Long chain carboxybetaines in antimicrobial formulations

Details Long chain carboxybetaines in antimicrobial formulations Long chain carboxybetaines in antimicrobial formulations

1999-04-09

2001-06-05

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06242486

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to the use of long chain carboxybetaines in antimicrobial formulations. These compositions are especially useful as disinfectants or antiseptic preparations against Staphylococcus, especially,
Staph. aureus
, and
Staph. epidermidis,
Salmonella, especially
Salmonella typhimurium,
Escherichia and Pseudomonas, especially
Ps. aeruginosa.
BACKGROUND OF THE INVENTION
A. Nosocomial Infections
A nosocomial infection (NI) is defined as a disease acquired by a patient at a health care facility (i.e. not the patient's original disorder). Many NI are caused by microorganisms that can naturally colonize the external surfaces of the body (e.g. skin, moist mucosal surfaces or GI tract), however, under certain conditions these “opportunists” can cause disease. For example, NI are often associated with invasive medical procedures, such as surgery and bronchoscopy, and with penetrating devices, such as catheters. Furthermore, intensive care patients are particularly at risk of NI, especially in surgical, pediatric
eonatal, burns and trauma units (Martin, M.A.
New Horizons
1:162-171, (1993)). The predominant causes of NI are gram positive bacteria (>40%), especially
Staphylococcus aureus
and
Staphylococcus epidermidis
, and gram negative bacteria (>40%), especially
Escherichia coli
, with the remaining NI being caused mainly by yeast and fungi (Vermaat et al.
American Journal of Infection Control
21:183-188, (1993)). Gram positive bacteria, such as
Staph. aureus
, are of particular concern due to their hardiness (ability to survive under non-physiologic conditions) and their inherent resistance to many antibiotics. Each year, NI affect an approximately 2 million patients, cause more than 60,000 deaths and incur an estimated $4.5 billion in added costs (
Morbidity and Mortality Weekly Reports
41:783-787, (1992); Pittet, D. & Wenzel, R. P.
Archives of Internal Medicine
155:1177-1184, (1995)). These figures have been increasing progressively over the last 10 years.
A component of NI that is an increasing problem is the incidence of drug-resistant microorganisms. This problem is highlighted in a recent monologue by Stuart B. Levy, M.D. (Levy, S. B.,
The Antibiotic Paradox. How Miracle Drugs are Destroying the Miracle.
, Plenum Press, New York (1992)), which describes a number of case studies involving outbreaks of multi-drug resistant (MDR) strains of bacteria. One example of this is the “golden staph” or methicillin-resistant
Staphylococcus aureus
(MRSA). The incidence of MRSA varies between health care facilities and countries, however, it can be greater than 50% of all
Staph. aureus
isolates, and appears to be increasing, especially in Japan (Lotsu et al.
Jour. Hosp. Infection,
27:275-283, (1995)). Disease caused by MRSA can be effectively treated with vancomycin, however, there is concern that inappropriate use of this antibiotic may lead to the emergence of vancomycin-resistant MRSA. Disease caused by this organism will be extremely difficult to treat, tantamount to a death sentence.
The incidence of NI, including MRSA, can be reduced by at least 30% by implementing suitable infection control measures, however, in the US, only 6%-9% of NI are actually being prevented (Hospital Infections Program, Centers for Disease Control and Prevention). Of particular concern is the fact that a common reservoir for MRSA is the nasal passages of health care workers, with hand contamination often being the route of transfer (Guidelines for management of patients with methicillin-resistant
Staphylococcus aureus
in acute care hospitals and long-term care facilities.
Connecticut Medicine
57:611-617 (1993); Wenzel, R. P.
Journal of Chemotherapy
6 suppl. 4:33-40, (1994)). Consequently, a major component of successful infection control programs is an emphasis on hand washing and effective use of sterilizing procedures, disinfectants and antiseptics (CDC Guidelines for Handwashing and Hospital Environmental Control).
Gram-negative microorganisms, as exemplified by
Salmonella, Pseudomonas
, and virulent strains of
E. coli
, are also important bacteria both clinically and also to the food industry.
Salmonella
is a major cause of food poisening—caused by the ingestion of meat (or items in contact with the meat) of diseased animals.
Pseudomonas
is widely distributed in water and air, on the skin and in the upper respiratory tract, and can be isolated from feces. It is clinically associated with other pyrogenic organisms in abdonimal acscesses, and can cause cystitis, otitis media, mastoiditis, enteritis in children and even septicemia.
As with gram positive microorganisms, such infections can be extremely difficult to treat. Prevention of such infections, especially clinically and in the food industry, is grounded on the effective use of sterilizing procedures, disinfectants and antiseptics. The effective use of reagents that could be used as disinfectants, or more importantly antiseptics, that could efficiently eliminate pathogenic microorganisms would help to alleviate the burden of medical costs attributable to such infections.
B. Disinfectants and Antiseptics
Germicidal activities are generally discussed in terms of sterilization, disinfectant properties and antiseptic qualities. Sterilization involves the use of chemical or physical means to totally eliminate microorganisms, viruses, fungi, spores, yeast and other saprophytic and infectious agents, independent of type or classification (e.g., autoclaving or irradiation).
Disinfectants are, by definition, germicidal agents used on inanimate objects. Disinfectants are typically chemical agents that are generally less broad in terms of their spectrum of activity, relative to sterilizing procedures. As a result, not all forms of a given category of organism are killed, but pathogenic forms are preferentially eliminated by design.
Antiseptics are, by definition, germicidal agents designed for use on living or biological tissue, primarily skin and hair. Antiseptics are typically milder chemical agents than disinfectants and, as a result, are generally less efficacious at eliminating infectious agents. For example, disinfectants usually incorporate organic reagents that would be unacceptable in antiseptic formulations due to toxicity, carcinogenic or mutagenic activity. Since routes of infection are typically through a breach in tissue, or via a natural opening, antiseptic formulations provide perhaps the most important line of defense.
Unfortunately, the dichotomy between toxicity and efficacy precludes many disinfectants from being used as antiseptics. Additionally, many microbial pathogens are resistant to commonly used disinfectants and antiseptics. There is a need for bactericidal compositions, especially disinfectant and antiseptic compositions, that are efficacious, and that are economical to make and use.
C. Detergents as Disinfectants and Antiseptics
In general, nonionic detergents have been reported to have minimal, if any, bactericidal activity, whereas ionic detergents, such as the quaternary amines, have been reported to have bactericidal activity (Cella, J. A. et al.,
J Am. Chem. Soc.
74:2061-2062 (1952)). Cella also reported that, in general, quaternary amine detergents that have longer alkyl chains also have greater bactericidal activity than their shorter chain counterparts.
However, ionic detergents are generally untenable as components in aqueous antiseptic and disinfectant formulations due to a lack of solubility in the presence of ions. If provided in the precipitated form, the reagent is less available and less efficacious. Nonionic detergents are, for the most part, unaffected by the presence of ions so, at a first glance, would appear to be suitable for antiseptic and disinfectant preparations. However, such detergents are not ideal for the purposes of decontamination, due to their relatively poor bactericidal activity.
A decrease in solubility in the presence of ions is called “salting-out.” When ionic detergents are placed in the presence o

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