Microbiology & Parasitology: Antimicrobial Therapy

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 grampositive 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 ribosomemRNA 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 gramnegative 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 bloodbrain 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

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• • • • •

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 antifungals 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 Nonnucleoside 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