Discussion in 'Pharmacy' started by Valery1957, Mar 31, 2019.

  1. Valery1957

    Valery1957 Well-Known Member

    Jan 10, 2019
    Likes Received:
    Trophy Points:
    Practicing medicine in:

    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%.
     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
     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
     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
    Pharmacology in Critical Illness
     Volume of distribution: Describes the
    relationship between dose and the resulting serum
     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
    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
    III. Acute kidney injury may complicate the ICU
    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
    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
     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
    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
     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
    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
     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
     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.

    Add Reply

Share This Page