Conference Lectures

Pharmacological principles & ICU challenges
Dr  Richa Saroa*, Dr Sidharth#     
(Government Medical College & Hosspital Chandigarh)

Antimicrobial dosaging in the critically ill patients remains a complicated and unresolved issue confronting the anaesthesiologists. While the importance of effective antimicrobial concentration at target site to reduce the mortality and morbidity cannot be undermined, the minimisation of development of resistance is an immense concern at the same time. Multiple factors like systemic inflammatory response syndrome (SIRS), fluid resuscitation and ionotropic support may lead to variations in the pharmacokinetics and pharmacodynamics of the commonly administered antibiotics in intensive care.
Effective drug concentrations are said to be attained when either the levels of the antibiotics is maintained above Minimum Inhibitory concentration (MIC) or at the Minimum Bactericidal concentration (MBC) for variable periods of dosing intervals.
Certain pharmacological principles are of paramount importance while prescribing the antibiotics in the ICU. The most important pharmacokinetic parameters that affects the drug response and safety are volume of distribution (Vd) and clearance (CL).
T1/2 = 0.693 × Vd/ CL
Increased drug clearance is likely to reduce T1/2 whereas increased Vd is likely to increase T1/2.
Vd describes the relationship between the amount of drug in the body and concentration in the plasma after distribution and absorption are completed. It is affected by age, weight, tissue binding, plasma protein binding, regional blood flow and physiochemical properties of the drug. Agents that are hydrophilic    
remain in plasma and have lower Vd whereas lipophillic drugs that are sequestrated outside circulation have higher VD.
In the absence of significant organ dysfunction, renal perfusion is usually increased with increased creatinine clearance and hence increased elimination of hydrophilic antibiotics. Thus dose of the hydrophilic antibiotics can be guided by measures of creatinine clearance.
Effect of Sepsis
Endotoxins from bacteria or fungi may stimulate the production of various endogenous mediators that may disrupt the vascular endothelium and cause either vasoconstriction or vasodialatation. The resultant changes may cause maldistribution of the blood flow, endothelial damage and subsequent increased capillary permeability. The leaking capillaries lead to shift of fluid from intravascular to extravascular compartment resulting in interstitial edema. This accumulation is further aggravated by decreased albumin concentration in acute phase of illness. The increased volume of distribution decreases the plasma drug concentration of the hydrophilic drugs. However it seems to have insignificant effect on lipophillic drugs that remain sequestrated outside the circulation because of the partitioning into the adipose tissues and also having higher Vd. (Table I)
With hepatic dysfunction present in more than half of the critically ill patients, drug clearance is reduced owing to reduced hepatic blood flow, decreased hepatocellular activity and decreased bile flow. The clearance of the medications that rely on flow dependent hepatic clearance is therefore reduced in shock. Critical illness may also compromise the cytochrome P-450 (CYP450) enzyme system and consequently may affect the metabolism of the drugs dependent on the same.
In ICU, standard initial management involves resuscitation with intravenous fluids and subsequently prescribing vasopressor agents for hypotension that persists despite adequate resuscitation. Therefore, patients in sepsis have usually higher cardiac indices than normal. In the absence of organ dysfunction, renal perfusion is usually increased with increased creatinine clearance and increased elimination of hydrophilic antibiotics.
End organ dysfunction may lead to decreased clearance and increased half life with a potential to cause toxicity from increased antibiotic concentration or accumulation of the metabolites of the antimicrobials administered in ICU.

                                                TABLE I
Hydrophillic antibiotics diffuse slowly into the deep seated infections. Therefore, higher than usual dosages may be required to treat deep seated infections with hydrophilic agents as opposed to the lipophillic antibiotics to ensure optimal pharmacodynamic exposure at the infection site. This underlines the importance of appropriate loading doses at the commencement of therapy independent of the renal function with hydrophilic antibiotics. Also timely and accurate maintenence doses should be based on daily renal functions.
Conversely, with lipophillic drugs, drug diluting effect is mitigated by rapid distribution of drug from the intracellular compartment to the interstitium which acts as a reservoir and the target concentration of the antimicrobial is therefore less relevant.
Hypoproteinemia
Hyponatremia with low serum albumin levels may be present in 40-50% of patients in ICU. It is associated with increase in unbound fraction of drug that is mainly available for distribution and clearance from the plasma. Thus, hypoalbuminemia leads to increase in total VD and clearance of the drug that are highly protein bound.
                             Kill characteristics of the antibiotics
These characteristics describe the pharmacokinetic measurements that represent optimal bactericidal activity. Pharmacodynamically different class of anti microbials have different types of kill characteristics on bacteria.
Concentration dependent Antibiotics - The efficacy of these anti microbials depend upon the achievement of high Cmax/ MIC ratio ( Cmax- peak plasma concentrations ) or AUC/MIC ratio (AUC- Area under plasma concentration time curve). Therefore high dosages with short course therapy with once daily regimen may be more bactericidal and prevent resistance development. This is especially true for fluroquinoloes and aminoglycosides.
Time dependent Antibiotics – The kill characteristics of these antibiotics depend upon the time for which the levels in tissues and plasma exceed a certain threshold. Therefore the best correlate of the therapeutic efficacy is the percentage of dosage interval for which drug concentration remains above the MIC for the infecting organism. Β- lactams, glycopeptides and oxazolidinones exhibit bactericidal properties in a time dependent fashion. Since the bactericidal action requires drug concentration to be four or five times higher than MIC, it is logical to administer continuous infusions which provides improved antibiotic profile than the intermittent dosages.
Post Antibiotic effect (PAE) PAE refers to continued suppression of bacterial growth even though the drug concentrations fall below MIC of the bacteria. β- lactams, fluroquinolones and aminoglycosides demonstrate significant and prolonged PAE.
Post β lactamse Inhibitor Effect (PLIE) PLIE refers to period of continued suppression of bacterial growth after removal of β lactamase inhibitor (suicide inhibitor). In vitro PLIE occurs with amoxicillin  in combination with clauvulanic acid and ceftazidime with sulbactum. It is thought that β lactam along with the suicide inhibitor utilizes the PLIE and enables the reduced dosages of β lacatms.
           Effect of renal replacement therapy on Antimicrobial therapy
Serum levels of all the drugs are affected by use of renal replacement therapy (RRT) whether in the form of Continuous RRT (CRRT) or intermittent hemodialysis(IHD). Only the free drug will be available for clearance during CRRT. Drugs that primarily have renal clearance, may be extracted by RRT and such patients may require higher than normal dosages to maintain the target site concentrations. This is true for β lactams, aminoglycosides, glycopeptides, levofloxacin and ciprofloxacin. Agents that are lipid soluble such as liposomal amphotericin cannot be removed by CRRT. Certain antibiotics like aminoglycosides adhere to the membrane used for CRRT which leads to the removal of the drug in large amount.
Conclusion
Pharmacotherapy in critically ill patients poses various challenges to intensivists. Polypharmacy and alteration in drug disposition are common in critically ill patients. Knowledge of pharmacokinetics and pharmacodynamic principles that can guide the design of a rational drug regimen is the need of the hour to achieve optimal and beneficial effects of the antimicrobials frequently prescribed in ICU.
Suggested Readings
1. Pea F and Viale P. Bench to bed side review: Appropriate antibiotic therapy in severe sepsis and septic shock- does the dose matter. Crit Care 2009; 13: 214- 26
2. Pinder M, Bellome R and Lipman J. Pharmacological principles of antibiotic prescription in the critically ill. Anesth Intens Care 2002; 30: 134-44
3. Roberts JA and Lipman J. Antibacterial dosing in Intensive Care. Clin Pharmacokinet 2006; 45(8): 755-73
4.   Roberts JA and Lipman J. Phramacokinetic issues for antibiotics in critically ill patients. Crit Care Med 2009;37(3): 840-51
5.Krishanan V and Murray P. Pharmacologic issues in critically ill. Clin Chest Med 2002; 24: 671-88.