Optimizing Antibiotic Dosing Strategies for the Treatment of Gram-negative Infections in the Era of Resistance

SUMMARY

Gram-negative organisms are an increasing source of concern within the healthcare setting due to their common presence as a cause of infection and emerging resistance to current therapies. However, current antimicrobial dosing recommendations may be insufficient for the treatment of gram-negative infections. Applying knowledge of an antibiotic’s pharmacokinetic/pharmacodynamic profile when designing a dosing regimen leads to a greater likelihood of achieving optimal exposure, including against gram-negative pathogens with higher MICs. Additionally, administering antibiotics directly to the site of infection, such as via aerosolization for pneumonia, is another method to achieve optimized drug exposure at the site of infection. Incorporating these treatment strategies into clinical practice will assist antimicrobial stewardship programs in successfully treating gram-negative infections.

KEYWORDS:

• Gram-negative bacteria
• resistance
• pharmacokinetics
• pharmacodynamics
• aerosolized antibiotics

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key Issues

• Infections caused by gram-negative organisms are associated with poor clinical outcomes, resulting in a large economic burden on the health-care system.

• Rates of gram-negative antimicrobial resistance are rising and have become a global concern.

• Due to the lack of effective antimicrobials, the application of PK/PD to dosing regimen design will improve obtainable exposure against gram-negative infections.

• For β-lactam antibiotics, combining larger doses with prolonged or continuous infusion will effectively increase the free drug time above the MIC (fT > MIC).

• The administration of higher doses with the appropriate dosing interval optimizes the maximum free concentration in relation to the MIC (ƒC_max/MIC) and area under the curve (ƒAUC) to MIC for aminoglycoside and polymyxin B antibiotics, essentially leading to a revival of their utility against gram-negative bacteria.

• Often higher antibiotic intravenous doses are required to achieve adequate drug concentrations at the site of infection, as seen with tigecycline concentrations in the ELF.

• Aerosolized administration of antibiotics has become a formulation of interest for the treatment of VAP due to the enhanced drug exposure at the site of infection.