Lecture 01.2014

MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS

Lecture one

Dr. G. Kattam Maiyoh

01/23/15 1GKM/KISIIU/MBSM713

/BIOC.AMIC.AGENS.LEC01

Importance of Microbes

• Life is microbial! (to the first approximation)– Micro-organisms colonise every

environment on earth– >80% of life’s history was bacterial

– You have more bacterial cells than human cells (10x more)

– Microbes play a key role in the biosphere

– Pathogenic microbes globally are the most important cause of human disease and death

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Importance of Infection• Has played a decisive role in history• Still major cause of death and misery worldwide• Examples of public anxieties

– Meningitis, Food poisoning– Mad cow disease– HIV

– Cholera– Emerging infections e.g. Ebola, swine flu– Hospital Infection (Nosocomial infections)

• Antibiotic-Resistant Superbugs


What are Antimicrobials???• Antimicrobials are drugs that destroy microbes,

prevent their multiplication or growth, or prevent their pathogenic action

– Differ in their physical, chemical, and pharmacological properties

– Differ in antimicrobial spectrum of activity

– Differ in their mechanism of action


• It is chosen so that it kills the desired microbes only, but not the cells in your (host) body.

• Each different type of antibiotic affects different bacteria in different ways.

• For example, an antimicrobial might inhibit a microbe’s ability to turn glucose into energy, or its ability to construct its cell wall.

• Therefore the microbe dies instead of reproducing.


It is a selective poison

Classification of Antimicrobials

• Based against the target organism– Antibacterial (antibiotics)– Antifungal– Antiviral– Antiprotozoan– Antihelminthics


History of Antimicrobials

• Mostly on antibiotics• (anti, "against"; bios, "life") An antibiotic is a

chemical substance produced by one organism that is destructive to another.

• The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's student Paul Vuillemin which means a process by which life could be used to destroy life.


Ancient History• The ancient Egyptians, the Chinese, and

Indians of central America all used molds to treat infected wounds.

• However, they did not understand the connection of the antibacterial properties of mold and the treatment of diseases.

Mould


Late 1800s• The search for antibiotics began in the late

1800s, with the growing acceptance of the germ theory of disease, a theory which linked bacteria and other microbes to the causation of a variety of ailments.

• As a result, scientists began to devote time to searching for drugs that would kill these disease-causing bacteria.


1871• The surgeon Joseph Lister, began researching the

phenomenon that urine contaminated with mold would not allow the successful growth of bacteria.

1890s• German doctors, Rudolf Emmerich and Oscar Low were

the first to make an effective medication that they called pyocyanase from microbes.

• It was the first antibiotic to be used in hospitals. However, the drug often did not work

• Learning check – why do you think the drug did not work some of the time?


1928: Fleming and Penicillin

Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be destroyed by the mold Penicillium notatum, demonstrating antibacterial properties.


1935- the first sulfa drug discovered

•German pathologist and bacteriologist Credited with the discovery of Sulfonamidochrysoidine (KI-730) – the first commercially available antibacterial antibiotic (marketed under the brand name Prontosil)

•1939 Nobel Prize in Physiology/ Medicine

Gerhard Domagk (1895–1964).


•1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin.

•1942•Invented manufacturing process for Penicillin G Procaine.

•Penicillin could now be sold as a drug.

•Fleming, Florey, and Chain shared the 1945 Nobel Prize for medicine for their work on penicillin.

Howard Florey (1898–1968)


Penicillin in summary• Penicillin was isolated in 1939.

• Concerted effort by a number of scientists;

• Originally noticed by a French medical student, Ernest Duchesne, in 1896

• Re-discovered by bacteriologist Alexander Fleming – Published investigations in 1929

• Dorothy discoved the molecular layout of penicillin – used x-rays

• 1939 Dr. Howard Florey demonstrate penicillin's ability to kill infectious bacteria.

• 1940_____________________________• 1942 _____________________________


1943•American microbiologist made the drug streptomycin from soil bacteria, the first of a new class of drugs called aminoglycosides.

•Streptomycin could treat diseases like tuberculosis, however;•The side effects were often too severe.

Selman Waksman (1888–1973)


1955Tetracycline was patented by Lloyd Conover, which became the most prescribed broad spectrum antibiotic in the United States.

1957•Nystatin was patented and used to cure many disfiguring and disabling fungal infections.

•Invented by Elizabeth Lee Hazen and Rachel Fuller Brown

•Researchers for the New York Department of Health


1981

•SmithKline Beecham patented Amoxicillin or moxicillin/clavulanate potassium tablets.

•First sold the antibiotic in 1998 under the trade names of Amoxicillin, Amoxil, and Trimox.

•Amoxicillin is a semisynthetic antibiotic.


Definitions• Chemotherapy The use of drugs to treat a

disease

• Antimicrobial drugs Interfere with the growth of microbes within a host

• Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe

• Selective toxicity A drug’s ability to kills harmful microbes without damaging the host

• Bacteriostatic/ Modes of action that either kill or

bacteriocidal inhibit growth of bacteria

• Spectrum of activity Range of effect within or between groups of microbes; narrow vs. broad-spectrum01/23/15 19GKM/KISIIU/MBSM713


Static vs. Cidal•The graphs show the growth curves for a

bacterium treated with two drugs.

•The upper curve shows the activity of a

bacteriostatic drug.

•The bacterial growth resumes when the

drug is withdrawn.

•The cidal drug, shown in the lower graph,

kills bacteria from the time of administration

to the culture.

• Penicillins, aminoglycoside, vanconmycin, bacitracin , the polymyxin, and colistin are bactericidal.

• Tetracyline , Fusidic acid , Macrolides, Sulfonamides and sulfones on the other hand, are bacteriostatic.


Classification of Antibiotics

• Bacteriostatic vs. Bactericidal


Principles of antimicrobial use!

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1. Identification of the Infective Organisms1. Identification of the Infective Organisms

History taking

Physical examination

Laboratory


History TakingHistory Taking

• Duration of fever

• Associated symptoms: Systematic review

• History of treatment

• Underlying diseases and Medication

• Occupation• Living place

• Traveling• Pets• Vaccination

and drug prophylaxis

• Illness in family

• Diseases outbreak

• Food consumption


Physical ExaminationPhysical Examination


Physical ExaminationPhysical Examination


Laboratory Investigation in the Diagnosis of Infectious AgentsLaboratory Investigation in the Diagnosis of Infectious Agents

Mandell, Douglas, and Bennett’s Principle and Practice of Infectious Diseases01/23/15 27GKM/KISIIU/MBSM713


2) Antimicrobial susceptibility

– Appropriate specimen collection and transport

– Disk diffusion susceptibility testing– Minimal inhibitory

concentration (MIC)


Underlying diseasesDrug allergyPregnancy/Breast feedingAgeGenetic or Metabolic abnormalitiesSites of infectionImmune statusHepatic and renal function

3) Determine host Factors3) Determine host Factors


4) Antimicrobial Factors4) Antimicrobial Factors

Spectrum

Mechanisms of action

Pharmacokinetic

Pharmacodynamic

Drug interaction

Side effect

Drug monitoring


Indications for Antimicrobial Indications for Antimicrobial Combinations TherapyCombinations Therapy

Prevention of the emergence of resistant organisms

Polymicrobial infections

Empirical therapy

As narrow as possible, as broad as necessary

Synergistic/Additive activity01/23/15 31GKM/KISIIU/MBSM713


Disadvantages of Inappropriate Use of Disadvantages of Inappropriate Use of Antimicrobial CombinationsAntimicrobial Combinations

Antagonism

Superinfection

Cost

Adverse effects


Reasons for Treatment FailureReasons for Treatment Failure

Delay in diagnosis or therapyWrong or incomplete diagnosis

No infectionNonbacterial infection (for antibiotics)Polymicrobial infection

Errors in susceptibility testingDecreased activity at site of infection

Chemical factor (pH and others)Antibiotic antagonism


Inadequate concentration of antibiotic at the site of infection

Improper doseDecreased absorption from food or drug interactionIncreased elimination of agentHigh protein bindingPoor delivery (eg. shock, vascular diseases)




Impaired immune defensesDevelopment of drug resistanceSuperinfectionOther host factors

Necrotic tissueForeign body


A major cause of antimicrobial overuse is “treatment”

of contaminated cultures or colonization.

Use Antimicrobials WiselyUse Antimicrobials Wisely

Treat infection, NOT contamination or colonization

Use local dataKnow your local antibiogramKnow your patient population

Not all infections need antimicrobial therapyhttp://www.cdc.gov


• When infection is cured

• When cultures are negative and infection is unlikely

• When infection is not diagnosed

Use Antimicrobials Use Antimicrobials WiselyWisely Stop antimicrobial treatment

http://www.cdc.gov01/23/15 37GKM/KISIIU/MBSM713


Mechanisms of Action of Antibacterials

– Protein synthesis inhibitors

– Cell wall synthesis inhibitors

– Plasma membrane-injuring agents

– Nucleic acid inhibitors

– Metabolic/enzyme inhibitors


The Action of Antimicrobial Drugs

Figure 20.201/23/15 39GKM/KISIIU/MBSM713


Protein Synthesis Inhibitors






• Penicillins– Natural penicillins: G, V

– Semisynthetic penicillins• “-cillin “ suffix• Carbapenems• Monobactam

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: e.g Penicilins


Penicillins



• Cephalosporins– 2nd, 3rd, and 4th

generations more effective against gram-negatives

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Cephalosporins



• Polypeptide antibiotics– Bacitracin

• Topical application

• Against gram-positives

– Vancomycin• Glycopeptide• Important "last line"

against antibiotic resistant S. aureus (e.g. MRSA)

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Polypeptides


• Antimycobacterium antibiotics– Isoniazid (INH)

• Inhibits mycolic acid synthesis

– Ethambutol• Inhibits incorporation of mycolic acid

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Anti-Mycobacterials





• Polymyxin B– Topical– Combined with bacitracin and neomycin in over-

the-counter preparation

Antibacterial Antibiotics Injury to the Plasma Membrane





• Rifamycin– Inhibits RNA synthesis by RNA polymerase– Antituberculosis

• Quinolones and fluoroquinolones– Ciprofloxacin– Inhibits DNA gyrase so blocks DNA polymerase– Urinary tract infections

Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis





– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis• Broad spectrum

Antibacterial Antibiotics Competitive Inhibitors



Figure 20.13

TMZ - Trimethoprim + Sulfamethoxazole: Synergism


Thank for your attention

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Health & Medicine

Lecture 01.2014