Principles of Chemotherapy.

Antimicrobial therapy takes advantage of the biochemical differences that exist between microorganisms and human beings.

1.Selection of Antimicrobial agents.

Selection of the most appropriate antimicrobial agent requires knowing

  • 1) the organism’s identity,
  • 2) the organism’s susceptibility to a particular agent,
  • 3) the site of the infection,
  • 4) patient factors,
  • 5) the safety of the agent, and
  • 6) the cost of therapy.

Identification of the infecting organism

  • A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the Gram stain, which is particularly useful in identifying the presence and morphologic features of microorganisms
  • It is generally necessary to culture the infective organism to arrive at a conclusive diagnosis and determine the susceptibility to
    antimicrobial agents.
  • Definitive identification of the infecting organism may require other laboratory techniques, such as detection of microbial antigens, DNA, or RNA, or an inflammatory or host immune response to the microorganism

Empiric therapy prior to identification of the organism

Ideally, the antimicrobial agent used to treat an infection is selected after the organism has been identified and its drug susceptibility established. However, in the critically ill patient, such a delay could prove fatal, and immediate empiric therapy is indicated.

Timing: Acutely ill patients with infections of unknown origin

Selecting a drug: Drug choice in the absence of susceptibility data is influenced by the site of infection and the patient’s history (for example, previous infections, age, recent travel history, recent antimicrobial therapy, immune status, and whether the infection was hospital- or community-acquired)

Determining antimicrobial susceptibility of infective organisms

After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in choosing antimicrobial therapy.

The minimum inhibitory and bactericidal concentrations of a drug can be experimentally determined

Minimum inhibitory concentration: The minimum inhibitory concentration (MIC) is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation.

Minimum bactericidal concentration: The minimum bactericidal concentration (MBC) is the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubation.

Effect of the site of infection on therapy

Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively eradicated.

Natural barriers to drug delivery are created by the structures of the capillaries of some tissues, such as the prostate, testes, placenta, the vitreous body of the eye, and the central nervous system.

The penetration and concentration of an antibacterial agent through these natural barriers are particularly influenced by the following:

  1. Lipid solubility of the drug- Lipid soluble drugs are easily passed through the membranes .
  2. Molecular weight of the drug- Low molecular weight drugs pass easily.
  3. Protein binding of the drug- High free drug concentration helps in crossing than protein binding.

Patient factors

In selecting an antibiotic, attention must be paid to the condition of the patient. For example, the status of the patient’s immune system, kidneys, liver, circulation, and age must be considered.

In women, pregnancy or breast-feeding also affects selection of the antimicrobial agent.

Safety of the agent

Antibiotics such as the penicillins are among the least toxic of all drugs because they interfere with a site or function unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol) have less specificity and are reserved for life-threatening infections because of the potential for serious toxicity to the patient.

Cost of therapy

Several drugs may show similar efficacy in treating an infection but vary widely in cost.

Although choice of therapy usually centers on the site of infection, severity of the illness, and ability to take oral medications, it is also important to consider the cost of the medication.

2.Route of Administration

The oral route of administration is appropriate for mild infections that can be treated on an outpatient basis.

In hospitalized patients requiring intravenous therapy initially, the switch to oral agents should occur as soon as possible.

However, some antibiotics, such as vancomycin, the aminoglycosides, and amphotericin B are so poorly absorbed from the gastrointestinal (GI) tract that adequate serum levels cannot be obtained by oral administration. Parenteral administration is used for drugs that are poorly absorbed from the GI tract and for treatment of patients with serious infections.

3.Determinants of Rational Dosing

Rational dosing of antimicrobial agents is based on their pharmacodynamics  and pharmacokinetic properties.

Three important properties that have a significant influence on the frequency of dosing are

  1. concentration dependent killing,
  2. time dependent killing, and
  3. post antibiotic effect (PAE).

4.Chemotherapeutic spectra

  • Narrow-spectrum antibiotics:  Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum.
  • Extended-spectrum antibiotics: Extended spectrum is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria.
  • Broad-spectrum antibiotics: Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species and are referred to as broad- spectrum antibiotics.
  • Administration of broadspectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a superinfection due to organisms such as Clostridium difficile, the growth of which is normally kept in check by the presence of other colonizing microorganisms.

5.Combination of Antimicrobial Drugs

It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility of superinfections, decreases the emergence of resistant organisms, and minimizes toxicity.

However, some situations require combinations of antimicrobial drugs. For example, the treatment of tuberculosis benefits from drug combinations.

6.Drug Resistance

Bacteria are considered resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. This is caused by

Genetic alterations leading to drug resistance and,

Altered expression of proteins in drug-resistant organisms

  • Modification of target sites
  • Decreased accumulation by limiting the permeability and by increasing the efflux of the agent
  • Enzymatic inactivationof the agent

7.Prophylactic use of Antimicrobial agents

Certain clinical situations, such as dental procedures and surgeries, require the use of antibiotics for the prevention rather than for the treatment of infections. Because the indiscriminate use of antimicrobial agents can result in bacterial resistance and superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential risks. The duration of prophylaxis should be closely observed to prevent the unnecessary development of antibiotic resistance.

8.Complications of Antimicrobial Therapy

Even though antibiotics are selectively toxic to an invading organism, it does not protect the host against adverse effects. For example, the drug may produce an allergic response or may be toxic in ways unrelated to the antimicrobial activity.

  • Hypersensitivity
  • Toxicity
  • Superinfections

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