Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-10-30
2001-06-26
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06251598
ABSTRACT:
BACKGROUND OF THE INVENTION
Clinical infection is the biological end result of a number of factors, including the nature of the invading organism its intrinsic virulence, the microenvironment of the invaded tissue or organ, and the responsiveness of the host. Any means by which bacteria can be introduced into the tissues can result in an infection. However, the nature of the introduction can influence the severity of the infection and can alter the host's ability to respond. As injuries, a cutaneous laceration, for example, differs from an extensive surgical dissection, which in turn differs from a perforated gastrointestinal viscus. Similarly, a lung infection (a pneumonia) occurring in an area of atelectasis is different from a lung infection that takes place as a result of an aspiration event. Mere presence of pathogens in intact or injured areas does not comprise an infection. A certain critical mass of organisms is necessary in order to sufficiently overcome the host defenses and cause an invasive infection. This level of bacteria is usually stated to be 10
5
organisms per gram of treatment. A variety of factors can influence the balance between microbial invader and host defenses sufficiently that infections develop at lower levels of bacterial exposure. Necrotic tissue or foreign bodies in a wound are termed adjuvant factors, understood to make infections likely to develop at lower concentrations. Local physiological factors such as impaired circulation also increase local susceptibility to infection. Systemic ailments like diabetes, uremia and AIDS are known to lower the host's resistance to infection, again making it easier for microbes to establish an infection in the tissues.
The severity of an infection in part relates to the extent of the injury that accompanies or precedes it. More severe injury (e.g., an extensive accidental or surgical trauma) interferes with host integrity more substantially, permitting freer access to host tissues and compromising intrinsic host defenses. The severity of an infection depends upon the number and kind of micro-organisms responsible for the infection. If a polymicrobial infection is diagnosed or suspected, early and aggressive antibiotic intervention is commonly warranted, often with broad-spectrum agents with activity against a number of possible invaders.
Certain virulence factors have been associated with specific microorganisms, making invasion carried out by these cells more destructive. Virulence factors are of three general types: 1) biological products produced and secreted by the infecting agent that attack cells in the host or that affect host homeostatic mechanisms to produce clinical disease; 2) structural components of the normal bacterial cell which, when shed within the host's internal environment or when released following death and lysis of the bacterial cell, have toxic effects on the host; 3) responses of the microorganism to antibiotics that make them resistant to these chemotherapeutic agents. Particular microorganisms characteristically manifest specific virulence factors. For example,
Staphylococcus aureus
produces coagulase, which acts as a powerful virulence factor. Staph. and Streptococcus species also produce leukocidins. As a further example, strains of
B. fragilis
produce superoxide dismutase, which converts superoxide anions to hydrogen peroxide; strains of
E. coli
produce catalase, which reduces hydrogen peroxide to water, thereby rendering possible a synergism between these two organisms. A wide variety of other virulence factors have been identified.
The most important structural virulence factor is bacterial endotoxin. Endotoxin is derived from the lipopolysaccharide outer membrane that is found in virtually all Gram negative bacteria. Endotoxin induces an extensive array of biological effects. It is understood directly to stimulate the complement cascade, to provoke platelet aggregation, to induce fever, to activate phagocytosis and the immune system, and to stimulate the synthesis of numerous cytokines. Kremer, et al., “Interleukin-1, -6 and tumor necrosis factor-alpha release is down-regulated in whole blood from septic patients”,
Acta Haemmatol.
95(3-4):268-273, 1996.
Factors relevant to host susceptibility include the ease of entry by which a microorganism first gains access to the host, the impediments placed in the microorganism's path as it spreads within the host, and the ability of the host ultimately to contain the invasion before suffering substantial injury. Certain hosts are known to be more vulnerable than others. Newborns, for example, are particularly prone to severe infections and sepsis. Similarly, pediatric patients can develop sepsis in response to bacterial infections that are much more benign in the adult population. Infections in the elderly are also more likely to progress to sepsis than similar infections in younger patients. Certain pathological conditions are also understood to increase the host's susceptibility to infections and sepsis. Severe trauma, such as that which characterizes major burns, predisposes the patient to microbial infections and sepsis to such an extent that these patients are considered immunocompromised hosts.
It would be desirable to identify those members of vulnerable populations at even more risk for overwhelming infection and its systemic consequences. For example, the newborn with a high temperature must be evaluated for foci of severe infection. This evaluation can include invasive measures such as lumbar puncture in order to rule out meningitis. Often the febrile newborn requires hospitalization and treatment with broad spectrum antibiotics until a source of the fever has been determined. If a subgroup of the newborn population could be identified as having greater risk or less risk of overwhelming infection, diagnostic and therapeutic measures could be tailored to the degree of risk. Lumbar puncture could be restricted to the high-risk infant, for example. Brik, et al., “Evaluation of febrile infants under 3 months of age: is routine lumbar puncture warranted?”
Isr. J Med. Sci.
33(2):93-97, 1997. Or, for example, low risk infants could be managed as outpatients or discharged quickly from the hospital, offering an important cost-saving in this era of managed care. Durongpisitkul, et al., “The appropriateness of early discharge of hospitalized children with suspected sepsis”,
J. Fam. Pract.
44(1):91-96, 1997. Infants or children at particular risk for certain severe systemic infections could be treated with infection-specific agents, or could be treated earlier or more aggressively.
Host defenses represent an important variable in determining the severity of a clinical infection. Non-specific host defenses serve to limit the initial extent of microbial invasion. Examples include the epiglottis mechanism of the trachea, the vibrissae of the nasal airway, the alveolar macrophage system and the acid environment of the stomach. More specific responses are set into motion on the cellular level once tissue injury or microbial contamination take place. As part of this specific response, the phagocytic-inflammatory components of host defense are initially mobilized with trauma or with the invasion of infecting agents. Phagocytosis and inflammation are intended to contain and destroy the organisms before they gain sufficient systemic access to cause a clinically significant infection. When a small scale infection is localized by these mechanisms, the clinical phenomena of cellulitis or abscess formation result. With more extensive microbial contamination, effective local containment may not be possible. Nonetheless, such containment is the goal of the phagocytic-inflammatory system of host defense.
A multitude of cellular functions contribute to the phase of specific host defense. First and foremost, in response to microbial invasion the host sets in motion the components of inflammation. Only when the stimulus of invading microorganisms becomes sufficiently pronounced do these inflammatory responses ris
di Giovine Francesco Saverio
Duff Gordon W.
Arnold, Esq. Beth E.
Foley, Hoag & Eliott LLP
Interleukin Genetics Inc.
Myers Carla J.
Quisel John
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