ANTIMICROBIAL THERAPY

GOAL OF ANTIMICROBIAL THERAPY

ADMINISTER A DRUG TO AN INFECTED PERSON THAT DESTROYS THE

INFECTIVE AGENT WITHOUT HARMING THE

HOST’S CELLS

CHARACTERISTICS OF AN IDEAL ANTIMICROBIAL DRUG

• Selectively toxic to the microbe• Microbicidal• Relatively soluble and functions even

when highly diluted in body fluids• Remains potent long enough to act

and is not broken down or excreted prematurely

• Not subject to the development of resistance

CHARACTERISTICS OF AN IDEAL ANTIMICROBIAL DRUG

• Complements or assists the body’s defenses

• Remains active in tissues or body fluids

• Readily delivered to the site of infection

• Not excessive in cost• Does not disrupt the host’s health

DEFINITION OF TERMS

• PROPHYLAXIS– Use of a drug to prevent imminent

infection of a person at risk• NARROW SPECTRUM– Antimicrobics effective against a limited

array of microbial types• BROAD SPECTRUM– Antimicrobics effective against a wide

variety of microbial types

ANTIMICROBIAL MECHANISM OF ACTION

ANTIMICROBIAL MECHANISM OF ACTION

CELL WALL INHIBITORS

• Act by causing to produce weak or incomplete cell walls that make the cell osmotically fragile, thus are –cidal drugs

CELL WALL INHIBITORS: REPRESENTATIVES PENICILLINS

AND CEPHALOSPORINS• Beta-lactams• Act by binding and

blocking the enzyme that cross-links the sugar molecules of the peptidoglycan complex interrupting completion of the cell wall

PENICILLIN DRUG PROFILE

DRUG MICROBES AFFECTED

Penicillin V & G Streptococci, Meningococci, Gram + and spirochetes

Oxacillin & Cloxacillin

Staphylococcal Infection

Ampicillin & Amoxicillin

Pen G + enterococci, Listeria, E. Coli, H. influenzae

Piperacillin Gram – rods including Pseudomonas

CEPHALOSPORIN DRUG PROFILE• 1st Generation

Cephalosporins– Cefazolin– Cephalexin– Effective against

Streptococci, and Staphylococci as well as E coli and Klebsiella pneumoniae

CEPHALOSPORIN DRUG PROFILE• 2nd Generation

Cephalosporins– Cefuroxime– Cefaclor– Effective for

Bacteroides fragilis and H influenzae

CEPHALOSPORIN DRUG PROFILE• 3rd Generation

Cephalosporins– Ceftazidime– Cefoperazone– Cefotaxime– With increased gram

negative coverage and can penetrate the blood brain barrier

– Active versus: H influenzae, Neisseria, Pseudomonas (ceftazidime)

CEPHALOSPORIN DRUG PROFILE• 4th Generation Cephalosporins– Cefepime– Combines the gram positive active of 1st

generation cephalosporins and a wider gram negative coverage compared with the 3rd generation

PENICILLIN AND CEPHALOSPORIN SIDE-EFFECTS

CELL WALL INHIBITORS: REPRESENTATIVES

VANCOMYCIN• Hinders the elongation of

the peptidoglycan structural complex

• Is one of the “last-resort” drugs used when resistance to all possible drugs against gram-positive bacteria

• Has no activity versus gram negative bacteria

• Is not absorbed orally and is given IV

• ADR: Chills, fever, phlebitis, oto- and nephrotoxicity– RED-MAN SYNDROME

ANTIMICROBIAL MECHANISM OF ACTION

PROTEIN SYNTHESIS INHIBITORS

• Inhibit translation by reacting with the ribosome-mRNA complex– TARGETS MAY

EITHER BE the 50S or 30S subunits

• Inhibitors at 50S Subunit– Chloramphenicol– Macrolides

• Inhibitors at 30S Subunit– Aminoglycosides– Tetracyclines

AMINOGLYCOSIDES• Irreversibly binds on

sites on the 30S subunit and cause misreading of mRNA leading to abnormal proteins

• Are bactericidal and effective against gram-negative organisms

• EXAMPLES: Streptomycin, gentamycin

• ADR: Oto- and nephrotoxic

TETRACYCLINE• Reversibly binds to the

30S subunit and distorting it in such a way that the anticodons of the charged tRNAs cannot align properly with the codons of the mRNA

• Broad spectrum and bacteriostatic

• Effective against Yersinia, Legionella, Mycoplasma

• ADR: Gastrointestinal disruption

CHLORAMPHENICOL

• A broad-spectrum drug that binds to the 50S subunit of the bacterial ribosome

• Is bacteriostatic and has good blood-brain barrier penetration

• Used for typhoid fever, brain abscesses

• ADR: aplastic anemia

MACROLIDES

• Act by binding to a receptor site at the 50S subunit preventing movement of the tRNA from one site to another

• Effective against Mycoplasma, Corynebacterium, Legionella, B. pertussis, gram-positive cocci

• Require less frequent dosing• EXAMPLES: Erythromycin, Azithromycin

and Clarithromycin• ADR: Gastrointestinal Irritation, Skin

rashes

MACROLIDES

ANTIMICROBIAL MECHANISM OF ACTION

DNA SYNTHESIS INHIBITORS: SULFA DRUGS AND

TRIMETHOPRIM• Act by competitive

inhibition, preventing the normal substrate of the enzyme to attach to the enzyme: In Folic Acid Synthesis

• Act synergistically• Sulfonamides and

Trimethoprim• Does not affect humans• Bacteriostatic• For UTI against Gram -

infections

DNA SYNTHESIS INHIBITORS:QUINOLONES

• Drugs that prevent DNA unwinding thus preventing DNA transcription

• Prevents supercoiling causing bacterial cells to unwind and burst

• Includes: Ciprofloxacin, Norfloxacin and Ofloxacin

• Act on both gram-positive and gram-negative bacteria

• ADR: Seizures and brain disturbances; cartilage det.

DNA SYNTHESIS INHIBITORS:RIFAMPIN

• Selectively inactivates the RNA polymerase

• mRNA synthesis is prevented

ANTIMICROBIAL MECHANISM OF ACTION

CELL MEMBRANE DISRUPTORS: POLYMIXINS

• Damages the cell membranes by interacting with membrane phospholipids, distorting the cell surface, causing leaking of proteins and other products.

• Effective against gram-negative bacteria

ANTIFUNGAL CHEMOTHERAPY

ANTIFUNGAL DRUGS

• Due to eukaryotic nature of fungi, treatment of fungal infections present special problems – Drugs effective against bacteria are

generally ineffective against fungi– Antifungals are often toxic to human

cells as well.

MECHANISMS OF ACTION

POLYENES

POLYENES

• Bind to fungal membranes causing loss of selective permeability

• Amphotericin B – the most versatile and effective of antifungals but is nephrotoxic

FLUCYTOSINE

FLUCYTOSINE

• An analog of cytosine which prevents attachment of normal cytosine during DNA and RNA synthesis.

• Used to treat cutaneous mycoses• When with amphotericin B, can be

used to effectively treat systemic mycoses

AZOLES

AZOLES

• Broad-spectrum anti-fungals that interrupt the synthesis of sterols which are components of the cell membrane

• Includes: Ketoconazole, Miconazole, Cotrimazole, for cutaneous mycoses

ANTIVIRAL CHEMOTHERAPY

ANTIVIRAL CHEMOTHERAPY

INHIBITION OF VIRUS ENTRY

• Fuzeon is a drug that prevents HIV infection by preventing HIV virus binding

• Amantadine prevents influenza virus fusion and uncoating

INHIBITION OF NUCLEIC ACID SYNTHESIS

• Acyclovir inactivates herpesvirus DNA polymerase preventing DNA replication

• Nucleoside and Non-nucleoside RT inhibitors stop the action of HIV RT

INHIBITION OF VIRUS ASSEMBLY/RELEASE

• Protease inhibitors insert into HIV protease resulting in the formation of a noninfectious virus

ANTIMICROBIAL RESISTANCE

HOW RESISTANCE OCCURS

MECHANISMS OF RESISTANCE

DRUG SUSCEPTIBILITY TESTING

FACTORS IN SELECTING THE PROPER ANTIMICROBIC DRUG• The Nature of

ORGANISM causing the INFECTION

• Though clinical experience may prompt empiric treatment, it is best to identify the infectious agent from body specimens like blood, stool, urine, etc.

FACTORS IN SELECTING THE PROPER ANTIMICROBIC DRUG• OVERALL

CONDITION of the Patient

• It is important to know the condition of the patient; weigh advantages and disadvantages of giving the drug, its benefits and adverse effects

FACTORS IN SELECTING THE PROPER ANTIMICROBIC DRUG• Determining the

DEGREE of SUSCEPTIBILITY of the ORGANISM to various DRUGS

• Testing is important for groups that have shown patterns of resistance to antibiotic therapy like:– Staphylococcus– Neisseria– Streptococcus

• More feasible in bacterial therapy

TERMS

• Minimum Inhibitory Concentration:– The smallest concentration of a drug

that visibly inhibits growth of microbes

• THERAPEUTIC INDEX– The ratio of the dose of the drug that is

toxic to humans as compared to its minimum inhibitory/effective dose (TI = Toxic dose / MIC)

ANTIBIOTIC SUSCEPTIBILITY TESTING

• Done by exposing a pure culture of the bacterium to several drugs and observing for effects.

• Kirby-Bauer method is a diffusion test that measures the zone of inhibition due to a drug when given to a pure culture on agar.

• E-Test: An alternative to the Kirby-Bauer method, uses a gradient strip

TREATMENT FAILURE

• Failure may be due to:– Inability of the drug to diffuse into the

target body compartment– A few resistant cells in the culture that

did not appear on sensitivity testing– An infection caused by more than one

pathogen, some of which are resistant to the drug