Chemotherapy
Pharm-D, 3rd Professional (2nd Semester)
Dr. Hamad Ali
(Ph. D., M. Phil., Pharm. D., R. Ph., B. Sc.)
Assistant Professor (Pharmacology)
Department of Pharmaceutical Sciences, PAF-IAST
Infection
• Infection- the invasion and multiplication of infectious agents such as
bacteria, viruses, fungi, or parasites in the body, which may cause harm.
• Result of breakdown in the host-parasite relationship & when the
balance is in favor of the pathogen
• Pathogens
• Conventional: Always cause disease, even in healthy individuals
Mycobacterium tuberculosis, Salmonella typhi, HIV.
• Conditional: Cause disease under specific conditions, such as
when they enter a new site or host. E. coli (from gut to urinary
tract).
• Opportunistic: Normally harmless, but can cause disease in
immunocompromised
individuals.
Candida
albicans,
Pseudomonas aeruginosa,
Defense against Infection
• Host factors influence the host-parasite interaction: Nutrition, Age,
Impairment of host-immune response
• Non-specific host defense
• Skin
• Normal flora
• Phagocytosis
• pH
• Specific host defense
• Antibody response: IgM, IgG, IgA
• Cell-mediated immunity, T cells
Aggressive Mechanisms of the Parasite
• Virulence: indicates the degree of pathogenicity
2 methods of producing disease:
• Invasiveness: Ability of an organism to spread within the body once it has entered
• Toxin production:
• Exotoxins: proteins, antigenically strong, produced by both Grampositive & -negative
• Endotoxins: Lipopolysaccharide produced mainly by Gram-negative
bacteria
• Combination
Epidemiology of Infection
• Source of infection:
• Endogenous (individual’s own flora)
• Exogenous (organism acquired from outside)
• Reservoirs:
• Human beings
• Active cases: Shedding the infective organism
• Unapparent infections: Asymptomatic people
• Carriers: long-term carriers
• Animals and animal products (Zoonosis)
• Food (poultry, milk) or food handlers (contamination)
• Water: contaminated with sewage (typhoid, cholera)
• Soil
- Air: TB
- Dust: droplets
Outbreaks of Infection
• Factors affecting outbreaks
• Number of susceptible hosts: direct correlation
• Pathogenicity: infectiousness and communicability (TB), virulence
(typhoid)
• Route of spread: water contamination, air-conditioning systems, blood
transfusion
• Carriers: meningococcal meningitis
• Climate
Types of infections
• Acute vs. chronic
• Community vs Hospital (nosocomial)
• Latent infections (herpes)
• Emerging infections
• Zoonosis
• Travel-associated infections
• Neonatal infections
• Infections in immunocompromised patients
Chemotherapy
Use of chemicals against the infectious agent (i.e. bacteria) or cancer
cells based on selective toxicity.
Principle of chemotherapy
Selective toxicity = the ability of a drug to kill a target cell or
organism with no or minimal effect on other host cells.
The term chemotherapy is used for both the treatment of cancer and
the treatment of infections due to the analogy between cancer cells and
infectious agents
Antibiotic: Antibiotics a chemical substance produced by microorganisms that
inhibits the growth of or kills bacteria. Antibiotics are used to treat bacterial
infections.
Properties of an antibiotic
1. Produced by a microorganism
2. Bactericidal (kills bacteria directly) or Bacteriostatic(inhibits bacterial growth)
in minimal concentration
3. They are the substance of a known chemical structure
4. Kill the microorganism through the antimicrobial pathway (selesctive toxicity)
Exemptions:
• Ethanol is not an antibiotic, although it is produced by microorganisms and kill
bacteria but uses in high concentrations and has no sensitive toxoxty, same as
H2O2, used as a disinfectant
• Antibodies: Kill microorganisms, but are produced by higher animals, so
antibodies are not antibiotics.
Antimicrobials
Antimicrobials are agents that kill or inhibit the growth of microorganisms,
including:
Bacteria (antibacterial)
Viruses (antiviral)
Fungi (antifungal)
Parasites (antiparasitic)
• Antimicrobial drugs can be natural, semisynthetic, and synthetic
• So, all antibiotics are antimicrobial, but not all antimicrobials are
antibiotics.
• Similarly, all antimicrobials are chemotherapeutics, but not all
chemotherapeutics are antimicrobials
History of Antimicrobial Therapy
• 2500 years ago, anti-infective substances were known:
• Chinese used moldy soya bean for carbuncles & boils
• Greeks (Hippocrates) used wine to treat wounds
• 1877: Pauster, “life destroys life”. When anthrax bacteria were introduced
into urine, their growth could be inhibited by other airborne microorganisms
• 1900s: Paul Ehrlich proposed the Concept of the "Magic Bullet“ that
specific chemicals could selectively target disease-causing organisms without
harming the host. syphilis was treated with Salvarsan
• In 1928, Fleming discovered penicillin
• 1936: Sulphonamides were discovered
• 1940s: Flory and Chain clinically used Penicillin
• 1950s: Golden age of antimicrobials– many antibiotics were discovered and
synthesized
Types of Antimicrobial Programs
1.
Empiric; used in the initial response to serious infections. A broad
spectrum is frequently chosen.
• Used due to favorable clinical response & uncertainty about the
causative microbes.
1. .Definitive when specific pathogen has been identified, a drug of
choice is usually prescribed. The goal is to achieve maximal
curative effect with narrow spectrum, cost effective and safe agent.
For mixed infections, broad spectrum are also used.
2. Prophylaxis or Suppression, certain infections can be prevented if
the cause is single specific organism e.g. surgical wound
infections. Although more prolonged prophylaxis may result in
resistant organisms.
Adjunct Measures
• For many infections, adjunctive measures such as surgical drainage
and washing must be added to the antimicrobial treatment to
achieve a cure (eg. Large abscesses respond faster when drained)
COMBINATION THERAPY
Combination therapy with two or more antibiotics is used in
special cases:
• To prevent the emergence of resistant strains
• To treat emergency cases during the period when an
etiological diagnosis is still in progress
• To take advantage of antibiotic synergistic and additive
effects.
COMBINATION THERAPY
1. Synergistic Effect: When two bactericidal antibiotics are used in
combination. One of the two drugs must show at least a 4-fold increase in
antibacterial activities (or a decrease in MIC to ¼) for a synergism is said to
exist between the two drugs. (e.g. penicillin + streptomycin)
• Antibiotic synergism occurs when the effects of a combination of antibiotics is
greater than the sum of the effects of the individual antibiotics. (eg 2+2 = 5)
2.Additive Effect: When two bacteriostatic agents with the same mechanisms of
action are used. (eg 2+2 = 4)
3.Antagonism: Usually, bacteriostatic antibiotics are antagonistic to bactericidal
agents. (e.g. Chloramphenicol has been shown to antagonize the bactericidal
activities of penicillin in the treatment of Pneumococcal meningitis.

CURRENT STATUS OF COMBINATION
THERAPY
Disadvantages
• Side effects or toxicity
• Superinfection: A new infection that develops during or after an existing
infection, caused by a different pathogen than the initial infection, and
potentially resistant to the treatment being used.
• Cross-infection with resistant strains
• Antagonism
• Increased cost
 Advantages
•
Mixed or unknown infections
•
Synergistic/additive effect
• Prevention or delay in the development of drug resistance
Factors Affecting Choice of the Antibiotics
Pathogen factors
• Possible infecting organism
• Susceptibility pattern
Host factors
• History of previous adverse reactions
• Hypersensitivity reactions
• Renal and Hepatic functions
• Site of Infection
• Age: major factor:
• contraindication in children: quinolone ( damage of cartilage)
• Absorption: Adult gastric PH reduces the absorption of penicillin
Drug-Related Factors
• Spectrum of antimicrobial agent
• Depending if therapy is needed before microbiological
cultures available ( best guess empirical)
• Monotherapy vs. combination:
• In mixed infections
• To attain synergy
• To reduce resistance development ( TB)
• Reduce toxicity
• Compromised hosts
Drug Related Toxicity
• Allergic reactions: Immediate or delayed HS
• GIT side effects: Nausea, vomiting, diarrhoea
• Liver toxicity
• Renal toxicity
• Neurological toxicity: Ototoxicity, Optic neuropathy,
Encephalopathy & convulsions, Peripheral neuropathy
• Haematological toxicity
Causes of Failure of Treatment
• Clinical condition not susceptible to treatment
• Failure to use the laboratory properly
• Limitations of laboratory methods and laboratory errors
• Wrong choice of antibiotics
• Wrong doses
• Inadequate duration
• Use of antagonistic combinations
• Development of antimicrobial resistance
Antimicrobial Resistant
• The major problem with antimicrobial drugs is the development
of resistant organisms.
• Antibiotic resistance mechanisms existed long before the clinical
use of antibiotics
• The resistance mechanisms are already present in nature, and
irrational use of antimicrobials cause the selection of resistant
microorganisms.
• Highly resistant Gram-negative organisms with novel
Mechanisms of resistance have been increasingly reported.
Acquired Resistance to Antimicrobial Drugs.
Acquired Antimicrobial Resistance is the ability of a microorganism to resist the
effects of medications that once could successfully treat them
This means standard treatments become ineffective, and infections persist,
increasing the risk of spread, severe illness, and death.
Mechanisms:
1) Microbes may elaborate drug-metabolizing enzymes (ie, penicillinase).
2) Microbes may cease active uptake of certain drugs
3) Microbial drug receptors may undergo change, resulting in decreased antibiotic
binding and action.
4) Microbes may synthesize compounds that antagonize drug actions.
5) Microbes may develop efflux mechanisms
How is Resistance Acquired?
A) Spontaneous mutation
B) Horizontal gene transfer (Conjugation, Transduction, and
Transformation )
Transmissible drug resistance
• Most of the clinically important acquired drug resistance are plasmidmediated (‘R’ factor)
• Plasmids
Extra-chromosomal piece of DNA
Capable of self-replication
• Code for antibiotic resistance and be transferred from resistant
to sensitive strains
Transmissible drug resistance
• Resistance (R-factor) transfer usually by conjugation but can be by
transformation and transduction.
• Conjugation mainly in Gram-negative bacteria (Transfer of DNA
(usually plasmids) between bacteria via direct contact) eg E.coli
• Transduction (Transfer of bacterial DNA by a bacteriophage), eg,
Salmonella
• Transformation (Bacteria take up free DNA fragments from the
environment) eg Pseudomonas
Causes of Antimicrobial Resistance
1.Overuse and misuse of antibiotics
1. .Taking antibiotics for viral infections (like colds or flu)
2. Incomplete antibiotic courses
2.Poor infection control in hospitals and clinics
1.Lack of hygiene and poor sanitation
4. Use of antibiotics in agriculture and livestock
5Global travel and trade (spreading resistant strains)
Delaying the Emergence of Resistance
1) Rational Use of Antimicrobial Agents
2) Use narrow-spectrum antibiotics whenever possible.
3) Newer antibiotics should be reserved for situations in which
older drugs are dangerous or no longer effective.
SELECTION OF
ANTIBIOTICS
Factors to take into consideration:
1) The identity of the infecting organism.
2) Drug sensitivity of the infecting organism
3) Host factors (site of the infection, status of host defenses).
Empiric therapy before completion of lab tests:
it may be necessary to begin treatment in patients
with serious infections BEFORE the lab results.
The minimal inhibitory concentration (MIC) refers to
the lowest concentration of an antibiotic that stops
visible growth.
The zone of inhibition around a disk impregnated with
an antibiotic
Classification of Antimicrobial Drugs
1. Based on basic chemical nucleus
2. Based on the mechanism of action
3. Based on the microorganism susceptibility
4. Based on the type of action
5. Based on the spectrum of activity
6. Based on origin
1. Based on the basic chemical
nucleus
Class- 1 β-Lactam Antibiotics: Contain a β-lactam ring
• Penicillin – Penicillin G, Amoxicillin
• Cephalosporins – Ceftriaxone, Cephalexin
• Carbapenems – Imipenem, Meropenem
• Monobactams – Aztreonam
Class 2. Aminoglycosides: Amino sugars linked by a glycosidic bond
eg: Streptomycin, Gentamicin, Amikacin
Class 3. Tetracyclines: Four fused hydrocarbon rings (tetracyclic)
eg: Tetracycline, Doxycycline, Minocycline
Class 4. Macrolides: Large macrocyclic lactone ring inhibits
eg, Erythromycin, Azithromycin, Clarithromycin
Class5. Glycopeptides: Peptide chains with sugar moieties
•
eg: Vancomycin, Teicoplanin
1. Based on the basic chemical
nucleus
Class-6. Quinolones and Fluoroquinolones: Contain quinoline ring, fluoro group in
fluoroquinolones
eg: Nalidixic acid, Ciprofloxacin, Levofloxacin, Norfloxacin
Class-7. Sulfonamides: Contain sulfonamide (-SO2NH2) group
eg: Sulfamethoxazole, Sulfadiazine, sulfadoxine
Class-8. Nitroimidazoles: Nitrogen-containing imidazole ring
eg: Metronidazole, Tinidazole
Class-9. Lincosamides: Amino acid derivatives with sugar-like structure
• eg, Clindamycin
Class-10. Azoles
e.g, Ketoconazole, itraconazole, miconazole
Class-11. Polyene antibiotics
e.g Nystatin, Amphotericin-B, Hamycin
1. Based on the basic chemical
nucleus
Class-12. polypeptide:
e.g. polymyxin-B, Bacitracin, colistin
Class-13 Nitrobenzene derivatives
eg: chloramphenicol
Class-14: Nicotinic acid derivatives
eg: Isoniazid
Class-15 diaminopyrimidine
• eg, Trimethoprim, pyrimethamine
Class-16 miscellaneous
e.g, Rifampin, ethambutol, pyrazinamide, griseofulvin, spectinomycin
2. Classification By Mechanism Of
Action
• Cass-1: Cell wall synthesis inhibitors
• Class-2: Cytoplasmic membrane
disruption
• Class-3: Protein synthesis inhibitors
• Class-4: Nucleic acid inhibitors
• DNA gyrase inhibitor
• DNA damage
• mRNA inhibitors
• Antimetabolite
• Nucleic Acids analogue
2. Classification By Mechanism Of
Action
Cass-1: Cell wall synthesis inhibitors
1. Sub-class: Beta-lactam
• Penicillin: Penicillin G, Amoxicillin, Cloxacillin
• Cephalosporins: Ceftriaxone, Cephalexin, Cefazolin
• Carbapenems: Imipenem, Meropenem
• Monobactams: Aztreonam
2. Subclass: Glycopeptide: Vancomycin
3. Subclass: Mycolic acid inhibitors: Isoniazid
4. Cyscloserin
5. Echinocandins (antifungal): caspofungin, micafungin, and
anidulafungin
2. Classification By Mechanism Of
Action
Class-2: Cytoplasmic membrane inhibitors- increase the permeability
of the membrane or inhibit the synthesis
Subclass: Membrane synthesis inhibitors
• Azol: ketoconazole, miconazole
• Alkylamines: terbinafine
Subclass: Cause leakage of cell membranes
Ployenes: Nystatin, Amphotericin B, Hamycin
Polypeptides: Polymyxin, Bacitracin
Class-3: Protein synthesis inhibitors
Subclass 1: 30S ribosomal inhibitors
• Tetracycline
• Aminoglycosides
• Subclass 2: 50S ribosomal inhibitors
• Macrolides
• Chloramphenicol
• Clindamycin
Class-4: Nucleic acid inhibitors
Subclass 1 : DNA gyrase inhibitor
Quinolone: nalidixic acid
Fluoroquinolones: ciprofloxacin
Subclass 2: Drugs cause DNA damage: Metronidazole
Subclass 3: mRNA Inhibitors: Rifampicin
Subclass 4: Antimetabolite
Sulfonamides: sulfamethoxazole
DHF reductase inhibitors: Trimethoprim, pyrimethamine
Subclass 5; Nucleic Acids analogues
Acyclovir
Ribavirin
Zidovudine
3. Classification Based on the Microorganism
Susceptibility
1. Antibacterial Egs, beta lactam (penicillin, Cephalosporins,
carbapenems, monobactam), vancomycin, Macrolides, Quinolone
Sulfonamides, tetracycline, aminoglycosides, chloramphenicol,
isoniazid etc
1. Antiviral (Acyclovir, Amantadine, Zidovudine)
1. Antifungal (amphotericin, ketoconazole, griseofulvin)
1. Antiprotozoal:
• Antimalarial: chloroquine, pyrimethamine
• Antileishmanial: sodium stibogluconate
• Antiamoebic: metronidazole
5. Based on the type of action
• Immunocompromised patient, the bacteriostatic drugs are
ineffective
Based on the origin
Subclass 1-Natural Antimicrobials
Tetracycline
From fungi
• Penicillin – Penicillium notatum or Penicillium
chrysogenum
Streptomyces griseus
• Cephalosporin (Cephalosporium acremonium )
• Griseofulvin – Penicillium griseofulvum
Streptomyces aureofaciens
Erythromycin
Streptomyces erythraeus
Chloramphenicol
Streptomyces venezuelae
Rifampin
Streptomyces rifamycinica
Actinomycin D
Streptomyces species
Vancomycin
Streptomyces orientalis
Neomycin
Streptomyces fradiae
From bacteria
Streptomycin
Subclass-2: Semi-Synthetic Antimicrobials
• Amoxicillin, Ampicillin – modified forms of penicillin
• Cefuroxime, Ceftriaxone – modified cephalosporins
• Azithromycin derived from Erythromycin
Subclass-3: Synthetic Antimicrobials
• Sulfonamides
• Fluoroquinolones (e.g., ciprofloxacin)
• Isoniazid
• Metronidazole
• Linezolid
Based on the spectrum
Narrow-Spectrum Antimicrobials
 Active against a limited group of bacteria (either Gram-positive or Gram-negative).
 Advantages: Less disruption to normal flora, lower risk of resistance.
Drug
Spectrum
Target
Penicillin G
Narrow
Mostly Gram-positive bacteria
Vancomycin
Narrow
Gram-positive bacteria (e.g.,
MRSA)
Isoniazid
Very narrow
Mycobacterium tuberculosis
Aztreonam
Narrow
Only Gram-negative aerobes
Based on the spectrum
.Broad-Spectrum Antimicrobials
 Active against both Gram-positive and Gram-negative bacteria.
 Advantages: Useful for empirical therapy when pathogen is unknown.
 Disadvantages: Can disrupt normal microbiota, leading to superinfections (e.g., candidiasis).
 Examples:
Drug
Spectrum
Target
Tetracyclines
Broad
Gram-positive, Gramnegative, atypicals
Chloramphenicol
Broad
Wide range incl. anaerobes
Fluoroquinolones
Broad
Respiratory & urinary
pathogens
Carbapenems
Broad
Very wide range (incl. MDR)
Amoxicillin + clavulanic acid
Broad
β-lactamase-producing
strains
Based on the spectrum
Extended-Spectrum Antimicrobials
 Originally narrow, but chemically modified to cover a wider range.
Drug
Original Class
Extended Activity
Aminopenicillins
Penicillin
Covers some Gram-negative
bacteria
Cephalosporins (high
generation )
Cephalosporins
Broader Gram-negative coverage
Piperacillin
Penicillin derivative
Covers Pseudomonas aeruginosa