INTRODUCTION TO ANTIMICROBIAL DRUGS
Copyright: Purdue Research Foundation, 1996
| BMS 445 Intro |
| Drug Groups |
| E-mail |
| Full Text |
| Slides/Graphics |
Main Topics
- Treatment hopeless before 1935
- Increasing resistance to standard antibacterials
- Paul Ehrlich, early 20th century
Father of chemotherapy
- Domagk -- 1930s: - Prontosil --> sulfanilamde
Prontosil -- a prodrug
- Fleming -- 1929 -- Penicillin discovered -- gram positives
- FLorey -- 1940 -- Penicillin -- first therapeutic use
- Waksman -- 1944 -- Streptomycin -- gram negatives
- 1947 -- Chloramphenicol -- broad spectrum
- 1948 -- Chlortetracycline -- broad spectrum
- Chemotherapeutic agent
- Pharmacodynamic agent
- Antibiotics can have following activities
- antibacterial
- antifungal
- antiviral
- antiparasitic
- anticancer
- Antimicrobial / Antibacterial
- Antiseptic
- Disinfectant
- Molds or fungi
e.g., Streptomyces spp., Penicillium spp.
- Bacteria
e.g., Bacillus spp.
- Synthetic or semisynthetic
[ Drug Listings ]
- Beta-lactam antibiotics
- Penicillins: derivatives of 6-aminopenicillanic acid. e.g., penicillin G
- Cephalosporins: derivatives of 7-aminocephalosporanic acid, e.g., cephalexin
- Macrolides: have a large ring structure. Sometimes referred
to as the "erythromycins." e.g.,
- Lincosamides: name derived from the first member found, e.g., lincomycin
- Aminoglycosides: composed of aminosugars linked by glycosidic
bonds to various bases. e.g., gentamicin
- Tetracyclines: have a rigid structure composed of 4 fused
benzene-like rings. e.g., tetracycline.
- Polypeptides: as the name says, aminoacids linked by peptide
bonds form a major component of the structure. e.g., vancomycin,
- Sulfonamides: derived from sulfanilamide, the first successful
antibacterial, e.g., sulfadiazine. Trimethoprim is
used to "potentiate" the sulfonamides.
- Fluoroquinolones: e.g., enrofloxacin (BAYTRIL)
- Miscellaneous: includes many drugs, such as chloramphenicol,
nitrofurantoin, and isoniazid that have only one or two representatives
of the class and are seldom referred to by their chemical nature
in clinical practice. Antituberculosis and antileprosy drugs belong to one
or more of the classes listed here, including miscellaneous.
- cell wall synthesis
- protein synthesis
- cytoplasmic membrane permeability
- nucleic acid ynthesis
- antimetabolic
- Definition of resistance
- Importance of location of organism
- MIC
- MBC
- Clinical Spectrum
- Broad Spectrum
- Gram positive
- Gram negative
- Rickettsia
- Mycoplasmas
- Penicillinase producing staphylococci
- Pseudomonas
- Protozoans
- etc.
- Cidal -- bactericidal
- Static -- bacteriostatic
Predictable:
- Human pathogens
- penumococci, gonococci, meningococci, and Haemophilus influenzae
- Animal pathogens
- Streptococcus agalactiae
- Streptococcus equi,
- any beta hemolytic streptococci
- Actinomyces pyogenes
Fairly unpredictable -- Senstivity tests advised
- staphylococci
- enterococci
- Escherichia coli
- Klebsiella spp.
- Pseudomonas aeruginosa
- Pasteurella haemolytica
- Proteus spp.
Antimicrobials may be ineffective against bacteria because of resistance that is
- Natural resistance is chromosomally mediated and is predictable
- Resistance Transfer Factor (RTF)
codon resembles that for F-pilus
- Resistance Factor (RF)
- Multiple Resistance
Basic biochemical mechanisms of resistance include:
INACTIVATION OF DRUG:
| biochemical mechanisms of resistance |
- Enzymatic alteration of drug --
Beta-lactams
Aminoglycosides
- Protection of other organisms -- Beta-lactamases from Staph
DECREASED ACCUMULATION:
| biochemical mechanisms of resistance |
Decreased intracellular accumulation
- Decreased penetration
- Increased removal
DECREASED AFFINITY / BINDING:
| biochemical mechanisms of resistance |
- Change in binding site so affinity for drug is lower
- Methicillin resistant staphylococci -- change in PBPs
- Streptomycin -- change of one amino acid
METABOLIC BY-PASS
| biochemical mechanisms of resistance |
- Increased amount of enzyme
- Trimethoprim -- increased DHF reductase
- Alternate pathway
Adverse effects of antimicrobials may be divided into three broad
categories:
- Beta-lactams
- more likely with parenteral than oral administration
- shift to different family of drugs
- Alteration of normal flora
- Skin
- Mucous membranes
- Gastrointestinal tract
- Reproductive tract
- Likely pathogens
- yeasts
- Clostridium difficile
- Superinfection / Suprainfection
- Antibiotic Associated Enterocolitis
- ACCESS!!
- ampicillin, tetracyclines, LINCOMYCIN, and
other broad spectrum antibacterials
- spectrum -- broad, effective against anaerobes
- also called Antibiotic Associated Pseudomembranous Enterocolitis (AAPE)
- Life threatening
- Respiratory paralysis -- neuromuscular paralysis -- aminoglycosides
- Severe
- Hearing loss (ototoxicity)-- aminoglycosides
- Nephrotoxicosis -- proximal tubular cells -- aminoglycosides
- Nephrotoxicosi -- tubular crystal formation -- Sulfonamides
- Decreased immune function -- many antibiotics
- Bone / tooth malformation -- tetracyclines
- Antibody production inhibited by -- amphotericin B, cefoxitin, doxycycline,
rifampin, cefotaxime, chloramphenicol, moxalactam, and trimethoprim-sulfamethoxazole.
- Microbiocidal activity impaired by -- amikacin,
cephalothin, gentamicin, sulfonamides, tetracycline, and tobramycin.
- Unpleasant
- Mild abdominal discomfort / pain -- erythromycin
- Dizziness -- minocycline
- Mild vomiting
- Loose stools to mild diarrhea
- Tooth discoloaration -- tetracyclines
- Godber, L.M., Walker, R.D., Stein, G.E., Hauptman, J.G., and
Derksen, F.J.: 1995. Pharmacokinetics, nephrotoxicosis, and in
vitro antibacterial activity associated with single versus multiple
(three times) daily gentamicin treatments in horses. Am. J. Vet.
Res. 56(5):613-618. important new concepts in this paper for
both medical and veterinary students. Good references, too. Also,
other papers in notebook that should be added. 5/31/95. NOT YET
ADDED TO THESE NOTES...
- You should be able to differentiate the terms antibiotic and
antimicrobial and other terms directed at specific types
of pathogens.
- What is the difference between the biochemical mechanisms OF resistance
to antimicrobials and the mechanisms by which organisms BECOME
resistant to drugs? You should be able to discuss both and to
assign an example to the appropriate category.
- Why do organisms that are variably sensitive to antimicrobials
present more of a problem to therapists than those that are consistently
sensitive?
- Why is R-factor transferred resistance of great concern to
the profession and public health officials? What ramifications does this have for
how one should use antibacterials?
- Why is it believed by some authorities that knowledge of categories of
drugs, e.g., aminoglycosides or sulfonamides, is of value?