Patients Undergoing Chemotherapy Question And Answers

General Considerations Definitions

Chemotherapy: Chemotherapy is the use of a chemical substance in infectious diseases to destroy microorganisms without damaging the host tissues.

Antibiotics: Antibiotics are substances produced by microorganisms that suppress the growth of or destroy other microorganisms at low concentrations, e.g. tetracyclines

Bacteriostatic drugs: Bacteriostatic drugs are agents that suppress the growth of bacteria, for example, Sulfonamides.

Bactericidal agents: Bactericidal agents are antimicrobials that kill bacteria, for example,Penicillins, cephalosporins

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Broad-spectrum antibiotics: Broad-spectrum antibiotics are so-called because, in addition to suppression of gram-positive and gram-negative bacteria, they also inhibit the growth of other microorganisms like rickettsiae, chlamydiae, mycoplasma, and some protozoa.

Mechanisms Of Action Of Antimicrobials

The structure and composition of the bacterial cell differ from the mammalian cells in many aspects hence antibacterials are more selective to bacteria and less toxic to human beings.

Thus, antibiotics target different sites on the bacterial cell:

• Cell wall: Antibiotics inhibit the synthesis of bacterial cell walls resulting in bacteria with weak cell walls that undergo lysis → hence bactericidal, for example, Penicillins.
• Cell membrane: Drugs alter the permeability of the cell membrane leading to leakage of cell contents followed by cell death, for example, Polymyxins, and amphotericin.
• Protein synthesis: Several antimicrobials act by interfering with protein synthesis. The bacterial ribosome has a 50S and a 30S subunit and the mammalian ribosome has 60S and 40S subunits which are involved in protein synthesis.
  • Aminoglycosides, and tetracyclines, inhibit the 30S while chloramphenicol and macrolides inhibit 50S ribosomal subunits in the bacteria and thereby inhibit protein synthesis.
  • Antibacterials may interfere with nucleic acid synthesis either by inhibiting DNA or RNA polymerase (for example, Rifampicin) or by inhibiting the enzyme DNA gyrase (quinolones).
• Metabolic pathway: Drugs like sulfonamides interfere with the metabolic pathway of the bacteria, block the enzymes involved in folic acid synthesis and thereby inhibit bacterial growth and multiplication.

Antimicrobials Classification:

1. Based on the site of action and mechanism of action: Antimicrobials may be classified as drugs that:

• Inhibit cell wall synthesis: Penicillins, cephalosporins, carbapenems, monobactam, vancomycin, teicoplanin, bacitracin, cycloserine.
• Act on cell membranes (causing leakage of cell contents): Polymyxins, amphotericin B, nystatin.
• Bind to ribosomes and inhibit protein synthesis:
• 50S—erythromycin, chloramphenicol, clindamycin, streptogramins, linezolid
• 30S—tetracyclines, aminoglycosides
• Inhibit DNA gyrase: Fluoroquinolones
• Inhibit DNA function (↓ DNA-dependent RNA polymerase): Rifampicin
• Interfere with metabolic steps (Antimetabolites): Sulfonamides, sulfones, trimethoprim, pyrimethamine

2. Based on the antibacterial spectrum:

• Narrow spectrum antibiotics
  • Penicillin G
  • Aminoglycosides
• Broad-spectrum antibiotics:
  • Tetracyclines
  • Chloramphenicol

3. Based on antibacterial activity:

• Bacteriostatic drugs:
  • Sulfonamides
  • Tetracycline
  • Linezolid
  • Chloramphenicol
  • Clindamycin
• Bactericidal drugs:
  • Penicillins
  • Cephalosporins
  • Aminoglycosides
  • Fluoroquinolones
  • Rifampicin
  • Metronidazole

Some drugs are bacteriostatic at low doses and bactericidal at higher doses, for example, Erythromycin. Some drugs are bacteriostatic to some microbes and ‘tidal’ to others, for example, Chloramphenicol is bactericidal to H. influenzae. S. pneumoniae and N. meningitidis, but bacteriostatic to other bacteria. Bactericidal drugs like vancomycin and penicillin are bacteriostatic to enterococci.

Factors that influence the successful chemotherapy of infection are:

• Site: The drug should reach the site of infection.
• Concentration: It should attain adequate concentration at the site.
• Host defense: Active host defenses reduce the antibiotic requirement.
• Sensitivity: The microorganism should be sensitive to the antimicrobial agent.

Resistance To Antimicrobial Agents

Resistance Definition: Resistance is the unresponsiveness of a microorganism to the antimicrobial agent. Resistance may be natural or acquired.

Bacteria acquire resistance through a change in their DNA. Such DNA changes may occur by:

Mutation:

• The mutation is a genetic change that occurs spontaneously. In any population of bacteria, a few resistant mutants may be present.
• When the sensitive organisms are destroyed by the antibiotic, the resistant mutants freely multiply.
• The mutation may take place in a single step (for example, Staph. aureus to rifampicin) or multiple steps where several gene modifications are made, (for example, Gonococci to penicillin G).

Transfer of genetic material:

• Many bacteria contain extrachromosomal genetic material called plasmids in the cytoplasm. These carry genes coding for resistance (called R-factors).
• These R-factors are transferred to other bacteria and spread resistance.

Transfer of genetic material may take place by:

1. Transduction: Plasmid DNA is transferred through bacteriophage.
2. Transformation: Resistant bacteria may release genetic material into the medium which is taken up by other bacteria.
3. Conjugation: Conjugation is the most important mode of spread of resistance. The R-factor is transferred from cell to cell by direct contact through a sex pilus or bridge and the process is known as conjugation.

The resistance acquired by the bacteria may be exhibited in the following ways:

• Production of enzymes: Enzymes that inactivate the drug, for example, β-lactamase by staphylococci; aminoglycoside inactivating enzymes by E. coli.
• Decreased accumulation: Decreased accumulation of the drug in the bacterium, e.g. resistance to tetracyclines by gram-positive and gram-negative bacteria.
• The altered target for the drug: For example, Binding sites for aminoglycosides on the ribosomes may be altered.
• Altered metabolic pathway—bacteria may produce folic acid by an alternative pathway.

Cross-resistance: Cross-resistance is the resistance seen among chemically related drugs-like resistance to other drugs of the same group, even when not exposed to them, for example, Resistance to one tetracycline means resistance to all other tetracyclines.

Prevention of Resistance to Antimicrobials:

• Antibiotics should be used only when necessary.
• Selection of the appropriate antibiotic.
• Correct dose and duration of treatment should be followed.
• A combination of drugs should be used as in tuberculosis to delay the development of resistance.

Selection Of An Antibacterial Agent

Various factors to be considered in the selection of an antibiotic are:

Patient Factors

1. Age of the patient: Chloramphenicol Gray baby syndrome in the newborn; sulfonamides— kernicterus in the newborn Sulfonamides displace bilirubin from the binding sites which reaches the CNS due to weak BBB in the neonate.
   • Ototoxicity due to aminoglycosides is more in the elderly with hearing impairment. Their weaker kidney function may further raise the aminoglycoside levels.
2. Host defense status: Higher antibiotic doses and bactericidal drugs are needed in immunosuppressed patients.
3. Site of infection: Antibiotics should reach the site of infection in adequate concentrations. The presence of pus, necrotic material, clots, and an anaerobic environment interfere with the activity of most antibiotics. Drugs that cross the BBB to be used for meningeal infections.
4. Renal and hepatic impairment → Higher plasma levels and more toxicity. Drugs like nalidixic acid, and cephalothin to be avoided.
5. Allergy: Since many antibiotics are obtained from microorganisms, allergic reactions are expected. History of allergy should be taken and if an allergy is known, an alternative one used.

Microbe Factors:

• Microbes should be sensitive to the antibacterial.
• Whenever possible, a culture sensitivity report should guide the drug selection.
• When not available, empirical therapy started to cover all the likely organisms.

Antibiotics are used in two ways:

• Empiric therapy: The antibiotic must cover all the likely pathogens. A combination of a broad-spectrum agent may be used. This therapy should be employed routinely. When the culture report is available, antimicrobial agents should be changed accordingly.
• Definitive therapy: When the microorganism is identified, specific antibacterial agents are given.

Drug Factors:

• Drugs should be effective against the particular microbe.
• Narrow-spectrum antibiotics are preferred.
• Bactericidal drugs for patients with poor host defense.
• Adequate dose and duration of therapy.
• The antimicrobial should be safe, for example, Penicillins are safe except for allergy.
• Cost—less expensive ones should be chosen.

Minimum inhibitory concentration (MIC):

MIC is the lowest concentration of the antimicrobial agent that prevents visible growth of the microorganism after 18–24 hours of incubation.

Concentration-dependent killing:

• The higher the antibacterial concentration attained, the better is the killing, that is, as the concentration of the antimicrobial agent increases in the plasma above the MIC, the rate and extent of bactericidal activity also increase, for example, Aminoglycosides, and quinolones.
• Thus, aminoglycosides may be given as single daily doses instead of thrice daily dosing.

Time-dependent killing:

• For some drugs, the longer the presence of the drug in the plasma, the greater is the bactericidal effect.
• For such drugs, the presence of the drug in the concentration above MIC for a longer period is needed and thus the drug levels need to be maintained as long as the bactericidal activity is required, for example, Beta-lactam antibiotics, and vancomycin.