Which antibiotic, azithromycin (Azithromycin) or amikacin (Amikacin), remains effective even when the Minimum Inhibitory Concentration (MIC) is below the therapeutic value?

From the Guidelines

Azithromycin is the antibiotic that acts even when its concentration falls below the minimum inhibitory concentration (MIC), due to its post-antibiotic effect (PAE) and prolonged persistent effect against gram-positive cocci and H influenzae. This property is attributed to its pharmacodynamic parameter, the AUC to MIC ratio, which correlates with efficacy, rather than the time above MIC (T MIC) 1. Azithromycin's prolonged effect is also due to its ability to concentrate within phagocytes and at infection sites, maintaining activity against bacteria even after serum levels decline. In contrast, amikacin, an aminoglycoside, exhibits concentration-dependent killing and requires maintaining levels above the MIC for effectiveness.

Some key points to consider when choosing between azithromycin and amikacin include:

• The AUC to MIC ratio that yields maximal efficacy with drugs from the macrolide and azalide class, such as azithromycin, is approximately 25 1.
• Azithromycin's long serum half-life and the long duration of subinhibitory concentrations of the drug may contribute to the selective pressure of azithromycin, allowing the growth and transmission of preexisting azithromycin-resistant strains 1.
• The standard adult dose of azithromycin is 500mg on day one followed by 250mg daily for 4 days, or a 3-day regimen of 500mg daily, which takes advantage of its PAE and prolonged effect.
• Amikacin, on the other hand, requires careful monitoring of peak and trough levels to ensure efficacy while avoiding toxicity, due to its concentration-dependent killing mechanism.

Overall, azithromycin's ability to act even when its concentration falls below the MIC makes it a more suitable choice for certain infections, particularly those caused by gram-positive cocci and H influenzae, due to its prolonged effect and PAE 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Antibiotic Efficacy at Sub-Therapeutic MIC Values

• Azithromycin has been shown to exhibit immunomodulatory effects and influence bacterial virulence factors, which may contribute to its clinical efficacy even when the minimum inhibitory concentration (MIC) is below the therapeutic value 2.
• Studies have demonstrated that azithromycin can accumulate in high concentrations within cells, particularly phagocytes, and be delivered to sites of infection, which may allow it to remain effective even at sub-therapeutic MIC values 3, 4.
• In contrast, there is limited evidence to suggest that amikacin, an aminoglycoside antibiotic, exhibits similar properties or remains effective at sub-therapeutic MIC values.

Mechanisms of Action

• Azithromycin's mechanism of action involves interference with bacterial protein synthesis by binding to the 50S component of the 70S ribosomal subunit, as well as immunomodulatory effects and influence on bacterial virulence factors 3, 2.
• The exact mechanisms by which azithromycin remains effective at sub-therapeutic MIC values are not fully understood, but may involve its ability to accumulate in high concentrations within cells and influence host responses 4, 2.

Clinical Relevance

• The clinical relevance of azithromycin's ability to remain effective at sub-therapeutic MIC values is significant, as it may allow for the use of lower doses or less frequent dosing, potentially reducing the risk of adverse effects and promoting better patient compliance 5.
• However, the potential for azithromycin to select for resistant bacterial populations at sub-therapeutic MIC values is a concern, and further research is needed to fully understand the implications of this phenomenon 4, 5.