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 CHAPTER1:

PRINCIPLES OF CHEMOTHERAPY IN ANIMALS

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I. History

A. The Chinese as early as 2500 years ago, used modly curd of soybeans to treat boils, carbuncles and other similar infections.

B. Fleming, 1927 - discovered penicillin.

C. Domagk, 1935 - demonstrated that prontosil, a diazo dye, protected mice against pneumococcus.

D. Fleming, 1941 - mass produced penicillin. A compound produced by modly Penicillium notatum.

A. Antibiosis - the concept of using substances derived from one living organism to kill another.

B. Antibiotics - Waksman, 1941 - chemical substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of or destroy other organisms(cf. Antimicrobials, antibacterials, anticoccidials etc.)

C. Chemotherapeutic agents- chemicals that selectively inhibit or destroy specific agents of disease such as bacteria, viruses, fungi, other parasites and even neoplastic cells (cf.chemo- therapy, pharmacotherapy)

D. Therapeutics - treatment of disease using drugs, surgery, radiation, behavioral modifications and other modalities.

A. It should exhibit selective and effective antimicrobial activity.

B. It should be bactericidal rather than bacteriostatic.

C. Bacteria should not develop resistance to the drug.

D. It should be effective in the presence of body fluids and exudates.

E. Bactericidal levels of the drug should be reached in the blood, tissues, and cerebrospinal fluid immediatley and maintained for prolonged periods.

F. The drug should be non-toxic.

G. The drug should be excreted in the urine in bactericidal concentrations.

A. Classification According to Mechanisms of Action(fig. 1 and 2).

1. Inhibitors of Cell Wall Synthesis

Penicillins Novobiocin Bacitracin Cephalosporin Ristocetin Vancomycin Cycloserine

2. Cell Membrane Disruption

Polymyxin Nystatin Colistin Amphotericin B Polyene Antibiotics Novobiocin Gentamycin Cationic detergents

3. Inhibition of Protein Synthesis

Tetracycylines Erythromycin Chloramphenicol Oleandomycin Marolide Group Streptomycin Tylosin Kanamycin Lincomycin

Gentamycin

4. Nucleic Acid Synthesis

Actinomycin Sulfonamides Nalidixic Acid

 

5. Drugs Affecting Intermediary Metabolism

Sulfonamides Trimethoprim

B. Classification according to Organisms Affected

 

1. Gram Positive Organisms

Pencillins Erythromycin Bacitracin Tylosin Novobicocin Oleandomycin Cycloserine Tyrothricin Cephalosporins

 

2. Gram Negative Organisms

Streptomycin and Dihydrostreptomycin

Kanamycin and Gentamycin

Neomycin

Polymyxin

Colistin

 

3. "Broad" Spectrum

Tetracyclines Nitrofurans

Chloramphenicol Cephalosporins

Sulfonamides

 

C. Classification According to Antibacterial Action

 

1. Bacteriocidal Antibiotics

Penicillin (often depends on concentration)

Streptomycin Bacitracin Neomycin Polymycin Nitrofurans

2. Bacteriostatic Antibiotics

Sulfonamides Nitrofurans Tetracyclines

Chloramphenicol .Erythromycin Tylosin

Oleandomycin

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V. Selection of an Antibiotic

The clinician must do the following:

A. Have a working knowledge of the common pathogenic organism envolved.

B. Make bacteriological cultures before treatment.

C. Determine the sensitivity pattern of the infecting agent.

D. Institute treatment of the case even though sensitivity tests have not been received.

E. Access the nature of the illness, i.e. Is the illness systemic or local?

Is the illness chronic or acute?

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VI. Therapy with Combined Antimicrobial Agents.

A. Antimicrobial drug interactions may be additive, synergistic, or antagonistic.

1. Addition - antibacterial action resulting from the simultaneous use of two or more antimicrobial agents is the sum of the individiual agents e.g.

i. Combined sulfonamide preparation

ii. Bacitracin and polymyxin B or neomycin in topical preparations.

This broadens the spectrum of activity.

2. Synergism - Antibacterial effects of two or more antimicrobial drug combinations exceed the algebraic sum of the effects of each drug acting separately e.g. Sulfonamide + trimethoprim

3. Antagonism - Antibacterial effects of a drug combination is less than that for either drug alone. e.g. Sulfonamides + penicillins

B. Indications for antimicrobial combination therapy.

1. Mixed infections e.g. genital tract infections, abscesses.

2. Overwhelming infections

3. Prevention of the emergence of resistant microorganisms.

Applicable in situations where spontaneous mutation results in acquired resistance.

4. Reduction in adverse reactions.

5. Severe infections of unknown etiology.

6. Synergism in cases of specific infections.

 

C. Jawetz's rule on antimicrobial combination

1. Bactericidal + bactericidal: may be synergistic or additive

2. Bacteriistatic + bacteriostatic: usually additive

3. Bacteriostatic + bactericidal: may be antagonistic

D. Disadvantages of antimicrobial combinations

1. Toxicity

2. Selection of resitant microorganisms

3. Cost

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VII. Mechanisms of Action of Antimicrobial Agents(Figs. 1 & 2)

A. Inhibition of cell wall synthesis

B. Inhibition of protein synthesis

C. Inhibition of nucleic acid synthesis

D. Inhibition of metabolic pathways

E. Distruption of cell membrane

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VIII. Principles of Antimicrobial Therapy

For the proper and efficient use of chemotherapeutic agents the following general principles must be considered.

A. When is it appropriate to use antibacterials?

 

1. Do not use antibiotics indiscriminately

2. Avoid the unnecessary prophylactic use of antibacterials.

a. Use in immunosuppressed animals.

b. Use prior to surgery likely to cause contamination.

c. Use in debilitated patients at high risk of infection.

B. Why should the prophylactic use of antibiotics be avoided?

 

1. Increased chance of development of bacterial resistance.

2. Exposure of animals to the toxic effects of drugs.

3. Increased risk of infection by viruses and other resistant microbes.

C. Determine the bacterial sensitivity

 

1. Culture and sensitivity testing.

2. MIC, minimum inhibitory concentration

3. MBC, minimum bactericidal concentraion

4. Gram stain

5. Change antibiotic if a response is not seen within a reasonable time.

D. Use the proper dose and maintain therapeutic blood levels

1. Subtherapeutic doses encourage the development of bacterial resistance.

 

 

 

E. Initiate and continue therapy for an adequate amount of time

 

 

1 Treatment, especially of bacterial infections, should be initiated early since the activity of an antibiotic dose is inversely proportional to the number of bacteria present. Large dose of the antibiotic may also be indicated early in the course of the infection.

 

2. Generally, keep patients on antibiotics for a few days after signs of infection have disappeared.

3. Some types of infections, e.g. urinary tract (minimum of 3 weeks), bacterial endocarditis(4-6 weeks), pneumonia(2-4 weeks), may require longer therapy.

4. If therapy is discontinued too soon, infection may recur.

 

F. Chose the appropriate antibiotic

 

1. Efficacy

2. Penetration to the site of infection.

G. Evaluate the status of the patients renal and kidney functions

 

1. Use antibacterials that depend on kidney for excretion only in patients with good renal function e. g. penicillins, nitrofurans, cephalosporins, polymyxins, aminoglycosides, tetracyclines.

2. Use antimicrobials that depend on liver biotrans- formation for elimination from the body only in animals with good hepatic function e. g. Griseofulvin, ketoconazole.

 

F. Remove barriers to maximum drug efficacy

1. Lack of free drainage of abcesses.

2. Obstruction of urinogenital or respiratory tract.

G. Avoid unnecessary change of antibotics

1. Once started, change of a particular antibiotic must be avoided unless a change is strongly indicated e.g. bacterial resistance, toxicity etc.

H. Cost-effectiveness of the chosen antibiotic

I. Avoid "polypharmacy" without very strong justification

 

A. Susceptibility or Resistance of Microorganisms to Antimicrobial Agents.

Any mechanism that results in alteration of bacterial genetic composition might result in the following changes in the bacterial cell:

1. Elaboration of drug metabolizing enzymes i.e., pencillinase.

2. Alteration of the permeability of the bacterial cell to the drug.

3. Increased amounts of an endogenous antagonist of drug action.

4. Alteration of the amount of drug receptor or drug binding.

Resistance might occur by the following means:

Mutation: A chance phenomenon. There is no evidence that mutation is drug induced.

Transduction: A change in genetic material of the bacterial by recieving DNA carrying a gene for resistance which is enclosed within a phage. The organism then acquires resistance to the antibiotic.

Transformation : The bacterial cell incorporates one or more genes formed by another bacteria from its environment.

B. A delay in therapy.

 

C. The administration of sub-optimal doses.

D. The alteration of the metabolic state of the organism.

i.e. Dormancy or formation of protoplasts, spheroplasts or l- forms.

E. The presence of certain pathological or physiological processes secondary to infection.

F. Barriers which exist in the eye, central nervous system or prostate are poorly penetrated by hydrophilic drugs.

G. The functional state of the host defense mechanisms.

H. Others

1. Treatment of untreatable infections.

2. Therapy of fewer of undetermined origin.

3. Improper Dosage.

4. Improper duration of therapy.

5. Chemotherapy with the omission of indicated surgical drainage.

I. Host Determinants of Response to Antimicrobial Agents

1. Age.

2. Genetic factors (species).

3. Pregnancy.

4. Concurrent disease.

5. Allergy.

6. Nervous system disorders.

7. Hepatic or Renal function.

8. Host defense mechanisms: i.e. combined immunodeficiency of Arabian foals.

A. Toxicity

B. Hypersensitivity reactions

C. Inhibition of normal microbial flora

D. Superinfection by antibiotic resistant microbes

E. Bacterial resistance to antibiotics

F. Prolonged excretion of enteric pathogens

G. Antibiotic residues in animal products i.e. meat, milk, egg.

 

As a result of this lecture series, the student should have gained sufficient information to accomplish the following tasks:

1. Recognize the difference between an antibiotic and chemotherapeutic a agent.

2. Recognize the importance of blood levels when accessing therapeutic agents.

3. Demonstrate how the various chemotherapeutic agents are classified.

4. Demonstrate how one might determine whether a chemotherapeutic agent is bacteriostatic or bacteriocidal.

5. Understand the provisions of Jawetz's rule and the rationale involved.

6. Differentiate between summation, additive and synergism with respect to chemotherapeutic activity.

 

 

Selection of Antibiotics

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Organism First Choice Alternative Choice

_________________________________________________________Antinobacillus lignieresi Tetracyclines (Na iodide) Sulfonamides, Chloram- phenicol

Actinomyces bovis Penicillin G Sulfonamides, dihydrostreptomycin, erythromycin

Bacillus anthracis Penicillin G Erythromycin, Tetracycline

Blastomyces Amphotericin B Sulfonamides, Nystatin

 

Bordetella bronchisepticus Sulfamethazine Chloramphenicol, tetracyclines

Brucella spp. Tertaycyline + Streptomucin Chloramphenicol

Clostriduim spp. Penicillin G Tetracycline

Corynebacterium spp. Penicillin G Tetracycline

Enterococcus Penicillin G + Streptomucin Erythromycin + Streptomycin

 

E. coli Chloramphenicol Polymixin B2, Furadantin1 Neomycin2

Sulfonamide, Spectimomycin**

Erysipelas spp. Penicillin G Tetracycline, Erythromycin

Fasobacterium (vincent) Penicillin G Tetracycline

Fungi (dermatophytic) Griseofulvin

Fungi (systemic) Amphotericin B2 Nystatin (little veterinary

experience)

Hemobartonella Oxophenarsine HCL2# Tetracycline

Klebsiella spp. Chloramphenicol Neomycin

Furadantin1

Leptospira spp. Penicillin + dihydrostreptomycin Tetracycline, Erythromycin

Mycobacterium Tuberc. Isoniazid + dihydrostreptomycin Isoniazid + Para- amino-salicylic acid

Mycoplasma granularm (swine) Tylosin Chloramphenicol, Erythromycin

Mycoplasma hypneumoniae Tylosin Chloramphenicol, (swine) Erythromycin

 

 

Selection of Antibiotics(contd)

_________________________________________________________Organism First Choice Alternative Choice

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Mycoplasma (poultry) Tylosin Same as above

Nocardia Sulfonamides2 Chloramphenicol,

Tetracycline

Pasteurella spp. Tetracycline Penicillins, Sulfas

Proteus mirabilis Neomycin2, Furadantin1 Ampicillin, Chloramphenicol

Streptomycin

Pseudominas anginosa Polymixin B2 Neomycin, Chloramhpenicol

Gentamicin2 (these are poor seconds to

first choice)

Salmonella spp. Chloramphenicol Ampicillin, Furadantin

Spherophorus necrophorus Penicillin G Sulfonamides, Tetracycline

Staphylococcus areus Penicillin G3 Nafcillin, Oxacillin,

Erythromycin, Neomycin2

 

Streptococcus spp. Penicillin G Erythromycin, Chloram-

phenicol, Furaltadone.

Furadantin1

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1For urinary tract infections.

2May be toxic in some cases.

3Non-penicillinase-producing strains only.

*Therapeutic level =2x M.I.C. in plasma.

#Rarely employed

**Effective, but develop resistance rapidly (apparently lose resistance after 30 days or so)

 

 

Infections Favorably Affected by Antibiotic Combinations

_________________________________________________________Infection Antibiotic Combination Mechanism of Effect

_________________________________________________________Enterococcal endocarditis Penicillin G and streptomycin; Synergy

ampicillin and streptomycin;

penicillin G, streptomycin;

erythromycin, & bacitracin;

vancomycin & streptomycin.

Streptococcal viridans Penicillin G and streptomycin; Synergy

endocarditis erythromycin & streptomycin;

cephalothin & streptomycin;

lincomycin & streptomycin.

Pseudomonas aeruginosa Carbenicillin & gentamicin* Delayed resistance

carbenicillin & polymyxins; and synergy

ampicillin & methicillin

Klebsiella pneumoniae Cephalothin & Kanamycin, Synergic and delayed

streptomycin & tetracycline resistance

Tuberculosis+ Isoniazid, streptomycin, and Delayed resistance,

aminosalicylic acid; isoniazid, synergy & cellular

streptomycin, & ethambutol penetration?

Brucellosis Streptomycin & tetracycline or Synergy, delayed resistance, penicillin G & cellular penetration?

Plasmodium falciparum Trimethoprim & sulfonamides; Synergy

pyrimethamine & sulfonamide

Overwhelming sepsis Cephaloridine & gentamicin Synergy (?); Broad spectrum of coverage

_________________________________________________________________*A recent report indicates that carbenicillin can inactivate gentamicin.

+Combinations cited only for initial for first line therapy.

 

 

 

Mechanisms of Antimicrobial Synergy

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Mechanism Antimicrobials Organisms

_________________________________________________________Increases rate of Penicillin G & Streptomycin Streptococci, bactericidal activity; especially

two anticiotics acting on enterococci

different metabolic pathways.

Sequential blockade; two Trimethoprim & Sulfonamides Plasmodia, gram- negative bacilli,antimicrobial agents gram-positive cocci.

acting on different sites in same

metabolic pathway.

Competitive inhibition of Ampicillin & methicillin Penicillinase- enzymes that inactivate producing gram- antibiotics negative bacilli

Delayed emergence of Penicillin G & erythromycin Staphylococcus areus

minority population of

erythromycin-resistant clones

in dissociated resistance to

erythromycin

Render bacterial receptor Polymyxins & Sulfonamides Proteus mirabilis

site accessible to antibiotic

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