Chemotherapy & Antibiotics

Principles of Antimicrobial therapy

• Administer a drug to an infected person that destroys the infective agent without harming the host’s cells

• Antimicrobial drugs are produced naturally or synthetically

Characteristics of the ideal microbial drug

• Selectively toxic to the microbe but nontoxic to host cells

• Microbicidal rather than microbiostatic

• Relatively soluble; functions even when highly diluted in body fluids

• Remains potent long enough to act and is not broken down or excreted prematurely

• Doesn’t lead to the development of antimicrobial resistance

• Complements or assists the activities of the host’s defenses

• Remains active in tissues and body fluids

• Readily delivered to the site of infection

• Reasonably priced

• Does not disrupt the host’s health by causing allergies or predisposing the host to other infections

Chemotherapeutic drug

Any chemical used in the treatment, relief, or prophylaxis of a disease

Prophylaxis

Use of a drug to prevent potential for infection of a person at risk

Antimicrobial chemotherapy

The use of chemotherapeutic drugs to control infection

Antimicrobials

All-inclusive term for any antimicrobial drug, regardless of its origin

Antibiotics

Substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms

Semisynthetic drugs

Drugs that are chemically modified in the laboratory after being isolated from natural sources

Synthetic drugs

Antimicrobial compounds synthesized in the laboratory through chemical reactions

Narrow (limited) spectrum

• Antimicrobials effective against a limited array of microbial types; for example, a drug effective mainly on gram-positive bacteria

• Target a specific cell component that is found only in certain microbes

Broad (extended) spectrum

• Antimicrobials effective against a wide variety of microbial types; for example, a drug effective against both gram-positive and gram-negative bacteria

• Target cell components common to most pathogens (ribosomes)

Origins of antimicrobial drugs

• Antibiotics are common metabolic products of aerobic bacteria and fungi

  • bacteria in genera Streptomyces and Bacillus

  • Molds in genera Panicillium and Cephalosporium

• By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space

Interactions between drug and microbe

• Antimicrobial drugs should be selectively toxic - drugs should kill or inhibit microbial cells without simultaneously damaging host tissues

• As the characteristics of the infectious agent become more similar to the vertebrae host cell, complete selective toxicity becomes more difficult to achieve and more side effects are seen

Antimicrobial drugs that effect the bacterial cell wall

• Most bacterial cell walls contain peptidoglycan

• Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse

• Active on young, growing cells

• Penicillins that do not penetrate the outer membrane and are less effective against gram-negative bacteria

• Broad spectrum penicillins and cephalosorins can cross the cell walls of gram-negative bacteria

Antimicrobial drugs that disrupt cell membrane function

• A cell with a damaged membrane dies from disruption in metabolism or lysis

• These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes

• Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria

• Amphotericin B and nystatin form complexxes with streols on fungal membranes which causes leakage

Drugs that affect Nucleic acid synthesis

• May block synthesis of nucleotides, inhibit replication, or stop transcription

• Chloroquine binds and cross-links the double helix; quinolones inhibit DNA helicases

• Antiviral drugs that are analogs of purines and pyrimidines insert in viral nucleic acid, preventing replication

Drugs that block protein synthesis

• Ribosomes of eukaryotes differ in size and structure from prokaryotes

• Antimicrobics usually have a selective action against prokaryotes

• Can also damage the eukaryotic mitochondria

• Aminoglycosides (Streptomycin, gentamycin) insert on sites on the 30S subunit and cause misreading of mRNA

• Tetracyclines block attachment of tRNA on the A acceptor site and stop further synthesis

Drugs that affect metabolic pathways

• Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis

• Competitive inhibition - drug competes with normal substrate for enzyme’s active site

• Synergistic effect - the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics

Major Antimicrobial drug groups

• Antibacterial drugs

  • Antibiotics

  • Synthetic drugs

• Antifungal drugs

• Antiprotozoan drugs

• Antiviral drugs

• About 260 different antimicrobial drugs are classified into 20 drug families

Antibacterial drugs that act on the cell wall

• Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring

• Primary mode of action is to interfere with cell wall synthesis

• Greater than ½ of all antimicrobic drugs are beta-lactams

• Penicillins and cephalosporins most prominent beta-lactams

Penicillin and its relatives

• Large diverse group of compounds

• Could be synthesized in labratory

• More economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic forms

• All consist of three parts:

  • Thiazolidine ring

  • Beta-lactam ring

  • Variable side chain dictating microbial activity

Subgroups and uses of penicillin

• Penicillins G and V most important in natural forms

• Penicillin is the drug of choice for gram-positive cocci (streptococci) and some gram-negative bacteria (meningococci and syphilis spirochete)

• Semisynthetic penicillins - ampicillin, carbencillin, and amoxicillin have broader spectra - gram-negative infections

• Penicillinase-resistant - methicillin, nafcillin, cloxacillin

• Primary problems - allergies and resistant strains of bacteria

Cephalosoprins

• Account for one-third of all antibiotics administered

• Synthetically altered beta-lactam structure

• Relatively broad-spectrum, resistant to most penicillinases, and cause fewer allergic reactions

• Some are given orally; many must be administered parenterally

• Generic names have root - cef, ceph, or kef

Generations of Cephalosporins

• 4 generations exist: each group more effective against gram-negatives than the one before with improved dosing schedule and fewer side effects

• First generation

  • cephalothin, cefazolin

  • msoteffective against gram-positive cocci and few gram-negative

• Second generation

  • cefaclor, cefonacid

  • most effective against gram-negative bacteria

• Third generation

  • cephalexin, ceftriaxone

  • broad-spectrum activity against enteric bacteria with beta-lactamases

• Fourth generation

  • cefepime

  • Widest range

  • Both gram-negative and gram-positive

Non Beta-lactam cell wall inhibitors

• Vancomycin

  • narrow-spectrum

  • Most effective in treatment of Staphylococcal infections in cases of penicillin and methicillin resistance or if patient is allergic to penicillin

  • Toxic and hard to administer

  • Restricted use

• Bacitracin

  • narrow-spectrum

  • Produced by a strain of Bacillus subtilis

  • Used topically in ointment

• Isoniazid (INH)

  • works by interfering with mycolic acid synthesis

  • Used to treat infections with Mycobacterium tuberculosis

Antibiotics that damage bacterial cell membranes

• Polymixins

  • narrow-spectrum

  • Peptide antibiotics with a unique fatty acid component

  • Treat drug resistant Pseudomonas aeruginosa and severe UTI

Drugs that act on DNA or RNA

• Fluoroquinolones

  • Work by binding to DNA gyrase and topoisomerase IV

  • Broad spectrum effectiveness

• Concerns have arisen regarding the overuse of quinoline drugs

  • CDC is recommending careful monitoring of their use to prevent ciprofloxacin - resistant bacteria

Drugs that interfere with protein synthesis

• Aminoglycosides

  • Composed of one or more amino sugars and an aminocyclitol (6C0 ring)

  • Binds ribosomal subunit

  • Products of various species of soil actinomycetes in genera Streptomyces and Micromonospora

  • Broad-spectrum

  • Inhibit protein synthesis

  • Especially useful against aerobic gram-negative rods and certain gram-positive bacteria

    • Streptomycin - bubonic plague, tularemia, TB

    • Gentamicin - less toxic, used against gram-negative rods

    • Newer - tobramycin and amikacin gram-negative bacteria

Tetracycline Antibiotics

• Broad-spectrum

• Block protein synthesis by binding ribosomes

• Treatment for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne, and protozoa

• Generic tetracycline is low in cost but limited by its side effects

Chloramphenicol

• Potent broad-spectrum drug with unique nitrobenzene structure

• Blocks peptide bond formation and protein synthesis

• Entirely synthesized through chemical processes

• Very toxic, restricted uses, can cause irreversible damage to bone marrow

• Typhoid fever, brain abscesses, rickettsial, and chlamydial infections

Macrolides and related antibiotics

• Erthromycin

  • Large lactone ring with sugars

  • Attaches to ribosomal 50S subunit

• Broad-spectrum, fairly low toxicity

• Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diphtheria, and as a prophylactic prior to intestinal surgery

• For penicillin-resistant - gonococci, syphilis, acne

• Newer semi-synthetic macrolides - clarithromycin, azithromycin

Drugs that block metabolic pathways

• Most are synthetic

• Most are important sulfonamides, or sulfa drugs - first antimicrobic drugs

• Narrow-spectrum

• Block the synthesis of folic acid by bacteria

  • Sulfisoxazole - shigellosis, UTI, protozoan infections

  • Silver sulfadiazine - burns, eye infections

  • Trimethoprim - given in combination with sulfamethoxazole - UTI, PCP

Agents to treat fungal infections

• Fungal cells are eukaryotic - a drug that is toxic to fungal cells is also toxic to human cells

• Five antifungal groups:

  • Macrolide polyene

    • Amphotericin B - mimic lipids, most versatile and effective, topical and systemic treatments

    • Nystatin - topical treatment

Antiviral Chemotherapeutic Agents

• Selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses

• Block penetration into host cell

• Block replication, transcription, or translation of viral genetic material

  • Nucleotide analods

    • Acyclovir - herpesvirus

    • Ribavirin - a guanine analog - RSV, hemorrhagic fevers

    • AZT - thymine analog - HIV

• Prevent maturation of viral particles

  • Protease inhibitors - HIV

Anitherpes drugs

• Many antiviral agents mimic the structure of nucleotides and compete for sites on replicating DNA

  • Acyclovir (Zovirax), Valacycovi r(Valtrex), Famiciclovir (Famvir), Peniciclovir (Denavir)

  • Oral and topical treatments for oral and genital herpes, chickenpox, and shingles

Drugs for treating HIV infections and AIDS

• Retrovirus offers 2 targets for chemotherapy:

  • Interference with viral DNA synthesis from viral RNA using nucleoside reverse transcriptase inhibitors (nucleotide analogs)

  • Interference with synthesis of DNA using nonnucleoside reverse transcriptase inhibitors

• Azidothymidine (AZT) - first drug aimed at treating AIDS, thymine analog

The acquisition of drug resistance

• Adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory

• Due to genetic versatility or variation

• Intrinsic and acquired

• Two ways:

  • Spontaneous mutations in critical chromosomal genes

  • Acquisition of new genes or sets of gene via transfer form another species

    • Originates form resistance factors (plasmids) encoded with drug resistance, transposons

Natural selection and drug resistance

• Large populations of microbes likely to include drug resistant cells due to prior mutations or transfer of plasmids - no growth advantage until exposed to drug

• If exposed, sensitive cells are inhibited or destroyed while resistance cells will survive and proliferate

• Eventually population will be resistant - natural selection

Interactions between drug and host

• Estimate that 5% of all persons taking antimicrobials will experience a serious adverse reaction to the drug - side effects

• Major side effects:

  • Direct damage to tissue due to toxicity of drug

  • Allergic reactions

  • Disruption in the balance of normal flora-superinfections possible

Considerations in selecting an antimicrobial drug

• Identify the microorganism causing the infection

  • Identification of infectious agent should be attempted as soon as possible

  • Specimens should be taken before antimicrobials are initiated

• Test the microorganism’s susceptibility to various drugs in vitro when indicated

  • Essential for groups of bacteria commonly showing resistance

    • Kirby-Bauer disk diffusion test

    • E-test diffusion test

    • Dilution test

      • Minimum inhibitory concentration (MIC) - smallest concentration of drug that visible inhibits growth

• The overall medical condition of the patient

The MIC and therapeutic index

• In vitro activity of a drug is not always correlated with in vivo effect

  • If therapy fails, a different drug, combination of drugs, or different administration must be considered

• Best to chose a drug with highest level of selectivity but lowest level toxicity - measured by therapeutic index - the ratio of the does of the drug that is toxic to humans as compared to its minimum effective dose

• High index is desirable