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