Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-08-26
2002-11-05
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S036000, C514S038000, C514S039000, C536S004100, C536S013600, C536S016800
Reexamination Certificate
active
06475992
ABSTRACT:
The present invention relates to a method of potentiating the activity of an antibacterial agent by using an aminoglycoside, and to novel compositions comprising an antibacterial agent and an aminoglycoside. It also relates to a method of treating bacterial infection by administration of the composition of the invention. More particularly, the invention relates to the use of an aminoglycoside to potentiate the activity of antibacterial agents acting at or near cell wall sites, such as &bgr;-lactams or cephalosporins. The invention also contemplates optimisation of the efficacy of aminoglycosides.
BACKGROUND OF THE INVENTION
A major problem in treatment of infections caused by bacteria, particularly hospital acquired infections, is that an increasing number of bacteria are becoming resistant to antibiotics. For example, many strains of Staphylococcus and Enterococcus are now resistant to most of the currently-available antibiotics. Other organisms, such as Pseudomonas, respond poorly. This problem is exacerbated by the ability of many bacteria to transfer resistance to other species of bacteria.
In laboratory testing, this manifests itself as a requirement for concentrations of antibiotics which are higher than the reported minimum inhibitory concentration (MIC) to inhibit the growth of the organisms.
One group of antibiotics which are clinically becoming less useful due to acquired resistance are the cephalosporins. Cephalosporins are conventionally believed to act at surface sites on the bacterial cell wall at or near the enzymes responsible for cell wall synthesis. In Gram-negative organisms with an outer cell wall, the action of cephalosporins is limited by access to these surface sites in the inner cell wall because of molecular size and other determinants of ability to penetrate porin structures in the outer cell wall, and by the action of enzymes (cephalosporinases) which break down the cephalosporins. These cephalosporinases are largely responsible for the emerging clinical resistance of bacteria to cephalosporins.
Although aminoglycoside antibiotics are active against a wide spectrum of organisms, their use has been severely limited by the toxic side effects which occur at the doses required to achieve the desired antibacterial effect.
Thus, there is a need to improve the efficacy of antibiotics, particularly cephalosporins. Three is also a need to reduce the toxicity of aminoglycoside antibiotics, particularly gentamicin.
It has conventionally been thought that aminoglycosides exert their antibacterial effects via a strictly intracellular mechanism involving inhibition of ribosomal activity. However, the present inventor has examined data on uptake of radioactively—labelled aminoglycosides, and now proposes that aminoglycosides also act at the cell surface so as to contribute to the process of entry into the cell. Thus the hypothesis underlying the present invention is that an important part of the action(s) of aminoglycoside antimicrobials involve creation of breaches in external cell walls of bacteria and in other external capsular layers or membranes composed of lipopolysaccharide or mucopolysaccharide constituents.
It was thought
1. that the exposure profiles necessary for this action of aminoglycosides were likely to differ from the concentration-time profiles found to apply to intracellular effect(s), and that novel exposure profiles might be identified which would allow avoidance of toxicity on mammalian systems;
2. that the breaches in external cell walls and capsular membranes and layers of bacteria could facilitate entry and access to sites of action of other antibiotics such as cephalosporins which acted at or near cell surfaces, and additionally, that enzyme degradation of antibiotics (e.g. cephalosporinases) might be by-passed.
It has now been surprisingly found that the activity of &bgr;-lactam antibiotics, including cephalosporins, can be potentiated by the use of a non-toxic amount of an aminoglycoside antibiotic.
The studies detailed herein, using gentamicin and tobramycin demonstrate that the concentration-time profiles producing the cell surface effect involve relatively prolonged exposures over many hours, at lower concentrations than those normally used clinically, where rapid onset (bolus) of high concentration exposure has been the characteristic approach to clinical dosing.
The potentiation of cephalosporin action by degrees in excess of 100 fold was also a surprising finding and suggests the efficiency of cell wall porin as exclusion barriers and the enzymatic (cephalosporinase) destruction of cephalosporins.
BRIEF DESCRIPTION OF THE INVENTION
In one aspect, the invention provides a method of potentiating the activity of an antibacterial agent active on bacterial cell wall, comprising the step of administering to a subject in need of such treatment said antibacterial agent and an aminoglycoside in an amount effective to attain a peak concentration of at least 4 mg/l of the aminoglycoside, and thereafter maintaining the aminoglycoside at a concentration of up to 4 mg/l for at least 1 hour.
Preferably, the antibacterial agent is active on bacterial cell wall and acts at or near the cell wall of the bacteria. Thus, the invention provides a novel action of an aminoglycoside at cell surfaces which results in the potentiation of the effect of one or more antibiotics acting at or near bacterial cell wall or sites thereof.
Preferably, the antibacterial agent is a &bgr;-lactam and most preferably, a cephalosporin or cephamycin.
The aminoglycoside is most preferably gentamicin or tobramycin.
In a preferred embodiment, the activity of cephalosporin is potentiated by administering to a subject an amount of gentamicin or tobramycin effective to produce a peak concentration of up to 18 mg/l plasma. This may be achieved by administration of 70-280 mg (1-4 mg/kg body weight) over 1-2 hours. Thereafter, the aminoglycoside is administered preferably at 5-20 mg/hr for 4-12 hours to maintain a plasma concentration of 1-4 mg/l. The aminoglycoside may further be maintained at a concentration of 1.0 mg/l plasma or less up to 24 hours.
Desirably, 300 mg of cephazolin as a specific example is administered over 24 hours, maintaining a plasma concentration at 2 mg/ml or more.
In a particularly preferred embodiment, the cell wall active antibacterial agent is at 2 mg/ml when the aminoglycoside is maintained at 1-4 mg/l, and for a further 8-24 hours thereafter.
The method of the invention thus provides a critical profile of aminoglycoside exposure in the animal or human body which is necessary for optimisation of the action of aminoglycoside(s), but more particularly, for the potentiation of one or more other antibiotics. This also allows the avoidance and/or minimisation of the known clinical toxic effects of aminoglycosides on hearing, posture and dynamic balance. The profile is achieved by taking account of transfer of antibiotics from blood to tissues. However, provision is made in the method such that the antibiotic concentrations in the inner ear (vestibular apparatus and organ of Corti) do not achieve concentrations known to be toxic, and to prevent those toxic concentrations from being present for periods of time known to be necessary for toxic effects to develop. (McLean A J, Ioannides-Demos L L, Spicer W J, Christophidis N, “Aminoglycoside dosing: one, two or three times a day?”, Med J Aust. 164:39-42, 1996).
The peak concentrations of aminoglycoside which are most desirable are 4-18 mg/l, and are preferably maintained at a minimum of 1-4 mg/l, depending on bacterial sensitivity as evidenced by MIC testing. Maintainance of this level would require a mass of some 5-15 mg per hour of gentamicin to be delivered to the circulation of an average patient at a uniform rate, although variations will be required as a result of differing body size, renal function and various disease conditions (McLean et al 1996, supra). The rate and amount of active agent to be delivered can be determined easily by a person skilled in the art.
In accordance with existing formulati
Larson & Taylor PLC
Owens, Jr. Howard V.
Pharmacy and Therapeutic Advisory Consultancy Pty LTD
Richter Johann
LandOfFree
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