Antimicrobial Dosing and Kill Characteristics

OVERVIEW

Antimicrobial dosing in critically ill patients is complex, and affected by many factors

• Dosing is different to non-critically ill patients
• Different antimicrobials have different kill characteristics, which can be demonstrated on a concentration vs time graph for antibiotic activity (see graph here)

ANTIMICROBIAL DOSING

Antimicrobial dosing in critically ill patients is complex

• there is increasing concern that antimicrobial dosing (e.g. beta lactams) in critically ill patients is often insufficient

Factors affecting dosing in the critically ill

• changes in GI absorption
• changes in volume of distribution (e.g. gentamicin in fluid resuscitated patients with capillary leak syndrome)
• poor penetrance or delivery to the target site
• changes in metabolism (e.g. drug interactions and individual variation)
• augmented renal clearance (common in certain ICU patient populations, e.g. young, trauma patients)

Evidence

• In patients from 68 ICUs across 10 countries, use of intermittent infusions (compared to extended and continuous infusions) and increasing creatinine clearance were risk factors for ‘minimum inhibitory concentration’ (MIC) target non-attainment with use of beta-lactams
• Felton et al (2014) found that pulmonary penetration of piperacillin/tazobactam is reduced in critically ill patients and found that intrapulmonary exposure is highly variable and unrelated to plasma exposure and pulmonary permeability

AUSTRALIAN THERAPEUTIC GUIDELINES DOSING RECOMMENDATIONS

Australian Therapeutic Guidelines advise that dose modification is usually necessary to achieve adequate drug exposure in critically ill patients with severe sepsis or septic shock (usually those requiring intensive care support). Examples given are:

• Cefotaxime
  • use an increased dose
  • i.e. cefotaxime 2 g [child: 50 mg/kg up to 2 g] IV, 6- or 8-hourly depending on the likely source of infection
• Ceftriaxone
  • use a 12-hourly dosing regimen
  • i.e. ceftriaxone 1 g [child: 25 mg/kg up to 1 g] IV, 12-hourly
• Cephazolin
  • use a 6-hourly dosing regimen for adults
  • i.e. cephazolin 2 g IV, 6-hourly)
• Flucloxacillin
  • use a 4-hourly dosing regimen
  • i.e. flucloxacillin 2 g [child: 50 mg/kg up to 2 g] IV, 4-hourly
• Gentamicin
  • 7 mg/kg LBW (or IBW for ease) is an appropriate loading dose in most critically ill patients with severe sepsis or septic shock
  • This is the dose predicted by pharmacokinetic/pharmacodynamic modelling achieve the target area under the concentration–time curve (AUC)
  • this higher dose is due to an increased volume of drug distribution and enhanced renal drug clearance in patients with septic shock
  • this dose also ensures that pathogens with a relatively high MIC to gentamicin (eg Pseudomonasaeruginosa) are adequately treated
  • a dose of 7 mg/kg is unlikely to cause toxicity in appropriately selected patients
  • However, there are currently no large studies showing a clinical advantage of using 7 mg/kg over daily gentamicin doses of 4 to 5 mg/kg
  • Lower doses are preferred in patients with known or likely pre-existing renal impairment (e.g. elderly > 80 years-old):
    • CrCl 40 to 60 mL/min: 5 mg/kg
    • CrCl <40 mL/min: 4 mg/kg
  • Do not delay gentamicin administration to ascertain renal function
  • Consider monitoring from the first dose, particularly if the patient’s renal function is not known
• Piperacillin+tazobactam (tazocin)
  • give 6-hourly rather than 8-hourly
  • consider giving the 6-hourly dose of piperacillin+tazobactam as an extended infusion over 3 to 4 hours (this increases the percentage time above MIC and may achieve better outcomes)
• Vancomycin
  • give a 25 to 30 mg/kg vancomycin loading dose to adults
  • although pharmacokinetic modelling data suggest a vancomycin loading dose of 30 to 35 mg/kg may be appropriate in critically ill patients in the ICU (who often have augmented renal clearance), clinical data support a dose of 25 mg/kg
  • see Therapeutic Guidelines for maintenance dosing based on renal function and trough levels

KILL CHARACTERISTICS

There are 3 major patterns of antimicrobial kill characteristics

• “concentration-dependent killing” (determined by Cmax)
• “time dependent killing” (determined by time above MIC)
• area under the concentration-time curve (determined by AUC above MIC)

Cmax

• Cmax = maximal or peak concentration
• “concentration-dependent killing”
• some antimicrobials depend on Cmax/MIC ratio as an important predictor of antimicrobial efficacy
• higher the concentration, greater the rate and extent of microbial killing
• eg. aminoglycosides should ideally have Cmax/MIC ratio of at least 8-10 to prevent resistance

Time above MIC

• Time above MIC is duration that the antibiotic levels are above the MIC
• “time dependent killing”
• The ideal dosing regimen for certain antimicrobials is to maximise the duration pathogens are exposed to them
• e.g. beta-lactams, clindamycin, erythromycin, linezolid
• for beta-lactams and erythromycin, maximum killing is seen when the time above MIC is 70% of dosing interval

AUC above MIC

• AUC above MIC is the area under the concentration-time curve that is above the MIC
• some antimicrobials are dependent on this for maximal killing effect
• 24h AUC/MIC is a predictor of efficacy
• eg. fluoroquinolones
  — for gram negative bacteria, optimal 24h AUC/MIC ~ 125
  — for gram positives bacteria, optimal 24h AUC/MIC ~ 40

References and Links

LITFL

• CCC — Minimum Inhibitory Concentration (MIC)
• CCC — Pharmacology and Critically Illness

Journal articles

• Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – Concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014 Jul 15. pii: S0169-409X(14)00147-1. doi: 10.1016/j.addr.2014.07.006. [Epub ahead of print] Review. PubMed PMID: 25038549. [Free Full Text]
• De Waele JJ, et al. Risk factors for target non-attainment during empirical treatment with beta-lactam antibiotics in critically ill patients. Intensive Care Med 2014;40(9):1340-51. PMID: 25053248
• Edwards G, Krishna S. Pharmacokinetic and pharmacodynamic issues in the treatment of parasitic infections. Eur J Clin Microbiol Infect Dis 2004;23:233-242. [Free Full Text]
• Felton TW, et al. Pulmonary penetration of piperacillin and tazobactam in critically ill patients. Clin Pharmacol Ther 2014;96(4):438-48. PMID: 24926779
• Groll AH, Kolve H. Antifungal agents: in vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis 2004;23:256-270.[Free Full Text]
• McKinnon PS, Davis SL. Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases. Eur J Clin Microbiol Infect Dis. 2004 Apr;23(4):271-88 [Free Full Text]
• Nuermberger E, Grosset J. Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial infections. Eur J Clin Microbiol Infect Dis 2004;23:243-255. [Free Full Text]
• Roberts JA, Abdul-Aziz MH, Lipman J. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet. Infectious diseases. 14(6):498-509. 2014. [pubmed] [free full text]
• Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009 Mar;37(3):840-51; quiz 859. doi: 10.1097/CCM.0b013e3181961bff. Review. PubMed PMID: 19237886.
• Schentag JJ, Gilliland KK, Paladino JA. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin Infect Dis. 2001 Mar 15;32 Suppl 1:S39-46. Review. PubMed PMID: 11249828. [Free Full Text]
• Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014 Jun;14(6):498-509. doi: 10.1016/S1473-3099(14)70036-2. Epub 2014 Apr 24. Review. PubMed PMID: 24768475.

FOAM and web resources

• Australian Therapeutic Guidelines, Antibiotics 2015
• INTENSIVE — Udy et al, 2014: Augmented Renal Clearance (2014)