Lecturer notes on veterinary pharmacology and toxicology for B.V.Sc & A.H Seventh semester student for educational purpose.This lecturer notes will be useful for all the veterinary students.Plesae send your comments,jibachhashah@gmail.com,mob.9845024121

1. Drug resistance and Multiple Drug
Therapy
Dr. Jibachha Sah
M.V.Sc(Veterinary Pharmacology)
Lecturer, Department of Pharmacology & Toxicology
College of Veterinary Science, NPI, Bhojard, Chitwan,
Nepal
B.V.Sc & A.H SEVENTH SEMESTER
Course Title: Veterinary Pharmacology & Toxicology (Chemotherapy)o
Welcome to my lecturer notes

2. Objectives
●Explain the concept of drug resistance
● Describe how microorganisms develop or acquire drug resistance
● Describe the different mechanisms of antimicrobial drug resistance
● Describe multiple drug therapy

3. CONTENTS
1.HISTORY OF DRUG RESISTANT
2.DEFINITION OF DRUG RESISTANT
3. EXAMPLES OF DRUG RESISTANT INFECTIONS
4. TYPES OF DRUG RESISTANCE
5. MECHANISM OF DRUG RESISTANCE
6. CAUSE OF ANTIBIOTIC RESISTANT
7.MULTIPLE DRUG THERAPY (MDT)
8. EXAMPLES OF MULTIDRUG THERAPY
9.SUMMARY

4. 1.HISTORY OF DRUG RESISTANT
December 11, 1945 Sir Alexander Fleming In his Nobel Prize lecture,
Fleming himself warned of the danger of resistance –“It is not difficult
to make microbes resistant to penicillin in the laboratory by exposing
them to concentrations not sufficient to kill them, and the same thing
has occasionally happened in the body and by exposing his microbes
to non-lethal quantities of the drug make them resistant.”
Paul Ehrlich, the father of modern chemotherapy, observed that,
during treatment of trypanosome infections, organisms sometimes
emerged that were resistant to the agent being used.

6. 2.DEFINITION DRUG RESISTANT?
Drug resistance is the reduction in effectiveness of a medication
such as an antimicrobial or an antineoplastic in treating a disease or
condition. When an organism is resistant to more than one drug, it
is said to be multidrug-resistant.
Examples of drug resistant infections?
Important examples are: methicillin-resistant Staphylococcus aureus
(MRSA), vancomycin-resistant Enterococcus (VRE), multi-drug-
resistant Mycobacterium tuberculosis (MDR-TB)

7. 3. TYPES OF DRUG RESISTANCE
It is unresponsiveness of a microorganism to an Antimicrobial agent(AMA )and it is
similar to the phenomenon of tolerance seen in higher organisms.
Types of resistance
● Natural
● Acquired
Natural resistance
●Some microbes have always been resistant to certain AMAs. This is because of the
lack of metabolic process or the target sites.
● grouped specific. Eg. gram negative organisms are not affected by penicillin,
M.tuberculosis insensitive to tetracyclines.
● This type of resistance do not produce any clinical problems
Acquired resistance
● It is the development of resistance by an organism due to use of an AMA over a period of
time (after an exposure).
● This poses a clinical problem in veterinary practice.
● Some bacteria acquire rapid resistance. Eg. Staphylococci, Coliforms and tubercle bacilli.

8. 4.Mechanism of resistant
The three fundamental mechanisms of antimicrobial resistance are
(1)enzymatic modification of the drug
(2) modification of the antimicrobial target and
(3) prevention of drug penetration or accumulation.

9. There are multiple strategies that
microbes use to develop resistance
to antimicrobial drugs.

10. (1)Enzymatic modification of the drug
Example:
1.For β-lactams antibiotic mechanism of resistant
mediated by β-lactamases enzyme.
2.Inactivation of rifampin commonly occurs
through glycosylation, phosphorylation, or adenosine
diphosphate (ADP) ribosylation,

11. 2.Prevention of Cellular Uptake or Efflux
Gram negative microbes may develop resistance mechanisms
that involve inhibiting the accumulation of an antimicrobial
drug, which then prevents the drug from reaching its cellular
target.
For example, resistance to β-lactams, tetracycline's,
and fluoroquinolones commonly occurs through active efflux
out of the cell.

12. 3.Target Modification
Genetic changes impacting the active site of penicillin-binding
proteins (PBPs) can inhibit the binding of β-lactam drugs and
provide resistance to multiple drugs within this class.
Other examples of this resistance strategy include alterations in
●Ribosome subunits, providing resistance to macrolides, tetracyclines,
and aminoglycosides;
●Lipopolysaccharide (LPS) structure, providing resistance
to polymyxins;
● RNA polymerase, providing resistance to rifampin;
● DNA gyrase, providing resistance to fluoroquinolones;
●Metabolic enzymes, providing resistance to sulfa drugs, sulfones,
and trimethoprim; and
●Peptidoglycan subunit peptide chains, providing resistance
to glycopeptides.

13. 6.Cause of antibiotic resistant:
1.Over-prescription of antibiotics
2.Patients not finishing the entire antibiotic course
3.Overuse of antibiotics in livestock and fish farming
4.Poor infection control in health care settings
5.Poor hygiene and sanitation
6.Absence of new antibiotics being discovered

14. 7.Multiple Drug Therapy (MDT)
Combination therapy or polytherapy is therapy that uses
more than one medication or modality .
Use:
Conditions treated with combination therapy
include tuberculosis, leprosy, cancer, malaria, and HIV/AIDS.
Example: leprosy in human patient

15. For patients with localized forms of leprosy and relatively few
leprosy bacilli in their bodies, two drugs, dapsone
and rifampicin, are given for a total of six months.
For patients with more widespread disease and relatively large
numbers of bacilli, three drugs—dapsone, clofazimine, and
rifampicin—are given for 24 months.

16. In human tuberculosis patient MDT
X-Ray of Tuberculosis Calcification Caused by Mycobacterium Tuberculosis Bacteria
The WHO approved drugs, isoniazid (INH), rifampin (RIF), ethambutol
(EMB), and pyrazinamide (PZA) are considered first-line anti-TB drugs
and form the core of standard treatment regimens.
Multiple drug therapy is often used in veterinary practice;
occasionally, inappropriate combinations of drugs may be
administered which interact to produce adverse responses.

17. Multidrug Therapy With Azithromycin, Rifampin, and Ethambutol for the
Treatment of Mycobacterium avium subsp avium in Ring-neck Doves (Streptopelia
risoria). All birds were treated with azithromycin (43 mg/kg), rifampin (45 mg/kg),
and ethambutol (30 mg/kg) administered orally once daily for 180 days. ( Journal of
Avian Medicine and Surgery Vol. 28, No. 4 (DECEMBER 2014), pp. 280-289)
Ring-neck Doves

18. First line drugs
Isoniazid (INH)
Pyrazinamide (PZA)
Rifampin (RIF)
Ethambutol (ETH)
Streptomycin (STR)
Second line drugs
Amikacin
Ethionamide
Quinolones
Capreomycin
Mycobacteria tuberculosis complex MDT

19. 9.SUMMARY
1.Which of the resistance mechanisms describes the
function of β-lactamase?
(i) Drug inactivation describes the function of β-lactamase.
2.Which of the resistance mechanisms is commonly effective against
a wide range of antimicrobials in multiple classes?
(i) The efflux pump is commonly effective against a wide range
of antimicrobials in multiple classes.

20. 3.Which of the resistance mechanisms is the most
nonspecific to a particular class of antimicrobials?
(i) The efflux pump is the most nonspecific to a
particular class of antimicrobials.
4. What are three resistance mechanisms
antimicrobials drugs?
(1)enzymatic modification of the drug
(2) modification of the antimicrobial target and
(3) prevention of drug penetration or accumulation.

21. 5. What is Multiple Drug Therapy (MDT) mean?
(i) use of 2 or more drug in a single-dosage formulation.
6.What are three contributing factor to antibacterial drug
resistance?
(i) misuse antimicrobial drugs
(ii) unnecessary prescriptions
(iii) unfinished prescriptions
7.What are the four factor contributing mechanism of action in
drug resistant?
(i) efflux pumping
(ii) modify antibiotic target
(iii) alters pathway
(iv) inactivates the antibiotic