Antibiotic Dosing Strategies-Clinical Background

I spent two rewarding weeks at the UQCCR and RBWH in Brisbane, Queensland, Australia as a part of  an observership programme in infectious diseases. I was assigned to prof.  Jason Roberts who is leading a team of researchers in the field of redefining antimicrobial use in order to reduce resistence. I took part in weekly rounds at the ICU unit discussing complex patients in terms of optimizing antimicorbial therapy. Attention is drawn to indications for antimicrobial use, the lenght of use and dosing. In terms of dosing I was faced with interesting approaches which are based on TDM of all antibiotics in clinical use.

University of Queensland, Centre for Clinical Research

Special attention is placed on critically ill because pharmacokinetic properties of antibiotics are greatly affected by critical ilness. To determine the influence that critical illness may exert on antibiotic pharmacokinetics it is prudent to split antibiotics into hydrophilic and lipophilic agents. Examples of hydrophilic antibiotics include widely used beta-lactams, aminoglycosides, lipopeptides (daptomycin), vancomycin, fosfomycin and other. In critically ill patients there are two major issues which we should consider. Volumen of distribution of these agents is limited to the extracellular enviornment meaning no reservoir within cells is available for retrograde diffusion into the interstitium. We know that in septic patients the volume of distribution increases greatly because of the sudden capillary leak, increased movement of albumin into tissues  and fluid shifts. Therefore the volume of distribution of hydrophilic antibiotics is increased greatly. The very first dose of hydrophilic antbiotics (loading dose) should therefore be higher than the one needed in clinically stable patients because the loading dose is directly proportional to the volume of distribution.  A proverb indicating ”there is only one opportunity to make a good first impression” states that an early adequate dosing is of crucial importance. Some practical examples. The need for higher than standard loading doses in septic patients was demonstrated for vancomycin. More than double loading dose compared to the standard (35 mg­/kg vs. 15 mg/kg) may be nedeed to quickly achieve the recommended target vancomycin concentration in septic patient (20 mg/l). For gentamicin a loading dose of 8mg/kg has been advised. The other important aspect in ctitically ill is maintenance dosing. Hydrophilic antibiotics are almost completely eliminated via the kidneys. The maintenance dose should therefore be adjusted to estimated or measured creatinine clearance. In ideal circumastancces this should be measured daily during critical illness because of frequent fluctuations. We should adjust dosing accordingly, but this is not limited only to decreased renal function!

The term I came across was ”augmented renal clearance (ARC).” Renal dysfunction is common in critical care settings, but the supra-normal function of the kidneys is infrequently considered by clinicians. ARC is defined as the enhanced renal elimination of circulating solutes as compared with an expected baseline. There are varying cut-offs to define ARC. Often this means renal clearance of serum creatinine greater than 130 mL/min/1.73m2 and 120 mL/min/1.73m2 for female gender. It is interesting that the majority of patients with ARC show levels of serum creatinine within the normal range. In comparison to patients with renal failure, where we see elevated levels of serum creatinine.

Centre for Clinical Research

The specific pathophysiology of ARC is far from being fully understood but factors like hyperdynamic circulation, increased cardiac output, diminished vascular resistence, administration of fluids and vasopresors seem like a good explanation though. From a practical point of view, whenever the estimated glomerular filtration rate values reported from the laboratory are considered normal, it is good to use the highest SMPC recommended doses of hydrophilic antibiotics in critically ill patients. Unless there is TDM available, but usually that is only the case for vancomycin and gentamicin.

Things seem somehow easier with lipophilic antibiotics. These include fluoroquinolones, macrolides, linezolid, tigecycline, rifampin, clindamycin and metronidazole. In the presence of critical illness, these agents often do not require any particular dosage adjustment in the presence of critical illness. Neither for the loading dose, nor the maintenance dose. The volume of distribution is already large due to lipophilic charachter and diffusion across the plasmatic membrane. Therefore, in the presence of increased volume of distribution, the intracelular compartment represents a reservoir for rapid equilibrium. There is no need to adjust the loading dose. Because they are eliminated mainly by the liver or other pathways (these metabolic pathways are usually preserved, although nonlinear), no dosage adjustments for the maintenace dose are usually needed in the critically ill. A notable exception is levofloksacin, which is renally cleared.

We can see that dosing is in the spotlight. Adequate serum concentrations of antimicrobials prevent developmnet of resistance. We can still go further. Adequate serum concentrations are not just growth preventing concentrations. On this point there is still a possibility that a small part of a colony presents with diminished susceptibility and is able to develop resistance mechanism. So aiming for the highest reasonably safe serum concentration increases the chances of achieving a so called resistance preventing concentration and that is something we should aim for.

The daily rounds at the micro-lab were dedicated to interpretations of isolates from clinical samples. During my stay there was a rare case of neuroboreliosis (rare for Australia) in a returning traveller from Slovakia. I even got a chance to visit a microsampling symposium which was held in Brisbane this week. It seems that we will soon be able to get lab resuslt from dried blood spots, no iv. lines needed.    

I  have widen my horizons in any possible directions. It has been a privilege to stay in Australia.