HC23: Principles of antibiotic pharmacotherapy

Goal of drug treatment

The main goal of drug treatment is to achieve a drug concentration within the body that is therapeutically relevant and appropriate. Knowledge about pharmacokinetics is relevant to determine the appropriate dose and to maintain drug concentrations within the therapeutic index. The most prescribed antibiotic is amoxycillin.

To describe the route of a drug, the ADME aspects are used:

• Absorption
• Distribution
• Metabolism
• Excretion

The processes of metabolism and excretion together form elimination.

Absorption

Absorption consists of the passage of a drug from its site of administration into the circulation. There are 3 main routes of administration for antibiotics:

• Oral
• Epithelial surfaces
• Intravenous injection

Transport:

During absorption, drug molecules are transported across the cell membranes. This can happen via:

• Passive transport → diffusion
• Active transport → carrier-mediated transport using energy (ATP)

Which form is used, depends on the physicochemical properties of the drug molecule:

• Molecular size
  • Drugs with a size smaller than 1000 dalton can be diffused over membranes
    • Bigger drugs need to be injected intravenously
• Relative lipid solubility
  • Drugs with a high lipid solubility can cross the membrane by diffusion
  • Hydrophilic drugs cross the membrane via carriers

Concentration-time curve:

Absorption can be shown in a concentration-time curve. 2 relevant parameters are:

• Cmax: the maximal plasma concentration
• tmax: time when the concentration is maximal

The therapeutic range of a drug lies between the MEC (minimal effective concentration) and MTC (maximal toxic concentration). A drug with a wide therapeutic range is preferable. Penicillins, for instance, are antibiotics with a very wide therapeutic range, while gentamycins have a narrow therapeutic range.

The concentration can be influenced by:

• The dose
• The dose frequency

Case:

A 21-year-old patient is treated with ciprofloxacin (chinolon) because of a severe and complicated cystitis. Ciprofloxacin should not be taken in combination with dairy products, like milk or yoghurt, because:

• It forms a complex with calcium, magnesium, zinc and iron
  • The drug will be too large to be transported across the cell membrane
• The absorption reduces
• The effectiveness reduces

Factors:

Several factors can influence absorption:

• Food intake
• Gastrointestinal motility
• pH at absorption site
• Drug-drug interaction

Bioavailability:

The bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation as an intact drug. This typically is less than 100%, due to:

• Poor absorption
• Metabolic degradation → first pass effect
  • If the drug is in the portal vein, it has to pass the liver before it reaches the systemic circulation

The bioavailability of oral drugs is less than 100%, while the bioavailability of intravenous drugs is 100%.

Distribution

It is relevant to know the distribution of a drug to determine whether a drug is able to reach the site of infection and to determine the effective dose.

Fluid:

Once administered, drugs are distributed over different body fluid compartments. The total body fluid forms 50-70% of the body weight. A man who weighs 70 kg has 40-46 L of water, which is distributed as follows:

• Extracellular water: 13-16 L
  • Plasma: 3 L
  • Interstitial: 10-13 L
• Intracellular water: 25-28 L
• Transcellular water: 0,7-2 L

Dependency:

Distribution of a drug is dependent on:

• Molecular size
• Lipid solubility
• Binding to proteins/tissue within compartments
  • If a drug binds to a protein, it becomes very large and will not be able to cross the plasma membrane

Volume of distribution:

The volume of distribution (Vd) is the volume of fluid required to contain the total amount of drug in the body at the same concentration as that of plasma. After intravenous administration, the volume of distribution can be calculated:

• Vd = D/C0
  • Vd = volume of distribution
  • D = dose
  • C0= concentration
    • Immediately after administration and distribution

The Vd of a drug is often provided as L/kg body weight. Based on the weight of a patient, the actual Vd can be calculated.

Cases:

Amoxicillin is administrated intravenously to a man of 75 kg in a dose of 750 milligrams. The peak plasma concentration after administration is 33 mg/ml. The Vd of amoxicillin can be calculated as follows:

1. Vd = 750/33 = 22,7 L
2. Vd = 22,7/75 = 0,3 L/kg

Gentamicin is administrated intravenously to a man with a weight of 70 kg in a dose of 300 mg. The apparent volume of distribution of gentamicin is 0,31 L/kg. The likely initial concentration after injection can be calculated as follows:

1. Vd = 70 x 0,31 = 21,7 L
2. C0= D/Vd = 300/21,7 = 13,8 mg/ml

Metabolism

Enzymes:

Changes in enzyme activity may interfere in drug metabolism and elimination:

• Enzyme-induction
• Enzyme-inhibition

Most drugs lose their pharmacological activity if they are metabolized by the CYP-enzymes in the liver.

Potent inhibitors of CYP-enzymes are:

• Erythromycin
• Clarithromycin
• Ciprofloxacin

These inhibitors induce a decreased enzyme activity. There is a decreased metabolism of drugs that are substrates for these enzymes and are metabolized by these enzymes.

Case:

A 62-year-old patient with pneumonia has been treated with antibiotics since 3 days. Today he visits the general practitioner because of severe myalgia and fatigue. In the past, he has suffered from hypercholesterolemia and he is allergic to penicillin. For his pneumonia, he was prescribed:

• Simvastatin
• Claritromycin

Because simvastatin is metabolized by the CYP3A4 enzyme, while claritromycin is an inhibitor of that enzyme, the metabolism and elimination of simvastatin is reduced. This causes increased plasma levels and side effects of simvastatin → myalgia and fatigue, which can increase the chance of myopathy and rhabdomyolysis.

Excretion

Renal excretion:

The renal clearance (CI) indicates the volume of plasma containing the amount of substance that is removed from the body by the kidney in unit time (ml/min).

Due to age or disease, the excretory function of the kidneys can change dramatically → it is important for clinicians to determine a particular patient's renal function before dosing a renally eliminated drug. This can be done based on the creatinine clearance, which indicated the glomerular filtration rate. Especially drugs with a very narrow therapeutic index, it is important to know the renal function.

Several drugs are mainly excreted renally (by the kidney):

• Penicillins
  • Benzulpenicillin
  • Amoxicillin
  • Flucoxacillin
• Gentamycin
  • Has a very narrow therapeutic index

Dosage:

The dosage of a drug also has to be determined:

• Single dose
  • If a patient has to be treated once
• Loading dose + maintenance dose
  • If a patient has to be treated for a longer time
  • Maintenance dose: frequency to keep the drug within the therapeutic range

Side effects

Antibiotic drugs can give multiple side effects:

• Penicillin
  • Allergic reactions
    • Rash
    • Bronchospasm
    • Fever
• Tetracyclin
  • Irreversible yellow-brown coloring teeth
  • GI problems
  • Photosensitivity
• Cephalosporin
  • Allergic reactions
• Erythromycin
  • Nausea
• Gentamycin
  • Ototoxicity
  • Nephrotoxicity
• Vancomycin
  • Nephrotoxicity
  • GI problems
  • Red man syndrome
  • Loss of hearing

Clinical example

A 58-year-old patient comes to the emergency room with the following symptoms:

• Severe right-sided chest pain, fever, and shivering since last night
• Coughing with sputum production (rusty in color)
• Difficulty to breath

His files contain the following information:

• Physical examination
  • Blood pressure: 140/82 mm Hg
  • Heart rate: 105 bpm
  • Respiratory rate: 32 breaths per minute
  • Temperature: 39,2 °C
• Chest
  • Inspiratory crepitation
  • Dullness to percussion
  • Chest X-ray: lobar infiltrate in the right lung
• Lab
  • White blood cells: 18,6 x 10⁹/L
• Gram strain (sputum)
  • Multiple gram-positive cocci in pairs

Symptoms indicate a serious disease state. The goal of treatment is to completely eradicate the bacterial infection with an effective and safe antibiotic:

• Effective
  • Mechanism-of-action (PD)
  • Route of administration (PK)
    Dosing
• Safe
  • Toxicities
  • Adverse side effects

An antibiotic against the gram-positive streptococcus pneumoniae is given:

• Benzyl penicillin
• Amoxicillin or feneticillin
• Alternative macrolides
  • Clarithromycin
  • Erytrhomycin