ldwide has led to a better understanding of tile relationsliip between the phH'macoldnetics mid phamlacodynamics of Hltimalafials, with the aim of improving the way in wliich we use these anti-parasitic agents. Understanding clinical pharmacokineties facilitates the design of the most appropriate dosage regimen, explains the reason for treatment failures and unexpected side effects, and elucidates the mechanism of drug interaction especially in combination therapy. In antimalarial treatment, for complete radical cure to be acliieved, it is essential that drug concentrations exceed the minimum inliibitoC¢ concentration (MIC) until the last parasite has been cleared from the blood. Antimalarials also differ in their inhibitory effects on the parasite asexual stages: chloroquine (CQ) acts more rapidly than sulfadoxine pyrimethamine (SP) against tile mid- to late trophozoite stage. Tile duration of treatment using &atgs with a short or long elimination halflife should be considered in relation to tile 48-hour parasite asexual cycle, effectively covering at least 2 parasite cycles and tile residuum of parasites in circulation. Like all other countries in the region, the Philippines was faced with a dilemma some 5 years ago of what treatment regimen to use following confirmed reports of high levels of treatment failures with CQ and SP monotherapy against Plasmodium falciparum malaria. Tile combination CQ+SP was an alternative, with SP still effective in several parts of tile
country. Hence the efficacy and kinetics of CQ+SP given sequentially or simultaneously were investigated in malaria patients in Palawan province. Results showed that the sequential regimen CQ given over 3 days followed by a tingle dose SP on Day 4 was well tolerated, had minimum fide effects and was as efficacious as CQ and SP given fimultHreously on Day 0. The simultaneous administration showed a shorter parasite and fever clearance time and parasite elimination halflffe. Both regimens achieved effective therapeutic concentrations in the serum, without much inter-individual variation in drug concentrations of tile 4 compounds chlm'oquine, des-ethylchlm'oquine (active metabolite), sulfadoxine and pyrimethamine.
$20. Tuberculosis: Immunology and Therapy $20.1 Immunology of TB W. Henry BOOM. Case Western Reserve ~;>ziversi~, Cleveland, OH, USA
M. tubereulosis remains one of the most successful human pathogens. The ability ofM. tubereulosis to elicit vigorous acquired immune responses and use of the macrophage as primary ceB to infect, suggest that the organism has evolved multiple strategies to survive and persist in the face of innate and acquired immune responses. Persistence of M. tuberculosis in othel;vise healthy persons is one of the hallmarks of this Ol~gHtism. Survival and persistence require not only resistance to microbicidal mechanisms of phagocytes but also avoidance of recognition by multiple T ceB subsets. The acquired immune response to M. tuberculosis requires participation by multiple T cells subsets. These include not only a central role for MHC-II restricted CD4+ T cells, but also MHC-I restricted CD8+, gamma-delta and CD-1 lestdcted T cells. These diverse T cell populations recognize a wide range of mycobacterial antigens, but share overlapping functions such as secretion of IFN ~ and TNF ~ CTL function, and ability to provide cob contact dependent help to macrophages. How T cell responses are regulated in vivo and their robs in different stages of M. tuberculosis infection mid in protective immunity remain to be detemfined. Better understanding of how M. tuberculosis avoids recognition and elimination by T cell mediated immunity is also necessary to improve detection and elimination of latent infection. Answers to these questions wiB impact on vaccine development as web as the understanding of the host-pathogen inteiaction in M. tuberculosis infection.
$20.2 Role of Immunotherapy in TB Douglas B. LOWRIE. National tnstirate for Medical Research, London, UK
Background: Tuberculosis is a disease that is driven by the acquired immune response to the tubercle bacillus, Mycobacterium tubereulosis. From the very earliest days, soon after the discovery of the bacterium by Robert Koch, it has been apparent that ff one attempts to achieve cure by stimulating acquired immunity, the disease can be made worse. Discussion: Scientific investigations have not yet been able to separate the effecter components of protective immunity from the effecter components of pathology, let alone define the regulatoc¢ pathways that deteixnine the balance between the two. Therefore it should come as no surprise that attempts to devise practical immunotherapeutie interventions to add on to conventional chemotherapy can sometimes find ways of exacerbating disease. The issue is not that it happens, or that it is not always predictable from our limited knowledge, but that it is vasiable under seemingly controlled conditions in laboratmy mice. This is hindering progress. Furthermore, the few clinical trials of potential immunotherapeutic agents that have been reported, such as interferon gamma, intedeukin 2 and heat killed M. vaeeae, have shown little evidence of benefit. However, we should not be discouraged. On the positive side, it has now been established in a number of independent studies in mice that dramatic therapeutic benefit can indeed be obtained by immune stimulation. Hitherto it had been far from clear that protection and pathology could in fact be separated. Much of this advance has come from studies of DNA vaccines and the results and implications will be discussed.