 Germicidal activity increases with increasing chain length (5-8 carbons)

 Most commonly used – ethanol and isopropanol

 No activity against spores

 Activity is more active in the presence of water hence 70% alcohol is more active than 95% alcohol.

 Common disinfectants used for skin surfaces

 Extremely effective when followed by treatment with iodophor

VII- Heavy metals

Soluble salts of Hg (mercury), arsenic, silver and other heavy metals

By forming mercaptides with sulfhydryl groups of cysteine residue

It examples as mercurials – merthiolate, mercurochrome

On the other hand the silver compounds – irritant and caustic effect; silver nitrate (propylaxis); sulfadiazine

cream, colloidal silver compounds used in ophthalmology.

 Antimicrobial agents Chemotherapy: The use of drugs to

treat a disease

 Antimicrobial drugs: Interfere with the growth of microbes within a host

 Antibiotic: It is of biological origin and Produced by a microbe, in order to inhibits other microbes

 Chemotherapeutic agent: synthetic chemicals

 Selective toxicity: Drug kills pathogens without damaging the host

 Therapeutic index: ratio between toxic dose and therapeutic dose or ratio of LD50 (lethal) to ED50

(effective).

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 Antimicrobial action – either Bacteriostatic (which inhibit microbes without destruction) or

bactericidal (destruct microbes and lyses them)

 Some factors effect antibiotics action in our body like:

Tissue distribution, metabolism, and excretion, passage through blood brain barriers (BBB); Unstable in

acid; half-life duration or it shelf life.

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Lecture Two

Selection of antibiotics

Factors to take into consideration:

 The identity of the infecting organism.

 Drug sensitivity of the infecting organism

 Host factors (i.e. site of the infection, status of host defenses).

 Empiric therapy prior to completion of lab tests: it may be necessary to begin treatment in

patients with serious infections BEFORE the lab results.

 Take samples for culture PRIOR TO INITIATION of treatment

HOST FACTORS

 Host defenses (immune system and phagocytic cells).

 Site of infection .To be effective an antibiotic must be present in the site of infection in a

concentration greater than MIC

(Endocarditis, meningitis, abscesses)

 Age (infants and elderly highly vulnerable to drug toxicity).

 Pregnancy and lactation

 Previous allergic reactions

 Genetic factors (i.e. hemolysis in patients with G-6PD deficiency if given sulfonamides).

Antibiotic combinations:

The result may be additive, potentiative or antagonistic.

Additive response: one in which the antimicrobial effect of the combination is equal to the sum of the effects

of the two drugs alone.

Potentiative interaction: one in which the effect of the combination is GREATER than the sum of the

effects of the individual agents.

Antagonistic response: in certain cases the combination of two antibiotics may be less effective than one of

the agents by itself (i.e. combination of a bacteriostatic with a bactericidal drug)

Disadvantages of antibiotic combinations

1) Increased risk of toxic and allergic reactions

2) Possible antagonism of antimicrobial effects

3) Increased risk of suprainfection

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Figure shows the four main Actions of Antimicrobial Drugs

Figure shows the Inhibition of Protein Synthesis by Antibiotics

Mechanism of Action Drugs

 Inhibition of Cell Wall Synthesis

Inhibit cross-linking of peptidoglycan by inactivating transpeptidases (PBPs)

Penicillins, Cephalosporins, Aztreonam, Imipenem

Bind to terminal D-ala-D-ala & prevent incorporation into growing peptidoglycan

Vancomycin, Teicoplanin

Inhibition of transglycosylation

Oritavancin, Teicoplanin, lipophilic vancomycin analogs, ramiplanin

Inhibit dephosphorylation of phospholipid carrier in peptidoglycan structure

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Bacitracin

Prevents incorporation of D-alanine into peptidoglycan

Cycloserine

 Inhibition of Protein Synthesis

Bind to 50S ribosomal subunit

Macrolides, Chloramphenicol, Clindamycin

Bind to 30S ribosomal subunit

Aminoglycosides, Tetracyclines

 Inhibition of Nucleic acid synthesis

Inhibition of DNA gyrase & topoisomerase

Quinolones

Inhibition of nucleic acid biosynthesis

Flucytosine, Griseofulvin

Inhibition of mRNA synthesis

Rifampin, Rifabutin, Rifapentine

 Alteration of Cell Membrane Function

Inhibition of ergosterol biosynthesis

Imidazole antifungals

Bind to membrane sterols

Polymyxins, Amphotericin B, Nystatin

 Alteration of Cell Metabolism

Inhibition of tetrahydrofolic acid production (cofactor for nucleotide synthesis)

Sulfonamides, Trimethoprim, Trimetrexate Pyrimethamine

Inhibition of mycolic acid biosynthesis

Isoniazid

Interference with ubiquinone biosynthesis & cell respiration

Atovaquone

Bind to macromolecules (Metronidazole, Nitrofurantoin)

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

Since the gram-positive cell wall contains only two major components it is much less complicated than the

gram-negative cell wall.

Teichoic acids are polymers that are interwoven in the peptidoglycan layer and extend as hair-like

projections beyond the surface of the gram-positive cell. They also are major surface antigens in those

organisms that possess them.

The peptidoglycan layer, or murein layer, of gram-positive bacteria is much thicker than that of gramnegative bacteria. It is responsible for maintaining the shape of the organism and often is referred to as the

cell wall.

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Penicillin is natural and semi synthetic penicillins contain β-lactam ring and natural penicillins produced by

Penicillium are effective against Gram + cocci and spirochetes while semi synthetic penicillins: made in

laboratory by adding different side chains onto β-lactam ring will lead to production of penicillin which are

resistant and broader spectrum of activity

Figure shows The Penicillins nucleus morphology

Figure shows The Penicillins Activity Cycle in the body

Penicillinase (β-lactamase): bacterial enzyme that destroys natural penicillins

Penicillinase resistant penicillins: methicillin replaced by oxacillin and nafcillin due to MRSA

Extended-spectrum penicillin: Ampicillin, amoxicillin; new: carboxypenicilins and ureidopenicillins (also

good against P. aeruginosa)

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Cephalosporin

Produced by fungi of genus Cephalosporium, it Structure and mode of action resembles penicillin, there is 4

Generations of cephalosporin

1. First-generation: Narrow spectrum, gram-positive

2. Second-generation: Extended spectrum includes gram-negative

3. Third-generation: Includes pseudomonads; mostly injected some oral.

4. Fourth-generation: Most extended spectrum

Cephalosporins are:

1. More stable to bacterial lactamase than penicillin

2. Broader spectrum and used against penicillin-resistant strains

Vancomycin

 It is a glycopeptides from Streptomyces

 Inhibition of cell wall synthesis

 Used to kill MRSA

 Emerging Vancomycin resistance: VRE and VRSA

Tetracyclines

A number of antibiotics, including tetracyclines, aminoglycosides, and macrolides, exert antimicrobial

effects by targeting the bacterial ribosome, which has components that differ structurally from those of the

mammalian cytoplasmic ribosomes. Binding of tetracyclines to the 30S subunit of the bacterial ribosome is

believed to block access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site,

thereby inhibiting bacterial protein synthesis.

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Tetracyclines are broad-spectrum antibiotics (that is, many bacteria are sensitive to these drugs.

Tetracyclines are generally bacteriostatic.

Aminoglycosides

Aminoglycosides inhibit bacterial protein synthesis. Susceptible organisms have an oxygen-dependent

system that transports the antibiotic across the cell membrane. All aminoglycosides are bactericidal. They

are effective only against aerobic organisms because anaerobes lack the oxygen-requiring transport system.

Gentamicin is used to treat a variety of infectious diseases including those caused by many of the

Enterobacteriaceae and, in combination with penicillin, endocarditis caused by viridans-group Streptococci.

Macrolides

Macrolides are a group of antibiotics with a macrocyclic lactone structure. Erythromycin was the first of

these to find clinical application, both as the drug of first choice and as an alternative to penicillin in

individuals who are allergic to β-lactam antibiotics. Newer macrolides, such clarithromycin and

azithromycin, offer extended activity against some organisms and less severe adverse reactions.

The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thereby inhibiting the

translocation steps of protein synthesis. Generally considered to be bacteriostatic, they may be bactericidal at

higher doses.

Fluoroquinolones

Fluoroquinolones uniquely inhibit the replication of bacterial DNA by interfering with the action of DNA

gyrase (topoisomerase II) during bacterial growth. Binding Quinolones to both the enzyme and DNA to

form a ternary complex inhibits the rejoining step, and, thus, can cause cell death by inducing cleavage of

the DNA.

Because DNA gyrase is a distinct target for antimicrobial therapy, cross-resistance with other more

commonly used antimicrobial drugs is rare but is increasing with multidrug-resistant organisms.

All of the Fluoroquinolones are bactericidal.

Carbapenems

Carbapenems are synthetic β-lactam antibiotics that differ in structure from the penicillins. Imipenem,

meropenem, doripenem, and ertapenem are the drugs of this group currently available. Imipenem is

compounded with cilastatin to protect it from metabolism by renal dehydropeptidase. Imipenem resists

hydrolysis by most β-lactamases.

This drug plays a role in empiric therapy because it is active against β-lactamase–producing gram-positive

and gram-negative organisms, anaerobes, and P. aeruginosa.

Meropenem and doripenem have antibacterial activity similar to that of Imipenem. However, ertapenem is

not an alternative for P. aeruginosa coverage because most strains exhibit resistance.

Ertapenem also lacks coverage against Enterococcus species and Acinetobacter species.

Trimethoprim-sulfamethoxazole

A combination called co-trimoxazole shows greater antimicrobial activity than equivalent quantities of

either drug used alone. The synergistic antimicrobial activity of Co-trimoxazole results from its inhibition of

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two sequential steps in the synthesis of tetrahydrofolic acid: sulfamethoxazole inhibits incorporation of

PABA into folic acid, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate. It is

effective in treating urinary tract infections and respiratory tract infections as well as in Pneumocystis

jiroveci pneumonia and ampicillin- and chloramphenicol-resistant systemic Salmonella infections.

It has activity versus methicilin-resistant S. aureus and can be particularly useful for community acquired

skin and soft tissue infections caused by this organism.

Drug Resistance

Intrinsic and acquired drug resistance modes:

In some species antimicrobial resistance is an intrinsic or innate property. For example, E. coli is

intrinsically resistant to Vancomycin because Vancomycin is too large to pass though porin channels in their

outer membrane.

Gram-positive bacteria, on the other hand, do not possess an outer membrane and thus are not intrinsically

resistant to Vancomycin. Bacteria also can acquire resistance to antimicrobial agents by genetic events

such as mutation, conjugation, transformation, transduction and transposition.

Mutation: Chromosomal resistance develops as a result of spontaneous mutation in a locus that controls

susceptibility to a given antimicrobial agent. Spontaneous mutation occurs at a relatively low frequency but,

when the bacteria are exposed to the antibiotic, only the mutant cell survives. It then multiplies and gives

rise to a resistant population. Spontaneous mutations may also occur in plasmids. For example, mutations in

plasmids containing genes for beta-lactamase enzymes can result in altered beta-lactamases often with

extended activity.