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2. Microbe Resistance
Pages 44-78

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From page 44...
... The bacterial strains staphylococci, enterococci, and pneumococci pose some of the most serious problems in terms of antimicrobial resistance. Scientists have now acquired detailed information about how these bacteria develop drug resistance.
From page 45...
... One issue considered during this session involved the effects of exposure to both anthrax and ionizing radiation at the same time, conditions that military personnel, in particular, might someday face. Based on a recent study in mice, scientists have been able to identify some fundamental factors that contribute to increased susceptibility to bacterial infections in general, and to B
From page 46...
... The Rockefeller University, New York, NY A major impact of the "chemical warfare" that humanity has been waging against the microbial world on an escalating scale since the discovery of antibiotics is the emergence of a vast variety of resistance mechanisms that have moved into virtually all pathogenic species viruses, bacteria, and protozoa alike. This emergence has occurred with a swiftness that, on an evolutionary scale, is truly remarkable.
From page 47...
... Next came reports on the increase in resistance level and in the frequency of resistant isolates. Eventually, multi-drug-resistant strains carrying resistance traits to different classes of antimicrobial agents also began to appear.
From page 48...
... armaments came from the microbial world (Tomasz, 20001. The current genomic revolution may offer clues for the production of new antimicrobial agents that would not have been invented by the microbial world during evolution.
From page 49...
... Thus, a possible deployment of new antimicrobial agents would not solve the basic dilemma of the antimicrobial armaments race that originates from its erroneous core philosophy: namely, the indiscriminate killing of bacteria by wide-spectrum antimicrobial agents. The fallacies of this philosophy have been pointed out repeatedly (Tomasz, 2000~.
From page 50...
... Compounds capable of inactivating the products of these genes should represent synergistic agents that together with p-lactam antibiotics would render resistant bacteria sensitive again to these classical antimicrobial agents. Resistance gene + auxiliary gene = resistance expressed .
From page 51...
... When this natural condition is combined with the close contact among children that is characteristic of day care centers, the high frequency of viral respiratory diseases in such centers, and the use (and misuse) of immense quantities of antimicrobial agents, the result is the creation of a bona fide "factory" of resistant pneumococci (Sa-Leao et al., 2000~.
From page 52...
... The European Community has recently initiated such a major project (EURIS, European Resistance Intervention Study) , which is aimed at identifying the most effective intervention strategies by which carriage of resistant pneumococci could be reduced among children attending day care centers in member countries (Sa-Leao et al., 2000~.
From page 53...
... First reports of chloroquine resistance were with P~smodium falciparum, the species responsible for the most acute and deadly form of human malaria (Payne, 1987~. By the 1970s, resistant P
From page 54...
... Although the exact patterns of PfCRT mutations differ according to the geographic origin of chloroquine-resistant parasites, all of these patterns include a key substitution for lysine at position ~ ~~ f ~ FIGURE 2-4 Schematic representation of PfCRT and positions of mutations associated with chloroquine resistance. The critical K76T mutation occurs in the first of the ten predicted transmembrane domains.
From page 55...
... These results suggest that loss of lysine's positive charge at PfCRT position 76 is a central feature of the chloroquine resistance mechanism. The fact that K76T is always found in the context of additional PfCRT mutations suggests that this key substitution requires accommodative or compensatory adjustments elsewhere in the protein.
From page 56...
... Results from these studies support a universal association of the PfCRT K76T mutation with chloroquine treatment failures and show that additional factors including immunity can affect the outcome resistant infections after treatment. The importance of immunity in treatment outcome has recently been demonstrated in a rodent mode!
From page 57...
... These results indicate that the Pgh-1 N86Y polymorphism does not have an important effect in chloroquine treatment failure but may relate to fitness adaptations in response to physiological changes from PfCRT mutations. Whether clinical chloroquine resistance might be affected by other Pgh-1 polymorphisms or modulatory determinants elsewhere in the P
From page 58...
... The search for new compounds with desirable pharmacokinetic profiles, low toxicity, and low production costs will be helped by improved understanding of the resistance mechanism at the molecular level. · Chemosensitizing agents that can be co-administered with chloroquine may have promise against chloroquine-resistant P
From page 59...
... DRUG RESISTANCE IN TREATMENT OF SCHISTOSOMIASIS Charles H
From page 60...
... These, too, will greatly expand the human use of anthelmintic drugs, raising the concern that resistance to anthelmintics will soon be with us. Common Threads of Drug Resistance in Helminths and Bacteria In a sense, anti-parasite drug treatment poses many of the same challenges founci in treating multiply-resistant bacterial infections: 1.
From page 61...
... retreatment (Gryseels et al., 2001~. In contemplating the phenomenon of bacterial drug resistance, the functional ecosystem for the emerging resistant strain is the individual human body.
From page 62...
... Of note, this resistance phenotype is sometimes lost in later generations after serial passaging in mice. It was noted that tolerant strains are less fecund, releasing fewer eggs per adult worm pair (Fallon et al., 1997~.
From page 63...
... haematobium, there was probably not sufficient time for this to occur; third, if the resistance trait is recessive or polygenic, sexual reproduction was predicted to slow its emergence by several generations; and fourth, crowding effects on fecundity in heavily infected humans was likely to delay the transmission of resistance genes as well. Most important, reduced reproductive fitness of the resistant strains was seen to substantially delay the arrival of clinically significant levels of drug resistance (King et al., 2000~.
From page 64...
... However, such measures will only delay and not prevent the eventual emergence of drug resistance. It is imperative that public health planners and health providers anticipate the emergence of praziquante!
From page 65...
... Bacteria transiocate from intestines 5-8 days after lethal doses of gamma radiation. We developed animal models of infection following irradiation to evaluate efficacy of therapeutic agents against endogenous and exogenous infections following sublethal and lethal doses of ionizing radiation (Brook et al., 19991.
From page 66...
... anthracis-Induced Polymicrobial Sepsis The experimental design for collecting scheduled microbiological specimens from sublethally irradiated mice that were challenged with intratracheal B anthracis Sterne spores, is shown in Figure 2-8.
From page 67...
... Antimicrobial Therapy for Sepsis After Irradiation The successful management of post-irracliation sepsis is a clifficult challenge (Brook et al., 1988; Brook and Elliott, 1991~. Antimicrobial agents
From page 68...
... Selected non-specific biological response modifiers (BRMs) , which enhance innate immunity by inducing cytokines naturally, or specific BRMs, such as cytokines, could augment specific antimicrobial agents, but this combined approach to therapy following irradiation remains essentially experimental (Peterson et al., 1994~.
From page 69...
... B6D2F~/ T female mice. Antimicrobial agents were given for 7, 14, or 21 days after intratracheal spore challenge (Elliott et al., 20021.
From page 70...
... To compare survival following therapy with penicillin and the two quinolones, ofloxacin and trovafloxacin, irradiated mice, 19 or 20 per group, were given 4.1 x 108 CFU B anthracis Sterne spores i.t.
From page 71...
... However, we evaluated the potential for B anthracis Sterne to develop antimicrobial resistance in vitro by passing growth of the bacteria sequentially in minimally inhibiting concentrations of quinolones and doxycycline.
From page 72...
... Therefore, once the toxins are formed, antimicrobial agents alone are not adequate to prevent mortality. By extending the general approach to treating sepsis following irradiation, successful management of anthrax following irradiation will include the following elements discussed below.
From page 73...
... 2001. Highlevel chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multi-drug resistance gene pfmdrl.
From page 74...
... Antimicrobial Agents and CI7emotI7erapy 43:1177-1182. De D, Krogstad FM, Cogswell FB, Krogstad DJ.
From page 75...
... Antimicrobial Agents and Chemotherapy 46:3463-3471. Elliott TB, Brook I, Stiefel SM.
From page 76...
... Antimicrobial Agents and Chemotherapy 40:1846-1854.
From page 77...
... 2000. Carriage of internationally spread epidemic clones of Streptococcus pneumoniae with unusual drug resistance patterns in children attending day care centers in Lisbon, Portugal.
From page 78...
... 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.


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