Daptomycin and Protein Synthesis Inhibitor Combination Therapy

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Solution Overview

Problem

Bacterial infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), pose a significant challenge due to the rapid development of resistance to available antibiotics, limiting treatment options and necessitating the prevention of daptomycin non-susceptibility in bacterial strains.

Innovation Solution

A therapeutic combination of daptomycin with a protein synthesis inhibitor, such as tedizolid, is used to prevent the development of daptomycin non-susceptibility in bacteria, where the protein synthesis inhibitor is administered at sub-inhibitory concentrations to maintain bacterial susceptibility to daptomycin, thereby delaying or preventing the emergence of resistant strains.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If daptomycin is used alone to treat bacterial infections, then the treatment is simple and cost-effective, but bacteria rapidly develop resistance reducing treatment efficacy

Engineering Contradiction:

Improvetreatment efficacyVSAvoidduration of bacterial susceptibility

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent combines daptomycin with a protein synthesis inhibitor antibiotic to create a therapeutic combination that prevents the development of daptomycin resistance. The protein synthesis inhibitor acts through a different mechanism of action, and when used together, they synergistically prevent bacterial resistance development while maintaining treatment efficacy.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The protein synthesis inhibitor is administered in advance or concurrently with daptomycin to preemptively block the development of resistance mechanisms. By establishing this protective mechanism before resistance can develop, the combination maintains bacterial susceptibility throughout the treatment course.

Inventive Principle:

Principle #10Preliminary action

2Duration of action of stationary object

If continuous and long term use of antibiotics is administered, then the infection is treated thoroughly, but bacteria develop resistance reducing the antibiotic's ability to treat effectively

Engineering Contradiction:

Improvetreatment durationVSAvoidantibiotic effectiveness

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The combination of daptomycin and protein synthesis inhibitor allows for continuous long-term treatment without loss of effectiveness. The dual mechanism of action ensures that while daptomycin kills bacteria, the protein synthesis inhibitor simultaneously prevents resistance development, maintaining antibiotic effectiveness throughout extended treatment periods.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent changes the therapeutic parameters by using sub-inhibitory concentrations of the protein synthesis inhibitor in combination with daptomycin. This parameter change allows the protein synthesis inhibitor to prevent resistance development without causing its own resistance issues or excessive toxicity, enabling prolonged effective treatment.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If higher doses of daptomycin are used to overcome resistance, then treatment efficacy is maintained, but toxicity to the patient increases

Engineering Contradiction:

Improvetreatment efficacyVSAvoidpatient toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the dosing parameters by using standard or reduced doses of daptomycin in combination with sub-inhibitory doses of protein synthesis inhibitor. This parameter change maintains treatment efficacy while avoiding the toxicity associated with high-dose monotherapy, as the combination prevents resistance at lower effective concentrations.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The combination effectively delays the emergence of daptomycin non-susceptibility in MRSA strains, maintaining their susceptibility until the infection is resolved, as demonstrated by reduced fold shifts in minimum inhibitory concentration (MIC) values, thereby extending the efficacy of daptomycin treatment.

Implementation Method 1

a protein synthesis inhibitor antibiotic, such as tedizolid, effective to prevent the development of daptomycin non-susceptibility

Methodology Applied

Scientific EffectProtein synthesis inhibition: Enzyme

Data Source

PatentUS8461188B2Therapeutic combination of daptomycin and protein synthesis inhibitor antibiotic, and methods of use

Publication Date: 2013.06.11 MERCK SHARP & DOHME LLC

AI summary

A therapeutic combination comprises an antibacterially effective amount of daptomycin, and an amount of protein synthesis inhibitor antibiotic effective to prevent the development of daptomycin non-susceptibility in bacteria. Related combination therapies and methods are also included.