ANTIBIOTICS THE ICU WEAPON DR.MAGDY KHAMES ALY CRITICAL CARE MEDICINE ZMH AL BATAYEH INTRODUCTIONS ICU patients are a special group of patients, they are usually suffering from multiple comorbidities and immune compromised that makes them more vulnerable to serious infection. The principles used to guide antimicrobial therapy in all patients can be applied to the critically ill patients, with some modification. In ICU patients with new onset of shock and organ dysfunction thought secondary to infection, prompt empiric broad-spectrum antimicrobial therapy is crucial. Each hour of delay in adequate antimicrobial therapy after the onset of hypotension has been associated with a mean decrease in survival of 7.6%. ANTIBIOTIC CHOICE • FACTORS CONSIDERED: Patient characteristics: I. Environmental history II. Immune status III. Prior antimicrobial exposure IV. Prior culture results Organisms characteristics: I. Local institutional pathogens II. Source and site of infection III. Degree of antibiotic resistance Pharmacology in Critical Illness Pharmacology in Critical Illness • It is the most important factor in determining the suitable antibiotic for infected critically ill patient. • Because altered physiology and pathophysiology in those patients the efficacy and toxicity of antimicrobial agents can be profoundly affected by : I. The alterations in tissue perfusion II. Volume of distribution III. Serum protein levels IV. Renal and hepatic function that occur in the critically ill patients. Pharmacology in Critical Illness Critically ill patients may demonstrate multiple organ derangements inciting pathophysiological changes that can affect PK/PD properties of drugs. These changes can occur within an individual patient and may deviate according to the varying stages of illness As such dosages being adequate at a given day may become inadequate some days later because of alterations in disease severity. Pharmacology in Critical Illness In addition, critically ill patients usually receive a wide range of drugs thereby adding to the possibility of drug–drug interactions. Basically the general principles of PK include absorption, distribution, metabolism, and elimination. Critical illness affects all of these processes thereby significantly influencing the PK of drugs Pharmacology in Critical Illness Absorption: refers to the process by which a drug leaves the site of administration (either by the enteral route, inhalation, topical, subcutaneously, intramuscular, or rectal) and concentrates in the circulation thereby representing the bioavailability. The amount of drug absorbed depends on drug characteristics (physicochemical properties, particle size, solubility, etc.) and properties of the organ/tissue of drug administration. Pharmacology in Critical Illness Absorption: I. shock will reduce regional blood flow and motility, resulting in delayed gastric emptying and diminished absorption of oral medications II. Vasopressors will not per se normalize regional perfusion as these drugs have differing effects on organ vascular beds and notably on splanchnic blood flow. III. Alternatively, during shock or use of vasopressors skin perfusion will be reduced thereby decreasing absorption of subcutaneously administered drugs. IV. Because of the issues of absorption intravenous drug administration is usually recommended during critical illness Pharmacology in Critical Illness Volume of distribution: Describes the relationship between dose and the resulting serum concentration. Critical illness and associated interventions affect the distribution of drugs. Sepsis, shock, burn injury, pancreatitis, and alterations in plasma protein binding are just a few examples of disease entities influencing Vd. Alternatively fluid resuscitation, as frequently necessary in critically ill patients will also lead to increased Vd. Pharmacology in Critical Illness • Drug metabolism: I. Mostly occurs in the liver and kidneys II. The ability of the liver to clear drugs is proportionate to blood flow and/or the hepatic extraction ratio of the drug, mainly driven by the cytochrome P450 enzyme system. III. Critical illness affects metabolic activity by alterations in plasma protein concentration, hepatic enzymatic activity and blood flow. IV. Many drugs used in critically ill patients may either induce or inhibit the activity of the various isoenzymes included in the cytochrome P450 complex. Pharmacology in Critical Illness • Drug elimination: I. Mostly by renal system II. Process can be disturbed during critical illness as renal clearance can be either enhanced or impaired. III. Acute kidney injury may complicate the ICU course. IV. Acute kidney injury may represent partial or complete loss of renal function. In the latter case renal replacement therapy will be necessary. Pharmacology in Critical Illness • Pharmacokinetic of antimicrobials in critically ill patients are of extremely important because: I. Their PK is particularly vulnerable for the pathophysiological alteration during critical illness II. Dosing is not titrated to an immediately observed effect III. Underdosing is associated with insufficient bacterial eradication and as such with bad outcome, while overdosing may provoke additional organ failure in a patient population already at increased risk for organ derangements. Pharmacology in Critical Illness Physicochemical properties of antimicrobial Pharmacology in Critical Illness According to the figure: Hydrophilic antimicrobials often need higher loading dosages and increased or decreased maintenance dosages in critically ill septic patients in comparison with non-critical stable patients. On the contrary, similar concentration-time profiles are observed for lipophilic agents in critically ill as well as non-critically ill patients. Pharmacology in Critical Illness • Pharmacokinetic and pharmacodynamic parameters of antibiotics: The most important PK parameters include the area under the plasma concentration time-curve (AUC0–24 h), the peak plasma concentration (Cmax), and the trough concentration or the concentration prior to the next dose (Cmin). Pharmacodynamics refers to the relationship between the antimicrobial concentration and the observed effect on the target pathogen. Crucial hereby is the in vitro susceptibility of the involved microorganism (minimal inhibitory concentration, MIC). Pharmacology in Critical Illness • Antibiotics are broadly classified in one or more of the following PK/PD categories: Non-concentration dependent, more commonly known as time dependent: Betalactam antimicrobials are examples of time-dependent agents. Concentration far exceeding that of the MIC will not contribute to better killing rates Concentration-dependent: Aminoglycosides and daptomycin are concentration-dependent agents. The usual target is a Cmax/ MIC that exceeds 8–10. Concentration-dependent with time-dependence: Examples are fluoroquinolones, tigecycline, linezolid and glycopeptides . Specific targets vary according to the antimicrobial. Pharmacology in Critical Illness Pathophysiological alterations in critically ill Regarding antibiotics, basically the five main issues affect PK: (1) Increased Vd (2) Alterations in protein binding (3) Augmented renal clearance (4) Impaired renal clearance (5) Hepatic dysfunction. Pathophysiological alterations in critically ill Increased volume of distribution (Vd): Edema formation and intravenous fluid administration contribute to a vast increase in total body water substantially increasing Vd of hydrophilic antibiotics.( sepsis) If initial loading dosages are not increased, it might take one to two days before stable serum concentrations are reached, thereby compromising clinical outcomes. Indeed, Vd of hydrophilic antimicrobials is not only increased by edema formation and fluid administration but also by several frequently performed interventions might contribute to this, such as mechanical ventilation, extra-corporal circuits (e.g. cardiopulmonary bypass or plasma exchange), and post-surgical drainage Extravasation of fluid in the pleural cavity may also trigger Vd expansion resulting in insufficient concentrations of hydrophilic antibiotics Pathophysiological alterations in critically ill Protein binding: Only the unbound fraction is pharmacodynamically active and can achieve drug efficacy or cause toxicity. Hypoalbuminemia frequently occurs during critical illness. More than 40% of patients admitted to ICUs have a serum albumin concentration of≤25 g/dL at baseline Protein binding is likely to be clinically relevant when the antimicrobial agent is highly protein bound (›85–90%) and predominantly cleared by glomerular filtration, as it occurs for some hydrophilic antimicrobials like ertapenem, daptomycin, ceftriaxone and teicoplanin Pathophysiological alterations in critically ill Protein binding: Lower serum protein concentrations result in greater proportions of unbound drug and may therefore temporarily result in high drug concentrations and optimal bacterial killing rates. Yet, as hypoalbuminemia is usually associated with increased Vd and drug clearance of highly protein bound hydrophilic antimicrobials, the free fraction will soon after administration be diluted over the increased total body water and more rapidly cleared. Pathophysiological alterations in critically ill Augmented renal clearance: Augmented renal clearance (ARC) refers to enhanced excretion of circulating metabolites, toxins, waste products, and drugs as compared to baseline as consequence of glomerular hyperfiltration. There is a variety of clinical conditions leading to ARC including sepsis, trauma, particularly burn injury, pancreatitis, autoimmune disorders, ischemia, and major surgery. The way in which ARC affects antimicrobial PK/PD depends on the basis of their bacterial kill characteristics. For time-dependent antimicrobials, such as beta-lactams, it is important to maintain adequate plasma concentrations throughout the dosing interval. Therefore, such antimicrobials are extreme vulnerable for the effects of ARC. Pathophysiological alterations in critically ill Augmented renal clearance: Pathophysiological alterations in critically ill • Augmented renal clearance: Continuous infusion of time-dependent antimicrobials has been suggested to maximize the duration of time that bacteria are exposed to adequate antimicrobial concentrations, especially when in the presence of multidrug resistant Gramnegative infections. Conversely, Cmax is rarely affected by ARC, being mainly dependent on the Vd of a given drug and not on its clearance. Therefore the clinical relevance of ARC on conditioning adjustments of maintenance dosages of concentrationdependent antimicrobials such as aminoglycosides is rather limited as Cmax / MIC is the most important PD index. Pathophysiological alterations in critically ill • Reduced renal clearance: Acute kidney injury (AKI) is a common complication in the ICU, particularly in the context of sepsis. In mild-to-moderately ill patients dose adjustments for renally cleared antimicrobials might be necessary for CLcr values below 50 mL/min although the need of this will vary according to the tolerability and to the safety of the antimicrobial agent. The type of dosage adjustments should be different for antimicrobials according to concentration-dependency or timedependency. Pathophysiological alterations in critically ill Reduced renal clearance: As a general rule, for concentration-dependent agents,like aminoglycosides and daptomycin, it is better to prolong the dosing interval while maintaining unmodified the dose amount in order to maximize Cmax/MIC ratio. Conversely, for time-dependent agents, like beta-lactam, it is better to reduce the dose amount while maintaining unmodified the dosing interval in order to maximize t N MIC. Additionally, some antimicrobial agents may present multiple elimination pathways that may compensate the decreased renal clearance in the presence of AKI, so that standard reductions of maintenance doses as recommended may potentially result in substantial under dosing in critically ill patients. Pathophysiological alterations in critically ill Reduced renal clearance: In the case of life-threatening AKI, renal replacement therapy (RRT) may be required. Three types of RRT are frequently performed in ICU patients: continuous, intermittent, or an in-between approach (SLED). RRT complicates predictions of antimicrobial concentrations as drug clearance may vary according to the mode of RRT, the dose of RRT delivered, filter material and surface area, and blood flow Therapeutic drug monitoring seems to be the way forward to optimize antimicrobial dosing in critically ill patients requiring RRT Pathophysiological alterations in critically ill Pathophysiological alterations in critically ill Hepatic dysfunction: Hepatic impairment may sometimes lead to accumulation of hepatically metabolized antimicrobials through reduced clearance. The Child–Pugh score is frequently used to guide dosage adjustment in clinical practice, despite not being validated in critically ill patients. Of note, the only antimicrobials for which dosage reduction is recommended for patients with Child–Pugh class C are metronidazole, tigecycline, and caspofungin Alternatively, liver failure is associated with reduced production of albumin leading to hypoproteinemia affecting Vd and protein binding. Pathophysiological alterations in critically ill Adequate antimicrobial therapy Three requirements need to be fulfilled: First, the antimicrobial agent(s) should be initiated as soon as possible after the onset of sepsis. Second, as therapy is to be initiated empirically, the antimicrobial spectrum of the agent should be broad enough to cover the potential causative microorganisms Finally, appropriate antimicrobial dosing is required to maximize microbial killing, minimize the development of multidrug antimicrobial resistance, and avoid concentration-related adverse drug reactions Key Points Dosing and choosing of antimicrobials during sepsis or critical illness in general are not easy. Understanding the altered physiology/pathology is the corner stone in managing and prescribing antibiotics in ICU Understanding the pharmacology of the medication the also very important to achieve desirable outcome Overall, the risk of suboptimal concentrations is higher than the risk of adverse effects due to overdosing, especially for hydrophilic antibiotics Suboptimal antimicrobial concentrations further trigger the development of multidrug resistance, which on its turn further complicates antimicrobial therapy through reduced odds of empiric appropriate treatment.