ADMINISTRATION OF ANTIBIOTICS

exp date isn't null, but text field is

Loading dose

The loading dose (LD) of a drug is calculated from the volume of distribution (V) and the required plasma concentration (Cp) where LD = V x Cp. The loading dose is different for hydrophilic antimicrobials and lipophilic antimicrobials because of the difference in volume of distribution. The V of hydrophilic antimicrobials is increased due to expansion of extracellular water volume due to increased permeability of vascular endothelium in infection, particularly sepsis and septic shock. The V of lipophilic antimicrobials is higher in obese individuals. The required Cp depends on the MICs of different antimicrobials and varies greatly.

For concentration-dependent antibiotics (e.g. aminoglycosides, fluoroquinolones and polymyxins), a high initial dose is essential for maximum bactericidal effect and a large initial dose is often chosen for time-dependent antibiotics to ensure good tissue penetration. Also, renal function plays no role in the calculation of the LD. Thus, a high initial dose of antibiotic is a standard practice. However, adverse effects of high doses of the drugs should be taken into consideration (e.g. CNS toxicity and seizures with high-dose penicillin particularly in those with renal failure).

Interval between dosing

For concentration-dependent antibiotics with strong post-antibiotic effects (e.g. aminoglycosides), high doses at longer intervals are better than lower doses at shorter intervals. This also reduces the toxicity (especially nephrotoxicity).

Extended-interval dosing of Aminoglycosides

Parenteral aminoglycosides at higher doses administered at an extended interval (once-daily dosing) has efficacy comparable with traditional intermittent administration but has potential advantages of decreased nephrotoxicity, ease of administration and reduction of administration and monitoring-related costs. Examples: For Gram-negative microorganisms

Amikacin         

  • Conventional dosing – 5mg/kg q8h or 7.5mg/kg q12h
  • High-dose extended-interval dosing – 15-20 mg/kg once daily over 60 mins

Gentamicin

  • Conventional dosing – 3-5 mg/kg/day in divided doses q8h                 
  • High-dose extended-interval dosing – 5-7mg/kg once daily over 120 mins

For time-dependent antibiotics like beta-lactams, the duration of the antibiotic level above the minimum inhibitory concentration (MIC) level is an important determinant of bacterial eradication and clinical response. Hence, they are given in prolonged infusions and at shorter intervals. Prolonged administration strategies for these beta-lactam antibiotics may include either a continuous IV infusion (over the entire dosing interval) or an extended IV infusion (over 2 to 4 hours) compared to traditional IV infusions over 30 to 60 minutes. Example:

Extended infusion of Piperacillin-tazobactam                       

Piperacillin-tazobactam

  • Traditional infusion method (over 30 mins) – every 6 to 8 hours
  • Extended infusion method (over 4 hours) – preferred when used every 8 hours

However for extended infusions, the beta-lactam drugs must be stable over that time and the stability can be influenced by the type of intravenous fluid used to reconstitute the drug, the concentration of the final solution, and the storage temperature.