Several important interactions between drug and pathogen have been discussed in the preceding pages. The following are the additional important in vivo factors. Environment In the host, varying environmental influences affect microorganisms located in different tissues and in different parts of the body—in contrast to the test tube or Petri dish, where the environment is constant for all members of a microbial population. Therefore, the response of the microbial population is much less uniform within the host than in the test tube.

A. State of Metabolic Activity

In the body, the state of metabolic activity is diverse— undoubtedly, many organisms exist at a low level of biosynthetic activity and are thus relatively insusceptible to drug action. These “dormant” microorganisms often survive exposure to high concentrations of drugs and subsequently may produce a clinical relapse of the infection. Bacteria that form biofilms frequently become metabolically less active (or dormant) when embedded in a biofilm matrix thus making them harder to eradicate with antibiotics than planktonic organisms.

B. Distribution of Drug

In the body, the antimicrobial agent is unequally distributed in tissues and fluids. Many drugs do not reach the central nervous system (CNS) or bone effectively. The concentration in urine is often much greater than the concentration in blood or other tissue. The tissue response induced by the microorganism may protect it from the drug. Necrotic tissue or pus may adsorb the drug and thus prevent its contact with bacteria.

C. Location of Organisms

In the body, microorganisms often are located within tis sue cells. Drugs enter tissue cells at different rates. Some (eg, tetracyclines) reach about the same concentration inside monocytes as in the extracellular fluid. With others (eg, gentamicin), the drug probably does not enter host cells at all. This is in contrast to the test tube, where microorganisms come into direct contact with the drug.

D. Interfering Substances

The biochemical environment of microorganisms in the body is very complex and results in significant interference with drug action. The drug may be bound by blood and tissue proteins or phospholipids; it may also react with nucleic acids in pus and may be physically adsorbed onto exudates, cells, and necrotic debris. In necrotic tissue, the pH may be highly acid and thus unfavorable for drug action (eg, aminoglycosides).

Concentration

In the body, microorganisms are not exposed to a constant concentration of drug; in the test tube, they are.

 A. Absorption

The absorption of drugs from the intestinal tract (if taken by mouth) or from tissues (if injected) is irregular. There is also a continuous excretion as well as inactivation of the drug. Consequently, the levels of drug in body compartments fluctuate continually, and the microorganisms are exposed to varying concentrations of the antimicrobial agent.

B. Distribution

The distribution of drugs varies greatly with different tissues. Some drugs penetrate certain tissues poorly (eg, CNS, prostate, and bone). Drug concentrations after systemic administration may therefore be inadequate for effective treatment. On surface wounds or mucous membranes such as the conjunctivae, local (topical) application of poorly absorbed drugs permits highly effective local concentrations without toxic side effects. Alternatively, some drugs applied topically on surface wounds are well absorbed. Drug concentrations in urine are often much higher than in blood.

C. Variability of Concentration

 It is critical to maintain an effective concentration of a drug where the infecting microorganisms proliferate. This concentration must be maintained for a sufficient length of time to eradicate the microorganisms. Because the drug is administered intermittently and is absorbed and excreted irregularly, the levels constantly fluctuate at the site of infection. To maintain sufficient drug concentrations for a sufficient time, the time–dose relationship must be considered. The larger each individual drug dose, the longer the permissible interval between doses. The smaller the individual dose, the shorter the interval that will ensure adequate drug levels.

 D. Postantibiotic Effect

 The postantibiotic effect is the delayed regrowth of bacteria after exposure to antimicrobial agents. It is a property of most antimicrobials except that most β-lactams do not show the postantibiotic effect with Gram-negative bacilli. The carbapenems do have a postantibiotic effect with the Gram-negative bacilli. Aminoglycosides and fluoroquinolones have prolonged (up to several hours) in vitro postantibiotic effects against Gram-negative bacilli.

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مواضيع ذات صلة

Antimicrobial Chemoprophylaxis

Measurement of Antimicrobial Activity

Clinical Implications of Drug Resistance

Origin of drug resistance

Resistance to Sulfonamide

Control of Antibiotics Overuse

International Distribution of Antibiotics: A Scandinavian Example

Rediscovery of Penicillin by a Basic Scientific Approach

Penicillin: the First Antibiotic

Sulfonamide: the First Antibacterial Agent Acting Selectively

Drug elimination

Drug distribution