Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving viable micro-organism
Reexamination Certificate
2001-08-01
2004-06-15
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving viable micro-organism
Reexamination Certificate
active
06750038
ABSTRACT:
BACKGROUND OF THE INVENTION
The following is offered as background information only and is not admitted to be prior art to the present invention.
The arsenal of drugs available to physicians for the treatment of infection is rapidly diminishing because potent classes of antibiotics such as the beta-lactams, macrolides, quinolones, tetracyclines and aminoglycosides, are falling victim to the phenomenon of bacterial resistance. For example, in a 1995 study, Fish, et al., reviewed 173 studies encompassing over 14,0000 patients, eight antibiotic classes and 225 individual treatment regimes (
Pharmacotherapy,
1995, 15(3):279-291). They found resistance reported in 4% of all organisms and 5.6% of all infections treated. Furthermore, the appearance of cross-resistance, the ability of a bacterial strain resistant to one antibiotic to resist one or more other, even structurally different, antibiotics, is also increasing. Bacterial cells can acquire antibiotic resistance in several ways. One of these is simply by natural selection. Within a group of bacteria of the same species there often will be found individual members which have one or more altered genes that confer resistance to a particular antibiotic. These altered genes may arise as the result of natural mutations or by assimilation of genes from other already resistant bacteria through such processes as conjugation.
When a species of bacteria is challenged by an antibiotic, susceptible members die while those which are resistant, survive, reproduce and pass on their resistance. The more antibiotics bacteria is exposed to, the greater the probability that they will develop general resistance to antibiotics. Thus, the indiscriminate use of antibiotics can act as an effective screening mechanism for bacteria leading eventually to extremely resistant strains. However, the clinician faced with an unknown infection in a patient often has no choice. Speed in initiating treatment is often crucial to the well-being of the patient so the clinician must often make an educated guess as to what treatment regime to try while he or she awaits identification of the actual causal organism, at which time a more directed treatment regime can be initiated. The initial treatment selected, of necessity, usually involves use of the broadest-spectrum, most potent antibiotics available, which, unfortunately is the perfect recipe for the development of super-resistant bacterial strains by the selection process discussed above.
Resistance is already well-established among several clinically important bacteria and is quickly limiting the utility of the most commonly prescribed antibiotics. In particular, resistant strains of Pseudomonas, Eschericia, Streptococcus, Staphlococcus, Enterococcus, Enterobacteriaceae, Mycobacteria, Klebsiella and Haemophilis have arisen and are threatening a host of otherwise successful antibiotic therapy strategies.
One way to combat the emergence of resistance is to determine as rapidly as possible the antibiotic susceptibility of a particular infection-causing bacteria. Not only is this important to the well-being of the patient, it will assist in the control of the proliferation of antibiotic resistance among bacteria strains by selective, targeted application of antibiotic treatment. The techniques presently available and in widest use, however, do not provide a sufficiently rapid method for such determination.
A standard approach to determining the most appropriate antibiotic treatment strategy is to first identify the causal bacteria species so that an antibiotic known to be effective against that species can be prescribed. This involves isolation of bacterial cells, increasing their numbers by growing them in a culture medium and then identifying the species (and possibly the strain) by their genetic characteristics, morphology, staining pattern, etc. The culturing approach has the advantage of creating a large number of intact microorganisms which allows relatively easy identification. However, the technique suffers from that fact that it often takes a substantial amount of time to, first, grow enough of the bacteria to identify, and, second, to actually evaluate the spectrum of physiological properties necessary to make a positive identification. In the meantime, the patient may be subjected to broad-spectrum drug treatment, which not only may not be entirely effective but, as discussed above, may exacerbate the emergence of resistant strains. Furthermore, even though the species of the infecting organism is identified, it may be a resistant strain which cannot be treated with a conventional antibiotic but, rather, may require a more specific treatment regime. Unfortunately, this is difficult to accomplish since any such specific regime will depend greatly on the nature of the target bacteria. Thus, it would be desirable to be able to determine the exact susceptibility of the actual infecting bacteria prior to initiating treatment.
U.S. Pat. No. 5,989,853, to Bochner, et al. (issued Nov. 23, 1999), purports to disclose a rapid means of microorganism identification. The procedure involves a multi-test format in which the organisms are suspended in a gel matrix containing an indicator and test substances such as carbon sources and anti-microbial agents. Carbon sources are selected that can differentiate between bacteria, that is, sources which are used by some bacteria and not others. Anti-microbial agents are similarly selected; i.e., the ones selected are specific for certain bacterial species thereby making them also useful for differentiating among species. This procedure, however, requires traditional culturing to obtain a sufficient population of bacteria for the procedure.
Johnson, et al., U.S. Pat. No. 6,043,048, issued Mar. 28, 2000, describe a method for the specific determination of beta-lactam antibiotic susceptibility in a target bacterial strain. The bacteria strain is placed on growth media in the presence of both an antibiotic which induces the production of &bgr;-lactam-detoxifying enzymes (a &bgr;-lactamase) and a beta-lactam indicator antibiotic (which kills or inhibits the growth of bacteria not capable of producing a &bgr;-lactamase. An essential-nutrient-containing fluorogenic compound is also added to the growth medium. A susceptible bacterial strain, that is, one which cannot be induced to produce beta-lactamase, will metabolize the nutrient-containing compound and will not cause the release the fluorogenic agent. Thus, in a culture of susceptible bacteria, no increase in fluorescence will be observed. Resistant bacteria, on the other hand, will metabolize the nutrient/fluorphor compound, resulting in increased fluorescence. This procedure has limited utility in that it only provides susceptibility/resistance information for those bacteria that rely on &bgr;-lactamases as the basis for their resistant.
Another disclosure, U.S. Pat. No. 5,925,884 to Robinson et al. (issued Jul. 20, 1999), describes an automated system for analyzing a bacterial infection for both identification of the causal agent and determination of antibiotic susceptibility. A sample of material to be analyzed is placed in a test card which has been pre-loaded with either bacterial strain specific growth media or various concentrations of different antibiotics. The cards are incubated and, at intervals, read in a transmittance analyzer (for identification by turbidity) or a fluorescence analyzer (for antibiotic susceptibility by release of a fluorophore). The patent indicates that results should be obtainable in from 2 to 18 hours depending on the incubation time required for the bacterial. However, independent literature indicates that the time is more in the range of 4 to 16 hours.
A procedure for identifying bacteria and determining minimum inhibitory concentrations (MIC) values of anti-microbial agents is disclosed in U.S. Pat. No. 4,448,534 to Wertz ( May 15, 1984). This procedure basically involves an instrumental procedure for analyzing growth in culture. That is, bacteria that can grow in the medium will cause higher tu
Bingham & McCutchen LLP
Essential Therapeutics, Inc.
Lilling Herbert J.
Rose Bernard F.
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