Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-06-21
2001-07-10
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S222500
Reexamination Certificate
active
06258797
ABSTRACT:
This invention relates to a method for preventing and combating infection or sepsis in or caused by the use of delivery systems. More particularly it relates to a method for preventing bacterial colonisation in delivery systems which involve the use of catheters and/or reservoirs of liquid for infusions and the resultant sepsis in vivo. In particular it includes a method for reducing or substantially eliminating infection or sepsis in a subcutaneously-implanted access port for drug delivery either by arterial or venous access or peridural administration.
Delivery systems are widely used in medicine as a means for introducing liquid material which might include medicaments, nutrition, or other active agents to a particular locus in a patient. Such systems frequently involve the use of catheters which, for many applications, are surgically or intravenously located and stitched into place for long-term administration of the desired material. Typical systems include central catheters such as may be used for total parenteral nutrition (TPN) used in e.g. short bowel syndrome (for the duration of life), with the risk of sepsis or endocarditis, as well as catheters and drains which are involved in peritoneal dialysis for those with terminal kidney failure, which, if infected, can lead to peritonitis with serious consequences.
One type of delivery system used for some years in the treatment of conditions in humans comprises a reservoir or chamber of small volume subcutaneously-implanted under the fascia having direct access via a catheter to the cardiovascular system. Such systems are known as port systems.
Such systems are often used in the treatment of malignant conditions. The treatment of malignant conditions in humans is becoming increasing sophisticated and the success rate is rising. Oncology has developed to the stage where particular medicaments or combinations of medicaments, e.g. combinations of cytostatics and metastasis inhibitors, in certain doses either as short or long term infusions or bolus injections can be successfully used to target particular types of malignancy and researchers have sought to develop ways by which regimes of chemotherapeutic medication, some of which can be highly toxic, can be administered to a patient at suitable dosage levels over a period of time. The use of i.v. infusion solutions and/or injections of anti-neoplastic agents can damage veins or cause severe complications such as spasm, paravasal necrosis, (thrombo)phlebitis and sepsis.
One type of reservoir includes a penetrable self-sealing membrane and can be filled or topped-up daily in vivo using a specially-designed syringe and needle. Such a reservoir allows slow continuous discharge of medication over a period of time at a dosage level that can be much more closely maintained and regulated then is the case with other forms of oral or parental administration. Because of the reduction in damage to the veins and discomfort of the patient, the technique clearly has a future but a complication which frequently occurs with serious results is that of infection and sepsis.
The reservoir and delivery system itself in this embodiment is usually implanted under local anaesthesia—below the collar bone in a small pocket created surgically on the fascia of the pectoral muscle is one site that has been used. Whilst all the normal precautions to prevent infection can be taken during implantation, it is in recharging of the device that infection and sepsis is most likely to occur. The system is recharged using the syringe and needle which is passed through the skin and through the self-sealing but penetrable wall of the device. It is difficult to remove all bacteria on the skin prior to recharging and it is inevitable during recharge that some bacteria, for example nosocomial pathogens, and especially resistant pathogens e.g. MRSA or VRE, will be introduced into the system however meticulous the disinfection of the entrance point. Given that therapy is intended to be long-term and that such delivery systems are capable of being recharged up to 2,000 times, there is plenty of opportunity and time for bacterial or fungal infection to take seat and develop into an extremely serious condition. The most common infections are Staphylococcal, such as from multi-resistant
Staphylococcus aureus
(90% penicillin-resistant and methicillin and oxacillin resistant) (MRSA) or from vancomycin-resistant Enterococci (VRE) though other causative organisms such as Streptococci, and rare fungi such as Pseudomonas have also been reported.
Staphylococcus epidermidis
is probably the most frequently reported causative organism.
This situation is exacerbated by the nature of the drug treatment itself. Despite the advances that have been made, oncological chemotherapy still involves treating a patient with materials that are cytotoxic and long-term treatment of this type inevitably weakens the patient's immune system. Anti-neoplastic chemotherapy and radiotherapy lead to immunosuppression in patients. Immunosuppression in patients with malignant tumours leads to reduction of neutrophile granulocytes and neutropenia. Thus, at the same time as an infection may be building up in a patient, his immune system is less capable of dealing with it. The success of anti-neoplastic treatment therefore depends also on the prophylaxis of nosocomial infections in these high-risk patients. Similar considerations apply to the use of such devices in administering medication for the treatment of AIDS.
Similar considerations can apply to other port systems. Other port systems are known for implantation in the arm, known as a peripheral venoid port catheter, for implantation in the peritoneum, for implantation in the hepatic artery and for spinal or epidural implantation.
It is estimated that such ports or catheter-based delivery systems give rise to infections in up to about 8% of cases. The frequency rate and fatality of sepsis does depend on the catheter site, and some of the risk can be reduced by suitable care of the entrance point. However, the consequences of sepsis are clearly dangerous and costly. Removal or replacement of the delivery system may well have to be carried out operatively, necessitating a further stay in hospital for the patient and further expense. The danger of general systemic infection is real and infection in the delivery system is difficult to treat with systemic antibiotics due to the minimal contact time they allow which is insufficient to combat the colonies of multi-resistant pathogens. In addition to this the possible intensive care costs are substantial. The treatment of a patient with severe sepsis can lead to problems such as ARDS (Adult Respiratory Distress Syndrome) necessitating polypragmasy and polypharmacy. The treatment of nosocomial pneumonia or endocarditis are particularly difficult.
Heart problems in particular can also be caused. If a cava catheter through which delivery of the medicament takes place is intubated into one of the veins returning to the heart, for example the cephalic or subclavian vein, the femoral vein, one of the jugular veins or the basilic vein near the elbow, it is guided using X-ray during implantation so that the catheter tip is close to the point of entry of the vena cava into the heart. The heart is accordingly often one of the first organs likely to become colonised by bacteria, fungi or viruses and the feared endocarditis septica has been frequently reported. Other complications include vascular lesions, thrombosis, embolism or phlebitis.
Because the infection has its seat of colonised bacteria within the delivery system, this will not be removed simply by treating the patient systemically with antibiotics. Furthermore, attempts have been made to try and apply antibiotics to the delivery system itself, but this gives rise to difficulties because of the development of resistance problems and because of toxic reactions in the bloodstream which arise when the antibiotic is flushed out of the delivery system with isotonic salt solution. This can result in a toxic allergi
Ed. Geistlich Soehne AG fuer Chemische Industrie
Reamer James H.
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