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6. Emerging Tools and Technology for Countering Resistance
Pages 159-195

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From page 159...
... And while many observers suggest that the genomics revolution may be opening promising new avenues for exploration, it has yet to populate the pharmaceutical development pipeline with new classes of compounds. The focus of this session of the workshop was on examining advances in our understanding of the genetics and biochemistry of a variety of pathogens, and on exploring how this knowledge might lead to novel approaches to developing new drugs and other tools and technologies to help counter the spread of antimicrobial resistance.
From page 160...
... Toward this end, the scientists have developed a new type of reagent, called lytic enzymes, that can prevent infection by specifically destroying pathogenic bacteria on mucous membranes. The enzymes might prove especially useful in hospitals, nursing homes, daycare centers, and other locations where bacterial infections often run rampant.
From page 161...
... Meanwhile, liberal use of antibiotics in the clinics, in agriculture, in aquaculture, and in animal husbandry was facilitating a quiet revolution in microbial populations. These events resulted in antibiotic-resistant organisms that were perfectly treatable a decade or two earlier.
From page 162...
... 162 ~ (a ~ ._ ~ o Q A in O Id ~ Q Q O X = .o (a o (a ._ X ~ Ai X ._ Q [d ~ 0 (a o O N i ILL to to oo a, ho CD ~ to at, to to CO Ct o o U
From page 163...
... Clinical resistance to linezolid emerged in a mere seven months after its introduction to the clinic (Fung et al., 2001~. In principle, the genes that would confer resistance to an antibiotic could be acquired or could evolve.
From page 164...
... Enzymes of class B are zinc-dependent, and the remaining three classes are enzymes that depend on a catalytic serine in their mechanisms of action. These serine-dependent enzymes experience acylation at the serine by the substrate, and the acyl-enzyme species subsequently undergoes an enzyme-promoted deacylation that liberates the enzyme for additional catalytic cycles and releases the product of the reaction (Bush and Mobashery, 1998; Massova and Mobashery, 1998~.
From page 165...
... These enzymes, in contrast to the cases of enzymes of classes A and C, pursue a symmetric mechanism for the two-step reaction by having a highly unusual carbamylated lysine that serves the role of a base for both steps of catalysis (Maveyraud et al., 2000; Golemi et al., 2001; Maveyraud et al., 20021. These observations argue for independent evolutions for all four classes of p-lactamases (Massova and Mobashery, 19981.
From page 166...
... The outer membrane is a bilayer sheath that encloses the entire organism. Nutrients penetrate this membrane by traversing the porin channels.
From page 167...
... These observations provide strong evidence that random mutation and selection would lead along a different evolutionary tangent depending on when the event takes place, in what organism, and what resources were available to the organism. USING PHAGE LYTIC ENZYMES TO CONTROL ANTIBIOTIC-RESISTANT PATHOGENIC BACTERIA ON MUCOUS MEMBRANES Vincent A
From page 168...
... Of the phage lytic enzymes that have been reported thus far, the great majority are amidases. The C-terminal domain of phage lytic enzymes has specificity for a cell wall substrate (Garcia et al., 1988; Lopez et al., 1992, 1997~.
From page 169...
... Similar results are seen with a pneumococcal-specific lysine; however, in this case, the enzyme was also tested against strains of pneumococci that were resistant to penicillin and the killing efficiency was the same. Unlike antibiotics, which are usually more broad in their spectrum and kill many different bacteria found in the human body, some of which are beneficial, the phage enzymes kill only the disease bacteria with little to no effect on the normal human bacterial flora.
From page 171...
... This was not surprising since the bonds cleaved by the phage enzymes are only found in bacteria and not mammalian tissues. Thus, it is anticipated that these enzymes will be well tolerated by the human mucous membranes.
From page 172...
... (A) After nasal and pharyngeal treatment with a total of 1,400 ,ug of Pal enzyme, no pneumococci were retrieved in the nasal wash, compared to buffer-treated colonized mice (p < 0.001~.
From page 173...
... Killing Biowarfare Bacteria Because phage enzymes are so efficient in killing pathogenic bacteria, they may be a valuable too! in controlling biowarfare bacteria.
From page 174...
... They may not only be used to control pathogenic bacteria on human mucous membranes, but may find utility in the food industry to control disease bacteria without the extensive use of antibiotics in feed or harsh agents to decontaminate. Because of the serious problems of antibiotic-resistant bacteria in hospitals, day care centers, and nursing homes, particularly staphylococci and pneumococci, such enzymes will be of immediate benefit in these environments.
From page 175...
... The industry needs regulatory assistance to lower antibiotic development costs, and in return they must produce a pipeline containing a wider variety of new chemical or biological entities that deserve use (but only) when they are needed.
From page 176...
... Patients who would contribute to superiority arguments are usually excluded from consideration in equivalence models, since both comparators must be active in order to retain the patient in the trial database used to determine equivalence. The alternative study design for this new antibiotic is a superiority trial.
From page 177...
... and time to bacterial eradication endpoints in the study of superior responses in failing patients, as well as in the study of antimicrobial resistance selection. The benefits of incorporating PK/PD measurements into superiority trials are clear.
From page 178...
... Every regimen has its own unique PK/PD predicted outcome, and very little of the overall clinical or microbiological outcomes is left as "random noise." This is most clearly apparent when PK/PD is linked to bacterial outcome in bacterially dependent conditions like nosocomial pneumonia (Schentag, l999b) , but it also works if you target the organism rather than the clinical symptoms in mild infections such as acute exacerbation of chronic bronchitis (AECB)
From page 179...
... in a) 25 Q o o o \, , _ ~ ~ ~ $ - 1 ~ O O O O O O O OAUIC<125 L 1 1 < '\ O O ~ O AUIC 125-250 1 1 1 1 ~ ~ ~ AUIC>250 , '\ A 1 1 1 1 ' ~ ~ 1 6 8 10 12 14 O ~ ~ Days of treatment FIGURE 6-10 Relationships between AUIC values and time to bacterial eradication in 74 patients treated with ciprofloxacin for nosocomial lower respiratory tract infection.
From page 180...
... The data were among the first to establish a predictability to emergence of resistance caused by selection pressure. Considering Resistance in Antibiotic Development If the focus of a new antibiotic becomes superiority to existing alternatives, it is necessary to focus on the microbe that fails conventional antibiotics.
From page 181...
... Measuring AUIC and Correlations with Selection Pressure Resistance One means of achieving equivalence even though you may have a superior antibiotic is to develop and market it at a marginally low dose. We would like to offer an example of an antibiotic developed at low dosing using equivalence design, now widely used in the community, where the selection pressure resulting from low AUICs is rapidly leading to resistance to the entire class it represents.
From page 182...
... 3. Every time levofloxacin is used in patients at its current low dose, its AUIC is below 100, which is the root cause of widespread selection pressure in the community (Schentag et al., 2001a)
From page 183...
... The clinical trials themselves clici not create enough selection pressure, because use was not monopolistic at that early time.
From page 184...
... 3. Widespread monopolistic use upon marketing, catalyzed by formularies and managed care practices trying to save money, lead to increasing selection pressure in communities with at-risk, reservoir populations.
From page 185...
... This allows prospective definition of when combination therapy is needed, and which antibiotic combinations will be most successful. Perhaps the most important benefit of expressing antibiotic action as microbiological eradication is that fewer patients are needed for statistical significance in superiority trials, which yields a substantial lowering of drug development costs and produces faster time to NDA approval.
From page 186...
... All of the following conditions discourage differentiation and force large numbers just to conclude equivalence (Powers et al., 2002~: Patients with symptoms but not caused by bacterial pathogens, Patients with self-limiting disease not dependent for cure on antimicrobial actions, and · Infected patients where the antimicrobial itself is barely active or inadequate, but there is still some activity of this comparator plus host defense. You conclude clinical cure in these settings regardless of what condition or drug produced it.
From page 187...
... · For antibiotics where there is no active comparator, studies of individual patient AUICs versus the standard AUIC target of 100 could be
From page 188...
... The current antibiotics development, regulatory, promotion, and clinical use pattern is illogical; the resulting selection pressure from aggressive equivalence-based marketing causes great ecological harm. We advocate changes in the drug development process for antibiotics, so as to achieve the following benefits: 1.
From page 189...
... Absence of compromise will raise antimicrobial development costs and likely aggravate resistance by fostering aggressive marketing and monopolistic use. All of the strategy outlined can be implemented relatively quickly, and further testing of the underlying principles would occur as the superiority trial designs achieve wider use.
From page 190...
... 1999. Carriage of respiratory tract pathogens and molecular epidemiology of Streptococcus pneumoniae colonization in healthy children attending day care centers in Lisbon, Portugal.
From page 191...
... 1988. Molecular evolution of lytic enzymes of Streptococcus pneumoniae and its bacteriophages.
From page 192...
... 1992. Structural analysis and biological significance of the cell wall lytic enzymes of Streptococcus pneumoniae and its bacteriophage.
From page 193...
... 2000. Vancomycin treatment failures in Staphylococcus aureus lower respiratory tract infections.
From page 194...
... 2001. Need for annual surveillance of antimicrobial resistance in Streptococcus pneumoniae in the United States: 2-year longitudinal analysis.
From page 195...
... Clinical Infectious Diseases 33:517-522. Whitney CG, Farley MM, Hadler J


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